Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Postapproval CMC Changes in the United States with a Focus on Biopharmaceuticals - Current Status and an Outlook in the Pharmaceutical Development ***

Anja Then-Kania (Abschlußjahr: 2011)

A variety of medical illnesses can presently only be treated by using biopharmaceuticals. Biopharmaceuticals thus constitute an extremely important class of pharmaceutical products, whose manufacturing is a complex field with respect to producing a safe and effective medicinal product.

Due to the very specific features of biopharmaceuticals the regulation of biopharmaceuticals differs in comparison to conventional drugs. The Food and Drug Administration (FDA), responsible for regulating drugs (both biopharmaceuticals and conventional drugs) in the U.S., approves biopharmaceuticals for marketing through the Biological License Application (BLA) and conventional drugs through the New Drug Application (NDA) process. The BLA and NDA is a request for permission to introduce a medicinal product into interstate commerce.

When a product is first approved, its manufacturing process represents the current technology standard for manufacturing and follows the current Good Manufacturing Practice (cGMPs) standard for regulatory compliance. After approval, market demand, technological advances, changed GMP standards, raw materials sourcing or manufacturing experience may require that the approved process needs to be modified. Therefore, process changes are an expected aspect of pharmaceutical manufacturing. However, it is known that biopharmaceuticals are very sensitive even to slight changes in the manufacturing process and due to all features of biopharmaceuticals, it is not expected that the quality attributes of the "pre-change" and the "post-change" material is identical. Nevertheless, it has to be proven that both materials should be "highly similar" to make satisfactory justification of the safety and efficacy of a medicinal product. This needs to be addressed in a comparability exercise. The assessment can occur on a quality level but might be sometimes supported by comparability bridging studies. After evaluating whether the changes of the manufacturing process have a minor, moderate or a substantial effect on the quality, safety and efficacy of a product by the applicant the FDA needs to be notified. Reporting to FDA is performed by an Annual Report for minor changes, by a Change Being Effected (CBE) Supplement (0 or 30) for moderate changes and a Prior Approval Supplement (PAS) for major changes. Especially for biopharmaceutical products, due to their complexity, the quality of a "pre-change" versus "post-change" product and thus its impact on safety and efficacy needs to be assessed. Therefore, it advisable or even mandatory to run a comparability exercise by using a comparability protocol.

In the pharmaceutical development, for conventional drugs as well as for biopharmaceuticals, the "traditional approach" and the "Quality by Design (QbD) approach" are conceivable. Currently, a clear trend towards QbD can be observed. The traditional approach is a more empirical and single variable approach, whereas the QbD approach is more scientific and risk-based from a regulatory point of view. The flexible regulatory QbD approach is a trend that challenges the conventional thinking in pharmaceutical development. It is already reflected in different International Conference on Harmonisation (ICH) guidelines Q8, Q9, Q10 and Q11 (consultation) as well as in FDA guidances meaning that this approach is more and more claimed and requested by the regulatory agencies in the United States (U.S.) as well as in Europe. It is expected that introduction of a QbD approach in development will have tremendous impact on the handling of Chemistry, Manufacturing and Control (CMC) changes in the maintenance phase of a product, both in terms of frequency and complexity of such changes.

It becomes obvious that establishing the QbD approach for biopharmaceuticals is sophisticated due to the usage of cell based systems and a complex manufacturing and purification process. However, this new QbD approach of handling postapproval CMC changes by the agencies may be on the one hand a great benefit for the pharmaceutical industry as it eases dealing with manufacturing changes. On the other hand it challenges the pharmaceutical industry in setting up a quite complex program for pharmaceutical development already at early clinical stages.

Handling postapproval CMC changes in a QbD setting is characterized by more regulatory change control flexibility and expanded change protocols. Furthermore, it allows the applicant a continuous evaluation and update of the process to ensure consistent product quality over time within the approved design space described in the dossier and facilitates a reduction of postapproval submissions as process changes within the design space will not require a review or approval by the agencies.

Introduction of QbD constitutes a clear change in the regulatory landscape as postapproval CMC changes will be driven by an increased reliance on quality systems change control, risk-based evaluation and reduced requirements for prior regulatory agency approval. Consequently, despite the complexity of the approach and the necessity of higher investments at early stages of pharmaceutical development, the QbD approach can be a great chance for the pharmaceutical industry.

Pages: 60