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 .