1. Pharmaceutical Product Quality Assurance Through CMC Drug Development Process Presented by Darlene Rosario (Aradigm) 21 October 2003 Meeting of the Advisory Committee for Pharmaceutical Science

2. IPAC-RS for ACPS 21 October 2003 2 Presentation Outline Purpose Pharmaceutical product quality is built-in Quality system development Registration requirements Validation Role of QC tests Pre-approval inspection Conclusions

3. IPAC-RS for ACPS 21 October 2003 3 Purpose of Presentation To demonstrate that product development assures that the final product is of appropriate quality

4. IPAC-RS for ACPS 21 October 2003 4 Pharmaceutical Product Quality Cannot Be Tested in - It Is Built in Pharmaceutical product quality is assured by –comprehensive development program –extensive manufacturing and environmental controls –rigorous validation procedures and requirements The high quality thus built into the final product is ensured through in-process controls and verified in a series of confirmatory tests before each manufactured batch is released to the market

5. IPAC-RS for ACPS 21 October 2003 5 Building-in of Quality Starts Early. Development Builds-in Quality The chemistry, manufacturing and controls (CMC) aspect of drug development is focused on producing medicines suitable for human use with specified quality, safety and efficacy characteristics The drug development program is geared towards –thorough understanding of the drug product’s performance –identification of drug product’s critical characteristics (which would be monitored on a batch-by-batch basis) –demonstration of drug’s safety and efficacy –ultimately leads to the review and approval of the drug

6. IPAC-RS for ACPS 21 October 2003 6 Relationship between Safety, Efficacy and Quality Every drug product (with its specifications) has been thoroughly tested in clinical trials for safety and efficacy –Specifications for release and stability testing may be equal to or tighter than the specifications for clinical trial batches Therapeutic indication and QC are considerations in establishing specifications

7. IPAC-RS for ACPS 21 October 2003 7 Drug Development Process

8. IPAC-RS for ACPS 21 October 2003 8 Quality is Always Part of the Picture - Built-In and Built-Up Quality Control and Quality Assurance Pre-INDPhase IPhase IIPhase III Commercial Manufacturing Specification/Manufacturing Development for the Product Less establishedFully established

9. QA & QC* Systems Evolve During Drug Development Quality assurance and quality control systems begin being established during early clinical trials and involve: –equipment validation (IQ, OQ, PQ) –manufacturing controls and limits –product specifications Process optimization continues through the development process, leading to –identification of critical in-process control parameters –final product specifications for QC purposes –final process validation Stability –Batches produced by the defined manufacturing process are studied at different storage conditions to verify consistent quality and performance of the product throughout shelf-life * QC generally means product testing, and QA an independent review of the results 9

10. IPAC-RS for ACPS 21 October 2003 10 Examples of QA & QC Considerations During Drug Development Evolution of documentation systems –SOP –change control –OOS system and procedures –trend analysis Evolution of QA and QC systems –internal audits –supplier audits –document review (e.g., SOP, batch records, specifications, data)

11. IPAC-RS for ACPS 21 October 2003 11 Chemistry Manufacturing Controls Evolve During Drug Development The goal is to have process and product performance determined by the time of validation, although some level of validation occurs along the continuum and eventually leads to the full-scale validation.

12. IPAC-RS for ACPS 21 October 2003 12 Examples of CMC Considerations During Drug Development Selection of appropriate technology and raw materials Optimization –of formulation and device –of manufacturing process –of specifications and analytical methods Careful selection and control of container closure systems Identification and control of critical manufacturing process parameters Process capability established Technical transfer to larger scale, i.e., scale-up Process validation

13. IPAC-RS for ACPS 21 October 2003 13 Process Registration Requirements Sponsor is required to describe how the product was developed Companies need to optimize, justify and register the entire “recipe” –ranges temperatures mixing times hold times etc. –quantities active ingredient excipients –raw material specifications –in-process limits –in-process methods –product specifications –etc.

14. IPAC-RS for ACPS 21 October 2003 14 Validation

15. IPAC-RS for ACPS 21 October 2003 15 What is Validation? Documented evidence that the manufacturing process consistently produces product that meets predetermined specifications –Defines product quality –Developed and validated based on a thorough understanding of the critical process parameters –Parameters are carefully controlled within the validated ranges to ensure a consistent manufacturing process. Manufacturing process validation consists of successfully manufacturing at least three full-scale batches in succession, which pass all in-process and product quality attributes

16. IPAC-RS for ACPS 21 October 2003 16 Validation is Always Part of the Picture Ongoing Validation (DOE, IQ, OQ, PQ, PV)* Pre-INDPhase IPhase IIPhase III Commercial Manufacturing * DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process Validation Specification Development Final process validation Re-validation The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product 6 sigma target

17. IPAC-RS for ACPS 21 October 2003 17 Role of QC Tests Each batch of orally inhaled and nasal drug products (OINDP), manufactured by the validated process, is tested to the critical QC attributes as defined during development –Confirms consistent performance The Delivered Dose Uniformity test for OINDP is one of several confirmatory QC tests of the finished product –a result of a long and careful development and characterization process –QC tests confirm the quality built-in through a well- understood and well-controlled manufacturing process

18. IPAC-RS for ACPS 21 October 2003 18 Pre-Approval Inspection Confirms Facility is Ready –Sponsor can do what they submit in the NDA –Process is validated or validation protocols are in place Validation required prior to launch –Thorough documentation review –Quality systems are established and capable –Confirms specifications are met Compliance versus Review Division –Specifications may change based on NDA review –Tighter than process capability

19. IPAC-RS for ACPS 21 October 2003 19 Conclusions Pharmaceutical quality is built-in through the entire drug development process –validation is key element of ensuring quality –in-process controls assure quality during manufacturing –Specifications established based on thorough understanding of process The sum of all release parameters confirms the batch quality

20. IPAC-RS for ACPS 21 October 2003 20Acknowledgements IPAC-RS Members –Aradigm –AstraZeneca –Aventis –Boehringer Ingelheim –Eli Lilly –GlaxoSmithKline –IVAX Members of IPAC-RS DDU Working Group IPAC-RS Secretariat –Kos Pharmaceuticals –Nektar Therapeutics –Novartis –Novo Nordisk –Pfizer –Schering-Plough