Unlicensed Medicines

This monograph describes the minimum quality standards required for Unlicensed Medicines for human use. The statements in this monograph are intended to be read in conjunction with individual monographs for unlicensed medicines or formulated preparations in the Pharmacopoeia, together with relevant General Notices, Appendices and Supplementary Chapters.

Individual monographs are intended to apply throughout the period for which the formulation is expected to be satisfactory for use.

An unlicensed medicine is one which is prepared, at the request of an authorised healthcare professional, to address patient medicinal requirements, unmet by current licensed medicines, according to the Medicines Act 1968 (see Supplementary Chapter V). Such products will be manufactured under a manufacturing specials licence or prepared extemporaneously under the supervision of a pharmacist.

This general monograph applies to those dosage forms that are routinely manufactured or prepared as unlicensed medicines and are usually presented as conventional-release formulations. These include:

• — Capsules

• — Liquids for Cutaneous Application

• — Ear Drops and Lotions

• — Eye Drops

• — Preparations for Irrigation

• — Nasal Preparations

• — Oral Liquids

• — Oral Powders

• — Parenteral Preparations

• — Rectal Preparations

• — Tablets

• — Topical Semi-solid Preparations

• — Vaginal Preparations

The production of unlicensed medicines should only be undertaken by competent staff, within suitable facilities and using equipment appropriate for the scale of manufacture and the specific dosage form.

In the UK, batch manufacture should be undertaken in facilities holding a UK Manufacturer's Specials Licence in compliance with the standards of Good Manufacturing Practice.

The following requirements are applicable to unlicensed medicines manufactured or prepared in accordance with medicines legislation. They are not intended to apply to repackaging and assembly activities. The requirements were previously included as guidance in Supplementary Chapter V of the British Pharmacopoeia 2007.

Best practice guidance on the labelling and packaging of medicines advises that certain items of information are deemed critical for the safe use of the medicine (see MHRA Guidance Note No. 25: Best Practice Guidance on Labelling and Packaging of Medicines). 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 (highlighted in bold).

1. The common name of the product.

2. A statement of the active ingredients expressed qualitatively and quantitatively per dosage unit or for a given volume or weight.

3. Route of administration.

4. Instructions for use, including any special warnings.

5. The pharmaceutical form.

6. The contents of the container by weight, volume or by number of doses.

7. Excipients of known effect. For injectable, topical (including inhalation products) and ophthalmic medicines, all excipients.

8. 'Keep out of reach and sight of children'. [Note 1]

9. The expiry date expressed in unambiguous terms (dd/mm/yy).

10. Any special storage precautions.

11. The manufacturer's MS number, where appropriate.

12. The manufacturer's name and address.

13. The batch number.

14. Statutory warnings required by SI 1994/3144 for particular actives, e.g. aspirin, paracetamol, etc.

For small containers certain details may be omitted, but the label should contain, as a minimum, the following information:

1. The common name of the product.

2. A statement of the active ingredients expressed qualitatively and quantitatively per dosage unit or for a given volume or weight.

3. Route of administration.

6. The contents of the container by weight, volume or by number of doses.

9. The expiry date expressed in unambiguous terms (dd/mm/yy).

13. The batch number.

In such cases, the label for the outer packaging should contain all the relevant label information.

Note 1: This is a statutory requirement for relevant medicinal products.

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 medicines must comply 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. In addition, where specified, they must comply with the following tests.

Where the label indicates that the preparation is sterile, it complies with the test for sterility (Appendix XVI A). While it is expected that the formulated preparation will demonstrate pharmacopoeial compliance when tested, it is recognised that it might not be practicable to carry out the pharmacopoeial test routinely.

In the manufacturing, packaging and storage of oral liquids, suitable measures are taken to ensure their microbial quality complies with Pharmacopoeial requirements throughout shelf-life; recommendations for microbial limits are provided in the section on Microbiological Quality of Pharmaceutical Preparations (Appendix XVI D). If necessary, an antimicrobial preservative may be added unless the formulation is required to be preservative-free.

During the preparation, storage and use of preservative-free oral liquids, due consideration should be given to the additional risks of microbial contamination that exist for such preparations. Numbers of viable organisms in starting materials and primary packaging materials should be minimised. Storage conditions of the finished product should prevent contamination and inhibit microbiological proliferation. The product shelf life during storage and use should be based on the risk and probability that the product may fail to meet the requirements of Appendix XVI D.

A test to determine the pH of the oral solution or oral suspension may be applied. As the pH may be formulation dependant, limits are only included in specific monographs in cases where the stability of the active substance is affected by pH.

Carry out the test for dissolution described under dissolution test for tablets and capsules, Appendix XII B1, using Apparatus 2. Unless otherwise stated in the individual monograph use 900 mL of an appropriate dissolution medium (as suggested in Supplementary Chapter I E, Table 2.9.3.-5) and rotate the paddle at 50 rpm.

Shake the container containing the oral suspension being examined for 30 seconds and accurately remove a volume containing one dose at a depth of 1 cm below the meniscus. Introduce the dose to the medium in the dissolution vessel. If sink conditions cannot be obtained, testing a partial dose of the suspension (10% to 20% of the usual dose) is preferable to using a surfactant.

Operate the apparatus at the specified rate. Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the rotating paddle, not less than 1 cm from the vessel wall. Where multiple sampling times are specified, replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution medium at 37° or, where it can be shown that replacement of the medium is not necessary, correct for the volume change in the calculation. Keep the vessel covered for the duration of the test and verify the temperature of the medium at suitable times. Perform the analysis using a suitable assay method. Repeat the test with a further five additional doses.

Unless otherwise specified in the individual monograph, the value of Q is 75% of the stated amount at 45 minutes.

Allow a suitable volume of the oral suspension being examined to settle, undisturbed, for 24 hours. Shake the container for 30 seconds and accurately remove one dose (usually 5 to 10 mL) at a depth of 1 cm below the meniscus. Shake the container again for 10 seconds and remove another dose. Repeat this procedure until 10 doses of the suspension have been removed. Assay the 10 doses individually according to the method specified in the individual monograph.

The preparation complies with the test if each individual dose is between 85% and 115% of the average dose. The preparation fails to comply with the test if more than one individual dose is outside these limits or if one individual dose is outside the limits of 75% to 125% of the average content.