CLEANING VALIDATION PROGRAM -- EU ANNEX 15 COMPLIANCE

Paul L. Pluta, PhDJournal of Validation Technology and Journal of GXP Compliance

University of Illinois at Chicago (UIC) College of PharmacyChicago, IL, USA

OUTLINE

• Annex 15 Qualification and Validation

• EMA Process Validation for Finished Products

• Annex 15 Cleaning Validation Requirements

• US FDA Process Validation Guidance

• Implementation Strategy

• Interactions – Throughout Discussion

ANNEX 15 QUALIFICATION AND VALIDATION

• Principles and general considerations

– Validation of facilities, equipment, utilities, and processes

– Supplementary for API manufacturing

– Evaluation and validation of changes

– Computerized systems

– ICH Q8, Q9, Q10, Q11 should also be considered

– Risk management should also be applied throughout lifecycle

– Retrospective validation not acceptable

– Outside data OK if justified.

• Organizing and planning

• Documentation including VMP

• Equipment, utilities, facilities, and systems – Stages of qualification

– URS, DQ, FAT, SAT, IQ, OQ, PQ, Requalification

• Processes

– Validation: Traditions, Continuous, Hybrid

• Transportation

• Packaging

• Test methods

• Cleaning

• Change control

EMA PROCESS VALIDATION FOR FINISHED PRODUCTS

• Regulatory submissions

• Lifecycle application

• Traditional, continuous, and hybrid approaches

• Supportive Documents: ICH Q8, Q9, Q10, Q11.

ANNEX 15 CLEANING VALIDATION REQUIREMENTS

• Fifteen individual statements

• Sources of variation should be identified

• Toxicological evaluation of residues

• Microbial considerations

• Recovery studies

Future meeting in November for discussion

10. CLEANING VALIDATION(Definition)

10.1 Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment. Simulating agents may be used with appropriate scientific justification. Where similar types of equipment are grouped together, a justification of the specific equipment selected for cleaning validation is expected.

• Simulation OK with justification

• Equivalent equipment OK with justification

10. CLEANING VALIDATION(Visual Cleanliness)

10.2 A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. It is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach.

• Visual cleanliness alone is not acceptable

• No “test until clean.”

10. CLEANING VALIDATION(Incomplete Cleaning Validation)

10.3 It is recognised that a cleaning validation programme may take some time to complete and validation with verification after each batch may be required for some products, e.g., investigational medicinal products. There should be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use.

• If cleaning validation not complete, must have sufficient data to use equipment.

10. CLEANING VALIDATION(Automated Cleaning Equipment)

10.4 Validation should consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment should be validated.

• Automated equipment must be validated.

10. CLEANING VALIDATION(Variables)

10.5 For all cleaning processes an assessment should be performed to determine the variable factors which influence cleaning effectiveness and performance, e.g., operators, the level of detail in procedures such as rinsing times, etc. If variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies.

• Validate worst case variables.

10. CLEANING VALIDATION(Residue Carryover)

10.6 Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.

10.6.1 Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and my become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances.

10.6.2 If it is not feasible to test for specific residues, other representative parameters may be selected, e.g., total organic carbon (TOC) and conductivity).

• Toxicologic evaluation of residues required.

10. CLEANING VALIDATION

(Microbial)

10.7 The risk presented by microbial and endotoxin contamination should be considered during the development of cleaning validation protocols.

• Consider microbial contamination as part of cleaning if necessary.

10. CLEANING VALIDATION(Dirty and Clean Hold Times)

10.8 The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken in account to define dirty and clean hold times for the cleaning process.

• Define dirty and clean hold times.

10. CLEANING VALIDATION(Campaigns)

10.9 Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of a campaign should be considered and be maximum length of a campaign (in time and/or number of batches) should be the basis for cleaning validation exercises.

• Campaigns should consider worst case conditions.

10. CLEANING VALIDATION(Cleaning Worst-Case Matrix)

10.10 Where a worst case product approach is used as a cleaning validation model, a scientific rationale should be provided for the selection of the worst case product and the impact of new products to the site assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity, and potency.

• Provide justification when using worst-case matrix.

10. CLEANING VALIDATION(Sampling Locations)

10.11 Cleaning validation protocols should specify or reference the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria.

• Sampling locations must be defined and justified.

10. CLEANING VALIDATION(Sampling and Recovery)

10.12 Sampling should be carried out by swabbing and/or rinsing or by other means depending on the production equipment. The sampling materials and method should not influence the result. Recovery should be shown to be possible from all product contact materials sampled in the equipment with all the sampling methods used.

• Swab and rinse sampling OK.

• Recovery studies for all equipment materials.

10. CLEANING VALIDATION(Repeatability)

10.13 The cleaning procedure should be performed an appropriate number of times based on risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.

• Number of lots required based on risk assessment.

10. CLEANING VALIDATION(Dedicated Equipment)

10.14 Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment of other appropriate measures should be used for each product as indicated in chapters 3 and 5 of EudraLex, Volume 4, Part I.

• Dedicated equipment considerations.

10. CLEANING VALIDATION(Manual Cleaning)

10.15 Where manual cleaning of equipment is performed, it is especially important that the effectiveness of the manual process should be confirmed at a justified frequency.

• Must revalidate manual cleaning processes at justified frequency.

US FDA PROCESS VALIDATION GUIDANCE (November, 2011)

• Stage 1. Design and development

• Stage 2. Performance qualification

• Stage 3. Monitoring and maintenance

US FDA GUIDE TO INSPECTIONSVALIDATION OF CLEANING PROCESSES (7/93)

I. Introduction

II. Background

III. General Requirements• Written procedures for cleaning.

• Dedicated fluidized bed dryer bags

IV. Evaluation of Cleaning Validation• At what point does equipment become clean?

• Is manual scrubbing needed?

• Variability?

• “Visually clean” between batches in campaign.

• Equipment design considerations and operator training.

• Dirty hold time and clean hold time (storage)

• Cleaning process written. SOP and “batch record” with signatures

• Analytical methods specificity, sensitivity, recovery

• Swab and rinse sampling. In-process sampling.

V. Establishment of Limits

VI. Other Issues• Placebo product

• Detergent residues

• “Test until clean” unacceptable.

PIC/S CLEANING VALIDATION (9/07)7. Cleaning Validation7.1 Principle7.2 Purpose and Scope7.3 General7.4 Documentation7.5 Personnel7.6 Equipment7.7 Microbiological Aspects7.8 Sampling7.9 Detergents7.10 Analytical Methods7.11 Establishment of Limits

WORLD HEALTH ORGANIZATIONANNEX 3, APPENDIX 3, CLEANING VALIDATION (2006)

1. Principle

2. Scope

3. General

4. Cleaning validation protocols and reports

5. Personnel

6. Equipment

7. Detergents

8. Microbiology

9. Sampling

10. Analytical methods

11. Establishing acceptable limits

CLEANING VALIDATION PROBLEMS

• Product problems – Residue properties, solubility, “dirty hold time,” and cleanability

• Equipment problems -- Non-uniform contamination, worst case sampling , equivalent equipment

• Cleaning Process -- Manual cleaning and documentation

• Laboratory – Residue stability, recovery, swab sampling reliability, and training.

• Culture – Cleaning is a process.

SELF-AUDIT QUESTIONS

• Is residue chemistry considered in developing cleaning procedure?• Is pH-solubility profile considered in worst-case matrix analysis?• Is residue “cleanability” considered in worst-case residue

determination?• Is non-uniform contamination considered in residue calculations?• Are most difficult-to-clean equipment locations proceduralized? • Are manual cleaning personnel qualified and requalified?• Are cleaning procedures quantitative and documented?• Are dirty hold times controlled?• Is residue stability considered in cleaning residue analytical?• Have analytical recovery studies been conducted? On

representative materials?• Are swab sampling personnel trained / qualified?

SUMMARY

• Specific points from EU Annex 15 reviewed– Total 15 key points

o Variation determinationo Worst case matrixo Dirty and clean hold times and campaignso Samplingo Risko Dedicated equipment

• Content equivalent to PIC/S, WHO, FDA (1993)– Wording sometimes identical

• Clarification of PDE / ADE evolving• Lifecycle approach evolving – not explicit in

current documents

CONTACT INFORMATION

PAUL L. PLUTA, PhDEditor-in-ChiefJournal of Validation TechnologyJournal of GXP ComplianceUBM Advanstar Communications

Adjunct Associate ProfessorUniversity of Illinois at Chicago (UIC) College of PharmacyChicago, IL, USA

Editor and Chapter AuthorCleaning and Cleaning Validation, Volume 1. Basics, Expectations, and Principles, 2009Cleaning and Cleaning Validation, Volume 2. Application of Basics and Principles, 2013PDA and Davis Healthcare International (DHI) Publishing

Contact: ppluta@uic.edu