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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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Use of Prescription Cascade

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Veterinary medicines are authorised for specific conditions for specific target species, based on assessed data. The conditions of use for each authorised veterinary medicine are listed in its Summary of Product Characteristics (SPC). The VMD’s Product Information Database contains the SPCs of all veterinary medicines authorised in the UK.

Where there is no suitable veterinary medicine authorised in the UK for the specific condition in the animal being treated, in particular to avoid unacceptable suffering, vets are permitted to use their clinical judgement to treat animals under their care in accordance with the cascade.

The cascade is a risk based decision tree. The steps, in descending order of suitability, are:

  • a veterinary medicine authorised in the UK for use in another animal species, or for a different condition in the same species

If there is no such product that is clinically suitable, either:

  • a human medicine authorised in the UK, or
  • a veterinary medicine not authorised in the UK, but authorised in another member state for use in any animal species in accordance with the Special Import Scheme; in the case of a food-producing animal the medicine must be authorised in a food producing species

If there is no such product that is suitable:

  • a medicine prescribed by the vet responsible for treating the animal and prepared especially on this occasion (known as an extemporaneous preparation) by a vet, a pharmacist or a person holding an appropriate manufacturer’s authorisation (ManSA).

In exceptional circumstances, where there is no suitable veterinary medicine available either as an authorised product or under the cascade, a vet may treat an animal with a medicine authorised in a country outside of the EU via the Special Import Scheme.

Prescribing decisions under the cascade should be made on a case by case basis. For example, if a suspected adverse event occurred when using a medicine in an animal, this does not mean that the cascade should always be used when treating other animals.

The prescribing vet is personally responsible for the choice of product and, as part of the Royal College of Veterinary Surgeons (RCVS) Code of Professional Conduct for Veterinary Surgeons, must obtain the owner’s consent for their animal to be treated under the cascade. They must also maintain accurate records.

The prescribing vet, or a person acting under their supervision, may administer a product prescribed under the cascade; however the prescription and use of the product remains the vet’s responsibility.

When using a product under the cascade, the vet should balance the expected benefits to the animal with the risks of using a medicine under the cascade. Risks could include those to:

  • the animal
  • the owner
  • the person administering the medicine
  • consumers of food which may contain residues of the veterinary medicine
  • the environment
  • wider public health, for example increased selection for antimicrobial resistance

When prescribing medicines under the cascade, vets must ensure that the evidence base for their prescribing decisions is robust and complies with Recognised Veterinary Practice (RVP). This is particularly important when prescribing medicines lower down the cascade; if the treatment does not comply with RVP it may require licensing by the Home Office as a regulated procedure under the Animal (Scientific Procedures) Act. Further guidance on RVP is available from the RCVS.

Dispensing

Only vets registered with the RCVS may prescribe medicines under the cascade.

A Suitably Qualified Person (SQP) may retail supply an authorised veterinary medicine that falls within the scope of the registration they hold, against a prescription from a vet for use under the prescribing cascade. A pharmacist may dispense authorised veterinary and human medicines, and extemporaneous preparations they have prepared against a prescription from a vet.

Food-producing species

The following conditions apply when prescribing a product under the cascade for use in food-producing species:

  • the pharmacologically active substances contained in the medicine must have an Maximum Residue Limit (MRL), but not necessarily in the species for which it is intended to be used. For more information see the table of allowed substances(Table 1) in EU Commission Regulation 37/2010
  • the vet responsible for prescribing the medicine must specify an appropriate withdrawal period
  • the vet responsible for prescribing the medicine must keep specified records

Setting withdrawal periods

A withdrawal period is the length of time that must lapse between the final administration of the medicine and the point the animal can be slaughtered to enter the food chain or when produce is taken.

The prescribing vet is required to specify an appropriate withdrawal period when prescribing or administering a medicine to food-producing animals under the cascade. When setting the withdrawal period, the vet must take into account known information about the use of the product on the authorised species when prescribing for another species.

If a product is used as authorised, for example, use of an imported product from another member state, the authorised withdrawal period should be followed.

Where the product is not used as authorised, for example, when a higher dose is used, or a species for which the product is not indicated is treated, then care needs to be taken to ensure that a suitable withdrawal period is set. This ensures that no residues of veterinary medicines above the MRL remain at the time of slaughter or when produce is taken.

The minimum statutory withdrawal periods are:

  • 7 days for eggs and milk
  • 28 days for meat from poultry and mammals
  • 500 degree days for fish meat

However, in cases where the authorised withdrawal periods are close to, or longer than, the ‘statutory minimum’ withdrawal periods, the vet should consider other factors when setting a suitable withdrawal period. Factors to consider include:

  • The length of the authorised withdrawal period(s)
  • The known pharmacokinetics of the active substance(s) in both the authorised species and the species being treated (if different)

The vet could, for example, increase the authorised withdrawal period by 50% (where a 30 day withdrawal period is authorised in cattle (meat and offal), a 45 day withdrawal period might be suitable for goats).

If a higher dose is given, then a longer period may be warranted.

Honey

As there is no minimum withdrawal period set for honey, the prescribing vet must set a suitable withdrawal period that will ensure no risk to consumer health. Further guidance is available by contacting the National Bee Unit.

Horses

A horse declared as non-food producing in its passport can be treated as a non-food animal under the cascade.

A horse that has not been signed out of the food chain in its passport must be treated as a food-producing animal under the cascade.

There is a list of substances essential for the treatment of horses. This legislation allows the use of certain substances in horses (declared as food or non-food producing in the passport) under the cascade and with a statutory withdrawal period of six months.

Further information about the use of medicines in horses is available on the Horse medicines and record keeping requirements guidance page.

Human medicines

Vets are not allowed to prescribe a human medicine simply because it is cheaper than using an authorised veterinary medicine.

Human medicines and veterinary medicines containing the same active substance may not be interchangeable.

Importing Medicines under the cascade

In order to legally import medicines for use under the cascade, an Import certificate must be obtained from the VMD under the Special Import Scheme. Failure to obtain a certificate for an imported veterinary product is an offence under the Regulations.

Further information on how to apply for an import certificate is published along with the link to the online application system.

Cascade use when new products come to market

If an authorised veterinary medicine becomes available while an animal is already being treated for a condition under the cascade, the prescribing vet should consider transferring the animal onto the authorised veterinary medicine. However, if the vet has concerns that changing the product could compromise the stability of the patient’s condition, it may be acceptable to continue treatment under the cascade. Any new cases should receive the authorised veterinary medicine.

Extemporaneous preparations

Extemporaneous preparations and the cascade

Extemporaneous preparations (also known as “veterinary specials”) are products that do not hold a marketing authorisation (MA). These products have not been assessed by the VMD against the same standards of quality, safety (for the target animal, user, consumer and environment) and efficacy as authorised veterinary medicines. They can legally be prescribed, supplied and used under the last tier of the cascade.

Vets should recognise that, as the last tier of the cascade, extemporaneous preparations carry a higher risk than authorised medicines and should take this into account when prescribing them. There are further requirements for labelling and record keeping under the cascade.

Manufacturers of extemporaneous products must be authorised, that is hold a ManSA, and comply with the general principles of good manufacturing practice (GMP). Their facilities, equipment and procedures are regularly inspected by the VMD to ensure they manufacture extemporaneous products to a set quality standard.

During inspections of veterinary practice premises (VPPs) both the VMD and RCVS will inspect supplies of products used under the cascade and associated records.

Registers

Further information on the manufacture of extemporaneous preparations can be found on the Apply for a manufacturing authorisation for veterinary medicines guidance page.

Exemptions for Small Pet Animals

Medicines marketed under the Exemption for Small Pet Animals are available over the counter and may be used in accordance with the product’s labelling. If vets wish to use one of these products not in accordance with its recommended use, this would be classed as use under the cascade and considered an extemporaneous preparation.

Stock of medicines

Vets may keep limited quantities of human medicines, imported medicines and extemporaneous preparations in their possession for the treatment of animals where cascade use is required. The amount held should be justified by the immediate clinical need under the cascade rules. These medicines should not be used as a first choice treatment in every situation. Vets should keep up to date with new authorisations and change their prescribing habits and stocking policies accordingly.

Labelling

The information that must be included on the label for products used under the cascade is listed in the Veterinary Medicines Regulations (VMR). If all or part of the information cannot be included on the label, vets may include it on a separate sheet.

It is the responsibility of the person supplying the medicine to ensure it is appropriately labelled.

Record keeping

As well as the normal record keeping requirements there are specific requirements for vets who administer or supply medicines under the cascade.

The RCVS requires that consent must be obtained from clients before prescribing medicines under the cascade. These must be kept for 5 years and made available upon request from a duly authorised person. The records that must be retained are listed in the VMR.

Adverse events

The VMD encourages vets to report adverse events to all medicines. This includes those prescribed under the cascade, including veterinary medicines used outside the terms of their marketing authorisation, human medicines and extemporaneous preparations. Guidance is available on reporting adverse events.

Practical considerations

Cascade use vs Authorised use

Authorised use is when a product is used in accordance with the clinical advice given on the product’s SPC. The SPCs for all authorised veterinary medicines are available on the Product Information Database.

A product’s SPC is based on assessed data and details the advice for correct administration, precautions and warnings to ensure safe and effective use of the product. The cascade permits deviations from the SPC when a suitable authorised product is not available. Any such deviations should be based on robust clinical reasons, with the individual prescribing vet taking responsibility for use under the cascade.

Use of a route of administration other than the authorised route

Use of an unauthorised route of administration could have serious consequences for the animal, the owner, the environment and the consumer if the product behaves differently when administered by a different route (for example, administering a vaccine intended for intramuscular administration in drinking water or feed).

Special considerations for the responsible use of antibiotics under the cascade

The VMD supports and encourages the responsible use of antibiotics. Please read our Summary Position Statement on this topic.

Special considerations for use of vaccines under the cascade

Where the SPC for a vaccine specifies a booster vaccination for a component after three years, but an annual booster vaccination is carried out this is cascade use.

Where an animal is to be revaccinated beyond the period of the authorised schedule, for example, an adult dog being revaccinated sometime after puppy vaccinations, there is no need for the vet to use the same product on the animal as was used previously. Vets should make a benefit:risk assessment taking into account current knowledge concerning the individual disease against which they are vaccinating. For example, there may be no real justification for administering a full primary puppy vaccination course for the World Small Animal Veterinary Association (WSAVA) recommended core antigens, such as Distemper, Adenovirus and Parvovirus, when a dog’s booster vaccination schedule has been allowed to lapse, as a single dose of vaccine may be sufficient to provide adequate immunity. This is not the case for other antigens, such as, leptospira and so it is important for vets to make a benefit:risk assessment in relation to the specific animal and its circumstances.

Simultaneous and concurrent use of vaccines

Where SPCs specifically state that two named vaccines can be administered concurrently or simultaneously, this will be authorised use.

Where there is no such SPC statement, concurrent or simultaneous administration represents cascade use. A decision to use a vaccine before or after any other veterinary medicine needs to be made on a case by case basis by the vet.

Examples of how the cascade may be applied

Individual characteristics

If a particular animal has characteristics, such as age, general condition or known sensitivity to a particular substance, which the vet judges to present unacceptable risks and to contra-indicate the use of the authorised product, they could conclude that no authorised product existed for that condition in that animal and consider other treatments.

Chronic infections

If a condition persists following treatment with an authorised product, the vet may consider in a particular case that there is no authorised treatment for that particular condition and that further use of medicines containing substances in the same chemical group is not appropriate. In such circumstances the vet can consider alternatives in accordance with the cascade.

Unavailability of product

If a product cannot be obtained despite a thorough search and in a reasonable time, the vet may conclude that in these circumstances it does not exist. In such circumstances the cascade should be followed to identify a suitable alternative. However, it is appreciated that there may be cases where urgency dictates that a vet uses whatever is to hand, whether authorised or not. The VMD publishes details of supply issues which have the potential to cause animal welfare issues and provides where possible information on alternative products.

If vets cannot obtain authorised products from their usual wholesaler, they may issue a written prescription for the animal owner to use with another supplier.

Animal owner considerations

The vet should take into account the animal owner’s ability to administer the medicine when prescribing. For example, a vet may conclude that an animal owner would have difficulties in administering the authorised product (for example due to age or disability). In the interest of animal welfare and treatment compliance the vet could consider an alternative treatment under the cascade.

Medicines commonly found around the home

Sometimes a vet may judge there is a need to alleviate a pet’s discomfort until a home visit can be made or the animal brought to the surgery. It would be unlikely that action would be taken if in an emergency a vet recommended that an animal owner could use a human medicine that the owner already has in their possession, such as, antihistamine tablets. This does not mean a pet owner should be encouraged to go into a pharmacy and ask for a human medicine for their pet.

 

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Naqua Ltd – Extemporaneous Manufacturer ManSA

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Naqua Ltd – Extemporaneous Manufacturer

 

In July of 2019 Naqua Ltd received a ManSA from the Veterinary Medicines Directorate which allows Naqua Ltd to manufacture and supply non sterile liquids for external use for animal health purposes.

 

If you are a veterinary surgeon within the EU, at the time of publishing this document, Naqua Ltd are allowed by law to supply and manufacture unlicensed medicine you have prescribed under the cascade.

Manufacturers of extemporaneous preparations for use under the cascade (ManSA)

You require a ManSA to legally manufacture and supply unauthorised extemporaneous veterinary medicines (also known as ‘Specials’) which have been specifically prepared to the order of a veterinary surgeon for use in accordance with the cascade.

The same guidance broadly applies to ManSAs as for ManAs, although a marketing authorisation (MA) is not required.

An unauthorised medicine which is a pharmaceutical equivalent of an available authorised medicine should not be placed on the market. A medicine should be regarded as a pharmaceutical equivalent if:

  • it contains the same amount of the same active substance(s) or, for liquid dosage, forms the same concentration
  • it is in the same dosage form
  • it meets the same or comparable standards considered in the light of the clinical needs of the patient at the time of use of the medicine

An authorised veterinary medicine obtainable from normal distribution channels in a reasonable time should be considered available for use. If an otherwise suitable authorised product becomes unavailable, it may be necessary for an unauthorised pharmaceutical equivalent to be manufactured and supplied. This should be seen as a temporary measure and should not be taken as justification for long term prescription/supply.

Supply in these circumstances should cease as soon as is possible, following re-instatement of the authorised product.

You may only supply an extemporaneous product to a veterinary surgeon if all of the following apply:

  • there is a genuine order from a veterinary surgeon registered in the UK
  • the product is formulated in accordance with the veterinary surgeon’s requirements
  • the product is for administration to an animal under the veterinary surgeon’s care on their direct personal responsibility

The order and distribution of extemporaneous products should be in response to a clinical need in specific animals. This should be a direct process between the prescribing vet and the manufacturer and they cannot be supplied via a third party such as a wholesale dealer.

All involved in the supply chain should be aware of the unauthorised status of the product. It should be clear from the product’s packaging that the product is unauthorised because there will be no MA number on it.

Further guidance on the prescribing cascade is available on GOV.UK

Manufacture and Assembly by ManSA holders

Your ManSA manufacturing and assembly site and its operations will be inspected for compliance with the VMR and the principles of GMP.

The VMR requires that manufacture or assembly is carried out under the supervision of appropriately qualified personnel, each of whom must be named on the ManSA. The personnel include:

  • a person responsible for Quality Control (QC)
  • a Production Manager (PM)
  • a person responsible for release (PRR), rather than a QP. The PRR may also be the QC or a nominated deputy

You must take adequate precautions to ensure that the product is of the quality required for its intended purpose and that it complies with any relevant pharmacopoeial monograph standards. Written records of manufacture, assembly and supply must be kept for five years and be made available to the VMD on request.

You must comply with the European Commission’s Notes for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via veterinary medicinal products.

Where possible GMP-assured API should be used.

You must ensure that any information you provide to the VMD relating to the evaluation of the safety, quality or efficacy of any medicine which you import, handle, store or distribute is not false or misleading.

Advertising extemporaneous products

You may advertise the services you provide and the different types of dosage forms that are available, for example capsules, syrups, etc.

You must not advertise or promote the specific substances that you can manufacture. However, you may provide lists of active substances and formulations with prices to a veterinary surgeon but only on request.

You may also provide placebo samples to a veterinary surgeon enquiring about your services. Further information can be found on the Advertise veterinary medicines legally guidance.

Requirements for testing extemporaneous products

You should conduct appropriate testing to ensure products meet in-house specifications. For a one-off unauthorised extemporaneous product, you must demonstrate consistency of manufacture. As a minimum there should be a standard procedure that can be validated even if the end product itself cannot be. However, there should be confirmation of homogeneity if this is appropriate to the preparation.

For a one-off unauthorised extemporaneous product, you should be able to provide justification for the specified shelf life. Such products should have a short shelf-life to reflect the fact there are no data to substantiate the validity of the stated expiry date.

However, if you are producing more regularly prescribed extemporaneous products that may be stored for a length of time waiting for orders, you should undertake real-time stability studies to justify the specified shelf-life. Depending on the nature of the products being manufactured data may be required to support the proposed shelf-life and on-going stability studies in accordance with GMP principles.

Labelling and record keeping requirements

You must ensure that extemporaneous products are labelled with the following, together with any additional information required by the terms of the ManSA:

  • the name of the veterinary surgeon who ordered the veterinary medicine
  • a precise description of the veterinary medicine
  • the date of production
  • the name of the authorisation holder and the address of the authorised site
  • the expiry date
  • any necessary warnings
  • instructions for use

You must also keep the following records for at least 5 years:

  • the name and address of the veterinary surgeon who ordered the medicine
  • a precise description of the veterinary medicine
  • the date of production
  • the expiry date
  • the date of supply to the veterinary surgeon.

Wholesale supply

As the holder of a ManA, ManSA or authorisation to manufacture ESPA products, you may store and distribute any veterinary medicine manufactured or assembled in line with your authorisation. If you buy or store any other veterinary medicine to supply to a wholesale dealer or retailer, you must hold a wholesale dealer authorisation (WDA).

If you wholesale supply a veterinary medicine that you have manufactured or assembled, you must:

  • comply with the principles of Good Distribution Practice (GDP)
  • only distribute the medicine to:
    1. a holder of a WDA relating to those products
    2. a holder of an authorisation granted by the competent authority of another EEA country authorising the supply of those products by way of wholesale dealing
    3. a person who may legally retail supply the product or who may legally administer the product
  • ensure the appropriate and continued suply of the veterinary medicine
  • only sell, or offer for sale or supply, the veterinary medicine in accordance with an MA unless it is an excempt medicine or is distributed to another Member State (MS) where it can be legally used as an unlicensed veterinary medicine

Inspection of Manufacturers

Sites that are the subject of a manufacturing application are subject to a pre-approval inspection. Once a manufacturing authorisation has been granted, the site facilities and processes will be routinely inspected on an ongoing basis. The re-inspection frequency is risk- based and will depend on the level of compliance with GMP found at the last inspection.

Inspection Process

Pre-approval inspection

  • Before issuing a ManA, ManSA or authorisation to manufacture an ESPA product, the VMD will have carried out a successful pre-approval inspection of your site, and any site(s) where quality control testing or other activity is contracted to a third party (unless the site has already been inspected by the VMD or the MHRA).

Scheduled inspection

  • The VMD will periodically inspect your site(s) basis based on risk, although inspections will take place at least every 36 months.
  • The VMD will inspect production facilities in non-EU or non-EEA countries that do not have a Mutual Recognition Agreement (MRA) with the EU before issuing a GMP certificate.

Process: pre-approval and scheduled inspections

  • The VMD’s inspector will agree an inspection date with you and issue an agenda(ODT, 9.37KB) before the inspection detailing the main areas for inspection. You should look at this in preparing for inspections.
  • The VMD will issue an inspection deficiency report(ODT, 17.6KB) within 30 days of the inspection.
  • You should respond to any deficiencies cited within 30 days of receiving it.
  • Once the VMD is satisfied with your response to the inspection deficiency report, it will issue a final GMP inspection report(ODT, 14.6KB) report and GMP certificate within 90 days of the last day of the inspection.

GMP certificates are only issued to ManA holders and authorised manufacturers of ESPA products, contract QC test sites and to manufacturing facilities located outside the EEA .

 

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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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