CLEANING PROCESSES AND CLEANING VALIDATION GUIDE
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© Validation in Partnership Ltd. 2007
GUIDANCE DOCUMENT REFERENCE VERSION
CLEANING PROCESSES AND CLEANING VALIDATION
Document Reference:
SGD-105-CLN Rev. 10
Date of Issue:
25 May 2007
Page:
1 of 176
Author: Title:
Company:
Regulatory Consultant
Validation in Partnership Ltd.
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DOCUMENT HISTORY Revision No.
Date:
01
September 2000
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August 2001
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February 2002
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October 2002
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November 2003
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December 2004
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January 2005
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February 2006
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March 2007
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May 2007
ABOUT THE AUTHOR Since 1995, Validation in Partnership has been an entirely independent organisation specialising in the successful management and support of validation and CGMP compliance projects for the life science industries supplying the European and American markets. With our proven in-house project staff and extensive network of vetted quality contract personnel, we pride ourselves on a pragmatic approach that focuses effort on process critical areas to ensure the optimum business solution to any compliance challenge. Supported by the most extensive regulatory database in existence, courtesy of which this guidance document has been compiled, our team and clients are secure in the knowledge they have instant access to up-to-the-minute regulatory fact, and our state of the art automated document generation system ensures the rapid delivery and consistent quality of your protocols and reports. Whatever your requirement, ... •
Managed Validation/Compliance Projects
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Skilled and Vetted Contract Personnel
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CGMP Compliance Reviews/Audits
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Gap Analysis and Remedial Action Plans
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Complete Site Validation Packages
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Validation Policies
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Validation Plans and Master Plans
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DQ, IQ, OQ, PQ
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Computer Systems Validation
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Process Validation
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Cleaning Validation
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CGMP Compliance Training
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SOPs
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Complete CGMP Compliance Assistance
… and whatever your industry sector … •
Finished Pharmaceuticals
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Engineering Design and Construction
… ViP is your perfect compliance partner.
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TABLE OF CONTENTS DOCUMENT HISTORY ....................................................................................................................................................................2 ABOUT THE AUTHOR .....................................................................................................................................................................2
1.
AUTHOR’S NOTE .................................................................................................................................................4
2.
PURPOSE..............................................................................................................................................................4
3.
SCOPE ...................................................................................................................................................................4
4.
INTRODUCTION ...................................................................................................................................................4
5.
GENERAL CLEANING CONSIDERATIONS.......................................................................................................5
6.
5.1
Premises .......................................................................................................................................................................5
5.2
Equipment...................................................................................................................................................................17
5.3
Personnel....................................................................................................................................................................32
5.4
Product and Components ..........................................................................................................................................35
5.5
Cleaning Procedures..................................................................................................................................................35
5.6
Cleaning Records .......................................................................................................................................................62
5.7
Analytical Test Methods .............................................................................................................................................72
5.8
Analytical Records......................................................................................................................................................76
5.9
Miscellaneous Considerations ...................................................................................................................................76
CLEANING VALIDATION CONSIDERATIONS ............................................................................................... 79 6.1
Cleaning Procedures..................................................................................................................................................84
6.2
Analytical Test Methods .............................................................................................................................................91
6.3
Cleaning Validation Protocols ....................................................................................................................................92
6.4
Direct/Indirect Sampling Methods............................................................................................................................134
6.5
Rinse Water Samples...............................................................................................................................................139
6.6
Placebo Cleaning Verification Batches....................................................................................................................141
6.7
Swabs .......................................................................................................................................................................142
6.8
Rinse Water Specifications ......................................................................................................................................144
6.9
Analytical Test Method Validation............................................................................................................................144
6.10
Establishment of Limits ............................................................................................................................................152
6.11
Cleaning Validation Reports.....................................................................................................................................162
6.12
FDA Viewpoints - Human Drug CGMP Notes.........................................................................................................163
6.13
FDA Viewpoints - Questions and Answers on CGMPs ..........................................................................................167
6.14
Miscellaneous Considerations .................................................................................................................................173
7.
REFERENCES ................................................................................................................................................. 176
8.
VIP CONTACT DETAILS ................................................................................................................................. 176
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AUTHOR’S NOTE This guidance document is one in a series produced by Validation in Partnership Limited to assist personnel in the life science industries in obtaining the regulatory perspective surrounding specific aspects of their work. We have long recognised that one of the issues in our industry is not that we do not possess sufficient regulatory guidance on specific topics, but that we possess too much, albeit in the wrong format to support its efficient use. Mountains of guidance documents, directives, warning letters and establishment inspection reports cover a multitude of topics in a multitude of formats. In creating this guidance document, we have used our regulatory database, the most extensive and searchable in existence, to extract individual statements from over 900 regulatory documents and compile them under logical headings to present them in a more usable form. The end product is not intended to steer the reader through the process of developing cleaning procedures and cleaning validation packages, but simply to highlight the regulatory points he or she will need to consider along the way. Indeed, there are certain points, FDA 483 inspectional observations and warning letter extracts within the guide, with which the author does not concur. However, since each one has been derived from a regulatory information source, they have been included for consideration. It is for this reason that each regulatory point has been provided with sufficient source reference to enable the reader to further investigate any point of contention in the context, in which the statement was made. We hope you find it useful.
2.
PURPOSE To provide the regulatory perspective on the development of cleaning processes and cleaning validation packages to meet the requirements of both the American (references shown in blue) and European (references shown in red) regulatory bodies.
3.
SCOPE This guidance is applicable to the cleaning of facilities, equipment and instrumentation used in the manufacture of finished pharmaceuticals and biological products (medicinal products), and active pharmaceutical ingredients (APIs).
4.
INTRODUCTION Cleaning plays a crucial role in maintaining compliant pharmaceutical and biological product manufacturing operations, and, as you will see, the regulators have quite a lot to say about it. The regulatory requirements for cleaning, as applicable to a company, should also define its scope for cleaning validation. After all, no cleaning process can be verified as effective unless validated. Effective cleaning ensures that the risk of contamination, caused by batch to batch residues, cleaning agents or the unintentional transfer of one process component or material residue into a subsequent product, is minimised. Cleaning validation, which provides documented evidence that the cleaning procedure/ process is consistently capable of removing these potential contaminants to meet predetermined levels of cleanliness, is the easiest thing in the world if, and only if, the cleaning process has been correctly developed.
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This ninth revision of the guidance document has been compiled from a detailed review of: • • • •
over 900 regulatory texts over 20,000 regulatory records over 4,200 warning letter extracts over 3,100 FDA 483 observations
The end product comprises more than 450 points for consideration when developing procedures and protocols associated with the areas of cleaning and cleaning validation. For ease of reference, the points are collated under logical headings and sub-headings, although it is appreciated that the grouping of the points is subjective. The term "points for consideration" should be emphasised, as the document is intended to form a series of regulatory prompts rather than a definitive list of word for word requirements. Each paragraph within the guide is supported by one or more regulatory references. American references are shown in blue, European references are shown in red and references applicable to both regulatory bodies are shown in green. Although this guide incorporates the latest annexes to the EU Guide to Good Manufacturing Practice, Eudralex Volume 4, the author has chosen to include a number of extracts from selected superseded documents (marked SUPERSEDED!) alongside those from the latest versions. The author believes that the earlier texts contain a number of useful prompts that have been omitted from the latest documents.
5.
GENERAL CLEANING CONSIDERATIONS
5.1 Premises 1.
Premises must be located, designed, constructed, adapted and maintained to permit effective cleaning in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products. Selected FDA 483 Observations (July 2006) Sterile Product Manufacture [VIP ID: 194012] “Buildings used in the manufacture, processing, placing, or holding of a drug product should have a suitable construction to facilitate cleaning, maintenance, and proper operations.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PRINCIPLE [VIP ID: 185552] “Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 6 - MANUFACTURE OF MEDICINAL GASES 3. PREMISES AND EQUIPMENT 3.1 Premises 3.1.2 [VIP ID: 186472] “…Premises should be clean and tidy to encourage orderly working and adequate storage.”
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PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 14 - MANUFACTURE OF PRODUCTS DERIVED FROM HUMAN BLOOD OR HUMAN PLASMA PREMISES AND EQUIPMENT 6 [VIP ID: 186990] “The premises used for the collection of blood or plasma should be of suitable size, construction and location to facilitate their proper operation, cleaning and maintenance.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 2 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE PREMISES AND EQUIPMENT 15 [VIP ID: 186218] “The layout and design of production areas and equipment should permit effective cleaning and decontamination (e.g. by fumigation).” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.42 Design and construction features (a) [VIP ID: 18] “Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.” PE 005-2 PIC/S GMP GUIDE FOR BLOOD ESTABLISHMENTS (July 2004) 7. PREMISES 7.1 [VIP ID: 185030] “Premises should be located, designed, constructed, utilised and maintained according to the intended activity. The planning and layout should be designed to permit operations to take place in a logical order corresponding to the sequence of operations. Premises should be designed to permit effective cleaning, sanitisation and maintenance and to minimise the risk of errors.” PI 008-2 PIC/S GUIDANCE DOCUMENT FOR INSPECTORS PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES (INSPECTION GUIDE) (July 2004) 13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES 13.2 PREMISES AND HYGIENE 13.2.8 [VIP ID: 189270] “The layout of premises and equipment must permit effective cleaning and maintenance in order to avoid cross contamination and build up of dust and dirt (GMP 3, principle). Therefore the walls, floors and ceilings should be smooth, free from cracks and open joints and should permit easy and effective cleaning and if necessary disinfection (GMP 3.9.).” COMMISSION DIRECTIVE 2003/94/EC OF 8 OCTOBER 2003 LAYING DOWN THE PRINCIPLES AND GUIDELINES OF GOOD MANUFACTURING PRACTICE IN RESPECT OF MEDICINAL PRODUCTS FOR HUMAN USE AND INVESTIGATIONAL MEDICINAL PRODUCTS FOR HUMAN USE (October 2003) Article 8 Premises and equipment 2 [VIP ID: 67330] “Premises and manufacturing equipment shall be laid out, designed and operated in such a way as to minimise the risk of error and to permit effective cleaning and maintenance in order to avoid contamination, cross contamination and, in general, any adverse effect on the quality of the product.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.1 Design and Construction 4.10 [VIP ID: 24532] “Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.1 Design and Construction 4.10 [VIP ID: 153640] “Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 14 - MANUFACTURE OF MEDICINAL PRODUCTS DERIVED FROM HUMAN BLOOD OR HUMAN PLASMA (March 2000) Premises and Equipment 6 [VIP ID: 141330] “The premises used for the collection of blood or plasma should be of suitable size, construction and location to facilitate their proper operation, cleaning and maintenance.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Principle [VIP ID: 358] “Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (January 1993) Premises and Equipment 15. [VIP ID: 1528] “The layout and design of production areas and equipment should permit effective cleaning and decontamination (e.g. by fumigation).” COMMISSION DIRECTIVE 91/356/EEC - PRINCIPLES AND GUIDELINES OF GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS FOR HUMAN USE - SUPERSEDED BY 2003/94/EC ! (June 1991) Chapter II Principles and Guidlines of Good Manufacturing Practice Article 8 - Premises and equipment 2. [VIP ID: 778] “Lay out, design and operation must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid contamination, cross contamination and, in general, any adverse effect on the quality of the product.”
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Additional consideration should be given to the design of premises, inspection/test methods and acceptance limits to be used after cleaning for investigational medicinal products where the toxicity, potency and sensitising potential are not be fully understood. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 13 - MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS PREMISES AND EQUIPMENT 5 [VIP ID: 186860] “The toxicity, potency and sensitising potential may not be fully understood for investigational medicinal products and this reinforces the need to minimise all risks of cross-contamination. The design of equipment and premises, inspection / test methods and acceptance limits to be used after cleaning should reflect the nature of these risks. Consideration should be given to campaign working where appropriate.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 13 - MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS (July 2003) PREMISES AND EQUIPMENT 5 [VIP ID: 64250] “The toxicity, potency and sensitising potential may not be fully understood for investigational medicinal products and this reinforces the need to minimise all risks of cross-contamination. The design of equipment and premises, inspection / test methods and acceptance limits to be used after cleaning should reflect the nature of these risks. Consideration should be given to campaign working where appropriate.”
2.
Building used in the manufacture, processing, packing, or holding of a drug product should be maintained in a clean and sanitary condition and should be free of infestation by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.56 Sanitation (a) [VIP ID: 47] “Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a clean and sanitary condition. Any such building shall be free of infestation by rodents, birds, insects, and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.7 Sanitation and Maintenance 4.70 [VIP ID: 24555] “Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.7 Sanitation and Maintenance 4.70 [VIP ID: 153870] “Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.”
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Extracted from FDA Warning Letter 00-NWJ-22 (March 2000) USA 02/03/2000 [VIP ID: 12970] “a) The class 100 area in Filling Room 41 used for the manufacture of sterile drug products was not maintained in a clean and sanitary condition even after having been cleaned and sanitized five times and after being found acceptable by the Quality Control Unit.” Extracted from FDA Warning Letter NYK 1999-20 (January 1999) USA 07/01/1999 [VIP ID: 13070] “Failure to maintain your facility in a clean and sanitary condition free of infestation by rodent or other vermin as required by 21 CFR 211.56(a), in that a live mouse was observed moving across the first floor from one of the packaging rooms to another manufacturing / production area.”
•
Storage areas should be clean and dry. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - Storage Areas 3.19 [VIP ID: 185590] “Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Storage Areas 3.19. [VIP ID: 377] “Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.”
•
Sample areas should be cleaned before and after different raw material components are sampled. Selected FDA 483 Observations (February 1999) Sterile Product Manufacture [VIP ID: 7075] “Sample areas should be cleaned before and after different raw material components are sampled.”
3.
Premises should be cleaned and, where applicable, disinfected according to detailed written procedures. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - General 3.2 [VIP ID: 185556] “Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures.”
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GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) V. RECOMMENDATIONS FOR COMPLYING WITH THE STATUTE C. Facility and Equipment para 1 [VIP ID: 183856] “Any facility, including a laboratory, used for production of investigational drugs for use in phase 1 studies should have adequate work areas and equipment for the intended task: - Appropriate equipment that will not contaminate the product or otherwise be reactive, additive, or absorptive with the product and that is properly maintained, calibrated, cleaned, and sanitized at appropriate intervals following written procedures” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 2. QUALITY MANAGEMENT 2.3 Responsibility for Production Activities (para 1) (5) [VIP ID: 24512] “The responsibility for production activities should be described in writing, and should include but not necessarily be limited to: 5. Making sure that production facilities are clean and when appropriate disinfected;” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - General 3.2. [VIP ID: 360] “Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures.”
•
Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.7 Sanitation and Maintenance 4.71 [VIP ID: 24556] “Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.7 Sanitation and Maintenance 4.71 [VIP ID: 153880] “Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.”
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To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves and cupboards. Doors should be designed to avoid those uncleanable recesses; sliding doors may be undesirable for this reason. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 23 [VIP ID: 186044] “To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid those uncleanable recesses; sliding doors may be undesirable for this reason.”
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Pipework, light fittings, ventilation points, ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - Production Area 3.10 [VIP ID: 185572] “Pipe work, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PREMISES 25 [VIP ID: 186048] “Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Production Area 3.10. [VIP ID: 368] “Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.”
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In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to permit the repeated application of cleaning agents, and disinfectants where used. Extracted from FDA warning letter VLN# 06200780 (January 2007) USA 05-Jan-07 2. a. [VIP ID: 194658] “"Failure to have adequate building design and construction used in manufacture, processing, packing, or holding of drug products to facilitate cleaning, maintenance, and proper operations. [21 CFR § 211.42(a)] For example, a. Your firm uses drop ceiling panels of porous, drywall-like material that is not easily cleaned in the formulation room (Class 10,000), entry room (Class 100,000), and processing room (Class 100,000). Numerous ceiling tiles were not seated flush with the metal frame revealing gaps between the ceiling tiles and the metal frame."”
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GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT B. Facilities 2. Aseptic Processing Area para 2 [VIP ID: 187392] “We recommend that conditions in the room where aseptic manipulations are conducted not present a challenge to the operating capability of the aseptic workstation. For example, the room should not be carpeted nor have overhanging pipes or hanging light fixtures. All areas of the production and processing room should be easily accessible for cleaning. Surfaces of the walls, floors, and ceilings in the aseptic work areas should be easily cleaned. Cleaning should be performed frequently to ensure consistent control of the environmental quality. In addition, the aseptic processing area (e.g., LAFW) should be situated in the section of the room with the lowest traffic and lowest activity. Cartons and boxes should not be stored or opened in the production area to minimize ingress of dust and particulate into the aseptic work area.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) IV. Buildings and Facilities E. Design (para 9) [VIP ID: 110510] “Cleanrooms are normally designed as functional units with specific purposes. The materials of construction of cleanrooms ensure ease of cleaning and sanitizing. Examples of adequate design features include seamless and rounded floor to wall junctions as well as readily accessible corners. Floors, walls, and ceilings should be constructed of smooth, hard surfaces that can be easily cleaned. Ceilings and associated HEPA filter banks should be designed to protect sterile materials from contamination. Cleanrooms also should not contain unnecessary equipment, fixtures, or materials.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Premises 22 [VIP ID: 63130] “In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimise the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants where used.”
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Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - Production Area 3.9 [VIP ID: 185570] “Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.” PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 8. STERILITY TEST FACILITIES 8.3 CLEAN ROOM FITTINGS AND SURFACES 8.3.2 [VIP ID: 190274] “The joints between ceiling/walls/floor should be coved to facilitate cleaning.”
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EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Production Area 3.9. [VIP ID: 367] “Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.”
5.
Open channel drains should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - Production Area 3.11 [VIP ID: 185574] “Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Production Area 3.11. [VIP ID: 369] “Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.”
6.
When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilised where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Equipment 34 [VIP ID: 63270] “When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and / or sterilised where appropriate, before processing recommences if the required standards of cleanliness and / or asepsis have not been maintained during the work.”
7.
Adequate, clean washing and toilet facilities should be provided for personnel. ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.1 Design and Construction 4.15 [VIP ID: 153690] “Adequate, clean washing and toilet facilities should be provided for personnel. These washing facilities should be equipped with hot and cold water as appropriate, soap or detergent, air driers or single service towels. The washing and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate.”
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Adequate lighting should be provided in all areas to facilitate cleaning. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.5 Lighting 4.50 [VIP ID: 24553] “Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.5 Lighting 4.50 [VIP ID: 153850] “Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.”
9.
In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to facilitate cleaning. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - Production Area 3.14 [VIP ID: 185580] “In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 7 - MANUFACTURE OF HERBAL MEDICINAL PRODUCTS PREMISES Storage areas 2 [VIP ID: 186614] “Special attention should be paid to the cleanliness and good maintenance of the storage areas particularly when dust is generated.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 7 - MANUFACTURE OF HERBAL MEDICINAL PRODUCTS PREMISES Production area 4 [VIP ID: 186618] “Specific provisions should be taken during sampling, weighing, mixing and processing operations of crude plants whenever dust is generated, to facilitate cleaning and to avoid cross-contamination, as for example, dust extraction, dedicated premises, etc.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Production Area 3.14. [VIP ID: 372] “In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 07 - MANUFACTURE OF HERBAL MEDICINAL PRODUCTS (January 1993) Premises Storage areas 2. [VIP ID: 1704] “Special attention should be paid to the cleanliness and good maintenance of the storage areas particularly when dust is generated.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 07 - MANUFACTURE OF HERBAL MEDICINAL PRODUCTS (January 1993) Premises Production area 4. [VIP ID: 1706] “Specific provisions should be taken during sampling, weighing, mixing and processing operations of crude plants whenever dust is generated, to facilitate cleaning and to avoid cross-contamination, as for example, dust extraction, dedicated premises, etc.”
10. Dedicated production areas should be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.4 Containment 4.41 [VIP ID: 24550] “Dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and / or cleaning procedures are established and maintained.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.4 Containment 4.41 [VIP ID: 153820] “Dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.”
11. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT PREMISES - Storage Areas 3.20 [VIP ID: 185592] “Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Storage Areas 3.20. [VIP ID: 378] “Receiving and dispatch bays should protect materials and products from the weather. Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.”
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12. Before packaging operations are begun, steps should be taken to ensure that the work area is clean. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5 PRODUCTION PACKAGING OPERATIONS 5.45 [VIP ID: 185792] “Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 4 DOCUMENTATION BATCH PACKAGING RECORDS 4.18 [VIP ID: 185678] “Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Packaging operations 5.45. [VIP ID: 567] “Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.”
13. Multi-product facilities should have cleaning and testing procedures in place that ensure prevention and/or detection of contamination by adventitious agents. To the extent possible, dedicated equipment and/or disposable parts (e.g., tubing) is recommended. For multi-product areas procedures should be established to prevent cross-contamination and demonstrate removal of the previously manufactured product from shared equipment and work surfaces, especially if live viral and vector processing occurs in a production area. GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. SPECIAL PRODUCTION SITUATIONS C. Biological and Biotechnological Products 2. Multi-Product Facilities [VIP ID: 183910] “In addition to the recommendation in section VI.B, we recommend that multi-product facilities have cleaning and testing procedures in place that ensure prevention and/or detection of contamination by adventitious agents. To the extent possible, dedicated equipment and/or disposable parts (e.g., tubing) is recommended. For multi-product areas, we recommend that procedures be established to prevent cross-contamination and that demonstrate removal of the previously manufactured product from shared equipment and work surfaces, especially if live viral and vector processing occurs in a production area.”
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GUIDANCE FOR INDUSTRY INDS - APPROACHES TO COMPLYING WITH CGMP DURING PHASE 1 DRAFT GUIDANCE (January 2006) VI. SPECIAL PRODUCTION SITUATIONS B. Multi-Product Facilities para 1 [VIP ID: 183898] “Ideally, we recommend that one product be produced in an area or room at any given time separate from unrelated activities. However, the same area or room could be used for multiple purposes, including production of other investigational products or laboratory research, provided that appropriate cleaning and control procedures are in place to ensure that there is no carry-over of materials or products or mix-ups. We recommend that in such cases, the design or layout of an area promote the orderly handling of materials and equipment, the prevention of mix-ups, and the prevention of contamination of equipment or product by substances, previously produced products, personnel, or environmental conditions.”
14. Bioburden inhibition studies should be performed for the sanitisation of critical production areas (e.g. filling lines). Selected FDA 483 Observations (July 1999) Sterile Product Manufacture [VIP ID: 7199] “Bioburden inhibition studies should be performed for the sanitization of critical production areas (e.g. filling lines).”
5.2 Equipment 1.
Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate its cleaning. Extracted from FDA warning letter CIN-07-30670-09 (January 2007) USA 11-Jan-07 4) [VIP ID: 194708] “Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use and for its cleaning and maintenance. [21 CFR § 211.63] For example, CP2 packaging line was modified in a manner that made it difficult for employees to remove the line cover. As a result, the line cover is not removed during line clearance operations and is only removed during preventative maintenance. Per firm personnel, unit dose strips can become caught in this area and are routinely found during maintenance.” Extracted from FDA warning letter 06-NWJ-14 (July 2006) USA 11-Jul-06 10) [VIP ID: 192248] “Failure to maintain equipment at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product [21 CFR § 211.67(a)]. Specifically, the [redacted] Packaging Hopper was found to be cracked. Cracked equipment cannot be easily cleaned to prevent crosscontamination between products.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.63 Equipment design, size and location [VIP ID: 52] “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.”
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21 CFR PART 820 - QUALITY SYSTEM REGULATION (April 2006) Subpart G--Production and Process Controls 21 CFR 820.70 Production and process controls. (g) Equipment. [VIP ID: 5810] “Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use.” GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) VII. Endotoxin Control (para 2) [VIP ID: 110880] “…Equipment should be designed to be easily assembled and disassembled, cleaned, sanitized, and / or sterilized.” Selected FDA 483 Observations (May 2004) Medical Device Manufacture [VIP ID: 122520] “Equipment used in a manufacturing process should be appropriately installed to facilitate maintenance, adjustment, cleaning, and use.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 5. PROCESS EQUIPMENT 5.1 Design and Construction 5.10 [VIP ID: 24558] “Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitization (where appropriate), and maintenance.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 5. PROCESS EQUIPMENT 5.1 Design and Construction 5.10 [VIP ID: 153900] “Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitization (where appropriate), and maintenance.”
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Pipework systems, valves and vent filters should be properly designed to facilitate cleaning and sterilisation. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 2 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE PREMISES AND EQUIPMENT 17 [VIP ID: 186222] “Pipework systems, valves and vent filters should be properly designed to facilitate cleaning and sterilisation. The use of "clean in place" and "sterilise in place" systems should be encouraged. Valves on fermentation vessels should be completely steam sterilisable. Air vent filters should be hydrophobic and validated for their scheduled life span.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (January 1993) Premises and Equipment 17. [VIP ID: 1530] “Pipework systems, valves and vent filters should be properly designed to facilitate cleaning and sterilization.”
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Tanks, containers, pipework and pumps should be designed and installed so that they may be readily cleaned and if necessary sanitised. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 9 PREMISES AND EQUIPMENT 2 [VIP ID: 186646] “Tanks, containers, pipework and pumps should be designed and installed so that they may be readily cleaned and if necessary sanitised. In particular, equipment design should include a minimum of dead-legs or sites where residues can accumulate and promote microbial proliferation.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 09 - MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS (January 1993) Premises and Equipment 2. [VIP ID: 1725] “Tanks, containers, pipework and pumps should be designed and installed so that they may be readily cleaned and if necessary sanitized. In particular, equipment design should include a minimum of dead-legs or sites where residues can accumulate and promote microbial proliferation.”
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Washing and cleaning equipment should be chosen and used in order not to be a source of contamination. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT EQUIPMENT 3.37 [VIP ID: 185626] “Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.” PI 008-2 PIC/S GUIDANCE DOCUMENT FOR INSPECTORS PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES (INSPECTION GUIDE) (July 2004) 13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES 13.3 EQUIPMENT 13.3.2 [VIP ID: 189286] “Washing and cleaning equipment should be chosen and used in order not to be a source of contamination (GMP 3.37). Therefore cleaning equipment should be stored separately and not within production or product storage areas.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Equipment 3.37. [VIP ID: 395] “Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.”
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The design of the equipment should be carefully examined and critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.6 Equipment 7.6.1 [VIP ID: 188678] “The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.6. Equipment 4.6.1. [VIP ID: 69240] “The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 1. Equipment Design (para 1) [VIP ID: 1331] “Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary type piping without ball valves should be used. When such nonsanitary ball valves are used, as is common in the bulk drug industry, the cleaning process is more difficult.”
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Validation of clean-in-place (CIP)/sterilise-in-place (SIP) systems may be difficult because of the potential incompatibilities in requirements for the design of these systems. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING 9.3 Equipment Cleaning and Sterilisation 9.3.2 Clean-in-place/sterilise-in-place (CIP/SIP). 9.3.2.1 [VIP ID: 189030] “Validation of these systems may be difficult because of the potential incompatibilities in requirements for the design of CIP and SIP facilities. All systems have dead legs to a greater or lesser extent and the required orientation of the dead legs differ for CIP and SIP. The orientation for CIP dead legs is slightly sloping so that the cleaning solution can enter and also drain away. The dead leg for SIP is vertically up so that steam can downwardly displace the air.”
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The use of 'clean in place' and 'sterilise in place' systems should be encouraged. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (January 1993) Premises and Equipment 17. [VIP ID: 1530] “…The use of 'clean in place' and 'sterilise in place' systems should be encouraged.”
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Particular attention should be paid to equipment design and qualification, validation and reproducibility of cleaning-in-place when dealing with Blow-Fill-Seal technology. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Blow/fill/seal technology 10 (para 2) [VIP ID: 62910] “Because of this special technology particular attention should be paid to, at least the following: equipment design and qualification, validation and reproducibility of cleaning-in-place and sterilisation-in-place, background cleanroom environment in which the equipment is located, operator training and clothing, and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling.”
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Hoses and delivery lines should not be too long to clean and drain. GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994) III. EQUIPMENT (para 7) [VIP ID: 3215] “With regard to transfer lines, they are generally hard piped and easily cleaned and sanitized. In some cases manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on the floor, thus significantly increasing the potential for contamination. Such contamination can occur by operators picking up or handling hoses, and possibly even placing them in transfer or batching tanks after they had been lying on the floor. It is also a good practice to store hoses in a way that allows them to drain rather than be coiled which may allow moisture to collect and be a potential source of microbial contamination. Observe manufacturing areas and operator practices, particularly when flexible hose connection are employed.” GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994) III. EQUIPMENT (para 2) [VIP ID: 3210] “In order to facilitate cleaning and sanitization, manufacturing and filling lines should be identified and detailed in drawings and SOPs. In some cases, long delivery lines between manufacturing areas and filling areas have been a source of contamination.”
2.
Fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart E -- Control of Components and Drug Product Containers and Closures Sec. 211.80 General requirements (c) [VIP ID: 69] “Bagged or boxed components of drug product containers, or closures shall be stored off the floor and suitably spaced to permit cleaning and inspection.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 7. MATERIALS MANAGEMENT 7.4 Storage 7.41 [VIP ID: 24654] “Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 7. MATERIALS MANAGEMENT 7.4 Storage 7.41 [VIP ID: 154620] “Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.”
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Equipment, containers and utensils should be clean. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.22 [VIP ID: 24567] “Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 9. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES 9.2 Packaging Materials 9.21 [VIP ID: 24691] “Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.” Extracted from FDA Warning Letter 2002-DT-18 (January 2001) USA 09/01/2001 [VIP ID: 42980] “Failure to assure that equipment is routinely maintained and cleaned according to a written program designed to assure proper performance, as required by 21 CFR 211.67. For example, see 483 observation 8.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.22 [VIP ID: 153990] “Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 9. PACKAGING AND IDENTIFICATION LABELLING OF APIs AND INTERMEDIATES 9.2 Packaging Materials 9.21 [VIP ID: 154990] “Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.” Selected FDA 483 Observations (June 1998) Product Manufacture [VIP ID: 6390] “Utensils, such as scoops, used for the weighing of raw materials should be cleaned, maintained and sanitized at appropriate intervals to prevent contamination.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Starting materials 5.32. [VIP ID: 554] “Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.”
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Containers for filling should be clean before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5 PRODUCTION PACKAGING OPERATIONS 5.48 [VIP ID: 185798] “Containers for filling should be clean before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Packaging operations 5.48. [VIP ID: 570] “Containers for filling should be clean before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles.”
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Cell culture equipment and fermentation equipment should be cleaned after use. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.3 Cell Culture/Fermentation 18.34 [VIP ID: 24847] “Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.4 Harvesting, Isolation and Purification 18.42 [VIP ID: 24854] “All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18.3 Cell Culture/Fermentation 18.34 [VIP ID: 156520] “Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18.4 Harvesting, Isolation and Purification 18.42 [VIP ID: 156590] “All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.”
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If the same equipment is used for different purification steps the equipment should be appropriately cleaned and sanitised before re-use. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.5 Viral Removal/Inactivation steps 18.53 [VIP ID: 24860] “The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18.5 Viral Removal/Inactivation steps 18.53 [VIP ID: 156650] “The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.”
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Isolators used for aseptic processing and sterility testing should be cleaned prior to exposure to a sporicidal process. PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 9. AN EXPANSION OF THE DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. 9.4 9.4.8 [VIP ID: 190534] “The isolator should be cleaned prior to the sporicidal process. The surfaces of packaged materials and all other items to be exposed to the sporicidal process within the isolator should be clean. All the surfaces inside the isolator should be clean prior to exposure to the sporicidal process. Apart from removing chemical residues that may contaminate subsequent production, the presence of deposits may enable microorganisms to survive the process by physical shielding or neutralization of the process of inactivation. The isolator should be designed to enable access to all surfaces for cleaning without major dismantling. Inlet and exhaust air pathways should be designed with this in mind. If clean in place systems are used, any risks that may arise from the presence of spray balls, drains and retained fluids should be identified and eliminated. Whichever cleaning method is used it should result in a visibly clean dry surface free from risk of residues.” PI 014-2 RECOMMENDATION ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING (July 2004) 7. DETAILED POINTS TO BE CONSIDERED FOR THE IMPLEMENTATION OF THE PRINCIPLES TO ISOLATORS SUBJECTED TO A SPORICIDAL PROCESS. THESE POINTS ARE EXPANDED UPON IN APPENDIX 1. 7.4 7.4.8 [VIP ID: 190476] “The isolator should be cleaned prior to the sporicidal process. The surfaces of packaged materials and all other items to be gassed within the isolator should be clean.”
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Containers and valves should be cleaned to ensure the absence of any contaminants such as fabrication aids (e.g. lubricants) or undue microbiological contaminants. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 10 PRODUCTION AND QUALITY CONTROL 6 [VIP ID: 186674] “Containers and valves should be cleaned using a validated procedure appropriate to the use of the product to ensure the absence of any contaminants such as fabrication aids (e.g. lubricants) or undue microbiological contaminants.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 10 - MANUFACTURE OF PRESSURISED METERED DOSE AEROSOL PREPARATIONS FOR INHALATION (January 1993) Production and Quality Control 6. [VIP ID: 1739] “Containers and valves should be cleaned using a validated procedure appropriate to the use of the product to ensure the absence of any contaminants such as fabrication aids (e.g. lubricants) or undue microbiological contaminants.”
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Stainless steel pipework used in the manufacturing process, connecting formulation tanks, holding tanks and transfer lines should be sanitised prior to use. Selected FDA 483 Observations (March 2000) Product Manufacture [VIP ID: 14530] “Stainless steel pipework used in the manufacturing process, connecting formulation tanks, holding tanks and transfer lines should be sanitized prior to use.”
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Plastic bins used to hold and store cleaned compound manufacturing equipment parts should be washed and/or sanitised. Selected FDA 483 Observations (November 2002) Product Manufacture [VIP ID: 51530] “Plastic bins used to hold and store cleaned compound manufacturing equipment parts should be washed and / or sanitized.”
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Repackaging equipment should be cleaned/sanitised between batches. Extracted from FDA Warning Letter 2003-NOL-01 (October 2002) USA 10/10/2002 [VIP ID: 49620] “Repackaging equipment is not cleaned nor sanitized between batches [21 CFR 211.67(a)];”
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Stainless steel stands and metal clamps used to hold sampling apparatus and peristaltic pump rotary pieces of equipment handled during connection of transfer tubing should be cleaned/ sanitised. Selected FDA 483 Observations (August 2003) Sterile Product Manufacture [VIP ID: 53180] “Stainless steel stands and metal clamps used to hold sampling apparatus and peristaltic pump rotary pieces of equipment handled during connection of transfer tubing should be cleaned / sanitized.”
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Manual cleaning of equipment rarely is a problem but procedures should be checked to ensure that O-rings and gaskets are removed during cleaning otherwise there can be a build up of product residues and/or dirt. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING 9.3 Equipment Cleaning and Sterilisation 9.3.1 Manual cleaning (see PIC/S Document PI 006, Cleaning validation) and sterilisation. 9.3.1.1 [VIP ID: 189018] “Manual cleaning of equipment rarely is a problem but procedures should be checked to ensure that O-rings and gaskets are removed during cleaning otherwise there can be a build up of product residues and/or dirt.”
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Components, containers and equipment should be handled after the final cleaning process in such a way that they are not recontaminated. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS SANITATION 49 [VIP ID: 186096] “Components, containers and equipment should be handled after the final cleaning process in such a way that they are not recontaminated.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Processing 49 [VIP ID: 63430] “Components, containers and equipment should be handled after the final cleaning process in such a way that they are not recontaminated.”
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Manufacturing equipment should be cleaned according to detailed and written procedures and stored only in a clean and dry condition. Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194320] “Written procedures should be established for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 3 PREMISES AND EQUIPMENT EQUIPMENT 3.36 [VIP ID: 185624] “Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.” Selected FDA 483 Observations (April 2006) Active Pharmaceutical Ingredient Manufacture [VIP ID: 193564] “There should be written procedures and records for the cleaning of all equipment used in manufacturing, such as filters, conveyor belts and housings, dryers and blenders.”
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PI 008-2 PIC/S GUIDANCE DOCUMENT FOR INSPECTORS PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES (INSPECTION GUIDE) (July 2004) 13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES 13.3 EQUIPMENT 13.3.1 [VIP ID: 189284] “Manufacturing equipment (as well as storing equipment) should be designed so that it can be easily and thoroughly cleaned (GMP 3.36.). It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition (GMP 3.36.).” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 3 - PREMISES AND EQUIPMENT Premises - Equipment 3.36. [VIP ID: 394] “Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.”
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Processing Instructions should include the methods, or reference to the methods, to be used for cleaning critical equipment. EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION Documents required - Specifications (Manufacturing Formula and Processing Instructions) 4.15. [VIP ID: 442] “The Processing Instructions should include: … b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); …”
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When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitising agents to prevent the contamination of equipment. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 4. BUILDINGS AND FACILITIES 4.7 Sanitation and Maintenance 4.72 [VIP ID: 24557] “When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labelling materials, intermediates, and APIs.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 4. BUILDINGS AND FACILITIES 4.7 Sanitation and Maintenance 4.72 [VIP ID: 153890] “When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labelling materials, intermediates, and APIs.”
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During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is clean. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 19. APIS FOR USE IN CLINICAL TRIALS 19.3 Equipment and Facilities 19.30 [VIP ID: 24869] “During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 19. APIs FOR USE IN CLINICAL TRIALS 19.3 Equipment and Facilities 19.30 [VIP ID: 156740] “During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.”
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There should be written procedures for the cleaning of the surface of bags of raw materials before charging. Selected FDA 483 Observations (April 2006) Active Pharmaceutical Ingredient Manufacture [VIP ID: 193562] “There should be written procedures for the cleaning of the surface of bags of raw materials before charging.”
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Before any processing or packaging operation begins, there should be recorded checks that the equipment is clean. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 4 DOCUMENTATION BATCH PROCESSING RECORDS 4.17 [VIP ID: 185676] “Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5 PRODUCTION PROCESSING OPERATIONS - INTERMEDIATE AND BULK PRODUCTS 5.35 [VIP ID: 185772] “Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.”
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EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION Documents required - Batch Processing Records 4.17. [VIP ID: 459] “Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION Documents required - Batch Packaging Records 4.18 [VIP ID: 471] “Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Processing operations: intermediate and bulk products 5.35. [VIP ID: 557] “Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Packaging operations 5.45. [VIP ID: 567] “Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.”
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Contamination of starting materials or products by residues of other materials or products on equipment must be avoided. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5 PRODUCTION PREVENTION OF CROSS-CONTAMINATION IN PRODUCTION 5.18 [VIP ID: 185738] “Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from … residues on equipment …” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Prevention of cross-contamination in production 5.18. [VIP ID: 528] “Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from … residues on equipment ...”
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After cleaning, equipment should be kept clean and precautions taken not to introduce contamination during subsequent handling. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 10 - MANUFACTURE OF PRESSURISED METERED DOSE AEROSOL PREPARATIONS FOR INHALATION (January 1993) Production and Quality Control 6. [VIP ID: 1739] “… After cleaning, valves should be kept in clean, closed containers and precautions taken not to introduce contamination during subsequent handling, e.g. taking samples.”
10. Cleaning equipment should be stored separately and not within production or product storage areas. PI 008-2 PIC/S GUIDANCE DOCUMENT FOR INSPECTORS PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES (INSPECTION GUIDE) (July 2004) 13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES 13.3 EQUIPMENT 13.3.2 [VIP ID: 189286] “…Therefore cleaning equipment should be stored separately and not within production or product storage areas.”
11. Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimise the risk of cross-contamination. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION 18.3 Cell Culture/Fermentation 18.38 [VIP ID: 24851] “Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL CULTURE/FERMENTATION 18.3 Cell Culture/Fermentation 18.38 [VIP ID: 156560] “Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.”
12. Electronic thermometers used to measure the temperature of cleaning chemicals during cleaning should be calibrated with a reference standard which is traceable to a national/international standard. Selected FDA 483 Observations (May 2000) Medical Device Manufacture [VIP ID: 15960] “Electronic thermometers used to measure the temperature of cleaning chemicals during cleaning should be calibrated with a reference standard which is traceable to a national / international standard.”
13. Smoke generating equipment used for clean room qualification should be cleanable. Selected FDA 483 Observations (March 1999) Sterile Product Manufacture [VIP ID: 7137] “Smoke generating equipment used for clean room qualification should be: 2) cleanable”
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14. Hand trucks used to move racks of sterilised components should be cleanable and sanitisable. Selected FDA 483 Observations (May 1999) Sterile Product Manufacture [VIP ID: 7220] “Hand trucks used to move racks of sterilized components should be cleanable and sanitizable.”
15. Flexible tubing (e.g. hoses) used in manufacturing should be hung such that they drain when not in use. Selected FDA 483 Observations (July 2002) Active Pharmaceutical Ingredient Manufacture [VIP ID: 47400] “Hoses used for the transfer of product or waste should: (b) correctly hung when not in use.”
16. Clean room goggles and ear protection covers should be disinfected prior to use or on a periodic basis, and records maintained. Selected FDA 483 Observations (January 2000) Sterile Product Manufacture [VIP ID: 14530] “Clean room goggles and ear protection covers should be disinfected prior to use or on a periodic basis, and records maintained.”
17. Equipment should be consistently cleaned in the same way it was during cleaning validation studies. Selected FDA 483 Observations (November 2006) Sterile Product Manufacture [VIP ID: 194202] “Cleaning practices should be correlated to cleaning validations.” Selected FDA 483 Observations (May 2002) Product Manufacture [VIP ID: 46990] “Equipment should be consistently cleaned in the same way it was during cleaning validation studies.”
18. Non dedicated transfer/storage bins should be supported by cleaning and usage records. Selected FDA 483 Observations (June 2002) Product Manufacture [VIP ID: 47230] “Non dedicated transfer / storage bins should be supported by cleaning and usage records.”
19. Piping and valves used in cleaning operations should be tagged and easily identifiable by the operator performing the cleaning function. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 1. Equipment Design (para 3) [VIP ID: 1333] “In larger systems, such as those employing long transfer lines or piping, check the flow charts and piping diagrams for the identification of valves and written cleaning procedures. Piping and valves should be tagged and easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both on prints and physically, have led to incorrect cleaning practices.”
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5.3 Personnel 1.
Personnel who perform cleaning routinely should be trained in the application of validated cleaning procedures. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.5 Personnel 7.5.1 [VIP ID: 188674] “Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8320] “Production operator training should: (2) hands on training for equipment cleaning operations” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.5. Personnel 4.5.1. [VIP ID: 69220] “Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 2 - PERSONNEL Training 2.8. [VIP ID: 345] “The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product.”
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Personnel concerned with cleaning in areas where radioactive products are manufactured should receive additional training specific to the products manufactured. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 3 - MANUFACTURE OF RADIOPHARMACEUTICALS PERSONNEL 1 [VIP ID: 186280] “All personnel (including those concerned with cleaning and maintenance) employed in areas where radioactive products are manufactured should receive additional training adapted to this class of products. In particular, the personnel should be given detailed information and appropriate training on radiation protection.”
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Personnel concerned with cleaning in areas where biological medicinal products are manufactured should receive additional training specific to the products manufactured. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 02 - MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (January 1993) Personnel 1. [VIP ID: 1514] “All personnel (including those concerned with cleaning, maintenance or quality control) employed in areas where biological medicinal products are manufactured should receive additional training specific to the products manufactured and to their work. Personnel should be given relevant information and training in hygiene and microbiology.”
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Personnel concerned with cleaning in areas where sterile products products are manufactured should receive additional training specific to the products manufactured. This training should include reference to hygiene and to the basic elements of microbiology. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS PERSONNEL 14 [VIP ID: 186026] “All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products, including reference to hygiene and to the basic elements of microbiology.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Personnel 14 [VIP ID: 63010] “All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile products. This training should include reference to hygiene and to the basic elements of microbiology.”
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Cleaning personnel training records should be available for all training carried out. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.5 Personnel 7.5.1 [VIP ID: 188674] “Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!! (October 1999) 4. Cleaning Validation 4.5. Personnel 4.5.1. [VIP ID: 69220] “Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.”
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Personnel carrying out manual cleaning procedures should be supervised at regular intervals. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.5 Personnel 7.5.2 [VIP ID: 188676] “It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.5. Personnel 4.5.2. [VIP ID: 69230] “It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals.”
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High standards of personal hygiene and cleanliness are essential for personnel involved in the cleaning of sterile preparations. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Personnel 16 [VIP ID: 63030] “High standards of personal hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable.”
5.
There should be a training tracking system to ensure that only trained personnel perform cleaning tasks. Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8320] “Production operator training should: (1) include a training tracking system to ensure that only trained personnel perform assigned tasks”
6.
Where contract cleaners are used in clean rooms their gowning protocols and personnel practices should be formally audited. Selected FDA 483 Observations (July 1998) Medical Device Manufacture [VIP ID: 6763] “Where contract cleaners are used in clean rooms their gowning protocols and personnel practices should be formally audited.”
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5.4 Product and Components 1.
Certain materials can be stored outdoors in suitable containers, provided the containers are appropriately cleaned before opening and use. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 7. MATERIALS MANAGEMENT 7.4 Storage 7.43 [VIP ID: 24656] “Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 7. MATERIALS MANAGEMENT 7.4 Storage 7.43 [VIP ID: 154640] “Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.”
2.
If bulk deliveries are made in non-dedicated tankers, there should be assurance of no crosscontamination from the tanker. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 7. MATERIALS MANAGEMENT 7.2 Receipt and Quarantine 7.22 [VIP ID: 24644] “If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following: (a) certificate of cleaning (b) testing for trace impurities (c) audit of the supplier.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 7. MATERIALS MANAGEMENT 7.2 Receipt and Quarantine 7.22 [VIP ID: 154520] “If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following: - certificate of cleaning - testing for trace impurities - audit of the supplier.”
5.5 Cleaning Procedures Cleaning procedures should: 1.
be specific and not include any ambiguous statements Selected FDA 483 Observations (July 2001) Product Manufacture [VIP ID: 40370] “Cleaning procedures should be specific and should not include statements such as: (1) "remove as much of liquid or solution from contact parts as possible" (2) "soak parts in acetone for at least a few hours"
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(3) "rinse or wipe with a small amount of acetone or alcohol solvent until there is no presence of dye and / or odor of liquid or solution" (4) "rinse with hot water until completely free from soap" (5) "repeat cleaning procedure if necessary”
2.
include a list of which personnel are trained and responsible for the cleaning of specific equipment. Selected FDA 483 Observations (January 2007) Packaging & Labelling [VIP ID: 194404] “Written procedures for cleaning and maintenance should include assignment of responsibility, description in sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (b) [VIP ID: 56] “Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: (1) Assignment of responsibility for cleaning and maintaining equipment;” Selected FDA 483 Observations (January 2006) Product Manufacture [VIP ID: 180320] “Written procedures for cleaning and maintenance should include a list of which personnel are trained and responsible for the cleaning of specific equipment.” Selected FDA 483 Observations (August 2005) Product Manufacture [VIP ID: 178300] “Procedures for the cleaning and maintenance of equipment should assign responsibility for cleaning and maintaining equipment.” GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 1 [VIP ID: 187394] “…We also recommend that each PET production facility establish and follow written procedures that address the following issues, where applicable: - Assignment of responsibility and frequency for cleaning and maintenance of equipment” Selected FDA 483 Observations (February 2005) Product Manufacture [VIP ID: 138130] “Equipment cleaning, maintenance and sanitation procedures should: a. Assign responsibility for the cleaning process”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.21 [VIP ID: 24566] “Written procedures should be established for cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include: (1) Assignment of responsibility for cleaning of equipment;” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.21 [VIP ID: 153980] “Written procedures should be established for cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include: - Assignment of responsibility for cleaning of equipment;” Selected FDA 483 Observations (August 1997) Product Manufacture [VIP ID: 2513] “Cleaning SOP's should assign responsibility for cleaning equipment…”
3.
include a description in sufficient detail of the methods, equipment, and materials used in cleaning the buildings and facilities, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning. Selected FDA 483 Observations (January 2007) Packaging & Labelling [VIP ID: 194404] “Written procedures for cleaning and maintenance should include assignment of responsibility, description in sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.” Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194324] “Written procedures for cleaning and maintenance should include description in sufficient detail of methods, equipment and materials used, instructions for protection of clean equipment from contamination prior to use, and parameters relevant to the operation.” Selected FDA 483 Observations (November 2006) Product Manufacture [VIP ID: 194232] “Procedures for the cleaning and maintenance of equipment should contain sufficient detail of the methods, equipment, and materials used in the cleaning and maintenance operation, and the methods of disassembly and reassembling equipment as necessary to assure proper cleaning and maintenance.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.56 Sanitation (b) [VIP ID: 48] “There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.”
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21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart C -- Buildings and Facilities Sec. 211.56 Sanitation (c) [VIP ID: 49] “There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling materials, or drug products and shall be followed. Rodenticides, insecticides, and fungicides shall not be used unless registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (b) [VIP ID: 56] “Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: (3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance;” Selected FDA 483 Observations (November 2005) Sterile Product Manufacture [VIP ID: 179710] “Written procedures for cleaning and maintenance should include a description in sufficient detail of methods, equipment and materials used and parameters relevant to the operation.” GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 1 [VIP ID: 187394] “…We also recommend that each PET production facility establish and follow written procedures that address the following issues, where applicable: - Description of cleaning and maintenance procedures in sufficient detail to include disassembly and reassembly of equipment” Selected FDA 483 Observations (October 2004) Product Manufacture [VIP ID: 124460] “Cleaning and maintenance procedures should include: c. a description in sufficient detail of the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance.” Selected FDA 483 Observations (June 2004) Product Manufacture [VIP ID: 122900] “Written procedures for cleaning and maintenance should include a description in sufficient detail of the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance.”
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PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.4 [VIP ID: 188668] “The cleaning process should be documented in an SOP.” Extracted from FDA Warning Letter 04-NWJ-12 (May 2004) 05/05/2004 [VIP ID: 127790] “8. Adequate written procedures for the cleaning and maintenance of equipment used in drug manufacture have not been established and followed (21 CFR 211.67(b)). For example, the cleaning validation study for the [redacted] Fluid Bed Dryer does not address the effectiveness of the cleaning process on all parts of the equipment. In addition, procedures for disassembly and cleaning of other major drug processing units have not been established.” Extracted from FDA Warning Letter 24-04 (February 2004) USA 02/02/2004 [VIP ID: 126330] “10. There was no cleaning validation for tanks #2, 3, 4. Furthermore, written procedures lacked sufficient detail for the cleaning and cleaning validation of tanks #1, 2, 3, 4 [ref. 21 CFR 211.67(a) & (b)].” Extracted from FDA Warning Letter 02-BLT-13 (January 2002) USA 03/01/2002 6 [VIP ID: 48050] “6. Failure to establish adequate written procedures that provide sufficient detail to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess, in that: c. The production area cleaning and maintenance procedure and production equipment cleaning and maintenance procedure does not sufficiently describe in detail any step in the cleaning or maintenance of the production area or of the production equipment (21 CFR 211.67). For example, your firm has four written procedures regarding the cleaning and maintenance of the production area and production equipment. However, the written procedures do not describe decontamination / cleaning solutions, decontamination / cleaning methods, or the preparation of cleaning and maintenance documentation to track these activities; " EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.72 [VIP ID: 24771] “The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.72 [VIP ID: 155760] “The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods.” Selected FDA 483 Observations (May 2000) Product Manufacture [VIP ID: 15900] “Utensil cleaning procedures should provide adequate instructions to disassemble sampling thieves for thorough cleaning.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.4. [VIP ID: 69190] “The cleaning process should be documented in an SOP.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION Documents required - Procedures and records (Other) 4.26. [VIP ID: 497] “There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for: … - maintenance, cleaning and sanitization; … Selected FDA 483 Observations (August 1997) Product Manufacture [VIP ID: 2513] “Cleaning SOP's should assign responsibility for cleaning equipment and describe in sufficient detail: (2) the methods to be used” GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION Detailed Cleaning Procedures [VIP ID: 119290] “Cleaning procedures should be detailed and provide specific understandable instructions. The procedure should identify equipment, cleaning method(s), solvents/detergents approved for use, inspection/release mechanisms, and documentation. For some of the more complex systems, such as clean-in-place (CIP) systems, it is usually necessary to provide a level of detail that includes drawings, and provision to label valves. The time that may elapse from completion of a manufacturing operation to initiation of equipment cleaning should also be stated where excessive delay may affect the adequacy of the established cleaning procedure. For example, residual product may dry and become more difficult to clean.” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (e) Cleaning of Product Contact Surfaces (para 3) [VIP ID: 3444] “Specific inspectional coverage for cleaning should include: 1. Detailed Cleaning Procedure: There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate. For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.” BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES A. Detailed Cleaning Procedure (para 1) [VIP ID: 1084] “There should be a written equipment cleaning procedure that provides details of what should be done and the materials to be utilized. Some manufacturers list the specific solvent for each BDP and intermediate.”
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consider non-contact parts into which product may migrate (e.g. premises, seals, flanges, mixing shaft, fans of ovens, heating elements etc.). PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CLEANING VALIDATION 38 [VIP ID: 187106] “Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.1 [VIP ID: 188640] “Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 38. [VIP ID: 21380] “Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts.”
5.
include air conditioning grills in solution preparation areas. Selected FDA 483 Observations (September 2002) Sterile Product Manufacture [VIP ID: 47840] “Cleaning procedures should include air conditioning grills in solution preparation areas.”
• Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units. Selected FDA 483 Observations (September 2002) Sterile Product Manufacture [VIP ID: 47810] “Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units.”
6.
include the between use cleaning of columns used in HPLC testing of drug formulations. Selected FDA 483 Observations (July 1999) Laboratories [VIP ID: 7500] “There should be written procedures documenting the between use cleaning of columns used in HPLC testing of drug formulations.”
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require that a major cleaning be executed between lots of products obtained from an approved drug substance supplier and a non-approved supplier. Selected FDA 483 Observations (January 2004) Product Manufacture [VIP ID: 71120] “Equipment cleaning SOPs for production lines should require that a major cleaning be executed between lots of products obtained from an approved drug substance supplier and a non-approved supplier, to prevent crosscontamination of impurities that may be present in the different drug sources.”
8.
define different procedures as required, for multi-use equipment cleaning, depending on what product or intermediate was last produced. GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (a) Multipurpose Equipment (para 1) [VIP ID: 3434] “…The cleaning program should take into consideration the need for different procedures depending on what product or intermediate was produced.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements (para 1) [VIP ID: 1323] “FDA expects firms to have written procedures (SOP's) detailing the cleaning processes used for various pieces of equipment. If firms have one cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, we expect the written procedures to address these different scenario. Similarly, if firms have one process for removing water soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed.”
9.
include diagrams and identify specific valves for clean-in-place (CIP) systems. GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (e) Cleaning of Product Contact Surfaces (para 3) [VIP ID: 3444] “Specific inspectional coverage for cleaning should include: 1. Detailed Cleaning Procedure: There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate. For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.” BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES A. Detailed Cleaning Procedure (para 2) [VIP ID: 1085] “For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.”
10. include diagrams or a narrative description of hard to clean areas. Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 19120] “Where cleaning SOPs or validation protocols make reference to 'Hard to Reach' areas, they should include diagrams or narrative descriptions of these areas.”
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11. provide instructions for the cleaning and storage of sampling equipment. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 6 QUALITY CONTROL SAMPLING 6.11 [VIP ID: 185856] “The sample taking should be done in accordance with approved written procedures that describe: - instructions for the cleaning and storage of sampling equipment.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 6 - QUALITY CONTROL Sampling 6.11. [VIP ID: 612] “The sample taking should be done in accordance with approved written procedures that describe: - instructions for the cleaning and storage of sampling equipment.”
12. include the method for protection of clean equipment from contamination prior to use. Selected FDA 483 Observations (January 2007) Packaging & Labelling [VIP ID: 194404] “Written procedures for cleaning and maintenance should include assignment of responsibility, description in sufficient detail of the methods if disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance, and instructions for protection of clean equipment from contamination prior to use.” Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194324] “Written procedures for cleaning and maintenance should include description in sufficient detail of methods, equipment and materials used, instructions for protection of clean equipment from contamination prior to use, and parameters relevant to the operation.” Selected FDA 483 Observations (September 2006) Sterile Product Manufacture [VIP ID: 194010] “Procedures for the cleaning and maintenance of equipment should include the protection of clean equipment from contamination prior to use. For example, bulk drug solution mixing tanks should be covered or held in a manner that would prevent environmental contamination while being stored in a non-classified storage area following cleaning.” Selected FDA 483 Observations (June 2006) Sterile Product Manufacture [VIP ID: 193766] “Procedures for the cleaning and maintenance of equipment should include requirements regarding the protection of clean equipment from contamination prior to use, and there should be data to support the established sterilization expiration date for sterilized filling equipment.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (b) [VIP ID: 56] “Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: (5) Protection of clean equipment from contamination prior to use;”
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GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 1 [VIP ID: 187394] “…We also recommend that each PET production facility establish and follow written procedures that address the following issues, where applicable: - Protection of clean equipment from contamination prior to use” Selected FDA 483 Observations (February 2005) Product Manufacture [VIP ID: 138130] “Equipment cleaning, maintenance and sanitation procedures should: c. Detail the method for protection of the cleaned equipment prior to use.” Selected FDA 483 Observations (October 2004) Product Manufacture [VIP ID: 124460] “Cleaning and maintenance procedures should include: e. instructions for protection of clean equipment from contamination prior to use.” Selected FDA 483 Observations (April 1998) Product Manufacture [VIP ID: 6391] “Utensils, such as scoops, used for the weighing of raw materials should be consistently washed and stored so as to remain clean.” Selected FDA 483 Observations (August 1997) Product Manufacture [VIP ID: 2513] “Cleaning SOP's should assign responsibility for cleaning equipment and describe in sufficient detail: (5) protection of cleaned equipment prior to use”
13. include directions for the use of cleaning and disinfecting agents. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 9. CLEANING, SANITISATION AND DISINFECTION 9.5 [VIP ID: 190292] “Records should be retained in respect of routine preparation of cleaning and disinfecting agents, directions for their use, and validation of their efficacy.”
•
Specifying which cleaning agent(s) will be used and at what concentration(s) (to include the cleaning of floors and table tops in processing areas). Extracted from FDA Warning Letter 2003-NOL-01 (October 2002) USA 10/10/2002 [VIP ID: 49860] “Written procedures are not established for the use of suitable cleaning and sanitizing agents designed to prevent the contamination of equipment, drug product containers, closures and packaging, or labeling materials [21 CFR 211.56(c)];”
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Extracted from FDA Warning Letter 02-BLT-13 (January 2002) USA 03/01/2002 6 [VIP ID: 48050] “6. Failure to establish adequate written procedures that provide sufficient detail to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess, in that: c. The production area cleaning and maintenance procedure and production equipment cleaning and maintenance procedure does not sufficiently describe in detail any step in the cleaning or maintenance of the production area or of the production equipment (21 CFR 211.67). For example, your firm has four written procedures regarding the cleaning and maintenance of the production area and production equipment. However, the written procedures do not describe decontamination/cleaning solutions, decontamination/cleaning methods, or the preparation of cleaning and maintenance documentation to track these activities;” Extracted from FDA Warning Letter DEN-01-45 (August 2001) USA 08/08/2001 [VIP ID: 44030] “4. Failure to establish and maintain design input procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, as required by 21 CFR 820.30(c). For example: (c) MIT failed to specifically identify and evaluate the selection of the cleaning chemicals used in the decontamination procedure.” Selected FDA 483 Observations (June 1999) Product Manufacture [VIP ID: 7236] “Cleaning procedures should specify which cleaning agent will be used.” Selected FDA 483 Observations (April 1997) Product Manufacture [VIP ID: 2539] “Cleaning procedures for processing areas should specify what cleanser and what concentrations for cleaners should be used for cleaning floors and table tops.”
14. require the rotation of sanitising agents (disinfectants) used in aseptic processing areas and surrounding clean rooms. Selected FDA 483 Observations (October 1997) Sterile Product Manufacture [VIP ID: 2486] “Sanitizing agents (disinfectants) used in the aseptic processing areas and the surrounding clean rooms should be rotated.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Sanitation 37. [VIP ID: 1450] “The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme. Where disinfectants are used, more than one type should be employed.”
15. require the removal or obliteration of previous batch identification. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (b) [VIP ID: 56] “Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: (4) Removal or obliteration of previous batch identification;”
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Selected FDA 483 Observations (October 2004) Product Manufacture [VIP ID: 124460] “Cleaning and maintenance procedures should include: d. instructions for removal or obliteration of previous batch identification.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 9. PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES 9.2 Packaging Materials 9.22 [VIP ID: 24692] “If containers are re-used, they should be cleaned in accordance with documented procedures and all previous labels should be removed or defaced.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 9. PACKAGING AND IDENTIFICATION LABELLING OF APIs AND INTERMEDIATES 9.2 Packaging Materials 9.22 [VIP ID: 155000] “If containers are re-used, they should be cleaned in accordance with documented procedures and all previous labels should be removed or defaced.” Selected FDA 483 Observations (August 1997) Product Manufacture [VIP ID: 2513] “Cleaning SOP's should assign responsibility for cleaning equipment and describe in sufficient detail: (4) removal of previous batch identification”
16. include specific instructions to ensure that repeat samples are not taken from identical locations. Selected FDA 483 Observations (October 1998) Product Manufacture [VIP ID: 6843] “Cleaning swab sample procedures should ensure that repeat samples are not taken from identical locations.”
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include specific instructions to ensure that micro and chemical samples are not collected from the same areas. Selected FDA 483 Observations (February 1997) Product Manufacture [VIP ID: 2470] “Cleaning validation protocols / SOPs should include specific instructions to ensure that microbiological and chemical samples are not collected from the same areas.”
17. include the requirement to clean product contact equipment following maintenance operations. Selected FDA 483 Observations (June 1998) Product Manufacture [VIP ID: 6715] “Cleaning should be performed after product contact equipment maintenance in accordance with a written procedure.”
18. state the minimum rinse time(s). Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40910] “Cleaning procedures should include specific details regarding rinse times and solvent quantities to be used.”
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Selected FDA 483 Observations (November 1998) Product Manufacture [VIP ID: 7037] “Cleaning procedures should state the minimum rinse time.” Selected FDA 483 Observations (November 1996) Product Manufacture [VIP ID: 135600] “Equipment cleaning procedures should describe how long the equipment should be washed rather than washing until "visibly clean".”
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Cleaning rinse times should specify if they are for individual pieces of equipment or for rinsing equipment together. Selected FDA 483 Observations (November 2006) Sterile Product Manufacture [VIP ID: 194204] “Cleaning rinse times should specify if they are for individual pieces of equipment or for rinsing equipment together.”
19. state the minimum rinse volume(s). Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40910] “Cleaning procedures should include specific details regarding rinse times and solvent quantities to be used.” Selected FDA 483 Observations (May 2000) Sterile Product Manufacture [VIP ID: 16060] “Lyophilizer cleaning validation should include: (1) a statement of minimum rinse volumes”
20. state the number of consecutive lots which can be manufactured without major cleaning. Selected FDA 483 Observations (February 2005) Product Manufacture [VIP ID: 138130] “Equipment cleaning, maintenance and sanitation procedures should: b. Explain the frequency for the cleaning procedure.” Selected FDA 483 Observations (January 1999) Product Manufacture [VIP ID: 7110] “The number of consecutive lots which can be manufactured without major cleaning should be stated.”
21. ensure that residual water is not left in equipment (such as pumps, tri-blenders, pipework and tanks etc.) following cleaning. HEALTH CANADA - GMP INTERPRETATION DECISION RECORDS 2003 EDITION (September 2003) 2.0 GMP QUESTIONS & ANSWERS (Grouped by Section of Division 2 Regulations) 2.1 PREMISES - C.02.004 2.1.4 [VIP ID: 65620] “WHAT IS THE ACCEPTABLE LIMIT FOR DEW POINT OF THE COMPRESSED AIR USED IN PNEUMATIC EQUIPMENT AND TO DRY THE MANUFACTURING TANKS AFTER CLEANING? …Similarly, it is important to make sure that residual water has been completely eliminated from hard to reach surfaces of the equipment after cleaning operations.”
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Selected FDA 483 Observations (March 2000) Product Manufacture [VIP ID: 15090] “Residual water should not be left in equipment (such as pumps and tri-blenders) following cleaning.” Extracted from FDA Warning Letter CBER 98-006 (December 1998) Germany 01/12/1998 [VIP ID: 13080] “Failure of equipment used in the manufacture, processing, packing, or holding of drug products to be of appropriate design, adequate size, and suitability located to facilitate operations for intended use and for its cleaning and maintenance in that the cleaning nozzle and hose used to clean lyophilizer #**** in the aseptic filling area is approximately - meters in length and there is no procedure describing the draining of the hose and nozzle to prevent standing water.[21 CFR 211.63].” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (5) assurance that residual water is removed from the product transfer lines” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 1. Equipment Design (para 5) [VIP ID: 1335] “Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.”
22. include the monitoring of the usage of cleaning tools. Selected FDA 483 Observations (May 2000) Medical Device Manufacture [VIP ID: 15970] “There should be written procedures to monitor the usage of cleaning tools.”
23. include provisions for controlling access to cleaning equipment (including mops and washing buckets) used in clean/packaging rooms. Selected FDA 483 Observations (May 2000) Medical Device Manufacture [VIP ID: 15980] “Access to cleaning equipment including mops and washing buckets used in clean / packaging rooms should be controlled.”
24. require the status (clean/dirty) of the equipment (including utensils and spare parts used in the manufacturing area) to be clearly identified. Selected FDA 483 Observations (May 2005) Active Pharmaceutical Ingredient Manufacture [VIP ID: 177290] “Utensils for API repackaging operations, which are stored as clean, should be identified as cleaned and there should be documentation to assure these utensils are clean.” Selected FDA 483 Observations (March 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 121800] “There should be a record to document the status of spare parts used in the manufacturing area, i.e. cleaned, to-becleaned, or the current status (e.g., not to be used).”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.26 [VIP ID: 24571] “Equipment should be identified as to its contents and its cleanliness status by appropriate means.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.26 [VIP ID: 154030] “Equipment should be identified as to its contents and its cleanliness status by appropriate means.” Extracted from FDA Warning Letter CBER-99-014 (March 1999) USA 18/03/1999 [VIP ID: 12090] “multi-use equipment including bulk storage containers, filling machines, hoses, and accessories were observed stored in room **** there was no designation to indicate whether the equipment was clean or dirty, An operator in room **** when questioned by our investigators regarding the status of reusable carboy containers, was uncertain whether the carboys were clean or dirty.” Extracted from FDA Warning Letter CBER-99-020 (May 1999) USA 03/05/1999 [VIP ID: 12070] “In the separation room of the Virus Production area the concentration tank tubing and connector were noted to be laying on the floor and the status (i.e., clean, dirty, in-use) of the tank was not identified.” GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS - CGMPR'S (October 1993) EQUIPMENT [21 CFR 211 Subpart D] (para 4) [VIP ID: 2637] “…Equipment must be identified as to its cleaning status and content.”
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Flexible tubing (e.g. hoses) used in manufacturing should carry distinctive identification to track its use and cleaning. Selected FDA 483 Observations (July 2002) Active Pharmaceutical Ingredient Manufacture [VIP ID: 47400] “Hoses used for the transfer of product or waste should: (a) be identified to indicate the cleaning status.” Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 16510] “Flexible tubing used in manufacturing should carry distinctive identification to track its use and cleaning.”
25. include periodic testing to assure that the surface has been cleaned to the validated level. Selected FDA 483 Observations (January 1999) Sterile Product Manufacture [VIP ID: 7106] “Manufacturing equipment and parts should be periodically tested for product/cleaning/sanitizing residues.”
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Selected FDA 483 Observations (September 1997) Product Manufacture [VIP ID: 2497] “Equipment cleaning validation should include: (3) Periodic testing of the equipment for product residue” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (e) Cleaning of Product Contact Surfaces (para 3) [VIP ID: 3444] “Specific inspectional coverage for cleaning should include: 2. Sampling Plan: After cleaning, there should be some periodic testing to assure that the surface has been cleaned to the validated level. One common method is the analysis of the final rinse water or solvent for the presence of the substance last used in that piece of equipment. There should always be a specific analytical determination for such a residual substance.”
26. require the dedication of equipment that contains tarry or gummy residues, that cannot be removed readily, for use only with limited portions of a synthesis. CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.6 Equipment 7.6.2 [VIP ID: 188680] “Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing)…” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (a) Multipurpose Equipment (para 1) [VIP ID: 3434] “…Equipment that contains tarry or gummy residues that cannot be removed readily should be dedicated for use only with limited portions of a synthesis.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements (para 1) [VIP ID: 1323] “…Bulk pharmaceutical firms may decide to dedicate certain equipment for certain chemical manufacturing process steps that produce tarry or gummy residues that are difficult to remove from the equipment.”
27. require the dedication of equipment for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit). CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.6 Equipment 7.6.2 [VIP ID: 188680] “Dedicated equipment should be used … for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).”
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28. include the definition of cleaning schedules, including, where appropriate, sanitising schedules. Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194320] “… Routine maintenance schedules and procedures should be established for equipment such as an oscillating granulator used in the production of powder products and this should include the care, cleaning, and maintenance of the mesh screen to prevent the formation of holes.” Selected FDA 483 Observations (October 2006) Product Manufacture [VIP ID: 194146] “There should be written procedures providing cleaning schedules for sanitation, including the cleaning of production areas and equipment between batches of same formulation drug products.” Selected FDA 483 Observations (October 2006) Sterile Product Manufacture [VIP ID: 194106] “Procedures for the cleaning and maintenance of equipment should include maintenance and cleaning schedules, including, where appropriate, sanitizing schedules. Specifically, a written procedure should be established to prevent drug product contamination.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (a) [VIP ID: 55] “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (b) [VIP ID: 56] “Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: (2) Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;” 21 CFR PART 820 - QUALITY SYSTEM REGULATION (April 2006) Subpart G--Production and Process Controls 21 CFR 820.70 Production and process controls. (g) (1) Maintenance schedule. [VIP ID: 5811] “Each manufacturer shall establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities, including the date and individual(s) performing the maintenance activities, shall be documented.” Selected FDA 483 Observations (August 2005) Product Manufacture [VIP ID: 178310] “Procedures for the cleaning and maintenance of equipment should include maintenance, cleaning and, where appropriate, sanitisation schedules.”
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Extracted from FDA Warning Letter CIN-06-27364-01 (October 2005) USA 17/10/2005 [VIP ID: 173520] “3. Failure to perform preventive maintenance and to establish written equipment maintenance schedules for the adjustment, cleaning and other maintenance of equipment to ensure that manufacturing specifications are met, as required by 21 CFR 820.70(g)(1 & 2). Specifically, the required weekly and monthly preventive maintenance checks on the [redacted] fabricating machine are not being performed; and there are no written procedures describing what checks/maintenance needs to be performed.” Extracted from FDA Warning Letter FLA-05-05 (November 2004) USA 02/11/2004 [VIP ID: 131510] “9. Failure to maintain schedules and procedures for equipment maintenance and calibration as required by 21 CFR 606.100(b)(15). Specifically, there is no written procedure for the maintenance of the Composeal Universal sealer used in the preparation of leuko-reduced blood components or for cleaning of the device after a blood spill (FDA 483 #11).” Extracted from FDA Warning Letter 2004-NOL-11 (January 2004) USA 14/01/2004 [VIP ID: 125990] “6. Your firm’s schedules for the adjustment, cleaning, and other maintenance of equipment were not established as required by 21 CFR 820.70(g)(1). Specifically, Multidex cleaning procedures do not describe minor cleaning and major cleaning frequencies.” Selected FDA 483 Observations (April 2003) Medical Device Manufacture [VIP ID: 52300] “Schedules should be defined for the adjustment, cleaning and maintenance of equipment.” Selected FDA 483 Observations (August 1997) Product Manufacture [VIP ID: 2513] “Cleaning SOP's should assign responsibility for cleaning equipment and describe in sufficient detail: (1) the cleaning schedules”
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Clean areas should be cleaned thoroughly in accordance with a written programme. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS - SUPERSEDED! (July 1996) Sanitation 37. [VIP ID: 1450] “The sanitation of clean areas is particularly important. They should be cleaned thoroughly in accordance with a written programme.”
29. consider the different physical properties and impurity profiles of raw materials sourced from different suppliers, since the raw materials may behave differently. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.7 [VIP ID: 188652] “Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.7. [VIP ID: 68980] “Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.”
30. consider the existence of conditions favourable to reproduction of micro organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.7 Microbiological Aspects 7.7.1 [VIP ID: 188682] “The existence of conditions favourable to reproduction of micro organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.7 Microbiological Aspects 7.7.2 [VIP ID: 188684] “The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.7. Microbiological Aspects 4.7.1. [VIP ID: 69260] “The existence of conditions favourable to reproduction of micro organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination.”
NOTE: The EC states that, generally, in the case of batch-to-batch production, it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.3 [VIP ID: 188644] “Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.23 [VIP ID: 24568] “Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carryover of contaminants (e.g. degradants or objectionable levels of micro-organisms).” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 8. PRODUCTION AND IN-PROCESS CONTROLS 8.5 Contamination Control 8.50 [VIP ID: 24684] “Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.3. [VIP ID: 68940] “Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.”
31. be very stringent for investigational products. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 13 - MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS (1997) - SUPERSEDED! (December 1996) Production Manufacturing operations 26. [VIP ID: 4610] “Where applicable virus inactivation/removal and/or other impurities of biological origin should be no less than for products authorised for marketing. Cleaning procedures should be very stringent and designed in the light of the incomplete knowledge of the toxicity of the investigational product. Where processes such as mixing have not been validated, additional quality control testing may be necessary.”
32. include the method of inspection of the cleaned equipment prior to use. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (b) [VIP ID: 56] “Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to, the following: (6) Inspection of equipment for cleanliness immediately before use.”
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GUIDANCE PET DRUG PRODUCTS - CURRENT GOOD MANUFACTURING PRACTICE (CGMP) DRAFT GUIDANCE (September 2005) VI. FACILITIES AND EQUIPMENT C. Equipment 1. Production Equipment para 1 [VIP ID: 187394] “…We also recommend that each PET production facility establish and follow written procedures that address the following issues, where applicable: - Inspection of equipment and calibration, if indicated, prior to use” Selected FDA 483 Observations (February 2005) Product Manufacture [VIP ID: 138130] “Equipment cleaning, maintenance and sanitation procedures should: d. Describe the method of inspection of the cleaned equipment prior to use”
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include specific criteria for the cleaning evaluation of manufacturing equipment during visual inspection before product manufacture. Selected FDA 483 Observations (November 2003) Product Manufacture [VIP ID: 72300] “Cleaning Validation Protocols should include: d. Specific criteria for the cleaning evaluation of manufacturing equipment during visual inspection before product manufacture.” Selected FDA 483 Observations (May 1999) Sterile Product Manufacture [VIP ID: 16070] “Lyophilizer cleaning procedures should include: (1) a visual check of check of equipment cleanliness”
33. require documentation of the cleaning process. Selected FDA 483 Observations (February 2005) Product Manufacture [VIP ID: 138130] “Equipment cleaning, maintenance and sanitation procedures should: e. Require documentation of the cleaning process.”
34. address how to clean dirty plastic and stainless steel containers that had previously contained weighed out components. Selected FDA 483 Observations (January 2002) Product Manufacture [VIP ID: 46270] “Standard Operating Procedures for compounding washing areas should address how to clean dirty plastic and stainless steel containers that had previously contained weighed out components.”
35. address how to clean HEPA filter grills. Selected FDA 483 Observations (September 2002) Sterile Product Manufacture [VIP ID: 47840] “Cleaning procedures should include air conditioning grills in solution preparation areas.”
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Extracted from FDA Warning Letter 2003-DAL-WL-01 (October 2002) USA 15/10/2002 5 [VIP ID: 48080] “5. Failure to have adequate systems to control contaminants in areas where air contamination occurs during production [21 CFR 211.46(c)]. For example, - There are numerous HEPA filter metal grills that have a build up of rust-like material and discoloration (e.g. Rotary **** Irrigation Filling, Part Fill Filling, and Manual Filling). Two HEPA filter grills are bent and reveal a buildup of moldlike and other unknown material and these grills are located immediately above the **** filling zone”
36. address how to clean cleanroom Air Handling Units (AHU). Selected FDA 483 Observations (September 2002) Sterile Product Manufacture [VIP ID: 47810] “Planned maintenance procedures for cleanroom Air Handling Units (AHU) should require cleaning of the units.”
37. address the control of cleaning labels where they comprise the sole documentation and verification for cleaning operations. Selected FDA 483 Observations (February 2005) Product Manufacture [VIP ID: 138120] “There should be procedures for the control of cleaning labels, where they comprise the sole documentation and verification for cleaning operations.”
38. include any special post-repair cleaning and calibration requirements. CDER 5/1/87 - GUIDELINE ON GENERAL PRINCIPLES OF PROCESS VALIDATION - MAY 1987 (REPRINTED FEBRUARY 1993) VIII. ELEMENTS OF PROCESS VALIDATION A. Prospective Validation 1. Equipment and Process - a. Equipment: Installation Qualification (para 5) [VIP ID: 854] “Once the equipment configuration and performance characteristics are established and qualified, they should be documented. The installation qualification should include a review of pertinent maintenance procedures, repair parts lists, and calibration methods for each piece of equipment. The objective is to assure that all repairs can be performed in such a way that will not affect the characteristics of material processed after the repair. In addition, special post-repair cleaning and calibration requirements should be developed to prevent inadvertent manufacture a of non-conforming product. Planning during the qualification phase can prevent confusion during emergency repairs which could lead to use of the wrong replacement part.”
39. include the cleaning of the surface of bags of raw materials before charging. Selected FDA 483 Observations (April 2006) Active Pharmaceutical Ingredient Manufacture [VIP ID: 193562] “There should be written procedures for the cleaning of the surface of bags of raw materials before charging.”
40. be collected and collated, or developed in draft documentation form from equipment supplier specifications and operating procedures as part of the Installation Qualification activity. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and Operational Qualification of equipment involved in the manufacture of pharmaceutical products. 5.2 Installation Qualification (l.Q.) - Overview Statement 5.2.2 [VIP ID: 188524]
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“Identification and documenting of maintenance requirements for each installed item and the collection and collation of supplier operating and working instructions, maintenance and cleaning requirements, should form the minimum documentation for a satisfactory Installation Qualification.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and Operational Qualification of equipment involved in the manufacture of pharmaceutical products. 5.3 Installation Qualification - Essential Elements - Installation Qualification 5.3.7 [VIP ID: 188538] “At the Installation Qualification stage the company should document preventative maintenance requirements for installed equipment. At this stage new equipment and the preventative maintenance requirements should be added to the preventative maintenance schedule of the pharmaceutical manufacturer.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 2. Design Qualification, Installation and Operational Qualification 2.2. Installation Qualification (IQ.) - Overview Statement 2.2.2. [VIP ID: 68340] “Identification and documenting of maintenance requirements for each installed item and the collection and collation of supplier operating and working instructions, maintenance and cleaning requirements, should form the minimum documentation for a satisfactory Installation Qualification.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 2. Design Qualification, Installation and Operational Qualification 2.3 Installation Qualification - Essential Elements Installation Qualification 2.3.7. [VIP ID: 68410] “At the Installation Qualification stage the company should document preventative maintenance requirements for installed equipment. At this stage new equipment and the preventative maintenance requirements should be added to the preventative maintenance schedule of the pharmaceutical manufacturer. Cleaning, including sanitisation and / or sterilisation requirements for the equipment, should be developed in draft documentation form from equipment supplier specifications and operating procedures. The draft cleaning documentation should be finalised following experience and observation at the Operational Qualification stage and then verified at the Performance Qualification stage.”
41. be formally developed as part of the Operational Qualification activity. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and Operational Qualification of equipment involved in the manufacture of pharmaceutical products. 5.4 Operational Qualification (O.Q) - Overview Statement 5.4.3 [VIP ID: 188544] “It is expected that during the Operational Qualification stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration schedules.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 2. Design Qualification, Installation and Operational Qualification 2.4. Operational Qualification (O.Q) - Overview Statement 2.4.3. [VIP ID: 68440] “It is expected that during the Operational Qualification stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning activities, maintenance requirements and calibration schedules.”
42. be finalised after satisfactory Operational Qualification. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION QUALIFICATION Operational Qualification 15 [VIP ID: 187060] “The completion of a successful Operational qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal "release" of the facilities, systems and equipment.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and Operational Qualification of equipment involved in the manufacture of pharmaceutical products. 5.3 Installation Qualification - Essential Elements - Installation Qualification 5.3.7 [VIP ID: 188538] “…The draft cleaning documentation should be finalised following experience and observation at the Operational Qualification stage and then verified at the Performance Qualification stage.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and Operational Qualification of equipment involved in the manufacture of pharmaceutical products. 5.5 Operational Qualification - Essential Elements 5.5.4 [VIP ID: 188554] “Draft cleaning procedures developed at the lnstallation Qualification stage should be finalised after a satisfactory Operational Qualification exercise and issued as standard operating procedures (SOPs).” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 2. Design Qualification, Installation and Operational Qualification 2.5. Operational Qualification - Essential Elements 2.5.4. [VIP ID: 68490] “Draft cleaning procedures developed at the Installation Qualification stage should be finalised after a satisfactory Operational Qualification exercise and issued as standard operating procedures (SOPs). Where applicable, these procedures should be validated as part of the Performance Qualification phase.”
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43. be verified/validated as part of the Performance Qualification activity where applicable. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and Operational Qualification of equipment involved in the manufacture of pharmaceutical products. 5.3 Installation Qualification - Essential Elements - Installation Qualification 5.3.7 [VIP ID: 188538] “…The draft cleaning documentation should be finalised following experience and observation at the Operational Qualification stage and then verified at the Performance Qualification stage.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 5. INSTALLATION AND OPERATIONAL QUALIFICATION - Recommendations for the Installation Qualification and Operational Qualification of equipment involved in the manufacture of pharmaceutical products. 5.5 Operational Qualification - Essential Elements 5.5.4 [VIP ID: 188554] “Draft cleaning procedures developed at the lnstallation Qualification stage should be finalised after a satisfactory Operational Qualification exercise and issued as standard operating procedures (SOPs). Where applicable, these procedures should be validated as part of the Performance Qualification phase.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 2. Design Qualification, Installation and Operational Qualification 2.5. Operational Qualification - Essential Elements 2.5.4. [VIP ID: 68490] “Draft cleaning procedures developed at the Installation Qualification stage should be finalised after a satisfactory Operational Qualification exercise and issued as standard operating procedures (SOPs). Where applicable, these procedures should be validated as part of the Performance Qualification phase.”
5.5.1 Specific Requirements - Ribbon Blenders Ribbon blender cleaning procedures should: 1.
address the ends of the ribbon blender where the horizontal bar enters the unit. GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION (January 1994) V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS) B. Post-Approval Prospective Validation Inspections 2. Manufacturing Procedures and Equipment a. Blenders - 2. Ribbon Blender (para 4) [VIP ID: 3125] “Cleaning problems, particularly at the ends of the ribbon blender where the horizontal bar enters the blender, have been identified.”
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require the disassembly and cleaning of seals/packing between batches of different products. GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION (January 1994) V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS) B. Post-Approval Prospective Validation Inspections 2. Manufacturing Procedures and Equipment a. Blenders - 2. Ribbon Blender (para 4) [VIP ID: 3125] “…If manufacturers do not disassemble and clean the seals/packing between batches, they should have data to demonstrate the absence of foreign contaminants between batches of different products processed in the blender.”
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If not, data should be developed to demonstrate the absence of foreign contaminants between batches of different products. GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION (January 1994) V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS) B. Post-Approval Prospective Validation Inspections 2. Manufacturing Procedures and Equipment a. Blenders - 2. Ribbon Blender (para 4) [VIP ID: 3125] “…If manufacturers do not disassemble and clean the seals/packing between batches, they should have data to demonstrate the absence of foreign contaminants between batches of different products processed in the blender.”
5.5.2 Specific Requirements - High Shear (high energy) Mixers High shear mixer cleaning procedures should: 1.
require the disassembly and cleaning of the intensifier bar between products. GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION (January 1994) V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS) B. Post-Approval Prospective Validation Inspections 2. Manufacturing Procedures and Equipment a. Blenders - 4. High Shear (high energy) Mixers (para 4) [VIP ID: 3131] “…Also, cleaning of the blender requires disassembly of the intensifier bar between products.”
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The intensifier bar in the centre of the blender rotates at very high speeds to break down smaller, harder agglomerates. The extremely high speed of the intensifier bar generates considerable heat that can sometimes result in charring of some sugar base granulations. GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION (January 1994) V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS) B. Post-Approval Prospective Validation Inspections 2. Manufacturing Procedures and Equipment a. Blenders - 4. High Shear (high energy) Mixers (para 4) [VIP ID: 3131] “The presence of an intensifier bar in the center of the blender which rotates at very high speeds breaks down smaller, harder agglomerates. A major disadvantage of this type of blender is that the extremely high speed of the intensifier bar generates considerable heat that can sometimes result in charring of some sugar base granulations.”
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The same comments are applicable to other high energy mixers which also rely on high speed choppers to disperse powders. GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION (January 1994) V DEMONSTRATION RUNS (VALIDATION OF THE PROCESS) B. Post-Approval Prospective Validation Inspections 2. Manufacturing Procedures and Equipment a. Blenders - 4. High Shear (high energy) Mixers (para 4) [VIP ID: 3131] “…It should be pointed out that these same comments are applicable to other high energy mixers which also rely on high speed choppers to disperse powders.”
5.5.3 Specific Requirements - Fluid Bed Dryer Bags Fluid bed dryer cleaning procedures should: 1.
require dryer bags, which are difficult to clean, to be dedicated to a specific product. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements (para 1) [VIP ID: 1323] “…Fluid bed dryer bags are another example of equipment that is difficult to clean and is often dedicated to a specific product.”
5.5.4 Specific Requirements - Lyophilisers Lyophiliser cleaning procedures should: 1.
require sampling from worst case locations as supported by validation. Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40510] “Cleaning samples taken from lyophilizers should: (1) be taken from worst case locations as supported by validation”
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require analysis of samples for the presence of oil vapour. Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40510] “Cleaning samples taken from lyophilizers should: (2) be analyzed for the presence of oil vapor”
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require analysis of samples for the presence of refrigerant residues. Selected FDA 483 Observations (August 2001) Sterile Product Manufacture [VIP ID: 40510] “Cleaning samples taken from lyophilizers should: (3) be analyzed for the presence of refrigerant residues”
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5.6 Cleaning Records The following points should be considered when developing cleaning record packages: 1.
Records should be kept of cleaning, sanitising, and inspection. Extracted from FDA warning letter VLN# 06200780 (January 2007) USA 05-Jan-07 4 [VIP ID: 194670] “Failure to keep records for the maintenance, cleaning, and sanitizing of equipment. [21 CFR § 211.67(c)] There were no equipment cleaning records for several of the product contact, multi-use formulation mixing rods. The investigators observed that there was no evidence to demonstrate that the mixing rods were dedicated to specific products.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION QUALIFICATION Qualification of established (in-use) facilities, systems and equipment 19 [VIP ID: 187068] “Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart D -- Equipment Sec. 211.67 Equipment cleaning and maintenance (c) [VIP ID: 63] “Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified in §§ 211.180 and 211.182.” Selected FDA 483 Observations (February 2005) Product Manufacture [VIP ID: 138130] “Equipment cleaning, maintenance and sanitation procedures should: e. Require documentation of the cleaning process.” Selected FDA 483 Observations (June 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 52780] “"Clean Room" cleaning steps performed should be documented.” Extracted from FDA Warning Letter DEN-03-07 (December 2002) USA 02/12/2002 [VIP ID: 60210] “5) Failure to maintain a written record of major equipment cleaning and maintenance [21 C.F.R. 211.182]. For example, the firm fails to maintain equipment cleaning and use logs for equipment used in the relabeling of drug products.” Extracted from FDA Warning Letter 2003-NOL-01 (October 2002) USA 10/10/2002 [VIP ID: 49850] “Records are not kept for the maintenance, cleaning, sanitizing, and inspection of repackaging equipment [21 CFR 211.67(c)];”
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Selected FDA 483 Observations (May 2002) Sterile Product Manufacture [VIP ID: 28140] “Records should be maintained of processing equipment use, maintenance, cleaning, malfunctions, and repairs.” Extracted from FDA Warning Letter KAN 2002407 (June 2002) USA 07/06/2002 [VIP ID: 48940] “Failure to keep records for the maintenance, cleaning, sanitizing, and inspection of equipment used in pharmaceutical production. (21 CFR 211.67(c)]” Extracted from FDA Warning Letter CHI-5-02 (October 2001) USA 15/10/2001 [VIP ID: 43460] “Failure to maintain equipment cleaning and use logs covering the maintenance, cleaning, sanitizing and inspection of equipment used in the production of pharmaceutical products [21 CFR 211.182]. The inspection revealed that your firm’s SOP #2.02 entitled Cleaning & Maintenance log book requires that these activities be recorded also.” Extracted from FDA Warning Letter CHI-57-01 (September 2001) USA 27/09/2001 [VIP ID: 43560] “Failure to maintain a written record of major equipment cleaning, maintenance and use [21 CFR 211.182].” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) QUALIFICATION Qualification of established (in-use) facilities, systems and equipment 19. [VIP ID: 21190] “Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 6. DOCUMENTATION AND RECORDS 6.2 Equipment Cleaning and Use Record 6.20 [VIP ID: 24597] “Records of major equipment use, cleaning, sanitization and / or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person who performed the cleaning and maintenance.” Extracted from FDA Warning Letter M3485n (February 2000) USA 23/02/2000 [VIP ID: 12930] “Failure to document cleaning of the filling machine and the mixing vessel. The last documented cleaning of this equipment was February 11, 1991.” GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURERS - CGMPR'S (October 1993) EQUIPMENT [21 CFR 211 Subpart D] (para 2) [VIP ID: 2635] “New equipment must be properly installed, and operate as designed. Determine if the equipment change would require FDA pre-approval and / or revalidation of the manufacturing process. The equipment must be cleaned before use according to written procedures. The cleaning must be documented and validated.”
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The amount of documentation necessary for executing various cleaning steps or procedures will vary depending upon the complexity of the system and cleaning process and the ability and training of operators. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 2. Cleaning Process Written Procedure and Documentation (para 1) [VIP ID: 1337] “Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required. We have seen general SOPs, while others use a batch record or log sheet system that requires some type of specific documentation for performing each step. Depending upon the complexity of the system and cleaning process and the ability and training of operators, the amount of documentation necessary for executing various cleaning steps or procedures will vary.”
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For relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 2. Cleaning Process Written Procedure and Documentation (para 2) [VIP ID: 1338] “…for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient.”
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When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself, which includes information about who cleaned it and when, is valuable. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 2. Cleaning Process Written Procedure and Documentation (para 2) [VIP ID: 1338] “When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself which includes information about who cleaned it and when is valuable.”
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Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and operator performance. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 2. Cleaning Process Written Procedure and Documentation (para 3) [VIP ID: 1339] “Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.”
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Appropriate evaluations must be made and, when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 2. Cleaning Process Written Procedure and Documentation (para 3) [VIP ID: 1339] “…Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.”
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When the equipment is dedicated to the manufacture of a single product, and provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence, cleaning can be recorded as part of the batch records. Extracted from FDA warning letter MIN 06-30 (July 2006) USA 27-Jul-06 8 [VIP ID: 192336] “The batch records lack records of the cleaning for dedicated equipment [21 CFR 211.182].” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart J -- Records and Reports Sec. 211.182 Equipment cleaning and use log [VIP ID: 223] “…If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.” Selected FDA 483 Observations (June 2004) Product Manufacture [VIP ID: 122630] “Records of cleaning for dedicated equipment should be maintained as part of the batch record and reviewed by the quality control unit.” GUIDANCE FOR INDUSTRY CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICAL GASES (May 2003) XI. RECORDS AND REPORTS B. Equipment Cleaning and Use Log para 2 [VIP ID: 181028] “…In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use must be part of the batch record (§ 211.182). The persons performing and double-checking the cleaning and maintenance must date and sign or initial the log indicating that the work was performed (§ 211.182).” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 6. DOCUMENTATION AND RECORDS 6.2 Equipment Cleaning and Use Record 6.21 [VIP ID: 24598] “If equipment is dedicated to manufacturing one intermediate or API, then individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.”
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ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 6. DOCUMENTATION AND RECORDS 6.2 Equipment Cleaning and Use Record 6.21 [VIP ID: 154300] “If equipment is dedicated to manufacturing one intermediate or API, then individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.” Extracted from FDA Warning Letter KAN 2000-009 (February 2000) USA 25/02/2000 [VIP ID: 12210] “Inadequate equipment cleaning documentation and procedures [21 CFR 211.182].” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (b) Equipment Cleaning and Use Log (para 2) [VIP ID: 3437] “An equipment cleaning and use log, while desirable and even preferable, is not the only method of determining prior use. Generally speaking, any documentation system that clearly identifies the previous batch and shows that the equipment was in fact cleaned is acceptable.”
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When the equipment is not dedicated to the manufacture of a single product, cleaning should be recorded in individual equipment logs. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 4 DOCUMENTATION PROCEDURES AND RECORDS - Other 4.28 [VIP ID: 185698] “Log books should be kept for major or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out.” 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart J -- Records and Reports Sec. 211.182 Equipment cleaning and use log [VIP ID: 223] “A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed.” Selected FDA 483 Observations (October 2004) Product Manufacture [VIP ID: 124520] “Written records of major equipment cleaning, maintenance, and use should be included in individual equipment logs.”
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PI 008-2 PIC/S GUIDANCE DOCUMENT FOR INSPECTORS PIC/S GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES (INSPECTION GUIDE) (July 2004) 13. BASIC GMP CRITERIA FOR SOURCE PLASMA ESTABLISHMENTS AND PLASMA WAREHOUSES 13.13 DOCUMENTATION 13.13.18 [VIP ID: 189578] “Log books should be kept for major or critical equipment recording (GMP 4.28), e.g. plasmapheresis machines, microhematocrit centrifuges, scales etc. and contain information about any validation, calibration, maintenance, cleaning or repair operations, including the dates and identity of people who carried out these operations (GMP 4.28.). They should also contain the approval of return to use after validation and planned maintenance (GMP-s 36) as well after major repairs.” Extracted from FDA warning letter NWE-06-02W (December 2001) USA 07/12/2001 [VIP ID: 44770] “You have failed to maintain individual equipment logs reflecting cleaning and use of processing equipment, such as tanks (kettles) and mixers [21 CFR 211.182, Form FDA 483 Observation 11].” Selected FDA 483 Observations (May 2000) Sterile Product Manufacture [VIP ID: 16070] “Lyophilizer cleaning procedures should include: (2) a separate cleaning log for the Lyophilizer” Extracted from FDA Warning Letter KAN 2000-009 (February 2000) USA 25/02/2000 [VIP ID: 12210] “Inadequate equipment cleaning documentation and procedures [21 CFR 211.182].” Selected FDA 483 Observations (June 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7244] “There should be equipment use and cleaning logs for multipurpose equipment.” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 4 - DOCUMENTATION Documents required - Procedures and records (Other) 4.28. [VIP ID: 508] “Log books should be kept for major or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out.”
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Equipment cleaning logs should be maintained for trailers, rail cars, and storage tanks, especially those installed at a health care facility or a hospital. GUIDANCE FOR INDUSTRY CURRENT GOOD MANUFACTURING PRACTICE FOR MEDICAL GASES (May 2003) XI. RECORDS AND REPORTS B. Equipment Cleaning and Use Log para 3 [VIP ID: 181030] “Equipment cleaning and use logs can be maintained for trailers, rail cars, and storage tanks, especially those installed at a health care facility or a hospital.”
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Where equipment logs are used, the persons performing and double-checking the cleaning shall date and sign or initial them to indicate that the work was performed. Entries in the log shall be in chronological order. Such Logs should be accurate and complete. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart J -- Records and Reports Sec. 211.182 Equipment cleaning and use log [VIP ID: 223] “…The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.” Selected FDA 483 Observations (May 2005) Active Pharmaceutical Ingredient Manufacture [VIP ID: 177300] “Equipment use logs used to represent production, cleaning or maintenance activities should be accurate and complete.” Selected FDA 483 Observations (July 2004) Product Manufacture [VIP ID: 123150] “Entries in equipment cleaning and use logs should be in chronological order. (the use of loose leaf unbound papers does not provide assurance that the entries are in chronological order)” Selected FDA 483 Observations (June 2004) Product Manufacture [VIP ID: 122640] “The times entries are made should be recorded in the equipment logs, e.g. the time cleaning was performed.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 6. DOCUMENTATION AND RECORDS 6.2 Equipment Cleaning and Use Record 6.20 [VIP ID: 24597] “Records of major equipment use, cleaning, sanitization and / or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person who performed the cleaning and maintenance.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 6. DOCUMENTATION AND RECORDS 6.2 Equipment Cleaning and Use Record 6.20 [VIP ID: 154290] “Records of major equipment use, cleaning, sanitization and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person who performed the cleaning and maintenance.”
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The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.6 [VIP ID: 188672] “The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.6. [VIP ID: 69210] “The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance.”
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Equipment cleaning batch records should document the completion of times, steps of equipment cleaning and completion of room cleaning. Selected FDA 483 Observations (February 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26920] “Equipment cleaning batch records should document the completion of times, steps of equipment cleaning and completion of room cleaning.”
6.
Filling rooms should have dedicated daily logs for sanitisation and cleaning. Selected FDA 483 Observations (August 1999) Sterile Product Manufacture [VIP ID: 7770] “Filling rooms should: (3) have dedicated daily logs for sanitization and cleaning”
7.
There should be records of equipment cleaning prior to sterilisation (e.g. nozzles, tubing and hoses). Selected FDA 483 Observations (December 2005) Sterile Product Manufacture [VIP ID: 180110] “There should be records of cleaning and wrapping of all equipment prior to sterilisation, e.g. nozzles, tubing and hoses.”
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Cleaning records should record the time equipment is cleaned in order to determine the time period between cleaning/wrapping and sterilisation. Selected FDA 483 Observations (December 2005) Sterile Product Manufacture [VIP ID: 180120] “Cleaning records should record the time equipment is cleaned and wrapped in order to determine the time period between cleaning/wrapping and sterilisation.”
8.
Cleaning/disinfection records should include: (a) clear plastic arm covers used during aseptic filling operations (b) aluminium identification strips placed on stainless steel trays containing filled vials (c) personnel shoe covers after entering the transfer lock and returning to the aseptic filling areas Selected FDA 483 Observations (June 2000) Sterile Product Manufacture [VIP ID: 16320] “Cleaning/disinfection records should include: (1) clear plastic arm covers worn during aseptic filling operations (2) aluminum identification strips placed on stainless steel trays containing filled vials (3) personnel shoe covers after entering the transfer lock and returning to the aseptic filling areas”
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Records should be kept of cleaning performed in such a way that the following information is readily available: (a) the area or piece of equipment cleaned (b) the person who carried out the cleaning (c) when the cleaning was carried out (d) the SOP defining the cleaning process (e) the product which was previously processed on the equipment being cleaned. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.5 [VIP ID: 188670] “Records should be kept of cleaning performed in such a way that the following information is readily available: -
the area or piece of equipment cleaned, the person who carried out the cleaning, when the cleaning was carried out, the SOP defining the cleaning process, the product which was previously processed on the equipment being cleaned.”
EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 6. DOCUMENTATION AND RECORDS 6.2 Equipment Cleaning and Use Record 6.20 [VIP ID: 24597] “Records of major equipment use, cleaning, sanitization and / or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person who performed the cleaning and maintenance.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.5. [VIP ID: 69200] “Records should be kept of cleaning performed in such a way that the following information is readily available: (a) the area or piece of equipment cleaned, (b) the person who carried out the cleaning, (c) when the cleaning was carried out, (d) the SOP defining the cleaning process, (e) the product which was previously processed on the equipment being cleaned.”
10. Records should be kept of the routine preparation of cleaning and disinfecting agents. PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 9. CLEANING, SANITISATION AND DISINFECTION 9.5 [VIP ID: 190292] “Records should be retained in respect of routine preparation of cleaning and disinfecting agents, directions for their use, and validation of their efficacy.”
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11. Clean-In-Place (CIP) alarms should be documented. Selected FDA 483 Observations (December 2003) Sterile Product Manufacture [VIP ID: 71040] “Clean-In-Place (CIP) alarms should be documented.”
12. There should be a record to document the cleaning and sanitisation of goggles worn by personnel in the classified areas. Selected FDA 483 Observations (December 2006) Sterile Product Manufacture [VIP ID: 194292] “There should be a record to document cleaning or sanitization of the goggles that are worn by personnel while in the Class 100 and Class 10,000 areas.” Selected FDA 483 Observations (October 2004) Sterile Product Manufacture [VIP ID: 124570] “There should be a record to document the cleaning and sanitization of goggles worn by personnel in the classified areas.”
13. Cleaning records should include a description of the cleaning method(s) used and identify what was actually cleaned and what cleaning agents were used to perform the cleaning operations. Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194288] “… There should be documentation of which cleaning procedures were actually followed, such as recording of times and water temperatures, and some indication that those involved in the cleaning had read the protocol and/or the cleaning procedures.” Selected FDA 483 Observations (June 2005) Active Pharmaceutical Ingredient Manufacture [VIP ID: 177600] “Cleaning records should include a description of the cleaning method(s) used and identify what was actually cleaned and what cleaning agents were used to perform the cleaning operations.”
14. There should be records documenting the cleaning of bins, which are used for the storage of powders and blends and the gravity feed delivery of powders and blends to encapsulation and tableting equipment, and also used for the storage, and transfer of bulk tablets and capsules and the delivery of bulk tablets and capsules to bottle filling lines. Selected FDA 483 Observations (March 2006) Product Manufacture [VIP ID: 193192] “There should be records documenting the usage and cleaning of bins, which are used for the storage of powders and blends and the gravity feed delivery of powders and blends to encapsulation and tableting equipment, and also used for the storage, and transfer of bulk tablets and capsules and the delivery of bulk tablets and capsules to bottle filling lines.”
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5.7 Analytical Test Methods Analytical test methods should: 1.
be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company. Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194324] “Cleaning validation, for equipment, which is not dedicated to one product, should include the evaluation of microbiological control, a recovery study performed to demonstrate the sensitivity and specificity (detection limit) of analytical equipment to demonstrate that residual product is removed after cleaning, documentation of the sampling method or location used in the cleaning validation and the establishment of time limitation of cleaning prior to next use.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CLEANING VALIDATION 37 [VIP ID: 187104] “Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.10 Analytical Methods 7.10.2 [VIP ID: 188698] “The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.74 [VIP ID: 24773] “Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method's attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.74 [VIP ID: 155780] “Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.10. Analytical Methods 4.10.2. [VIP ID: 69370] “The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.”
2.
include a description of the type of analytical equipment used. Selected FDA 483 Observations (January 1999) Product Manufacture [VIP ID: 7094] “Cleaning validation protocols should include provisions for: 7) a description of the type of analytical equipment used”
3.
include parameters for the sensitivity of the analytical methods. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.74 [VIP ID: 24773] “Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method's attainable recovery level should be established.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.74 [VIP ID: 155780] “Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established.” Selected FDA 483 Observations (June 1999) Product Manufacture [VIP ID: 7235] “Cleaning validation protocols should include: 3) parameters for the sensitivity of the analytical methods” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements (para 4) [VIP ID: 1326] “FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.”
4.
define system suitability linearity requirements for test methods utilising standard curves. Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (3) system suitability linearity requirements for test methods utilizing standard curves”
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include the requirement for printing standard curves when the instrument has the capability. Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (4) printing out of standard curves where the instrument has the capability”
6.
include tests to show the precision (reproducibility) of the instrument at the time of use. Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (5) tests to show the precision (reproducibility) of the instrument at the time of use”
7.
address the detection of all possible residues. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) CHAPTER 5 PRODUCTION PREVENTION OF CROSS-CONTAMINATION IN PRODUCTION 5.19 [VIP ID: 185740] “Cross-contamination should be avoided by appropriate technical or organisational measures, for example: g) testing for residues and use of cleaning status labels on equipment.” Selected FDA 483 Observations (August 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6766] “BPC cleaning validation should include: 6) analytical procedures for the detection of all possible residues” Selected FDA 483 Observations (February 1998) Product Manufacture [VIP ID: 6329] “Cleaning validation protocols should include: 3) testing for the removal of sanitizing agents and detergents” EC GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (January 1998) CHAPTER 5 - PRODUCTION Prevention of cross-contamination in production 5.19. [VIP ID: 529] “Cross-contamination should be avoided by appropriate technical or organisational measures, for example: (g) testing for residues and use of cleaning status labels on equipment.” Selected FDA 483 Observations (July 1997) Sterile Product Manufacture [VIP ID: 2518] “Cleaning Validation should include: (2) an assay for residual cleaning agents”
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include a statement that cleaning swab samples should not be composited prior to analysis. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April 2006) Subpart E -- Control of Components and Drug Product Containers and Closures Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures (c) [VIP ID: 75] “Samples shall be collected in accordance with the following procedures: (4) If it is necessary to sample a component from the top, middle, and bottom of its container, such sample subdivisions shall not be composited for testing.” Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40920] “Cleaning swab samples taken from different locations from each piece of equipment should not be combined into one sample and tested as such.” Selected FDA 483 Observations (October 1998) Product Manufacture [VIP ID: 6845] “Cleaning validation swab samples should not be composited prior to analysis.”
9.
include provisions for microbiological testing of swab samples. Selected FDA 483 Observations (January 1999) Sterile Product Manufacture [VIP ID: 7105] “Cleaning validation should include: 1) testing for microbial contamination” Selected FDA 483 Observations (January 1999) Product Manufacture [VIP ID: 7094] “Cleaning validation protocols should include provisions for: 2) microbiological testing of swab samples”
10. include the formula used to calculate the amount of possible contamination based on analysis. Selected FDA 483 Observations (October 1997) Product Manufacture [VIP ID: 2480] “The procedure for the collection of rinse water samples should take into account: 5. formula used to calculate the amount of possible contamination based on analysis”
11. include directions for the handling of unused data. Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (8) procedures governing how unused data is handled”
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12. include directions for the handling of negative results. Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (7) directions for the handling of negative results”
•
A negative test may be the result of poor sampling technique. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.10. Analytical Methods 4.10.3. [VIP ID: 69380] “…A negative result may also be the result of poor sampling techniques.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 3. Analytical Methods [VIP ID: 1340] “Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below).”
5.8 Analytical Records 1.
Test method results should be reported with reference to the limit of detection of the analytical equipment. i.e. "less than the detection limit" rather than 0.0. Selected FDA 483 Observations (November 1997) Laboratories [VIP ID: 6242] “Test method results should be reported with reference to the limit of detection of the analytical equipment. i.e. "less than the detection limit" rather than 0.0.”
5.9 Miscellaneous Considerations In addition to the more specific points for consideration generated as part of the review the following general notes were also compiled: 1.
Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations. 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS (April, 2003) Subpart C - Buildings and Facilities 21 CFR 211.56 (d) “Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.”
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Environmental monitoring should include monitoring of the sanitisation fluid container used by operators to sanitise gloved hands and surfaces during the aseptic filling of products. Selected FDA 483 Observations (July 1998) Sterile Product Manufacture [VIP ID: 6297] “Environmental monitoring should include monitoring of the sanitization fluid container used by operators to sanitize gloved hands and surfaces during the aseptic filling of products.”
3.
Where non-disposal gloves are used during the weighing of more than one material, they should be routinely cleaned following the weighing of each material. Selected FDA 483 Observations (April 1998) Product Manufacture [VIP ID: 6389] “Where non-disposal gloves are used during the weighing of more than one material, they should be routinely cleaned following the weighing of each material.”
4.
Disinfectants and detergents dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS SANITATION 38 [VIP ID: 186074] “Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.” PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING 9.4 Disinfection 9.4.1 [VIP ID: 189032] “There should be documented procedures describing the preparation and storage of disinfectants and detergents. These agents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grade A and B areas should be sterile at the time of use. If spray bottles are used they should be sterile before being filled and have a short in-use shelf life.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Sanitation 38 [VIP ID: 63310] “Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised. Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.”
•
Sterile filtered disinfectants and sanitising agents used in an aseptic core should be periodically monitored. PI 007-2 RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSES (July 2004) 9. IMPORTANT FACTORS IN VALIDATION OF ASEPTIC MANUFACTURING 9.4 Disinfection 9.4.1 [VIP ID: 189032] “…Disinfectants and detergents used in Grade A and B areas should be sterile at the time of use. If spray bottles are used they should be sterile before being filled and have a short in-use shelf life.”
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Selected FDA 483 Observations (April 1998) Sterile Product Manufacture [VIP ID: 6347] “Sterile filtered disinfectants and sanitizing agents used in an aseptic core should be periodically monitored.”
5.
Disinfectants and sanitising agents should be sterile filtered prior to introduction into an aseptic core. Selected FDA 483 Observations (April 1998) Sterile Product Manufacture [VIP ID: 6348] “Disinfectants and sanitizing agents should be sterile filtered prior to introduction into an aseptic core.”
•
Strains of factory isolates from firms controlled environments should be used in the evaluation of sanitising solutions. Selected FDA 483 Observations (April 1999) Sterile Product Manufacture [VIP ID: 7177] “Strains of factory isolates from firms controlled environments should be used in the evaluation of sanitizing solutions.”
6.
Environmental monitoring should include the trending of isolates. Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 15660] “Environmental monitoring should include: (1) trending of isolates”
•
Monitoring of clean areas should be undertaken regularly in order to detect the development of resistant strains. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Sanitation 37 [VIP ID: 63300] “... Monitoring should be undertaken regularly in order to detect the development of resistant strains.”
7.
All concentrations of disinfectants should be evaluated for detrimental effects on the microbial growth media used. Selected FDA 483 Observations (July 1998) Sterile Product Manufacture [VIP ID: 6759] “All concentrations of disinfectants should be evaluated for detrimental effects on the microbial growth media used.”
8.
Aseptic fill surface disinfectants should be sporicidal. Selected FDA 483 Observations (July 1998) Sterile Product Manufacture [VIP ID: 6757] “Aseptic fill surface disinfectants should be sporicidal.”
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Where disinfectants are used in clean areas, more than one type should be employed. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Sanitation 37 [VIP ID: 63300] “... Where disinfectants are used, more than one type should be employed. ...”
10. Carts used to transport partially stoppered vials should be sanitised and monitored for viable contamination. Selected FDA 483 Observations (May 1999) Sterile Product Manufacture [VIP ID: 7202] “Carts used to transport partially stoppered vials should sanitized and monitored for viable contamination.”
11. The manufacturer should ensure, either by a written commitment or by a contract that he is notified by the detergent supplier of any critical changes in the formulation of the detergent. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.9. Detergents 4.9.2. [VIP ID: 69350] “The composition of detergents should be known to the manufacturer. … The manufacturer should ensure, either by a written commitment or by a contracts that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.”
6.
CLEANING VALIDATION CONSIDERATIONS 1.
Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products or active pharmaceutical ingredients (APIs). PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION GLOSSARY - Definitions of terms relating to qualification and validation which are not given in the glossary of the current PIC/S Guide to GMP, but which are used in this Annex, are given below. Cleaning Validation [VIP ID: 187124] “Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.1 Principle 7.1.3 [VIP ID: 188632] “Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products or active pharmaceutical ingredients (APIs).”
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PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.1 Principle 7.1.4 [VIP ID: 188634] “Objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) GLOSSARY (2) [VIP ID: 21480] “Cleaning Validation Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.”
2.
The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerised systems, and persons responsible for design, review, approval and documentation of each validation phase, should be documented. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.1 Validation Policy 12.10 [VIP ID: 24748] “The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval and documentation of each validation phase, should be documented.”
3.
The first step is to focus on the objective of the validation process, and we have seen that some companies have failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean the equipment. Several questions need to be addressed when evaluating the cleaning process: GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation (para 1) [VIP ID: 1329] “The first step is to focus on the objective of the validation process, and we have seen that some companies have failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean the equipment. Several questions need to be addressed when evaluating the cleaning process…”
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For example, at what point does a piece of equipment or system become clean? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - At what point does a piece of equipment or system become clean?”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. [VIP ID: 68950] “Several questions should be addressed when evaluating the cleaning process. For example: (a) at what point does a piece of equipment or system become clean? …” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation (para 1) [VIP ID: 1329] “…For example, at what point does a piece of equipment or system become clean?”
•
What does visually clean mean? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - What does visually clean mean?” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. [VIP ID: 68950] “Several questions should be addressed when evaluating the cleaning process. For example:… (b) what does visually clean mean?”
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Does it have to be scrubbed by hand? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - Does the equipment need to be scrubbed by hand?” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. [VIP ID: 68950] “Several questions should be addressed when evaluating the cleaning process. For example: … (c) does the equipment need to be scrubbed by hand? …”
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GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation (para 1) [VIP ID: 1329] "…Does it have to be scrubbed by hand?"
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What is accomplished by hand scrubbing rather than just a solvent wash? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - What is accomplished by hand scrubbing rather than just a solvent wash?” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. [VIP ID: 68950] “Several questions should be addressed when evaluating the cleaning process. For example: … (e) what is accomplished by hand scrubbing rather than just a solvent wash?” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation (para 1) [VIP ID: 1329] “What is accomplished by hand scrubbing rather than just a solvent wash?”
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How variable are manual cleaning processes from batch to batch and product to product? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - How variable are manual cleaning processes from batch to batch and product to product?” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. [VIP ID: 68950] “Several questions should be addressed when evaluating the cleaning process. For example: … (f) how variable are manual cleaning processes from batch to batch and product to product? …” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation (para 1) [VIP ID: 1329] “How variable are manual cleaning processes from batch to batch and product to product?”
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What is the most appropriate solvent or detergent? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - What is the most appropriate solvent or detergent?” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. [VIP ID: 68950] “Several questions should be addressed when evaluating the cleaning process. For example: … (g) what is the most appropriate solvent or detergent?...”
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Are different cleaning processes required for different products in contact with a piece of equipment? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - Are different cleaning processes required for different products in contact with a piece of equipment?” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. [VIP ID: 68950] “Several questions should be addressed when evaluating the cleaning process. For example: … (h) are different cleaning processes required for different products in contact with a piece of equipment?”
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How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment? PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.4 [VIP ID: 188646] “Several questions should be addressed when evaluating the cleaning process. For example: - How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.4. (i) [VIP ID: 68950] “(i) how many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?”
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The answers to these questions are obviously important to the inspection and evaluation of the cleaning process since one must determine the overall effectiveness of the process. Answers to these questions may also identify steps that can be eliminated for more effective measures and result in resource savings for the company. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation (para 1) [VIP ID: 1329] “The answers to these questions are obviously important to the inspection and evaluation of the cleaning process since one must determine the overall effectiveness of the process. Answers to these questions may also identify steps that can be eliminated for more effective measures and result in resource savings for the company.”
6.1 Cleaning Procedures Cleaning procedures should: 1.
be validated. Extracted from FDA Warning Letter W/L 07/05 (January 2005) USA 25/01/2005 [VIP ID: 134240] “Failure to establish written procedures for the cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product [21 CFR 211.67(b)]. For example, cleaning methods have not been validated.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.1 Principle 7.1.2 [VIP ID: 188630] “Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients (APIs). In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to an acceptable level.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.2 [VIP ID: 188642] “Cleaning procedures for product changeover in the case of marketed products should be fully validated.”
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PI 012-2 RECOMMENDATION ON STERILITY TESTING (July 2004) 9. CLEANING, SANITISATION AND DISINFECTION 9.4 [VIP ID: 190290] “Prior to implementation, all cleaning, sanitising and disinfecting procedures should be validated from a microbiological perspective with respect to minimum disinfectant contact times and efficacy. Cleaning and disinfecting agents should be purchased to agreed and documented specifications.” Extracted from FDA Warning Letter 2004-DAL-WL-19 (June 2004) 15/06/2004 [VIP ID: 127710] “8. Failure to clean, maintain and sanitize equipment and utensils at appropriate intervals to prevent malfunctions and contamination that would alter the safety, identity, strength, quality or purity of the drug product [21 CFR 211.67(a)]. …In addition, the production and commercial distribution of liquid pharmaceutical products was initiated in December 2002, without equipment cleaning validation studies being conducted.” Extracted from FDA Warning Letter 2003-DAL-WL-18 (August 2003) USA 27/08/2003 [VIP ID: 56930] “4. Failure to validate significant reprocessing processes (cleaning, disinfecting, packaging, and steam sterilization) with a high degree of assurance [21 CFR 820.75] [FDA 483 Item 6]. Our inspection documented that your facility could not locate any recognized sterilization standards during the inspection.” Extracted from FDA Warning Letter FLA-03-23 (February 2003) USA 04/02/2003 [VIP ID: 54800] “a. Failure to perform process validation studies on the manufacturing process of the bulk solution and equipment cleaning processes (21 CFR Part 211)” Extracted from FDA Warning Letter FLA-03-12 (January 2003) USA 08/01/2003 [VIP ID: 55160] “Written procedures for equipment cleaning and maintenance are incomplete, and the cleaning procedure has not been properly validated [21 CFR 211.67].” Extracted from FDA Warning Letter CIN-03-13127 (November 2002) USA 12/11/2002 [VIP ID: 56520] “2. Your cleaning procedure for product contact equipment surfaces has not been shown capable of reducing microbial and endotoxin contamination to acceptable levels. And this procedure, SOP #101, General Sanitation Procedure, lacks sufficient detail to ensure that cleaning is performed consistently and acceptably from batch-tobatch. Specifically, the procedure lacks minimum time limits for cleaning agent contact, method of wash and rinse, and volume of cleaning agent(s) to be used. A sanitation cleaning procedure should include such information to ensure adequacy and reproducibility of cleaning. As an example, while your letter of March 27, 2002 (item 3B) points out that endotoxin removal can be effected with a "hard flush" of surfaces your procedure does not, in fact, specifically require a "hard flush."…” Extracted from FDA Warning Letter W/L 05-03 (October 2002) USA 29/10/2002 [VIP ID: 57180] “5. Failure to clean and maintain equipment and utensils at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product [21 CFR 211.67(a)]. Specifically, you have failed to adequately complete the validation studies for current cleaning procedures specified for the PK Blender, and tableting equipment utilized for production of human drugs.”
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Extracted from FDA Warning Letter WL-CIN-12414-02 (February 2002) USA 21/02/2002 8 [VIP ID: 48390] “8. Your cleaning procedures have not been validated. There are 12 production [mix] tanks and 19 hold tanks. Only one OTC formulation has a dedicated mix tank. None of the hold tanks are product specific. [21 CFR 211.67]” Extracted from FDA Warning Letter 02-NSV-13 (February 2002) USA 11/02/2002 [VIP ID: 48310] “The inspection revealed a failure to validate cleaning procedures, routine release of and failure to investigate outof-specification test results for a mouthwash product, failure to conduct statistical analysis for products on long term stability, failure to perform stability on all manufactured products, failure of a second individual to confirm the weight of a drug and failure to accurately identify components used in drug manufacturing.” Extracted from FDA Warning Letter WL-24-02 (January 2002) USA 14/01/2002 1 [VIP ID: 48080] “1. Failure to ensure that cleaning methods used in cleaning production equipment will sufficiently prevent contamination that would alter the safety, identity, strength, quality, or purity of drug products [21 CFR 211.67]. Specifically, no documented evidence exists to demonstrate the effectiveness of cleaning methods and agents used in cleaning of all production equipment and utensils to ensure that residues have been reduced to acceptable levels. Cleaning validation is limited to only glassware.” Extracted from FDA Warning Letter WL-23-02 (December 2001) USA 27/12/2001 [VIP ID: 45510] “Failure to write production and process control procedures designed to assure your drug products have the required identity, strength, quality and purity [211.100(a)]. For example, you have no process validation data for any of your drug products, and you have no validation that your cleaning and sanitation procedures prevent significant cross contamination from multi-use manufacturing process equipment. Products manufactured at your facility include ingredients such as lead acetate and sulphur.” Extracted from FDA Warning Letter CHI-11-02 (December 2001) USA 21/12/2001 [VIP ID: 43360] “Failure to establish and follow written procedures for cleaning and maintenance of equipment, including utensils used in the manufacture, processing, packing or holding of a drug product [21 CFR 211.67(b)(3)]. The instant inspection revealed that no cleaning validation studies have been performed.” Extracted from FDA Warning Letter 2002-NOL-10 (November 2001) USA 13/11/2001 [VIP ID: 43160] “The CGMP for finished pharmaceuticals deviations documented during the inspection include, but are not limited to, the following: (3) Failure to validate the cleaning of equipment used in drug product manufacturing process(es);” Extracted from FDA Warning Letter 02-PHI-01 (October 2001) USA 25/10/2001 [VIP ID: 42370] “2. Your firm has not demonstrated that cleaning procedures remove product residuals from non-dedicated equipment. In addition, your firm does not have written procedures for cleaning and does not document that cleaning was accomplished in accordance with written procedures.”
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Extracted from FDA Warning Letter CHI-5-02 (October 2001) USA 15/10/2001 [VIP ID: 43470] “Failure to establish and utilize adequate equipment cleaning procedures and related test methods [21 CFR 211.67(b)]. The inspection disclosed that your firm has not conducted any cleaning validation studies for the cleaning of the formulation tanks, kettles, pumps, and pipes and for the filling equipment.” Extracted from FDA Warning Letter WL-03-02 (October 2001) USA 04/10/2001 [VIP ID: 45430] “Failure to ensure that cleaning methods used in cleaning production equipment will sufficiently prevent contamination that would alter the safety, identity, strength, quality, or purity of drug products [21 CFR 211.67]. Specifically, no documented evidence exists to demonstrate the effectiveness of cleaning methods and agents used in cleaning production equipment to ensure that residues have been reduced to acceptable levels.” Extracted from FDA Warning Letter 2001-DAL-WL-33 (August 2001) USA 01/08/2001 [VIP ID: 42490] “For example, you have failed to establish and document in writing the responsibilities and authority of a Quality Control Unit designed to assure the quality and purity of each batch of drug product (21 CFR 211.22). You have failed to train employees in CGMPS relative to their job functions in drug production [21 CFR 211.25(a)]. You have failed to validate, for example, the: drug production processes (21 CFR 211.100); computerized control systems used for maintaining laboratory data and drug product distribution information (21 CFR 211.68); and the cleaning process for common equipment used in drug and cosmetic production processes (21 CFR 211.67).” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.70 [VIP ID: 24769] “Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps.” Extracted from FDA warning letter CHI-38-01 (July 2001) USA 06/07/2001 [VIP ID: 43420] “Cleaning verification testing methods for ****, ****, and **** are not validated. A similar observation was cited on the FDA 483 (item #2) for the February 1998 inspection and **** committed at that time to correcting this observation.” Extracted from FDA Warning Letter CHI-38-01 (July 2001) USA 06/07/2001 [VIP ID: 43410] “Adequate cleaning procedures have not been established in that **** has not conducted cleaning validation studies for non-dedicated manufacturing equipment. For example, the cleaning procedures have not been validated to demonstrate removal of API residues, cleaning agents, and impurities in buildings 1, 2 & 7.” Extracted from FDA warning letter CBER-01-023 (July 2001) USA 24/07/2001 [VIP ID: 43280] “Failure to establish and follow written procedures for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product [21 CFR 211.67(b)] in that: a. The cleaning of the ultrafiltration / diafiltration (UF / DF) unit used in the manufacture of **** has not been adequately validated.”
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Extracted from FDA Warning Letter 2002-DT-18 (January 2001) USA 09/01/2001 [VIP ID: 43000] “Failure to establish and follow equipment cleaning validation procedures designed to assure appropriate cleaning procedures are in place as required by 21 CFR 211.67. FDA Warning Letter CHI-38-01 (July 2001)” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.70 [VIP ID: 155740] “Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps.” Extracted from FDA Warning Letter 2001-DAL-WL-19 (May 2001) USA 01/05/2001 [VIP ID: 28740] “Failure to adequately validate the cleaning processes for your drug products [21 CFR 211.67]. For example, there is no cleaning validation in place for drug products and the associated equipment utilized in drug manufacturing. The same equipment is used to manufacture hydrocortisone and benzoyl peroxide drug products.” Extracted from FDA Warning Letter 2001-DAL-WL-23 (May 2001) USA 11/05/2001 [VIP ID: 28540] “Failure to validate the cleaning procedures for drug product manufacturing and packaging equipment [21 CFR 211.67].” Extracted from FDA Warning Letter 01-NSV-09 (March 2001) USA 20/12/2000 [VIP ID: 29020] “Our inspection revealed the following deviations from CGMP concepts: inadequate validation of the manufacturing process, incomplete batch records, inadequate cleaning procedure validation, deficient master label files, incomplete standard operating procedures, inadequate calibration of laboratory equipment, incomplete annual reviews, deficient reverse osmosis water system controls, and inadequate raw material control procedures.” Extracted from FDA Warning Letter CBER-01-011 (February 2001) Canada 08/02/2001 [VIP ID: 28510] “8. Failure to determine that equipment is cleaned, maintained, and sanitized at appropriate intervals to prevent malfunction or contamination that would alter the safety, identity, strength, quality or purity or other established requirements [21 CFR 211.67], in that: a. there are no cleaning validation data for tank **** b. cleaning validation of tanks **** was not successful; c. there are no cleaning validation data for ****; and d. there was no test performed for residual **** after cleaning tank **** prior to manufacture of **** lot ****.” Extracted from FDA Warning Letter 01-NWJ-14 (January 2001) USA 05/01/2001 [VIP ID: 39730] “No cleaning validation studies were completed to show that the method of cleaning the compacting equipment is sufficient to remove all traces of the previous product, which may be an industrial product. Without documentation that your cleaning procedure is valid for all products, you cannot assure that cross-contamination is not occurring. For example, our investigator observed that prior to the September 2000 campaign of **** the compactor was used to process an industrial product containing Teflon.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.1. Principle 4.1.2. [VIP ID: 68870] “Cleaning procedures must strictly follow carefully established and validated methods of execution. In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to a predetermined level.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.2. [VIP ID: 68930] “Cleaning procedures for product changeover should be fully validated.” Selected FDA 483 Observations (April 1999) Sterile Product Manufacture [VIP ID: 7165] “Sterile manufacturing process validation should include microbiological evaluation of: 5) effectiveness of the cleaning/sanitizing procedures” GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION (January 1994) III PRODUCT DEVELOPMENT B. PRE-APPROVAL INSPECTIONS To evaluate the proposed manufacturing process the following areas must be covered during the pre-approval inspection: 7. Equipment [VIP ID: 3103] “…Manufacturers must validate their cleaning processes for the new drug/dosage form. FDA Warning Letter CBER01-023 (July 2001)” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) I. Introduction (para 1) [VIP ID: 1316] “Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 10 - MANUFACTURE OF PRESSURISED METERED DOSE AEROSOL PREPARATIONS FOR INHALATION (January 1993) Production and Quality Control 6. [VIP ID: 1739] “Containers and valves should be cleaned using a validated procedure appropriate to the use of the product to ensure the absence of any contaminants such as fabrication aids (e.g. lubricants) or undue microbiological contaminants.” BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES (para 1) [VIP ID: 1081] “Validation of the cleaning procedures for the processing of equipment, including columns, should be carried out. This is especially critical for a multi-product facility. The manufacturer should have determined the degree of effectiveness of the cleaning procedure for each BDP or intermediate used in that particular piece of equipment.”
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Manufacturing area surface cleaning procedures should be validated. Selected FDA 483 Observations (January 1999) Sterile Product Manufacture [VIP ID: 7090] “Manufacturing area surface cleaning procedures should be validated.”
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It is not acceptable to repeat the cleaning until an acceptable result is achieved. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CLEANING VALIDATION 41 [VIP ID: 187112] “"Test until clean" is not considered an appropriate alternative to cleaning validation.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NON-STERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.10 [VIP ID: 188658] “It is usually not considered acceptable to "test until clean". This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of "test until clean" should not be required. The practice of "test until clean" is not considered to replace the need to validate cleaning procedures.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 41. [VIP ID: 21410] “"Test until clean" is not considered an appropriate alternative to cleaning validation.” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2526] “Cleaning should not be repeated until acceptable results are obtained.” Selected FDA 483 Observations (November 1996) Product Manufacture [VIP ID: 135600] “Equipment cleaning procedures should describe how long the equipment should be washed rather than washing until "visibly clean".”
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Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilised by some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be utilised and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated since these retests actually document the presence of unacceptable residue and contaminants from an ineffective cleaning process. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues c. Test Until Clean [VIP ID: 1354] “Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilized by some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated since these retests actually document the presence of unacceptable residue and contaminants from an ineffective cleaning process.”
2.
revalidated following revision. Selected FDA 483 Observations (October 2004) Product Manufacture [VIP ID: 124470] “Cleaning procedures should be consistent with the procedures identified in the firm's cleaning validation.” Selected FDA 483 Observations (December 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7066] “Revised cleaning procedures should be validated.”
6.2 Analytical Test Methods Analytical test methods should: 1.
be validated at the expected concentrations. Selected FDA 483 Observations (January 2005) Product Manufacture [VIP ID: 128940] “Cleaning validation packages should include: (2) test methods used to analyze cleaning validation samples shown to be validated at the expected concentrations” Selected FDA 483 Observations (August 2004) Product Manufacture [VIP ID: 123670] “Test methods used to evaluate residue levels that remained on equipment after cleaning should be validated for accuracy, precision, specificity, linearity, limit of quantitation, and limit of detection.” Extracted from FDA Warning Letter SJN-01-13 (September 2001) Puerto Rico 05/09/2001 [VIP ID: 44990] “Failure to validate, as part of your method transfer studies, all analytical methods used during cleaning validation studies, to demonstrate that they have the accuracy, sensitivity, specificity, and reproducibility as required by CFR 211.165(e) and to assure that equipment used for the manufacturing of human drugs is being thoroughly cleaned as required by 21 CFR 211.67(a).”
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Selected FDA 483 Observations (April 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 27440] “API Cleaning validation should include: (3) Validated analytical methods which are sensitive enough to detect the acceptable level of residue / contaminant.” Selected FDA 483 Observations (January 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26550] “Laboratory test procedures used to analyze cleaning swabs and cleaning solutions should be validated.” Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26030] “Analytical methods used in release, cleaning validation and stability testing should be validated.” Selected FDA 483 Observations (March 1999) Product Manufacture [VIP ID: 7142] “Cleaning agent residue test methods should be validated.”
6.3 Cleaning Validation Protocols There should be documentation specifying how cleaning processes will be validated. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements (para 2) [VIP ID: 1324] “FDA expects firms to have written general procedures on how cleaning processes will be validated.”
6.3.1 General Cleaning validation protocols should: 1.
not be executed until all of the associated analytical methods have been validated. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.10 Analytical Methods 7.10.1 [VIP ID: 188696] “The analytical methods should be validated before the Cleaning Validation Study is carried out.” Selected FDA 483 Observations (June 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 52760] “Cleaning validation should include: (a) the validation of analytical methods prior to use.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!! (October 1999) 4. Cleaning Validation 4.10. Analytical Methods 4.10.1. [VIP ID: 69360] “The analytical methods should be validated before the Cleaning Validation Study is carried out.”
2.
include/reference the analytical methods to be used. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.72 [ViP ID: 24771] “The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled.” Selected FDA 483 Observations (June 1999) Product Manufacture [VIP ID: 7235] “Cleaning validation protocols should include: 2) a description of the analytical methods to be used” REG 07/01/93 GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July, 1993) III. General Requirements (para 4) “FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.”
3.
include/reference the limit of detection and the limit of quantitation of the analytical methods to be used. Selected FDA 483 Observations (March 2001) Laboratories [VIP ID: 27260] “Analytical methods used in cleaning validation should be shown to have suitable sample preparation, HPLC operating conditions, and / or limits for quantification and detection.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (k) [VIP ID: 69130] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (k) analytical methods including the limit of detection and the limit of quantitation of those methods,”
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state the title of the individual(s) responsible for performing and approving the validation study. CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Responsibilities for performing and approving the validation study,” Selected FDA 483 Observations (January 1999) Product Manufacture [VIP ID: 7094] “Cleaning validation protocols should include provisions for: 4) the title of the individual(s) responsible for performing and approving the validation study” Selected FDA 483 Observations (March 1997) Product Manufacture [VIP ID: 2550] “The cleaning validation protocol should address who is responsible for performing and approving the validation study, and address when revalidation will be required.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements (para 3) [VIP ID: 1325] “FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.”
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The Cleaning Validation Protocol should be formally approved by the Plant Management to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.2 [VIP ID: 188664] “The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.2. [VIP ID: 69170] “The Cleaning Validation Protocol should be formally approved by the Plant Management to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports.”
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state the objective of the validation process. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - The objective of the validation process,” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (a) [VIP ID: 69030] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (a) the objective of the validation process,”
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include a description of the equipment to be used. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Description of the equipment to be used,” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (c) [VIP ID: 69050] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (c) description of the equipment to be used,”
7.
state the cleaning procedures to be used for each product, each manufacturing system or each piece of equipment, including the rationale for use. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment,”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.72 [VIP ID: 24771] “The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled.” Extracted from FDA Warning Letter 320-01-06 (December 2000) India 19/04/2001 [VIP ID: 29310] “4. Cleaning validation studies for multiple use equipment were inadequate in a that the validation protocol did not identify the cleaning procedure, total surface area was not considered during the validation study, recovery studies were not done to validate the swab sampling method or filtering of rinse samples, some rinse samples were not analyzed, dates of analyses were inaccurate, and analytical data on rinse samples were not checked by a second person. [FDA-483 items 9, 10]” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.72 [VIP ID: 155760] “The protocol should also indicate the type of samples to be obtained and how they are collected and labelled.” Selected FDA 483 Observations (December 1999) Product Manufacture [VIP ID: 14310] “Cleaning validation protocols should: (1) include a specific sample collection method” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (e) [VIP ID: 69070] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (e) cleaning procedures to be used for each product, each manufacturing system or each piece of equipment,” Selected FDA 483 Observations (June 1999) Product Manufacture [VIP ID: 7235] “Cleaning validation protocols should include: 1) sampling procedures” REG 07/01/93 GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July, 1993) III. General Requirements (para 4) “FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and analytical methods to be used including the sensitivity of those methods.”
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include API cleaning procedures. Selected FDA 483 Observations (October 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19890] “Cleaning validation should be completed for API chemical process / synthesis trains and dryer bending / finishing trains.” Selected FDA 483 Observations (August 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19570] “API cleaning procedures should be validated.”
9.
state the cleaning agent to be used. Extracted from FDA warning letter 07-NWJ-06 (February 2007) USA 01-Feb-07 7. c) [VIP ID: 194846] “Your firm's cleaning validation studies were found to be inadequate and, as a result, there was no assurance that equipment is adequately cleaned between the manufacture of different drug products. [21 CFR 211.67(b)] For example: c) Cleaning validation studies do not indicate whether a cleaning agent was used when cleaning the equipment process train. Equipment cleaning SOPs prior to March, 2006, indicated that equipment could be cleaned "using hot water or approved cleaning agent and water if necessary.”
10. state the number of cleaning cycles to be performed consecutively. Selected FDA 483 Observations (January 2006) Active Pharmaceutical Ingredient Manufacture [VIP ID: 180390] “Cleaning validation studies conducted to prove that cleaning procedures are effective in removing previous peptide, reagent, solvent, cleaning agent, or other potential residues from manufacturing equipment and utensils are deficient if the studies are performed and concluded based on only one validation run.” CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - The number of cleaning cycles to be performed consecutively,” Selected FDA 483 Observations (September 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 70330] “Cleaning validation studies conducted to prove that cleaning procedures are effective should be performed and concluded based on more than one validation run.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (f) [VIP ID: 69080] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (f) the number of cleaning cycles to be performed consecutively,”
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11. state the number of batches required to complete the validation. Selected FDA 483 Observations (July 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 123320] “Cleaning validation studies conducted to prove that cleaning procedures are effective in removing previous peptide, reagent, solvent, cleaning agent, or other potential residues from manufacturing equipment and utensils should be performed and concluded based on multiple validation runs.” Selected FDA 483 Observations (September 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 70330] “Cleaning validation studies conducted to prove that cleaning procedures are effective should be performed and concluded based on more than one validation run.” Selected FDA 483 Observations (April 2000) Product Manufacture [VIP ID: 15420] “Process validation and cleaning validation protocols should state the number of batches required to complete the validation.”
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Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CLEANING VALIDATION 40 [VIP ID: 187110] “Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.6 [VIP ID: 188650] “At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 40. [VIP ID: 21400] “Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.6. [VIP ID: 68970] “At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.”
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12. reflect actual worst case production conditions. (e.g. validation after the maximum number of consecutive same product runs and/or the longest production campaigns) Selected FDA 483 Observations (August 2007) Product Manufacture [VIP ID: 193904] “Validation runs should be performed using worst case scenarios (i.e., most difficult to clean drug residues, maximum holding time prior to or after equipment cleaning, etc.) to justify the currently-in-use equipment cleaning procedures.” Selected FDA 483 Observations (July 2005) Product Manufacture [VIP ID: 178120] “Cleaning procedures should be validated to support the longest production campaigns.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.71 [VIP ID: 24770] “Validation of cleaning procedures should reflect actual equipment usage patterns.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.71 [VIP ID: 155750] “Validation of cleaning procedures should reflect actual equipment usage patterns.” Selected FDA 483 Observations (February 1999) Product Manufacture [VIP ID: 7118] “Cleaning validation should reflect actual worst case production conditions, e.g. validation after the maximum number of consecutive same product runs.” Selected FDA 483 Observations (April 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6370] “Cleaning validation should include cleaning after a campaign.”
13. include any routine monitoring requirements. CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Any routine monitoring requirement,” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (g) [VIP ID: 69090] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (g) any routine monitoring requirement,”
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14. include sampling procedures, including the rationale for why a certain sampling method is used. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Sampling procedures, including the rationale for why a certain sampling method is used,” Selected FDA 483 Observations (November 2003) Product Manufacture [VIP ID: 72300] “Cleaning Validation Protocols should include: a. Specific instructions for sample collection and their frequency.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (h) [VIP ID: 69100] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (h) sampling procedures, including the rationale for why a certain sampling method is used,”
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include the taking of bioburden samples from sample sites before cleaning. Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 193140] “Cleaning validation of equipment should include demonstration of worst case conditions such as the taking of bioburden samples from sample sites before cleaning.” Selected FDA 483 Observations (August 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 19580] “There should be data to support the effectiveness of the cleaning procedures in reducing the bioburden on equipment used to manufacture APIs intended for parenteral use.”
15. clearly define the sample locations. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Clearly defined sampling locations,”
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Selected FDA 483 Observations (November 2003) Product Manufacture [VIP ID: 72300] “Cleaning Validation Protocols should include: b. Identification of the exact sampling points for rinse residue tests.” Selected FDA 483 Observations (January 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 51940] “Cleaning validation should include: (a) a description of the swab method to include where the samples are taken, how the samples are collected, and the amount of samples collected. (b) the amount of rinse samples collected, and the location from where they are taken.” Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40930] “The exact/precise location of swab samples should be documented in cleaning validation studies.” Selected FDA 483 Observations (November 2000) Product Manufacture [VIP ID: 26190] “Cleaning validation should include: (2) a clear description of all sampling locations” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (i) [VIP ID: 69110] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (i) clearly defined sampling locations,” Selected FDA 483 Observations (October 1998) Product Manufacture [VIP ID: 6844] “The exact location of cleaning validation swab samples should clearly identified.” Selected FDA 483 Observations (August 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6766] “BPC cleaning validation should include: 4) precise identification of rinse sample locations” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (7) identification of rinse sample collection locations”
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16. include a description of the swab method to include how the samples are collected and the amount of samples collected. Selected FDA 483 Observations (July 2007) Sterile Product Manufacture [VIP ID: 193844] “Validation data should be provided to support the surface monitoring procedure using the swab technique, and recovery data should be available relating to the qualification of laboratory personnel in the execution of this technique.” Selected FDA 483 Observations (January 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 51940] “Cleaning validation should include: (a) a description of the swab method to include where the samples are taken, how the samples are collected, and the amount of samples collected.”
17. define and justify the area to be swabbed for sampling. Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194286] “… The surface area to be swabbed should be specified in the protocol or documented, the total surface area of the equipment should be taken into account when setting the acceptance criterion and there should be written justification for the acceptance criterion.” Extracted from FDA Warning Letter 320-05-03 (July 2005) Italy 21/07/2005 [VIP ID: 169210] “3. Test methods and techniques are not adequate for their intended purposes. 21 CFR 211.160 a. Your justification of the use of a swabbing area of [redacted] is not adequate. We acknowledge that the USP section [redacted] includes a sampling area of [redacted]. However, this procedure is for a microbiological test, and your sampling is for chemical residues. We recommend using an area of at least 100 cm2 for this purpose. The swabbing is to detect low-level chemical residues of a sensitizing nature. Smaller sampling areas under these conditions have not been shown to be sufficient to ensure the detection of low levels of chemical residue in a containment monitoring program.” Selected FDA 483 Observations (June 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 52760] “Cleaning validation should include: (b) a scientific rationale for the sampling sizes to determine residuals.” Selected FDA 483 Observations (January 2003) Product Manufacture [VIP ID: 51880] “Cleaning validation protocols should define the area to be swabbed for sampling.”
18. data to support sampling procedures with swab techniques for microbiological surface monitoring of equipment. Selected FDA 483 Observations (March 2006) Laboratories [VIP ID: 193212] “There should be validation data to support sampling procedures with swab techniques for microbiological surface monitoring of equipment used in the manufacture of ointments, suspensions and solid dosage products, and recovery data should be available relating to the qualification of personnel in the execution of these techniques.”
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19. recovery data relating to the qualification of personnel in the execution of swab techniques for microbiological surface monitoring. Selected FDA 483 Observations (July 2007) Sterile Product Manufacture [VIP ID: 193844] “Validation data should be provided to support the surface monitoring procedure using the swab technique, and recovery data should be available relating to the qualification of laboratory personnel in the execution of this technique.” Selected FDA 483 Observations (March 2006) Laboratories [VIP ID: 193212] “There should be validation data to support sampling procedures with swab techniques for microbiological surface monitoring of equipment used in the manufacture of ointments, suspensions and solid dosage products, and recovery data should be available relating to the qualification of personnel in the execution of these techniques.”
20. identify and provide a scientific rationale for the amount of rinse samples to be collected. Selected FDA 483 Observations (June 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 52760] “Cleaning validation should include: (b) a scientific rationale for the sampling sizes to determine residuals.” Selected FDA 483 Observations (January 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 51940] “Cleaning validation should include: (b) the amount of rinse samples collected, and the location from where they are taken.”
21. include the rotation of sampling areas within the different equipment parts (specifically in the case of cleaning validation for the evaluation of microbial load reduction in manufacturing or filling equipment). Selected FDA 483 Observations (February 2006) Product Manufacture [VIP ID: 193126] “In the case of cleaning validation for the evaluation of microbial load reduction in manufacturing or filling equipment, the evaluation should include the rotation of sampling areas within the different equipment parts.”
22. include a justification for viable sample sites. Selected FDA 483 Observations (October 2003) Sterile Product Manufacture [VIP ID: 70580] “There should be documented justifications for viable monitoring sampling sites sampled during routine cleaning of equipment and viable sample sites sampled during cleaning validations.”
23. include specific instructions to ensure that repeat samples are not taken from identical locations. Selected FDA 483 Observations (October 1998) Product Manufacture [VIP ID: 6843] “Cleaning swab sample procedures should ensure that repeat samples are not taken from identical locations.”
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include specific instructions to ensure that micro and chemical samples are not collected from the same areas. Selected FDA 483 Observations (February 1997) Product Manufacture [VIP ID: 2470] “Cleaning validation protocols / SOPs should include specific instructions to ensure that microbiological and chemical samples are not collected from the same areas.”
24. include diagrams or a narrative description of hard to clean areas. Selected FDA 483 Observations (February 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26940] “Equipment cleaning batch records should describe the hardest to clean areas.” Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 19120] “Where cleaning SOPs or validation protocols make reference to 'Hard to Reach' areas, they should include diagrams or narrative descriptions of these areas.” Selected FDA 483 Observations (March 1999) Product Manufacture [VIP ID: 7162] “Cleaning validation should include: 1) identification of the hardest to clean areas”
25. require swabbing the hardest to clean areas (gaskets, sample ports, glass windows, etc.). Selected FDA 483 Observations (August 2007) Product Manufacture [VIP ID: 193906] “The efficacy of currently-in-use equipment cleaning procedures should not be based only on the routine analysis of rinse samples, but should also evaluate the most difficult to clean surfaces and/or areas of the equipment with the use of swabs.” Selected FDA 483 Observations (August 2007) Product Manufacture [VIP ID: 193908] “Cleaning validation runs, executed in order to validate a new cleaning procedure using a new detergent, should include a study to assess and/or evaluate the capability of the swab (used to sample the most difficult areas to clean in the equipment) recovery of detergent residues from the cleaned equipment surface.” Selected FDA 483 Observations (November 1999) Product Manufacture [VIP ID: 8830] “Cleaning validation should include: 2) swabbing of difficult to clean areas (gaskets, sample ports, glass windows etc.)” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8310] “Cleaning validation (matrix) studies should address and evaluate: (5) cleaning difficulties”
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Selected FDA 483 Observations (December 1998) Sterile Product Manufacture [VIP ID: 7067] “Cleaning validation should include: 3) swab samples from the hardest to clean areas” Selected FDA 483 Observations (July 1998) Product Manufacture [VIP ID: 6747] “Cleaning validation should include swabbing of the most difficult to clean areas.” Selected FDA 483 Observations (April 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6371] “Cleaning validation swab samples should be collected from the hardest to clean areas of each individual item of equipment.” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (3) sampling the hardest to clean areas”
26. state the sampling frequency. Selected FDA 483 Observations (November 2003) Product Manufacture [VIP ID: 72300] “Cleaning Validation Protocols should include: a. Specific instructions for sample collection and their frequency.”
27. include the demonstration of endotoxins reduction for rubber closure components (stoppers, pistons and caps) used in sterile product manufacture. Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 15040] “Cleaning validation of washing processes for rubber closure components (stoppers, pistons and caps) should include the reduction of endotoxins.”
28. address microbiological and where appropriate endotoxin contamination. Selected FDA 483 Observations (December 2005) Sterile Product Manufacture [VIP ID: 179960] “Cleaning validation of process equipment should include an evaluation of the cleaning procedure for the removal of endotoxin.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.75 [VIP ID: 24774] “Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).”
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Selected FDA 483 Observations (February 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26930] “Cleaning of APIs intended for parenteral use should be completed from a microbiological perspective.” Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26310] “Cleaning validation of parenteral drug products should address microbiological and endotoxin contamination.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.75 [VIP ID: 155790] “Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).”
29. include microbial load reduction for oral solid dosage manufacturing equipment. Selected FDA 483 Observations (February 2006) Product Manufacture [VIP ID: 193120] “Cleaning procedures for oral solid dosage manufacturing equipment should be validated for microbial load reduction.”
30. include clear acceptance criteria with a supporting rationale for setting the specific limits. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CLEANING VALIDATION 36 [VIP ID: 187102] “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.” Extracted from FDA warning letter 2006-DT-23 (June 2006) USA 02-Jun-06 1 [VIP ID: 192114] “…In addition, the acceptance criteria for "clean" are not defined.” CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - The acceptance criteria, including the rationale for setting the specific limits,”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 36. [VIP ID: 21360] “Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.25 [VIP ID: 24570] “Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.25 [VIP ID: 154020] “Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (l) [VIP ID: 69140] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (1) the acceptance criteria, including the rationale for setting the specific limits,” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) III. General Requirements (para 3) [VIP ID: 1325] “FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.”
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include the correlation between detergent and product residue acceptance criteria and maximum daily therapeutic dose limits where applicable. Selected FDA 483 Observations (April 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 52380] “Cleaning validation should include the correlation between detergent and product residue acceptance criteria and maximum daily therapeutic dose limits.”
31. include data on recovery studies where appropriate. Selected FDA 483 Observations (January 2005) Product Manufacture [VIP ID: 128940] “Cleaning validation packages should include: (3) swab recovery analysis”
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PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Data on recovery studies where appropriate,” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (j) [VIP ID: 69120] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (j) data on recovery studies where appropriate,”
32. address the control of residues of the solvents used in the manufacturing process. ICH HARMONISED TRIPARTITE GUIDELINE IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2) (October 2006) 3. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES 3.3 Solvents [VIP ID: 184444] “The control of residues of the solvents used in the manufacturing process for the new drug substance should be discussed and presented according to the ICH Q3C Guideline for Residual Solvents.”
33. address tests and acceptance criteria for inorganic impurities. ICH HARMONISED TRIPARTITE GUIDELINE SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS: CHEMICAL SUBSTANCES Q6A (October 1999) 3. GUIDELINES 3.3 Specific Tests / Criteria 3.3.1 New Drug Substances f) [VIP ID: 151170] “Inorganic impurities: The need for inclusion of tests and acceptance criteria for inorganic impurities (e.g., catalysts) should be studied during development and based on knowledge of the manufacturing process. Procedures and acceptance criteria for sulfated ash / residue on ignition should follow pharmacopoeial precedents; other inorganic impurities may be determined by other appropriate procedures, e.g., atomic absorption spectroscopy.”
34. include an assessment of the effectiveness of the rinse samples. Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470] “API Cleaning Validation protocols should include: e. assessment of the effectiveness of the rinse samples.”
35. include data on the evaluation for the PAD (Pharmaceutically Active Dose) value that was determined. Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470] “API Cleaning Validation protocols should include: f. data on the evaluation for the PAD (Pharmaceutically Active Dose) value that was determined.”
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36. address what to do in the event of a cleaning failure. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26510] “Cleaning validation protocols should address what to do in the case of a cleaning failure.”
37. define acceptance/failure criteria prior to tests being executed. Selected FDA 483 Observations (July 2005) Medical Device Manufacture [VIP ID: 178220] “Cleaning validation protocols should define acceptance/failure criteria prior to tests being executed.”
38. state whether acceptance criteria are to be applied to individual samples or averages. Selected FDA 483 Observations (November 2000) Product Manufacture [VIP ID: 26190] “Cleaning validation should include: (3) a statement as to whether acceptance criteria are to be applied to individual samples or averages”
39. include a demonstration that the testing of unclean equipment yields unacceptable results. Selected FDA 483 Observations (January 1999) Product Manufacture [VIP ID: 7096] “Cleaning validation should include recovery tests and a demonstration that the testing of unclean equipment yields unacceptable results.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling c. Routine Production In-Process Control Monitoring [VIP ID: 1347] “…During validation, the firm should document that testing the uncleaned equipment gives a not acceptable result for the indirect test.”
40. demonstrate the adequate removal of media used as part of media fills. Extracted from FDA Warning Letter FLA-03-19 (January 2003) USA 06/01/2003 [VIP ID: 58520] “4(c). Your firm did not validate and approve according to established procedures a process whose results cannot be fully verified by subsequent inspection and test, as required by 21 CFR 820.75(b). Specifically: (c) Your firm has not determined whether the cleaning process for the BFS machine adequately removes media used as part of media fills.”
41. consider vapours, such as oil vapours, when compressed air is used as part of the cleaning process. GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994) XI. PACKAGING (para 2) [VIP ID: 3239] “Another problem in the packaging of Oral Liquids is the lack of cleanliness of containers prior to filling. Fibers and even insects have been identified as debris in containers, and particularly plastic containers used for these products. Many manufacturers receive containers shrink-wrapped in plastic to minimize contamination from fiberboard cartons. Many manufacturers utilize compressed air to clean containers. Vapors, such as oil vapors, from the compressed air have occasionally been found to present problems. Review the firm's systems for the cleaning of containers.”
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42. provide an indication of when revalidation will be required. Extracted from FDA warning letter - Unreferenced (October 2006) Belgium 11-Oct-06 8 [VIP ID: 192736] “Failure to ensure that when changes or process deviations occur, that the process is reviewed and evaluated, a revalidation is performed where appropriate and the results are documented. (21 CFR 820.75(c)) For example: (a) The cleaning process specified in SOP [redacted], for the cleaning of vials, caps and rubber stoppers was not evaluated for revalidation when the process was changed in [redacted]. The change eliminated the requirement to heat (maximal temperature) during the minimum [redacted] cleaning phase.” PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION REVALIDATION 45 [VIP ID: 187120] “Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.” Extracted from FDA warning letter 2006-DT-23 (June 2006) USA 02-Jun-06 2 [VIP ID: 192116] “Failure to review and evaluate the process and perform revalidation where appropriate when changes or process deviations occur, and failure to document such activities, as required by 21 CFR 820.75(c). Your firm did not have documentation of the revalidation of a process conducted in response to changes or process deviations.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - When Re-validation will be required.” COMPLIANCE PROGRAM GUIDANCE MANUAL FOR FDA STAFF: DRUG MANUFACTURING INSPECTIONS PROGRAM 7356.002 (February 2002) PART III - INSPECTIONAL INVESTIGATIONAL OPERATIONS C. System Inspection Coverage PRODUCTION SYSTEM [VIP ID: 61590] “For each of the following, the firm should have written and approved procedures and documentation resulting therefrom. The firm's adherence to written procedures should be verified through observation whenever possible. These areas are not limited to finished products, but may also incorporate components and in-process materials. These areas may indicate deficiencies not only in this system but also in other systems that would warrant expansion of coverage. When this system is selected for coverage in addition to the Quality System, all areas listed below should be covered; however, the depth of coverage may vary depending upon inspectional findings. - change control; the need for revalidation evaluated”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) REVALIDATION 45. [VIP ID: 21450] “Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (n) [VIP ID: 69160] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (n) when Re-validation will be required” Selected FDA 483 Observations (January 1999) Product Manufacture [VIP ID: 7094] “Cleaning validation protocols should include provisions for: 6) an indication of when revalidation will be required Selected FDA 483 Observations (March 1997) Product Manufacture [VIP ID: 2550] “The cleaning validation protocol should address who is responsible for performing and approving the validation study, and address when revalidation will be required.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 14 - MANUFACTURE OF PRODUCTS DERIVED FROM HUMAN BLOOD OR HUMAN PLASMA - SUPERSEDED! (January 1993) Production and quality control 15. [VIP ID: 4783] “The efficacy of cleaning procedures and sterile docking should be regularly controlled and validated.”
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Re-validation should be considered under the following circumstances: (a) re-validation in cases of changes to premises, equipment, products or processes, (b) periodic re-validation at defined intervals. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 6. NON-STERILE PROCESS VALIDATION 6.6 Re-validation 6.6.5 [VIP ID: 188618] “The need for periodic Re-validation of non-sterile processes is considered to be a lower priority than for sterile processes. In the case of standard processes on conventional equipment a data review similar to what would be required for Retrospective Validation may provide an adequate assurance that the process continues under control. In addition the following points should also be considered: (e) Cleaning and hygiene programme still appropriate,”
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PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.8 [VIP ID: 188654] “Control of change to validated cleaning procedures is required. Re-validation should be considered under the following circumstances: (a) Re-validation in cases of changes to equipment, products or processes, (b) Periodic Re-validation at defined intervals.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.8. [VIP ID: 68990] “Control of change to validated cleaning procedures is required. Re-validation should be considered under the following circumstances: (a) re-validation in cases of changes to premises, equipment, products or processes, (b) periodic re-validation at defined intervals.”
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Re-validation should include more than one run and one set of results. Selected FDA 483 Observations (September 2004) Sterile Product Manufacture [VIP ID: 124000] “Revalidation of equipment cleaning and sanitization validations should include more than one run and one set of results.”
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Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.9 [VIP ID: 188656] “Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.9. [VIP ID: 69000] “Manual methods should be reassessed at more frequent intervals than clean-in-place (CIP) systems.”
43. include the rationale for the cleaning of additional products introduced when validation is complete. Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 19280] “Cleaning validation protocols should address: (2) the rationale for the cleaning of additional products introduced when validation is completed.”
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44. address all the products (to include pharmaceutical compounds and intermediates) processed using a particular item of equipment. Extracted from FDA warning letter 07-NWJ-06 (February 2007) USA 01-Feb-07 7. a) [VIP ID: 194842] “Your firm's cleaning validation studies were found to be inadequate and, as a result, there was no assurance that equipment is adequately cleaned between the manufacture of different drug products. [21 CFR 211.67(b)] For example: a) Cleaning validation was performed for the process trains without evaluating for sample recovery for numerous products, including: Amidal Nasal Decongestant; Amigesic Caplets, 750mg; Carisoprodol and Aspirin Tablets, USP, 200mg/325mg; Carisoprodol Tablets, USP, 350mg; Chlorzoxazone Tablets, USP, 250mg and 500mg; Digoxin Tablets, USP, 0.25mg.” Selected FDA 483 Observations (March 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7153] “Cleaning validation should demonstrate the effectiveness of the cleaning procedure for each pharmaceutical compound and intermediate used in the equipment.” Selected FDA 483 Observations (January 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 7086] “Cleaning validation should demonstrate the effectiveness of the cleaning method for each bulk pharmaceutical compound and intermediate used in the equipment.” Selected FDA 483 Observations (April 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6369] “Cleaning validation should include all the products processed using a particular item of equipment.” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (1) all marketed products”
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Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the "worst case" can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing". PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CLEANING VALIDATION 39 [VIP ID: 187108] “For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a "worst case" approach can be carried out which takes account of the critical issues.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.5 [VIP ID: 188648]
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“Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the "worst case" can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing".” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.11 Establishment of Limits 7.11.2 [VIP ID: 188704] “The approach for setting limits can be: - product specific Cleaning Validation for all products, - grouping into product families and choosing a "worst case" product, - grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect).” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 39. [VIP ID: 21390] “For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a "worst case" approach can be carried out which takes account of the critical issues.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.3. General 4.3.5. [VIP ID: 68960] “Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the "worst case" can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing".” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!! (October 1999) 4. Cleaning Validation 4.11. Establishment of Limits 4.11.2. [VIP ID: 69400] “The approach for setting limits can be: (a) product specific Cleaning Validation for all products, (b) grouping into product families and choosing a "worst case" product. (c) grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect).”
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Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 15 - QUALIFICATION AND VALIDATION CLEANING VALIDATION 42 [VIP ID: 187114] “Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.”
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PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.3 General 7.3.11 [VIP ID: 188660] “Products which simulate the physicochemical properties of the substance to be removed may be used instead of the substances themselves, where such substances are either toxic or hazardous.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 42. [VIP ID: 21420] “Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous.”
45. evaluate the cleaning of all equipment and ancillary equipment that can be used for each product category. Selected FDA 483 Observations (June 2002) Product Manufacture [VIP ID: 47110] “Cleaning validation should evaluate all of the cleaning procedures used for each product category.” Selected FDA 483 Observations (October 1999) Sterile Product Manufacture [VIP ID: 8670] “Cleaning validation should be completed for ancillary equipment.”
46. consider all product classes. Selected FDA 483 Observations (July 1997) Sterile Product Manufacture [VIP ID: 2518] “Cleaning Validation should include: (4) all product classes”
47. include other products, processes and equipment for which the planned validation is valid according to a "bracketing" concept. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Other products, processes, and equipment for which the planned validation is valid according to a "bracketing" concept,” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (m) [VIP ID: 69150]
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“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (m) other products, processes and equipment for which the planned validation is valid according to a "bracketing" concept,”
48. evaluate all of the cleaning procedures used for each product category. Selected FDA 483 Observations (June 2002) Product Manufacture [VIP ID: 47120] “Cleaning validation should evaluate the cleaning of all equipment that can be used for each product category.”
49. include the rationale / justification for the selection of products to be tested for 'worst case' scenario. Extracted from FDA Warning Letter [NO REFERENCE] (August 2005) Germany 30/08/2005 [VIP ID: 171820] “3. Failure to adequately validate a process that cannot be fully verified by subsequent inspection and test, as required by 21 CFR 820.75(a). For example the process validation documentation for the ultrasonic cleaning process utilizing [redacted] lacks information to document that implants were cleaned according to the validation test plan using worst case conditions.” Selected FDA 483 Observations (January 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 71280] “Cleaning validation should include testing under worst case conditions (e.g., highest product bioburden, shortest rinse time, greatest number of components, minimum drying time).” Selected FDA 483 Observations (December 2003) Product Manufacture [VIP ID: 71020] “The effectiveness of Equipment Cleaning Procedures used in the manufacture of solid dosage form pharmaceuticals should be demonstrated (where done) through validation studies using worse case products/conditions.” Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 19280] “Cleaning validation protocols should address: (1) the rationale / justification for the selection of products to be tested for 'worst case' scenario.”
50. consider the most clinically significant (to include toxicity/potency) products. Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470] “API Cleaning Validation protocols should include: c. toxicological evaluation.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.71 [VIP ID: 24770] “Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.”
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ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.71 [VIP ID: 155750] “Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8310] “Cleaning validation (matrix) studies should address and evaluate: (6) product toxicity / potency” Selected FDA 483 Observations (July 1997) Sterile Product Manufacture [VIP ID: 2518] “Cleaning Validation should include: (3) the most clinically significant products”
51. include the most difficult to clean products. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.71 [VIP ID: 24770] “Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.71 [VIP ID: 155750] “Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8310] “Cleaning validation (matrix) studies should address and evaluate: (4) most difficult to clean product”
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Choosing the most insoluble product with the highest blend may not always be the worst case for cleaning validation. Consideration should also be given to excipients. A hard to clean excipient may bond with a relatively soluble active ingredient to adhere to equipment walls. Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8310] “Cleaning validation (matrix) studies should address and evaluate: (1) removal of potential product degradents, drug/cleaning agent reaction products and excipients
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(2) ability of analytical methods to detect potential product degradents, drug/cleaning agent reaction products and excipients” Selected FDA 483 Observations (September 1997) Product Manufacture [VIP ID: 2499] “Choosing the most insoluble product with the highest blend may not always be the worst case for cleaning validation. Consideration should also be given to excipients. A hard to clean excipient may bond with a relatively soluble active ingredient to adhere to equipment walls.”
52. consider water/solvent solubility for all products. Selected FDA 483 Observations (June 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40130] “Water / solvent solubility should be known for all products listed in a cleaning validation decision matrix.”
53. consider chemical variations (active decomposition materials) which may be difficult to remove. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.11. Establishment of Limits 4.11.5. [VIP ID: 69430] “In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.”
54. all primary packing operations of prescription and over-the-counter pharmaceutical products packed in multi-use rooms. Extracted from FDA Warning Letter W/L 77-00 (September 2000) USA 22/09/2000 [VIP ID: 20230] “1. Failure to establish and follow procedures for cleaning and maintenance of equipment [$211.67(b)]. For example, cleaning validation has not been performed for any of your packaging lines. In addition, Standard Operating Procedures (SOPS) regarding cleaning were not followed and resulted in `foreign` tablets present in product.” Selected FDA 483 Observations (November 1999) Packaging & Labelling [VIP ID: 137600] “Cleaning validation should be conducted for all primary packing operations of prescription and over-the-counter pharmaceutical products packed in multi-use rooms.”
55. include detergent residue testing. Selected FDA 483 Observations (September 2006) Sterile Product Manufacture [VIP ID: 194008] “Cleaning validation should include determination of cleaning or sanitizing solution residues following the cleaning or sanitizing of drug contact surfaces.” Selected FDA 483 Observations (December 2001) Sterile Product Manufacture [VIP ID: 45990] “Stopper washer validation should include: (d) Validated detergent residue methods.”
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Selected FDA 483 Observations (November 2000) Product Manufacture [VIP ID: 26190] “Cleaning validation should include: (4) detergent residue testing”
56. demonstrate the removal of surfactant cleaners. Selected FDA 483 Observations (January 2003) Product Manufacture [VIP ID: 51870] “Cleaning validation should include an evaluation to determine whether the cleaning process will remove surfactant cleaners.”
57. demonstrate the removal of sanitising solutions. Selected FDA 483 Observations (January 2003) Product Manufacture [VIP ID: 51860] “Cleaning validation should include an evaluation to determine whether the cleaning process will remove sanitizing solutions.”
58. demonstrate the removal of cleaning agent(s). CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.9 Detergents 7.9.1 [VIP ID: 188692] “The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures.” Selected FDA 483 Observations (July 2001) Product Manufacture [VIP ID: 40380] “Cleaning validation should address the following critical issues: (2) the removal of all cleaning agents including soap and acetone” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.9. Detergents 4.9.1. [VIP ID: 69340] “The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures.” Selected FDA 483 Observations (March 1999) Product Manufacture [VIP ID: 7141] “Equipment should be tested for the presence of cleaning agent residues.” Selected FDA 483 Observations (February 1998) Product Manufacture [VIP ID: 6329] “Cleaning validation protocols should include: 3) testing for the removal of sanitizing agents and detergents”
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Selected FDA 483 Observations (November 1997) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6260] “Cleaning validation should include cleaning agent residue analysis.” Selected FDA 483 Observations (September 1997) Product Manufacture [VIP ID: 2497] “Equipment cleaning validation should include: (1) Residue testing for the cleaning agent” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (8) assurance of the removal of the cleaning agent”
59. address possibility of detergent breakdown. CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.9 Detergents 7.9.1 [VIP ID: 188692] “…The possibility of detergent breakdown should be considered when validating cleaning procedures.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.9. Detergents 4.9.1. [VIP ID: 69340] “…The possibility of detergent breakdown should be considered when validating cleaning procedures.”
60. include the entire time period during which cleaning agents are rotated. Selected FDA 483 Observations (October 1998) Sterile Product Manufacture [VIP ID: 6855] “Cleaning validation should include the entire time period during which cleaning agents are rotated.”
61. adhere to the hold times specified in procedures. Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 193134] “Cleaning validation studies of dedicated and non-dedicated manufacturing equipment should adhere to the hold times specified in procedures.”
62. include the maximum length of time between the end of processing and each cleaning step. Selected FDA 483 Observations (August 2007) Product Manufacture [VIP ID: 193904] “Validation runs should be performed using worst case scenarios (i.e., most difficult to clean drug residues, maximum holding time prior to or after equipment cleaning, etc.) to justify the currently-in-use equipment cleaning procedures.”
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Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 193132] “Cleaning validation studies of dedicated and non-dedicated manufacturing equipment should include validation of dirty hold times.” Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 193136] “Cleaning validation and dirty hold times should be established for non-dedicated manufacturing equipment.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - The interval between the end of production and the beginning of the cleaning procedures,” Selected FDA 483 Observations (October 2003) Sterile Product Manufacture [VIP ID: 70560] “Media fills should reflect the routine aseptic filling processes and address: - dirty hold time validations. - cleaning validation or dirty hold times for non-dedicated equipment.” Selected FDA 483 Observations (August 2003) Product Manufacture [VIP ID: 53040] “There should be data to support the maximum hold time from the end of manufacture to the start of cleaning.” Selected FDA 483 Observations (April 2003) Active Pharmaceutical Ingredient Manufacture [VIP ID: 52390] “Cleaning validation should include the establishment of time limits for initiating equipment cleaning after production.” Selected FDA 483 Observations (January 2002) Product Manufacture [VIP ID: 46160] “The length of time between the end of processing and each cleaning step should be identified and controlled.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 38. [VIP ID: 21380] “…The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4 Documentation 4.4.1. (d) [VIP ID: 69060]
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“A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (d) the interval between the end of the production and the beginning of the cleaning procedures,” GUIDE TO INSPECTIONS OF ORAL SOLUTIONS AND SUSPENSIONS (August 1994) III. EQUIPMENT (para 2) [VIP ID: 3210] “In order to facilitate cleaning and sanitization, manufacturing and filling lines should be identified and detailed in drawings and SOPs. In some cases, long delivery lines between manufacturing areas and filling areas have been a source of contamination. Also, SOPs, particularly with regard to time limitations between batches and for cleaning have been found deficient in many manufacturers. Review cleaning SOPs, including drawings and validation data with regard to cleaning and sanitization.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 1. Equipment Design (para 4) [VIP ID: 1334] “Always check for the presence of an often critical element in the documentation of the cleaning processes; identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process.” Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26080] “A limit should be set for the time between equipment use and cleaning.” Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 15280] “Cleaning validation should include the evaluation of: (2) equipment hold times between use and cleaning” Selected FDA 483 Observations (December 1999) Product Manufacture [VIP ID: 14310] “Cleaning validation protocols should: (2) address cleaning time frames” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8310] “Cleaning validation (matrix) studies should address and evaluate: (3) worst case time frames between cleaning” Selected FDA 483 Observations (January 1999) Sterile Product Manufacture [VIP ID: 7105] “Cleaning validation should include: 3) establishment of the maximum length of time equipment is allowed to remain dirty prior to cleaning” Selected FDA 483 Observations (September 1998) Product Manufacture [VIP ID: 6808] “The maximum time between the end of liquid/ointment production and the start of cleaning should be defined in the cleaning procedures.”
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Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (6) assurance of effectiveness under actual production time frames (after max time following production)” Selected FDA 483 Observations (March 1997) Product Manufacture [VIP ID: 2549] “The length of time between the end of processing and each cleaning step should be identified and controlled.”
63. include the maximum length of time between cleaning and the use of manufacturing equipment. Selected FDA 483 Observations (December 2006) Product Manufacture [VIP ID: 194324] “Cleaning validation, for equipment, which is not dedicated to one product, should include the evaluation of microbiological control, a recovery study performed to demonstrate the sensitivity and specificity (detection limit) of analytical equipment to demonstrate that residual product is removed after cleaning, documentation of the sampling method or location used in the cleaning validation and the establishment of time limitation of cleaning prior to next use.” Selected FDA 483 Observations (August 2006) Product Manufacture [VIP ID: 193904] “Validation runs should be performed using worst case scenarios (i.e., most difficult to clean drug residues, maximum holding time prior to or after equipment cleaning, etc.) to justify the currently-in-use equipment cleaning procedures.” PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.7 Microbiological Aspects 7.7.2 [VIP ID: 188684] “The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.” Selected FDA 483 Observations (December 1999) Product Manufacture [VIP ID: 14310] “Cleaning validation protocols should: (2) address cleaning time frames” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8310] “Cleaning validation (matrix) studies should address and evaluate: (3) worst case time frames between cleaning” Selected FDA 483 Observations (June 1999) Product Manufacture [VIP ID: 7250] “There should be an established time limit between the cleaning and usage of equipment in liquid pharmaceutical manufacture.” Selected FDA 483 Observations (June 1998) Product Manufacture [VIP ID: 6713] “The time limit between equipment cleaning and usage should be established.”
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Selected FDA 483 Observations (August 1997) Sterile Product Manufacture [VIP ID: 2508] “A time limit for the length of time between cleaning and the use of manufacturing equipment should be established.”
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include the establishment of an expiration date for clean equipment. Selected FDA 483 Observations (January 1999) Sterile Product Manufacture [VIP ID: 7105] “Cleaning validation should include: 2) establishment of an expiration date for clean equipment”
64. include the maximum length of time between cleaning and drying of equipment where appropriate. PE 009-5 GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (August 2006) ANNEX 1 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS SANITATION 50 [VIP ID: 186098] “The interval between the washing and drying and the sterilisation of components, containers and equipment as well as between their sterilisation and use should be minimised and subject to a time-limit appropriate to the storage conditions.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 01 - MANUFACTURE OF STERILE MEDICINAL PRODUCTS (September 2003) Processing 50 [VIP ID: 63440] “The interval between the washing and drying and the sterilisation of components, containers and equipment as well as between their sterilisation and use should be minimised and subject to a time-limit appropriate to the storage conditions.”
65. include a demonstration of the expiration dating of opened disinfectant concentrates used in the cleaning of critical manufacturing areas. Selected FDA 483 Observations (February 2006) Sterile Product Manufacture [VIP ID: 193138] “Cleaning validation should include demonstration of the expiration dating of opened disinfectant concentrates used in the cleaning of critical manufacturing areas.”
66. include when appropriate, the conditions of storage of equipment before and after cleaning. NOTE:
This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.
EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.7. Microbiological Aspects 4.7.2. [VIP ID: 69270] “The period and when appropriate, the conditions of storage of equipment before and after cleaning and the time between cleaning and equipment re-use, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.”
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67. assess such parameters as flow rate, agitator speed and mixing time. Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (4) assessment of the flow rate of the water, agitator speed and mixing time”
68. include minimum flow rates, flush times and flush quantities specified in cleaning procedures.. Selected FDA 483 Observations (March 2005) Sterile Product Manufacture [VIP ID: 138870] “Equipment cleaning validation studies should demonstrate that cleaning is effective at the minimum flow rates, flush times and flush quantities specified in cleaning procedures.”
69. include minimum rinse times and / or minimum cleaning solution contact times. Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 15280] “Cleaning validation should include the evaluation of: (1) minimum rinse times (3) and / or minimum cleaning solution contact times”
70. demonstrate that the rinse contacts all of the product contact surfaces. Selected FDA 483 Observations (December 1998) Sterile Product Manufacture [VIP ID: 7067] “Cleaning validation should include: 2) demonstration that the rinse contacts all product contact surfaces”
71. confirm that residual water is removed from the equipment following cleaning. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.7 Microbiological Aspects 7.7.3 [VIP ID: 188686] “In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.” Selected FDA 483 Observations (March 2000) Product Manufacture [VIP ID: 15090] “Residual water should not be left in equipment (such as pumps and tri-blenders) following cleaning.” Selected FDA 483 Observations (March 2000) Product Manufacture [VIP ID: 15120] “Stainless steel pipework used in the manufacturing process, connecting formulation tanks, holding tanks and transfer lines should be drained following cleaning/sanitization.”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.7. Microbiological Aspects 4.7.3. [VIP ID: 69280] “In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.” Extracted from FDA Warning Letter CBER 98-006 (October 1998) Germany 01/12/1998 [VIP ID: 12220] “Failure to clean, maintain and sanitize equipment at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 CFR 211.67(a) and 600.11(b)].” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2534] “Cleaning Validation should include: (8) assurance of the removal of the cleaning agent” REG 07/01/93 GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July, 1993) IV. Evaluation of Cleaning Validation 1. Equipment Design (para 5) “Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.”
72. include the production equipment used during media fill runs. Selected FDA 483 Observations (December 1999) Sterile Product Manufacture [VIP ID: 14260] “Cleaning validation should include the production equipment used during media fill runs.”
73. include non-dedicated equipment. Selected FDA 483 Observations (August 2000) Sterile Product Manufacture [VIP ID: 19450] “Cleaning validation should be performed for non-dedicated equipment.”
74. include product transfer hoses. Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 15230] “Cleaning / Depyrogenation validation should be completed for product transfer hoses.”
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Cleaning/depyrogenation validation of tubing used in sterile filtration should include data for the level of endotoxins on the tubing prior to depyrogenation. Selected FDA 483 Observations (March 2000) Sterile Product Manufacture [VIP ID: 15270] “Cleaning / depyrogenation validation of tubing used in sterile filtration should include data for the level of endotoxins on the tubing prior to depyrogenation.”
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75. include miscellaneous items used during aseptic operations, such as pens, calculators, cable cutters, walkie-talkies and printer paper. Selected FDA 483 Observations (March 2005) Sterile Product Manufacture [VIP ID: 138860] “Cleaning validation should be performed to demonstrate sanitisation of miscellaneous items used during aseptic operations, such as pens, calculators, cable cutters and walkie-talkies, and there should be documentation that these items are routinely sanitised.” Selected FDA 483 Observations (May 2004) Sterile Product Manufacture [VIP ID: 122260] “There should be documented evidence to demonstrate that printer paper used to record the weight checks performed during aseptic filling is cleaned, sanitized or sterilized prior to entry into the filling zone in order to prevent the potential for microbial contamination.”
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Validation data should be generated to show that the procedure used to sanitise / disinfect materials taken into the sterile fill rooms (i.e. writing pens, mops, and mop buckets) are effective. Selected FDA 483 Observations (November 2002) Sterile Product Manufacture [VIP ID: 51590] “Validation data should be generated to show that the procedure used to sanitize / disinfect materials taken into the sterile fill rooms (i.e. writing pens, mops, and mop buckets) are effective.”
76. include an assessment of the spray ball coverage where applicable. Selected FDA 483 Observations (August 2005) Sterile Product Manufacture [VIP ID: 178370] “Cleaning validation for the CIP process for a vessel used in the aseptic formulation of product should include an assessment of sprayball coverage for the vessel and swab sampling of the transfer lines, where applicable.” Extracted from FDA Warning Letter CBER-05-006 (December 2004) USA 09/12/2004 [VIP ID: 133260] “3. There is no indication that prior to August 2004 there were periodic preventive maintenance programs or procedures to prevent malfunctions or contamination for the [redacted] tanks, In addition, the cleaning validation did not include an assessment of the spray ball coverage for the tanks.” Extracted from FDA Warning Letter CBER-05-006 (December 2004) USA 09/12/2004 [VIP ID: 133230] “8. Your firm failed to establish and follow written procedures to assure the cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product. [21 CFR 211.67(b) and 600.11(b)] For example, cleaning validation for the clean-in-place (CIP) process Vessel [redacted] which is utilized in the aseptic formulation of trivalent bulk influenza vaccine, did not include an assessment of the spray ball coverage for the vessel. The spray ball is used for cleaning product contact equipment. In addition, the study did not include swab sampling of the product transfer lines.”
77. address Clean in Place (CIP) systems. Selected FDA 483 Observations (May 2002) Sterile Product Manufacture [VIP ID: 28110] “Clean in Place (CIP) systems for sterile product tanks should be validated.”
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6.3.2 SOPs 1.
Cleaning validation SOPs should reference the cleaning validation protocols. Selected FDA 483 Observations (November 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26070] “Cleaning validation SOPs should reference the cleaning validation protocols.”
2.
There should be an established procedure for cleaning validation recovery studies. Selected FDA 483 Observations (August 2005) Active Pharmaceutical Ingredient Manufacture [VIP ID: 178570] “There should be an established procedure for cleaning validation recovery studies.”
3.
There should be a general procedure on how cleaning processes will be validated. Selected FDA 483 Observations (August 2005) Active Pharmaceutical Ingredient Manufacture [VIP ID: 178580] “There should be a general procedure on how cleaning processes will be validated”
6.3.3 Fluid Bed Dryer Fluid bed dryer cleaning validation studies should: 1.
require swab samples to be collected from the removable tray/bowl, and top portion, i.e. the filter plenum. Selected FDA 483 Observations (November 2006) Product Manufacture [VIP ID: 194188] “During cleaning validation studies for a fluid bed dryer, swab samples should not just be collected from the removable tray/bowl, but also from the top portion, i.e. the filter plenum, …”
2.
include an evaluation of the cleaning process for non dedicated filter bags. Selected FDA 483 Observations (November 2006) Product Manufacture [VIP ID: 194188] “During cleaning validation studies for a fluid bed dryer, swab samples should not just be collected from the removable tray/bowl, but also from the top portion, i.e. the filter plenum, and there should be an evaluation made of the cleaning process for non dedicated filter bags.”
3.
require cleaning validation samples to be collected on the same day the equipment is used, if the fluid bed dryer is routinely cleaned after use. Selected FDA 483 Observations (November 2006) Product Manufacture [VIP ID: 194188] “… Cleaning validation samples should only be collected from the fluid bed dryer on the same day the equipment is used, if the fluid bed dryer is routinely cleaned after use.”
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6.3.4 Tablet Press 1.
Tablet Press cleaning validation should include the identification of the punches and dies used. Selected FDA 483 Observations (March 2001) Product Manufacture [VIP ID: 27360] “Tablet Press cleaning validation should include the identification of the punches and dies used.”
6.3.5 Sterile Injectable Products Cleaning validation of sterile injectable products should include: 1.
complete solubility studies between the cleaning agent(s) and all active and inactive ingredients. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26300] “Cleaning validation of sterile injectable products should include: (a) Complete solubility studies between the cleaning agent(s) and all active and inactive ingredients.”
2.
investigation of any unusual residues observed. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26300] “Cleaning validation of sterile injectable products should include: (c) Investigation of any unusual residues observed.”
6.3.6 Centrifuge Centrifuge CIP cleaning validation protocols should address: 1.
spray temperature.
2.
volume.
3.
time.
4.
visual inspection of equipment condition following cleaning. Selected FDA 483 Observations (September 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 8110] “Centrifuge CIP cleaning validation should include: (1) (2) (3) (4)
spray temperature volume time visual inspection of equipment condition following cleaning”
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6.3.7 Lyophilizer Lyophilizer cleaning validation protocols should include: 1.
the requirement to sample the chamber both before and after cleaning to confirm the absence of oil vapour which may have migrated back to the chamber from the vacuum pump. GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Lyophilization Cycle and Controls (para 11) [VIP ID: 2779] “In order to minimize oil vapor migration, some lyophilizers are designed with a tortuous path between the vacuum pump and chamber. For example, one fabricator installed an oil trap in the line between the vacuum pump and chamber in a lyophilizer with an internal condenser. Leakage can also be identified by sampling surfaces in the chamber after lyophilization for contaminants. One could conclude that if contamination is found on a chamber surface after lyophilization, then dosage units in the chamber could also be contaminated. It is a good practice as part of the validation of cleaning of the lyophilization chamber to sample the surfaces both before and after cleaning.”
2.
testing the ram (where fitted) for microbiological contamination. GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Lyophilizer Sterilization/Design (para 9) [VIP ID: 2793] “In some of the larger units, the shelves are collapsed after sterilization to facilitate loading. Obviously, the portions of the ram entering the chamber to collapse the shelves enters from a non-sterile area. Attempts to minimize contamination have included wiping the ram with a sanitizing agent prior to loading. Control aspects have included testing the ram for microbiological contamination, ...”
3.
testing the ram (where fitted) for residues of hydraulic fluid. GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Lyophilizer Sterilization/Design (para 9) [VIP ID: 2793] “In some of the larger units, the shelves are collapsed after sterilization to facilitate loading. Obviously, the portions of the ram entering the chamber to collapse the shelves enters from a non-sterile area. Attempts to minimize contamination have included wiping the ram with a sanitizing agent prior to loading. Control aspects have included testing the ram for … residues of hydraulic fluid, ...”
4.
testing the ram hydraulic fluid (where used) for its bacteriostatic effectiveness. GUIDE TO INSPECTIONS OF LYOPHILIZATION OF PARENTERALS (July 1993) Lyophilizer Sterilization/Design (para 9) [VIP ID: 2793] “In some of the larger units, the shelves are collapsed after sterilization to facilitate loading. Obviously, the portions of the ram entering the chamber to collapse the shelves enters from a non-sterile area. Attempts to minimize contamination have included wiping the ram with a sanitizing agent prior to loading. Control aspects have included testing the … fluid for its bacteriostatic effectiveness. ...”
5.
the maximum challenge of glass fragments from broken/cracked vials as observed through routine production. Selected FDA 483 Observations (January 2005) Sterile Product Manufacture [VIP ID: 138020] “There should be cleaning validation studies or specific procedural requirements to address the elimination of glass particles from broken vials, or residuals from product spilled as a result of breakages on machines.”
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Selected FDA 483 Observations (February 2002) Sterile Product Manufacture [VIP ID: 46420] “Lyophilizer CIP validation should include the maximum challenge of glass fragments from broken/cracked vials as observed through routine production.”
6.
the screens or wire electrodes that have product contact during lyophilization. Extracted from FDA Warning Letter WL-24-02 (January 2002) USA 14/01/2002 1 [VIP ID: 48080] “1. … There is no cleaning validation for screens or wire electrodes that have product contact during lyophilization. Our investigators also observed foreign substances on production screens and trays.”
6.3.8 Non-dedicated (multi-use) Primary Packaging Equipment Non-dedicated (multi-use) primary packaging equipment cleaning validation protocols should include: 1.
microbial evaluations for use in risk assessment.
2.
the identification of worst case toxicity/potency and cleanability/solubility products.
3.
assessment of all equipment train configurations.
4.
the documentation of the cleaning of equipment at the time of occurrence in equipment cleaning and use logs.” Selected FDA 483 Observations (May 2004) Packaging & Labelling [VIP ID: 122290] “Cleaning validation of non dedicated (multi-use) primary packaging equipment should include: a. microbial evaluations for use in risk assessment. b. the identification of worst case toxicity/potency and cleanability/solubility products. c. assessment of all equipment train configurations. d. the documentation of the cleaning of equipment at the time of occurrence in equipment cleaning and use logs.”
6.3.9 Stopper Washers Stopper Washer validation protocols should: 1.
include the demonstration of consistent detergent concentrations during each cycle. Selected FDA 483 Observations (February 2002) Sterile Product Manufacture [VIP ID: 46410] “Stopper Washer validation should include demonstration of consistent detergent concentrations during each cycle.”
2.
include particulate monitoring of rinse waters. Selected FDA 483 Observations (July 2001) Sterile Product Manufacture [VIP ID: 40270] “Particulate monitoring should be performed on the rinse waters from vial washers and stopper washers.”
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include spiking the stoppers with known amounts of endotoxin to determine if the washer is effective in de-pyrogenating stoppers. Selected FDA 483 Observations (December 2001) Sterile Product Manufacture [VIP ID: 45990] “Stopper washer validation should include: (a) Spiking the stoppers with known amounts of endotoxin to determine if the washer is effective in de-pyrogenating stoppers.”
6.3.10 HPLC Columns HPLC Column cleaning validation protocols should: 1.
include critical cleaning specifications, for example:. •
pressure/flow rates.
•
volume of WFl/NaOH that was used in the equipment flushing
•
time of flush.
•
temperature of the WFI used during the cleaning / flushing process.”
Selected FDA 483 Observations (September 2004) Sterile Product Manufacture [VIP ID: 124310] “Column cleaning validations should include critical cleaning specifications, for example: a. pressure / flow rates. b. volume of WFl / NaOH that was used in the equipment flushing c. time of flush. d. temperature of the WFI used during the cleaning / flushing process.”
6.3.11 Cleaning/Sanitising Agents Cleaning/sanitising agent validation protocols should: 1.
include the determination of the lot to lot variability of the cleaning agent. Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (1) determination of the lot to lot variability of the cleaning agent”
2.
include certificates of analysis for the cleaning agent(s). Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (2) certificates of analysis for the cleaning agent”
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include the periodic challenging of sanitisers with new resistant isolates such as Bacillus lichenformis and Bacillus thurigenesis. Selected FDA 483 Observations (April 2000) Sterile Product Manufacture [VIP ID: 15660] “Environmental monitoring should include: (2) periodic challenging of sanitizers with new resistant isolates such as Bacillus lichenformis and Bacillus thurigenesis”
4.
include the evaluation of the cleaning agent(s) composition. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.9 Detergents 7.9.2 [VIP ID: 188694] “The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.9. Detergents 4.9.2. [VIP ID: 69350] “The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted.” Selected FDA 483 Observations (September 1998) Product Manufacture [VIP ID: 6827] “Cleaning validation should include: 1) evaluation of cleaning agent composition”
5.
address the function of each cleaning agent ingredient. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.25 [VIP ID: 24570] “Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 5. PROCESS EQUIPMENT 5.2 Equipment Maintenance and Cleaning 5.25 [VIP ID: 154020] “Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.”
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Selected FDA 483 Observations (September 1998) Product Manufacture [VIP ID: 6827] “Cleaning validation should include: 2) the function of each cleaning agent ingredient”
6.
demonstrate that the cleaning agent dilution procedure produces the optimum level for cleaning and disinfection. Selected FDA 483 Observations (October 1998) Sterile Product Manufacture [VIP ID: 6856] “The cleaning agent dilution procedure should be demonstrated to produce the optimum level for cleaning and disinfection.”
7.
demonstrate the effectiveness of the cleaning agents to establish satisfactory levels of kill within an acceptable exposure time against isolated environmental contaminants. Selected FDA 483 Observations (December 2002) Product Manufacture [VIP ID: 51780] “The suitability of equipment cleaning agents should be validated to confirm their effectiveness.” Selected FDA 483 Observations (October 2000) Sterile Product Manufacture [VIP ID: 20020] “The effectiveness of each of the cleaning agents to establish satisfactory levels of kill within an acceptable exposure time against isolated environmental contaminants should be evaluated.”
8.
demonstrate the compatibility between the cleaning agent(s) and the drug product(s). Selected FDA 483 Observations (October 1999) Product Manufacture [VIP ID: 8590] “The compatibility between cleaning agents and drug products should be determined.”
6.4 Direct/Indirect Sampling Methods The following points should be considered for direct/indirect sampling: 1.
There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.8 Sampling 7.8.2 [VIP ID: 188690] “There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions).”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.8. Sampling 4.8.2. (para 1) [VIP ID: 69300] “There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.8. Sampling 4.8.2. (para 2) [VIP ID: 69330] “A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.” GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION Sampling Plan For Contaminants [VIP ID: 119300] “As part of the validation of the cleaning method, the cleaned surface is sampled for the presence of residues. Sampling should be by an appropriate method, selected based on factors such as equipment and solubility of residues. For example, representative swabbing of surfaces is often used, especially in hard to clean areas and / or where the residue is relatively insoluble. Analysis of rinse solutions for residues has also been shown to be of value where the residue is soluble and / or difficult to access for direct swabbing. Both methods are useful when there is a direct measurement of the residual substance. However, it is unacceptable to test rinse solutions (such as purified water) for conformance to the purity specifications for those solutions, instead of testing directly for the presence of possible residues.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling [VIP ID: 1341] “There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.” BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES B. Sampling Plan [VIP ID: 1086] “After cleaning, there should be some routine testing to assure that the surface has been cleaned to the validated level. One common method is the analysis of the final rinse water or solvent for the presence of the cleaning agents last used in that piece of equipment. There should always be direct determination of the residual substance.”
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A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.8 Sampling 7.8.2 [VIP ID: 188690] “…A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling. A. Direct Surface Sampling (i) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used. B. Rinse Samples (i) Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant. (ii) A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.” EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.73 [VIP ID: 24772] “Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and / or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.73 [VIP ID: 155770] “Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.8. Sampling 4.8.2. (para 1) a. [VIP ID: 69310] “Direct Surface Sampling The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used.”
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An advantage of direct sampling is that "dried out" or insoluble residues can be sampled by physical removal. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling a. Direct Surface Sampling (para 2) [VIP ID: 1343] “Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal.”
3.
Cleaning validation should include swab testing, and not rely solely on rinse water analysis. Selected FDA 483 Observations (December 2000) Sterile Product Manufacture [VIP ID: 26500] “Cleaning validation should include swab testing, and not rely solely on rinse water analysis.” Selected FDA 483 Observations (May 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 16010] “Bulk pharmaceutical ingredient equipment cleaning validation should include swab samples.”
4.
Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated. EU GUIDE TO GOOD MANUFACTURING PRACTICE PART II: BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS (October 2005) 12. VALIDATION 12.7 Cleaning Validation 12.73 [VIP ID: 24772] “Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and / or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).” ICH HARMONISED TRIPARTITE GUIDELINE GOOD MANUFACTURING PRACTICE GUIDE FOR ACTIVE PHARMACEUTICAL INGREDIENTS Q7A (November 2000) 12. VALIDATION 12.7 Cleaning Validation 12.73 [VIP ID: 155770] “Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.8. Sampling 4.8.2. (para 1) b. [VIP ID: 69320] “Rinse Samples Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling b. Rinse Samples (para 1) [VIP ID: 1344] “Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.”
5.
A disadvantage of indirect (rinse) samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED!! (October 1999) 4. Cleaning Validation 4.8. Sampling 4.8.2. (para 1) b. [VIP ID: 69320] “Rinse Samples Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant and the appropriate volume of the samples.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling b. Rinse Samples (para 2) [VIP ID: 1345] “A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. ...”
•
An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling b. Rinse Samples (para 2) [VIP ID: 1345] “… An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.”
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6.5 Rinse Water Samples 1.
Rinse water samples should be analysed separately for the presence of product and cleaning agent residues. Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 19290] “Cleaning rinse samples should be analyzed separately for active and detergent residues, not just for total impurities.” Selected FDA 483 Observations (January 1999) Product Manufacture [VIP ID: 7094] “Cleaning validation protocols should include provisions for: 3) testing for cleaning solution residues” Selected FDA 483 Observations (December 1998) Product Manufacture [VIP ID: 7069] “Cleaning water rinses should be analyzed for the presence of cleaning agent residues.” Selected FDA 483 Observations (December 1998) Sterile Product Manufacture [VIP ID: 7067] “Cleaning validation should include: 1) rinse/swab sample recovery studies” Selected FDA 483 Observations (May 1997) Sterile Product Manufacture [VIP ID: 2525] “Cleaning rinse water samples should be tested for residual drug product.”
•
Check to see that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates. Selected FDA 483 Observations (November 2003) Product Manufacture [VIP ID: 72300] “Cleaning Validation Protocols should include: c. Rinse water testing for the detection of active ingredient residues. (Only conducting USP water tests on rinse samples is not enough).” GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION Sampling Plan For Contaminants [VIP ID: 119300] “…Analysis of rinse solutions for residues has also been shown to be of value where the residue is soluble and / or difficult to access for direct swabbing. Both methods are useful when there is a direct measurement of the residual substance. However, it is unacceptable to test rinse solutions (such as purified water) for conformance to the purity specifications for those solutions, instead of testing directly for the presence of possible residues.”
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GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling b. Rinse Samples (para 3) [VIP ID: 1346] “Check to see that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.”
2.
Rinse water samples should account for the fact that the residue may not be homogeneously distributed through the rinse (possibly the first portion of the rinse contains a different amount than the other portions). PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.11 Establishment of Limits 7.11.4 [VIP ID: 188708] “One cannot ensure that the contaminate will be uniformly distributed throughout the system.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.11. Establishment of Limits 4.11.4. [VIP ID: 69420] “One cannot ensure that the contaminate will be uniformly distributed throughout the system.” Selected FDA 483 Observations (October 1997) Product Manufacture [VIP ID: 2482] “Rinse sampling should account of the fact that the residue may not be homogeneously distributed through the rinse (possibly the first portion of the rinse contains a different amount than the other portions).”
•
It is an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.11 Establishment of Limits 7.11.4 [VIP ID: 188708] “… It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.11. Establishment of Limits 4.11.4. [VIP ID: 69420] “... It is also an invalid conclusion to make the assumption that a residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.”
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GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues a. Placebo Product (para 3) [VIP ID: 1352] “Some firms have made the assumption that a residual contaminant would be worn off the equipment surface uniformly; this is also an invalid conclusion. ...”
3.
The results from the analysis of rinse waters are meaningless unless the following information is known: • the volume of the rinse. • the rinse contact surface area. • the time of contact with surface area. • the temperature of the rinse. Selected FDA 483 Observations (October 1997) Product Manufacture [VIP ID: 2480] “The procedure for the collection of rinse water samples should take into account: 1. 2. 3. 4.
the surface area involved time of contact with surface area volume of rinse temperature of rinse”
Selected FDA 483 Observations (October 1997) Product Manufacture [VIP ID: 2481] “The volume of the rinse must be known if the rinse sample result is to be meaningful.”
6.6 Placebo Cleaning Verification Batches The following points should be considered for companies verifying cleaning using a placebo batch: 1.
One cannot assure that the contaminant will be uniformly distributed throughout the system. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues a. Placebo Product (para 2) [VIP ID: 1351] “One cannot assure that the contaminate will be uniformly distributed throughout the system.”
•
For example, if the discharge valve or chute of a blender are contaminated, the contaminant would most likely be concentrated in the initial discharge portion of the placebo batch. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues a. Placebo Product (para 2) [VIP ID: 1351] “…For example, if the discharge valve or chute of a blender are contaminated, the contaminant would probably not be uniformly dispersed in the placebo; it would most likely be concentrated in the initial discharge portion of the batch.”
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If the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo batch. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues a. Placebo Product (para 2) [VIP ID: 1351] “…Additionally, if the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo.”
3.
The assumption that a residual contaminant would be worn off the equipment surface uniformly is invalid. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues a. Placebo Product (para 3) [VIP ID: 1352] “Some firms have made the assumption that a residual contaminant would be worn off the equipment surface uniformly; this is also an invalid conclusion. ...”
4.
The analytical power may be greatly reduced by dilution of the contaminant in the placebo batch. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues a. Placebo Product (para 3) [VIP ID: 1352] “... Finally, the analytical power may be greatly reduced by dilution of the contaminate. ...”
5.
Swab and/or rinse samples should be used in conjunction with the placebo method. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) VI. Other Issues a. Placebo Product (para 3) [VIP ID: 1352] “… Because of such problems, rinse and / or swab samples should be used in conjunction with the placebo method. [VIP NOTE: This sentence would appear to contradict an earlier stated preference of swabs over rinses. We believe this should have read "…,swab and / or rinse samples…".]”
6.7 Swabs 1.
Swab samples should consider the possible non-uniformity of the residue.
•
If a residue is found, it may not necessarily be at the maximum detectable level due to the random sampling, such as taking a swab from a limited area on a piece of equipment. GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION Equipment Residue Limits (para 2) [VIP ID: 119320] “Because surface residues will not be uniform, it should be recognized that a detected residue level may not represent the maximum amount that may be present. This is particularly true when surface sampling by swabs is performed on equipment.”
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GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (e) Cleaning of Product Contact Surfaces (para 5) [VIP ID: 3446] “Another factor to consider is the possible non-uniformity of the residue. If residue is found, it may not necessarily be at the maximum detectable level due to the random sampling, such as taking a swab from a limited area on that piece of equipment.” BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES C. Analytical Method/Cleaning Limits (para 3) [VIP ID: 1089] “Another factor to consider is the possible non-uniform distribution of the residue on a piece of equipment. The actual average residue concentration may be more than the level detected.”
2.
The results from the analysis of swabs are meaningless unless the swab surface area is known. Selected FDA 483 Observations (November 2000) Product Manufacture [VIP ID: 26190] “Cleaning validation should include: (5) swab areas” Extracted from FDA Warning Letter 320-01-06 (October 2000) India 19/04/2001 [VIP ID: 29310] “4. Cleaning validation studies for multiple use equipment were inadequate in a that the validation protocol did not identify the cleaning procedure, total surface area was not considered during the validation study, recovery studies were not done to validate the swab sampling method or filtering of rinse samples, some rinse samples were not analyzed, dates of analyses were inaccurate, and analytical data on rinse samples were not checked by a second person. [FDA-483 items 9, 10]” Selected FDA 483 Observations (May 2000) Product Manufacture [VIP ID: 16110] “Cleaning validation swab surface area sampling sizes should be clearly defined.”
3.
The same swabbing procedure should be used for cleaning validation and swab recovery studies. Selected FDA 483 Observations (November 2000) Product Manufacture [VIP ID: 26200] “The swabbing procedure used during cleaning validation should be the same as that used for the swab recovery study.”
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6.8 Rinse Water Specifications 1. For parenteral products, final rinse water should meet the specifications of WFI, USP. GUIDANCE FOR INDUSTRY STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING - CURRENT GOOD MANUFACTURING PRACTICE (September 2004) VI. Components and Container/Closures B. Containers/Closures 1. Preparation (para 2) [VIP ID: 110760] “Pre-sterilization preparation of glass containers usually involves a series of wash and rinse cycles. These cycles serve an important role in removing foreign matter. We recommend use of rinse water of high purity so as not to contaminate containers. For parenteral products, final rinse water should meet the specifications of WFI, USP.”
6.9 Analytical Test Method Validation Analytical test method validation protocols should: 1.
demonstrate that the methods used to collect cleaning samples are reliable, and that therefore the results are representative and reproducible. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.10 Analytical Methods 7.10.3 [VIP ID: 188700] “The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.” Selected FDA 483 Observations (May 2002) Laboratories [VIP ID: 46790] “Analytical method used for testing swabs in cleaning validation studies should be shown to have suitable sample preparation, HPLC operating conditions, and / or limits of quantitation and detection prior to use.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.10. Analytical Methods 4.10.3. [VIP ID: 69380] “The analytical methods should be challenged in combination with the sampling methods used, to show that the contaminants can be recovered from the equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.” Selected FDA 483 Observations (September 1997) Product Manufacture [VIP ID: 2498] “Data should be generated to show that the methods used to collect cleaning samples are reliable, and that therefore the results are representative and reproducible.”
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include the determination of the limit of detection and quantitation of the test method for products, product degradents, cleaning agents, drug/cleaning agent reaction products and excipients. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.4 Documentation 7.4.1 [VIP ID: 188662] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: - Analytical methods including the limit of detection and the limit of quantitation of those methods,” Selected FDA 483 Observations (May 2002) Laboratories [VIP ID: 46790] “Analytical method used for testing swabs in cleaning validation studies should be shown to have suitable sample preparation, HPLC operating conditions, and / or limits of quantitation and detection prior to use.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 37. [VIP ID: 21370] “Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.” Selected FDA 483 Observations (July 2001) Product Manufacture [VIP ID: 40380] “Cleaning validation should address the following critical issues: (4) the adequacy of test methods and limit of detection (LOD)/limit of quantization (LQD) of such test methods” Selected FDA 483 Observations (July 2001) Product Manufacture [VIP ID: 40380] “Cleaning validation should address the following critical issues: (3) the adequacy of using rinse samples to evaluate cleanliness of the percent recovery obtained from rinse samples” Selected FDA 483 Observations (November 2000) Product Manufacture [VIP ID: 26190] “Cleaning validation should include: (1) calculation of the limit of detection” Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19680] “Cleaning analytical method validation should include the determination of the limit of detection and quantification.” Selected FDA 483 Observations (September 1999) Product Manufacture [VIP ID: 8310] “Cleaning validation (matrix) studies should address and evaluate: (2) ability of analytical methods to detect potential product degradents, drug/cleaning agent reaction products and excipients”
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EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.4. Documentation 4.4.1. (k) [VIP ID: 69130] “A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: (k) analytical methods including the limit of detection and the limit of quantitation of those methods,” Selected FDA 483 Observations (September 1988) Product Manufacture [VIP ID: 6800] “Limits of detection and quantitation should be established for the residual solvent analytical method.” Selected FDA 483 Observations (February 1998) Product Manufacture [VIP ID: 6329] “Cleaning validation protocols should include: 2) limits of detection” Selected FDA 483 Observations (February 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6317] “Minimum detectable chemical residue levels should be determined for products and cleaning agents.” Selected FDA 483 Observations (April 1997) Product Manufacture [VIP ID: 2538] “Cleaning validation should include the determination of the limit of detection of the test method.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits (para 1) [VIP ID: 1348] “…It is important to define the sensitivity of the analytical methods in order to set reasonable limits.”
•
Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. Selected FDA 483 Observations (August 2007) Laboratories [VIP ID: 193978] “The specificity of test methods should be documented. For example, instructions for the identification and quantification of peaks when using integrators should be provided, and integrated peaks in the swab samples taken during cleaning validation runs eluting close to the retention time of the standard peak should be identified or quantified during the validation exercise.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 3. Analytical Methods [VIP ID: 1340] “Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample.”
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include accuracy, precision, specificity and linearity. Selected FDA 483 Observations (October 2007) Laboratories [VIP ID: 194168] “A laboratory should establish scientifically sound rationale for cleaning analytical methods, which show linearity ranges that do not correspond to the acceptance criteria for active ingredient residues.” Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19870] “Cleaning validation of processing equipment should include: b) analytical method validation to include accuracy, precision, specificity, linearity etc.”
4.
include the evaluation of the method against more sensitive test methods where available (e.g. HPLC), to ensure adequate specificity and sensitivity of impurity detection. Selected FDA 483 Observations (April 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6372] “Cleaning validation analytical methods should be evaluated against more sensitive test methods where available (e.g. HPLC), to ensure adequate specificity and sensitivity of impurity detection.”
5.
include recovery studies that require the application of an active to a coupon or template which replicates the equipment surface. Extracted from FDA warning letter 07-NWJ-06 (February 2007) USA 01-Feb-07 7. b) [VIP ID: 194844] “Your firm's cleaning validation studies were found to be inadequate and, as a result, there was no assurance that equipment is adequately cleaned between the manufacture of different drug products. [21 CFR 211.67(b)] For example: b) Recovery studies were performed for numerous drug products by applying a known amount of active pharmaceutical ingredient directly to a swab, instead of applying the active to a coupon or template which would replicate the equipment surface from which the active pharmaceutical ingredient should have been swabbed. The products involved, included: Busipirone HCl Tablets, Hydrocodone Bitartrate and Homatropine Methylbromide Tablets, Mirtazapine Tablets, Oxycodone and Acetaminophen Capsules USP.”
6.
include a challenge to the sampling method (i.e. swabbing) to show that the recoveries can be obtained at the specified limits. Selected FDA 483 Observations (January 2003) Product Manufacture [VIP ID: 51890] “Cleaning validation should include a challenge to the sampling method (i.e. swabbing) to show that the recoveries can be obtained at the specified limits.”
7.
include percent recovery studies on rinse/swab samples. Selected FDA 483 Observations (August 2004) Product Manufacture [VIP ID: 123660] “Cleaning procedures for Vacuum Blenders should be validated to include: a. a percent recovery study for the rinse water sampling method.”
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Selected FDA 483 Observations (April 2002) Sterile Product Manufacture [VIP ID: 46670] “Recovery studies should be performed to qualify the swab method and material utilized for swabbing product contact surfaces at the conclusion of an aseptic fill.” Selected FDA 483 Observations (March 2002) Product Manufacture [VIP ID: 46580] “Cleaning validations should include recovery study data.” Selected FDA 483 Observations (January 2002) Product Manufacture [VIP ID: 46280] “Cleaning validation should include: (a) Recovery studies for the swab sampling method used.” Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40940] “Cleaning validation should include recovery studies.” Selected FDA 483 Observations (July 2001) Product Manufacture [VIP ID: 40380] “Cleaning validation should address the following critical issues: (3) the adequacy of using rinse samples to evaluate cleanliness of the percent recovery obtained from rinse samples” Selected FDA 483 Observations (April 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 27440] “API Cleaning validation should include: (2) Residue recovery data showing the efficiency of removal of target residues (including APIs) from equipment contact surfaces.” Selected FDA 483 Observations (January 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26540] “Cleaning validation should include tests to demonstrate the swabbed residues can be extracted from the cotton balls used for swabbing.” Extracted from FDA Warning Letter 320-01-06 (December 2000) India 19/04/2001 [VIP ID: 29310] “4. Cleaning validation studies for multiple use equipment were inadequate in a that the validation protocol did not identify the cleaning procedure, total surface area was not considered during the validation study, recovery studies were not done to validate the swab sampling method or filtering of rinse samples, some rinse samples were not analyzed, dates of analyses were inaccurate, and analytical data on rinse samples were not checked by a second person. [FDA-483 items 9, 10]” Selected FDA 483 Observations (September 2000) Product Manufacture [VIP ID: 19870] “Cleaning validation of processing equipment should include: a) percent recovery studies for swabbing methods”
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Selected FDA 483 Observations (May 2000) Product Manufacture [VIP ID: 16120] “Cleaning validation should include swab recovery studies for products and detergents.” Selected FDA 483 Observations (November 1999) Product Manufacture [VIP ID: 8830] “Cleaning validation should include: 1) percentage recovery” Selected FDA 483 Observations (December 1998) Sterile Product Manufacture [VIP ID: 7067] “Cleaning validation should include: 1) rinse/swab sample recovery studies” Selected FDA 483 Observations (August 1998) Product Manufacture [VIP ID: 6796] “Cleaning validation should include recovery studies.” Selected FDA 483 Observations (September 1997) Product Manufacture [VIP ID: 2497] “Equipment cleaning validation should include: (2) Percent recovery studies on rinse samples”
•
The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 3. Analytical Methods [VIP ID: 1340] “…The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results.”
•
The worst case result should be used to calculate a swab recovery factor for cleaning validation, to ensure that the actual contamination is not higher than calculated. Selected FDA 483 Observations (October 1997) Product Manufacture [VIP ID: 2483] “The worst case result should be used to calculate a swab recover factor for cleaning validation, to ensure that the actual contamination is not higher than calculated.”
8.
include an assessment of the variability between swabs (applicator tips) Selected FDA 483 Observations (April 2000) Laboratories [VIP ID: 15360] “Cleaning validation of cleaning agents (detergents) should include: (6) assessment of the variability between swabs (applicator tips)”
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include the determination of the type of sampling materials used (the sampling medium and solvent used for extraction from the medium) and its impact on the test data. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling a. Direct Surface Sampling (para 1) [VIP ID: 1342] “Determine the type of sampling material used and its impact on the test data since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.”
•
For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Selected FDA 483 Observations (January 2002) Product Manufacture [VIP ID: 46280] “Cleaning validation should include: (b) Assurance that the type of swab used does not contribute interference to the analytical method.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) IV. Evaluation of Cleaning Validation 4. Sampling a. Direct Surface Sampling (para 1) [VIP ID: 1342] “…For example, the adhesive used in swabs has been found to interfere with the analysis of samples.”
10. include raw data regarding standard and sample preparations, equipment used, reference standards used etc. Selected FDA 483 Observations (September 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40950] “Cleaning validation studies should include raw data regarding standard and sample preparations, equipment used, reference standards used etc.”
11. include testing to determine the types of residues obtained from the detergent(s) used. Selected FDA 483 Observations (July 2000) Product Manufacture [VIP ID: 19300] “Cleaning validation should include testing to determine the types of residues obtained from the detergent(s) used.”
12. include all surfaces the disinfectant is used on (such as glass, plastic and epoxy painted surfaces), not just stainless steel. Selected FDA 483 Observations (March 2003) Product Manufacture [VIP ID: 52180] “The qualification of disinfecting agents used to sanitize surfaces in aseptic processing areas (APA) should address all surfaces in the area not just stainless steel (such as glass, plastic and epoxy painted surfaces).” Selected FDA 483 Observations (April 2002) Product Manufacture [VIP ID: 46680] “Disinfectant qualification should include all surfaces the disinfectant is used on, not just stainless steel.”
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13. include the determination of the solubility of product and excipient residues in the rinse solvent. Selected FDA 483 Observations (August 2004) Product Manufacture [VIP ID: 123660] “Cleaning procedures for Vacuum Blenders should be validated to include: b. a solubility study to determine which products are hardest to clean” Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470] “API Cleaning Validation protocols should include: a. an evaluation of product solubility.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 13 - MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS (July 2003) PREMISES AND EQUIPMENT 5 [VIP ID: 64250] “…Account should be taken of the solubility of the product in decisions about the choice of cleaning solvent.” Selected FDA 483 Observations (June 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 40130] “Water / solvent solubility should be known for all products listed in a cleaning validation decision matrix.” Selected FDA 483 Observations (August 1998) Active Pharmaceutical Ingredient Manufacture [VIP ID: 6766] “BPC cleaning validation should include: 5) determination of the solubility of the residues in the rinse solvent”
14. include the following for production Spectrophotometers used to determine the contaminant concentration in rinse samples: • assurance that passing test results are within the limits of detection. • justification for the use of sample blanks. • assurance that reported sample test results are accurate. • written procedures for testing rinse samples using blank standards. • information or data on negative absorbance test results.” Selected FDA 483 Observations (September 2003) Laboratories [VIP ID: 70180] “Method validation for production Spectrophotometers used to determine the contaminant concentration in rinse samples to assure effectiveness of manual cleaning processes between production runs should include: -
assurance that passing test results are within the limits of detection. justification for the use of sample blanks. assurance that reported sample test results are accurate. written procedures for testing rinse samples using blank standards. information or data on negative absorbance test results.”
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15. challenge the ruggedness of the method by using different laboratories, analysts, days and equipment. Selected FDA 483 Observations (October 1999) Laboratories [VIP ID: 136760] “The validation of analytical methods used to evaluate the effectiveness of equipment cleaning procedures should challenge the ruggedness of the method by using different laboratories, analysts, days and equipment.”
6.10 Establishment of Limits The following points should be considered when establishing the cleaning validation acceptance limits: 1.
Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?". The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion. BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES C. Analytical Method/Cleaning Limits (para 1) [VIP ID: 1087] “Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?" The sensitivity of modern analytical apparatus has lowered some detection thresholds below parts per million (ppm), down to parts per billion (ppb).” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (e) Cleaning of Product Contact Surfaces (para 3) [VIP ID: 3444] “Specific inspectional coverage for cleaning should include: 3. Analytical Method/Cleaning Limits: Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?". The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.”
2.
FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries. GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits (para 1) [VIP ID: 1348] “FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries.”
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The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable. PI 006-2 RECOMMENDATIONS ON VALIDATION MASTER PLAN INSTALLATION AND OPERATIONAL QUALIFICATION NONSTERILE PROCESS VALIDATION CLEANING VALIDATION (July 2004) 7. CLEANING VALIDATION 7.11 Establishment of Limits 7.11.1 [VIP ID: 188702] “The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - QUALIFICATION AND VALIDATION (September 2001) CLEANING VALIDATION 36. [VIP ID: 21360] “…The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable.” Selected FDA 483 Observations (December 1999) Active Pharmaceutical Ingredient Manufacture [VIP ID: 14010] “API cleaning validation protocols should state the acceptable limits for the amount of active ingredient or other chemicals remaining after cleaning.” EU GUIDE TO GOOD MANUFACTURING PRACTICE: ANNEX 15 - VALIDATION MASTER PLAN DESIGN QUALIFICATION, INSTALLATION AND OPERATIONAL QUALIFICATION, NON-STERILE PROCESS VALIDATION, CLEANING VALIDATION - SUPERSEDED! (October 1999) 4. Cleaning Validation 4.11. Establishment of Limits 4.11.1. [VIP ID: 69390] “The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.” GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS (July 1994) V. CLEANING VALIDATION Equipment Residue Limits (para 1) [VIP ID: 119310] “Because of improved technology, analytical methods are becoming much more sensitive and capable of determining very low levels of residues. Thus, it is important that a firm establish appropriate limits on levels of post-equipment cleaning residues. Such limits must be safe, practical, achievable, verifiable and must ensure that residues remaining in the equipment will not cause the quality of subsequent batches to be altered beyond established product specifications. During inspections, the rationale for residue limits should be reviewed.” GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS (May 1994) PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS Equipment (e) Cleaning of Product Contact Surfaces (para 4) [VIP ID: 3445] “The residue limits established for each piece of apparatus should be practical, achievable, and verifiable. When reviewing these limits, ascertain the rationale for establishment at that level.” GUIDE TO INSPECTIONS OF VALIDATION OF CLEANING PROCESSES (July 1993) V. Establishment of Limits (para 1) [VIP ID: 1348] “…The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable.”
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Date:
: 25 May 2007
BIOTECHNOLOGY INSPECTION GUIDE (November 1991) CLEANING PROCEDURES C. Analytical Method/Cleaning Limits (para 2) [VIP ID: 1088] “The residue limits established for each piece of apparatus should be practical, achievable, and verifiable.”
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The manufacturer should be able to document, by means of data, that the residual level permitted is scientifically sound. Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470] “API Cleaning Validation protocols should include: d. data for the maximum allowable limit not to exceed.” Selected FDA 483 Observations (May 2004) Active Pharmaceutical Ingredient Manufacture [VIP ID: 122470] “API Cleaning Validation protocols should include: b. justification for the acceptance criteria.” Selected FDA 483 Observations (April 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 27440] “API Cleaning validation should include: (1) Approved specifications for acceptable residue limits based on a scientific rationale such as safety.” Selected FDA 483 Observations (January 2001) Active Pharmaceutical Ingredient Manufacture [VIP ID: 26560] “Cleaning residue limits should be supported by a scientific rationale backed up by research.” Selected FDA 483 Observations (May 2000) Active Pharmaceutical Ingredient Manufacture [VIP ID: 16020] “There should be a scientific justification for the specification for residuals stated in the cleaning validation (simply stating
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