Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory Requirements concerning Development Pharmaceutics and Manufacturing of a Medicinal Product: A Critical Analysis from Pharmaceutical Technological View

Dr. Dorith Stauch-Steffens (Abschlußjahr: 2002)

Up to now, specifications of the finished product, analytical methods and appropriate validation studies occupy most of the space in part 2 of an application dossier. When the GMP-guideline was set up, the authors directly required: "Quality has to be produced; it cannot be tested into the product afterwards." Because the manufacturing process and the validation are part of GMP, and are controlled by the competent authority, they often are neglected in the dossier. Another reason may be that the validation on full production scale batches has not been completed at the date of submission.

This thesis deals with the question, which information concerning development and manufacturing should be submitted in the dossier seen from pharmaceutical-technological view? The most suitable place to put this information in is the topic Development Pharmaceutics. This is A.4 in the old NtA-format or topic 3.2.P.2. in the CTD. For that, the requirements of the Guidelines Note for Guidance on Development Pharmaceutics, Note for Guidance on Process Validation, and Note for Guidance on Manufacture of the Finished Dosage Form are discussed; the influence of the new CTD-format is investigated. As all three guidelines have to cover the total variety of possible formulations, the demands are written quite generally. The essential require is that preformulation and formulation studies should be submitted which define critical parameters of the formulation or critical steps of the manufacturing process which influence the quality of the finished product. Also the analytical methods for controlling them should be submitted. Some examples are listed, e.g. mixing processes and appropriate content uniformity, dissolution testing for solid dosage forms.

Examples from selected excipients (lactose, MCC, calcium phosphate) are provided and the problems connected to their diversity are discussed. The chemical and analytical description of these excipients in the pharmacopoeial monographs is not sufficient to describe the properties of these excipients and what is more to help to understand their functionality in formulations. It is generally acknowledged that effective pharmacotherapy does not only depend on the proper active substance, but also on the proper formulation. Excipients are vital components of product formulations, which means that the selection, concentration, and quality of the excipient influence the outcome of the pharmacotherapy. In order to properly discuss the impact of an excipient first the specific function of that excipient in the formulation and manufacturing process has to be understood. Whereas the drug substance is typically of high purity and well characterised, excipients are often natural substances whose physical and chemical properties are more difficult to quantify.

And as an exact description of all starting materials is important for the quality of the finished product, it becomes clear that a statement "complies with Ph. Eur." will often not be sufficient to characterize an excipient. Some more distinct information of excipients' functionality as well as critical process parameters should be submitted under Development Pharmaceutics.

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