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GMP News No. 165
28 January 2002
Revision of the
In order to understand the meaning of theabove-mentioned revised NfG, please find some background informationregarding the granting of a marketing authorisation and the CTD (CommonTechnical Document) below:
According to the Directive 65/65/EEC, nomedicinal product may be placed on the market of a Member State unless amarketing authorisation has been issued by the competent authorities ofthat Member State.
According to Directive 75/318/EEC theparticulars and documents accompanying an application for marketingauthorisation should be presented in four parts (Part 1: Summary of thedossier, Part 2: Chemical, pharmaceutical and biological testing ofmedicinal products, Part 3: Toxicological and pharmacological tests; Part4: Clinical Documentation) in accordance with the requirements set out inthe Annex of Directive 75/318/EEC and taking account of the guidancepublished by the Commission in The rules governing medicinal productsin the European Community.
Part 2, section C ('Controls of StartingMaterials') of the Annex to Directive 75/318/EEC is concerning the datarequired for the 'starting materials', which means all the constituents ofthe medicinal product and, if necessary, its container.
Further details regarding the datarequired for active substances for marketing authorisation are laid downin the Note for Guidance on Summary of Requirements for ActiveSubstances in Part II of the Dossier (CPMP/QWP/297/97). For newchemical active substances, the requirements are set out in theabove-mentioned revised CPMP guideline Note for Guidance on Chemistryof the New Active Substance (CPMP/QWP/130/96/Rev1), forbiotechnologically-derived new active substances, the requirements aredescribed in the guidelines in Volume III of The Rules GoverningMedicinal Products in the European Union and in the EuropeanPharmacopoeia.
In order to reduce time and resourcesused to compile applications for the registration of human pharmaceuticalsand to simplify the exchange of regulatory information among regulatoryauthorities, the Expert Working Group on Quality of the InternationalConference on Harmonisation of Technical Requirements for Registration ofPharmaceuticals for Human Use (ICH) has developed a guideline for a commonformat for the technical documentation, a Common Technical Document (CTD).The Common Technical Document was first proposed in July 1995, the firstconcept paper was written in 1996, in November last year the CTD wasreleased at step 4 of the ICH procedure. The implementation of the CTD ismandatory from July 2002.
Therefore, the Note for Guidance onChemistry of the New Active Substance (CPMP/QWP/130/96/Rev1) has beenprepared in accordance with the new format of the dossiers for marketingauthorisation, the Common Technical Document (CTD). In this document thesubheadings of the CTD have been included for the sake of clarity. Thedeadline for comments is 30 June 2002.
Now another aspect mentioned in the NfG:
The revised Note for Guidance onChemistry of the New Active Substance (CPMP/QWP/130/96/Rev1) gives adefinition of an active substance starting material. That is no new aspectand no topic of the revision – but in consideration of the fact that theICH Q7a 'GMP Guide for Active Pharmaceutical Ingredients' is published asAnnex 18 to the EC-GMP-Guide, this aspect should be given special emphasiswith regard to regulatory compliance in API manufacture.
According to Annex 18, GMP for APIsapplies to the steps after the introduction of the defined 'API StartingMaterial' into the process. An 'API Starting Material' according to ICHQ7a is (…) a raw material, intermediate, or an API that is used inthe production of an API and that is incorporated as a significantstructural fragment into the structure of the API. An API StartingMaterial can be an article of commerce, a material purchased from one ormore suppliers under contract or commercial agreement, or producedin-house. API Starting Materials normally have defined chemical propertiesand structure (…)'.
According to this NfG the intermediateand/or substance considered as active substance (AS) starting materialshould be proposed and justified by the applicant. The AS startingmaterial should be fully characterised according to identity and purity.In addition, the steps prior to the step where the starting materialappears should be provided in the form of a flow chart in order to make itpossible for the assessor to judge the adequacy of the choice andspecifications of the AS starting material. '(…) Generally the fulldescription of the process should cover all the synthetic steps criticalfor the safety (impurities) and the efficacy (structural part responsiblefor the activity) of the active substance (…)'.
With this, the Note for Guidance givessome more detailed information on the API starting material than ICH Q7aand can therefore help to define the 'API starting material' with regardto the regulatory compliance of the process.
For more details, the complete Notefor Guidance on Chemistry of the New Active Substance(CPMP/QWP/130/96/Rev1) can be downloaded from the EMEA homepage. Downloadlink