Get Proactive With Your Stability Program
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The document discusses the stability testing processes for drug substances and products as conducted by the life science business of Merck KGaA, operating as MilliporeSigma in North America. It emphasizes planning and alignment with manufacturing for stability studies, including considerations for environmental factors, assay selection, and project management. Key takeaways highlight the importance of understanding critical quality attributes and establishing robust protocols for analysis over time.
Get Proactive With Your Stability Program
- 1. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Get Proactive with your Stability Program Pamela Hamill, Ph.D. Greg Pirozzi, Ph.D.
- 2. The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada
- 3. “Provide evidence of how the quality of a Drug Substance (DS) or Drug Product (DP) varies with the influence of environmental factors – Temperature, Humidity and Light to establish a shelf life or retest period” - Guidance: ICH Q1(A) R2 – 2003 3 • Physico-chemical and structural attributes • Purity/impurities • Biological activity Assessment of Critical Quality Attributes over time Stability study types Real Time Accelerated Stress
- 4. 4 Stability testing in biologics manufacturing Banks Master Cell banks Working Cell banks Batches of Product Purified Bulk Drug Substance (DS) Final Drug Product (DP) Bioreactor Purified Bulk Substance Final Drug Product Unprocessed Bulk Product Process Chromatography Formulation development, fill & finish Research Cell Line Master Cell Bank Production Working Cell Bank Production Upstream Bioprocessing Downstream Bioprocessing Other • Shipping • Process hold steps Material types requiring stability testing
- 5. Considerations in timeline planning for GMP stability: Overview 5 Batch Release/T0 time point for GMP stability study Establish/validate assays: Feasibility and planning Generate samples to assess stability- indicating properties Source of Reference Standard/representative material to establish and validate methods GMP study protocol (min 2 months, to allow for review & signature) Planning/alignment with manufacturing schedule and sampling plan For outsourced studies, scope out stability conditions needed and identify providers Start Phase I Clinical Trial Minimum 12 months 3-6 months Data
- 6. 6 6 6 Stability studies enable understanding how these attributes change over time under different environmental conditions • Select assays that address these important attributes • Challenge with samples with known altered physicochemical and purity profiles Structural variability and consequences-mAb example Sources of structural variability RISKS Differences or changes in physico-chemical properties, post-translational modification and higher order structure can significantly affect product quality attributes and present risk to: N-Glycosylation Oxidation Deamidation Aggregation - -
- 7. “Analytical procedures should be fully validated and stability indicating” ICH Q1A (R2) Plan Ahead • Build in contingency for custom methods aimed at product specific attributes • What if approach needs to change? Challenge stability- indicating properties Allow time to assess performance 1 3 2 4 Establishing Methods 7 Reflect knowledge of CQA in assay choices
- 8. 1 Plan ahead to ensure there will be sufficient representative material to; • Establish assays and assess their performance • Support testing for all timepoints in the program (for methods that need RS) • Avoid bridging studies 2 If bridging a references or changes in critical materials is unavoidable, have the strategy planned before the study starts • Establish protocols and acceptance criteria in advance Reference standards & critical reagents 8
- 9. Critical manufacturing document Details samples, volumes, intended use, and destination Lot size will determine # of samples required Complex & lengthy process Multiple batches/fills Close coordination with CMO Manufacturing Alignment Sampling Plan 9 Align the GMP manufacturing and sampling plan
- 10. Conducting your study In-house vs outsourced Do you have capacity and expertise in-house to manage the project for the duration? Can one provider meet all your requirements? If multiple providers are needed, what are the logistical and project management considerations? 10
- 11. Challenging assays to assess stability-indicating properties 2 3 1 11 ? Source of samples with altered properties? • Stress testing? Where/when? • Outsourcing? • Requirements (conditions, timing) Planning to align with method development
- 12. Assays Required Repeat testing Testing specifications Time Points Final sample disposition instructions Test samples & retains Other required materials Study conditions Objective/ Scope GMP Stability Protocol 12
- 13. 13 Advanced Planning & Contingency in timelines Alignment with manufacturing Assay Selection • Focus on CQAs • Suitability for stability testing key takeaways
- 14. Greg.Pirozzi@milliporesigma.com Pamela.Hamill@milliporesigma.com Greg Pirozzi, Ph.D. Pamela Hamill, Ph.D. © 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved. The vibrant M and BioReliance are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources.