Technical Report No. 49 Points to Consider for Biotechnology ...

Points to Consider forBiotechnology CleaningValidationTechnical Report No. 49ISBN: 978-0-939459-30-8© 2010 Parenteral Drug Association, Inc.All rights reserved.

Table of Contents1.0 Introduction ..................................................31.1 Purpose/Scope ............................................... 32.0 Glossary of Terms ........................................53.0 Cleaning Process Designand Development ..........................................63.1 Introduction .................................................... 63.2 Cleaning Process Controls (Inputs)and Measurements (Outputs) ......................... 63.2.1 Cleaning Cycle Design ........................ 63.2.2 Physical-Chemical Aspects ................ 73.3 Measurements Used to DetermineCleaning Effectiveness .................................... 83.4 Equipment and PlantDesign Considerations .................................... 83.4.1 Piping .................................................. 83.4.2 Automated vs. Manual Systems ......... 93.4.3 Centralized CIP vs. DiscreteCleaning of Isolated Equipment ........... 93.4.4 Clean Out of Place (COP) .................... 93.5 Soil Evaluation and Categorization .................. 93.5.1 Soil Categories .................................... 93.5.2 Soil Removal ..................................... 103.5.3 Cleaning ComparabilityBased on Soil and Surface ................ 113.5.4 Soil Selection forLaboratory Evaluations ..................... 123.6 Performing CleaningDevelopment Experiments ............................ 123.6.1 Parameter Selection .......................... 133.6.2 Parameter Interactions ...................... 133.7 Cleaning Process Scale-Up ........................... 133.7.1 Setting Process Controls ................... 143.7.2 Introduction of New Soilsto a Validated Cleaning System ........ 143.8 Applying the “Design Space”Concept to Cleaning Processes .................... 154. 0 Acceptance Limits .......................................174.1 Key Issues in Limits for Actives .................... 174.1.1 Establishing Limits for Actives inFormulation and Final Fill .................. 184.1.2 Establishing Limits forActives in Bulk Manufacture ............. 184.1.3 Limits Based on Toxicity Data ........... 194.2 Limits for Cleaning Agents ............................ 204.2.1 Limits for Commodity Chemicals ...... 204.2.2 Limits for FormulatedCleaning Agents ................................ 204.3 Bioburden Limits ........................................... 214.4 Endotoxin Limits ........................................... 214.5 Visual Clean Criterion .................................... 214.6 Modifying Limits ........................................... 225.0 Sampling Methods ......................................235.1 Sampling Method Selection .......................... 235.1.1 Direct Sampling Methods ................. 235.1.2 Rinse Sampling ................................. 235.1.3 Swab Sampling ................................. 245.1.4 Comparison of Swaband Rinse Sampling .......................... 255.2 Placebo Sampling ......................................... 265.3 Sampling for Microbialand Endotoxin Analysis................................. 265.4 Sampling Recovery Studies .......................... 265.4.1 General Considerations ..................... 265.4.2 Swab Recovery ................................. 275.4.3 Rinse Recovery ................................ 275.4.4 “Recovery” in Visual Inspection ........ 285.4.5 Recovery for Bioburdenand Endotoxin Sampling ................... 285.5 Training and Qualification of Samplers .......... 295.5.1 Key Issues for Trainingfor Swab Sampling ........................... 295.5.2 Key Issues for Trainingfor Rinse Sampling ............................ 305.5.3 Training for Visual Inspection ............ 306.0 Analytical Methods ...................................316.1 Specific Analytical Methods ......................... 316.2 Impact of Inactivation/Degradationof the Active ................................................. 316.3 Nonspecific Analytical Methods ................... 326.3.1 Total Organic Carbon (TOC) ............... 326.3.2 Total Protein ...................................... 336.3.3 Conductivity ...................................... 336.3.4 Visual Inspection............................... 346.4 Microbial Test Methods ................................ 356.4.1 Endotoxin .......................................... 356.4.2 Bioburden ......................................... 356.5 Analytical Method Validation ........................ 356.5.1 General Principles ............................. 366.5.2 Compendia Methods ......................... 376.5.3 Visual Inspection............................... 376.5.4 Bioburden Methods .......................... 376.5.5 Use of a Contract Laboratory ............ 377.0 Cleaning Validation Protocols ..............397.1 Cleaning Verification Protocols...................... 39

7.2 Key Issues Based on Regulatory Changes .... 397.2.1 Number of Runs in a Protocol ........... 397.2.2 Worst-Case Process Conditions ........ 398.0 Maintenance of Validated State ............418.1 Critical Parameter Control ............................. 418.2 Control by Cycle Feedback ........................... 418.3 Process Alarms ............................................. 418.4 Change Control ............................................. 428.5 Evaluation of Cumulative Changes ................ 428.6 Periodic Monitoring....................................... 438.7 Trending ........................................................ 439.0 Master Planningfor Cleaning Validation ............................449.1 Elements of a Comprehensive Plan ............... 449.2 Harmonization of Site Cleaning Programs ..... 459.3 Cleaning Validation Activitiesas a Function of Clinical Stage ..................... 4510.0 Risk Assessment and Management .......4710.1 Introduction ............................................... 4710.2 Techniques and Tools for RiskManagement and Assessment .................. 4811.0 Special Considerations .............................4911.1 Grouping/Family Approach ........................ 4911.1.1 Product Grouping ......................... 4911.1.2 Equipment Grouping .................... 4911.1.3 Introduction of a New Productor New Equipment Into a Group ... 4911.1.4 Conclusion ................................... 5011.2 Cleaning Agent Issues ............................... 5011.2.1 Sodium Hydroxide Wash ............. 5011.2.2 Acid Wash ................................... 5011.2.3 Formulated Detergents ................ 5011.2.4 Issues in Selection ....................... 5111.3 Special Equipment Issues.......................... 5111.3.1 Chromatography Columns ........... 5111.3.2 Tangential Flow Filtration(TFF) Filter Systems .................... 5111.3.3 Centrifuges .................................. 5211.4 Multi-Host Facilities .................................. 5211.5 Non-product Contact Surfaces .................. 5211.5.1 Equipment for Buffers .................. 5211.5.2 Equipment for Media ................... 5311.5.3 Lyophilizers .................................. 5311.5.4 Packaging Equipment .................. 5411.6 Viruses, Mycoplasma and Prions .............. 5411.6.1 Control Steps ............................... 5411.6.2 Control by Cleaning ...................... 5411.6.3 Conclusion ................................... 5511.7 Single-Use Equipment ............................... 5511.8 Process Analytical Technology .................. 5511.8.1 PAT for CleaningProcess Control ........................... 5611.8.2 PAT MeasurementTools for BiotechnologyCleaning Processes...................... 5711.8.3 Additional Considerations for PAT5711.9 Product Changeover .................................. 5711.10 Clean Hold Considerations ......................... 5812.0 Regulatory Issues .......................................6013.0 References.....................................................6214.0 Suggested Reading .....................................6415.0 Appendix – Carryover Calculations .....6516.0 List of Acronyms .........................................68Tables IndexTable 3.2.1Table 3.5.1Table 3.5.2Cleaning ProcessSteps (Examples) ....................... 7Process SoilCategorization (Example) ......... 10surface Materials forBiopharmaceutical ProductionProcesses ................................ 11Table 5.1.2Table 5.1.4Table 10.1Comparison of CIP GrabSampling versus SeparateCIP Sampling Rinse .................. 24Comparison of Swab Samplingand Rinse Sampling ................. 25CPP and CQA Considerations thathave Potential Risk Impact to aCleaning Process ..................... 47

1.0 IntroductionCleaning validation plays an important role in reducing the possibility of product contamination frombiopharmaceutical manufacturing equipment. It demonstrates that the cleaning process adequatelyand consistently removes product residues, process residues and environmental contaminantsfrom the cleaned equipment/system, so that this equipment/system can be safely used for themanufacture of defined subsequent products (which may be the same or a different product).As used in this Technical Report, “product” may be a drug product, bulk active, intermediate, oranother type of formulation. If “drug product” is intended, that terminology will be utilized. Whilecleaning validation for biotechnology manufacturing has many of the same elements as for otherpharmaceutical manufacturing, there are enough differences such that a separate Technical Reportfocusing on biotechnology cleaning validation is appropriate.Previous PDA documents on cleaning validation, including the 1998 PDA Technical Report No. 29,Points to Consider for Cleaning Validation and the 1996 monograph Cleaning and Cleaning Validation: ABiotechnology Perspective provide valuable insights for biotechnology manufacturers. (1,2) However, thisreport presents more updated information that is aligned with life cycle approaches to validation andthe International Conference on Harmonisation (ICH) guidelines Q8(R2), Pharmaceutical Development,Q9, Quality Risk Management, and ICH Q10, Pharmaceutical Quality System. (3-6) This report also aimsto present information in a way that readers can easily utilize to assist in creating a cleaning validationprogram for their equipment and facilities.The Biotechnology Cleaning Validation Task Force was composed of European and North Americanprofessionals from biotechnology manufacturers, cleaning chemical suppliers, regulatory agencies andconsulting companies. This report also underwent a global, technical peer review to ensure concepts,terminology, and practices presented are reflective of sound science and can be used globally.Note: For ease of use, this Technical Report includes a list of acronyms used throughout the document.Refer to Section 16.0.1.1 Purpose/ScopeThe focus of this Technical Report is on biotechnology manufacturing. Biotechnology manufacturingincludes bacterial and cell culture fermentation. While some might exclude plasma fractionation andegg-based vaccine manufacturing from the strict definition of biotechnology, many of the practices andguidance in this report are applicable to plasma fractionation and egg-based vaccine manufacturing.Therefore, examples given will be for biotechnology manufacturing. We have also included a lifecycle cleaning validation approach, including design/development of the cleaning process, processqualification (the protocols runs), and ongoing validation maintenance. These practices and theassociated guidance in this Technical Report are based on technical considerations and should beapplicable in all regulatory environments.The intent of this Technical Report is not to provide a detailed plan or detailed road map for abiotechnology manufacturer to perform cleaning validation. Rather, as the title suggests, it presents“points to consider” as one designs a cleaning validation program for biotechnology manufacturingbased on an understanding of one’s manufacturing and cleaning processes. In cleaning validation,there are generally multiple ways to accomplish the same goal of a compliant, scientifically soundand practical cleaning validation program. Where options are given, the rationales for such optionsare also generally given. The Biotechnology Cleaning Validation Task Force that developed thisdocument hopes that it will be used in that spirit. Based on an understanding of the unique nature ofany individual situation, different approaches or additional issues should also be considered.Technical Report No. 49© 2010 Parenteral Drug Association, Inc.3

This report should be considered a resource to help guide the development or evaluation of a cleaningvalidation program. It is not intended to establish mandatory standards for cleaning validation. Itis intended to be a single-source overview for biotechnology manufacturers that complementsexisting guidance and reference documents, listed in Section 13.0. The reader should also be awarethat a specific topic may be discussed in several sections of this Technical Report. Therefore, a morecomplete perspective may be obtained by considering all relevant sections about a certain topic.4 © 2010 Parenteral Drug Association, Inc. Technical Report No. 49