Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Requirements for active pharmaceutical ingredients in marketing authorization applications

Dr. Eva-Maria Möllenhoff (Abschlußjahr: 2005)

Language: English
 
Active pharmaceutical ingredients (APIs) are used in the manufacture of drug medicinal products and, when used in the production of a drug, become an active ingredient of the drug product. The substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body. APIs can be, depending on their origin, divided into inorganic substances, herbal drugs and herbal drug preparations, organic substances isolated from material of animal or human origin and organic substances (synthetic, semi-synthetic or isolated from herbal sources or micro-organisms).

Information on the chemistry, manufacture and controls (CMC) for an API must be submitted to support the approval of an application for marketing authorisation (MAA) or a marketing authorisation variation (MAV) of a medicinal product. The requirements for active substance in the quality part of a documentation has been investigated for the three ICH regions, Europe, United States of America and Japan.

API registration in Europe
APIs can be classified into new active substances used for the first time in a medicinal product, existing active substances not described in the European Pharmacopoeia (Ph.Eur.) or into existing active substances described in the Ph.Eur. or a pharmacopoeia of an EU member state. Depending on the kind and classification of the active substance, the required data may be submitted in the following ways:
For new active substances either full details of manufacture or an active substance master file (ASMF) can be used. For existing substances not described in a pharmacopoeia full details of manufacture or an ASMF is applicable. For substances described in a pharmacopoeia full details of manufacture, an ASMF or a certificate of suitability of monograph of the European Pharmacopoeia (CEP) is possible. In very exceptional cases the applicant may submit other supportive data to qualify the impurities.

The content of information to be provided for the quality part of the a dossier is regardless the class of the active substance virtually the same and should be provided in CTD-format (CTD-format is not required for veterinary products). It includes general information on the substance, the details on the manufacture, the characterisation of the substance including the impurity profile, the specifications and analytical methods used, the reference substances, the packaging material, and the stability. For pharmacopoeial substances compliance with the requirements of the pharmacopoeia must be shown. Current guidelines as well as general monographs of the Ph.Eur. must be followed.

Information on the API is never evaluated on its one by the competent authorities. Whereas the information on the full details of manufacture are directly incoorporated into the submission documentation, ASMFs are compiled by the manufacturers of the active substance as an independent document which is provided to the applicant and included in his marketing authorisation application prior to submission. A CEP needs to be requested by the EDQM. In case the manufacturer of a substance is able to proove that the quality of the substance is suitably controlled by the relevant monographs of the Ph.Eur. a CEP can be issued. This certificate can then be used by the manufacturer of medicinal products in his applications for marketing authorisation. The applicant should include a copy of the most current CEP in the dossier together with a written assurance that no significant changes in the manufacturing method have taken place following the granting of the certificate or its last revision.

In case the information about the API needs to be updated the changes should be classified in three categories (notification/minor/major = type IA/type IB/type II) depending on the potential impact of the change on the quality of the active substance based on the Commission Regulation (EC) No. 1084/2003 and 1085/2003 concerning the examination of variations to the terms of marketing authorisation for medicinal products for human use and veterinary medicinal products. CEPs need to be renewed every 5 years.

API registration outside Europe
In the USA and in Japan similar systems are in place. It is possible to provide either full details of manufacture or a drug master file. Drug Master files can not only be used for active substance but also for e.g. excipients, packaging materials or medical devices. The master file system is a voluntary registration system; it is not compulsory.

Whereas Japan requires submission of documentation in CTD-format, it is not required in the USA. The documentation to be provided in USA exceeds the European especially in terms of manufacturing details. Japan has introduced the master file system which corresponds with the European system on 1 April, 2005.

After submission master files will be formally assess in terms of format and content. They are not approved or disapproved. They are finally evaluated in the approval process of the drug product. The US-DMF must contain a complete list of each person being authorized to incorporate by reference any information in the file.

A holder must notify each affected applicant of any change in the DMF. Notice should be provided well before making the change in order to permit the sponsor/applicant to supplement or amend any affected application(s) as needed. Both the applicant and the master file holder contribute to establishing and maintaining the quality of the drug product by manufacturing and controlling the drug substance in accordance with the information submitted in the application and, by reference, in the master file. Classification of change follow in the US CFR &#x;.70: supplements and other changes to an approved application (506A), Guidance for industry: changes to an approved NDA and ANDA (including questions and answer guidance) and BACPAC (bulk active post approval changes). In Japan PFSB/ELD Notification No. 0210001 from the director of the Evaluation and Licensing Division, Phamraceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, 10 February 2005 is used to identify changes with impact on quality, efficacy or safety.

The decision which system is used needs to be considered very carefully. Whereas full details provide complete information, drug master files (and CEPs in Europe) can be used to protect data. This allows to save manufacturer's know-how and to keep intellectual properties confidential. Another critical parameter are the timelines from preparation and compilation of documents until approval of the drug product. It should be further considered if docuemts will be submitted worldwide. Due to different requirements to format and content preparation of one documentation might not be sufficient. CEPs are not recognised worldwide, although manufacturers whatever their location in the world can use the procedure. Especially for internationally operating companies submission as well as maintenaining the drug substance information updated everywhere may cause problems.

Pages: 99 (incl. annexes)
Annexes: 4