The Committee for Proprietary

The reader may wonder why process validation is included. This is simply a matter of consideration of the content of guidelines issued in the past that relate to development pharmaceutics. The first such pan-European guideline, adopted by the Committee for Proprietary Medicinal Products (CPMP) in 1988, included advice on both development pharmaceutics and process development. Later versions of the guidelines on development pharmaceutics and on process development have addressed these topics separately, but the historical and practical perspectives suggests that both need to be discussed here. 

EMEA Final Opinion of the Committee for Proprietary Medicinal Products Pursuant to Article 12 of Council Directive 75/319/EEC as Amended for Medicinal products Chlormezanone. www.emea.eu.int/pdfs/human/phv/ EN/037597en.pdfi last accessed on 16th December 2003. 

The Committee for Proprietary Medicinal Products (CPMP) within the European Agency for the Evaluation of Medicinal Products (EMEA) has also issued a Note for Guidance on the pharmacokinetic and clinical evaluation of mod-ified-release oral products, which provides some information on the development and evaluation of an IVTVC (5). 

The Committee for Proprietary Medicinal Products [8] applied the BCS, with certain requirements, to dispense with bioequivalency tests if the active pharmaceutical ingredient is class I and the in vitro dissolution of the finished dosage form is fast [9], An active substance is considered highly soluble if the amount contained in the HDS of an IR product is dissolved in 250 ml of each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0, 4.6, and 6.8). There should be linear and complete absorption, which indicates HP to reduce the possibility of an IR dosage form influencing the bioavailability [8], The similarity of the dissolution profiles of the test and reference products is demonstrated in each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0,4.6, and 6.8). If there is rapid dissolution of the product, where at least 85% of the active substance is dissolved within 15 min, no further comparison of the test and reference is required. Further requirements include that excipients be well established and have no interaction with the pharmacokinetics of the active substance and that the method of manufacture of finished product... 

The EMEA has been established by the Commission and is situated in London. Technical and scientific support for ICH activities is provided by the Committee for Proprietary Medicinal Products (CPMP) of the EMEA. 

Ten years later, three directives sought to further promote public health and the free movement of medicinal products within the community. Directive 75/318/EEC [2] set analytical, pharmacotoxicological, and clinical standards for testing proprietary medicinal products, Directive 75/319/EEC [3] established the Committee for Proprietary Medicinal Products (CPMP) and its partial mutual recognition procedure, whereas Directive 75/320/EEC [4] established a Pharmaceutical Committee to examine problems in implementing the pharmaceutical directives. 

The principal scientific bodies of the EMEA are the Committee for Proprietary Medicinal Products (CPMP) and the Committee for Veterinary Medicinal Products (CVMP). These committees have two members from each member state as well as from Norway and Iceland which are appointed to give independent scientific advice to the EMEA. 

From this and other guidelines have developed current principles of good clinical practice ( GCP ) centred on ethical review by committee, with a favourable opinion being at least a moral precondition of the commencement of any human research project. In 1989, the CPMP (the Committee for Proprietary Medicinal Products) adopted GCP guidelines (based on a previous 1987 version) for the European Union. Although they were not in themselves legally enforceable, the pharmaceutical industry saw compliance with the guidelines... 

The present guidance does not lay down detailed requirements for specific classes of biological products, and attention is therefore directed to other guidelines issued by the Committee for Proprietary Medicinal Products (CPMP), e.g. the note for guidance on monoclonal antibodies and the note for guidance on products of recombinant DNA technology The Rules Governing Medicinal Products in the European Community, Volume III). 

The efforts to develop a harmonized system concerning direct safety, efficacy, and quality go back to 1965, when the first harmonized directive was issued [95]. Ten years later, the Committee for Proprietary Medicinal Products (CPMP) was established [96]. In 1989, the International Conference on Flarmonization (ICFI) was founded, and the EMEA began operation on January 1,1995 [97]. The EMEA serves as an advisory board, but is responsible for coordinating the approval, manufacturing, and inspection of medical products between the CPMP and member states regulatory bodies [98]. 

It was noted in this draft, "The Committee for Proprietary Medicinal Products (CPMP) is keen to have the information on the quinine actinometer formally published and accepted as an internationally recognized standard. 

The Committee for Proprietary Medicinal Products (CPMP) guideline calls for a full explanation and justification for including antioxidants in the formu-lation. It further states that antioxidants should only be included in a formulation if it has been proven that their use cannot be avoided. Thus, it is imperative to first try inert gas (nitrogen or argon) in the head-space to prevent oxidation. If the antioxidant has to be included, its concentration must be justified in terms of efficacy and safety. Antioxidants such as sulfites and metabisulfites are especially undesirable. 

A major issue in performing virus validation studies is determining which viruses should be used. The Committee for Proprietary Medicinal Products (CPMP) has issued guidelines on the selection of viruses to evaluate in validation studies. Processes must be validated for their capacity to inactivate/remove relevant viruses, or viruses that are known to contaminate plasma or other materials in the production process. If relevant viruses cannot be easily propagated in cell culture or assayed, then validation studies should include specific model viruses with characteristics similar to relevant viruses. If relevant viruses do not represent viruses with... 

Whenever an application is refused because one of the situations set out in Article No. 1 Subparagraphs b. and c. has arisen, INFARMED shall notify its decision together with the respective grounds to the Committee for Proprietary Medicinal Products, hereinafter referred to as the Committee. 

MAs and variations thereto follow the requirements of the Europecm Directives in all respects. Assessment and legal procedures are carefully constructed to be in compliance with the European legislation and guidelines of the Committee for Proprietary Medicinal Products (CPMP). Data requirements and presentation format follow those laid down by Directives. Advice on planned applications can be sought from the MCA, and this is particularly recommended in the case of applicants planning to make use of the European Mutual Recognition Procedures. 

In 1997, the Committee for Proprietary Medicinal Products (CPMP) of the European Union issued a "points to consider" document4 on the assessment of the potential for QT interval prolongation by noncardiovascular medicinal products. The CPMP document was followed by the Canadian draft in 2001, the Health Canada/USA draft in 2002, and the International Conference on Harmonization on preclinical guidelines (ICH) S7A (in vivo)5 and S7B (in vitro).6... 

Ten years later, a pair of Directives extended the provisions of 65/65. Directive 75/318 defined testing and protocol standards, while Directive 75/319 introduced the Committee for Proprietary Medicinal Products (CPMP) and what is now known as the mutual recognition procedure (MRP) for MA (see below). Nine years later, the structure of the CPMP was adjusted by Regulation 726/2004, and now forms the CHMP (see below). These three fundamental Directives represent the basis of pharmaceutical regulation that is common to the whole of Europe the creation of the EMEA in 1995 (by Regulation 2309/93, two years earlier) provided the machinery that implements these Directives. 

Preservatives should not usually be included in parenteral formulations except where a multidose product is being developed. The Committee for Proprietary Medicinal Products (CPMP) Notes for Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal Products states that the physical and chemical compatibility of the preservative (or antioxidant) with the other constituents of the formulation, the container and closure must be demonstrated during the development process. The minimum concentration of preservative should be used, which gives the required level of efficacy, as tested using pharmacopoeial methods. Certain preservatives should be avoided under certain circumstances, and preservatives should be avoided entirely for some specialised routes. The guidelines also require that both the concentration and efficacy of the preservative are monitored over the shelf life of the product. In multidose injectable products, the efficacy of the preservative must be established under simulated in-use conditions. Table 9.2 shows some of the most commonly encountered preservatives in licensed products and their typical concentrations. 

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