SC V Unlicensed Medicines
This section gives guidance to prescribers, manufacturers and suppliers of unlicensed medicines on the legal and ethical considerations of such medicines. It also provides guidance on the standards for the preparation and manufacture of unlicensed medicines.
Introduction
The term “unlicensed medicine” means either a medicine prepared under a Manufacturer’s ‘Specials’ Licence or a medicine that is prepared extemporaneously under the supervision of a pharmacist.
Unless exempt, medicines for human use must have a Marketing Authorisation (also known as a Product Licence) before being placed on the market in the UK. There is an exemption provided by the medicines legislation to allow the supply of unlicensed medicines which are also known as ‘Specials’1. A ‘Special’ may only be supplied to meet the special needs of an individual patient and may only be manufactured by the holder of a Manufacturer’s ‘Specials’ Licence. The decision on whether an individual patient has special needs is made by the authorised healthcare professional responsible for the patient’s care.
The UK medicines legislation also allows a pharmacist to prepare an unlicensed medicine for supply in accordance with an authorised healthcare professional’s prescription2. Such circumstances can arise where no licensed product is available or where the formulation of the licensed product is not suitable. This activity is known as extemporaneous preparation.
The use of unlicensed medicines in the UK is widespread, mainly in the hospital sector and also in primary care. There are a number of reasons for this including:
An unlicensed medicine by its very nature will not have been licensed by the UK Licensing Authority or the European Commission and, therefore, will not have been assessed by them for its safety, quality or efficacy. Since ‘Specials’ are manufactured in accordance with Good Manufacturing Practice (GMP), in facilities licensed by the Medicines and Healthcare products Regulatory Agency (MHRA), there is some assurance of the manufacturing quality and hence the safety related to quality. However, the intrinsic safety and efficacy of ‘Specials’ are not assessed and are the responsibility of the prescriber.
Legal Requirements
‘Specials’
The legislative provision for the supply of unlicensed medicines known as ‘Specials’ is contained in Article 5(1) of EU Directive 2001/83/EC, as amended3. This states inter alia that, in order to fulfil special needs, medicinal products supplied in response to a bona fide unsolicited order, and formulated in accordance with the specifications of an authorised healthcare professional, and for use by an individual patient under their personal direction, may be excluded from the requirements in the Directive to have a Marketing Authorisation. This exemption is transposed into UK law through The Human Medicines Regulations 2012 (“the 2012 Regulations”) under Regulation 167 which relates to the “Exceptions to Requirement for Marketing Authorisation etc” in order to fulfil special patient needs. Regulation 167 is subject to a number of conditions which are:
It should also be noted that ‘Specials’ may be imported to fulfil the special needs of an individual patient. Importation should be in accordance with the 2012 regulations relating to Manufacturing and Wholesale Dealing4 and importers of such products must hold the requisite licences. Imported ‘Specials’ are outside the scope of the General Monograph on Unlicensed Medicines. However, where an individual monograph exists for an imported ‘Special’, then the product must comply.
Extemporaneous Preparations
The 1968 Medicines Act (“the Act”) allows a pharmacist to prepare or dispense a product which does not have a Marketing Authorisation in response to a prescription from an authorised healthcare professional. The exemptions which apply to pharmacists are contained in Section 10 of the Act. Under the exemptions, the licensing requirements of the 2012 Regulations for a Marketing Authorisation or relevant Manufacturer’s Licence do not apply when preparing or dispensing a medicinal product in a registered pharmacy, a hospital, a care home service or a health centre, by or under the supervision of a pharmacist in accordance with a prescription given by an authorised healthcare professional. Under Section 10 of the Act a pharmacist may also prepare a stock of medicinal products for dispensing under the same conditions and procure the preparation or dispensing of an unlicensed product in accordance with the prescription of an authorised healthcare professional.
In addition, Regulation 4 of the 2012 Regulations sets out further provisions in relation to activities conducted under Section 10 of the Act which pharmacists have to follow. These provisions relate to information and labelling provisions that must appear on the packaging of a pharmacy prepared and dispensed medicine.
Ethical Considerations and Guidance
The underlying principle of medicines legislation is that, subject to specific exemptions, no medicinal product may be placed on the market without an appropriate Marketing Authorisation. The exemptions from the formal licensing requirement allow a practitioner to prescribe and a pharmacist to supply an unlicensed medicine subject to certain conditions. However, in these circumstances both the prescriber and the pharmacist have a duty of care to the patient receiving the unlicensed medicine.
In developing an unlicensed medicine an appropriate risk assessment should be undertaken, which includes consideration of the suitability and fitness of purpose of the drug product. The risk assessment should also consider the contribution of the excipients to the safety profile of the unlicensed medicine.
Following recommendations from the Commission on Human Medicines restricting the amount of chloroform in oral medicines, the use of chloroform as an ingredient in unlicensed preparations should be avoided.
The MHRA have issued guidance on the supply of Unlicensed Medicines known as ‘Specials’ in the UK which advises on the manufacture, importation, distribution and supply of such products5. It also advises that where a suitable licensed equivalent product is available, an unlicensed product must not be used.
The Royal Pharmaceutical Society (RPSGB) has issued guidance for registered pharmacies on preparing unlicensed medicines, the procurement and supply of ‘Specials’ and on the prescribing of ‘Specials’6,7,8. This guidance aims to support pharmacists and their teams to work with prescribers, patients and carers to ensure the safe and appropriate procurement and supply of ‘Specials’.
Since there is a greater demand for unlicensed medicines for the treatment of children, due to the lack of suitable licensed formulations, a joint committee of the Royal College of Paediatrics and Child Health (RCPCH) and the Neonatal and Paediatric Pharmacists Group (NPPG) has published a statement providing guidance to health professionals and parents who prescribe, dispense or administer medicines for children9. It recognises the need to use some unlicensed medicines in paediatric practice since for many medicines authorised for children there is no appropriate dosage form, whilst for other medicines there is no paediatric authorisation but their use is established. The RCPCH and NPPG Joint Committee on Medicines have also produced information leaflets for parents and older children on the use of unlicensed medicines10.
Communications to those patients or carers of patients who receive unlicensed medicines can be of paramount importance. Patients need to be reassured that unlicensed medicines are not “second-class” healthcare products and that the treatment has been carefully thought out by the prescriber and is in the best interests of the patient. Where a medicine has been manufactured in a licensed ‘Specials’ facility, the manufacturing activities will have been approved by the MHRA, thus providing some assurance of product quality. Patients and carers may not always know that the medicines they have received are unlicensed but both prescriber and pharmacists should be prepared to discuss these issues if they are raised.
Labelling of Unlicensed Medicinal Products
The labelling of medicines is a critical contributor to patient safety. Licensed medicines must comply with the requirements of EU Directive 2001/83/EC, Title V, Articles 54-69 as amended in respect of their labelling and Patient Information Leaflets. However, this regulatory requirement does not extend to unlicensed medicines. There is a need for a standard, consistent approach to the labelling of unlicensed medicines so that purchasers and suppliers are aware of the composition and status of the product and can make a more informed judgement with regard to their liabilities. This is particularly relevant to those products produced on a batch scale by licensed ‘Specials’ manufacturers.
Best practice guidance on the labelling and packaging of licensed medicines advises that certain items of information are deemed critical for the safe use of the medicine11. These critical items of information, which should be located together on the pack and appear in the same field of view, are: name, strength, route of administration, dosage and warnings. This guidance is equally applicable to unlicensed medicines. Advice on warning statements is also available and may be applicable to unlicensed medicines12.
Standards for Preparation and Manufacture of Unlicensed Medicines
In the UK unlicensed medicines will be prepared either by the holder of a Manufacturer’s ‘Specials’ Licence, within the exemption provided by Regulation 167 of the 2012 Regulations, or under the supervision of a pharmacist, within the exemption provided by Section 10 of the Act.
As a general rule, it is expected and advised that batch manufacture of medicines for human use should be undertaken in licensed manufacturing units and that preparation under the Section 10 exemption will be of individual products to fulfil the requirement of an authorised healthcare professional’s prescription. It is recognised, however, that there will be overlap between these two activities. Manufacturer’s ‘Specials’ Licence holders can manufacture single individual preparations and limited batch preparation is possible under the exemption provided in Section 10 of the Act. Manufacturer’s ‘Specials’ Licence holders are inspected regularly by MHRA GMP inspectors. The continuation of their licence is conditional upon compliance with GMP requirements. It is for this reason that it is advised that batch manufacture of unlicensed medicines is carried out in such licensed units. Unlicensed preparation activities under the supervision of a pharmacist are not inspected by the competent authority and are not independently audited. The following guidance applies equally well to products manufactured under a Manufacturer’s ‘Specials’ Licence and those prepared under the exemption provided by Section 10 of the Act , but is more relevant to preparation under the Section 10 exemption.
The manufacture or preparation of unlicensed medicines should be in accordance with appropriate current standards of GMP and, where applicable, good dispensing practice.
The manufacture or preparation of unlicensed medicines should only be undertaken by competent staff within suitable facilities and using equipment appropriate for the scale of manufacture and specific dosage form.
Where such a monograph is available, the medicinal substance and any excipients must comply with the specific monograph requirements of the Pharmacopoeia.
The medicinal substance and any excipients must also comply with the General Monograph for Substances for Pharmaceutical Use and, where appropriate, the provisions of Supplementary Chapter IV J on the Control of Impurities in Substances for Pharmaceutical Use and the General Monograph for Products with Risk of Transmitting Agents of Animal Spongiform Encephalopathies.
Unlicensed medicinal products must comply with the requirements of the General Monograph for Pharmaceutical Preparations, with the requirements of the General Monograph for Unlicensed Medicines and with the requirements of the relevant General Monograph for the specific dosage form. Where a BP monograph for a formulated preparation is available, the product must comply.
Further guidance on tests to be applied to the finished dosage form is also contained in Supplementary Chapters III C (Monograph Development: Guidance to Manufacturers), III D (Monograph Development: Methods of Analysis) and III F (Validation of Analytical Procedures).
Bibliography
1 Regulation 167 of The Human Medicines Regulations 2012 (Supply to fulfil special patient needs).
2 Section 10 of the Medicines Act 1968 (Exemptions for pharmacists).
3 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to Medicinal Products for Human Use.
4 Part 3 of The Human Medicines Regulations 2012 (Manufacturing and Wholesale Dealing).
5 MHRA Guidance Note No. 14: The Supply of Unlicensed Medicinal Products (‘Specials’).
6 Medicines Ethics and Practice – The professional guide for pharmacists, Royal Pharmaceutical Society, July 2016.
7 Professional Guidance for the Procurement and Supply of Specials, Royal Pharmaceutical Society, December 2015.
8 Prescribing Specials – Guidance for the prescribers of Specials, Royal Pharmaceutical Society, April 2016.
9 The use of unlicensed medicines or licensed medicines for unlicensed applications in paediatric practice, February 2000, Royal College of Paediatrics and Child Health.
10 Medicines for Children: Information for parents and carers, 2000. Royal College of Paediatrics and Child Health.
11 Best Practice Guidance on the Labelling and Packaging of Medicines; MHRA, 2012.
12 British National Formulary, Appendix 3: Cautionary and advisory labels for dispensed medicines.