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.

This article provides a compilation of summaries of many of the presentations at the two- day workshop held in conjunction with the Annual Meeting of American Association of Pharmaceutical Scientists (AAPS) on October 21-22, 2011 in Washington, D.C. The workshop program comprised of twenty presentations encompassing many scientific aspects impacting pharmaceutical stability. The diverse topics included Current FDA thinking on stability practices, phase appropriate method design utilizing QbD concepts, stability indicating spectroscopic methods, design of stability studies for global requirements, strategies for controlling genotoxic impurities in drug products, regulatory perspectives for leachable impurities etc. A session on stability studies of biopharmaceuticals was also included. In other words the workshop topics included most aspects of the “science behind pharmaceutical stability”. The program also included a regulatory round table in which questions were received from the attendees and answered by a panel of regulatory experts from industry.

The presentation summaries have been prepared by the individual speakers, some speakers did not submit the summary of their presentations and therefore those could not be included.

Current FDA Thinking on Stability Practices for New Drug Products (Small Molecules)

Ramesh K. Sood, Ph. D.

The talk was divided into two sections addressing stability considerations at the Investigational New Drug (IND) stage and at the New Drug Application (NDA) stage. He discussed the regulatory and scientific reasons for including the appropriate stability data to support various stages of clinical investigations at the IND stage and to support a NDA for marketing pharmaceutical products in the United States. The CFR [312.23(a)(7)(iv)(a) and 312.23(a)(7)(iv)(b)] states that the IND should provide information sufficient to support stability of the drug substance and drug product to assure their stability during planned clinical studies. It was emphasized that stability data commensurate with the duration of the clinical study are required in all phases of the IND to demonstrate that the drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical studies. He provided some general observations from submitted INDs showing how these submissions addressed these statutory requirements to ensure that the clinical products will remain suitable for their intended use during the course of clinical studies.

The second half of his presentation addressed the need to have appropriate stability data submitted to support an NDA for marketing a pharmaceutical product in United States. It was emphasized that each pharmaceutical product that is to be marketed in the United States needs to have an expiration dating period assigned. This expiration period is assigned to all pharmaceutical products when packaged and stored under the pre-determined circumstances. The data to support such expiration period is generated by studying the stability of the product using carefully designed stability studies. He elaborated on consideration for designing and executing a proper stability study that would generate appropriate stability data to support a proposed expiration period. Finally he presented two case studies which demonstrated how the Agency was able to assign the proposed expiration period in one case and how the data provided in the second case did not support the proposed expiation period.

Design of Stability Indicating Methods Utilizing QbD Concept – a Phase-Appropriate Approach

Dilip R. Choudhury, Ph. D.

The importance of development and manufacture of pharmaceutical products utilizing Quality-by-Design (QbD) approach is well acknowledged by the industry and regulatory agencies. To achieve QbD-based product and process development, it is imperative that analytical methods be designed and developed utilizing a QbD approach as well. The question that is frequently asked is when to start using the QbD approach in drug development and analytical method design since many development candidates do not progress beyond Phase1 or 2 because of failure to meet the clinical objectives.

A unique approach was presented on design of stability-indicating methods utilizing QbD concept in a phase-appropriate manner from the beginning of clinical development. The Analytical Target Profile (ATP) is defined early on to describe the method performance requirements to measure a specific critical quality attribute (CQA) of the drug product. A specific method can be designed to meet the pre-defined performance requirements. Method performance requirements in ATP can be defined in a phase appropriate manner.

The presentation discussed a lifecycle approach to analytical method design and development starting with the early stage method. Critical method parameters are identified during early stage method design and a systematic optimization of critical method parameters is performed utilizing commercially available on-line software. Such optimization has significant advantages over manual optimization of parameters and can be achieved with minimal scientist time. Critical evaluation of data must, however, be performed. Risk assessment of the method is performed at key stages of development. The principle of continuous learning and improvement is applied as the method evolves in parallel with drug development process.

Another advantage of this approach is that since the core method is developed during early development, and the method evolves with the changes in drug product formulation, the final method incorporates the knowledge of the impact of the critical method parameters and formulation and process variables on the method performance. It also provides a convenient means of tracking impurities as a function of formulation and process parameters. The method life cycle parallels the product development life cycle.

In conclusion, applying QbD concept to the design of analytical methods in a phase appropriate manner provides a scientifically sound method at all stages of drug development with good understanding of method risks, critical method parameters and provides better assurance of the robustness and long term performance of the method.