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Pharmaceutical Product Quality Assurance Through CMC Drug Development Process PowerPoint Presentation
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Pharmaceutical Product Quality Assurance Through CMC Drug Development Process

Pharmaceutical Product Quality Assurance Through CMC Drug Development Process

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Pharmaceutical Product Quality Assurance Through CMC Drug Development Process

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  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. Presentation Outline • Purpose • Pharmaceutical product quality is built-in • Quality system development • Registration requirements • Validation • Role of QC tests • Pre-approval inspection • Conclusions

  3. Purpose of Presentation • To demonstrate that product development assures that the final product is of appropriate quality

  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. 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. 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. Drug Development Process

  8. Quality is Always Part of the Picture - Built-In and Built-Up Quality Control and Quality Assurance Less established Fully established Commercial Manufacturing Pre-IND Phase I Phase II Phase III Specification/Manufacturing Development for the Product

  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. 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. 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. 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. 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. Validation

  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. Validation is Always Part of the Picture Commercial Manufacturing Pre-IND Phase I Phase II Phase III Final process validation Specification Development Re-validation Ongoing Validation (DOE, IQ, OQ, PQ, PV)* * DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process Validation • The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product • 6 sigma target

  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. 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. 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. Acknowledgements • 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