DEVELOPMENT PHARMACEUTICS AND PROCESS VALIDATION Guideline Title Development Pharmaceutics and Process Validation Legislative basis Directive 75/318/EEC as amended Date of first adoption April 1988 Date of entry into October 1988 force Status Last revised 1988 Previous titles/other None references Additional Notes This note for guidance concerns the application of Part 2, sections A.4 and B of the Annex to Directive 75/318/EEC as amended with a view to the granting of a marketing authorisation for a medicinal product. CONTENTS I DEVELOPMENT PHARMACEUTICS 1. INTRODUCTION 2. CONSTITUENTS 3. COMPOSITION 4. CONTAINER II PROCESS VALIDATION 3
DEVELOPMENT PHARMACEUTICS AND PROCESS VALIDATION I. DEVELOPMENT PHARMACEUTICS 1. INTRODUCTION Pharmaceutical development studies may need to be carried out to establish that the type of dosage form selected and the formulation proposed are satisfactory for the purpose specified in the application. They also aim to identify those formulation and processing aspects that are crucial for batch reproducibility and which therefore need to be monitored routinely. Because of the great variety in active substances and dosage forms, this note for guidance is only an illustration of the type of information which has been found useful in establishing the factors which affect quality of a finished product. 2. CONSTITUENTS 2.1 Active substances 2.1.1 Compatibility The compatibility of the active substance(s) with the excipients should, where necessary, be demonstrated. 2.1.2 Physical characteristics It may be necessary to study the effect of such parameters as e.g. crystal form, moisture content and particle size of the active substance on the formulation. The latter may be of importance in bioavailability, content uniformity, suspension properties, stability and for eye irritation studies. Having identified a parameter as being critical, its control should then be reflected in the active substance specification, or dealt with by other appropriate means. 2.1.3 Overage Overages are primarily employed to cover losses during manufacture, i.e. manufacturing overage, and/or during shelf life, stability overage. The inclusion of any overage should be justified. 2.2 Excipients 2.2.1 An explanation should be provided with regard to the function of the excipients in the formulation. 2.2.2 Excipient compatibility should be established where relevant. 5
3AQ1a 2.2.3 Where unusual excipients are used in the manufacture of the product, e.g. the matrix of a slow release preparation, full information on the composition and function of the excipient in the formulation of the product should be furnished together with any documentation which may be available to demonstrate safety of the raw material. A new substance introduced as an excipient will be regarded in the same way as a new active substance, unless it is already approved for use in food by the same route of administration. 3. COMPOSITION 3.1 Liquid dosage forms 3.1.1 Physical parameters a) p H Evidence should be presented to show that the effect of ph within the specified range of the formulation has been investigated. Consideration should be given to the effect of ph on active constituent(s), and, where relevant, on the antimicrobial efficacy. Should such a study show positive results any long-term effects would need to be investigated during stability studies. b ) others Depending on the formulation, such parameters as ease of dissolution and redispersion, particle size, aggregation, rheological properties, etc. should also be considered during pharmaceutical development studies. In the formulation of parenteral products, consideration may have to be given to such factors as tonicity adjustment, globule size of emulsions, particle size and shape as well as changes in crystal form, etc. 3.1.2 Additives preservatives, antioxidants, others. The concentration of additive(s) incorporated into the formulation should be shown by experimental results to be optimum for the intended usage. Consideration should therefore be given to such factors as storage, reconstitution and dilution before use and frequency of opening the pack when choosing suitable level(s) of additive(s) and designing tests to establish efficacy of a preservative system. Large packs intended for dispensing purpose may require more stringent testing. Both antibacterial and antifungal efficacy should be demonstrated and the test should include suitable positive and negative controls. Testing conditions and the results thereby obtained must be reported. 3.1.3 Compatibility with other products This is of particular importance for products to be administered intravenously. Where the data sheet gives instructions for dilution before administration, data should be presented to demonstrate physical and chemical compatibility with the recommended diluents over the recommended or anticipated period of use. 6
3.2 Semi-solid dosage forms 3.2.1 Physical parameters a) p H Evidence should be presented to show that the effect of ph within the specified range of the formulation, where relevant, including preservative activity, has been investigated. Where a significant effect is observed, any long-term effects would need to be investigated during stability studies. b ) others Where the active substance is suspended rather than dissolved, particle size control and particle size aggregation should be taken into consideration during development studies. Rheology studies may also need to be carried out during the development of semi-solids. 3.2.2 Additives preservatives, antioxidants, others. The concentration of additive(s) incorporated into the formulation should be shown by experimental results to be optimum for the intended usage. Consideration should therefore be given to such factors as storage, reconstitution, dilution before use and frequency of opening the pack when choosing suitable level(s) of additive(s) and designing tests to establish the efficacy of the preservative system. In such tests, both antibacterial and anti fungal efficacy should be demonstrated and the test should include suitable positive and negative controls. Testing conditions and the results thereby obtained must be reported. 3.3 Solid dosage forms 3.3.1 Dissolution The dissolution apparatus used in the testing of both unmodified and modified release preparations should be either of those described in the European Pharmacopoeia. Where these prove unsuitable, dissolution test equipment described in the National Pharmacopoeia of the Member State should be adopted as second choice, or, failing this, any other method. However, justification for the use of a method other than European Pharmacopoeia must be put forward. a) Unmodified release preparations Dissolution tests must be performed during development and stability studies in order to establish whether such testing would need to be done during stability studies and routinely as part of the finished product specification. b ) Modified release preparations The choice of dissolution test conditions and release rates adopted for assessing batch reproducibility needs to be justified. This should take account of in vivo studies carried out to establish the release and absorption profile of the product and would, if feasible, consist of a study correlating in vitro release rates to in vivo results to allow meaningful batch 7
3AQ1a reproducibility evaluation. Such a correlation would be of particular importance for medicinal products containing active substances with a narrow therapeutic window. A significant change in composition, method or site of manufacture or equipment, control tests on starting materials or finished product may however necessitate further in vitro correlation studies or in vivo bioavailability studies. 3.3.2 Homogeneity The European Pharmacopoeia includes a requirement for uniformity of content of singledose preparations where the amount of active constituent is less than 2 mg per dose or less than 2% by mass of the total mass. Notwithstanding this requirement, the adequacy of the mixing process in obtaining the required homogeneity of the mixture ought to be considered for all solid dose forms i.e., tablets, powders, etc. 4. CONTAINER Appropriate studies should be performed to demonstrate the integrity of the container and closure. A possible interaction between product and container may need to be considered. 4.1 Sorption to container Data should be presented to show that consideration has been given to the possibility of sorption of the active constituent(s) and additive(s) from liquid or semi-solid formulations i f relevant to safety or stability. These phenomena are known to occur with rubber closures and with both glass and plastic containers and administration sets. Where evidence exists for significant sorption to administration sets, the data sheet should include an appropriate reference to this fact. 4.2 Leaching Data should be presented to show that there is no significant leaching of any pack component, including label adhesive, into liquid or finely divided solid preparations over the shelf life period, where relevant. 4.3 Dose reproducibility If a dosing device is used, evidence should be presented that a reproducible dose of the product is delivered under testing conditions, which, as far as possible, are relevant for the use of the product by the patient. 8
II. PROCESS VALIDATION Whereas development pharmaceutics is concerned with establishing that the proposed formulation is satisfactory for the purpose specified, process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality. While process validation is generally a concept more closely associated with Good Manufacturing Practice (GMP) and therefore falling into the area of inspections, if a non-standard method of manufacture is used or if certain aspects of the method of manufacture are crucial for product quality, efficacy or safety but cannot necessarily be detected by analytical means, data on process validation may be required i n applications for marketing authorisation for a medicinal product. Areas mostly concerned are process environment, process equipment and the manufacturing process itself, the latter being the most important one. Thus data may be required to establish e.g. that: non-standard sterilisation conditions provide an acceptable level of assurance of product sterility, or the manufacturing process for a modified release system will only vary to an extent that will still yield a product of the desired quality and not have any effect on product efficacy or safety. 9