Commission Directive 2009/9/ECShow full title

PART 2: U.K. PHARMACEUTICAL (PHYSICO-CHEMICAL, BIOLOGICAL OR MICROBIOLOGICAL INFORMATION (QUALITY))

Basic principles and requirements

The particulars and documents which shall accompany the application for marketing authorisation pursuant to the first indent of Article 12(3)(j) shall be submitted in accordance with the requirements below.

The pharmaceutical (physico-chemical, biological or microbiological) data shall include for the active substance(s) and for the finished veterinary medicinal product information on the manufacturing process, the characterisation and properties, the quality control procedures and requirements, the stability as well as a description of the composition, the development and presentation of the veterinary medicinal product.

All monographs, including general monographs and general chapters of the European Pharmacopoeia, or failing that, of a Member State are applicable.

All test procedures shall fulfil the criteria for analysis and control of the quality of the starting materials and the finished product and should take account of established guidance and requirements. The results of the validation studies shall be provided.

All the test procedure(s) shall be described in sufficiently precise detail so as to be reproducible in control tests, carried out at the request of the competent authority; any special apparatus and equipment, which may be used shall be described in adequate detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall be supplemented, if necessary, by the method of preparation. In the case of test procedures included in the European Pharmacopoeia or the pharmacopoeia of a Member State, this description may be replaced by a detailed reference to the pharmacopoeia in question.

Where relevant, chemical and biological reference material of the European Pharmacopoeia shall be used. If other reference preparations and standards are used, they shall be identified and described in detail.

In cases where the active substance has been included in a medicinal product for human use authorised in accordance with the requirements of Annex I to Directive 2001/83/EC the chemical, pharmaceutical and biological/microbiological information provided for in Module 3 of that Directive may replace the documentation related to the active substance or the finished product, as appropriate.

The chemical, pharmaceutical and biological/microbiological information for the active substance or the finished product may be included in the dossier in CTD format only where the competent authority has publicly announced this possibility.

In the case of any application for an animal species or for indications representing smaller market sectors the CTD format may be followed without prior agreement of the competent authorities.

A. QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS U.K.

1. Qualitative particulars U.K.

“Qualitative particulars” of all the constituents of the medicinal product shall mean the designation or description of:

• the active substance(s),

• the constituents of the excipients, whatever their nature or the quantity used, including colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances,

• the constituents, intended to be ingested or otherwise administered to animals, of the outer covering of the veterinary medicinal products, such as capsules, gelatine capsules.

These particulars shall be supplemented by any relevant data concerning the immediate packaging and if relevant the secondary packaging and, where appropriate, its manner of closure, together with details of devices with which the medicinal product will be used or administered and which will be supplied with the medicinal product.

2. Usual terminology U.K.

The usual terminology to be used in describing the constituents of veterinary medicinal products means, notwithstanding the application of the other provisions of Article 12(3)(c):

• in respect of constituents which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States, the main title at the head of the monograph in question, with reference to the pharmacopoeia concerned,

• in respect of other constituents, the international non-proprietary name (INN) recommended by the World Health Organisation (WHO), which may be accompanied by another non-proprietary name, or, failing these, the exact scientific designation; constituents not having an international non-proprietary name or an exact scientific designation shall be described by a statement of how and from what they were prepared, supplemented, where appropriate, by any other relevant details,

• in respect of colouring matter, designation by the “E” code assigned to them by Council Directive 78/25/EEC(1).

3. Quantitative particulars U.K.

3.1. In order to give “quantitative particulars” of all the active substances of the veterinary medicinal products, it is necessary, depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological activity, either per dosage-unit or per unit of mass or volume, of each active substance. U.K.

Units of biological activity shall be used for substances, which cannot be defined chemically. Where an International Unit of biological activity has been defined by the World Health Organisation, this shall be used. Where no International Unit has been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the substances by using where applicable the European Pharmacopoeia Units.

Whenever possible, biological activity per units of mass or volume shall be indicated. This information shall be supplemented:

• in respect of single-dose preparations, by the mass or units of biological activity of each active substance in the unit container, taking into account the usable volume of the product, after reconstitution, where appropriate,

• in respect of veterinary medicinal products to be administered by drops, by the mass or units of biological activity of each active substance contained per drop or contained in the number of drops corresponding to 1 ml or 1 g of the preparation,

• in respect of syrups, emulsions, granular preparations and other pharmaceutical forms to be administered in measured quantities, by the mass or units of biological activity of each active substance per measured quantity.

3.2. Active substances present in the form of compounds or derivatives shall be described quantitatively by their total mass, and if necessary or relevant, by the mass of the active entity or entities of the molecule. U.K.

3.3. For veterinary medicinal products containing an active substance which is the subject of an application for marketing authorisation in any Member State for the first time, the quantitative statement of an active substance which is a salt or hydrate shall be systematically expressed in terms of the mass of the active entity or entities in the molecule. All subsequently authorised veterinary medicinal products in the Member States shall have their quantitative composition stated in the same way for the same active substance. U.K.

4. Development pharmaceutics U.K.

An explanation shall be provided with regard to the choice of composition, constituents, immediate packaging, possible further packaging, outer packaging if relevant, the intended function of the excipients in the finished product and the method of manufacture of the finished product. This explanation shall be supported by scientific data on development pharmaceutics. The overage, with justification thereof, shall be stated. The microbiological characteristics (microbiological purity and antimicrobial activity) and usage instructions shall be proven to be appropriate for the intended use of the veterinary medicinal product as specified in the marketing authorisation application dossier.

B. DESCRIPTION OF THE MANUFACTURING METHOD U.K.

The name, address and responsibility of each manufacturer and each proposed production site or facility involved in manufacturing and testing shall be indicated.

The description of the manufacturing method accompanying the application for marketing authorisation pursuant to Article 12(3)(d), shall be drafted in such a way as to give an adequate synopsis of the nature of the operations employed.

For this purpose it shall include at least:

• mention of the various stages of manufacture, so that an assessment can be made of whether the processes employed in producing the pharmaceutical form might have produced an adverse change in the constituents,

• in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity of the finished product,

• the actual manufacturing formula, with the quantitative particulars of all the substances used, the quantities of excipients, however, being given in approximate terms insofar as the pharmaceutical form makes this necessary; mention shall be made of any substances that may disappear in the course of manufacture; any overage shall be indicated and justified,

• a statement of the stages of manufacture at which sampling is carried out for in-process control tests and the limits applied, where other data in the documents supporting the application show such tests to be necessary for the quality control of the finished product,

• experimental studies validating the manufacturing process and where appropriate a process validation scheme for production scale batches,

• for sterile products, where non-pharmacopoeial standard sterilisation conditions are used, details of the sterilisation processes and/or aseptic procedures used.

C. CONTROL OF STARTING MATERIALS U.K.

1. General requirements U.K.

For the purposes of this paragraph, “starting materials” shall mean all the constituents of the veterinary medicinal product and, if necessary, of its container including its closure, as referred to in Section A, point 1, above.

The dossier shall include the specifications and information on the tests to be conducted for quality control of all batches of starting materials.

The routine tests carried out on each batch of starting materials must be as stated in the application for marketing authorisation. If tests other than those mentioned in a pharmacopoeia are used, this shall be justified by providing proof that the starting materials meet the quality requirements of that pharmacopoeia.

Where a Certificate of Suitability has been issued by the European Directorate for the Quality of Medicines and HealthCare for a starting material, active substance or excipient, this Certificate constitutes the reference to the relevant monograph of the European Pharmacopoeia.

Where a Certificate of Suitability is referred to, the manufacturer shall give an assurance in writing to the applicant that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of Medicines and HealthCare.

Certificates of Analysis shall be presented for the starting materials in order to demonstrate compliance with the defined specification.

1.1. Active substances U.K.

The name, address, and responsibility of each manufacturer and each proposed production site or facility involved in manufacturing and testing of an active substance shall be indicated.

For a well-defined active substance, the active substance manufacturer or the applicant may arrange for the following information to be supplied in a separate document directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File:

(a)

a detailed description of the manufacturing process;

(b)

a description of the quality control during manufacture;

(c)

a description of the process validation.

In this case, the manufacturer shall however provide the applicant with all the data which may be necessary for the latter to take responsibility for the veterinary medicinal product. The manufacturer shall confirm in writing to the applicant that he shall ensure batch to batch consistency and not modify the manufacturing process or specifications without informing the applicant. Documents and particulars supporting the application for such a change shall be supplied to the competent authorities those documents and particulars shall also be supplied to the applicant where they concern the applicant’s part of the Active Substance Master File.

Additionally, information on the method of manufacture, on quality control and on impurities as well as evidence of the molecular structure shall be provided where a Certificate of Suitability for the active substance is not available:

1.

Information on the manufacturing process shall include a description of the active substance manufacturing process that represents the applicant’s commitment for the manufacture of the active substance. All materials needed in order to manufacture the active substance(s) shall be listed, identifying where each material is used in the process. Information on the quality and control of those materials shall be provided. Information demonstrating that materials meet standards which are appropriate for their intended use shall be provided.

2.

Information on quality control shall contain tests (including acceptance criteria) carried out at every critical step, information on the quality and control of intermediates and process validation and/or evaluation studies as appropriate. It shall also contain validation data for the analytical methods applied to the active substance, where appropriate.

3.

Information on impurities shall indicate predictable impurities together with the levels and nature of observed impurities. It shall also contain information on the safety of these impurities where relevant.

4.

For biotechnological veterinary medicinal products, evidence of molecular structure shall include the schematic amino acid sequence and relative molecular mass.

1.1.1. Active substances listed in pharmacopoeias U.K.

The general and specific monographs of the European Pharmacopoeia shall be applicable to all active substances appearing in it.

Constituents fulfilling the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with Article 12(3)(i). In this case the description of the analytical methods and procedures shall be replaced in each relevant section by an appropriate reference to the pharmacopoeia in question.

In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State is insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the applicant, including limits for specific impurities with validated test procedures.

The competent authorities shall inform the authorities responsible for the pharmacopoeia in question. The marketing authorisation holder shall provide the authorities of that pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.

In the absence of a European Pharmacopoeia monograph for an active substance, and where the active substance is described in the pharmacopoeia of a Member State, that monograph may be applied.

In cases where an active substance is described neither in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia may be accepted if its suitability is demonstrated; in such cases, the applicant shall submit a copy of the monograph accompanied by a translation where appropriate. Data to demonstrate the ability of the monograph to adequately control the quality of the active substance shall be presented.

1.1.2. Active substances not in a pharmacopoeia U.K.

Constituents which are not given in any pharmacopoeia shall be described in the form of a monograph under the following headings:

(a)

the name of the constituent, meeting the requirements of Section A point 2, shall be supplemented by any trade or scientific synonyms;

(b)

the definition of the substance, set down in a form similar to that used in the European Pharmacopoeia, shall be accompanied by any necessary explanatory evidence, especially concerning the molecular structure. Where substances can only be described by their manufacturing method, the description shall be sufficiently detailed to characterise a substance which is constant both on its composition and in its effects;

(c)

methods of identification may be described in the form of complete techniques as used for production of the substance, and in the form of tests which ought to be carried out as a routine matter;

(d)

purity tests shall be described in relation to each individual predictable impurity, especially those which may have a harmful effect, and, if necessary, those which, having regard to the combination of substances to which the application refers, might adversely affect the stability of the medicinal product or distort analytical results;

(e)

tests and limits to control parameters relevant to the finished product, such as particle size and sterility shall be described and methods shall be validated where relevant;

(f)

with regard to complex substances of plant or animal origin, a distinction must be made between the case where multiple pharmacological effects render chemical, physical or biological control of the principal components necessary, and the case of substances containing one or more groups of principles having similar activity, in respect of which an overall method of assay may be accepted.

Those data shall demonstrate that the proposed set of test procedures is sufficient to control the quality of the active substance from the defined source.

1.1.3. Physico-chemical characteristics liable to affect bioavailability U.K.

The following items of information concerning active substances, whether or not listed in the pharmacopoeias, shall be provided as part of the general description of the active substances if the bioavailability of the veterinary medicinal product depends on them:

• crystalline form and solubility coefficients,

• particle size, where appropriate after pulverisation,

• state of hydration,

• oil/water coefficient of partition,

• pK/pH values.

The first three indents are not applicable to substances used solely in solution.

1.2. Excipients U.K.

The general and specific monographs of the European Pharmacopoeia shall be applicable to all substances appearing in it.

Excipients shall comply with the requirements of the appropriate European Pharmacopoeia monograph. Where such a monograph does not exist reference may be made to the pharmacopoeia of a Member State. In the absence of such a monograph reference may be made to the pharmacopoeia of a third country. In this case the suitability of this monograph shall be demonstrated. Where appropriate, additional tests to control parameters such as particle size, sterility, residual solvents shall supplement the requirements of the monograph. In the absence of a pharmacopoeial monograph a specification shall be proposed and justified. The requirements for specifications as set out in section 1.1.2 (a to e) for the active substance shall be followed. The proposed methods and their supporting validation data shall be presented.

Colouring matters for inclusion in veterinary medicinal products shall satisfy the requirements of Directive 78/25/EEC, except for certain veterinary medicinal products for topical use, such as insecticidal collars and ear tags, where the use of other colouring matters is justified.

Colouring matters shall meet the purity criteria as laid down in Commission Directive 95/45/EC(2).

For novel excipients, that is to say excipient(s) used for the first time in a veterinary medicinal product or by a new route of administration, details of manufacture, characterisation, and controls, with cross references to supporting safety data, both clinical and non-clinical, shall be provided.

1.3. Container-closure systems U.K.

1.3.1. Active substance U.K.

Information on the container-closure system for the active substance shall be given. The level of information required shall be determined by the physical state (liquid, solid) of the active substance.

1.3.2. Finished product U.K.

Information on the container-closure system for the finished product shall be given. The level of information required shall be determined by the route of administration of the veterinary medicinal product and the physical state (liquid, solid) of the dosage form.

Packaging materials shall comply with the requirements of the appropriate European Pharmacopoeia monograph. Where such a monograph does not exist reference may be made to the pharmacopoeia of a Member State. In the absence of such a monograph reference may be made to the Pharmacopoeia of a third country. In this case the suitability of this monograph shall be demonstrated.

In the absence of a pharmacopoeial monograph, a specification shall be proposed and justified for the packaging material.

Scientific data on the choice and suitability of the packaging material shall be presented.

For novel packaging materials in contact with the product, information on their composition, manufacture and safety shall be presented.

Specifications and, if appropriate, performance data shall be presented for any dosing or administration device supplied with the veterinary medicinal product.

1.4. Substances of biological origin U.K.

Where source materials such as microorganisms, tissues of either plant or animal origin, cells or fluids (including blood) of human or animal origin or biotechnological cell constructs are used in the manufacture of veterinary medicinal products, the origin and history of starting materials shall be described and documented.

The description of the starting material shall include the manufacturing strategy, purification/inactivation procedures with their validation and all in-process control procedures designed to ensure the quality, safety and batch to batch consistency of the finished product.

When cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used for the production and beyond.

Seed materials, cell banks and pools of serum and, whenever possible, the source materials from which they are derived shall be tested for extraneous agents.

When starting materials of animal or human origin are used, the measures used to ensure freedom from potentially pathogenic agents shall be described.

If the presence of potentially pathogenic extraneous agents is inevitable, the material shall be used only when further processing ensures their elimination and/or inactivation, and this shall be validated.

Documentation shall be supplied to demonstrate that the seed materials, cell seeds, batches of serum and other material originating from animal species relevant for the transmission of TSE comply with the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products(3), as well as with the corresponding monograph of the European Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the Quality of Medicines and HealthCare, with reference to the relevant monograph of the European Pharmacopoeia, may be used to demonstrate compliance.

D. CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF THE MANUFACTURING PROCESS U.K.

The dossier shall include particulars relating to the product control tests that may be carried out at an intermediate stage of the manufacturing process, with a view to ensuring the consistency of the technical characteristics and the production process.

These tests are essential for checking the conformity of the veterinary medicinal product with the formula when, exceptionally, an applicant proposes an analytical method for testing the finished product which does not include the assay of all the active substances (or of all the excipient components subject to the same requirements as the active substances).

The same applies where the quality control of the finished product depends on in-process control tests, particularly if the substance is essentially defined by its manufacturing method.

Where an intermediate product may be stored prior to further processing or primary assembly, a shelf life for the intermediate product shall be defined on the basis of the data resulting from stability studies.

E. TESTS ON THE FINISHED PRODUCT U.K.

For the control of the finished product, a batch of a finished product comprises all the units of a pharmaceutical form which are made from the same initial quantity of material and have undergone the same series of manufacturing and/or sterilisation operations or, in the case of a continuous production process, all the units manufactured in a given period of time.

The application for marketing authorisation shall list those tests, which are carried out routinely on each batch of finished product. The frequency of the tests which are not carried out routinely shall be stated. Release limits shall be indicated.

The dossier shall include particulars relating to control tests on the finished product at release. They shall be submitted in accordance with the following requirements.

The provisions of the relevant monographs and general chapters of the European Pharmacopoeia, or failing that, of a Member State, shall be applicable to all products defined therein.

If test procedures and limits other than those mentioned in the relevant monographs and general chapters of the European Pharmacopoeia, or failing this, in the pharmacopoeia of a Member State are used, this shall be justified by providing proof that the finished product would, if tested in accordance with those monographs, meet the quality requirements of that pharmacopoeia for the pharmaceutical form concerned.

1. General characteristics of the finished product U.K.

Certain tests of the general characteristics of a product shall always be included among the tests on the finished product. These tests shall, wherever applicable, relate to the control of average masses and maximum deviations, to mechanical, physical or microbiological tests, organoleptic characteristics, physical characteristics such as density, pH, refractive index. For each of these characteristics, standards and tolerance limits shall be specified by the applicant in each particular case.

The conditions of the tests, where appropriate, the equipment/apparatus employed and the standards shall be described in precise details whenever they are not given in the European Pharmacopoeia or the pharmacopoeia of the Member States; the same shall apply in cases where the methods prescribed by such pharmacopoeias are not applicable.

Furthermore, solid pharmaceutical forms having to be administered orally shall be subjected to in vitro studies on the liberation and dissolution rate of the active substance or substances, unless otherwise justified. Those studies shall also be carried out where administration is by another means if the competent authorities of the Member State concerned consider this necessary.

2. Identification and assay of active substance(s) U.K.

Identification and assay of the active substance(s) shall be carried out either in a representative sample from the production batch or in a number of dosage units analysed individually.

Unless there is appropriate justification, the maximum acceptable deviation in the active substance content of the finished product shall not exceed ± 5 % at the time of manufacture.

On the basis of the stability tests, the manufacturer shall propose and justify maximum acceptable deviation limits in the active substance content of the finished product up to the end of the proposed shelf life.

In certain cases of particularly complex mixtures, where assay of active substances which are very numerous or present in very low amounts would necessitate an intricate investigation difficult to carry out in respect of each production batch, the assay of one or more active substances in the finished product may be omitted, on the express condition that such assays are made at intermediate stages in the production process. This simplified technique may not be extended to the characterisation of the substances concerned. It shall be supplemented by a method of quantitative evaluation, enabling the competent authority to have the conformity of the medicinal product with its specification verified after it has been placed on the market.

An in vivo or in vitro biological assay shall be obligatory when physico-chemical methods cannot provide adequate information on the quality of the product. Such an assay shall, whenever possible, include reference materials and statistical analysis allowing calculation of confidence limits. Where these tests cannot be carried out on the finished product, they may be performed at an intermediate stage, as late as possible in the manufacturing process.

Where degradation occurs during manufacture of the finished product, the maximum acceptable levels of individual and total degradation products immediately following manufacture shall be indicated.

Where the particulars given in Section B show that a significant overage of an active substance is employed in the manufacture of the medicinal product or where the stability data show that the assay of the active substance declines on storage, the description of the control tests on the finished product shall include, where appropriate, the chemical and, if necessary, the toxico-pharmacological investigation of the changes that this substance has undergone, and possibly the characterisation and/or assay of the degradation products.

3. Identification and assay of excipient components U.K.

An identification test and an upper and lower limit test shall be obligatory for each individual antimicrobiological preservative and for any excipient that is liable to affect the bioavailability of the active substance, unless the bioavailability is guaranteed by other appropriate tests. An identification test and an upper limit test shall be obligatory for any antioxidant and for any excipient liable to adversely affect physiological functions, with a lower limit test also included for antioxidants at time of release.

4. Safety tests U.K.

Apart from the toxico-pharmacological tests submitted with the application for marketing authorisation, particulars of safety tests, such as sterility and bacterial endotoxins, shall be included in the analytical particulars wherever such tests must be undertaken as a matter of routine in order to verify the quality of the product.

F. STABILITY TEST U.K.

1. Active substances(s) U.K.

A retest period and storage conditions for the active substance shall be specified except in the case where the active substance is the subject of a monograph in the European Pharmacopoeia and the manufacturer of the finished product fully retests the active substance immediately before its use in the manufacture of the finished product.

Stability data shall be presented to support the defined retest period and storage conditions. The type of stability studies conducted, protocols used, the analytical procedures used and their validation together with the detailed results shall be presented. The stability commitment with a summary of the protocol shall be provided.

However, where a Certificate of Suitability for the active substance from the proposed source is available and specifies a retest period and storage conditions, stability data for the active substance from that source are not required.

2. Finished product U.K.

A description shall be given of the investigations by which the shelf life, the recommended storage conditions and the specifications at the end of the shelf life proposed by the applicant have been determined.

The type of stability studies conducted, protocols used, the analytical procedures used and their validation together with the detailed results shall be presented.

Where a finished product requires reconstitution or dilution prior to administration, details of the proposed shelf life and specification for the reconstituted/diluted product are required, supported by relevant stability data.

In the case of multi-dose containers, where relevant, stability data shall be presented to justify a shelf life for the product after it has been broached for the first time and an in-use specification shall be defined.

Where a finished product is liable to give rise to degradation products, the applicant shall declare these and indicate the identification methods and test procedures.

The conclusions shall contain the results of analyses, justifying the proposed shelf life and if appropriate, the in-use shelf life, under the recommended storage conditions and the specifications of the finished product at the end of the shelf life, and in-use shelf life if appropriate, of the finished product under these recommended storage conditions.

The maximum acceptable level of individual and total degradation products at the end of shelf life shall be indicated.

A study of the interaction between product and container shall be submitted wherever the risk of such interaction is regarded as possible, especially where injectable preparations are concerned.

The stability commitment with a summary of the protocol shall be provided.

G. OTHER INFORMATION U.K.

Information relating to the quality of the veterinary medicinal product not covered in the previous sections may be included in the dossier.

For medicated premixes (products intended for incorporation into medicated feedingstuffs), information shall be provided on inclusion rates, instructions for incorporation, homogeneity in-feed, compatibility/suitable feedingstuffs, stability in-feed, and the proposed in-feed shelf life. A specification for the medicated feedingstuffs, manufactured using these pre-mixes in accordance with the recommended instructions for use shall also be provided.

(1)

OJ L 11, 14.1.1978, p. 18.

(2)

OJ L 226, 22.9.1995, p. 1.

(3)

OJ C 24, 28.1.2004, p. 6.