Stability Studies

Overview

All active ingredients and pharmaceutical products need to remain stable over time and over a wide range of conditions. Rigorous stability testing is therefore a crucial component of the development process.

3R Pharma Consulting can help clients design stability studies that are scientifically based and meet all relevant regulatory requirements, in particular guidelines Q1A(R2), B, D, and E issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

Apart from scientific and technical advice based on its long-term experience, 3R Pharma provides clients with fully detailed reports and summaries that include statistical analysis of stability data.

Testing regimes

Stability studies need to measure scientifically how active ingredient (API) or finished product (FPP) quality varies over time under the influence of temperature, humidity, light and other environmental factors. The stability study should also consider any product factors that may influence stability such as excipient interactions; packaging materials, etc… Studies must also assess any interactions between ingredients in fixed-dose combination.

The influence of environmental factors becomes particularly relevant in products intended for global markets.

Stability study designs need to be constructed around a number of compulsory requirements that include:

• Stress testing: Stress tests on API or FPP should be selected to identify intrinsic molecular stability, any likely degradation pathways and validate the analytical procedures used. The nature of the stress testing will vary between different APIs and FPPs
• Batch selection: Stability tests should be based on at least three primary batches of the API manufactured to minimum pilot scale by the same synthesis route as production batches, and using a manufacturing method that models full scale production
• Container closure: Stability studies should also be conducted on ingredients or products packaged in a container closure system that accurately simulates the packaging proposed for storage and distribution
• Testing frequency: The frequency and time scale of tests is also a key part of the design, with tests needing to be spaced and repeated sufficiently to establish stability profile over intended shelf life. Thus for APIs with a proposed life of, say, three years, tests should be carried out every three months over the first year, every six months over the second year, and annually thereafter throughout the proposed re-test period or shelf-life
• Testing frequency: The frequency and time scale of tests is also a key part of the design, with tests needing to be spaced and repeated sufficiently to establish stability profile over intended shelf life. Thus for APIs with a proposed life of, say, three years, tests should be carried out every three months over the first year, every six months over the second year, and annually thereafter throughout the proposed re-test period or shelf-life

The ICH guidelines also provide for use of bracketing (only testing those samples on the extremes of relevant design factors at all time points) and matrixing (designing study schedule to test only selected subsets of possible sample and factor combinations at specified time points) techniques to reduce the cost and timescales of stability studies. Contrary to widespread belief, bracketing and matrixing can be applied to pharmaceutical studies, provided these are based on solid scientific rationale.

Where the stability study produces out of specification (OOS) results, these need to be handled carefully and fully in accordance with ICH, MHRA and other guidelines. For example, it will be necessary to establish an assignable cause and determine whether it is a batch or more general problem.
For current global markets, successful stability studies also need to take account of commercial factors that include:

• Regulatory requirements for global stability submissions
• Problematic storage environments
• Application of QbD (Quality by Design) concepts
• Leveraging stability data to expedite regulatory approval
• Assessing stability issues for nutraceuticals, generics, biologics and other new technologies
• Potential stability issues for repackaged and composite products
• Toxicology concerns from emerging impurities
• Physical effects on product stability
• Potential temperature excursions during storage and shipping
• Quantifying impurities and degradation on products in development

Capabilities

3R Pharma Consulting has world-recognized credentials in stability testing. The organization’s founder and managing director, Dr. Manuel Zahn, was a member of the American Association of Pharmaceutical Scientists (AAPS) Stability Workshop and co-author of the resulting book that defines stability programs for 21st century global markets.

3R Consulting’s stability testing services include:

• Designing cost-effective stability protocols for global markets, including Climatic Zone IVA (hot and humid) and IVB (hot and very humid) environments
• Application of bracketing and matrixing protocols to stability studies
• Evaluation and statistical analysis of data
• Generation of stability reports and summaries
• Advice on stability within temperature controlled pharmaceutical logistic chains to comply with Good Storage, Good Distribution and Cool Chain Distribution practice guidelines
• Assessing impact of temperature excursions on product quality
• Investigation of trends using statistical data
• Assessment and corrective action on OOS results>

Quality & Certification

Since 2009, Dr. Zahn has been certified as an API Auditor by the European Chemical Industry Council’s Active Pharmaceutical Ingredients Committee (APIC).

Dr. Zahn is a member of the Advisory Board of Pharma iQ and of the following organisations:

• American Association of Pharmaceutical Scientists (AAPS)
• Parenteral Drug Association (PDA)
• European Compliance Academy (ECA)
• European QP Association (QPA)
• Deutsche Gesellschaft für Regulatory Affairs (DGRA)
• International Society for Pharmaceutical Engineering (ISPE)

Media Contact

Dr. Manuel Zahn, Managing Director, 3R Pharma Consulting GmbH
Tel: +49 (0) 7083 527 6870
Email: [email protected]

Resources

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Supplier Information
Supplier: 3R Pharma Consulting GmbH
Address: Wildbader Str. 3, 75335 Dobel, Germany
Tel: +49 (0) 7083 527 6870
Website: www.3rpc.com