Product Protection Control Strategies for Non-Sterile Drug Substance Manufacturing

Transcription

1 Protection Control Strategies for Non-Sterile Drug Substance Manufacturing Michael Hendershot, Research Scientist Technical Services / Manufacturing Sciences Eli Lilly & Company

2 Contents Purpose of a Protection Control Strategy Types and Sources of Contamination Contamination Controls & Measures Pitfalls with Aging and New Facilities Applying Quality Risk Management Principles

3 What is a Protection Control Strategy? A risk-based approach to control and measure the stuff our patients do not want in our products.

4 Potential Drug Substance Sources of Contamination Environmental Microorganisms & toxins Pests Human skin, hair, etc. Raw material packaging Gowning Related Corrosion Equipment wear/shedding Lubricants Cleaning residues Cross-contamination Degradants

5 Elements of Protection Control Strategies Measures

6 Architectural Finishes Facility Layout & Flow Mechanical & Utilities HVAC Supply, Filtration, Flow, & Balance Physical segregation of process steps and products Equipment Materials of Construction

7 Gowning Facility Cleaning & Sanitization Equipment CIP & SIP Preventive/Predictive Water sanitization & flushing Filter & resin lifetime Employee training/qualification

8 Fermentation Recovery Purification Final Purification Final Bulk Contamination *Sensitivity of Contamination to Stage Step Open & Closed ing Filtration, Sterilization, Inactivation Number and Complexity of Unit Operations Disposable & usable equipment Extractables & Leachables *ISPE, Biopharmaceutical Manufacturing Facilities, Volume 6, 2 nd Edition (2013)

9 Nutrient rich vs limiting ph Neutral vs extremes High water content vs low water content Natural vs refined raw materials Preservatives & antibiotics Organic solvents vs aqueous

10 Measures Measur es Raw material & utility testing Intermediate & final drug substance testing Environmental Monitoring of classified spaces Cleaning Validation & visual inspections Walk-thrus & Inspections Facility Monitoring System

11 Pitfalls of Aging Facilities Measures Reliance on measures to compensate for inadequate infrastructure. Accepting or ignoring signals/trends thought to be related to infrastructure. Not re-evaluating maintenance frequencies as facility and equipment age Stretching the definition of normal & expected wear Avoiding assessing risks in fear of what it will tell you. Bias when assessing risks

12 Pitfalls of Designing a New Facility? Many of the other product protection elements may be unknown or not well defined Overreliance on infrastructure Underestimating the cost of maintenance Inefficient people, equipment, and materials flow

13 Risk Management tools Quality Risk Management *ICH Q9 Quality Risk Management Model Initiate Quality Risk Management Risk Assessment Risk Identification Risk Analysis Measures Prob. of Detection Risk Evaluation Risk Communication Risk Control Risk Review Risk Reduction Risk Acceptance Output / Result of the Quality Risk Management Review Events unacceptable Prob. of Occurrence *ICH Harmonized Tripartite Guideline, Quality Risk Management Q9, Step 4 version (2005).

14 Severity Focus on patients Mode of delivery Additional removal capability at drug product steps Toxicology opinions

15 Summary Protection Control Strategy: A risk-based approach to control and measure the stuff our patients do not want in our products. Must understand all possible sources of contamination Controls limit the probability of contamination. Measures only detect contamination types they are designed to detect. Every facility, process, & product are different thus have different risk profiles. Severity MUST be patient focused.