Masterstudiengang "Drug Regulatory Affairs"


New aspects in comparability studies of biotechnological products subject to changes in the manufacturing process

Dr. Sabine Schiemann (Abschlußjahr: 2005)

Language: English

The manufacture of biotechnological products is a complex process that involves continuous refinement throughout product development, post-approval and marketing. Alterations in the process used to manufacture a biotechnological product can result in wide differences in physicochemical properties as well as changes in biological activity, potency and immunogenicity. These changes can alter both the clinical efficacy and safety of a protein.

Reasons to alter the manufacturing process include the benefits of better yields, scale-up, new technologies and increased purity, as well as new formulations or product delivery systems. Although such changes are often intended to benefit the patient, it is essential that any change in the manufacturing process does not adversely affect the safety or efficacy of the product. This requires comparing pre-change and post-change material to assess if differences in the product are present after a manufacturing change has been implemented, and if so, whether they might affect safety and efficacy of the post-change product.

As analytical techniques became more sophisticated and sensitive in the last twenty years, the ability to assess the impact of a change in the manufacturing process increased to the point where it was reasonable to consider the concept of comparability. The results of those considerations were several regulatory guidance documents issued by the authorities in the EU and USA.

The FDA was the first to provide a mechanism to evaluate the impact of changes in the manufacturing process on the efficacy and safety of the post-change product. In 1996 the FDA guidance concerning demonstration comparability of biotechnological products (“Comparability guidance”) was published. Moreover, the guidance “Changes to an approved application for specified biotechnology and specified synthetic biological products”, issued by the FDA in 1997, describes the use of comparability protocols to changes prior to product approval as well as post-approval. Preparing a comparability protocol in terms of changes in a manufacturing process allows an applicant not only to gain agreement on what would be necessary to validate a manufacturing change, but also to reduce the reporting category for a specific change.

In the EU, the CHMP has published two guidelines which encompass comparability studies of a change introduced by one manufacturer into its own process for a given product either before the granting of a marketing authorisation or after the granting of a marketing authorisation and for a product claimed to be similar to another one already authorised (biosimilars). In the guideline EMEA/CPMP/BWP/3207/00/Rev.1 the extent of comparability studies depending on the impact of the change on quality criteria are described whereas the guideline EMEA/CPMP/BWP/3097/02/Final focuses on the extent of non-clinical and clinical studies.

The need for a harmonised guidance concerning the appropriate assessment of comparability of biotechnological products subject to changes in the manufacturing process has emerged over the last years and finally resulted in the ICH guideline Q5E which came into force in June 2005.
According to ICH Q5E demonstrating product comparability after manufacturing changes is most relevant for products that already have been approved by the competent authorities or those in late-stage development. Products made by the modified process must have the same chemical, physical, and biological attributes as the pre-change products to which they are being compared, inferring that the post-change has the same clinical efficacy and safety as the pre-change product.

In earlier stages of development, demonstrating comparability is less critical because definitive safety and efficacy have not yet been shown. Due to Q5E significant emphasis is placed on analytical testing for comparability, but the studies can also include non-clinical and clinical data.
Furthermore, the implementation of “Process Analytical Technologies” (PAT) in biotechnological processes may open new possibilities to design and develop well understood processes that will consistently ensure a predefined quality at the end of the manufacturing process. The use of PAT for analytical measurement in manufacturing processes can contribute to increased understanding of the process and more flexible regulatory approaches.

In conclusion, the harmonised guidance ICH Q5E concerning the appropriate assessment of comparability of biotechnological products subject to changes in the manufacturing process is a useful regulatory tool as it sets the boundaries and expectations of the regulatory authorities in the EU, the USA and Japan and very much helps biotechnological manufacturers define the scope of their responsibilities and activities and under which conditions they have to perform comparability studies. In addition, the newly established PAT initiative provides productivity improvement tools which can contribute to increased understanding and control of the biotechnological manufacturing process.

Pages: 40