Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Changes to biological medicinal products (Case Study: Vaccines) ***

Dr. Ingeborg Cebulla (Abschlußjahr: 2004)

By Commission Directive 2003/63/EC it is the first time that a proper definition for biological medicinal products has been given in the European pharmaceutical legislation. Biological medicinal products contain an active substance, which is a biological substance. Furthermore, for the characterisation and the determination of the quality of a biological medicinal product a combination of physicochemical-biological testing, together with the production process and its control is necessary.

Vaccines are a very heterogeneous group of pharmaceuticals belonging to the biological medicinal products. They contain immunogenic substances capable of inducing specific, active and protective host immunity against infectious disease. Most commonly vaccines are used prophylactically. What is different from most chemically synthesised medicinal products is that vaccines are mainly administered to healthy people in particular to infants and children.

The manufacturing of vaccines is based on biological processes with their inherent variability. In particular, the manufacturing of the active substance of vaccines is sensitive to external factors such as pH-value, oxygen content, growth medium and so on. The inherent variability of vaccine production has led to the establishment of national and international batch release. Furthermore, vaccine production requires seed-lot systems in order to prevent the unwanted drift of properties, which might ensue from repeated sub-cultures or multiple generations. In addition, vaccines can only be poorly characterised by means of physicochemical or biophysical methods. Control of biological medicinal products usually involves biological analytical techniques that have a greater variability than physicochemical determinations.

Since October 1, 2003 variations have to follow Commission Regulation 1084/2003 for marketing authorisations of medicinal products granted by member states, and Commission Regulation 1085/2003 for centrally authorised medicinal products. The old regulations were revised in particular to reduce the regulatory workload for the competent authorities and industry. However, vaccines are often excluded from type I variations by the conditions detailed in the regulations. Although it is recognised that for vaccines the manufacturing process is an intrinsic part of the quality, several variations are regarded to be classified as being too stringent or restrictive. Due to the upgrade to type II variations for biological medicinal products, they do not adequately benefit from the new regulations compared to chemically synthesised products.

Essential similarity, in particular the same qualitative and quantitative composition in terms of active substance cannot always be proven for biological medicinal products, in particular not for conventional vaccines. Therefore, the term "similar biological medicinal product" has been introduced into the European pharmaceutical legislation. In contrast to generics, for which no safety and efficacy studies have to be performed, for "biosimilar" medicinal products the type and amount of data on toxicology and clinical data must be determined on a case by case basis in accordance with the relevant scientific guidelines.

The comparability claim will not be applicable to vaccines, as they are very complex entities. Even small differences in their physicochemical nature or production process can result in major differences in their biological properties, which could result in a loss of safety or efficacy. However, identity is not possible to show, as vaccines cannot be highly purified and characterised by analytical methods. Therefore, changes in the manufacturing process of vaccines could only lead to the conclusion that the pre- and post-change product is "comparable".

Two specific procedures applicable only for vaccines are being discussed. These are the annual update for human influenza vaccines and the VAMF procedure. Although every year a new composition i. e. a change in the active substance is necessary for influenza vaccines, only a type II variation instead of an extension application is necessary. This takes the limited time for the manufacturing, licensing and clinical trials into consideration.

Two working documents on the VAMF procedure are currently under discussion. The VAMF will be similar to a DMF but in contrast to that, the VAMF will be only evaluated by the EMEA. The evaluation will result in a certificate of compliance, which will be valid throughout the EU. Quality changes to the VAMF will be handled as a two step process. In the first phase the technical impact of the variation will be assessed centrally by the EMEA and a certificate of compliance to Community legislation will be issued. However, in the second step the impact on the individual medicinal product will be assessed on the MA basis by the competent authority.

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