Opinion on starting materials used in human and veterinary medicinal products, for which there is a consumer health/safety concern that needs to be addressed by laying down and enforcing a GMP requirement adopted by the Scientific Committee on Medicinal Products and Medical Devices on 21 October 1998

 

Executive Summary

In response to the question posed by DG III as to whether there are starting materials for which there is a consumer health/safety concern that needs to be addressed by laying down and enforcing GMP requirements the Scientific Committee for Medicinal Products and Medical Devices is of the opinion that:

- in principle, appropriate GMP should applicable to as broad a range of starting materials as possible

- the extent to which implementation of GMP by the manufacturer is subject to control by inspectors is considered to be not a scientific but an administrative/organisational/regulatory problem

- obligation of GMP application should not be linked to the intrinsic risk of a given substance and the usefulness of a nominative list of Starting Materials to which GMP would be applicable would be very limited

A number of scientific principles are proposed which could give guidance to manufacturers and authorities when assessing the need to apply or ensure GMP. Such principles may find their place in the appropriate GMP guidance to be drafted more than in a directive.

Full Opinion

Terms of Reference (Request from DG III concerning "Starting Materials used in human and veterinary medicinal products, for which there is a consumer health/safety concern that needs to be addressed by laying down and enforcing a GMP requirement". XXIV/SCMPMD/98.064 (8 September 1998)

The Committee is asked the following:

"Are there any starting materials (apart from active substances), used in human and veterinary medicinal products, for which there is a consumer health/safety concern that needs to be addressed by laying down and enforcing a GMP requirement? If so which are these starting materials. Moreover, the SCMPMD is asked to furnish a risk assessment for each starting material identified in response to this question."

- For the purposes of the above-mentioned draft proposal starting materials means any component of a medicinal product (i.e. active substance(s) and the excipients;

- For biological medicinal products, (such as vaccines, serums, toxins, allergen products and medicinal products derived from blood or plasma), starting materials means any component as well as any source material such as micro-organisms, tissues of either plant or animal origin, cells or fluids (including blood) of human or animal origin and biotechnological cell constructs;

- For radiopharmaceuticals, starting materials mean any component as well as any irradiation target material"

Context of the question

The question is asked in the frame of a draft legislative proposal on Good Manufacturing Practice (GMP) for starting materials of medicinal products and inspection of manufacturers (Draft Proposal for a European Parliament and Council Directive on good manufacturing practice for starting materials of medicinal products and inspection of manufacturers (1 September 1998) as communicated in a "Note for the attention of Mme. De Sola, Head of Unit DGXXIV B2" of 8 September 1998)

The present EU legislative framework for GMP is laid down in Directives 75/319/EEC (Council Directive75/319/EEC, of 20 May 1975, on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products (OJ No L 147 of 9.6.1975, p. 13), as last amended by Council Directive 93/39/EEC (OJ No L 214 of 24.8.1993, p. 22) and 81/851/EEC (Council Directive 81/851/EEC, of 28 September 1981, on the approximation of the laws of the Member States relating to veterinary medicinal products (OJ No L 317 of 6.11.1981, p.1), as last amended by Council Directive 93/40/EEC (OJ No L 214 of 20.08.1993, p. 31). With the exception of biological medicinal products (Council Directive 75/318/EEC, of 20 May 1975, on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products (OJ No L 147 of 9.6.1975, p. 1) as last amended by Council Directive 93/39/EEC (OJ No L 214 of 24.8.1993, p. 22)./ Council Directive 81/852/EEC, of 28 September 1981, on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of veterinary medicinal products (OJ No L 317 of 6.11.1981, p. 16) as last amended by Council Directive 93/40/EEC (OJ No L 214 of 20.08.1993, p. 31), it applies only to the manufacturing of medicinal products but not to the manufacture of their starting materials. In line with the general principle of quality assurance, which is that quality should be built into the product, DG III considers that manufacture of starting materials should comply with specific GMP which is appropriate to their manufacture and that it is necessary to introduce a legal basis for the inspection of starting material manufacturers to confirm compliance with these GMP. Appropriate detailed guidelines will be drafted and it will be the duty of the Member States to take all appropriate measures to ensure manufacture in compliance with these guidelines. In the present proposal (Draft Proposal for a European Parliament and Council Directive on good manufacturing practice for starting materials of medicinal products and inspection of manufacturers (1 September 1998) as communicated in a "Note for the attention of Mme. De Sola, Head of Unit DGXXIV B2" of 8 September 1998) appropriate GMP would apply to:

- "any components which are active substances,

- any components which are preformulated products having an influence on the bioavailability of the active substance,

- the starting materials listed in the Annex. (The starting materials listed in the Annex are those which are not active ingredients and for which there is a public health concern that needs to be addressed by ensuring manufacture in compliance with the detailed guidelines on good manufacturing practice for starting materials. The Annex will be revised as necessary...)"

In addition, for the above three classes of starting materials, the Member States would have the obligation to ensure manufacture in compliance with the appropriate GMP. Moreover, regarding GMP ensurance by the Member States, the proposal states that:

- "The competent authority of the Member State concerned shall carry out inspections of manufacturers of starting materials, used in the manufacture of medicinal products, whenever the competent authority considers this to be necessary.

- The competent authority of the Member State concerned shall carry out inspections of starting material manufacturers at the specific request of:

a) another Member State,

b) the Commission or the Agency, as the case may be

- The European Department for the Quality of Medicines may ask the Commission or the Agency to request such an inspection when the starting material concerned is the subject of a European Pharmacopoeia monograph, compliance with which is mandatory pursuant to Community law.

- The competent authority of the Member State concerned may carry out inspections of starting material manufacturers at the specific request of the starting material manufacturer himself."

The specific question from DG III relates to the third class of starting materials for which appropriate GMP would be applied and for which evaluation of compliance by Member States would be mandatory, i.e. "the starting materials listed in the Annex ... for which there is a public health concern that needs to be addressed by ensuring manufacture in compliance with the detailed guidelines on good manufacturing practice for starting materials". DG III seeks guidance from the SCMPMD as to the composition of the list in the Annex.

Assessment

1) The Scientific Committee for Medicinal Products and Medical Devices is of the opinion that Good Manufacturing Practice is to be considered primarily as a complementary measure covering the manufacturing/processing aspects of medicinal products. The inherent quality characteristics of a Starting Material itself (in particular e.g. the inherent toxicity of a given molecule) are not affected by GMP measures. It is therefore important to make the distinction between the intrinsic risk of a substance and the risk on which GMP could have an impact. GMP and the corresponding inspection, through principles like traceability, documentation, training of staff, e.g. can offer an important added value and, together with appropriate testing measures, contribute substantially to the total quality assurance of the product.

2) In the present EU legislation, principles of GMP apply only to the manufacturing process of the medicinal product from the step at which starting materials are used for the formulation of the medicinal product. In addition, for biological medicinal products, principles of GMP apply also to the manufacturing starting materials from their source (raw) materials (e.g. the manufacturing of a virus suspension from seed and cell material) (Council Directive75/319/EEC, of 20 May 1975, on the approximation of provisions laid down by law, regulation or administrative action relating to medicinal products (OJ No L 147 of 9.6.1975, p. 13), as last amended by Council Directive 93/39/EEC (OJ No L 214 of 24.8.1993, p. 22). / Council Directive 81/851/EEC, of 28 September 1981, on the approximation of the laws of the Member States relating to veterinary medicinal products (OJ No L 317 of 6.11.1981, p. 1), as last amended by Council Directive 93/40/EEC (OJ No L 214 of 20.08.1993, p. 31)./ Council Directive 75/318/EEC, of 20 May 1975, on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products (OJ No L 147 of 9.6.1975, p. 1) as last amended by Council Directive 93/39/EEC (OJ No L 214 of 24.8.1993, p. 22)./ Council Directive 81/852/EEC, of 28 September 1981, on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of veterinary medicinal products (OJ No L 317 of 6.11.1981, p. 16) as last amended by Council Directive 93/40/EEC (OJ No L 214 of 20.08.1993, p. 31). It is the opinion of the SCMPMD that, in the process of extending the application of GMP principles to the manufacturing of starting materials, as intended by the DG III proposal (Draft Proposal for a European Parliament and Council Directive on good manufacturing practice for starting materials of medicinal products and inspection of manufacturers (1 September 1998) as communicated in a "Note for the attention of Mme. De Sola, Head of Unit DGXXIV B2" of 8 September 1998), a definition of starting materials should be used which allows the application of appropriate GMP, not only to the active substance(s) and all excipients but also to ancillary substances i.e. substances used in production but which do not become components of the final product. E.g. : chemical impurities contained in solvents, gases, precipitating agents etc.. or a microbiological contamination from serum used as a growth medium component could contaminate the medicinal product although, by the present definitions (existing and proposed), these substances would not be covered by GMP principles for Starting Materials.

3) In the same line of thoughts, concerning the second class of starting materials for which appropriate GMP would apply and evaluation of compliance by Member States would be mandatory, i.e. "any components which are preformulated products having an influence on the bioavailability of the active substance", the restriction of mandatory GMP application and obligation for Member States to ensure compliance, to those products having an influence on bio-availability, as stated in the proposal, is regarded as inappropriate. In general and as stated in point 1. of this assessment, obligation of GMP application and its ensurance should not be linked to the intrinsic risk of a given substance and risk assessment based on the nature of the substance only is bound to give an incomplete picture. It is therefore proposed to change the corresponding wording to allow, in principle, application/enforcement of GMP to all preformulated products.

4) Whereas the SCMPMD is of the opinion that GMP should be, in principle, applicable to as broad a range of starting materials as possible, the extent to which implementation of GMP by the manufacturer is subject to control by inspectors is considered to be not a scientific but an administrational/organisational/regulatory problem.

5) The SCMPD acknowledges that all aspects of the GMP rules currently applied to the manufacturing of medicinal products may not be appropriate for all Starting Materials and that specific guidance is needed for Starting Materials. On the other hand, these GMP rules could and should be applicable to some Starting Materials of biological origin such as blood and blood derivatives.

6) The SCMPMD is of the opinion that the usefulness of a nominative list of Starting Materials to which GMP would be applicable and its ensurance mandatory, would be very limited. Such a list would almost by definition be incomplete and would need continuous adaptation. Furthermore, the same starting material may in some cases be used as an active compound in one medicinal product, in others as an excipient. Rather than establishing a list, it was attempted to lay down a number of scientific principles which could give guidance to manufacturers and authorities when assessing the need to apply and enforce the principles of GMP to a given substance. These principles may find their place in the appropriate GMP guidance to be drafted more than in a directive. Such principles would include:

- Particular susceptibility of the starting material to contamination by infectious agents (e.g. proteins, carbohydrates, starting materials of biological origin - human, animal or plant - in general)

- Particular susceptibility of the starting material to chemical contamination (e.g. liquids are considered more susceptible than solids through solubilisation processes - e.g. chemically contaminated glycerol, ...)

- The intended use of starting materials (e.g. those for use in manufacturing of sterile products, ...)

- Particular risk associated with a contamination of other products by the starting material (e.g. allergens, toxins, hormones, cytostatics, ...)

- Particular risk of cross contamination in multi-purpose plants and areas (e.g. production of gelatins of different grades, simultaneous or sequential production of starting materials for the pharmaceutical industry and for the food industry, ...)

- Particular risk of alteration by physical factors of the substance (e.g. hygroscopic, thermal & light sensitivity)