Formulation, Marketing Authorisation

A Member State may, in accordance with legislation in force and to fulfil special needs, exclude from Chapters II to V [which set out the requirements for applying for a marketing authorisation] medicinal products supplied in response to a bona fide unsolicited order formulated in accordance with the specifications of an authorised health professional and for use by his individual patients on his direct personal responsibility. ... 

Once the clinical and safely evaluation studies for a new medicinal product have shown it to be safe, effective and of acceptable quality, the pharmaceutical company will usually want to submit a Marketing Authorisation Application (MAA) or New Drug Application (NDA) to the regulatory authorities. The chemistry, manufacturing and controls (CMC) section will form a major part of the application. For an MAA in Europe, a development pharmaceutics section is required to describe how the product was developed, and to explain the rationale for the selection of the formulation, pack, manufacturing process and specifications. Also required for Europe are expert reports for each of the pharmaceutical, safety and clinical parts of the application. These have to be written by experienced scientists nominated by the pharmaceutical company who have to critically appraise the development programme for the product. The pharmaceutical expert must acknowledge the acceptability of the CMC part of the application. 

The term OL medicine may be used to describe a drug in an adequate dosage form for administration to children (e.g. liquid formulation) but which is being used outside the specification terms of the product licence (or marketing authorisation). For example, in the UK, there is an adult licensed liquid preparation of atenolol but it is not licensed for children. OL may also be given ... 

Thus the pharmacist must be careful when choosing the excipients. Pre-formulation studies to identify incompatibilities can be time-consuming but are required to prove that no instability of the active substance will occur during preparation and storage. In the case of the use of licensed products to prepare capsules or powders, it might be difficult to obtain information from the manufacturer. Thus, it is usually safe to dilute crushed tablet with the excipient that is used in the tablet formulation, based on the market authorisation holder who has ensured their compatibility. 

An approach that tries to solve the problem more at the source is the so-called green pharmacy. In order to stimulate the development of more easily degradable medicines, both for human as well as for veterinary medicines, European guidelines are formulated. At the application stage to get a marketing authorisation the manufacturer has to give information about the effects of the medicine on the environment as well as an evaluation of those effects and measurements which have to be taken to prevent or reduce these effects [33-35]. When veterinary products are concerned, authorities can even deny the registration if the environmental risk is considered too big. Market authorisation can... 

However, the cost of simple substitution and shallow innovation can be substantial. The new EU regulations on Registration, Evaluation and Authorisation of Chemicals (REACH) are expected to result in a large number of chemicals that are currently freely available to vanish from the market. Formulated commercial products such as inks, adhesives and paints can contain up to 60 individual chemicals in one formulation. If one of these is withdrawn as a result of REACH, the potential costs of reformulation can be very high. 

This directive is concerned with the authorisation and the placing on the market of biocidal products. It attempts to establish a list of active substances that may be used in biocidal products within the EC. In order to assess which substances should be included in the list, a system of registration, authorisation and periodic evaluation is legislated with this Directive. Once approved, active substances will be incorporated into Annex I of the directive. The system of registration is created for active substances, which pose a low riskfor humans, animals and the environment and will be incorporated in Annex lA. In Annex I B so called basic substances such as are listed. For products of higher concern, usually not an active substance, an authorisation system is established, that includes the formulation of dossiers on these products which need to be submitted to the respective national authority. In Annex I B... 

Supply on a particular patient basis encompasses various categories of unauthorised use of medicinal products. A product maybe imauthor-ised because it has been specially formulated for use it may be at the clinical trial stage of development, but be requested by doctors for use outside a trial it may have been authorised previously and then withdrawn from the market for commercial reasons, or because of safety, efficacy or quality concerns or it may be authorised currently, but for a different indication or patient population, or in a different country. 

Choice As the second review regulation is enacted we will see the immediate removal of non-identified active substances and the gradual removal of identifi-ed/non-notified active substances (and their formulated biocidal products) from the market. Cost-driven product line rationalisation by the formulators in preparation for authorisation will similarly lead to a reduction in the number of biocidal products. Ultimately there will be less choice for the end-user. Undoubtedly the industries supported by these biocides may be presented with the following potential issues (1) a decrease in functional protection, (2) hygiene decline, resistance/tolerance, (3) process modifications, (4) end-product re-formulation and (5) higher costs. 

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