EJECUCIÓN DEL CONTRATO 28. Responsable del contrato

8.4.1 Introduction

The EC is involved in the control of radiopharmaceutical products in two ways. The first of these is the EURATOM Directives which are concerned with the production, supply, transport, and use of radioactive materials. (ARSAC’s remit owes its origins to these Directives.) The second is the specific control of radiopharmaceuticals introduced with Directive 89/343/EEC.

The effect of the adoption of Directive 89/343/EEC is to bring radiopharmaceuticals under the aegis of the pharmaceutical Directives 65/65/ EEC et seq. The Directive has effect throughout the EC, so that all radiopharmaceuticals will become the subject of national laws in each Member State, implementing the Directive by the effective dates.

The data requirements in the original pharmaceutical Directives, particularly 75/318/EEC, do not take into account the special nature of many radiopharmaceutical products. Certain modifications are required to take account of these.

Directive 89/343/EEC itself introduces two new areas of data requirement. Article 3 requires for generators a general description of the system together with 106 SEC. 8.2] RADIOPHARMACEUTICAL AND RELATED DEFINITIONS

a detailed description of the components of the system which may affect the composition or quality of the daughter nuclide preparation. Article 4 requires for radiopharmaceuticals full details of internal radiation dosimetry and additional detailed instructions for extemporaneous preparation and quality control of such preparations, and, where appropriate, maximum storage time during which any intermediate preparation such as an eluate or the ready-to-use pharmaceutical conforms to its specifications. Since these are included in the Directive itself they have mandatory effect.

There is at the time of writing no guideline on data requirements for radiopharmaceuticals, nor does the Notice to Applicants apply. (In fact there is a specific statement in the Notice to Applicants that it does not apply to radiopharmaceuticals!) A new supplement is also needed for the recently published EC Guide to Good Pharmaceutical Manufacturing Practice to cover the special aspects of radiopharmaceuticals manufacture.

At the time of writing (August 1990) four draft documents are at various stages of circulation for comment by interested parties. These are a draft amendment to the Annex to Directive 75/318/EEC (which relates to the technical data requirements for applications for marketing authorisation); draft guidance notes for radiopharmaceuticals and for radiopharmaceuticals based on monoclonal antibodies; and a draft supplement to the good manufacturing guide. A draft revision for the Notice to Applicant is in hand but is not yet out for consultation. The following sections are, therefore, based on what might happen: the final outcome depends on the account taken of comments submitted by the interested parties following the consultation process, and may differ in some or many respects from what is discussed below.

8.4.2

Predicted data requirements for radiopharmaceuticals under EC Directives

8.4.2.1 Introduction

The following notes are intended to identify only those areas of difference from the normal requirements applying to all products under the pharmaceutical Directives, the guidance notes, and the Notice to Applicants.

8.4.2.2

Pharmaceutical, chemical, biological, and microbiological data requirements

(a)

Qualitative particulars

In the case of ready-made radiopharmaceuticals and precursors the name of the radionuclide is stated. For generators the name of the mother and the daughter radionuclides are stated. The nature of any added material present, especially in kits, which is essential for the radiolabelling process is stated.

(b)

Quantitative particulars

For radioactive materials the amount of radioactivity is stated in terms of MBq (etc.) at a stated time and date, with the time zone used being specified. A statement of the specific activity of the radioactive material and an indication of whether it is present in carrier-free or carrier-added condition is useful. The normal requirement to declare the content of active ingredient by weight normally does not apply.

(c)

Development particulars

The chemical and radiochemical purity and the biodistribution of the material are discussed. The maximum and minimum volumes and radioactivity recommended for the preparation of the radiolabelled material are justified. If special purity requirements are necessary for radiolabelling media, these are established in this section. In the case of radiopharmaceutical kits, the development of a suitable test by which the user is able to ascertain the suitability of the radiolabelled product for use in patients is described in this section.

(d)

Method of preparation

For radioactive materials, information is required on the nuclear reactions used to prepare the radionuclide as well as the separation processes applied. For sterile products, particular attention is paid to the maintenance of sterility, possibly in the presence of radioactivity, and the validation of the process of manufacture since the manipulation concerned are often complex.

For radiopharmaceutical kits a description is also included in this section of the radiolabelling process which is used to obtain the finished radiopharmaceutical. Particular attention is paid to any special manipulations 108 SEC. 8.2] RADIOPHARMACEUTICAL AND RELATED DEFINITIONS

necessary. For radioactive compounds, information is supplied on the specificity of the radiolabelling process and of the specific activity of the product.

(e)

Control of starting materials

For radioactive materials the controls extend to any irradiation target material. Chemical purity and isotopic abundance are discussed. The significance of any permitted impurities is discussed in terms of the nuclear reactions that may result under the conditions of irradiation employed.

Where a European Pharmacopoela monograph is available for the material it is expected to apply. In certain circumstances additional purity standards are required, for example where the manufacturing method produces impurities not controlled by the pharmacopoeial specification. In the absence of a European Pharmacopoeia monograph one from the pharmacopoeia of a Member State may be used (subject to the same proviso). The proposed use of other pharmacopoeial specifications needs to be justified.

If ingredients are not the subject of acceptable pharmacopoeial monographs it is necessary to provide adequate information to justify a proposed specification. For a radioactive material this includes tests for identity, radionuclidic and radiochemical purity, specific activity, and a validated and properly calibrated assay procedure.

(f)

Control tests on the finlshed product

In the case of kits, some form of radiolabelling efficiency test is expected to form part of the release and check specifications.

The assay limits for radioactive components may be within ±10 per cent of the nominal amount, since the normal limits of ±5 percent expected for therapeutically active ingredients involves operatives in unnecessary exposure to radioactivity.

Radionuclidic purity and specific activity of radioactive material are controlled.

For radiopharmaceutical kits that do not contain radioactive material, therapeutically active ingredients are expected to comply with the normal nominal ±5 per cent requirement. Deviation from this is justified in specific applications. Control tests for radiochemical purity of radiolabelled material are included in the release and shelf life specifications.

With generators, information is included on testing for both the mother and the daughter radionuclides and consideration is given to the inclusion of adequate controls on the elution of the mother radionuclide or any other unwanted material.

Identity tests for radioactive materials include methods for characterisation of emission types and energy levels.

Impurity controls reflect any potential effects on radiochemical purity and biodistribution, based on potential effects on human patients.

Excipients essential for radiolabelling are assayed and identified.

In the case of radiopharmaceuticals containing a short-lived radionuclide it is recognised that it may be necessary to release the product for sale before all the necessary quality control tests have been completed. In such cases the stage at which the decision is taken to release the product for sale is stated. The full release testing programme should be undertaken in all cases as a monitor for the production process. The finished product specification should differentiate between those tests undertaken on a routine basis and those undertaken on an occasional basis (with a statement on the frequency with which the tests will be applied). For certain terminally sterilised products it is possible that acceptable justification can be advanced for parametric release. This depends on the adequacy of the facility, staff, and quality system concerned. It is not usual for the requirement for a product to comply with a sterility test if tested to be deleted from the finished product specification, however. In the case of aseptically prepared products a sterility test is likely to be required on a routine basis.

(g)

Dosage form-related points

It is unlikely that the weight of radioactive material needs to be stated for solid dosage forms. Dosage expressions in terms of the amount of radioactivity (in MBq, etc.) are more usual.

In the case of parenteral products it is likely that a rabbit pyrogens test or a limulus amoebocyte lysate test for endotoxins will be permitted, provided that the latter is validated. However, once a choice is made between the two tests, the other will not be permitted as an alternate release criterion. Products intended for the intrathecal route normally are expected to be tested by using a validated limulus amoebocytelysate endotoxin test.

(h) Stability testing

Data are required for all products. With products containing radionuclides it is sometimes necessary to investigate the effects of radioactive decay on the overall stability of the product.

In the case of radiopharmaceutical kits it is necessary to report on the stability of both the kit and the reconstituted/radiolabelled product. Particular attention is paid to the radiochemical purity and the biodistribution of the product as prepared for clinical use. For a product presented in a multi-dose vial, data are 110 SEC. 8.2] RADIOPHARMACEUTICAL AND RELATED DEFINITIONS

submitted on the effects of removal of a number of doses from the vial, as is likely to be done in the clinic, on the stability of the remaining product.

8.4.2.3

Toxicological and pharmacological data requirements (a)

General

It is recognised that the radiation associated with radiopharmaceutical products is inevitably associated with toxicity: this is unavoidable in the case of diagnostic products and is the wanted effect in the case of therapeutic agents. The toxicity of the chemicals, etc., included in radiopharmaceuticals and the radiation toxicity are therefore considered separately.

Toxicology studies are, as far as possible, carried out by using non-radioactive product either without using a radioactive material at all or allowing the radioactive component to decay before carrying out the tests in those cases where the radiolabelling process modifies the ligand. Distribution and elimination studies are carried out using radiolabelled material since the low concentrations of material used would otherwise not be easily detectable. Where radioactive material is used it is prepared by the radiolabelling procedure described for the clinic.

No-carrier-added radionuclides or simple salts are unlikely to require additional toxicity studies where the toxicity of the non-radioactive equivalent material is known and is available for submission.

(b)

Subacute toxicity studies

The normal recommendations are followed, the duration of the necessary studies being dependent on the number of doses to be given to humans and the period over which they will be given.

(c)

Mutagenic potential

All new chemicals are evaluated for mutagenic potential be using studies designed to identify gene and chromosome mutations. Both radiolabelled and unlabelled mater ials are investigated.

(d)

Carcinogenic potential

The evaluation of the carcinogenic potential is presented. In many cases this is a paper exercise based on the absence of demonstrable genotoxicity in the mutagenicity studies. If no specific studies have been undertaken, this is stated in the summary of product characteristics.

(e)

Reproductive studies

The claims for use of the product determine whether such studies are required. If the product is likely to be given to the same patient repeatedly, studies may be required. If studies are reported, the chemical and radiation aspects are discussed separately.

(f)

Pharmacodynamlcs

In most cases it is not expected that radiopharmaceutical products will have measurable pharmacodynamic effects. However, this is not a reason for not looking for such effects in the various studies.

(g) Pharmacokinetics

Animal biodistribution studies are reported for diagnostic radiopharmaceuticals to assess the in vivo stability of the radiolabelled complex.

(h)

Radiation dosimetry

Data are provided to identify the target organs and to establish the systemic tolerance. Calculated absorbed radiation dose estimates and effective dose equivalents are reported.

8.4.2.4

Clinical data requirements

Controlled clinical trials are reported wherever possible. Controlled and uncontrolled trials are summarised separately. Adverse events encountered in the trials are reported together with a summary of the investigations undertaken to find them. In the case of some radiopharmaceuticals it is more relevant to 112 SEC. 8.2] RADIOPHARMACEUTICAL AND RELATED DEFINITIONS

compare the radiopharmaceutical product with products or techniques of proven value. The use of healthy volunteers is avoided wherever possible.

Diagnostic or therapeutic efficacy is established for each claimed indication. An adequate discussion is included on the possibility of interaction between the radiopharmaceutical product and other radiopharmaceuticals or other products likely to be in use in the target population group(s).

The radiation dose recommended is established from the results of the clinical trials, due account being taken of any accepted guidelines on the amount of radioactive material to be administered for particular procedures.

8.4.3

Labelling and instruction leaflets

8.4.3.1 Introduction

Directive 89/343/EEC requires that radiopharmaceuticals labels are in accordance with the requirements of the regulations for the safe transport of radioactive materials laid down by the International Atomic Energy Agency.

8.4.3.2

Directive 89/343/EEC specific requirements

The Directive requires the following information to appear:

(a) On the label on the shielding

— The name of the product (brand name, common name accompanied by a trade mark or the name of the manufacturer, or a scientific name accompanied by a trade mark or the name of the manufacturer).

— Where the product contains only one active ingredient, the International Nonproprietary Name (INN) or the usual common name of that ingredient if the main title is a brand name.

— A qualitative and quantitative statement of the active ingredients using INNs or usual common names.

— The manufacturer’s batch number. — The marketing authorisation number.

— The name/corporate name and address of the person placing the product on the market, and where applicable the manufacturer.

— The method of administration. — The expiry date in plain language. — Any special storage conditions.

— The pharmaceutical form and contents (volume, weight, number of unit dosage forms).

— An explanation of the codings used on the vial and the amount of radioactivity per dose/vial/number of capsules/number of millilitres in the container.

(b) On the label on the vial

— The name or code of the product, including the name or chemical symbol of the radionuclide.

— The batch identification and expiry date. — The international symbol for radioactivity. — The name of the manufacturer.

— The amount of radioactivity (as above).

However, a draft revision to the labelling requirements included in Directive 65/ 65/EEC is presently under development. It is not clear whether this will affect the labelling required for radiopharmaceuticals.

8.4.3.3

European Pharmacopoeia requirements

The general monograph on radiopharmaceutical preparations in the European Pharmacopoeia includes the following labelling requirements:

(a) On the container

— The name of the preparation. — The name of the manufacturer. — An identification number.

— For liquid preparations, the total radioactivity in the container or the radioactive concentration per millilitre at a stated date and, if necessary, time, and the volume of liquid in the container.

— For solid preparations, the total radioactivity at a stated date and, if necessary, time.

— For capsules, the radioactivity of each capsule at a stated date and, if necessary, hour, and the number of capsules in the container.

(b) On the package:

— That the preparation is intended for medical use. — The route of administration.

— The expiry date (or period of validity).

— The name and concentration of any added antimicrobial preservative. 114 SEC. 8.2] RADIOPHARMACEUTICAL AND RELATED DEFINITIONS

— Any special storage requirements.

8.4.3.4