QUALITY OF PROLONGED RELEASE ORAL SOLID DOSAGE FORMS Guideline Title Quality of Prolonged Release Oral Solid Dosage Forms Legislative basis Directive 75/318/EEC as amended Date of first adoption October 1992 Date of entry into November 1992 force Status Last revised 1992 Previous titles/other None/ III/3172/92 references Additional Notes This note for guidance concerns the application to prolonged release oral solid dosage forms of Part 2, sections B, D, E and F of the Annex to Directive 75/318/EEC as amended, with a view to the granting of a marketing authorisation for a new medicinal product. CONTENTS 1. INTRODUCTION 2. DEFINITIONS 3. DEVELOPMENT PHARMACEUTICS 4. MANUFACTURING PROCESS VALIDATION 5. CONTROL TESTS 6. STABILITY 7. CHANGES TO PRODUCTS 167
QUALITY OF PROLONGED RELEASE ORAL SOLID DOSAGE FORMS 1. INTRODUCTION Pharmaceutical dosage forms may be developed in which the rate of release of active substance(s) has in some way been modified compared with conventional formulations. Such modification in release of active substances may have a number of objectives, but the intention of this note for guidance is to cover those formulations in which the release of the active substance is prolonged in some way in order to maintain therapeutic activity, to reduce toxic effects or for some other therapeutic purpose. The details required in the application for marketing authorisation will reflect: the therapeutic intention the nature of the active substance the nature of the formulation the route of administration and data must be provided in the various sections of the dossier in support of the application taking into account these various requirements. The note for guidance will cover the various parts 2.A to 2.F of the application for marketing authorisation and highlight areas which need to be addressed. It is clear therefore that this note for guidance will cross-refer to other quality guidelines, to the Notice to Applicants and in particular to the note for guidance Clinical Testing of Prolonged Action Forms with Special Reference to Extended Release Forms. The note for guidance concerns quality aspects, including in vitro testing, of oral solid dosage forms in which release of active substance forms the rate-limiting step in absorption. While the note for guidance is intended to be specific for prolonged release oral solid dosage forms, many of the principles discussed will be relevant to other prolonged action dosage forms intended for administration via other routes. 2. DEFINITIONS It is important to clearly define the terminology used to describe the different types of release models to which the note for guidance relates. The definitions of various types of release characteristics should be considered in relation to the pharmacokinetic properties and to the therapeutic intention of the formulation (see note for guidance Clinical Testing of Prolonged Action Forms with Special Reference to Extended Release Forms), and are correlated as closely as possible with pharmacopoeial definitions. The more general terms prolonged release can be applied to a range of different release models; terms such as controlled release and sustained release are looser than those defined and should be avoided. 169
3AQ19a 2.1 Modified release This term is defined in the European Pharmacopoeia as a modification of the rate or place at which the active substance is released. Modified release products cover a wide range of release models, the principal types of which would include delayed release and prolonged release products. It is the intention of this note for guidance to focus only on pharmaceutical aspects of prolonged release oral solid dosage products. 2.1.1 Delayed release A modified release product in which the release of active substance is delayed for a finite lag time, after which release is unhindered [e.g. enteric coated or Gastro resistant (Ph. Eur.) oral tablets or capsules which remain intact in the stomach and only disintegrate i n the higher ph of the small intestine]. Delayed release results in a longer Tmax but with Tmax and elimination half life unchanged. 2.1.2 Prolonged release A product in which the rate of release of active substance from the formulation after administration has been reduced, in order to maintain therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose. 3. DEVELOPMENT PHARMACEUTICS 3.1 Therapeutic objectives The therapeutic objectives and rationale for developing the prolonged release product should be provided. Pharmacokinetic and physico-chemical characteristics of the active substance relevant to the development of the product should be given. 3.2 Principle of the prolonged release system The prolonged release system should be described: the manner in which prolonged release is intended to be achieved (membrane type, matrix, etc.); single non-disintegrating unit or multi-unit pelletised preparation etc.; release mechanism and kinetics if known (diffusion, erosion, osmosis, etc. or combinations of these). 3.3 Testing of the prolonged-release system 3.3.1 In vitro testing The release rate should be tested in vitro by a dissolution test method which has been shown to discriminate between batches with acceptable and unacceptable in vivo performance. Test conditions providing the most suitable discrimination should be chosen. The dissolution apparatus should be one of those described in the European Pharmacopoeia. The continuous flow-through method of the European Pharmacopoeia monograph may be of 170
particular value in testing poorly soluble substances. The use of methods other than the official methods in the European Pharmacopoeia should be justified. The choice of rotation speed should be justified by carrying out the test at different speeds and the speed giving appropriate discrimination between batches with acceptable and unacceptable bioavailability should be chosen. The test medium should preferably be aqueous-based; organic or aqueous-organic media should be avoided. For poorly soluble substances, a minimal content of an appropriate surfactant may be added. Buffer solutions at a number of ph values spanning the physiological rate (ph 0.8-2, stomach; ph 5-6.5, jejunum; ph 6-7.5, ileum; Davis et al 1989) should be used to determine the relationship between dissolution and ph. The data obtained could usefully be represented using three-dimensional dissolution profiles (i.e. % dissolved as a function of time and ph). In order to achieve adequate discrimination, it may be necessary to limit the solubility of the medicinal product and still achieve sink conditions in the dissolution medium. It may also be necessary to consider the ionic strength and surface tension of the medium. The volume of medium used should preferably ensure sink conditions which may be assumed if the amount of substance in solution does not exceed 30% of the saturation concentration. The solubility of the substance in the chosen dissolution medium should be stated. Identical test conditions should be used for different strengths of the same product. The robustness of the dissolution test should be determined by examining the effect on the dissolution rate of variations in temperature, ph and speed of rotation. Dissolution profiles should be determined for: each strength of the prolonged release product if more than one strength is to be marketed; halved tablets where the release mechanism permits tablets to be broken in half for dosage purposes; any changes in the composition of the product during development. At each time point individual dosage unit results (n _ 6), the mean value and a measure of variability should be presented. The definitive dissolution profile and the corresponding specification will be based on i n vitro results of batches used in in vivo testing and will provide an assurance that batches will routinely give the desired in vivo behaviour. It may be necessary to validate the specification for any variations in the substance or excipients, e.g. the particle size or polymorphic form of the active substance, the gelling properties or particle size of the release-controlling excipients. The content of any key excipient which has a determining effect on the release of the active substance should not vary outside validated limits. These limits should be established on a case by case basis during the development of each product. 3.3.2 In vivo testing A summary of the bioavailability testing should be given. The data should include batch numbers, formulations (if different from the proposed marketing formulation) and dissolution results of batches used in in vivo studies. 171
3AQ19a Bioavailability studies should preferably be performed on at least pilot production scale batches. Where these are not available, studies could be performed on non-production scale batches provided it is demonstrated by valid in vitro testing that subsequent production batches comply with the same model. 3.3.3 In vitro-in vivo comparison To justify the specification limits of the in vitro dissolution test, an attempt should be made to establish a meaningful correlation between in vitro release characteristics and In vivo bioavailability parameters. In order to accomplish this, a number of techniques may be employed. These include, In order of decreasing predictive power: a) comparison of the in vitro dissolution curve of the product with the in vivo dissolution curves generated by deconvolution of plasma level data or by other appropriate methods; b) comparison of the mean in vitro dissolution time of the product to either the mean i n vivo residence time or the mean in vivo dissolution time of the product derived by using the principles of statistical moment analysis; c) comparison of the mean in vitro dissolution time to one mean pharmacokinetic parameter, e.g. Tmax. Other approaches are acceptable especially if the above methods fail to demonstrate a correlation. Examples of other approaches include demonstrating bioequivalence of the proposed formulation to formulations with dissolution profiles at the upper and lower limits of the specification, or alternatively, the specification limits may be derived from the spread of in vitro dissolution results of batches used in bioavailability testing the choice of approach should be justified by the applicant. 4. MANUFACTURING PROCESS VALIDATION Precise details of the manufacturing process should be given. Critical process parameters which can significantly affect the release of the substance (e.g. tablet hardness, coating procedure, moisture content) should be identified. If an in vitro-in vivo correlation has been established, limits for the critical parameters should be validated by dissolution testing of the product made under different processing conditions to demonstrate that allowable variations in these parameters do not result in unacceptable changes to the dissolution profile. If the manufacturing process has been validated using small-sized batches the effect of scale up on the dissolution characteristics of the product should be established. 5. CONTROL TESTS 5.1 In-process (if necessary) A dissolution specification which may be applied to Intermediate products (e.g. cores, pellets) may be the same or different from that to be applied to the finished product. If different, an explanation for the limits chosen should be provided. 172
5.2 Finished product The finished product specification normally includes a dissolution test. The dissolution specification is of importance not only to ensure consistent substance release from batch to batch at time of manufacture but also to set acceptance limits for the dissolution of the product during its shelf life. The dissolution specification should be deduced from the profile(s) obtained during the development of the product and revalidated with at least pilot production scale batches. Selection of specifications should take into account pharmacokinetics, pharmacodynamics and in vitro assay precision. The specification should clearly state the number of dosage units to be tested and whether or not the limits apply to individual dosage unit results or to the mean value. In the latter case the individual dosage unit results should be controlled so that they do not lie substantially outside the specification limits. If retesting is proposed in the event of non compliance with the specification the number of units to be retested and the limits to be applied should be specified and justified. A minimum of three points should be included in the specification: an early time point to exclude dose dumping at least one point to ensure compliance with the shape of the dissolution profile and one to ensure that the majority of the substance has been released. Where both upper and lower limits are specified at any time point the difference between them should not usually exceed 20% of the labelled content of active substance in the formulation unless wider limits have been shown to provide reproducible and acceptable i n vivo performance. Where an in vitro-in vivo correlation has not been satisfactorily established it may be necessary to carry out additional control tests on the finished product. For example the content of any release-determining excipients may need to be controlled within an upper and lower limit on each batch of product (see note for guidance Specifications and Control tests on the Finished Product). 5.3 Validation of the dissolution assay Analytical validation is required for the dissolution assay procedure (see note for guidance Validation of Analytical Procedures: Methodology). The assay method should be validated for specificity and linearity over the expected concentration range; accuracy and precision should be determined at the low as well as the high end of the expected concentration range. The stability of the active substance in solution in the medium should be addressed. 5.4 Batch results Batch analytical results should be provided for at least three batches one of which should be production scale for each product strength. Individual dosage unit dissolution results should be included. 6. STABILITY It must be demonstrated that the dissolution profile of the active substance is maintained within specification throughout the proposed shelf life of the product. The results of dissolution testing should include mean values of individual dosage units together with maximum and minimum values for all the batches undergoing the stability tests. 173
3AQ19a 7. CHANGES TO PRODUCTS Where the dissolution specification has been correlated with in vivo results minor changes to the data may be acceptable on the basis of in vitro testing. Minor changes include changes to the composition (e.g. nature and/or quantity of excipients which do not influence the release characteristics) method or site of manufacture or manufacturing equipment. Other changes may however necessitate further in vitro-in vivo correlation studies or in vivo bioavailability studies. 174