Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory guidance on comparability studies for biological products following changes to the manufacturing process and analytical procedures

Dr. Martin Wendland (Abschlußjahr: 2008)

Language: English

The development of biological products usually involves substantial changes to the manufacturing process and is commonly accompanied by improvements in the analytical tools used for product characterization. The manufacturer has to ensure that such changes to the process and analytical procedures do not confer an adverse effect on quality, safety and efficacy of the product.

Compared with chemically-defined medicinal products, biological products are subject to a manufacturing process that is complex and less well controlled, and in combination with inherent biological features (e.g. post-translational modifications) this can lead to a heterogeneity and/or variability of the product. Furthermore, the development of sensitive and suitable analytical procedures applied for the characterization of biological products is a challenging task requiring state of the art technology.

The aim of this thesis is to summarize regulatory guidance for process and analytical development with regard to the assessment of product comparability.
The historical development leading to the current regulatory views and requirements on comparability studies is briefly described.

The content of four guidance documents with high relevance for comparability studies is detailed:

• ICH Q5E on "Comparability of biological products subject to changes"
• FDA Guidance on "Comparability protocols"
• EMEA/CHMP/BMWP/101695/2006 on "Non-clinical and clinical issues"
• EMEA/CHMP/BMWP/14327/2006 on "Immunogenicity assessment"

The principles and approaches to be applied for comparability studies as described in the regulatory guidance documents is further supplemented with practical considerations and approaches derived from publications, scientific meetings and own experience.

A series of case studies is presented and discussed to illustrate in a practical way the principles for assessing comparability including methodical approaches, the extend of characterization and comparability studies, and the comparison and evaluation of quality data. The case studies refer to products from early to late development stages and provide valuable insights into successful strategies and include warnings on possible pitfalls. A discussion on the need for supportive non-clinical and clinical studies is included in selected case studies.

It is concluded that changes to the manufacturing process and analytical procedures need to be planned well in advance. A precise development plan and program including a detailed comparability protocol is a prerequisite to ensure that pre- and post-change products will be sufficiently characterized. Only then a qualified assessment of product comparability is possible.

Pages: 95