Pharmaceutical Stability: Scientific and Regulatory Considerations for Global Drug Development and Commercialization - Pharmaceutical Technology

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Pharmaceutical Stability: Scientific and Regulatory Considerations for Global Drug Development and Commercialization
A two-day workshop on the "science behind pharmaceutical stability" was held in conjunction with the Annual Meeting of American Association of Pharmaceutical Scientists (AAPS) on Oct. 21-22, 2011 in Washington, DC.

Drug Product Fingerprints: stability-indicating spectroscopic tests

John Bobiak, Ph.D.

The overall quality of drug products relies on management and mitigation (i.e. control) of risks. One approach to managing risk elements considers severity, probability, and detectability of critical events (e.g. form conversion of API, formation of impurities, compositional variations, etc.), and instituting control(s) around each element. Thus, analytical methods fill the need to detect critical quality attributes. Detection, however, is merely one part of the risk management process- a system of actionable controls is responsible for mitigating risk and ensuring quality.

Control strategies for drug products rely on stability data to identify acceptable ranges for ingredients, processing conditions, and storage/ shipping conditions. In one example, degradation product and impurity testing of drug products was waived by proving that: 1) Process-related impurities contained in the drug substance were the only source of impurity content of the drug product, 2) No new impurities or degradants were formed during the manufacture of drug product, and 3) No new impurities or degradants were formed at the long-term storage, accelerated, and stress conditions used in long term stability studies. This testing waiver was complimented with other at-line and online tests to develop a proposal for real-time-release testing (RTRt) of the drug product.

Another example described the use of molecular spectroscopy to monitor form conversion during a drug product stability program. Stressed drug products were analyzed by near infra-red (NIR) as well as powder x-ray diffraction (PXRD), dissolution, and impurity testing. Throughout the investigation, NIR and PXRD identified change of crystallinity at moderate and extreme conditions; the dissolution method did not identify crystallinity changes of the API (BCS I), and impurities were detected in samples of lowest crystallinity. The use of NIR provided detailed understanding of the impact of storage conditions, temperature excursions and packaging types on crystallinity.

In summary, both traditional and emerging techniques offer insight to stability profiles. Stability-indicating tests are an integral part of control strategies for new drug products.

Method Validation at Pre- and Post- Approval Stages Utilizing QbD Approaches

Mark Alasandro, Ph. D.

The use of DOE/QbD method validation approaches was discussed to support stability programs. Such approaches are needed to ensure methods have the accuracy and precision to detect stability changes and provide an understanding of the method variability. Often, method variability alone can suggest stability changes that trigger unnecessary investigations and reformulation activities. Another need is to support pre- and post- approval formulation and process changes without unnecessary method revalidations.

A unique approach was presented using DOE to validate a range of formulations, so formulation changes within this range do not require revalidation. This is coupled with accelerated stability modeling tools to ensure formulation and process changes do not generate new degradation products requiring revalidation. These combined tools minimize the impact of pre- and post-approval changes.

Case studies were presented using DOE/QbD to define a formulation operating range. This can be done without more work than needed using a traditional approach. Other key DOE outputs include a determination of critical method validation parameters that need to be monitored and controlled, such as resolution between critical pairs. A case study was also presented using DOE to assess intermediate precision to ensure there is no increase in method variability.

Another key DOE/QbD output is the Accuracy to Precision model. This shows the balance between accuracy and precision and its influence on product acceptance/failure rates. This can justify moving to new technologies as long as the change meets the accuracy to precision acceptance criteria. An example is discussed starting in early development with a generic gradient HPLC method; and, then going to a product specific gradient method, an isocratic HPLC method; and, finally, to a UPLC or PAT method for product commercialization. This use of DOE/QbD and accelerated stability models provides powerful tools for developing a lean stability program based on sound science and statistical rigor.


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