Pharmaceutical quality requirements

Transcription

1 Pharmaceutical quality requirements through development to commercial medicinal product December 4, 2014 Karin Walhagen Biomedicine the Profession Biomedicine Master Program at Lund University

2 Patient Safety Safety

3 Outline Drug product lifecycle Why Quality Control? FDA GMP regulations ICH Guidelines Quality Risk Management Quality Systems Take home message References

4 PHARMACEUTICAL DRUG PRODUCT LIFE CYCLE Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation Investigational products

5 Drug Development - Cooperation is everything! Non-clinical Clinical Tech-ops Technical Operations responsible for manufacture after launch CRO Pharmaceutical R&D Patent Contract research organisation CMO Contract manufacturing organisation Regulatory QA

6 Why do we need Quality Assurance? Quality Safety Purity Efficacy What does the customer want? Effective product Suitable for its intended purpose Consistent in its performance

7 Why requirements? Defect products can generate severe side-effects or no effect at all A consumer cannot detect (through smell, touch, or sight) that a drug product is safe or if it will work. Therefore, it is important that drugs are manufactured under controlled conditions and practices to assure that quality is built into the design and manufacturing process at every step.

8 Why GMP? To assure proper design, monitoring, and control To assures the identity, strength, quality, and purity of drug products To establish strong quality management systems GMP helps to prevent instances of contamination, mix-ups, deviations, failures, and errors.

9 Who did What, When and Why? Record data as observed at the time of the observation/event Date and Sign (operator/test executor) Write legible Use permanent ink or print NEVER PENCIL Reference raw data and keep it available In God we trust all others must have raw data

10 Who sets the requirements? FDA Food and Drug Administration (US) EMA European Medicines Agency National Authorities e.g. Läkemedelsverket, Medical Products Agency (Sweden)

11 What are the challenges of GMP in Development? Development of drug products is a process of evolving product knowledge: - risk assessment of the manufacturing processes - Design of experiments - Control space, design space, knowledge space - validation and verification processes In development we need to be flexible towards changes, as knowledge increases, thus implementation of GMP provides certain challenges. Ensure that trial subjects are not placed at risk Ensure consistency between batches of the same IMP to not jeopardize results of clinical trials The increased complexity in manufacturing operations requires a highly effective quality system

12 Starting materials different batches/suppliers Reagents from different suppliers Purification RP Freeze-drying Several batches in clinical studies Drug Substance

13 Buffer agent Preservative Acid/base Isotonicity agent Drug Substance Drug Product multidose solution for injection Primary container closure Antioxidant Stabilising agent Several batches in clinical studies

14 How Much of the Product Can We See? Release testing (Specification) Characterisation Manufacturing processes In-process testing Release of raw materials Batch records etc

15 Quality Guidelines Harmonisation achievements in the Quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities etc

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17 Development Approaches Traditional approach to development Narrow set points and operating ranges based on observed dated Focus on release testing (end-product) Limited flexibility in operational ranges Enhanced approach to development Systematic identification of sources of variability Earlier and more efficient controls Can provide more flexibility in operation

18 ICH Q8: PHARMACEUTICAL DEVELOPMENT Design a quality product and its manufacturing process to consistently deliver the intended performance of the product Knowledge space gained from pharmaceutical development, manufacturing, testing, characterisation, design of experiment provide scientific understanding Traditional Control space limited knowledge sensitive to changes Design Space Control Space Design space is combination and interaction of input variables and process parameters that demonstrates consistent product quality Knowledge Space

19 ICH Q9: QUALITY RISK MANAGEMENT (QRM) Risk Identification Risk Assessment Risk Analysis Risk Evaluation Risk Communication Risk Control Risk Reduction Risk Acceptance Result of QRM Risk Review

20 ICH Q10: PHARMACEUTICAL QUALITY SYSTEM Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation Investigational products GMP Management Responsibilities PQS elements Process Performance and Product Quality Monitoring System Corrective Action Preventive Action (CAPA) system Change management system Management Review Eneblers Knowledge Management Quality Risk Management

21 Use different batches of starting materials/excipients to capture variation in quality of the DS and DP Use Critical Thinking Keep patient safety in focus Perform risk assessments for both DS and DP Regular update on risk assessments and how to mitigate risks, Peform DoE to improve manufacturing ranges and to investigate interactions between process factors and to identify design space Use small scale models to imitate real processes Know when GMP and pre-gmp can be used during development Know the rules and regulations incl. guidelines Use your network between different departments cooperation is everything Opinions don t change my mind - data do

22 Take home message Pharmaceutical quality requirements focus on patient safety If it is not documented you did not do it (GMP) Quality Risk management - DoEs The process gives the product Design space Critical thinking use state-of-the-art scientific sound knowledge

23 References FDA; US Food and Drug Administration FDA - cgmp: m FDA - CDER; Center for Drug Evaluation and Research: efault.htm EMA, European Medicines Agency: EU Legislation Eudralex; Vol. 4 GMP guidelines Läkemedelsverket; Medical Products Agency Sweden: ICH; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines

24 Where can you find the GMP Regulations? 21 CFR Part 210 & 211 (US) GMP Directive; EudraLex Vol. 4 (EU) Annex 13 on IMP material Eudralex Vol.4 EudraLex is the collection of rules and regulations governing medicinal products in the European Union