Fundamental Cleaning Principles

Cleaning Validation Principles: Developing, Deploying and Maintaining Your Cleaning Validation Program Cleaning Validation

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Cleaning Validation Principles • ISPE Welcome and Opening Remarks • Course Leader Introduction • Housekeeping • • • • •

Breaks Lunch Emergency Egress ISPE Membership Evaluations

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• Rules of the Road • Overview of Notebooks • Glossary / Acronyms • Index to Materials

Cleaning Validation

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Cleaning Validation Principles Table of Contents Section 1 2 3 4 5 6 7 8 9 10 11

Description Regulatory Requirements for Cleaning Validation Fundamentals of Cleaning Validation Cleaning Validation Master Plans Equipment Characterization SOP Development for Cleaning Selecting Residues, then Developing and Maintaining Limits Methods Validation and Recovery Studies Engineering Studies and Cycle Development Cleaning Validation Protocols Field Execution -- Collecting and Testing Samples Cleaning Validation Reports and Beyond! Cleaning Validation

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Cleaning Validation Principles Learning Objectives • Creation of scientifically sound rationales, rationales validation protocols and reports • Identification and characterization of potential residues including product, processing aids, cleaning agents and adventitious agents • Selection of appropriate analytical methodology for your selected residues • Determination of suitable sampling techniques and the selection of sampling locations that represent challenging locations for your cleaning process • Calculation of residue limits that meet all necessary regulatory requirements

Cleaning Validation

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Cleaning Validation Principles Job-Focused Skills • Learning to manage the challenges of limits limits, validation strategies and maintaining the validated state in: • Multi-product facilities • Campaign-based production environments

• Differentiating the requirements for cleaning validation lid ti ffor: • Manual • Semi-automatic • Automatic cleaning Cleaning Validation

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Cleaning Validation Principles Job-Focused Skills, cont. • Determining scientific grouping or bracketing approaches • Comprehending common cleaning validation pitfalls • Accomplishing analytical method validation and recovery study requirements in cost-effective studies • Evaluating your cleaning practices through internal selfaudits • Practicing what you have learned through hands-on exercises

Cleaning Validation

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Class Introductions • • • • • •

Name Department Company Types of Products Your Company Produces Status of Your Cleaning Validation Efforts What Topics / Questions You Came to Learn About

• This course is designed to address the concerns for all pharmaceutical dosage forms forms, including the production of APIs • The principles are broadly applicable to IVD and consumer products, as well • If you have a question for your industry, please ASK!!

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Module 1 Regulatory R Requirements i t for f Cleaning Validation: “Limit”ing the Risk Cleaning Validation

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FDA Regulatory Timeline (Relatively Speaking) 1997 – HACCP Adopted for Food Industry 1992/3 – MidAtlantic Cleaning Validation Inspection 1986 – Process Validation Guidance Guide Finalized as National Document

1978 – Last significant Update to Finished Pharmaceutical CGMPs

1992 – First E-Rec Rule Draft – Not Finalized Until 1996 (P11)

1997 – Quality System Inspection Technique Techniq e (QSIT) for Devices 1996 – 2001 SUPAC Drafted

Aseptic Processing Bulk Pharmaceutical Chemical Solid Dosage Form Semi-Solid Dosage Form Biotechnology Laboratories (QC and Micro)

2001 – Drug Inspection Program (6 Subsystems of Quality) Piloted Finalized in 2002 1998 – API Draft Guidance Issued

1996 – Quality System Regulation Issued for Devices

1991 – 1993 Inspection Guides Issued • • • • • •

2002 – 2004 Ri k B Risk-Based d Inspection Approach Identified & Rolled Out

1996 – Proposed Revision to GMPs

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Significant Sources of Regulation on Cleaning and Cleaning Validation • Worldwide GMPs, (Especially EU Annex 15 (¶ 36) (2006) & GMP Part II (formerly Appendix 18) (2005)

• US FDA, Guide to Inspections of Validation of Cleaning Processes (1993) • Pharmaceutical Inspection Convention (PIC), Recommendations on…Cleaning Validation (2001) g Validation Guidelines • Canadian HPFB,, Cleaning (2001) • WHO Supplementary Guidelines on GMP: Validation (2005)

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Worldwide cGMPs Design and construction features and Equipment design, size, and location

21 CFR 211.42 21 CFR 211.63

EU 3.1 – 3.25 EU 3.34 – 3.44

Any building or equipment used in the manufacture, processing, packing, or holding of a drug product shall be of: • Suitable size

• All surfaces can be readily contacted by cleaning process; accessed for inspection

• Suitable construction

• Coved corners, free-draining, non-reactive, non-additive, non-absorptive materials of construction

• Suitable location

• Location appropriate to cleaning utilities / supplies; away from walls or other interfering surfaces

to facilitate cleaning, maintenance, and proper operations. Cleaning Validation 11

Worldwide cGMPs (continued) Sanitation Equipment cleaning and maintenance

21 CFR 211.56 21 CFR 211.67

EU 4.26 EU 4.28

• Written procedures for cleaning and for use of cleaning and sanitizing agents shall be followed and shall: • Assign responsibility for sanitation • Describe in sufficient detail: • • • •

Schedules Methods Equipment Materials to be Used

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.

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Worldwide cGMPs (continued) Equipment cleaning and maintenance

21 CFR 211.56 21 CFR 211.67

EU 4.26 EU 4.28

More specifics with regard to the procedures to be established: As before

• Responsibilities, Schedules, Methods, Equipment, Materials • Methods of Disassembling and Reassembling to ensure proper cleaning and maintenance • Removal or obliteration of previous batch identification • Protection of clean equipment from contamination prior to use • Inspection of equipment for cleanliness immediately before use • Records shall be kept of maintenance, cleaning, sanitizing, and inspection Cleaning & Use Log Record retention

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Worldwide cGMPs (continued) Equipment cleaning and use log

21 CFR 211.182

EU 4.28 – 4.29

A written record of major equipment cleaning, maintenance and use showing, for each batch processed: • Date • Time • Product • Lot number • Signature and date of person(s) performing • Signature and date of person(s) double-checking For dedicated equipment, the records of cleaning, maintenance, and use shall be part of the sequentially numbered batch record (if no separate log is kept). Cleaning Validation 14

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European Requirements – EC Guide to GMP Overall, wording and content nearly identical to various US requirements Pertinent Sections: Section 3: Premises and Equipment (3.34 – 3.44 equipment design for cleanability)

Section 5: Production (5.19 cross-contamination; 5.21 – 5.24 Validat. & Change Ctrl)

Annex 2: Manufacture of Biologicals (15, 17 – design to promote cleanability)

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European Requirements – EC Guide to GMP Overall, wording and content nearly identical to various US requirements Pertinent Sections: Annex 15: Qualification and Validation (36 – 42 – Cleaning Validation; 45 - Revalidation) – see next

GMP Part II: GMP for APIs (5.2 – Equipment Maintenance and Cleaning; 6 2 – Equipment Cleaning and Use Record; 6.2 12.7 – Cleaning Validation) – aligns with ICH Q7A

Cleaning Validation

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Definition of Cleaning Validation • Documented evidence to ensure that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration batch size, dosing, toxicology, equipment size, etc. - World Health Organization

• Note that this definition immediately employs “risk-based” language Cleaning Validation 17

Cleaning Validation – Sections 36 – 42 of EU Annex 15 on Qualification and Validation g validation should confirm effectiveness • Cleaning of cleaning procedures; rationales should be logical for: • Limits for carry-over of drug product residue, cleaning agents and microbial contamination • Should be based on material to be cleaned

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Cleaning Validation – Sections 36 – 42 of EU Annex 15 on Qualification and Validation • Sufficiently sensitive validated analytical methods should be employed • Product contact surfaces only for validation; although non-product contact parts should be considered • Intervals should be validated for: • Time between use and cleaning • Time between cleaning and reuse

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Cleaning Validation – Sections 36 – 42 of EU Annex 15 on Qualification and Validation • Worst-case approaches for similar materials / processes may be employed • Typically three consecutive trials should be performed • “Test Until Clean” is not an appropriate substitute for validation

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Cleaning Validation – Sections 36 – 42 of EU Annex 15 on Qualification and Validation • Products which simulate the physiochemical properties of the residues may be used where those materials are either toxic or hazardous Revalidation - Section 45 of EU Annex 15 • Facilities, systems, equipment and processes, including g cleaning, g, should be p periodically y evaluated to confirm that they remain valid; a review with evidence may suffice if no significant changes were made Cleaning Validation 21

Guide to Inspections of Validation of Cleaning Processes (1993) SOP Requirements • For F each h major j piece i off equipment: i • Between batches of same product • Between batches of different products

Dedicate where equipment is difficult to clean or hazardous

• For cleaning validation process, requiring: • Cleaning validation protocols • S Sampling li procedures d • Analytical methods • Limits (“acceptable level”)

• Final Report • Approval by management Cleaning Validation 22

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Guide to Inspections of Validation of Cleaning Processes (1993) (continued) Evaluation of Cleaning Process • Examine objectives of the validation process, written procedure and documentation At what point does a piece of equipment or system become clean? • Examine training and level of Does it have to be scrubbed by experience of the cleaning operators hand? What is accomplished by hand • Examine allowed length of time scrubbing? How variable are manual cleaning between the end of processing and processes from batch to batch and each cleaning step and its potential product to product? effect on the cleaning process • Examine a e steps taken ta e to p prevent e e t microbiological c ob o og ca contamination co ta at o

IQ / OQ Elements to Consider • Examine equipment design especially when using CIP • Assure proper identification of process equipment to ensure correct implementation of cleaning procedures

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Guide to Inspections of Validation of Cleaning Processes (1993) (continued) Scientific Design of Analysis • D Determine t i th the specificity ifi it and d sensitivity iti it off th the analytical method(s) used to detect residuals or contaminants • Testing of rinse solutions should include testing for residues or contaminants rather than for water quality

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Guide to Inspections of Validation of Cleaning Processes (1993) (continued) Scientific Design of Analysis • Challenge analytical methods in combination with the sampling method(s) to show recovery • Sampling techniques include direct surface sampling and sampling of rinse solutions. • “Test until clean” systems should not be used. The

need d ffor retesting t ti may indicate i di t th thatt the th cleaning l i process is not validated.

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Guide to Inspections of Validation of Cleaning Processes (1993) (continued) Scientific Limits Determination • FDA does not intend to set limits • Determine how the firm established their residue limits: • Sensitivity of analytical methods is critical to establish valid limits • Logical, practical, achievable and verifiable • Scientifically justifiable

• Three examples given: 10ppm, biological activity levels as 1/1000 off normall therapeutic th ti dose d and d organoleptic l ti levels • Cleaning Agents - “...no or very low detergent levels UhOh! Don’t use words such as “absence, no or none” remain after cleaning...” when creating your procedures or rationales!! Cleaning Validation 26

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Guide to Inspections of Validation of Cleaning Processes (1993) (continued) Other Important Statements: • Microbiological aspects of equipment cleaning should be considered; there should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation; equipment should be dried before storage • “When variable residue levels are detected following cleaning, one must establish the effectiveness of the process and operator performance.” • “Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. … Any indirect test method must have been shown to correlate with the condition of the equipment.” Cleaning Validation 27

Guide to Inspections of Validation of Cleaning Processes (1993) (continued) Other Important Statements: • “There 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.” • “Rinse and/or swab samples should be used in conjunction with the placebo method” (when it is justified for use) • “The firm should challenge the analytical method in combination bi ti with ith th the sampling li method(s) th d( ) used d tto show h th thatt contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc.” Does not mean that these values presented here are “acceptance criteria” for recovery.

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Guide to Inspections of Validation of Cleaning Processes (1993) (continued) Other Important Statements: • “In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove…. the issue of byproducts needs to be considered if equipment is not dedicated.” • “When cleaning is between batches of the same product (or different lots of the same intermediate in a bulk process) the fi need firm d only l meett a criteria it i of, f "visibly " i ibl clean" l " for f the th equipment. Such between batch cleaning processes do not require validation.” Not scientifically justifiable!! Does not consider by-products, cleaning agent, micro, the area in which the equipment is cleaned / stored, etc.

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PIC/S, Canadian and WHO Guidance on Limits Limits shall be logical, practical, achievable, verifiable; for example, the most stringent of the following first three criteria: • No more than 0.1% (1/1000th) of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product • No more than 10 ppm of any product will appear in another product • No visible residue on the equipment after cleaning procedures are performed * * Based on spiking studies that show the visible level • Also, for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods (or may require dedication)

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US - May 1996 Proposed Revision to cGMPs Being Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation • (a) The manufacturer shall validate all drug product manufacturing processes including, but not limited to, computerized systems that monitor and/or control the manufacturing process. • The manufacturing process includes all manufacturing steps in the creation of the finished product including, but not limited to, to the following procedures: Cleaning, Cleaning weighing, measuring, mixing, blending, compressing, filling, packaging, and labeling. Cleaning is not only considered a step in the manufacturing process, but it is the FIRST step in getting ready for the next process.

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US - May 1996 Proposed Revision to cGMPs Being Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation (continued) • (b) Validation protocols that identify the product and product specifications ifi ti and d specify if th the procedures d and d acceptance t criteria it i for the tests to be conducted and the data to be collected during process validation shall be developed and approved. • The protocol shall specify a sufficient number of replicate process runs to demonstrate reproducibility of the process and provide an accurate measure of variability among successive runs

Number of runs to be justified. Rule of three typically applies. Th Three may b be th the minimum!! i i !!

• Validation documentation shall include evidence of the suitability of materials and the performance and reliability of equipment and systems. The manufacturer shall document execution of the protocol and test results. Cleaning Validation 32

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US - May 1996 Proposed Revision to cGMPs Being Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation (continued) • ((c)) The manufacturer shall design g or select equipment q p and processes to ensure that product specifications are consistently achieved. • The manufacturer's determination of equipment suitability shall include testing to verify that the equipment is capable of operating satisfactorily within the operating limits required by the process. • Parts of the process that may cause variability or otherwise affect product q p quality y shall be tested. Considerations for worst-cases in cleaning validation include: • Maximum hold times • Maximum residue loads • Minimum process parameters during validation

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US - May 1996 Proposed Revision to cGMPs Being Revised as Part of Risk-Based GMPs ¶ 211.220 Process validation (continued) • ((d)) There shall be a quality q y assurance system y in p place which requires q revalidation whenever there are changes in packaging, component characteristics, formulation, equipment, or processes, including reprocessing, that could affect product effectiveness or product characteristics, and whenever changes are observed in product characteristics. Change control considerations include: • Cleaning agents • Cleaning process parameters • Cleaning procedures • Training procedures • Formulation • Equipment • Environments / storage locations for clean equipment • Introduction of a new product (as it might affect the limit for an existing product – see limits section)

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Module 2: Fundamentals of Cleaning Validation: Emphasis on Fun!

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First, Some Definitions Cleaning Validation • Documented evidence that provides a high degree of assurance that a cleaning process can reproducibly produce a clean piece of equipment in accordance with the designated specifications • Generally cleaning validation applies the “rule of three” for the number of validation trials to be three completed

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First, Some Definitions Verification • documented evidence that provides a high degree of assurance that a single cleaning event can produce a clean piece of equipment in accordance with the designated specifications, suitable for the next use • Generally verification is used for development batches where three may not be made or for infrequently manufactured products; when three runs have been completed they may be summarized as a validation if all conditions used in the three studies were the same Cleaning Validation 37

First, Some Definitions • Certification – depending on the firm, certification often has the same meaning as verification; some companies diff differentiate ti t certification tifi ti as an expected t d process that th t will ill occur after each production event as a change over process, for example • Monitoring – a routine evaluation of cleaning to determine whether the original cleaning validation conditions are still being achieved; may involve fewer samples or less invasive p g techniques q sampling • Engineering Trials – experimental cleaning trials that help to evaluate whether a cleaning process for a new / revised product or process will be effective; still requires validated test methods and sampling procedures Cleaning Validation 38

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Fundamentals of Cleaning Cleaning depends upon process control… T ime A ction C oncentration / Chemistry T emperature Cleaning also depends upon the conditions of cleaning cleaning… W ater I ndividual Performing Cleaning N ature of Soil S urface Being Cleaned

T.A.C.T. W.I.N.S. Example

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Influences on Cleaning Product Type Manufacturing Process Hold Times Campaign Length

Equipment Type – Major, Minor, Dedicated, Non-Dedicated R l in Role i the th Process P – Upstream, U t Downstream Materials of Construction Surface Finish Geometry / Complexity

Surface

Soil

Chemistry

Water Quality Time Action / Type of Cleaning – Manual (Individual), CIP, COP Concentration Temperature

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Equipment Categories Major Equipment equipment i t critical iti l tto th the manufacturing process (usually has a unique identification number)

Minor Equipment apparatus and utensils (such as scoops, hoses, beakers) which perform a support function

Attributes of Each Category • Generally large and significant contributor to overall contamination • May be dedicated

• Generally small but may be g y concentrated used for highly materials • May or may not be dedicated

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Equipment Categories Major Equipment equipment i t critical iti l tto th the manufacturing process (usually has a unique identification number)

Minor Equipment apparatus and utensils (such as scoops, hoses, beakers) which perform a support function

Consequences of Each Category • Significant S f contamination contributor; position / role in process will be highly critical • Generally easy to track for cleaning status • Generally not a significant contributor but we can contributor, can’tt leave them out of our program • Difficulties arise in tracking of small parts through the cleaning process

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Equipment Categories Dedicated Equipment q p equipment which is used for the manufacture of one product only

Non-Dedicated Equipment equipment i t commonly l used d ffor several products or processes

Attributes of Each Category • Lower risk of crosscontamination

presents • Multi-use nature p significant crosscontamination concerns

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Equipment Categories Consequences of Each Category

Dedicated Equipment equipment which is used for the manufacture of one product only

• Potentially higher risk of degradant and impurity build-up, especially if campaigned

Non-Dedicated Equipment -

• Validation will be required f each for h product d t (or ( representative from a grouping / bracketing) • May also be at risk for degradants and impurities if campaigning is observed

equipment commonly used for several products or processes Remember the precautions stated earlier for the Guide to Inspection of Cleaning Validation Processes with regard to the pitfalls in not validating the cleaning of dedicated equipment.

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Types of Cleaning Attributes of Each Type

Manual Cleaning - scrub brushes and high pressure hoses used by an operator t to t remove product d t residue

Automated Cleaning (e.g., CIP – (Clean-In-Place) - cleaning performed by a control system or microprocessor which automatically controls functions of wash, rinse and dry Semi-Automated Cleaning (e.g., (e g COP – Clean-Out-of-Place) cleaning performed in a parts washer or sink; often requires manual intervention or disassembly; may be automated

•

Adaptable to varying soil loads

•

Highly dependent upon training

•

Reproducible if equipment is qualified for use

•

Will not recognize variability in the incoming soil condition

•

Often combines strengths and weakness of the above

•

May depend upon accurate load placement / disassembly for proper cleaning

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Types of Cleaning Manual Cleaning - scrub brushes and high pressure hoses used by an operator to remove product residue

Automated Cleaning (e.g., CIP – (Clean-In-Place) - cleaning performed by a control system or microprocessor which automatically controls functions of wash, rinse and dry

Semi Automated Cleaning (e.g., Semi-Automated (e g COP – Clean-Out-of-Place) cleaning performed in a parts washer or sink; often requires manual intervention or disassembly; may be automated

Consequences of Each Type •

Lack of inherent reproducibility may require extensive monitoring over time

•

Detailed procedures a must!

•

Need to ensure that cleaning validation considers the worstcase soil loads or that production can adequately identify outliers for study in the future

•

Detailed procedures and load maps are typically required

•

May require monitoring as with manual above

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Position / Role in Process Attributes of Each Position

Upstream – equipment i t early l in i the th manufacturing process, for example primary reactors, initial culture, initial blending

Downstream – equipment used later in the manufacturing or finishing process including such process steps as final crystallization, purification or viral reduction, filling equipment or tableting equipment

•

Ma ha May have e unreacted nreacted starting materials present on equipment

•

In-process materials may still be “crude” in that they have not yet undergone purification

•

Residues are less likely to be homogeneously distributed throughout the batch as often there is limited mixing after the upstream processes

•

Product is often purified

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Position / Role in Process Consequences of Each Position

Upstream – equipment early in the manufacturing f t i process, for f example l primary reactors, initial culture, initial blending

•

Additional residues may need to be considered for cleaning validation

•

Sampling sites will have to be selected highly critically to ensure that nonhomogeneous distribution of residues does not adversely affect portions of batch

•

Limits may need to be more conservative to accommodate the critical nature of many sampling sites

•

Be careful that purification processes don’t concentrate contaminants

Downstream – equipment used later in the manufacturing or finishing process including such process steps as final crystallization, purification or viral reduction, filling equipment or tableting equipment

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Precautions with Purification Processes • Purification processes are generally intended to remove process-related impurities only • Don’t falsely assume that residues from prior cleaning operations will be successfully removed by purification without validation

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Precautions with Purification Processes • Remember that cleaning validation affects the next product to be produced – don don’tt assume that the residues from a prior process will be compatible with the next product or purification process If part of your rationale intends to use the purification process as part of your basis for residue or limits selection, remember that FDA stated in Human CGMP Notes that impurities are intended to come from the starting materials or the manufacturing process itself and not from elements left over from the cleaning process Cleaning Validation 51

Module 3: Cleaning Validation Master Pl Plans: It is i Always Al Good to Have a Plan Cleaning Validation 52

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Transformation of Data – Knowledge Management Source: The Certified Quality Manager Handbook, 2nd Ed., ASQ

Wisdom

Wisdom is derived from the collective database of knowledge, built from experience and values, by being able to see the connectivity among seemingly disparate knowledge sets enabling deductive solutions. solutions

Knowledge

Knowledge is built through the correlation and integration of information with policies, procedures and regulations.

Information

Information has meaning, but the meaning is based on the interpretation of the user of the information. Data is meaningless unless something is done with it.

Data

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Transformation of Data – For Cleaning Validation You will achieve wisdom when you understand whether or not your policies, procedures and master plans adequately support the complexity of your plant! Often in-depth in depth analysis such as risk and impact assessments are necessary to become truly enlightened! Establish policies, procedures and master plans that integrate the information collected about your plant. Relate the various forms of data to understand the equipment, cleaning process and product residue interactions.

Collect information about your equipment, products and processes.

Wisdom

Knowledge

Information

Data

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So What Data Need to Be Collected? Data Required

Required For …

Formulation Attributes (i.e., dosage, toxicity, concentration, excipients, degradants, impurities)

• • • • •

Equipment Characteristics (i.e., materials of construction, geometry, surface area, cleaning procedure, cleaning agent, disassembly requirements)

• • • •

Analytical y method selection Sampling method selection Limits determination Worst-case determination (if grouping / bracketing) Segregation requirements (if hazardous)

Materials of Construction for Recovery Studies Surface Area for Limits Determination Hard to clean sampling locations or “hot spots” Sampling locations where non-homogeneous contamination is likely or “critical sites” • Worst-case determination (if grouping / bracketing) • Segregation requirements (if highly difficult to clean effectively)

So What Data Need to Be Collected? Data Required

Required For …

Process Attributes (i.e., batch size, upstream / downstream, extreme temperatures / holds, etc.)

• • • • •

Residue selection Limits determination Sampling location selection Worst-case determination (if grouping / bracketing) Segregation requirements (if hazardous)

Standard Operating Procedures

• • • •

Process parameters for validation Witnessing requirements Sampling locations Grouping / Bracketing (if applicable)

So what activities convert these Data into Information? . . .

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Engineering

Operations

Validation and Technical Operations

Cleaning Validation Master Plan or Policy and SOPs for Cleaning Validation Equipment Characterization

Cleaning SOP Defintion

Critical Process Parameters Product Attributes

Product Grouping / Bracketing

Cleaning Agent Usage Matrix

Residue Selection

Quality Control

Hard to Clean Locations

Sampling Sites And MOC

Sampling Method Selection

Limits Definition

Methods Validation

Equipment Train Definition

Equipment Grouping / Bracketing

Recovery Studies

Hold Time Definition Engineering Runs / Cycle Development

Worst-Case W tC Definitions Campaign Definition

Protocol Definition

Protocol Execution and Summary Report Preparation

Now We Have Data and Information, Where Does the Knowledge Come From?… • Knowledge is the integration of Information with policies policies, procedures and regulations

Wisdom Knowledge

• We must first start by creating our policies or master plan for cleaning as well as the SOPs that will govern our Cleaning Validation Program

Information Data

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What is a Master Plan*? Our Needs for an Effective Program:

Roles of the Master Plan:

• Single source for information • Consistent understanding by all team members • Assessment of what needs to be done and by whom • Effective control of strategies to ensure that they are consistent • Less time spent by regulators in our facility

• High Level Philosophy • Framework for consistent riskbased decision-making • Inventory of actions and projects, resource planning, scheduling • Location to consolidate our scientific rationales • Single source for regulatory review

* Frequently Master Plans are called Project Plans, Validation Plans or Policies, depending on the site’s document hierarchy

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What are Typical Master Plan Sections? 1. 2. 3. 4. 5.

Introduction Objective and Scope Description and Background References Responsibilities Validation Approach • Strategy and organization • Inventory of qualification activities to be accomplished

6. Acceptance Criteria (as appropriate) 7 Procedures & Format (as appropriate) 7. 8. Risk / Hazard / Failure Analysis (or may be in separate document) 9. Planning & Scheduling (as appropriate, high level, typically) 10. Appendices

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Master Plan Contents • Introduction Objective and Scope - Goals of the Master Plan and brief content insight as well as boundaries of the Validation Project j and of the Master Plan Typical scope boundary elements: • Production areas included: marketed production, clinical trial materials, R&D, laboratories, contract manufacturer / packagers • Types of Residues / Analysis included: chemical, microbiological

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Master Plan Contents • Description and Background - overview and orientation to the facility, process, technology or project; may include product overviews overviews, as appropriate Typical elements: • Program progress to date or significant iterations • Dosage forms, forms primary manufacturing processes processes, significant attributes of products (e.g., toxic, potent), production characteristics (e.g., batch, campaign)

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Master Plan Contents References - pertinent internal and external documents Examples include: • Scientific rationales, SOPs, risk analyses, literature supporting key rationales or strategies

Avoid excessive generic references (e.g., GMPs) Responsibilities – high level overview of key project participants – sufficient detail here may supercede the need to continue to reiterate responsibilities in protocols Department QC Engineering Validation Operations

Responsibilities Methods Validation Recovery Studies Analysis of Samples Surface Area Calculations Materials of Construction ID Protocol and Report Preparation Cleaning in accordance with SOPs Collecting samples

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Master Plan Contents (continued) Validation Approach – highlight the key elements of the validation program • Scientific rationales (see next slide) – the basis for the selection of the validation testing and trade-offs • Basis for the selection of validation priorities (e.g., New product introductions, worst-case products, multi-purpose equipment, etc.) • Project management overview of the responsibilities for the oversight of the cleaning validation program • Inventory of validations to be accomplished or already accomplished li h d iin support off the h plan l

Cleaning Validation is as much about what you choose not to do as it is about what you choose to do. Ensure your scientific rationales defend both! Cleaning Validation 64

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Scientific Rationales Will be Needed for … • • • • •

Product grouping / bracketing rationale Equipment grouping / bracketing rationale Residue selection criteria Limit selection and calculation rationale Analytical approach (specific / direct vs. non-specific/ indirect / screening) • Sampling method selection • Sampling site selection criteria • Others? (e.g., disassembly philosophy, campaign or minor clean strategies, etc.) Document these well as these will serve as the guideposts for future personnel or auditors navigating your cleaning validation program.

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Master Plan Contents (continued) Acceptance Criteria For cleaning validation, the acceptance criteria section typically refers to the way in which the acceptance criteria will be calculated; if more than one criterion applies, the acceptance criteria section will need to define how the terms will be applied

Visually Clean and 1/1000th of a Therapeutic Dose or 10 ppm in the next batch, whichever is lower

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Master Plan Contents (continued) Procedures & Format Refers to Reference section for the procedures and formats to be followed; in some cases samples of specific documentation samples or outlines of document headings may be included Scope – Products and Procedures Equipment Boundaries / Train Definition Pre-Requisites (e.g., methods validation, recovery studies, IQ, OQ of equipment, training, etc.) Validation Study Design Sampling Plan Acceptance Criteria

Cleaning Validation 67

Master Plan Contents (continued) • Risk / Hazard / Failure / Criticality / Impact Analysis – may be provided here or in a separate document to substantiate scientific rationales rationales, priorities priorities, trade-offs trade offs, overall approach approach, CTQs or critical parameters • Planning & Scheduling – include or reference a project schedule for major milestones; if referenced, ensure that it exists; if included, remember the audience and keep it high level • Appendices – sample flow diagrams for key processes, specimen documentation formats, supporting documentation for the approach, data tables of key product attributes, tables including product-specific limits, etc. Cleaning Validation 68

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 34

Other Possible Master Plan Contents • Master Plans may also capture compliance and regulatory g y requirements q beyond y validation in order to ensure that the project correctly integrates these activities with the completion of validation • This is especially valid if the program is undergoing any significant changes in strategy or if corrective ti actions ti have h b been id identified tifi d

Cleaning Validation 69

Other Possible Master Plan Contents • For example: • SOP development • Training package preparation and training of operators / technicians • Development of test methods or in-process controls • Vendor audits / surveillance / visits • Factoryy / Site Acceptance Tests ((FAT / SAT)) / Commissioning and/or Qualification Activities for new CIP or COP systems

Cleaning Validation 70

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Master Plan Maintenance • Maintain a Revision History • Circulate approved copies of the Validation Project Plan to all involved departments • Keep the Master Plan up to date with regard to changes in priorities and schedule • Place the Master Plan on a periodic review cycle to ensure that there is frequent challenge to scientific rationales and current approaches to validation

Cleaning Validation 71

Summary Reports for Master Plans • In some cases, where a plan is developed for a specific project such as a new product i t d ti introduction, a summary reportt tto th the plan l can provide project closure • In other cases, an annual summary can provide updates on critical activities / accomplishments f from prior i year while hil providing idi hi highlights hli ht off goals l for next year

Cleaning Validation 72

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Summary Reports for Master Plans • Summary report to a Master Plan can provide: • Closure to validation activities for regulators or change control purposes • Mechanism to describe and defend deviations from the original plan • Location to tie together disparate validation protocols and reports and their conclusions in a high level overview

Cleaning Validation 73

Standard Operating Procedures for Cleaning Validation • Develop an infrastructure of procedures that define the validation program responsibilities and activities. • Possible topics to include (in a single or in several SOPs): • • • • • • •

Equipment Characterization (New and Existing) Standard Operating Procedure Development for Cleaning Developing and Maintaining Limits Calculations Cleaning Validation Methods Validation and Recovery Studies g g Studies / Cycle y Development p Engineering Developing Cleaning Validation Protocols and Reports Collecting and Testing Cleaning Validation Samples

• These topics will form the outline of the remaining sections of the presentation Cleaning Validation 74

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Module 4: Equipment Characterization: Do nott L Lose “Site” “Sit ” off What you Are Cleaning!

Cleaning Validation 75

Equipment Characterization • We’ve already examined that the surface is a critical to the success off the cleaning • So let’s examine what we can do about it: • • • •

Equipment Design / Construction Equipment Characterization Sampling Site Selection Documentation of Equipment Characterization

Cleaning Validation 76

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Equipment Design and Construction Production equipment and facilities should be designed to be cleanable and maintainable in accordance with CGMPs – other critical attributes may apply depending on the nature of your production process • Coved corners • Welded seams • Sealed joints or crevices, when necessary (with temperature / chemical resistant caulk or sealant) • Sanitary clamp type connections • Minimize dead leg opportunities (not only length of T but also orientation of lines) • Positive slope (typically minimum for long runs of 1/8th in/ft or 10.4mm/m) • Free-draining • Non-additive, non-reactive, non-absorptive materials of construction • Smooth, polished finishes (ex: 20 – 25 µin or 0.5 – 0.625 µm Ra on 316L SS) Cleaning Validation 77

Existing Equipment Design Survey • Survey the equipment (see example of potential tool on the next slide) • Identify weaknesses in the design • Identify risks associated with the weaknesses Product Contact ? • Mitigate as possible Yes

When ranking, it may also be helpful to rank each Critical Site section of the (i.e., location likely to be equipment equ p e t by tthe e non-homogeneously non homogeneously distributed in next batch or nature of its location which is likely to be product contact:

No Non-Critical or Incidental Contact

in contact with highly concentrated active)

High Risk

Low Risk Cleaning Validation 78

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 39

Example of Design Survey Risk Assessment Characteristic

High Rating

Low Rating

Equip. Section Surveyed

Possible Mitigations / Actions for High Ratings

Positive Slope / Free Draining

Non-free draining

Free draining

Reengineering Forced flow and forced drying

Non-additive / Non-reactive / Non-absorptive MOC

MOC not appropriate for easy cleaning

MOC appropriate

Reengineering Special considerations for cleaning action / chemistry Enhanced inspection / testing to confirm cleanliness

Smooth, polished finishes

Finish was not designed to be smooth or finish has significant damage

Finish is smooth, polished and in tact

Refinishing surfaces Enhanced cleaning action / chemistry Enhanced inspection / testing to confirm cleanliness 79

Example of Design Survey Risk Assessment Characteristic

High Rating

Low Rating

Equip. Section Surveyed

Possible Mitigations / Actions for High Ratings

Coved Corners

Not coved and critical product contact

Coved or non-critical surface

Tool selection for cleaning Special instructions during cleaning

Joints

Not sealed or sealant inappropriate to rigors of cleaning

Sealed with the correct material or not critical to p product / cleaning contact

Replace sealant Use different chemistry or tool for that location More frequent PM and replacement

Dead leg survey

Dead legs are present or orientations that would hold up product and fluids

No dead legs or poor orientations

Reengineering Disassembly for cleaning or disassembly after CIP for inspection and additional off-line cleaning

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80

Equipment Design Risk Assessment Results Product Risk  High

Low

Equipment Design Risk High

Reengineering to mitigate is your best course of action

Reengineering is still best, but procedural improvements may suffice

Low

Equipment q p is not No worries! likely to be a problem, but take care in your cleaning program design

Equipment Characterization Goals of Equipment Characterization are to: Gather • Equipment design data: • MOC / finish / geometry • Difficult to clean locations • Cleaning SOP #s and Cleaning Agent types • E Equipment i t surface f area data d t • Equipment train data

Develop • MOC list for recovery studies • Sampling site identification • Sampling method determination • Cleaning procedure and cleaning agent correlation to equipment for grouping / bracketing • Equivalency rationales for grouping / bracketing • Limit determination

Cleaning Validation 82

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Equipment Characterization Field Assessments •

•

Set Priorities for Equipment – (new, non-dedicated major, downstream, nondedicated minor, upstream, etc.) Identify potential equivalent equipment

Cleaning Validation 83

Equipment Characterization Field Assessments •

Initiate the Assessment: •

Identify product contact materials of construction for processing equipment and their locations •

•

•

•

•

Use drawings, vendor certifications, field inspections

Identify the approximate percentage of surface area that each MOC comprises (may be approximate) Calculate or contact vendor for the product contact surface area calculations for the total piece of equipment List the cleaning SOPs and cleaning agents in use for the equipment Interview operations personnel for hard to clean locations Cleaning Validation 84

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Equipment Characterization Field Assessments (cont’d) Grouping or Bracketing

Repeat the review for any potential equivalent members R i Review for f equivalency i l should h ld include: i l d • Make / Model / Geometry / Features • Scale / Size / Capacity • Materials of Construction / Surface Finish • Installation and Operational Qualification Equivalence • Same Position / Role in the Process Equivalency will also be determined based on: • Cleaned with same procedure • Cleaned with identical cleaning agent • Overlap in products produced on those pieces Grouping / bracketing equipment will then drive: Number / organization of cleaning validation trials Cleaning Validation 85

Equipment Characterization Field Assessments (cont’d) Identify sampling locations and sampling techniques p g locations should be selected based on: Sampling • Hard to clean locations or complex geometries – hot spots • Locations that might disproportionately contribute residue to the next process (e.g., filling needles, discharge valves, punch and dies, chromatography skid fraction collection valves and piping, etc.) – critical sites • Materials of construction or surface finishes with an affinity for the residue • Role in process that is likely to lead to build build-up up or difficult to clean residue

Number of sampling locations should be based on the: • Number of locations that fit the descriptions above • Overall size of the equipment Cleaning Validation 86

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Documenting Sampling Site Selection Rationales Through Risk Assessment Sampling S li Location

Critical C iti l Site

Hot Spot

Role in Process Likely Affi it to Affinity t MOC t Lead to L d tto or surface finish Residue

Ranking

Risk assessment technique aids in ensuring that sampling sites are effectively rationalized and eliminates some of the subjectivity • Rankings can be scaled as H, M, L or given a number scale

Methods for identifying sampling locations include: • Interviewing operators for difficult to clean locations • Witnessing cleaning procedures to identify weaknesses in cleaning • Conducting screening studies such as Riboflavin testing

Module 4 – Equipment Characterization Slide 88

Sampling Methods - Survey

Baby in the Bathwater

* May get a different rating depending upon technique Sampling Method 

Swab

Rinse (see Baby)

Placebo

Coupon

Direct Surface Analysis

Good

Poor *

Moderate*

Good *

N/A

Technique Dependent

Yes

No

No

No

No *

Hard to Reach Locations

Poor

Good

Good

Poor

Poor

Physical Removal

Adaptable to Irregular Surfaces

Somewhat

Yes

Somewhat

No

No *

Controlled Area Sampling

Yes

No *

No

Yes

Yes

Non-Invasive

No

Can Be

Yes

Yes *

No

Adaptable to On-Line Monitoring

No

Yes

No *

No

No

Can Use Solvents

Yes

Yes

No

Yes

N/A

Solubility of Residue Contact Time Homogeneity of Rinse Solution Recovery

Ability of Placebo to Remove Residue (e.g., solubility) Homogeneity of Residue in Placebo for Detection Recovery

Ability to Defend that Soiling and Cleaning of Coupon is Equivalent to the Production Equipment Recovery

Surface Character-ization Qualification of Method Limit of Detection

Highly Dependent On…:

Site Selection Training Recovery

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 44

Example of Equipment Characterization Documentation 1. 2. 3.

4.

Equipment Name Equivalent Equipment IDs Equipment Description & Role i the in th Process P • Key Design Features • Key Performance Attributes (esp. those that affect cleaning) • Critical Sites or Hot Spots • Rationales for Equivalency (as required) Materials of Construction • Material • Location • % of Total Surface Area

5.

Sampling Site Selection Rationale and Sampling Method

6.

Digital Photographs of Sampling Sites •

Highlighted sampling area

•

Text description of sampling location

7.

Calculation of Sampling Site Surface Area

8 8.

Calculation of Equipment Surface Area

Appendix – Sampling Data Sheet*

* To be discussed in Limits section

Cleaning Validation 89

Establish an Equipment Use Matrix Equipment Name

Cleaning SOP

Cleaning Agent

Product A

Product B

Tank 11 (600 L)

SOP 1234

CleanAll 345

X

Tank 12 (500 L)

SOP 1234

CleanAll 345

X

X

Transfer Line 101 (2”)

SOP 6789

SonicCare 657

X

X

Pump 602 (diaphragm)

SOP 4567

CleanAll 345

X

X

•

Matrix helps to establish which products share equipment in order to determine the maximum shared equipment train between products (esp. if you use equipment surface area instead of X’s)

•

Can assist in seeing logical relationships for equipment groupings / bracketing

•

Records similarities and differences between pieces based on cleaning SOPs and cleaning agents

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 45

Ensure That Your Characterization Work Also Assesses The Following Identify materials that should be reviewed against cleaning agent and cleaning tools to look for compatibility issues

•

Develop rationales for those materials that will not need to be included in sampling and recovery studies based on elements such as:

•

Position P iti iin th the process Overall percentage of surface area Similarity to other locations or materials of construction

• • •

Cleaning Validation 91

Ensure That Your Characterization Work Also Assesses The Following •

Materials that are candidates for dedication or for making g them disposable, p such as those that are: • • • •

Likely to have a high affinity to product Likely to be extremely difficult to clean In contact with highly concentrated residues Used as ancillary components

Cleaning Validation 92

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Discuss the Following: Can sampling size legitimately be based on the following? (Why or why not?) • Easy to discern part of the equipment (i.e., specific fixture, or identifiable part such as 1 agitator blade) • Convenient number (e.g., 100 cm2) • Different sizes for each sample collected

Cleaning Validation 93

Discuss the Following: Do you think there will be a maximum and a minimum surface area that is legitimate to collect? (Don’t give a specific numeric value, just think about why this might be the case)

Cleaning Validation 94

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Module 5: SOP Development for Cl Cleaning i Reproducibility is No Accident Cleaning Validation 95

FDA Perspectives on Manual Cleaning Pre-1993 – Manual Cleaning Can’t Be Validated • Industry Concern • Manual Cleaning Impossible to Eliminate

1993 – Manual Cleaning Can Be Validated • Requires Detailed Procedures • Requires Effective Training • Requires Periodic Monitoring So what are the elements that we need to control in order to ensure that we meet FDA’s expectations?

Cleaning Validation 96

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Manual Procedures v. Automated Processes Manual Procedures

Automated Processes

• Rely on trained staff

• Less reliance on people

• Rely on detail in procedures for reproducibility; compliance with procedure is paramount

• Rely on cycle parameters, parameters instrumentation and controls for reproducibility

• Few requirements for IQ / OQ of the cleaning g process • Few effective means of monitoring unless sampled periodically

• Validation of instruments and controls in IQ / OQ is key • Monitoring is chiefly performed through instrumentation and documentation such as alarm and cycle records

Both require T.A.C.T. !

Cleaning Validation 97

Fishbone Diagram Also called an Ishikawa Diagram or Cause and Effect diagram is used to show (and group) the contributors to a problem through brainstorming or the review of a process flow. Controlling the elements on the “ribs” of the fishbone (or at least the most critical elements along the ribs) will help to ensure that the problem is corrected or controlled. The groups that are present on the ribs of the fishbone may vary; below are some of the more common categories. “Mother Nature” (or environment)

Methods

Manpower Preventing Unsuccessful Cleaning Validation

Materials

Measurement

Machinery Cleaning Validation 98

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Fishbone Diagram for Cleaning Validation “Mother Nature”

Methods

(or environment)

Cleaning Procedure T.A.C.T.

Clean equip. storage conditions

Tools for cleaning

Residues Water Quality

Materials

Experience

Sampling method

Temperature Rel. Humidity

Cleaning agent

Training

Analytical method

HVAC Classification

Analysis y Sampling

Manpower

Recovery

Calibration of Instruments

Measurement

Attention to detail Other distractors

Cleaning equipment i t Manufacturing equipment

Materials of construction

Preventing Unsuccessful Cleaning V lid ti Validation

Geometry

Machinery

Cleaning Validation 99

Q Question: How do we ensure control over these key elements?

Cleaning Validation 100

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A: Detailed SOPs • Materials List with part numbers and descriptions • Responsibilities List • Preparation • Cleaning • Inspection

• Procedures • • • • •

Specific to categories of equipment Step-wise and sequenced Concise, clearly written in simple language, yet detailed Incl de T.A.C.T. Include TACT Reference distinct measures or metrics to determine achievement of T.A.C.T. parameters • Include documentation requirements • Include diagrams for clarity Cleaning Validation 101

SOP Contents • • • • • • • • • • •

Preparation Procedures Documentation Procedures Disassembly Procedures Cleaning Procedures Completion Procedures Inspection Procedures Drying Procedures Wrapping / Covering / Storage Procedures Post-Cleaning Documentation Procedures Equipment Expiration Procedures Pre-Use Inspection Procedures

• • • • • • • •

Preparation of area, tools & cleaning agent Status Tags, Checklists, Cleaning & Use Log Exploded diagrams or digital photos Step-Wise, Tools, TACT, Measures Cleaning of Tools, Baskets, Carts Methods & Tools, Locations for Inspection Environment / Controls Materials, Handling, Location

•

Re-Tagging, Cleaning & Use Log

• •

Dating Requirements, Re-Cleaning Requirements Verification of Expiration, Integrity of Wraps / Covers

Cleaning Validation 102

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SOP Contents Peculiar to Cleaning Validation • Time after use before cleaning • Maximum interruption p within a cleaning gp process (such as hold times after a pre-rinse or time before a final rinse) • Time after cleaning before use • Cleaning Frequency (if tied to levels of cleaning such as major clean and minor clean) Elements Affecting Cleaning That Would Be Included in Batch Records or Master Cleaning Policy • Maximum number of batches and/or days in a campaign

Cleaning Validation 103

Batch Record-Like Format • • • •

Enables formal review of cleaning procedures Enforces consistency between operators Enforces sequence q of activities Captures accomplishment of T.A.C.T. through documented completion of key steps, including: • • • • • • •

Preparation of cleaning agent Disassembly checklist Pre-rinse, Wash, Final Rinse Drying Inspection Covering and Storage Cleaning and Storage of Tools

• Captures start / stop times and critical process parameter achievement Cleaning Validation 104

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Special Considerations for Sanitization or Disinfection Procedures • Cleaning steps must be specified prior to the application of the sanitant • Contact time with chemical sanitant is critical • Method of application may need to be demonstrated to reliably leave sufficient “liquid” on the surface to effect the sanitization • Expiration p dates for formulated sanitizers are particularly important • Aseptic techniques should be taught and practiced Cleaning Validation 105

Special Considerations for Sanitization or Disinfection Procedures • Other validation considerations: • Sanitant efficacy must be demonstrated in the presence of known residues from processing or cleaning at the levels that are typically present after an effective cleaning procedure; ensure the cleaning agent residues don’t inactivate the sanitant • Re-use of a sanitizing solution must be validated as they often lose efficacy quickly when contaminated with residues / debris Cleaning Validation 106

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Challenges in Creating Effective SOPs • Too tight v. Too loose control limits • Excessive investigations • Limited reproducibility p y

• Too much v. Too little detail • Using clockwise 50cm circular motions and the amount of pressure that it takes to see if a pineapple is ripe, wipe the white, lint-free wipe 25 times then reverse to a counter-clockwise motion in the same position for an additional 25 circles. When complete, move 50cm to the left, repeat, it will take 125 - 50cm circles to clean the full circumference at the top level, when the full circumference has been wiped in this manner, move down 50cm and repeat for the next row … • Rinse, wash, rinse

• Defining scope and applicability of SOP • Determining extent of cross-referencing v. including documents / forms Cleaning Validation 107

Tips for Evaluating Existing SOPs • • • • • • • •

Witness process Review the actual cleaning performed against the SOP Are all tools / steps identified? Ensure critical process control steps have a measurable or observable parameter Consider how the parameter is assured -- is documentation the answer? Witness several different operators performing the cleaning tasks - look for variability in current practices Revise the SOP to reflect current practices Retrain all operators accordingly Cleaning Validation 108

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Don’t Forget • • • • •

Safety S f t precautions ti Personnel protective equipment MSDS availability to personnel Gowning requirements Procedures for f handling off deviations

Cleaning Validation 109

Effective Training Goals of Operator Training • • • •

Reproducibility p y of cleaning g technique q Effective cleaning Good record keeping Safe operation

Operators must understand • • • •

Importance of each step Sequence of steps Effective techniques Good documentation practices

Skill-based training recommended Cleaning Validation 110

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Inspector Training • Formal training / certification of inspectors needed • Inspection p p procedures should be formalized in sops p • Non-invasive methods where possible • Consistent techniques • Aided inspection where possible

• Inspection requirements should identify • • • • •

Gowning / safety / protective measures Difficult to clean locations on the equipment Extent of disassembly for inspection Standardized inspection tools / techniques Types of residue: product / cleaning process related, foreign materials, wear and tear Cleaning Validation 111

Common Mistakes with Inspection • • • • •

No written procedures for what or how Dissimilar levels of disassemblyy for inspection p Insufficient tools for inspection Lack of certification or formal training Lack of procedures for what to do upon failed visual inspection – • • • •

Spot cleaning sufficient? Full recleaning? Retraining required Reporting / trending failures so that CAPA can be made

Cleaning Validation 112

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Training Tools / Methods • • • •

Video taping Sid b Side by side id performance f and d iinspection ti Apprenticeship Challenge inspection sets for tool use (e.g., boroscope, mirror, etc.) Sensitivity to the importance of cleaning - $ value of the next batch General training in “aseptic” technique – priceless!

Cleaning Validation 113

Problems to Spot During a Site Walkthrough • Procedure creep!! • “Hurryy up! p I need that!” • Shortchanging parameters – most commonly due to lack of controls / instrumentation for TACT elements • Differences in disassembly • “Old” cleaning fluids sitting around and unlabelled buckets • Failure to clean utensils • No recleaning upon expiration • Insufficient investigations of cleaning failures Cleaning Validation

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114

Module 6: Selecting Residues, then Developing p g and Maintaining Limits: “How Clean is Clean?” Is So Cliché Cleaning Validation 115

Residue Selection – or What Materials Do We Need to Set Limits For? Potential residues for consideration include: • • • • • • • • • • •

API ((drug g substance)) Excipients / Colorants / Dyes / Fragrances / Flavors Preservatives Degradants / Impurities Starting materials / Processing Aids Mother Liquors / Solvents Lubricants Bioburden Mycoplasma / Prions / Viral Particles Endotoxin Particulate Cleaning Validation 116

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How Do We Choose? • First we identify which materials represent the greatest risk to the next process • High potency / high toxicity / allergenic • Affect the ability to perform the next process correctly • Create a condition that is unacceptable to consumer (e.g., muddied fragrance, off-color, off-texture) • Hardest to clean / remove

Cleaning Validation 117

How Do We Choose? • Next check to see if there is justification to look for one residue as a “representative” or “worstcase” when compared p to the other selected residues • Establish limits for the chosen materials based on: • Pharmacologic / toxic properties • Percent carryover • Permissible baseline (e.g., (e g micro)

Cleaning Validation 118

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What About Multi-Product Facilities? • Grouping or bracketing may be employed • Keyy factors in g grouping p g / bracketing g related p products: • Same or worst-case high risk residues present at the same or higher concentration in the product • Similar manufacturing processes • Cleaned with same procedures / cleaning agents • Equivalent or worst-case excipients / formulations • Most difficult to clean or equivalent difficulty in cleaning

• After groups are formed: • Test the “worst-case” or “representative” family member • If bracketing, test the extremes of the family

Cleaning Validation 119

FDA Guidance on Limits Guide to Inspection of Cleaning Validation, 7/93 • FDA does not intend to set limits • Rationales should be logical, practical, achievable and verifiable • Sensitivity of analytical methods is critical to establish valid limits 10ppm biological activity • Three examples given: 10ppm, levels as 1/1000 of normal therapeutic dose and organoleptic levels

Cleaning Validation 120

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What Limits are Commonly Employed In Industry? • Exactly the three examples cited by FDA! -- they also correspond to one of the first published articles on the definition of limits by Eli Lilly i Ph in Pharmaceutical ti l T Technology h l • How can companies use all three?

mg / mL 

Equipment must be visually clean and must meet 1/1000th of a T.D. (see X’s on chart below) or 10 ppm in the next batch, whichever is lower…..

x

> 10 ppm ppm, therefore default to 10 ppm in the next batch as your limit 10 ppm in next batch

x

< 10 ppm, therefore default to this safety based limit

Cleaning Validation 121

Precautions with FDA Guidance Documents • Cleaning Agents - “...no no or very low detergent levels remain after cleaning...” • Watch out for words such as: • Absence • No • None

Cleaning Validation 122

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The Three Types of Limits There are three basic types of limits for chemical contamination: t i ti • Limits associated with the nature of the substance being cleaned (in other words, its pharmacological properties) • Limits associated with the percentage of ppm,, for example p contamination  10 pp • Limits which are associated with the process by which they are manufactured, cleaned or analyzed (e.g., visibly clean, limit of detection, etc.)

Cleaning Validation 123

What’s In a Limit? Well, In Layman’s Terms … • We need to determine how much of the product we just cleaned • Will be administered to each patient taking the next product • But, in order to make this number useful…. • We need to determine how much that will represent in the next batch (especially as batch sizes may vary)and then translate that number to a value in terms of how much that might represent on the surface for us to sample / measure • Lastly, we want the amount that is a residual to be “safe” and therefore we may add a safety factor Cleaning Validation 124

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What’s In a Limit? Some Other Considerations • We want to be conservative – we don’t want patients to be ingesting materials that they weren’t weren t prescribed • We need to recognize that some materials are more hazardous to patients than others based on their pharmacologic effects • We need to recognize that there are aspects of our manufacturing process that change from lot to lot that need to be incorporated in our strategy … • Batch size • Equipment train

Cleaning Validation 125

What’s In a Limit? Exploring the Nature Term We need to determine how much of the product we just cleaned May be expressed as any of the following: • Toxicity or LD50 (with appropriate safety factors) • Therapeutic Dosage • Allergenic levels • Minimum pharmacological effect level • No Observable Effect Level (NOEL) It is always most conservative to select the smallest amount

NatureJC

Overall fraction gets small

Cleaning Validation 126

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The Nature Term Why Select One Over The Other? • Potency, dosage or min. pharm. effect levels will mean that a dose may receive up to the amount required to elicit a pharmacologic response • Allergenic limits are common for products which have a well-established allergenic history for products where the allergenic p g response p is below the therapeutic response

Cleaning Validation 127

The Nature Term Why Select One Over The Other? • Toxicity limits are often difficult to apply as they are often in non non-primate primate species, however they have a lot of value for products which have no therapeutic or dose-based index (e.g., cleaning agents) -- industry needs good guidance on the safety factors to apply to these limits -- usually used in a NOEL or ADI (Acceptable Daily Intake) approach

Cleaning Validation 128

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What’s In a Limit? Exploring the Dose Term Will be administered to each patient taking the next product • The amount of the next product that might be administered

DoseNP

• May include attributes such as: • The size of the dose (e.g., Mg) and generally reflects the total dose weight (i.e., Including excipients) • The Th number b off d doses or • Term of the administration (to incorporate aspects of cumulative effect)

• Always most conservative to over-estimate this term

Overall fraction gets small

Cleaning Validation 129

What’s In a Limit? Exploring the Batch Term We need to determine how much that will represent in the next batch ((especially p y as batch sizes may y vary) y)

BatchNP

•

• •

The amount of the next product to be made which will be contaminated by residue from the product just completed May be expressed as batch size (e.g., L or Kg) or in the number of dosage units (e.g., tablets) It is most conservative to work with the smallest possible size (larger batch sizes will “dilute” your residue which is safer… when calculating limits we want to pick the worst-case assumptions) Overall fraction gets small Cleaning Validation 130

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What’s In a Limit? Exploring the Size Term Then translate that number to a value in terms of how much that might g represent p on the surface for us to sample / measure

Size

• Size of the equipment

• May represent the full shared, maximum or next product’s equipment surface area of an equipment train • Could also take into consideration a smaller area, or single piece of q p but only y when using g an individual dose or p portion of the equipment batch as the batch term in order to assess hot spots or critical sites • It is always conservative to over-estimate the surface area of the equipment Overall fraction gets small Cleaning Validation 131

The Size Term Equipment Train Example Residue contamination will be cumulative through a train into the next product, therefore most companies use a train-based train based term in the size position of the equation as the most conservative. The train-based calculation will include the charging equipment through the finishing / filling equipment. Note: This approach does not prevent us from sampling an individual piece of eq ipment rather than the whole equipment hole train -- more on this in a minute... Limits are expressed as weight per unit area, therefore any unit area must live up to the established limit. Cleaning Validation 132

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What’s In a Limit? Exploring the Safety Factor Term Lastly, we want the amount that is a residual to be “safe” safe and therefore we may add a safety factor

SF

• SF is any convenient number, usually a multiple of 10 (e.g., 10, 100, 1000, 10000) • SF are optional (in most cases -- they are not optional when using terms such as LD50) • SF compensate for the number of non-conservative assumptions made in the calculation of the remainder of the limit • The larger the SF, the greater the reduction in the limit (as the equation is multiplied by the reciprocal or 1/SF)

Cleaning Validation 133

Safety Factor There are a number of considerations for the determination of an appropriate safety factor. In a single facility, several different safety factors may be applied depending upon some or all of the following: (note that list is not necessarily all inclusive) • Number and type of conservative assumptions for distribution of residue, batch size, surface areas, dosage dose size, dosage, size etc. etc • Therapeutic category • Relative toxicity • Route of administration / dosage form • Potential use and misuse of product Cleaning Validation 134

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Common Application of 1 / SF Commonly 1/SF are applied to limits on a uniform basis within a plant, for example: • • • • •

Topical rx products = 1/10 to 1/100 Oral dosage products = 1/100 to 1/1000 Parenteral / ophthalmic products = 1/1000 to 1/10,000 Research / investigational products = 1/10,000 to 1/100,000 Oncological products = 1/100,000 to ?

This approach, applies consistency to the application of a non-standard t d d tterm.

Cleaning Validation 135

In Summary, All Terms Considered Together Nature (Pharmacology-Based) Limits NatureJC

x

BatchNP

Size

x

DoseNP

x

1 SFopt

Where: Nature = pharmacology of the active ingredient from the batch we just completed Batch = batch size or volume or number of dosage units of the next product Size = square surface area of shared or maximum equipment train Dose = amount (total dose weight) to be given per patient, daily or per regime of the next product SF = safety factor, an optional or variable term depending upon the other considerations in the limit JC – Just Completed product; NP – Next Product

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Other Considerations When reviewing the equation, other considerations of use may drive the selection of specific terms:

Route of administration

More sensitive? Increase safety factor

Examples: Topical p drug gp product contaminating g a suppository pp y Oral liquid contaminating an inhalant Inhalant contaminating an intraocular product Cleaning Validation 137

Other Considerations (continued) When reviewing the equation, other considerations of use may drive the selection of specific p terms: Potential product misuse / environment of use Examples:

Greater dose than directions? Increase dose term

Prescription drug product carryover into an over-thecounter cold medicine Prescription carryover into a topical antibacterial ointment

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Other Considerations (continued) When reviewing the equation, other considerations of use may drive the selection of specific terms:

Duration of use / term of administration

Longer duration? Increase dose term

Examples: Intravenous antibiotic carryover into a intravenous sucrose solution for fluids replacement Potent compound carried over into an hepatically stored drug product

Cleaning Validation 139

Other Considerations (continued) When reviewing the equation, other considerations of use may drive the selection of specific terms:

Type of patient likely to receive the next product

Use the smallest dose / value in the Nature term and the highest value in the Dose term

Examples: Adult dosage product carryover into a pediatric formulation Carryover into products that are intended for AIDS patients, geriatric patients or cancer patients

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Other Considerations (continued) When reviewing the equation, other considerations of use may drive the selection of specific terms:

More conservative value selection and/or higher safety factors the more pure the product becomes or the closer it gets to finished dosage (or the more likely contaminants will become concentrated) *

Position / role of the individual pieces of equipment in the process *

* ((upstream p v. downstream,, critical sites,, homogeneous v. non-homogeneous distribution, etc.)

Examples:

Critical sites such as fillers and tablet presses (see next slide) API drying trains esp. at the discharge valves UF / DF skids in biopharmaceutical processing Cleaning Validation 141

Other Considerations (continued) • Critical sites offer the opportunity for all residual contamination to be distributed to a single dose or single portion of the next batch • Limits can be calculated that take this possibility into account, as follows: Single or limited doses

Other approaches include:

NatureJC

x

BatchNP

Size

x

DoseNP

x

Surface area of critical sites

1

•

IIncreasing i the th safety f t factor f t for f these locations

•

Justifying the routine limits through the understanding of material consumed at start-up

Or

SFopt

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 71

Using 0.1% Of A Therapeutic Dose, How Would You Calculate Your Limit? • Several tanks were determined to be equivalent, only one is used for each process trial trial, each tank has a different surface area -- how would you calculate the limits? • You make the same product in two strengths -- one for mothers and one for babies. What would your strategy be for setting limits? Which product would you dirty the equipment with for your cleaning trials?

Cleaning Validation 143

Limits and the Calculation of Results The limit and the calculation of results form two sides of the same equation.

Limit

>

Result

It is possible to take terms from either side of the equation and move them to the other side of the equation provided that we reverse their position, equation, position numerator to denominator and denominator to numerator.

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Limits for Cleaning NatureJC Size

x x

BatchNP

x

DoseNP

1

>

SFopt

Result

x Rinse or Diluent Volume

Surface Area x Recovery (decimal) Sampled

• In this case both sides of the equation yield a result that is expressed as mass per unit surface area. • In the box, you can see highlighted several terms that are considered the Maximum Allowable Carryover or MAC. • Recent R t criticisms iti i off MAC approach h and d their th i validity lidit … • If we were to use the MAC as our limit, we would need to move the equipment train term over into the result as the numerator.

Commonly Asked Question Q: If we calculate our limit based on a train based approach, doesn’t that prohibit us from releasing equipment on a piece by piece basis? A: No! We can still release on a piece by piece basis – the ratio formed by the equipment train and the surface area sampled is all we need! By forming this ratio, we can ensure that no unit of surface area has more than the MAC. NatureJC

x

BatchNP DoseNP

Also sometimes called MAC or Maximum Allowable Carryover

x

1 SFopt

>

Size

x Result x Rinse or Dil. Vol.

Surface Area x Recovery (decimal) Sampled As we can see, in either equation form, the equipment train surface area and the surface area sampled forms a ratio of the fraction of surface area that was sampled to what is available

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In Other Words . . . By dividing the allowable carryover by the equipment surface area, we are determining how much residue every square unit of surface area of the equipment is permitted to have. When we interpret our results, we divide by the amount of surface area sampled in order to compare mass per unit surface area to mass per unit surface area. This approach assumes uniform contamination, which we know is not always true, however we are conservative by picking those locations that we know are hard to clean and likely to have the highest concentration of residue. In this approach every sample must pass the limit. It is inappropriate to average or factor the results. Cleaning Validation 147

Limits for Cleaning Agents • Cleaning agents constituents do not have a therapeutic index • To determine safety for cleaning agents, companies often turn to the only available information with regard to activity, the LD50 • LD50 are specific to an animal model (e.g., rat, guinea pig, mice, etc.) and to the route of administration (e.g., oral, topical, i.v., i.p., s.c., etc.) • Because we want to ensure that the carryover quantity is safe for the person receiving the next dose, we can’t use the LD50 directly in the nature term • Instead, most firms first calculate either an ADI or Acceptable Daily I t k or a No Intake N Observed Ob d Eff Effectt Level L l • The form for the NOEL or ADI equation is the same as the pharmacologic properties limits

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Limits of Cleaning Agents The typical equation for the NOEL based on an LD50 for oral routes of administration in rats, appears as follows:

NOEL = LD50 mg/kg x (5.6 x 10-4) x 70 kg Conversion factor and safety factor to convert oral rat LD50 to oral human NOEL

Average adult body weight

Note: it would be conservative to use a pediatric weight here or to leave off this term altogether, although the safety factor included just prior is often considered to more than make up for this term.

Note: the safety factor makes up for: differences in person to person response, a variety of potential dose / response curves that might make this material a worst case, converting to a level at which No Observed Effect is detected.

Ref: Doursan and Stara, J. Regulatory Toxicology and Pharmacology, 3, 224-238, 1983. Other Refs: D.W. Layton, et al., J. Regulatory Toxicology and Pharmacology, 7, 96 1987. Doursan, Toxicology, Vol. 1, No. 1, pp. 35-48, 1986. Doursan, Toxicology and Industrial Health, Vol. 4, No. 4, pp. 23-33, 1985.

Cleaning Validation 149

Limits of Cleaning Agents

LD50 mg/kg x (5.6 x 10-4) x 70 kg x BatchNP

1 x

Size

x

DoseNP

SFopt

Result

>

x Rinse or Diluent Volume

Surface Area Sampled

x Recovery (decimal)

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Let’s Examine The Last Two Limit Approaches: • Limits based on pharmacological properties ti • Percentage Contamination Limits (e.g., 10 ppm) • Process Capability Limits (e.g., (e g visually clean, process capability or analytical detection) Cleaning Validation 151

Percentage Contamination • Defined by the amount of one product allowed in any other product w/w or v/v • Examples such as ppm or ppb are quite common - where x parts of any product are allowed in every million (billion) parts of the subsequent product; where x may be any convenient value • Note that if x is a convenient value, it is clearly not related to product safety

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Percentage Contamination • Remember that when defining ppm limits you will need to clearly state whether the concentration is per swab, per sample, per batch, etc., in order to determine an accurate carryover quantity (per swab and per sample are bad choices here if your sample system is variable or might vary in the future)

Cleaning Validation 153

Uses of Percentage Contamination

mg / mL 

• May be used for safe compounds * • As a quality default used in conjunction with a safety-based limit • May be applicable to products with an established w/w impurity profile ((e.g., p g , 0.1% or 1000 pp ppm)) **

x

> 10 ppm, therefore default to 10 ppm in the next batch as your limit 10 ppm in next batch

*

This is still problematic from the stand point that you should understand the interaction of the products that you manufacture -- if you decide to use a % contam. limit, be sure to be conservative!!! ** Note that on this approach, the FDA has commented publicly that impurities are those substances which naturally arise from your manufacturing process and are not intended to be those materials that are “left over” from the cleaning process -- be careful how you word your rationale if you are using an impurity profile as your basis

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Percent Contamination Approach: 10 ppm in the Next Batch 10 mg g JC 1 kg NP

x Batch NP x Size Units work as follows: mg JC x kg NP kg NP x cm2

Note: Limit

>

Result is still the case here, as well.

JC – Just Completed product; NP – Next Product

Cleaning Validation 155

Process Capability Limits • Cleaning process capability • Analytical detection levels • Visual detection levels Issues: • Limit may decrease as methods improve • Not related to product safety

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Process Capability Limits Despite their weaknesses, there are some advantages too, and companies still use these limits: • Visually Clean -- Good In Conjunction With Safety-based Limits; E Excellent ll t All All-over Pre-screening P i R Requirement i tB Before f S Sampling li • Analytical Detection Levels -- May Be Used If There Is Clear Evidence That The Analytical Detection Level Is Well Below What Is Required For Safety • Cleaning Process Capability -- Starting To Be Used By Firms As An “Alert” Limit When Trending Monitoring Or Changeover Results mg/mL

Safety-based limit +3 Mean Time

Cleaning Validation 157

Data Reporting Form Now that we have our limit, how do we determine if our laboratory result meets the limit? To be completed by Sampling Personnel [A, B, C, D (E&F swabs only) at the time of container preparation; (E&F rinse only) G and H at the time of sample collection]

A Sample ID

B Equipment

C Location

D Sample Type S–Swab; R-Rinse

E Diluent Type

F Sample Diluent Volume (mL)

G Sample Size (cm2)

H Sampling Technician

Initials / Date

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Data Reporting Form - continued Pharm. Tech.

A Sample ID ((from above))

To be completed by Laboratory Operations at time of analysis

I * Laboratory Result (mg / mL)

J Residue per Sample (mg) (I x F)

Laboratory Operations

L Recovery Factor ** (% / 100)

K Resid. / Unit SA 2 (mg / cm ) (J / G)

Quality Assurance

M Adjust. Residue 2 (mg / cm ) (K / L)

N *** Limit (per Approved Limit Matrix)

O Is M < N? Yes - Pass No - Fail

* include all dilution factors; ensure that all units match ** from recovery study or worst-case (e.g., 50%) *** document source if other than protocol Acceptance Criteria Cleaning Validation 159

Data Reporting Form - continued Department

Activity

Laboratory Operations

Analysis By: (Reference Notebook Pages / Chromatogram #s in the Comments Section)

Laboratory Operations

Results Calculated By:

Laboratory Operations

Calculations Verified By:

Quality Assurance

Sign and Date to indicate completion of the Limit and Pass / Fail criteria. Include source for limits in Comments Section, below if they are not the standard Acceptance Criteria.

Signature & Date

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What Else Might You Need To Include In This Spreadsheet? You may need to extrapolate the actual residue id quantity tit ffrom a specific ifi active ti group or ion that was assessed in the assay (such as in TOC) form of: y = mx + b Assay Respo onse

y

m

y = mx + b b Analyte Concentration

x

Cleaning Validation 161

Setting Limits in a Facility Select the worst-case limit from possible product combinations for each product or, apply the overall worst-case to all products. Previous Product Prod. A Prod. B P d C Prod.

Next Product Prod. A Prod. B -0.052 0 0.015 015

Prod. C

0.107 -0 0.085 085

0.177 0.309 --

* expressed in mg / cm2

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Points to Remember on Setting Limits • Limits may change through the life of your program • Cleaning affects the NEXT product produced, not the one that you that you are cleaning • The introduction of new products therefore, has the greatest potential impact on the existing products in the plant

Cleaning Validation 163

Points to Remember on Setting Limits • However, some of the biggest influencers on the limits for cleaning are the three terms that represent the NEXT product – the batch size, daily dose and shared equipment train as the magnitude of these terms often outweighs the Nature term • This balance between the new and the existing must be maintained through your change control program and the reassessment of established limits

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Setting Limits in a Facility & New Product Introductions Previous Product Prod. A Prod. B Prod. C Prod. D

Prod. A -0.052 0.015

Next Product Prod. B 0.107 -0.085 0.010

Prod. C

Prod. D

0.177 0.309 --

0.045

New products add to matrix in both directions, resulting in possible new limits for both individual products and worst-case groups!

Cleaning Validation 165

Work with the Team to Create a Limits Rationale • Document your assumptions • Record your trade trade-offs offs and off off-sets sets (i.e., less conservative assumptions in one area my be off-set by conservative assumptions in another) • When selecting the worst-case from a group / bracket, define the population from which that worst-case was derived

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Microbiological Residues, their Control and Establishing Effective Limits Cleaning Validation 167

What Microbiological Residues Should Be Considered And When? Bioburden and endotoxin are typically included in the cleaning validation program if these contaminants are required to be limited in your final product based on your product specifications • Bioburden includes bacteria, yeast and molds that are present in your water system and environment and can be contributed by your raw materials, equipment and personnel • Endotoxin is a lipopolysaccharide present in the cell membranes of the gram negative microorganisms; it is released when the organisms die and can cause a fever in patients when introduced to the blood stream Cleaning Validation 168

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What are the Characteristics of Microbiological and Endotoxin Contamination? • Bioburden is living and endotoxin is derived from living systems therefore pyroburden and bioburden levels will be heavily dependent upon environmental conditions • Is equipment dry, covered and closed? • Is the environment aseptic or at least a clean manufacturing area that limits viable and nonviable particulate levels, temperature and relative humidity? (both for manufacturing and clean equipment storage) • How drastically do environmental conditions change based on season of the year? Cleaning Validation 169

What are the Characteristics of Microbiological and Endotoxin Contamination? • Like environmental monitoring, bioburden and pyroburden assessments are not one-time activities • It is recommended that the levels be subject to routine monitoring with alert and action limits and suitable corrective actions associated with exceeding each of these limits

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Precautions With Microbiological And Endotoxin Contamination • Several mechanisms can be employed for the elimination of these residues including: removal (e.g., flushing, wiping) and destruction / inactivation (e.g., chemical treatment, dry heat) • Destruction of microbiological contamination can increase the possibility of endotoxin contamination unless the destruction methodology is also an effective depyrogenation process (e.g., dry heat)

Cleaning Validation 171

Precautions With Microbiological And Endotoxin Contamination • Cleaning and sanitization / disinfection cannot be performed in a single step: • Residues will inhibit the penetration of chemical agents • Rinsing, such as that typically following cleaning procedures, may introduce additional bioburden • Agents typically used for sanitization / disinfection are typically poor cleaning agents as detergency is generally not optimal for the designated residues

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What Is Used To Derive Microbiological And Endotoxin Limits? • Guidance for limits should be taken from: • Product specification requirements for limiting specific categories or total levels of contamination • Historical monitoring results – (especially useful once a trend has been established and when the product permitted levels are significantly higher than experiential levels) [N t N [Note: Nott allll products d t will ill require i endotoxin d t i lilimits] it ]

Cleaning Validation 173

What Is Used To Derive Microbiological And Endotoxin Limits? • Both action and alert limits are typically established • Considerations in establishing these limits include product sensitivity [i.e., micro vulnerability] which can be determined through water activity measurements and/or historical data • For those products which are ultimately sterilized sterilized, we should ensure that we understand the challenge levels performed for our sterilization process validation Cleaning Validation 174

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Frequency Distribution Approach to Setting Alert and Action Limits 95% Alert Limit / 99% Action Limit

< <

# CFU

# of Occurrences

% Occurrences

Total Frequency

0

59

19.67%

19.67%

1

67

22.33%

42.00%

2

47

15.67%

57.67%

3

24

8.00%

65.57%

4

32

10.67%

76.34%

5

18

6.00%

82.34%

6

27

9.00%

91.34%

7

11

3.67%

95.01%

8

5

1.67%

96.68%

9

3

1.00%

97.68%

10

2

0.67%

98.35%

11

3

1.00%

99.35%

>11

2

0.67%

100 %

Total Samples = 300

Microbiological Residues Help Identify the Source of Contamination • Speciate the representative colony forming units in order to trend typical flora and identify potential sources / causes Type of Contaminant Common Causes (not exhaustive, just typical)

• Typical types of contaminants and sources of contamination, include:

Bacillus species

• HVAC • Environment • Sanitizer efficacy

Gram positive bacteria

• Personnel • Gowning • Aseptic techniques

Gram negative bacteria

• Water • Environment

Mold

• HVAC • Environment

Yeast

• Personnel • Gowning • Aseptic Technique

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 88

176

Sampling Techniques for Microbial and Endotoxin Residues • As with chemical residues, the sampling techniques for microbial bioburden and endotoxin (py (pyroburden)) must be qualified to ensure that there is no interference and to ensure that the technique recovers the residues appropriately. • Common surface sampling techniques include: • Swab - applicable to both micro and endotoxin (although not as common for endotoxin); ensure that you determine recovery • Rinse - applicable to both micro and endotoxin, however large volumes can make this undesirable for sensitivity; can be filtered for micro purposes • RODAC - applicable to micro only, direct surface measurement through media press-plates, requires scrupulous cleaning after sampling

Cleaning Validation 177

Other Tips on Micro Programs • Time between sanitization and sampling should be standardized in order to get a consistent picture of bi b d bioburden • Consideration should be given to measuring bioburden both after cleaning and after storage, before use • Keep chemical cleaning and bioburden / endotoxin reduction programs under separate protocols • Chemical cleaning programs can then be concluded while monitoring continues for bioburden and endotoxin

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Module 7: Methods Validation and Recovery Studies: It all comes down to your data! Cleaning Validation 179

Assay Methods • Assay methods are preferred to be specific to the analyte g methods ((e.g., g , non-specific) p ) may y be used • Screening provided that all analyte identified is attributed to the worst case residue limit • Assay methods most commonly employed are those which the company already have in their laboratory • Assayy methods and sampling p g methods must be demonstrated to be suitable through methods validation in conjunction with the sampling method / extraction system and through recovery studies

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Goals of Test Method Validation • Demonstration that a test method is predictable (e.g., linear, accurate, precise, specific, rugged) across the range of interest • Demonstration that the sample preparation, instrument and method instructions are all appropriate for use and reproducible

Goals of Test Method Transfer • To demonstrate that a test method can be reproduced p reliably by a different laboratory on different instrumentation often with different personnel prior to first use official use

Cleaning Validation 181

Elements and Acceptance Criteria for Methods Validation • Industry standard practice for methods validation is taken from USP and ICH guidance on methods validation • These guidances often focus on traditional analysis methods such as chromatography and spectroscopy, yet you may be using more novel methods such as direct surface analysis using an IR probe or Ion Mobility Spectrometry (IMS) therefore modified approaches may be called for • When deviating from industry standard practice, practice or your site procedures for methods validation (which are typically written for product release or stability methods), remember that your policy or protocols should contain the rationale for the selection of the approach and the acceptance criteria Cleaning Validation 182

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The Four ICH and USP Assay Types Category I Assay

Analytical methods for quantitation of major components of bulk drug substances or active ingredients (including preservatives) i fi in finished i h d pharmaceutical h ti l products. d t

Category II Assay

Analytical methods for determination of impurities in bulk drug substances or degradation compounds in finished pharmaceutical products. These methods include quantitative assays and limit tests.

Category III Assay A

Analytical methods for determination of performance characteristics (e.g., dissolution, drug release).

Category IV Assay

Identification tests.

Cleaning Validation 183

Method Validation Requirements for Various Assay Types Assay Category II Impurities

Analytical Performance Attributes

Assay Category I Potency

Limit Tests

Assay Category III Performance

Assay Category IV Identity

Quantitative

Accuracy y

Yes

Yes

*

*

No

Precision

Yes

Yes

No

Yes

No

Specificity

Yes

Yes

Yes

*

Yes

Detection Limit

No

No

Yes

*

No

Quantitation Li it Limit

No

Yes

No

*

No

Linearity

Yes

Yes

No

*

No

Range

Yes

Yes

*

*

No

* May be required. Depends upon the nature of the specific test. Robustness should be considered for any type of method!

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Methods Validation for Cleaning Studies • Linearity is critical to establish as we recognize that our limits may change over the life of our program • If we treated cleaning validation as a strict limits test and didn’t assess linearity we wouldn’t be able to reinterpret our results if the limits changed • Once we’ve determined that we need linearity linearity, this naturally leads us to understand that we need to understand our accuracy and precision

Fail Pass

• Intuitively we know that Quantitation Limit and Detection Limit will be critical to any trace analyte assay • Specificity is a good attribute to understand for specific / direct methods, but is not as critical if we are using a screening method such as TOC

What Other Elements Are There? • Although the table of method validation criteria is good, there are other characteristics that are also defined, including: • Intermediate I t di t P Precision i i (f (formerly l called ll d R Ruggedness) d ) • Robustness • System Suitability • Sensitivity • Intermediate precision and robustness can be very helpful p in cleaning g validation where we recognize g that we may have significant variability introduced by day to day testing, slight changes in analyte or assay conditions

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What Other Elements Are There? • System Suitability is a key for complex methods where you want to assure that there is sufficient control over the analytical y system y before interpreting your results • Sensitivity can be interpreted from the linearity determination, and, when required can be determined more specifically through experimentation • Let’s discuss each attribute in more detail

Cleaning Validation 187

Elements of Test Method Validation

incre easing response (e.g., absorbance, ppm C, etc.)

Accuracy

The closeness of test results obtained by the method to the true or accepted value. It provides an indication of any systematic error or bias in the method and should be determined across the method’s range. range Typical acceptance criterion of 0.995 in most cases (>0.98 for trace analytes such as in cleaning validation may be appropriate).

Cleaning Validation 197

Elements of Test Method Validation Range

The interval between the upper and lower levels of analyte (inclusive) over which the linearity, accuracy and precision have been suitably validated. Typically this will correspond to the range used in the recovery studies.

Range does not have any “acceptance criteria”, rather range for the assay is “reported”. It is expected, however g of 80% to 120% will be achieved. that a minimum range You may have noticed, that if planned properly, the requirements of linearity, accuracy, precision and range can all be ascertained from a single experiment. Cleaning Validation 198

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Other Elements For Consideration Robustness

The determination of the suitable limits for critical test parameters to show reliability during normal use. A measure of a method’s method s capacity to remain unaffected by small small, but deliberate variations in method parameters (i.e., pH, concentration, temperature, flow rate, wavelength, etc.). This may be particularly important if residuals from the cleaning process might affect the assay (e.g., pH).

System Suitability

The assessment of a system’s performance and precision as a measure of day to day accuracy and precision of the method. System suitability is required to be performed at least daily for each chromatographic method. The definition and confirmation of system suitability parameters, therefore, is often included in validation testing. It is generally expected that the system suitability standard will perform better than the analyte under measurements of precision 80% 80% recovery

Cleaning Validation 217

Acceptance Criteria for Recovery Studies • Recoveries of less than 50% should be investigated, g , and swab methods,, swab material and diluents should be optimized, as necessary • Be careful when interpreting results -- avoid averaging across a population of samplers lowest recovery is most conservative • Consider an RSD acceptance criteria between results such as 10 or 15% -- ensure that the value selected makes sense based on the assay precision Cleaning Validation 218

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Discuss the Following: • What is the consequence of using a coupon in your recovery studies that is smaller than your routine sample size? • What is the consequence of using a coupon in your recovery studies that is larger than your routine sample size? • What are the possible considerations when recovery is low for a compound? • What do you investigate when individuals don’t get the same y for a compound p one operator p to the next? recovery • What do you investigate if a single individual doesn’t get the same recovery sample to sample? Would your answer change if multiple personnel suffered the same failure?

Cleaning Validation 219

Methods Validation and Recovery Studies • Testing and acceptance criteria must be defined in a protocol p • The protocol for the method and the recovery study may be one document provided that all criteria are included

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Methods Validation and Recovery Studies -continued • If no SOP draft exists, protocol must define the critical method p parameters / method set-up; p; method must include: • • • •

Instrumentation and instrumentation operating parameters Specifications for standardization or calibration of method Instructions for how to prepare sampling kits Instructions for how to sample (if not already included in a standalone procedure) • Conditions of storage and test of samples • Calculation / reporting of results

Cleaning Validation 221

Methods Validation and Recovery Studies-continued • Results must be collected and reported in protocol or bound laboratory p y notebook;; good g documentation practices apply • Summary report should be prepared which interprets the results and reports key values such a LOQ, Q, recoveryy

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Types of Test Methods • Specific / Direct methods • methods that can uniquely identify an analyte; be careful as not all specific methods are effective at quantifying analytes; all method validation considerations to this point should be considered

• Non-Specific / Indirect / Screening methods • while linearity, accuracy and precision apply, generally specificity does not as a screening method is one that does not typically yp y uniquely q y identify y the analyte(s) y ( ) ((e.g., g, TOC)

Cleaning Validation 223

Types of Test Methods • Biological assays •

due to the lack of complete characterization of many g residuals,, their p propensity p y to denature or biological degrade in the presence of cleaning conditions, biological materials often have more relaxed limits associated with methods validation; the key is to ensure adequate reproducibility to ensure a valid test

• Microbiological tests • because the materials being measured are living organisms, g their behavior is less p predictable than conventional chemical assays; keys here include the verification that competitive, inhibitory or enhancing materials do not influence the results achieved

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Examples of Potential Cleaning Validation Chemical Test Methods Specific / Direct Methods

Non-Specific / Indirect Methods

High Performance Liquid Chromatography (HPLC)

pH

Gas Chromatography (GC)

Conductivity

Atomic Absorption (AA)

Total Organic Carbon (TOC)

Inductively Coupled Plasma (ICP)

Gravimetric Analysis

Spectrophotometry S t h t t (UV, (UV Vis, Vi IR IR, Near-IR, Mid-IR, FTIR)

Ph t electron Photo l t emission i i

Ion Mobility Spectroscopy (IMS)

Visual

Specific or Direct Methods Specific / direct methods are often seen as being more desirable due to their ability to uniquely identify the contaminant – however, this may also limit their usefulness!! Disadvantages • They are often unable to screen for a wide variety of compounds such as those that might be present in a complex solution (e.G., Media in a fermentation process) • Can be expensive to develop; especially if the current “product release method” isn’t effectively modified for trace analytes • They may be subject to background interference from other residues which may prohibit identification of the target analyte • Ability to identify an analyte uniquely does not always correspond with the ability to “quantify” an analyte! Cleaning Validation 226

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Specific or Direct Methods Specific / direct methods are often seen as being more desirable due to their ability to uniquely identify the contaminant – however, this may also limit their usefulness!! f l !! Advantages • Can be highly sensitive • Can frequently also be used on related compounds such as degradants or impurities formed from the primary molecule

Cleaning Validation 227

Non-Specific or Indirect or Screening Methods Non-specific / indirect / screening methods, as stated previously are typically less desirable for the determination of contamination Disadvantages • They lack the specificity to identify a specific analyte • Users often fail to justify assay for their use • They may be subject to background interference from other residues (although with some methods this can be turned into an advantage by conservatively attributing it all to the worstcase residue!)

Advantages • Can be highly sensitive • Can be effective on multi-constituent compounds

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FD483 Observation “Equipment cleaning validation consisted of only testing Purified Water rinses for pH and conductivity. It was not tested for chemical cleaning agents or product.” This 483 points out the concern of the FDA that non-specific techniques do not provide assurance that products can be detected by the non-specific methods

Some residues however, are detected effectively and sensitively by these analytical techniques techniques, so it is important to justify the technique (and limits!) to your analytes. Conc. 0.125% 0.250% 0.500%

Agent A 1.0 2.0 4.0

Agent B 0.1 0.2 0.4 Cleaning Validation 229

Potential Biopharmaceutical Impurities and Contaminants and Commonly Used Methods for Determination; 0.5 - 10ppm Level Representative Biotech Process Impurities & Contam

TOC

Media/Nutrients Metabolites Endotoxin DNA/Nucleic Acids Carbohydrates Lipids Proteins: Native Denatured Stabilizers Filt Extractables Filter E t t bl Leachable Column Comp. Cleaning Agents: Organic Inorganic

ELISA Lowry SDS/ RIA Protein PAGE

LAL HPLC

Ion AA / Chrom ICP

+ + + + + +

+ + +

+ -

+ -

+ -

+ + + +

+ + + +

-

+ + + + +

+ -

+ + -

+ -

-

+ + + + +

+ + +

-

+ -

-

-

-

-

+ -

+ +

+

TOC – Total Organic Carbon ELISA / RIA – Enzyme Linked Immunosorbant Assay / Radio Immunolabeled Assay SDS PAGE – Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis LAL – Limulus Amoebocyte Lysate (endotoxin test) HPLC – High Performance Liquid Chromatography AA / ICP – Atomic Absorption / Inductively Coupled Plasma

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Total Organic Carbon • TOC is popular due to: • Wide availability of instrumentation • Simple sample preparation and analysis • Ability to evaluate multi-constituent residues to low levels

• Organic carbon + OH- -----> HCO3• Instrument measures the conductivity of the HCO3• Microprocessor subtracts off the conductivity of the bicarbonate present due to the CO2 dissolved in water • Microprocessor measures slope of conductivity curve and once it reaches a plateau, it determines the value (maximum TOC in ppm) • Readily oxidizable substances will provide a quick readout

Cleaning Validation 231

How Do We Assess A TOC Result? • Amount of carbon in a compound is determined • Empirically • Through the analysis of the pure sample • Swab or rinse water sample is analyzed • ppm of carbon must be translated to the amount of residual material left behind on the surface

ppm C

Conservative assumption all residue found is from the most toxic or potent substance

y = mx + b mg / mL product

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Ion Mobility Spectrometry – New Approach • Samples are ionized and flow down a “drift tube” with a low flow gas carrier; m.w. and geometry govern drift and time to strike detector region forming an ion spectrum • Great technique for low level detection (nanogram levels are common) • Spectra characteristics for your substance (likely in the presence of your cleaning agent) need to be established • Sample needs to be aerosolized by instrument • ROI may be justified based on shorter equipment quarantine

Visually Clean • Baseline cleanliness conditions should be documented, especially for legacy equipment • Visual threshold can be quantified and should be, if used as a primary indicator – be careful of inspection technique equivalency if conducting quantification • May be appropriate for dedicated equipment or noncritical limits (non-toxic or non-product contact surfaces) f ) • Remember that this approach is not safety related unless specifically compared to a safety based limit.

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Current Issues in Methods Validation • Investigation and outcomes from unknown peaks • • • •

Establish an investigation strategy Determine what “unknowns” testing will be conducted Will look-back on past three lots be performed? What will be assumed about the quantity of the unknown material?

• Selection of analytical techniques for “alternate” times of cleaning (e.g., receipt of new equipment, after maintenance, etc.) • Determination of methods for the validation of equipment expiration (residues are unlikely to be product product-related, related more typical would be particulate, bioburden and/or endotoxin)

• Correlation of results from monitoring methods (may be nonspecific / indirect) to validation methods (may be specific / direct)

Cleaning Validation 235

Module 8: Engineering Studies and Cycle Development p – Just say “No!” to Experimentation During Validation Cleaning Validation 236

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Engineering Studies or Cycle Development Goals of Engineering Studies: • Identify successful cleaning parameters (TACT) • Optimize cleaning parameters (not always a goal!) • “Dry Dry run” run a protocol

Engineering studies can: • Prevent the inclusion of failures in “untried” processes in your validation (i.e., permits test until clean) • Permit the establishment of parameters for equipment that is peripheral or outside of current grouping/bracketing elements

Common Co o uses o of e engineering g ee g stud studies es include: c ude • New process equipment • New cleaning equipment • New / revised products

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Engineering Studies or Cycle Development • Random testing, especially when starting from a known, successful process can be effective but often isn’t time or cost effective • Optimized parameters are often not developed if a random or use of a previous process is followed • Alternative approaches include the consideration of tools such as Design of Experiment to maximize the data available from a minimal number of trials Cleaning Validation 238

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Sample 3 Variable Screening DOE Run Order (randomize)

Time

Temperature

Concentration

1 2

8

Low

Low

Low

1

High

Low

Low

3

2

Low

High

Low

4

4

High

High

Low

5

3

Low

Low

High

6

5

High

Low

High

7

7

Low

High

High

8

6

High

High

High

• Here it is assumed that the “action” is constant for your system. • If you only are varying two parameters (e.g., your water is only available at a single temperature), your experimental design will be cut in half

A graphical view of the same experiment

8

7 3

4

H

Temperature

Experiment

L

H 5 1

Time

6

H

2

Gathering and Analyzing Results • Engineering studies are a potential good use of screening methods – especially if you aren’t trying to achieve a limit, but rather understand the relationship of one result to another • Use analysis of variance (ANOVA) techniques to examine results • ANOVA can tell you what parameters were most influential in achieving a “clean” system and which factors are most influential on each other (dependent variables) based on their interactions Cleaning Validation 240

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Other Development Considerations Use bench studies with coupons and controlled parameters to perform initial screening – you won’t tie up p equipment q p and yyou may yg go to the field with one or more of the parameters (or levels) eliminated from consideration • Test tube dissolution studies • Coupon evaluation Some cleaning agent vendors will also provide services to perform initial temperature temperature, time and concentration screening for you – multiple levels may not be considered for each parameter but it can, as above, eliminate some of the possible parameters or levels

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Documentation and Engineering Studies • Documentation for engineering studies is typically less formal (or fewer approvals) than for validation studies • Ensure you reliably record the experimental design, including all failures, as these will be beneficial in future failure investigations and further optimization • Ensure that intended “studies” on the plant floor are cleared through change control in order to ensure that the necessary precautions for material and equipment segregation / quarantine are in place • Engineering studies are not an excuse to use dirty equipment in production – if production is to follow the engineering studies ensure that testing confirms cleanliness with validated analytical methods, validated sampling procedures and safety-based limits

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Validation is Not the Time for Experimentation

Validation is intended to demonstrate process control.

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Module 9: Creating Cleaning Validation P t Protocols l – The Heart and Soul of Your Validation Cleaning Validation 244

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Understand Your Objectives Take stock of your decisions to this point: • What equipment is the subject of your study and what boundaries will be observed? • What residues will you be assessing? Can you assess them in a single trial or will multiple trials be required? • Active / Excipient • Micro • Particulate

• What groupings / bracketings of equipment / products have been created and which will be used as part of the validation rationale? • What analytical methods / sampling methods will be in use? Make sure you identify them clearly for each analyte along with the procedure(s) to be followed.

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Understand Your Objectives Take stock of your decisions to this point: • What locations on the equipment will be sampled? Do you have your sampling map prepared? • What key parameters will you be studying / observing (T.A.C.T.)? • Will you simply be monitoring them or do you intend to challenge them? • Will you need to have multiple operators / shifts performing the cleaning procedures? • Will you be witnessing the cleaning?

• How will your equipment be soiled? • R Routine i production d i – single i l b batch h • Routine production – campaign (# of days / # of batches) • Intentional worst-case soiling – is a justification available for this being worst-case

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Understand Your Objectives Take stock of your decisions to this point: • What is the maximum time after use before cleaning? Will the maximum be explored? • What are your limits? Do you have a clear list of all calculations that need to be included for the interpretation of your results? • What documentation of cleaning will be included as part of the validation record? • Will your study include an equipment expiration study or will that be a separate study? • What is the time after cleaning before next use? • What are the conditions of storage? (covers, environment, etc.)

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Worst-Case Conditions to Challenge In Validation Studies • Worst-case conditions are typically included in validation • Worst-case conditions can help us assure that our procedures / process are robust • By demonstrating robustness, we are including an inherent safety factor that will help to assure that if we see minor changes in soil load, or person to person differences that our process will still be successful Cleaning Validation 248

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What Worst-Case Conditions Should Be Considered? Worst-Case … • Hold times before cleaning

Rationale … • Residues may dry on surfaces or, if hygroscopic may pick up moisture

•

Personnel / Shifts

•

May provide representative data with regard to person-to-person or shift-to-shift robustness

•

Process parameters

•

Reducing process parameters (e.g., 5 minutes less wash time) will ensure that full parameter is l successful f l always

•

Starting soil conditions such as maximum campaign length and/or maximum batch size

•

Will ensure that any condition that is less severe in terms of soil load will be successful

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Typical Cleaning PQ Protocol Contents • Scope / Purpose • define the equipment, procedures, practices to be challenged; be sure to include references to any groupings i / bracketing b k ti off equipment i t / products d t that th t will also be considered validated based on a successful outcome

• Responsibilities • participants in the validation and their roles in the studies

• Background • optional section to describe any pre-work leading to this point; references may be included to cycle development, prior trials or linked validation studies Cleaning Validation 250

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Typical Cleaning PQ Protocol Contents • Experimental Design • this section should define the key decisions and rationales, such as: • Equipment design or definition / boundaries • Soil selection criteria • Analytical method selection / sampling method • Sampling site selection • Worst-case conditions to be challenged (soil load, h ld ti hold times, cleaning l i parameters, t etc.) t ) • Limits to be applied

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Typical Cleaning PQ Protocol Contents • References • Include those documents that support the accomplishment of the validation, avoid extraneous generic references • • • • • • • •

Cleaning SOPs Training programs Rationales IQ / OQ performance of cleaning equipment and automation Analytical method / sampling method SOPs Analytical method validation summary report Recovery study summary report Failure Investigation / OOS procedure to be followed Cleaning Validation 252

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Typical Cleaning PQ Protocol Contents • Validation Procedure – details of each data sheet to be executed and attached to the validation, including all documentation to be completed and attached • Acceptance Criteria – include limits (or their source) and all calculations required for the interpretation of results

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Typical Cleaning PQ Protocol Contents • Revalidation conditions / parameters • Monitoring conditions / parameters • Data sheets for execution 1. Instrument and Calibration Checklist 2. Equipment Boundaries (if to be field verified) 3. Standard Operating Procedures / Training 4. Methods Validation / Recovery Studies (if to be field verified) 5. Witnessing of Cleaning 6. Rinse Samples Order of these 7. Visual Assessment activities is cleaning process dependent! 8. Swab Samples 9. Post-Sampling Activities 10. Deviation Summary

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Meaning of Consecutive Successful • Validation guidelines often refer to FDA’s requirement for “consecutive successful trials” • Consecutive successful in these cases means consecutive trials without intervening failures – it does not mean without intervening production • Defend the timing of your cleaning evaluations as part of your strategy • When you have a failure, be sure you understand and investigate whether they are: • Extrinsic failures – not p process related, therefore repeat p only y the failed run (e.g., utility breakdown, failure to follow SOP, etc.) • Intrinsic failures – process related, therefore repeat the entire validation

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Issues with Campaign Manufacture When getting ready for submission and launch we . . .

Batch #1

Batch #2

PV 1 CV 1 In real life we . . .

Batch #1

Batch #2

Batch #3

PV 2 CV 2 Batch #3

Batch #4

PV 3 CV 3 Batch #...n

Validation should reflect real life. We also need to have data to Cleaning support inspections such as the PAI. Consider collecting data Event later as part of the life cycle under monitoring programs. Cleaning Validation 256

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When Are We Through? Batch #1

Batch #2

Batch #3

Batch #4

Batch #10 Cleaning Event Sample / Test

Batch #1

Batch #2

Batch #8

Batch #3

Cleaning Event Sample / Test

Batch #1

Batch #2

Batch #6 Cleaning Event Sample / Test

How long a campaign have we validated?

Cleaning Validation 257

Time After Cleaning Before Use – Hold Time Studies or “Equipment Expiration” • Equipment should be stored DRY and COVERED or CLOSED • Microbial propagation will depend upon: • Conditions of storage (e.g., Temperature and relative humidity of environment, quality / cleanliness of covers, degree of cleanliness and dryness of equipment) • Location of storage (e.g.., Clean equipment storage room, in the room in which cleaning is conducted or in a production room that is used for other purposes before equipment reuse) • Genus and species of contamination • Starting population

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Time After Cleaning Before Use Hold Time Studies or “Equipment Expiration”

++

+

Clean Equipment Storage

++

Manufacturing Corridor

+

Clean Equipment Storage

Manufacturing Corridor

• Beware!! Rooms retrofitted to equipment storage uses may not have the proper pressurization to hold the equipment in a “clean” state

• Other precautions include: • Consider whether reuse of cover material is wise • Keep equipment away from aerosols aerosols, dust generating activities • Keep foot traffic in clean equipment storage area to a minimum • Ensure that personnel entering to retrieve equipment have on clean gloves, gowns, booties, etc. • Prevent relocation from clean manufacturing to uncontrolled areas and back again Cleaning Validation 259

Time After Cleaning Before Use Hold Time Studies or “Equipment Expiration” Residues to consider include: • Particulate (e.g., environmental dust) • Bioburden Bi b d • Endotoxin • Product -- generally only when equipment is stored in the production space during other processes or when the equipment is stored in the cleaning room where dirty equipment is brought Analytical and sampling methods may differ from those used during the cleaning validation: • Rinse sampling for particulate • TOC analysis (difficulty here is setting limits) • Visual assessment (difficulty here is establishing whether residues would be assessable at appropriate limits for visual detection) Cleaning Validation 260

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Time After Cleaning Before Use Hold Time Studies or “Equipment Expiration” Study Elements • Understand typical hold times for equipment • Use the 80:20 rule – handle the 20 as outliers requiring complete rere cleans prior to use – don’t try to validate to the absolute extremes, you are unlikely to be permitted to hold equipment that long! • Ensure that routine (or intentional) interventions with equipment / storage areas, etc. will occur during study

Options / Considerations for Studies: • Justify that pre-use rinses will be sufficient to remove residues prior to processing and eliminate the need for these studies entirely • Group equipment into broad categories that are handled in similar fashions after cleaning and study representative members (e.g., closed vessels v. open tools) • Because residues, especially bioburden, will change over time, keep the equipment expiration studies as part of the routine bioburden assessment (i.e., ongoing) rather than discrete validation studies (i.e., 3 runs) Cleaning Validation 261

Module 10: Collecting and Testing Validation Samples Do not Break the Chain

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Laboratory Methods Transfer and Validation Confirmation • Confirm that all test methods required to support the validation have been validated or transferred with the appropriate ruggedness • Ensure that there are clear references to the analytical methods and sampling methods in the validation protocol • If the method is sensitive and sample stability was evaluated as part of the methods validation validation, ensure that appropriate procedures / tools are in place to properly handle the samples after collection and to record and control the time between sampling and testing

Cleaning Validation 263

Sampling • For each analytical method, within the protocol or in an appropriately detailed SOP or method identify: method, • Proper sampling technique • Appropriate sampling container and tools • Controls and standards to be sampled and tested along with the “unknowns” • Personnel / department qualified to collect sample • Sound S d sampling li plan l that th t does d nott bias bi the th results lt of one sample based upon the collection of another

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Sampling • Ensure that trained personnel are available at the intended times of field execution • Ensure that data collection in the data collection sheets for the protocol is appropriate for capturing all results and control samples

Cleaning Validation 265

Field Execution Goals The goals of field execution are to: • Witness operations • Compare actual results to acceptance criteria • Document the testing conducted Key capabilities of personnel participating in validation include: • Understanding of the operating principles of the equipment that is being cleaned • Clear understanding of the validation protocol requirements • Attention to detail and effective documentation skills

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Field Execution – Tools to Take to the Field Materials & resources needed for field execution • Approved protocol on file • Official copy of blank attachments / checklists • Appropriate SOPs, sampling and analytical methods, sampling maps, etc. • Trained operators to perform the cleaning • Qualified sampling technicians • Calibrated C lib d test instruments i (if any)) • Designated sampling containers and labels, supplies and tools Training should be conducted in job-specific procedures as well as general “clean” / aseptic practices

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Field Execution – Good Execution Practices • Prior to validation conclude and summarize experimentation – ensure that all systems are in good working order with current preventive maintenance calibration and p • Ensure that all supporting rationales are documented and approved • Ensure that protocol and monitoring conducted in the field demonstrate process control • Take notes in the protocol in an identified comments section, not within a separate notebook • Ensure that observations are recorded, initialled and dated in case of future investigation or review Keep comprehensive notes – Others should be able to follow the work and repeat it. Cleaning Validation 268

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Field Execution – Points to Consider • Get into the field to the equipment - no validation from your desk • No original data should be destroyed • Write information directly on attachments or official data sheets for the purposes of validation - NO transcribing • Show calculations • Protect documentation DRAFT • Use binders & sheet protectors COPY • Attach and label raw data printouts where available • Protocol P t l number, b attachment tt h t number, b page number, initials, date Protocol #: _________ • Use ink stamps or Attachment #: _______ clear laser labels

Test Step #: Page ______ of ______ Cleaning Validation 269

Field Execution – Good Documentation Practices • Complete all datasheet spaces p • Unused datasheet spaces • N/A or N/R as local procedures require • Justify the omission if the information is required as part of the test

• Errors in datasheets • Single line through, initial and date – original remark must be readable • Put correct information above the lined out information • If the correction rationale is unclear state the rationale adjacent to the error or in the comments section

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Field Execution – Good Documentation Practices • Always use dark indelible ink • If using symbols to relate to notes on pages pages, ensure that there is no opportunity to confuse the symbols in use • Always show a sample calculation for any calculations performed; if using a spreadsheet, consider the q qualification of the spreadsheet p and/or print the spreadsheet such that formulae are revealed

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Chain of Custody • Be scrupulous on sample identification • Ensure that sampling paperwork clearly identifies the sample collection location and the sample identity • If sampling conditions vary (e.g., diluent or rinse volume and surface area sampled) ensure that the sample conditions are tied closely to the sample • Considerations for sampling paperwork includes: • Time of collection, time of submission and time of test (when critical to sample integrity) • The list of samples submitted to the laboratory • The Th correlation l ti off tests t t to t be b conducted d t d on each h sample l (e.g., ( active, cleaning agent, bioburden, etc.) • Storage location and conditions (ideally circular charts if temperature is critical) • Initials of personnel performing collection, storage, preparation, testing and data analysis Cleaning Validation 272

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Data Reporting Form Add the timing requirements and assays called for on the sampling form or create a separate chain of custody to be issued with the sampling form. To be completed p by y Sampling p g Personnel [A, [ , B,, C,, D (E&F ( swabs only) y) at the time of container preparation; (E&F rinse only) G and H at the time of sample collection]

A Sample ID

B Equipment

C Location

D Sample Type S–Swab; R-Rinse

E Diluent Type

F Sample Diluent Volume (mL)

G Sample 2 Size (cm )

H Sampling Technician

Initials / Date

Cleaning Validation 273

Deviations in Field Execution • Deviations do not mean that the validation is a failure • Deviations require a formal investigation and determination of the impact to the validation as well as the appropriateness of reusing the equipment for the next process • Extrinsic failures – not process related, therefore repeat only the failed run (e.g., utility breakdown, failure to follow SOP, etc.) • Intrinsic failures – process related, therefore repeat the entire validation

• Follow FDA’s guidance relative to conduct of failure investigations

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FDA’s Proposed Revision to the GMPs Failure Investigation Guidelines (1996) Procedures / Written record must be available for: • Identifying the cause of the failure or deviation • Criteria C it i ffor d determining t i i whether h th out-of-specification t f ifi ti results lt were caused by sampling or laboratory error • Criteria for the exclusion of any test data found to be invalid due to laboratory or sampling error • Criteria for additional sampling and testing, if necessary, during the investigation • Criteria for extending the investigation to other batches or other p products • Review and evaluation of the investigation, including all test results, by the quality control unit • Criteria for final approval or rejection of the batch involved, and for taking action on other batches and products

Cleaning Validation 275

Real Situations – How Would You Handle….. • You drop a sample on the way back to the laboratory - does d iit iinvalidate lid the h trial? i l? • Your visual inspection passes, you swab the surface and the swab comes away with a stain, upon analysis no product is detected -- does the trial pass? • Your rinse sample passes and your swab sample fails -- what h t is i your corrective ti action? ti ? H How d does thi this affect ff t your monitoring strategy? • What happens if you can’t achieve your limit?

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Module 11: Validation Reports p and Beyond y “To Infinity and Beyond” – Toy Story™

Cleaning Validation 277

Validation Reports • Approval Page - corresponding signatures to those approving the protocol pre-implementation • Purpose / Scope – reiterate the goals and boundaries of the validation; referencing supported groupings / bracketing may again be appropriate • Background – reiterate any pertinent relational information with regard to other studies • Description – provide sufficient description of the system to ensure that this document can stand alone as a summary to the executed protocol • Procedures / Test Methods / Equipment – define those elements used to execute the protocol – remember that these now represent the validated operational / process state

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Validation Reports • Results - provide a summary of results and state whether acceptance criteria were met; use tables and graphs to present data effectively; reference deviations that occurred and point to the deviation section; provide evidence of how the acceptance criteria were met • Deviations – list the deviations and their resolutions, state the impact to the validation and/or to follow-on production, if any • Revalidation – state the conditions under which revalidation would be required (e.g., change in key process parameter, change in cleaning agent, modification to equipment, formulation, etc.) • Conclusion – state whether the initial goals of the protocol were met; reiterate any groupings / bracketing that are supported by the validation; clearly state any procedure amendments or requirements as a result of the qualification • Follow the summary with the executed protocol

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Review and Approve Reports • Ensure that all groups agree with the validity of the data collected and the conclusions reached • Ensure su e that a a all accep acceptance a ce ccriteria e a have a e bee been met e • Ensure that all groups agree that the pertinent regulatory and policy requirements have been met – especially if there were any failure investigations as a result of OOS or deviations • Ensure that all g groups p understand any y directions for future production (e.g., procedures to be followed for cleaning, additional disassembly procedures, inspectional requirements, etc.)

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Maintenance of the Validated State Programs that maintain the validated state: • • • • •

Preventive Maintenance Calibration Change Control Monitoring Revalidation

Cleaning Validation 281

Preventive Maintenance Definition • Planned activities (generally specified by the equipment / system manufacturer) which ensure that equipment operates correctly • Ensures ongoing operation of equipment without fault • Ensures continued compliance with the initial validation parameters • Required R i d iin th the CGMP CGMPs • Preventive maintenance is NOT repairs or modifications Cleaning Validation 282

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Preventive Maintenance and Cleaning For automated systems, ensure that: • Cleaning agent dispensing apparatus is functional and not clogged • Ensure spray balls / spray devices are not clogged and are freely rotating (as appropriate) • Ensure valves are operating properly and are in good repair • Wear • Corrosion • Shedding

• Leaking (e.g., (e g spray nozzles)

For manual systems, ensure that: • Cleaning tools are routinely inspected and replaced as necessary for: Cleaning Validation 283

Calibration Definition • Testing (and adjustment if necessary) of instruments to ensure that they indicate accurately, t l in i accordance d with ith recognized i d standards, across their full or intended operating range • Required for safety of product, equipment and employees • Required in the GMPs

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Calibration Considerations • Requires demonstration of traceability to appropriate calibrated standards • Before each operation, confirm calibration status of all process equipment or instrumentation • Incidents which might affect the calibration should be reported to ensure that the calibration can be verified and / or repeated, as necessary • Ensure that procedures are clear with regard to the notification required when “adjustments” are necessary -- define the p permissible range g carefully! y • IQ / OQ should verify that the instrument range and accuracy are suitable to the process control capability desired

Cleaning Validation 285

Calibration and Cleaning • Calibration is required for all instruments that are assuring T.A.C.T. • Consider C whether sensors ((e.g., proximity sensors on a dynamic spray ball) are part of the calibration or PM program • Ensure that instruments that are used for both process monitoring / control and cleaning monitoring g / control are suitable in accuracy y and range to both tasks

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Change Control Definition • Intent is to maintain validated state (i.e., process control) via review and approval of changes made • Document changes made for: • Process improvements (planned changes) • Repair / replacement (planned or unplanned)

Cleaning Validation 287

Change Control Scope Change Control, must exist* for: • • • •

Equipment Computer software Computer hardware Process directions / procedures / forms (i.e., controlled documentation) • Processes and formulations • Raw materials / components • Test methods / sampling methods * Programs may or may not be separate for these different programs

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Change Control and Cleaning Consider the necessity to review your cleaning approach when any of the following change: • • • • • • • •

Solvent or cleaning agent to be used for cleaning Batch size or dose size Formulation, pre-cursors or intermediates Processing conditions Process equipment Procedures for cleaning, sampling or testing Campaign length Hold times / hold conditions

Cleaning Validation 289

Monitoring Definition Demonstrates consistency of initial cleaning results by reconfirming the results through intermittent sampling of equipment after cleaning validation is complete • Most often applied for manual cleaning to confirm the continued good practices of the operators and to ensure that there is no “drift” with time • May also be applied at times of changeover after a long campaign • Biologics facilities often perform “verification” or “certification” activities for facilities change-over which is really a form of monitoring Cleaning Validation 290

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Monitoring Considerations Monitoring sampling techniques may be less intrusive and somewhat h t less l iintensive t i th than th the original i i l sampling li such h as the following examples: • Rinse sampling used preferentially over swabbing • Screening methods used rather than specific methods • May only look for one key analyte Difficulty is correlating monitoring techniques and results to validation techniques and results

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Monitoring Benefits • Can be predictive of undetected change in the system • Can help to ensure consistency of training and personnel performance with time • Can provide evidence for failure investigations / rationales p issue • Can demonstrate that there is no build-up • Can be used to add data to demonstrate suitability of long campaign lengths or “minor” cleaning activities

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Revalidation Definition • Intent is to reconfirm initial validation results • Frequency / Motivation: • Change based program • Time based program (e (e.g., g annual)

Cleaning Validation 293

Revalidation Drivers • • • •

Change control history P Preventive ti maintenance i t hi history t Calibration records Process control results (esp. automated systems) • Monitoring results / trending Re-perform validation studies in whole or in part, as necessary based on whether the data from the ongoing process and in-process controls demonstrates consistency

Cleaning Validation 294

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Revalidation and Cleaning • May not be required if monitoring is frequent (in essence monitoring is a form of revalidation) • May not be required if automated cleaning systems have in-line analysis (e.g., pH, TOC, conductivity, etc.) • May be performed under different conditions than the original validation such as different groupings / bracketing, g, different worst-case conditions,, or elimination of “easy” to clean systems / sampling sites based on original data analysis

Cleaning Validation 295

Module 12 – Wrap Wrap-Up Up We’ve Now Seen The Trees, Let’s Look at the Forest

CLEANING VALIDATION PRINCIPLES

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Module 12: WrapUp – W have We h Now N Seen S the Trees, Let us Look at the Forest Cleaning Validation 297

Engineering

Operations

Validation and Technical Operations

Cleaning Validation Master Plan or Policy and SOPs for Cleaning Validation Equipment Characterization

Cleaning SOP Defintion

Critical Process Parameters Product Attributes

Product Grouping / Bracketing

Cleaning Agent Usage Matrix

Residue Selection

Quality Control

Hard to Clean Locations

Sampling Sites And MOC

Sampling Method Selection

Limits Definition

Methods Validation

Equipment Train Definition

Equipment Grouping / Bracketing

Recovery Studies

Hold Time Definition Engineering Runs / Cycle Development

Worst-Case W tC Definitions Campaign Definition

Protocol Definition

Protocol Execution and Summary Report Preparation

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 149

298

Fundamentals of Cleaning Validation Methods Validation Recovery Studies OOS Failure Investigations Laboratory Control System Limits Rationales Audits All Systems S t are Compliant

Quality System

Production System Management

Materials System

Cleaning Agents Tools for Cleaning

Policies / SOPs / WI Training Validation Change Control Discrepancy Investigation

Packaging & Labeling System

Compliance w/ SOPs Equipment Logs Facilities & Sampling of Equip. Equipment System Design / Layout to prevent x-contam & promote cleanability

Line Clearance Cleaning Validation 299

Regulatory Expectations • Management Responsibility and Involvement • Careful compliance to procedures and underlying GMPs • Scientifically sound rationales for cleaning validation • Science and precision in testing and reporting Self-identify identify gaps, plan for filling them, stick to the • Self plan! Use risk-based approaches for prioritization of gaps. • Effective maintenance of the validated state Cleaning Validation 300

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 150

Questions?

Cleaning Validation 301

Glossary of Cleaning Related Terms Term or Acronym

Definition

API

Active Pharmaceutical Ingredient (drug substance)

BPC

Bulk Pharmaceutical Chemical (drug substance); term replaced by international term API

Bracketing

See grouping

Campaign Production

Production in which multiple batches of the same product are produced sequentially; for the period of the campaign, the equipment is dedicated to that product; depending on the product, cleaning between batches may be less extensive than at the end of the campaign

CAPA

Corrective and Preventive Actions – actions to be taken upon the occurrence of a failure in order to ensure that the immediate failure is corrected t d and d to t preventt it from f recurring i

Change-Over

(may also be termed Cleaning Certification or Cleaning Verification) Term used frequently in the biotechnology and API industries to indicate the end of a campaign when the production equipment is being cleaned and turned around for the next campaign and/or next product; while cleaning processes are typically validated, extensive testing is typically done at the time of change over

Cleaning Validation Principles © 2011 ISPE. All rights reserved. Page 151

Glossary of Cleaning Related Terms Term or Acronym

Definition

CIP

Clean-In-Place; refers to automated cleaning performed where the equipment was used with little disassembly

Cleaning Validation

Establishing documented evidence that an approved cleaning procedure will consistently provide equipment (or other product or incidental-product contact surface) which is suitable for processing pharmaceuticals, biopharmaceuticals or medical devices

Cleaning Verification

Sometimes also called cleaning “certification”, a verification activity is typically a single cleaning run; the sampling and testing is often the same intensity as a validation run, however this term is used when it is not expected that multiple trials of the same formulation or process will be conducted, therefore a true “validation” may not be possible; if multiple runs are performed over time, a validation summary can be written after three consecutive successful trials conducted under the same conditions / procedures

COP

Clean-Out-Of-Place; generally refers to an automated or semi-automated process such as an high flow or ultrasonic bath or parts washer

Critical Sites

Locations that will disproportionately contribute residue to the next dose, next batch or portion of the next batch

Glossary of Cleaning Related Terms Term or Acronym

Definition

CTQ

Critical to Quality – attributes that are determined to be critical to the final quality of the product or process

EU

European Union

Family

See grouping

Grouping

A mechanism by which related equipment, products and/or procedures may be collectively tested, generally through the evaluation of a worstcase representative from the grouping

HACCP

Hazard Analysis and Critical Control Point – FDA risk-based method employed by food plants to look for carryover residues of highest risk and employ methods to control / eliminate them

H tS Hot Spott

L Locations ti that th t are difficult diffi lt to t clean l on the th equipment i t (may ( or may nott also be a critical site)

HVAC

Heating Ventilation and Air Conditioning

IMS

Ion Mobility Spectroscopy

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Glossary of Cleaning Related Terms Term or Acronym

Definition

LD50

Lethal Dose 50 – Amount of product required to kill 50% of an animal population; LD50 are available for most materials without a therapeutic index; LD50 should always reference animal and route of administration

LOD (or DL)

Limit of Detection (or per ICH, Detection Limit)

LOQ (or QL)

Limit of Quantitation (or per ICH, Quantitation Limit)

MOC

Materials of Construction

NOEL

No Observed Effect Level

OOS

Out of Specification

Organoleptic

Of the five senses; generally means visual detection in the cleaning validation context

PAI

Pre-Approval Inspection (FDA process prior to approval of a new drug)

Glossary of Cleaning Related Terms Term or Acronym

Definition

PM

Preventive maintenance – documented procedures which are performed periodically to ensure the proper working condition of the equipment frequently including the replacement of its wear parts and and replenishment of its lubricants

Ppm or ppb

Parts per million or parts per billion

Protocol

A written, approved test plan that describes the testing and analysis required to demonstrate that a cleaning procedure is valid

QSIT

Quality System Inspection Technique – US FDA Inspection Approach based on Quality Subsystems throughout the factory

Ra

Roughness average – measurement of the finish of metals, esp. stainless steel

Reengineering

Activities performed to redesign equipment to better meet GMP or process requirements

RODAC

Replicate Organism Detection and Counting – RODAC plates are a common method to sample for microbial contamination on flat surfaces; RODAC plates contain agar which can be directly pressed against a surface for recovery

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Glossary of Cleaning Related Terms Term or Acronym

Definition

RSD

Relative Standard Deviation

SUPAC

Scale-Up and Post Approval Changes – FDA initiative to define changes and the mandatory documentation / filing required

T.A.C.T.

Time – Action – Concentration / Chemistry – Temperature These represent the parameters that must be controlled in every cleaning procedure if it is to be successful

TACTWINS

A variation of tact that also includes the conditions of cleaning: Time – Action – Concentration / Chemistry – Temperature – Water – Individual – Nature of Soil -- Surface

T.D.

Therapeutic Dose

Template

A tool used in swab sampling to outline the area to be sampled as a guide to the sampler; must also be used in recovery studies

TOC

Total Organic Carbon

WHO

World Health Organization

Index to Training Materials Topic Campaign Production Change Control

Slide #s 219, 224 – 225 247, 253 – 255, 260 33

Topic Manual Cleaning Master Plan

Slide #s 41 – 42, 82 – 87 53 – 63

Methods Validation

CIP

41 – 42, 84

D t R Data Reporting ti

140 – 143

Microbiological Residues M it i Monitoring

157 – 182, 194 – 205, 231 148 – 156

Dedicated Equipment

25, 39 – 40

Change Over

23, 33 23 33, 83 83-84, 84 139 139, 256-258, 261

Engineering Trials

33, 51, 206 – 213

Protocols

Equipment Characterization

51, 65 – 80

Purification

28, 66, 156, 214 – 229 43 – 45

Recovery Studies

183 – 194

Equipment Expiration

226 – 229

Regulations

EU Regulations Failure Investigations Field Execution

16 – 18 240 – 241 230 – 241

Reports Residue Selection Revalidation

Flow Chart

51

Sampling

Grouping or Bracketing

74, 103, 146, 207, 215, 220 19 – 25

8 – 30, 83, 104, 264 63, 194, 243 – 246 101 –103 18, 30, 222, 245, 259 – 261 24, 33, 72 – 81, 155 – 158, 171, 179, 183 – 194

Scientific Rationales

53, 56 – 58

SOPs

87 – 95

T.A.C.T. Training

34 – 36, 88, 207 41, 83, 95 – 98

Verification vs. Validation

32

Guide to Inspection of Cleaning Validation Inspection Limits Maintenance of the Validated State

96 - 98 104 – 139, 144 – 153 247 - 261

Cleaning Validation 308

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