Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Regulatory Requirements to the Quality of Parenteral Medicinal Products according to the Common Technical Document ***

Claudia Schmolze (Abschlußjahr: 2002)

Summary
Based on the Directives 2001/83/EC and 91/356/EEC there are several guidelines and recommendations providing interpretation and descriptions for the marketing authorisation dossier and the requirements according to good manufacturing practices (GMP) for manufacture and quality control of parenteral medicinal products. It was the intention of this master thesis to work out the regulatory requirements of parenteral medicinal products including chemical drug substances based on the GMP requirements for manufacture and quality control with an analysis and evaluation in comparison to non-parenteral medicinal products. In addition some suggestions for further guidelines and a procedure for simplification should be provided.
First as a basic background the GMP requirements for manufacture and quality control of parenteral medicinal products were briefly described. The main requirements of parenteral medicinal products are to be sterile, without or defined limits of bacterial endotoxins or pyrogens, particulate matter, pH and osmolarity. These requirements result to the need for an implementation of a sterilisation method. Sterilisation methods can be divided into:

• Terminal sterilisation like steam, dry heat, radiation and gas sterilisation
• Aseptic processing with or without aseptic filtration

In addition two special technologies, like isolator technology and the blow-fill-seal technology were further described. Each single sterilisation process requires specific test methods in monitoring and process validations.
Subsequently, the regulatory requirements of parenteral medicinal products were evaluated based on information regarding GMP according to the format of the Common Technical Document (CTD).
For the regulatory evaluation only the different parts of CTD sections were evaluated. At pharmaceutical development some differences between parenteral and non-parenteral medicinal products are shown for cases of excipients acting as antioxidants or antimicrobial preservations and for the choice of an appropriate sterilisation method.
At manufacture, in particular at description of manufacture, the in-process control and process validation the requirements differ in comparison to non-parenteral medicinal products. The requirements were emphasised for terminal sterilisation processes, aseptic processing with/ without filtration and for special technologies like isolator and blow-fill-seal technology regarding the required information and additional documents, if applicable.
At documentation of excipients the differences in comparison to non-parenteral medicinal products were shown by sterilised excipients for aseptic processing, specific requirements on water as excipient, and for antioxidants or antimicrobial preservations.
The control of the drug product covers the required quality control at final release of parenteral medicinal products, like sterility, bacterial endotoxins or pyrogens, particulate matters, pH, and osmolarity. In addition the content of extractables form container-closure system, impurities/ degradation products, and the uniformity of dosage units are required for non-parenteral medicinal products as well.
For the control of the container-closure system the requirements differ for the use in aseptic processing and in blow-fill-seal technology in comparison to non-parenteral products.
Specific requirements for parenteral medicinal products at stability are given for the in-use stability and the stability after first opening.
The documentation of the drug substance is only specific when applied in aseptic processing without filtration. In such a case the same requirements as required for sterile drug products is needed.
Finally it was discussed and concluded that the main differences in the marketing authorisation dossier between parenteral and non-parenteral medicinal products in pharmaceutical development and manufacture are caused by the choice and use of a sterilisation method. These are the consequences of the need for parenteral medicinal products regarding the clinical tolerance.
Furthermore, it is suggested to revise the guidelines CPMP – NfG on pharmaceutical development and CPMP – NfG on manufacture of the finished drug product to adapt the definition and division of standard and non-standard processes. Especially for non-standard processes like aseptic processing, isolator technology and for blow-fill-seal technology it is suggested to develop regulatory CPMP guidelines based on the PIC/PICS Guidelines and on experiences with authorised products.
Finally, a procedure for a Certificate of Suitability, applicable for sterilisation procedures for excipients, containers and closures of parenteral medicinal products that is assessed and issued by the EDQM on compliance is suggested as a simplification.