COMPLIANCE WITH EU ANNEX 15: VALIDATION AND QUALIFICATION

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1 COMPLIANCE WITH EU ANNEX 15: VALIDATION AND QUALIFICATION Paul L. Pluta, PhD Journal of Validation Technology Journal of GXP Compliance University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL USA

2 OBJECTIVES Review EU Annex 15 Validation and Qualification Consistency with other major guidances Identify common themes Discuss potential approaches Discuss compliance issues.

3 EU ANNEX 15 QUALIFICATION AND VALIDATION Principles and general Organizing and planning Documentation including VMP Equipment, utilities, facilities, and systems Stages of qualification and requalification Process validation Transportation Packaging and utilities Test methods Cleaning validation Change control

4 PRINCIPLES AND GENERAL Principle: Qualification and validation applicable to manufacture of medicinal products and active substances. GMP requirement Change management Consistency with ICH Q8, Q9, Q10, Q11 General: Quality risk management approach throughout lifecycle Documented justification

5 ORGANIZING AND PLANNING All qualification and validation should consider life cycle of facilities, equipment, utilities, process, and product Trained personnel Quality system and quality oversight VMP documentation Policy Organizational structure / roles / responsibilities Facilities, equipment, etc. Change control Qualification / validation strategy Quality risk management approach Data integrity

6 DOCUMENTATION INCLUDING VMP Good documentation practices Approved documents Validation protocols: critical systems, attributes, parameters, acceptance criteria Justified and documented changes to protocols during execution Results, reviews, conclusions Formal release to next stage of qualification and validation

7 EQUIPMENT, UTILITIES, FACILITIES, SYSTEMS, AND PACKAGING STAGES OF QUALIFICATION Stage identification: URS DQ FAT / SAT IQ OQ PQ

8 REQUALIFICATION Evaluate equipment, facilities, utilities, and systems at appropriate frequency Confirm state of control Justified time period Assess small changes over time.

9 PROCESS VALIDATION Thirty-two statements (plus sub-statements) ; 4+ pages General Concurrent validation Traditional process validation Continuous process verification Hybrid approach Ongoing process verification during lifecycle

10 GENERAL Applicable to all pharmaceutical dosage forms Robust product development process Traditional or continuous verification Retrospective validation not acceptable Bracketing acceptable multiple products Critical and non-critical parameters and attributes Underlying process knowledge.

11 CONCURRENT VALIDATION Strong benefit-risk ration for patient Documented and available to Qualified Person for certification.

12 TRADITIONAL PROCESS VALIDATION Number of batches based on quality risk management principles Three batches usual CPP, CQA, and acceptance criteria. Process validation protocol requirements.

13 CONTINUOUS PROCESS VERIFICATION QbD development Science-based control strategy PAT and multivariate SPC tools

14 HYBRID APPROACH Combination traditional and continuous process verification approaches.

15 ONGOING PROCESS VERIFICATION DURING LIFECYCLE State of control maintained throughout product lifecycle. Ongoing process verification. Document in product quality review.

16 VERIFICATION OF TRANSPORTATION Consistent with marketing authorization Defined routes Seasonal variation Risk assessment Variables Delays Failure of monitoring devices, others Continuous monitoring if necessary

17 VALIDATION OF PACKAGING Variation in equipment processing during primary packaging Primary and secondary packaging equipment should be qualified Qualification at minimum and maximum operating ranges for critical parameters.

18 QUALIFICATION OF UTILITIES Quality of steam, air, water, gases, etc. Seasonal variation Risk assessment.

19 Validated test methods TEST METHODS No product influence on microorganisms No influence of sanitizing agents on clean room surfaces.

20 CLEANING VALIDATION Fifteen individual statements Sources of variation should be identified Toxicological evaluation of residues Microbial considerations Recovery studies

21 DEFINITION 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

22 VISUAL CLEANLINESS 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.

23 INCOMPLETE CLEANING VALIDATION 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.

24 AUTOMATED CLEANING EQUIPMENT 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.

25 CLEANING VALIDATION VARIABLES 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.

26 RESIDUE CARRYOVER 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. 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. 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.

27 CLEANING VALIDATION MICROBIAL 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.

28 DIRTY AND CLEAN HOLD TIMES 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.

29 CAMPAIGNS 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.

30 CLEANING WORST-CASE MATRIX 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.

31 SAMPLING LOCATIONS 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.

32 SAMPLING AND RECOVERY 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.

33 REPEATABILITY 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.

34 DEDICATED EQUIPMENT 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.

35 MANUAL CLEANING 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.

36 CHANGE CONTROL Handle within Quality System Change marketing authorization if needed Quality Risk Management Post-change effectiveness

37 LIFECYCLE APPROACH TO PROCESS VALIDATION FDA, 2011 Definition: Collection and evaluation of data, from the process design stage throughout commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation involves a series of activities over the lifecycle of the product and process. Three stages of activities: Stage 1 Process Design Development and scale-up activities Stage 2 Process Qualification Reproducible manufacturing Stage 3 Continued Process Verification Routine manufacturing STAGE 1 AND STAGE 3 EMPHASIS NEW PARADIGM ABOVE CONCEPTS APPLICABLE TO ALL PROCESSES, EFU, ETC. 37

38 STAGE 1: QUALITY BY DESIGN (QbD) Quality target product profile (QTTP) Critical quality attributes (CQA) Critical material attributes (CMA) Critical process parameters (CPP) Design space Scale-up and technology transfer Identify input variables Input variable control strategy Continuous improvement Other considerations: PAT, risk analysis DEVELOPMENT PROCESS DEFINED GLOBAL GUIDANCES 38

39 STAGE 2: DEMONSTRATION Process Performance Qualification (PPQ) Confirm the process design and development work Demonstrate that the commercial manufacturing process performs as expected. Based on sound science and experience. Higher level of testing and sampling. Process is reproducible and will consistently deliver quality products. 39

40 STAGE 3: MONITORING AND MAINTENANCE Assuming good development of the process, identification of potential variation, and control of same, the manufacturer must maintain the process under control over the product lifetime. Control must accommodate expected changes in materials, equipment, personnel, and other changes throughout the commercial life of the product based on risk analysis. 40

41 VALIDATION PHILOSOPHY Validation is confirmation. Acceptable (passing) results are expected. Validation is not R&D Final stage of development process Optimization Fine-tuning Debugging 41

42 VALIDATION HISTORY AND EVOLUTION 1978 GMP includes Validation Development VALIDATION Control Lifecycle approach UNDERSTANDING PQ MONITORING 42

43 APPLICATION AREAS LIFECYCLE APPROACH APPLICATION Processes: Manufacturing, cleaning, analytical, all processes Equipment processes: HVAC, water Equipment, facilities utilities, computers, Quality systems APROACH Design and understanding Demonstrate Monitor and maintain USE SAME APPROACH FOR ALL VALIDATION / QUALIFICATION 43

44 ICH GUIDANCES Q8: Pharmaceutical Development QbD Q9: Quality Risk management Q10: Pharmaceutical Quality System Q11: Development and Management of Drug Substances

45 SUMMARY EU ANNEX 15 VALIDATION AND QUALIFICATION Common themes of major guidances Development and understanding Lifecycle approach applications Quality risk management Maintain state of control -- post validation and post changes EU: Cleaning validation emphasis

46 PAUL L. PLUTA, PhD Editor-in-Chief Journal of Validation Technology Journal of GXP Compliance IVT / UBM Life Sciences / Advanstar Communications Associate Professor of Biopharmaceutics University of Illinois at Chicago (UIC) College of Pharmacy Chicago, IL, USA Pharmaceutical industry experience: 30+ years Contact: ppluta@uic.edu