Manufacture of investigational medicinal product

The manufacture of all investigational medicinal products (including placebo) that are intended for a clinical trial must be authorised and conducted according to Good Manufacturing Practice (GMP). This should be supervised and certified by a Qualified Person . An import authorisation is required for any product from outside the EU, which should also be manufactured to GMP standards. (See Ghapters 11 and 12 for information on GMP, manufacturing authorisations and Qualified Persons.) 

Batches should be tailor-made for the proposed trial, and should be labelled with information as appropriate regarding the product, sponsor, investigator, subject and trial, together with the statement For clinical trial use only . In addition, where the medicine will be used outside ofthe clinical site, the statement Keep out of reach of children should be added. There should be full accountability for the distribution, storage and fate of the drug product at both the manufacture and trial sites. 

Protocol Title Protocol Code No Protocol version  

Co-ordinating lnvestigator (Multi-centre trial) / Principal lnvestigator (Single centre trial) 

Please list with relevant pagination the contents of this application. 

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Annex 12 Use of Ionising Radiation in the Manutacture ot Medicinal Products Annex 13 Manufacture of Investigational Medicinal Products Annex 14 Manufacture of Products derived from Human Blood or Human Plasma Annex 15 Qualification and validation... 

European commission, enterprise directorate general. In Good Manufacturing Practices, Annex 13, Manufacture of Investigational Medicinal Products, Vol. 4 November 2001 Draft 1. 

Guide to Good Manufacturing Practices, Annex 13, Manufacture of Investigational Medicinal Products, July 2003. The Rules Governing Medicinal Products in the European Community, Vol. 4, Biostatistical Methodology in Clinical Trials in Applications for Marketing Authorizations for Medicinal Products, Committee for Proprietary Medicinal Products [CPMP] EEC 111/3630/92-EN, 1994. 

During manufacture of investigational medicinal products, it may be that different products are handled in the same premises and at the same time, and this reinforces the need to minimise ail risks of contamination, including cross-contamination and product mix up, by using appropriate procedures. 

Definitions given below apply to the words as used in this Guide. They may have different meanings in other contexts. An additional glossary of terms relating to clinical trials is provided in Annex 13, Manufacture of investigational medicinal products. 

Manufacture of Investigational Medicinal Products, Annex to the EC Guide to Good Manufacturing Practice, EEC 111/3004/91-EN, Brussels, 1992. 

In the UK SI 2004 1031 was implemented, incorporating into British law the requirement of the EU Directive 2001/20/EC. Finally the EU-issued Directive 2005/28/EC, which lays down principles and detailed guidelines for GCP in investigational medicinal products for human use and the requirements for authorisation of the manufacturing of investigational medicinal products, required member states to implement it into law by 29 January 2006. In the UK, the GCP Directive was implemented in August 2006. 

Annex 13 Manufacture of investigational medicinal products Annex 14 Manufacture of products derived from human blood or human plasma... 

Member States shall take all appropriate measures to ensure that the manufacture or importation of investigational medicinal products is subject to the holding of authorisation. 

Verification of compliance of investigational medicinal products with good clinical and manufacturing practice... 

Good Manufacturing Practice of investigational medicinal products (7/1993) Ref No. III/3004/91... 

Production of Investigational Medicinal Products needs a manufacturing license. This brings about compliance with GMP, for the dosage forms involved and the availability of a... 

Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use. 

Directive 2005/28/EC, which lays down the principles and detailed guidelines for GCP as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products... 

An Investigational Medicinal Product Dossier (IMPD) is intended to be more comprehensive than an IB, in that it should contain summaries of available quality data in addition to the safety and efficacy information that constitutes the main part of the IB. In total, it should provide information on the chemistry, manufacture, control and stability ofthe medicinal product, together with the results of non-clinical and clinical studies. In order to avoid repetition, the IB can be cross-referenced for non-clinical and clinical results. Ideally, the IMPD should follow the same structure as that which will be used later for the marketing authorisation application. For products with existing marketing authorisations, the Summary of Product Characteristics may replace the IMPD to varying extents (see Chapter 6). 

The Competent Authorities are obliged to appoint Inspectors for checking that all activities associated with clinical trials are conducted in compliance with the regulations. The inspectors can inspect any sites concerned with the clinical trial, particularly the trial site (GCP), the manufacturing site of the investigational medicinal product (GMP), any laboratory used for analyses in the clinical trial (GLP), and/or the sponsor s premises. 

Activities Carried out Manufacture of active substance Manufacture of finished product Manufacture of intermediate or bulk Q Packaging only Importing Laboratory testing Batch control and batch release Storage and distribution Investigational medicinal products Other ... 

Most of the information sought is similar to the FDA s IND requirements. One major difference is that a Qualihed Person has to certify that the investigational medicinal product (IMP) is manufactured according to GMP The Competent Authority has the right to inspect the manufacturing facility for GMP compliance, the preclinical facility for GLP compliance, and the clinical trial sites for GCP compliance. 

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