Cleaning Guide Sample

© Validation in Partnership Ltd. 2007

GUIDANCE DOCUMENT REFERENCE VERSION

CLEANING PROCESSES AND CLEANING VALIDATION

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SGD-105-CLN Rev. 09

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12 March 2007

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Author: Title:

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Regulatory Consultant

Validation in Partnership Ltd.

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DOCUMENT HISTORY Revision No.

Date:

01

September 2000

02

August 2001

03

February 2002

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October 2002

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November 2003

06

December 2004

07

January 2005

08

February 2006

09

March 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

•

Skilled and Vetted Contract Personnel

•

CGMP Compliance Reviews/Audits

•

Gap Analysis and Remedial Action Plans

•

Complete Site Validation Packages

•

Validation Policies

•

Validation Plans and Master Plans

•

DQ, IQ, OQ, PQ

•

Computer Systems Validation

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Process Validation

•

Cleaning Validation

•

CGMP Compliance Training

•

SOPs

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Complete CGMP Compliance Assistance

… and whatever your industry sector … •

Finished Pharmaceuticals

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Biotechnology

•

Active Pharmaceutical Ingredients

•

Veterinary Products

•

Medical Devices

•

Cosmetics

•

Equipment Manufacture

•

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.”

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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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