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Naqua can toll manufacture, pack or fill medicines that comply with this legislation

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The Vm symbol

An authorised product will have an authorisation number preceded by the symbol Vm on its product literature, e.g. labels. This offers users a clear guarantee that the product has been assessed and approved in accordance with the instructions on the product literature.

A product subject to an MA issued by the European Commission (EC) will not have the Vm symbol on its product literature; instead an identifier with the following format will be used – EU/2/01/011/001.

Product types

Products tend to be classed as pharmaceutical or biological.

Products containing biological active substances are known as biological veterinary medicines. A biological substance is produced or extracted from a biological source which needs, for its characterisation and determination of quality, a combination of physiochemical-biological testing together with the production process and its control.

The following are considered to be biological veterinary medicines:

  • immunological veterinary medicine which is a product administered to animals to produce active or passive immunity, or to diagnose the state of immunity to desensitise against allergens, or to produce an affect based on interaction of antigens with specific antibodies
  • veterinary medicine derived from blood and plasma
  • veterinary medicines falling within the scope of Part A of the Annex to Regulation No. 2309/93

Authorisation routes

There are four routes that can be used to get an MA:

  • National
  • Centralised
  • Mutual Recognition
  • Decentralised

These routes determine the procedures, processes and timelines used in processing an application for a new MA. Once granted, the authorisation will be centrally authorised, or nationally authorised even if submitted under the mutual recognition or decentralised routes.

Nationally authorised products

A product that has been assessed and approved on a national basis only, i.e. there has been no interaction with other EU MSs.

Centrally authorised products

A centrally authorised product is one that has been assessed and approved on a community level involving all EU MSs. A pan-European authorisation is issued by the European Commission (EC) permitting the marketing, sale and supply of the product in all EU MSs including the UK.

The European Medicines Agency (EMA) organises the process of evaluation using scientific expertise from all EU MSs. If a positive opinion is given by the CVMP after a product has been evaluated, it is sent to the EC. If the EC also has a favourable opinion, it makes a formal decision to authorise the product and the EMA grants a single MA that is valid in all EU MSs. Note, whilst the EC will usually endorse a positive opinion, it has the right to reject it.

Although the VMD does not issue an MA for products authorised by the centralised procedure, the outcome is the same: the product is authorised for sale and supply in the UK.

The centralised procedure is compulsory for some products and optional for others. some products are not eligible for the centralised procedure.

Mutually recognised products

A mutually recognised product is one that has been assessed and approved on a European level involving at least two EU MSs, i.e. evaluated via the mutual recognition or decentralised procedure.

The mutual recognition procedure (MRP) is a European authorisation route resulting in a mutually recognised product.

Mutual recognition must be used when a product is already authorised in at least one EU MS on a national basis and the MAH wishes to obtain an MA for the same product in at least in one other EU MS.

The MS that has already authorised the product is known as the Reference MS (RMS). The RMS submits their evaluation of the product to the other MSs; known as a Concerned MSs (CMS). The CMS is asked to mutually recognise the MA of the RMS.

If the application is successful, the CMS will then issue an MA for that product permitting the marketing of that product in their country. Please note if the UK acts as RMS this means the product was initially authorised in the UK on a national basis; therefore, once the MRP has been successfully completed, the authorisation route of the UK MA will change from ‘National’ to ‘Mutually Recognised’.

The decentralised procedure (DCP) is a European authorisation route resulting in a mutually recognised product.

The difference between MRP and DCP is that a product must already be authorised in at least one MS on a national basis in order for MRP to be used. DCP may be used if the product is not authorised in any EU MS and a company wishes to authorise it in several or all EU MSs simultaneously, but only if the centralised procedure is not mandatory, or the company does not wish to use the centralised procedure (where it is optional), or the product is not eligible for the centralised procedure.

One of the proposed MSs will be asked by the MAH to act as the RMS. The RMS does the initial evaluation of the product and issues a draft assessment report including a list of unresolved issued. The CMS either agree with the RMS’s evaluation or they ask further questions/raise objections.

If all the issues are resolved and the application is successful, each MS will then issue an MA for that product permitting it to be marketed in their country.

There are seven different legal bases upon which an application for an MA may be applied for; these reflect the type and content of the data submitted in support of the application.

All references refer to Directive 2001/82/EC, as amended by 2004/28/EC.

  • Article 12(3) – based on a full dossier using the MAH’s own propriety data, or
    a mixture of their own data and some bibliography
  • Article 13(1) – generics
  • Article 13(3) – generic hybrids
  • Article 13(4) – biosimiliars
  • Article 13(a) – bibliographic (well-established use)
  • Article 13(b) – fixed combination
  • Article 13(c) – Informed consent

You may also apply to extend an existing MA, under Regulation 1234/2008 as amended by 712/2012 to create a new stand-alone MA.

The data and documents required in support of an application for an MA are set out in Volumes 6a and 6b of the European Notice to Applicants and in Annex I to Directive 2001/82/EC, as amended.

You may also apply for the following types of MA:

  • Exceptional MAs – provisional or limited
  • Marketing Authorisation for Parallel Import (MAPI); further information

The data and documents required to support an application for an exceptional MA or MAPI are provided in the application forms.

Generics

You may apply for a generic MA by referring to the safety and efficacy aspects of a data package submitted in support of an already authorised veterinary medicine, which is referred to as the reference product.

In addition to a full quality data package, you would need to provide an environmental risk assessment for the product and a user risk assessment. The type of user risk assessment provided depends on the degree of similarity between the generic and reference products.

For generics of injectable products the submission of injection site residues data are necessary, unless a biowaiver exempts the application from the need for residues studies.

You must demonstrate that the generic product is bioequivalent to the reference product, unless an exemption from demonstrating bioequivalence applies. The reference product must have been authorised for at least 10 years, or part of the Global Marketing Authorisation where 10 years has lapsed from original authorisation, before the generic product can be placed on the market. For applications for generic products, which are based on reference products authorised after October 2005, the application can be submitted after eight years of authorisation, but the generic product cannot be marketed until the 10 year data protection period has expired.

In some cases the data protection period for the reference product may be extended to 13 years. For products indicated for the treatment of bees and fish the protection period of the reference product is automatically 13 years.

The SPC of the generic product should follow the SPC of the reference product.

Generics of biological products are not possible unless the Master Seed and / or working seed and production process are the same.

Reference product – the reference product must be authorised in accordance with any of the following articles: 12(3), 13(a), 13(b), 13(c) or 13(d), ie. you cannot use a product authorised in accordance with article 13 (generic) or 13(3) (generic-hybrid), a MAPI, or exceptional MA as a reference product.

Generic-Hybrids

A hybrid MA follows the same principles as those for generic applications, but such applications are required under the following two scenarios:

  • if you are not able to demonstrate bioequivalence to the reference product through bioavailability studies
  • where bioequivalence can be demonstrated to the reference product, but you want to make changes, eg. in the active substance(s), or changes to the therapeutic indications, strength or pharmaceutical form, withdrawal period or to the route of administration.

Example of a hybrid MA: The reference product is indicated for use in cats and dogs and is administered orally. You want your product to include cats and dogs, but want an injectable product. You refer to the reference product to cover some of the safety and efficacy data requirements, but produce your own data to support the change in the route of administration.

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ManA – GMP Approval for Packing – Filling – Manufacturing – Batch Release – Labelling – Import & Export

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Manufacturing Authorisation (ManA)

You must obtain a ManA if you carry out any of the following manufacturing or assembling activities for an authorised veterinary medicine:

  • any process carried out in the course of making the medicine except for dissolving or dispersing the product in, or diluting or mixing it with some other substance used as a vehicle for the purpose of administering it
  • enclosing the medicine in a container which is labelled before it is sold or supplied (primary packing)
  • labelling the container (where the medicine is already enclosed in the container in which it is to be sold or supplied ie secondary packing) before the medicine is sold or supplied; this includes the over-labelling of medicines
  • importing veterinary medicine from a non-EU or European Economic Area (EEA) country and subsequently releasing the medicine to the market (batch certification)

You do not need a ManA to:

  • prepare, divide up, change the packaging or presentation of a veterinary medicine where this is done solely for retail supply, by or under the supervision of a veterinary surgeon or pharmacist in a registered veterinary practice premises or pharmacy (except a pharmacist may not break the immediate packaging of sterile products)
  • manufacture a veterinary medicine based on radio-active isotopes
  • manufacture a veterinary medicine for administration for research purposes in accordance with an Animal Test Certificate (ATC) or a licence issued under the Animals (Scientific Procedures) Act (A(SP)A) 1986

Duties of the ManA holder

You must comply (where appropriate to the manufacturing steps performed) with the following legal requirements relating to the manufacture and assembly of veterinary medicines:

  • manufacture the veterinary medicine in accordance with its Marketing Authorisation (MA)
  • ensure the services of a registered Qualified Person (QP(s) are continuously available
  • possess a current EU GMP certificate and ensure the veterinary medicine is produced in accordance with GMP
  • ensure Quality Assurance (QA) and Quality Control (QC) systems are in place
  • make evidence of any control testing performed in accordance with the product’s MA available to the VMD, on request
  • ensure the finished product is labelled with:
    1. registered name, strength and pharmaceutical form
    2. batch number
    3. expiry date
    4. storage requirements
    5. any warnings required for safe handling of the product
  • ensure a representative sample of the finished product is retained and made available for testing upon request by the VMD.

Compliance with GMP

GMP is defined as the part of Quality Assurance which ensures that products are consistently produced and controlled in accordance with the quality standards appropriate to their intended use.

The principles and guidelines for GMP are defined in Eudralex volume 4.

GMP requirements for active substances as starting materials

The active substance (also known as the Active Pharmaceutical Ingredient or API) must have been manufactured in accordance with Eudralex Volume 4, Part II. However, the following materials are exempted from the full application of Part II:

  • ectoparasiticidal active substances for veterinary use
  • substances that are used exclusively for topical application to the unbroken skin of animals and which are ectoparasiticidal, anti-bacterial or anti-fungal agents

You may only use API from suppliers registered on the MA to manufacture the veterinary medicine.

The suitability of an API supplier must be evaluated by the ManA holder prior to use. This is usually obtained by:

  • supplier audit, and
  • provision of a QP statement certificate of GMP

Transmissible Spongiform Encephalopathy (TSE)

The ManA holder must comply with the European Commission document EMEA/410/01–Rev 2 Notes for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via veterinary medicinal products.

Required Personnel

A ManA holder must appoint the following personnel:

Qualified Person (QP)

At least one QP must be named on the authorisation. The QP must be available on a continuous basis and live in the EEA. The QP’s role and responsibility is defined in Eudralex Volume 4, Chapter 2 and Annex 16.

QPs must meet specific educational and vocational requirements. They are usually expected to be members of the Royal Pharmaceutical Society, the Royal Society of Chemistry or the Royal Society of Biology. These professional bodies jointly undertake assessment of the candidate’s eligibility on behalf of the VMD. Exceptionally, the VMD can appoint someone as a QP on a restricted named-site basis only.

QPs must comply with the QP Code of Practice. Guidance on the professional duties and responsibilities of the QP is in Eudralex Volume 4 Annex 16.

Production Manager (PM)

An applicant for a ManA must nominate a suitably qualified Production Manager (PM). Their responsibilities are defined in Eudralex Volume 4, Chapter 2.

Quality Control (QC)

An applicant for a ManA must nominate a suitably qualified Head of Quality Control (QC). The Head of QC cannot be the same person as the PM but they may also be the QP. Their responsibilities are defined in Eudralex Volume 4, Chapter 2.

Batch certification

The VMD can issue a ManA solely to authorise the holder to certify and release batches of products for which they hold the MA where the medicine has been manufactured by a contract manufacturer.

The QP named on a ManA granted solely for the purpose of batch certification may either take responsibility for all manufacturing stages conducted by the contract manufacturer or may take account of the confirmation of the batch by the contract manufacturer’s QP. Ultimate responsibilty for batch certification of the batch lies with the certifying QP.

Record-keeping requirements

The record requirements are defined in the Veterinary Medicines Regulations (VMR). The records for each batch must include:

  • the name of the product
  • the quantity manufactured, assembled or supplied
  • the date of manufacture, assembly or supply
  • the batch number and expiry date
  • the name and address of the recipient, where supplied
  • all certification provided by the QP related to the batch

All records and certificates must be kept for at least five years from the date that the batch is placed on the market or one year after the expiry of the batch whichever is the longer.

Export to a third country

Veterinary medicines manufactured in the UK should be produced to the same standards irrespective of where they will be used. If you are manufacturing medicines in the UK exclusively for export to third country (a non-EU or EEA country) you need a ManA and must comply with GMP.

The VMD will inspect your manufacturing site to ensure you comply with the EU GMP principles.

Manufacture of products under the Exemption for Small Pet Animals

Medicines manufactured under Schedule 6 of the Veterinary Medicines Regulations (the Exemption for Small Pet Animals) must comply with GMP and be manufactured by the holder of a manufacturing authorisation issued under:

  • Directive EC No 2001/82 as amended (sites in UK and EU)
  • a certificate issued by the competent authority (sites in Australia, Canada, New Zealand and Switzerland)
  • a certificate issued by the Secretary of State (sites in all other countries)

There are no restrictions on the retail supply within the UK of products manufactured under the exemption but they may only be wholesale supplied by the holder of a WDA.

There are no restrictions on the importation of products which fully comply with this exemption.

Further guidance on the exemption is available on GOV.UK

 

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