1. Quality and Compliance Challenges for Biopharmaceutical Products Ramon Rivera Gonzalez, Ph.D. Director Quality Assurance Amgen Manufacturing, Limited

2. 2 Outline  Background Information  Regulatory and Process Challenges  Quality by Design  Risk Management  Process Analytical Technology  Key Quality Systems Deviations/Nonconformities Corrective and Preventive Actions  Biological Product Deviations  FDA and EMEA Observations

3. 3 Biotechnology Biotechnology is a set of scientific techniques used to derive valuable products from living organisms Applications  biopharmaceutical drugs  agriculture  waste management

4. 4 Background information  FDA- “sterile drugs should be manufactured by aseptic processing only when terminal sterilization is not feasible”.  Parenterals -Drug administration other than by the mouth or rectum- ex. Injection, infusion or implantation. –Biological products (vials or syringes) solubility, stability, maintain activity

5. 5 Biotechnology BIOLOGY CHEMISTRYENGINEERING

6. 6 Biological Products Manufacturing

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8. 8 Bacterial Systems (+) –Grow fast –Easy to maintain –High yield (-) –Endotoxins –Low expression or extracellular secretion –No post-translational modifications machinery E. coli

9. 9 Mammalian Cells (+) –Adequate conformation –Post-translational modifications –Preferred for complex proteins (-) –Grow slower than bacteria –Maintenance is expensive –Usually lower yield –Limited manufacturing applications CHO Mammalian

10. 10 Quality and the Product Life Cycle  Adherence to regulations  Control and maintenance of documentation  Quality of suppliers, components and raw materials  Reliability and consistency  Monitor/audit of the manufacturing process  Deviations, unexpected situations - product impact  Correction and prevention - CAPA  Lot release/rejection decision  Customer complaints  Continuous improvement

11. 11 Quality Systems Emphasis  Quality Management  Quality Assurance  Risk Management –Evaluation analysis and quality risk management tools  Preventive Action  Promote product and process improvement (i.e., continuous improvement)  “Continuous Improvement” of the Quality System

12. 12 Regulatory Environment Challenges  Transfer of CBER products to CDER  GMPs for the 21 st. Century  Aseptic Processing Guideline  Risk management  Increased scrutiny of product insert claims  Focus on patient safety  Process Analytical Technology (PAT)

13. 13 Regulatory Environment Challenges  Quality by Design  Bioterrorism  Animal-derived materials  Country-specific regulatory requirements –Mexico, Brazil, Saudi Arabia, Japan  Biogenerics in EU  State of the art technology –Isolators

14. 14 Major Process Challenges Sterile vs. Aseptic Requires the application of microbiological contamination control to prevent infectious organisms to be present in the sterile product Demonstrate “CONTROL” of the process, while technical complexity increases Characterization to identify variability components Application of science and new technologies Maintenance of the cell lines Contamination risks Personnel as “incubators” Source of microbial load

15. 15  “Quality can not be tested into products; it has to be built in by design”  Product quality and performance requires efficient design of manufacturing processes  Product specifications based on deep understanding of how formulation and process factors impact product performance  It provides a framework for continuous "real time" assurance of quality and continuous Improvement Quality by Design

16. 16 The importance of Design  Multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide an assurance of quality  Operating within design parameters will produce a product meeting designed quality attributes  Working within the design parameters is not considered a reportable change  Movement outside of design space is considered a change – subject to regulatory approval

17. 17 Risk Management  What are the potential hazards to process and product ? Identify potential hazards both prospectively and in a reactive mode  Applies to components, container closure, raw materials, dosing devices, manufacturing process, drug substance, intermediates  How these factors influence variability of process, product performance, product safety and efficacy?

18. 18 Risk Management  Risk management is a regulatory expectation for a modern quality system  Risk assessment, risk control, risk communication and risk review throughout product lifecycle  Decisions should be based upon process and product understanding Balance between the use of risk management and compliance with GMPs  Always include intended use, patient safety and availability

19. 19 Process Analytical Technology  “…any system for continuous analysis and/or control of manufacturing processes based on real-time measurements, or rapid measurements during processing.” Source; FDA Human Drug cGMP Notes, Q1 2002

20. 20 Process Analytical Technology  “At line” - the sample is removed, isolated from, and analyzed in close proximity to the process stream  “On-line” - the sample is diverted from the manufacturing process, and may be returned to the process stream  “In-line” – the sample is not removed from the process stream and can be invasive or non-invasive Source: FDA PAT Guidance

21. 21 PAT - Benefits  Enhancement of process understanding  Sources of variability identified and explained  Meet requirements for validating and controlling process  Quality attributes can be accurately and reliably predicated  Continuous improvement  Integration of development, manufacturing, QA and knowledge management  Acceptability of in-process materials and final product based on process data

22. 22 Management Controls  Written quality policy and objectives  Management reviews – regulations and quality objectives – attendance documented – results, action plans/corrective actions documented  Internal audits –auditors no direct responsibility for matters being audited

23. 23 Deviations/Nonconformities  Classification based on impact/risk  Investigations need to be thorough, stand-alone –Root cause analysis –Product impact Stability data, intrinsic vs. extrinsic, historical data –Toxicological/health hazard evaluations based on route of administration to patient –Corrective and Preventive actions

24. 24 Corrective and Preventive Actions (CAPA)  Corrective = correct existing nonconformity  Prevention = potential recurrence of nonconformity Regulatory expectations: –Identify sources of problems/nonconformities Unfavorable trends –Prioritize based on risk –Defined action plans –Timely implementation –Measure and document effectiveness –Reviewed by Management

25. 25 If a deviation/nonconformity involves distributed product…  Evaluate per 21CFR600.14 – Biological Product Deviation (BPD)  “must report any event and any information relevant to the event associated with the manufacturing, to include testing, processing, packing, labeling or storage, or with the holding or distribution, of a licensed biological product if the event meets the following criteria: (1)Either; (i)Represents a deviation from cGMP, applicable regulations, applicable standards, or established specifications that may affect the safety, purity or potency of that product; or (ii)Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; and (2)Occurs in your facility or a facility under contract with you; and (3)Involves a distributed biological product

26. 26 Some points regarding BPDs  Distributed = biological product has left the control of the licensed manufacturer Contract manufacturing  The decision to report should be based on whether the event had the potential to affect safety, purity, or potency of the product  The license holder is required to file at a date not to exceed 45 calendar days from the date that you, your agent, or another person, acquire information reasonably suggesting that a reportable event has occurred  Must report even if the investigation determined that there was no impact

27. 27 BPD- Reportable Examples  Raw materials that failed specifications used in manufacturing  Aseptic processing not performed according to procedures  Stability testing not performed at required interval  Missing information in label (product type, lot number, storage temperature, concentration)  Distributed product prior to completion of required testing  Product release prior to validation of manufacturing process  Biological Drug Substance stored at the incorrect temperature

28. 28 BPD – Non-reportable Examples  Raw material did not meet specification and was rejected prior to its use  Testing performed incorrectly, invalidated and repeated and found acceptable prior to distribution  Product labeled with a shortened expiration date (not due to failure to meet specification)  Product shipped to the incorrect facility  Customer order filled incorrectly (wrong product, wrong amount), but labeled correctly

29. 29 EMEA Observations  Critical = give rise to product that could be harmful to patient  Major = result in product not meeting marketing authorization, major deviation from EU GMP  Other = usually lack information to be classified

30. 30 EMEA 1995 - 2005  Critical Design and maintenance of premises Potential for microbiological or chemical/physical contamination  Major/Other Potential for microbial contamination Documentation- Quality system elements/procedures Unauthorized activities requiring regulatory filing Design and maintenance of equipment and premises

31. 31 FDA Observations (1996-2006)  Failure Investigations (Nonconformities) –Failure to conduct investigations –Failure to extend investigations to related batches and products –Averaging OOS results with in-specification results to support release –Delays in starting the investigation –Incomplete investigation into root cause –Failure to take immediate corrective action –Failure to address product impact

32. 32 FDA Observations (1996-2006)  Record keeping –Batch Production and Control records do not include complete information –“post-it” notes with hand-written original data –Lack of procedures –No revision history for procedures  Validations –Discrepancies against Master Validation Plan –Inadequate cleaning validation –Inadequate process validation –Inadequate validation of analytical methods

33. 33 In Summary  The successful application of quality systems for the manufacturing of biological products requires the comprehensive synergy between: regulations, science/new technologies, process knowledge, Management accountability and efficient risk management

34. 34 Questions?