SC III C. Monograph Development: Guidance to Manufacturers

Bulk drug substances

Each monograph, taken as a whole, should provide a reliable basis for making an independent judgement as to the quality of the substance in the interests of the protection of the public. General guidance as to the types of test required and the level of control considered appropriate can be obtained by reference to current BP monographs for similar chemical entities where such are available. In general any monograph for a bulk drug substance should include the features listed below.

Attention is drawn to the General Notices of the Pharmacopoeia, to the general methods described in the Appendices, to the basis of pharmacopoeial requirements as described in Supplementary Chapter I and to other information provided in the Supplementary Chapters of the Pharmacopoeia.

1. Definition/Characteristics Brief description of physical form of material; whether hygroscopic. It would be helpful if information concerning polymorphism could be provided (see Supplementary Chapter I B).

2. Solubility Solubility in water, alcohol and at least one common organic solvent, expressed quantitatively or using defined BP terms.

3. Identification Qualitative tests capable of unequivocally establishing the identity of the substance. Infrared spectrometry is preferred, or if this is not possible, 2 or 3 identification tests to identify different characteristics of the substance may be used. A test for the counter ion should be included where appropriate.

4. Impurities (see also Supplementary Chapter I A) Both related substances and any other impurities that may be present in the substance as a result of the method of manufacture or from degradation on storage. It would be helpful to know the nature of such impurities, the reason for their presence (for example, by-product of synthesis, hydrolysis product, etc.), the amounts that may be encountered in material prepared under conditions of Good Manufacturing Practice and the manner in which the proportions may vary on storage. An indication of the toxicity of any impurities in relation to that of the substance itself and methods for their detection and control would enable the Committee preparing the monograph to decide whether control tests are necessary and, if so, the methods and limits to be applied. In many cases, it is possible to limit impurities in chromatographic tests using a dilute solution of the substance being examined, and this is the preferred approach, wherever possible. In other cases, for example, where the response factor of an impurity is significantly different from that of the substance (outside the range 0.8 to 1.2), or where a stringent limit is necessary for toxicity reasons, a reference material is required (see paragraph 11 below and Supplementary Chapter III E).

Impurities other than related substances that might require control include inorganic impurities and residues of solvents and reagents used during synthesis and purification. Non-specific purity tests such as light absorption, specific optical rotation and sulfated ash should also be considered.

5. Transparency In keeping with BP policy on monograph transparency a suitable statement will be added to appropriate new monographs for medicinal substances giving the identities of impurities known to be limited by the specifications. It is to be emphasised that such statements are not intended to be exclusive and other, unnamed impurities may also be limited. Manufacturers are requested to provide information for such statements (see paragraph 4 above).

6. Assay Method and proposed limits calculated with reference to the anhydrous, dried or solvent-free material as appropriate. For bulk drug substances, it has been BP policy generally to use a robust and precise method of assay (such as titration) rather than a specific, but sometimes less precise, stability-indicating method (such as liquid chromatography). Wherever possible, control of potential impurities is provided separately by means of specific impurity tests (see paragraph 4 above). It is appreciated, however, that a manufacturer may use, and therefore propose, a chromatographic method for both related substances and assay. In such circumstances, each case is judged on its merits on the basis of the data provided, which must relate to validated methods. Such methods normally require the establishment of a reference material of the substance with a declared content (see paragraph 11 below and Supplementary Chapter III E). Adequate means of demonstrating system suitability will need to be included in the monograph so that the analyst has an assurance that the results are accurate. As stated above, each monograph, taken as a whole, should provide a reliable basis for making an independent judgement as to the quality of the substance.

7. Other tests A test for water or for loss on drying is usually required.

8. Storage Any special storage conditions such as protection from light.

9. Labelling Any special labelling statements (see Supplementary Chapter I G).

10. Preparations Pharmaceutical dosage forms normally available and information on dose.

11. Samples A quantity of the material sufficient to carry out in duplicate all the tests and the assay in the proposed specification should be supplied (10 g is usually suitable). This sample should be taken from a typical production batch, that is, it should not be specially purified. In addition appropriate amounts of possible impurities should be supplied (0.1 to 0.5 g is usually suitable).

Many monographs require the use of one or more reference substances (BPCRS); these are established by the Laboratory before publication of the monograph (see Supplementary Chapter III E). If a reference substance for assay purposes is required (see paragraph 6 above) or for impurity control (see paragraph 4 above), please indicate if adequate supplies will be available. About 50 g of material is required to establish a reference material for an assay standard and about 10 g of a named impurity (see also Supplementary Chapter III E). If it is perceived that an ongoing supply of sufficient quantities of material(s) will not be possible, this should be drawn to the attention of the BP Secretariat so that an alternative approach may be considered.

When sending samples, Material Safety Data Sheets that comply with COSHH Regulations should be supplied for all materials including impurities, so that Pharmacopoeia staff are aware of possible hazards when handling these materials.

12. Supporting data Appropriate and relevant validation data relating to the proposed analytical procedures and methodology should be provided (see Supplementary Chapter III F). In particular, data to demonstrate the stability indicating nature of methods (i.e. forced degradation studies) and information identifying both synthetic impurities and degradation products should be provided. Additionally, appropriate and relevant batch and stability data to support the proposed specifications should be provided. This information will be kept confidential to the BP Secretariat and Laboratory and to the relevant Expert Advisory Group(s) of the British Pharmacopoeia Commission.

13. Advice The BP Secretariat is pleased to provide advice to manufacturers on the nature and extent of data required. It is appreciated that for some older products information on the identity of impurities and/or validation data for methods is not as substantial as that which is required for new chemical entities and advice in these cases is available. A list of contact points in the Secretariat is to be found in Supplementary Chapter III A.

Formulated preparations

Each monograph, taken as a whole, should provide a reliable basis for making an independent judgement as to the quality of the preparation in the interests of the protection of the public. General guidance as to the types of test required and the level of control considered appropriate can be obtained by reference to current BP monographs for the same dosage form of similar chemical entities where such are available. Reference should also be made to any general monograph for the dosage form in question for general requirements and any exceptions to, or modifications of, those requirements noted. In general any monograph for a formulated preparation should include the features listed below.

Attention is drawn to the General Notices of the Pharmacopoeia, to the general methods described in the Appendices, to the basis of pharmacopoeial requirements as described in the Introduction and Supplementary Chapter I and to other information provided in the Supplementary Chapters of the Pharmacopoeia.

1. Definition/Description A definition of the preparation in terms of the active ingredient(s) together with information on its presentation.

For sterile preparations (parenteral, ophthalmic and others) this should include information on the nature of the vehicle; the nature of any additives (eg antimicrobial preservatives, buffers) present; the method of sterilisation. In addition, for parenteral preparations information should be provided on whether it is a solution, a suspension, a dry powder or a concentrate for dilution.

For topical semi-solid preparations this should include information on the type of basis (water-in-oil, oil-in-water, etc) and the particle size of the active ingredient, if significant.

For tablets this should include whether or not they are coated. Where tablets are coated, the reason for coating should be provided.

Information concerning polymorphism should be included where relevant (see Supplementary Chapter I B).

2. Content statement Proposed limits as a percentage of the stated content of the active ingredient in the terms declared on the label (see Supplementary Chapter I F).

The purpose of the assay in preparation monographs is to determine whether the content of the active ingredient is within acceptable limits of the labelled claim and the limits are therefore of necessity stated in terms of the moiety declared on the label. That is, the same method of expression is used in the content statement as under the headings Assay and Labelling. The preferred means of expression is in terms of the therapeutically active part of the molecule. It should be noted that the mode of expressions chosen for the assay limits in the monograph for the bulk drug substance in no way circumscribes that which may be used in the monograph for the formulation.

3. Identification Identification tests should be based on those for the parent drug substance where applicable, with details of any necessary preliminary treatment such as extraction. Infrared spectrometry is preferred. A single liquid-chromatographic method for Identification, control of impurities, and Assay should be supplemented by an additional test for identification.

4. Impurities [As under Bulk drug substances] Additional information on any impurities arising on manufacture or storage of the dosage form.

The tests applied to the bulk drug substance, including those for impurities arising in manufacture of the bulk drug substance, should be applied, wherever possible - with any necessary modification - in order to demonstrate that material of pharmacopoeial quality has been used in making the formulation.

5. Transparency In keeping with BP policy on monograph transparency a suitable statement will be added to appropriate new monographs for formulated preparations giving the identities of impurities known to be limited by the specifications. It is to be emphasised that such statements are not intended to be exclusive and other, unnamed impurities may also be limited. Manufacturers are requested to provide information for such statements (see paragraph 4 above).

6. Assay The method of assay will not necessarily be that used for the bulk drug substance. For formulated preparations a specific, stability-indicating method is preferred. Such methods normally require the establishment of a reference material of the substance with a declared content (see paragraph 11 below and Supplementary Chapter III E).

7. Other tests Tests such as pH and clarity and colour of solution may be necessary depending on the type of dosage form. In addition, for single-dose preparations a test for uniformity of content and, in the case of solid dosage forms, a dissolution test may be required (see Supplementary Chapter I E).

8. Storage Any special storage conditions/containers.

9. Labelling Any special labelling statements (see Supplementary Chapter I G).

Please provide sample labels, outer packages, leaflets and a copy of the relevant Summary of Product Characteristics (SmPC) or data sheet.

10. Strengths available/Dose While no longer included in the published monograph, this information is of assistance during monograph development.

11. Samples A quantity of the formulation sufficient to carry out in duplicate all the tests (including those under paragraph 7) and the assay in the proposed specification should be supplied. Samples should be taken from a typical production batch.

The following suggested quantities are provided as a rough guide of the order of sample size for each strength of different dosage forms:

Liquid formulations

In addition appropriate amounts of possible impurities (arising from synthesis or degradation) should be supplied (approximately 200 to 500 mg, unless the impurity is required for use as a reference standard, see below)

Many monographs require the use of one or more reference substances (BPCRS); these are established by the Laboratory before publication of the monograph (see Supplementary Chapter III E). If a reference substance is required for assay purposes (see paragraph 6 above), or for impurity control (see paragraph 4 under bulk drug substances), please indicate if adequate supplies will be available. About 50 g of material is required to establish a reference material for an assay standard and about 10 g of a named impurity (see also Supplementary Chapter III E).

When sending samples, Material Safety Data Sheets that comply with COSHH Regulations should be supplied for all materials including impurities, so that Pharmacopoeia staff are aware of possible hazards when handling these materials.

12. Supporting data Appropriate and relevant validation data relating to the proposed analytical procedures and methodology should be provided (see Supplementary Chapter III F). In particular, data to demonstrate the stability indicating nature of methods (i.e. forced degradation studies) and information identifying both synthetic impurities and degradation products should be provided. Additionally, appropriate and relevant batch and stability data to support the proposed specifications should be provided. This information will be kept confidential to the BP Secretariat and Laboratory and to the relevant Expert Advisory Group(s) of the British Pharmacopoeia Commission.

13. Advice The BP Secretariat is pleased to provide advice to manufacturers on the nature and extent of data required. It is appreciated that for some older products information on the identity of impurities and/or validation data for methods is not as substantial as that which is required for new chemical entities and advice in these cases is available. A list of contact points in the Secretariat is to be found in Supplementary Chapter III A.