GMP News No. 165
28 January 2002
Revision of the
In order to understand the meaning of the above-mentioned revised NfG, please find some background information regarding the granting of a marketing authorisation and the CTD (Common Technical Document) below:
According to the Directive 65/65/EEC, no medicinal product may be placed on the market of a Member State unless a marketing authorisation has been issued by the competent authorities of that Member State.
According to Directive 75/318/EEC the particulars and documents accompanying an application for marketing authorisation should be presented in four parts (Part 1: Summary of the dossier, Part 2: Chemical, pharmaceutical and biological testing of medicinal products, Part 3: Toxicological and pharmacological tests; Part 4: Clinical Documentation) in accordance with the requirements set out in the Annex of Directive 75/318/EEC and taking account of the guidance published by the Commission in The rules governing medicinal products in the European Community.
Part 2, section C ('Controls of Starting Materials') of the Annex to Directive 75/318/EEC is concerning the data required for the 'starting materials', which means all the constituents of the medicinal product and, if necessary, its container.
Further details regarding the data required for active substances for marketing authorisation are laid down in the Note for Guidance on Summary of Requirements for Active Substances in Part II of the Dossier (CPMP/QWP/297/97). For new chemical active substances, the requirements are set out in the above-mentioned revised CPMP guideline Note for Guidance on Chemistry of the New Active Substance (CPMP/QWP/130/96/Rev1), for biotechnologically-derived new active substances, the requirements are described in the guidelines in Volume III of The Rules Governing Medicinal Products in the European Union and in the European Pharmacopoeia.
In order to reduce time and resources used to compile applications for the registration of human pharmaceuticals and to simplify the exchange of regulatory information among regulatory authorities, the Expert Working Group on Quality of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has developed a guideline for a common format for the technical documentation, a Common Technical Document (CTD). The Common Technical Document was first proposed in July 1995, the first concept paper was written in 1996, in November last year the CTD was released at step 4 of the ICH procedure. The implementation of the CTD is mandatory from July 2002.
Therefore, the Note for Guidance on Chemistry of the New Active Substance (CPMP/QWP/130/96/Rev1) has been prepared in accordance with the new format of the dossiers for marketing authorisation, the Common Technical Document (CTD). In this document the subheadings of the CTD have been included for the sake of clarity. The deadline for comments is 30 June 2002.
Now another aspect mentioned in the NfG:
The revised Note for Guidance on Chemistry of the New Active Substance (CPMP/QWP/130/96/Rev1) gives a definition of an active substance starting material. That is no new aspect and no topic of the revision but in consideration of the fact that the ICH Q7a 'GMP Guide for Active Pharmaceutical Ingredients' is published as Annex 18 to the EC-GMP-Guide, this aspect should be given special emphasis with regard to regulatory compliance in API manufacture.
According to Annex 18, GMP for APIs applies to the steps after the introduction of the defined 'API Starting Material' into the process. An 'API Starting Material' according to ICH Q7a is ( ) a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties and structure ( )'.
According to this NfG the intermediate and/or substance considered as active substance (AS) starting material should be proposed and justified by the applicant. The AS starting material should be fully characterised according to identity and purity. In addition, the steps prior to the step where the starting material appears should be provided in the form of a flow chart in order to make it possible for the assessor to judge the adequacy of the choice and specifications of the AS starting material. '( ) Generally the full description of the process should cover all the synthetic steps critical for the safety (impurities) and the efficacy (structural part responsible for the activity) of the active substance ( )'.
With this, the Note for Guidance gives some more detailed information on the API starting material than ICH Q7a and can therefore help to define the 'API starting material' with regard to the regulatory compliance of the process.
For more details, the complete Note for Guidance on Chemistry of the New Active Substance (CPMP/QWP/130/96/Rev1) can be downloaded from the EMEA homepage. Download link