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ARGOM Appendix 2: Guidelines on quality aspects of OTC applications
7. Control of finished product
This section of the application should include the following information:
- A critical summary (for applications in CTD format, the summary included in module 2.3.P.5 does not need to be duplicated).
- A copy of the release specifications applied by the medicine manufacturer.
- A copy of the expiry specifications (stability specifications are not generally suitable as expiry specifications - see 'Section 7.1 Finished product specifications').
- A justification for the specifications (consult 'Section 7.8 Justification of specifications').
- Test methods and validation data, where required (consult 'Section 7.9 Analytical procedures and validation').
The critical summary should include a brief description of the tests, limits and test methods at batch release and expiry [e.g. assay (capillary GC): 95.0 105.0%] together with a brief assessment of their suitability. For dissolution tests, brief details of the apparatus, medium and limit should be provided [e.g. dissolution (paddle at 50 rpm, 900 mL of water, Q=80% at 30 minutes)]. Where analytical test methods in the finished product specifications differ from those used for stability testing this must be stated. Where the expiry specifications differ from the batch release specifications, this should be clearly stated.
It is also recommended that the application include analytical batch data for the finished product for a minimum of two pilot or production scale batches of the product. This should preferably be in the form of Certificates of Analysis generated by the medicine manufacturer's laboratories.
7.1 Finished product specifications
The finished product specifications are a set of tests and limits that are applied to the product in order to ensure that every batch is of satisfactory and consistent quality throughout its shelf life. The specifications must monitor all parameters where variation would be likely to affect the safety or efficacy of the product; and must ensure compliance with any applicable default standard(s) or Therapeutic Goods Order(s).
Usually, tighter limits are applied at batch release to critical parameters to allow for analytical error during batch release testing and to allow for possible changes to the product during storage (e.g. decomposition of the active). Where different tests and limits are applied at batch release and expiry, this must be clearly indicated in the application.
The expiry specifications indicate the limits that the product is required to comply with if it was to be tested during the approved shelf life. The stability specifications (tests and limits applied in the stability studies) are not necessarily suitable as expiry specifications, as they often do not include all of the tests and limits that the product is expected to comply with over the shelf-life.
Note: The expiry specifications should include all of the tests that are included in the batch release specifications (or contain an annotation referring to these additional requirements); however, the inclusion of certain tests and limits in the expiry specifications, such as an identification test, does not imply a requirement for any actual testing additional to that specified in the release and stability specifications.
See further discussion of release and expiry specifications in 'Section 7.8 Justification of specifications'.
7.2 Medicines subject to individual pharmacopoeial product monographs
Where the product is the subject of an individual product monograph in only one of the BP, the Ph. Eur., or the United States Pharmacopoeia-National Formulary (USP/NF) (the default standard pharmacopoeias) then the requirements of that monograph, the general monograph for the dosage form if the relevant pharmacopoeia includes one, and any additional requirements referred to in the general notices of the relevant pharmacopoeia (such as appendices and general chapters) constitute a default standard for that product. The expiry specifications must include all of the tests and limits required by that default standard, however, an alternative validated test method may be substituted if it is demonstrated, for the product, that it is equivalent or superior to the test method used by the standard.
Where the product is the subject of individual product monographs in more than one of the default standard pharmacopoeias, then the expiry specifications must include all of the tests and limits required by one of the default standards (including requirements in general monographs, appendices, and general chapters where these are relevant). Sponsors should note that the Therapeutic Goods Order (TGO) 78 Standard for tablets and capsules currently requires tablets and capsules that are the subject of an individual product monograph in the BP to comply with that monograph, even when there is also a relevant USP monograph. This requirement is currently under review. It is not acceptable to combine the requirements of two or more default standards without ensuring full compliance with at least one default standard. The sponsor should nominate in the application the default standard that they intend to adopt.
It may also be necessary to include tests and limits to control critical parameters specific to the product that are not covered in the default standard monograph. For example, a test and limits for preservative content is generally required for products containing preservatives (see 'Section 9.6.6 Preservative efficacy').
The specifications must also ensure compliance with any relevant Therapeutic Goods Orders, for example, the TGO 77 Microbiological standards for medicines and TGO 78 Standard for tablets and capsules.
7.3 Medicines not subject to individual pharmacopoeial product monographs
If there is no individual monograph for the product, any relevant BP, Ph. Eur. or USP/NF general monograph for the dosage form will still constitute a default standard. The specifications for such products must include all of the requirements in at least one of these default standards. Sponsors should note that the general notices of the relevant pharmacopoeia may also require the product to comply with the requirements of any applicable appendices or general chapters.
The specifications must also ensure compliance with any relevant Therapeutic Goods Orders, as discussed above for products subject to individual pharmacopoeial monographs.
If there are individual monographs for similar products these should be consulted when determining appropriate tests and limits to include in the specifications. For example, for an oral tablet for which there is currently no pharmacopoeial monograph it may be useful to consult published monograph(s) for other oral dosage form(s) containing one or more of the same active ingredients (alone or in combination with different active ingredients).
7.4 Related substances
The finished product specifications should include tests and limits for substances related to the active substance (synthetic impurities and degradants).
For a product that is subject to the requirements of an individual default standard monograph which includes requirements for related substances, it will generally be adequate to include these requirements in the specifications. However, active substances from different suppliers may have different impurity profiles that are not addressed by the pharmacopoeial test procedure. Similarly, the excipients in a finished product can vary among manufacturers and may have the potential to cause the formation of impurities that are not addressed by the pharmacopoeial procedure. Manufacturers are expected to take these factors into account when verifying the pharmacopoeial tests and limits for use with the proposed product49.
For the same reasons, the absence of tests and limits for related substances should be justified even if the product is subject to the requirements of an individual default standard monograph that includes no requirements for control of related substances.
For products that are not subject to the requirements of an individual default standard monograph or Therapeutic Goods Order, the following guidelines apply.
- For products containing new active ingredients, degradation products should be reported, identified and/or qualified if they are present at levels above those described in the EU document Note for guidance on impurities in new medicinal products ICHQ3B(R) (CPMP/ICH/2738/99).
- For well established OTC medicines, when not subject to pharmacopoeial limits, the following expiry limits on impurities can generally be applied without a detailed justification:
- Individual impurities: not more than 1% (relative to the active)
- Total impurities: not more than 3% (relative to the active)
- For other products, such as those recently down-scheduled from S4, requirements for control of degradation products will be assessed on a case-by-case basis.
The results of stability studies should be taken into account when setting impurity limits. There may be some products for which lower limits on impurities are appropriate. Unless otherwise agreed to for a particular product, limits on impurities in finished products apply to impurities from all sources.
For products that have more than one active ingredient, the limits on impurities associated with one active are usually determined separately from the limits for impurities associated with the other active(s). In such cases, the limit on an impurity should usually be expressed relative to the content of the relevant active ingredient. Additional guidance can be obtained from the relevant appendices and general chapters of the BP, Ph. Eur. and USP/NF.
- See also USP <1226> Verification of Compendial Procedures
7.5 Tablets and capsules
Tablets and capsules must comply with either the TGO 78 Standard for tablets and capsules. Sponsors should also consult Guidance on Therapeutic Goods Order No.78 Standards for tablets and capsules for further clarification on the requirements for tablets and capsules. It does not form part of TGO 78 and is intended only to assist sponsors to achieve compliance with TGO 78.
7.5.1 Dissolution and disintegration testing
Where the TGO 78 requires compliance with a 'suitable' dissolution test, or where a dissolution test is considered appropriate for other reasons, for example modified release products, it is expected that the dissolution test method has been validated to assure product quality and performance. Any relevant dissolution test methods described in the BP and USP should be considered during the development of the dissolution method. The dissolution method and supporting validation data should be submitted for evaluation, including details of the apparatus, rotational speed, dissolution medium and limit.
Under TGO 78, tablets or capsules that are not required to comply with a dissolution test are required to comply with the relevant test for disintegration in the BP general monographs for Tablets or Capsules. Under these circumstances, the BP disintegration test and limits should be included in the expiry specifications, regardless of whether a dissolution test is also proposed.
For modified release products, the conditions under which the active substance is released, and the timing of release, are normally critical parameters for product performance. Therefore, modified release products will be expected to include appropriate dissolution testing in the finished product specification.
7.5.2 Subdivision of tablets
Where the directions for use permit the subdivision of tablets (e.g. 1/2 tablet doses) the efficacy of the break-mark(s) must be assessed during the development of the product, in respect of uniformity of mass of the subdivided parts, in order to ensure that the consumer will receive the intended dose. Test results should be submitted to demonstrate that this is the case. For products that are subject to the BP or Ph. Eur. as the default standard the sponsor must submit the results of testing according to the test detailed in the BP general monograph for Tablets - Subdivision of tablets.
7.6 Microbiological requirements
The TGO 77 Microbiological Standards for Medicines specifies the minimum microbiological requirements with which a medicine must comply throughout its shelf life.
The guidance document Guidance on Therapeutic Goods Order No. 77 Microbiological Standards for Medicines provides a plain English explanation of the various requirements of TGO 77 and their application. It does not form part of TGO 77 and is intended only to assist sponsors to achieve compliance with TGO 77.
For further information regarding microbiological requirements consult 'Section 9.6.5 Microbial content testing' and 'Section 9.6.6 Preservative efficacy', as well as 'Section 10 Microbiological testing'.
7.7 Solvent/Sterilant residues
Solvent residues must be appropriately controlled in the finished product, in accordance with the Residual Solvents requirements of the relevant default standard and the corresponding ICH guidance documents; which are listed in 'Section 2 Active substances: 2.2.4 Solvent/Sterilant residues'.
In particular, sponsors should ensure that no 'Class 1' solvents have been used in the manufacture of the medicine.
The limits applying to solvent/sterilant residues are also discussed in 'Section 2 Active substances, 2.2.4 Solvent/Sterilant residues' and 'Section 6 Control of excipients').
7.8 Justification of specifications
The justification for the finished product specifications should take into account the results from stability studies as well as tests and limits in relevant monographs. Where relevant, the justification may address relevant clinical or toxicological data. The tests and limits should also be considered in terms of the supporting validation data. A detailed justification for any unusual features in the finished product specifications should be included.
7.8.1 Release specifications
The limits applied at batch release should be justified in terms of their ability to ensure that the product will comply with the expiry specification throughout the product shelf life. Any changes or unusual variability in the results obtained in the stability studies should be taken into account. Usually, tighter limits are applied at batch release to critical parameters to allow for analytical error during batch release testing and to allow for possible changes to the product during storage (e.g. decomposition of the active).
The TGA expects that all of the tests included in the finished product release specifications will be performed on all batches at release, except where a reduced schedule of tests has been approved by the TGA.
A reduced schedule of tests at batch release (periodic, rotational or skip testing) is the testing of certain parameters at a predetermined interval or on pre-selected batches, rather than testing of every batch. An example of a reduced schedule of tests is testing every fifth batch of a tablet formulation for friability conditional on the first three production batches found to be satisfactory in this respect. Any proposal for a reduced schedule of tests at batch release must be detailed in the application and justified. The extent of justification required will depend on the type of product and parameter proposed for reduced testing. Details of the reduced schedule of tests must be included on the finished product release specifications.
7.8.2 Expiry specifications
Any expiry limits which are less stringent than those commonly applied to the relevant dosage form should be justified in detail.
Note: TGO 78 allow wider limits for content of some active ingredients.
Some commonly applied expiry limits are:
|In tablets and capsules:||92.5 - 107.5% of stated content as required by TGO 78|
|In most other products, e.g. topical products and oral liquids:||90.0 - 110.0% of stated content|
|Upper limit:||120% of stated content|
|Lower limit for preservative:||The lowest concentration for which effectiveness has been demonstrated by preservative efficacy testing in stability studies|
|Lower limit for antioxidants:||The lowest concentration for which absence of significant oxidation of the product has been demonstrated in stability studies|
For medicines that may reasonably be expected to contain significant quantities of ethylene oxide or ethylene chlorohydrin the limits are as described in the Note for Guidance on Limitations to the Use of Ethylene Oxide in the Manufacture of Medicinal Products (CPMP/ICH/159/01):
- Ethylene oxide: not more than 1 microgram per gram
- Ethylene chlorohydrins: not more than 50 micrograms per gram
Where the default standard has stricter specific requirements, these take precedence.
7.9 Analytical procedures and validation
Details must be provided for all analytical methods that are used in the finished product specifications and the stability studies, together with validation data where appropriate (e.g. for assay of active ingredient, preservatives, and related substances). Where the test methods used in the stability studies differ from those of the finished product specifications this should be clearly stated and justified. Where a test method is included in a relevant pharmacopoeial monograph, the pharmacopoeial reference must be given. Where a test method is not included in a pharmacopoeial monograph, a full copy of that test method must be provided.
Supporting validation data is required for all critical assay methods, including assay methods that are described in a relevant pharmacopoeial monograph. The sponsor cannot assume that a test method described in a pharmacopoeial monograph is suitable for all formulations to which the monograph applies.
Applications will not be accepted for evaluation where:
- the analytical methods used are not stated
- the results of validation testing are not given or where the issue of validation is not addressed.
The validation data for critical assays should be in accordance with the ICH guideline Note for Guidance on Validation of Analytical Procedures: Text and Methodology Rev 1 (CPMP/ICH/381/95). For some of the most common categories of tests, the performance parameters for which validation data are normally expected are summarised in the following table.
|Performance parameter||Identification test||Quantitative test for impurities||Limit test for impurities||Assay|
|Robustness||see note below|
+ Performance Parameter is normally evaluated
- Performance Parameter is not normally evaluated
-/+ Performance Parameter may be required in some cases
Note: Where robustness testing has not been performed as part of method validation, the suitability requirements that are applied in the test method should be comprehensive enough to control any potential lack of robustness that may be present.
Additional sources of information on method validation include the following (much of the guidance on validation of compendial procedures also applies to validation generally):
- BP Supplementary Chapter SC III F. Validation of Analytical Procedures
- USP chapters <1225> Validation of Compendial Procedures
Sources of information on requirements for establishing the suitability of compendial procedures for analysis of the proposed formulation include the following:
- information under the subheading Published Methods in BP Supplementary chapter SC III D. Monograph Development, stating what users can and cannot expect from published methods
- USP chapter <1226> Verification of Compendial Procedures
A copy of the validation report should be provided. The report should include (or be accompanied by) a summary clearly stating the results obtained for each parameter assessed, as well as the acceptance criteria and a conclusion as to whether the results were acceptable. Where a chromatographic procedure is used, the report should also include (or be accompanied by) a selection of relevant chromatograms associated with the validation of specificity. For example, reference chromatograms, sample chromatograms, placebo chromatograms, and chromatograms of known degradants and/or chromatograms obtained in forced degradation studies should be provided.
Note: The inclusion of this summary is recommended in order to facilitate evaluation of the data; however, for applications in CTD format where an appropriate summary is included in module 2.3.P.5, this does not need to be duplicated.
7.9.1 Stability indicating assays
Active ingredient assays should be demonstrated to be capable of reliably quantifying a decrease in the amount of the active ingredient due to degradation (i.e. a stability indicating assay). Pharmacopoeial methods are not necessarily stability indicating.
126.96.36.199 Well-known degradants
When the identity of all degradants is well known, sensitivity to degradation may be established by demonstrating that the known degradants do not interfere with the analysis. It may be appropriate to analyse known degradants as pure substances and also when mixed with excipients, sample extract and/or reference solution.
The potential for interference from excipient degradants should also be considered (refer to 'Section 188.8.131.52 Forced degradation studies').
184.108.40.206 Forced degradation studies
When the identity of the degradants is not clear or when the sponsor does not have access to authentic specimens of the degradants, forced degradation studies should be undertaken. Commonly used forcing degradation conditions include treatment with some or all of the following (as appropriate to the product):
- an aqueous solution of a mineral acid
- an aqueous solution of sodium hydroxide
- an aqueous solution of a strong oxidising solution such as hydrogen peroxide
- heating the product
- exposing the product to direct sunlight (or another source of ultraviolet light) for a prolonged period.
Interference by excipient degradants can also be assessed by subjecting placebo blends to the forcing conditions.
The following information should be provided for evaluation:
- tabulated recovery data for the non-degraded product and following treatment under the different degradation conditions.
- copies of relevant chromatograms (in the case of chromatographic assays), comparing the impurity profiles.
- results of peak purity analysis (for HPLC assays), if an appropriate detector and software are available.
- if the product contains more than one active, the sponsor should address whether degradants from one active can interfere with assay of the other active.
The primary purpose of forced degradation studies is to validate the assay method rather than to establish the stability of the finished product. In order to demonstrate that the assay method is sensitive to degradation, some degradation of the active ingredient must be shown. If degradation has not occurred under the conditions used, the study may be repeated using more forcing degradation conditions. Where degradation of the relevant active ingredient is intrinsically difficult to achieve, a justification should be provided for not submitting the usual data.
It is valuable to demonstrate that a decrease in the active ingredient content is accompanied by a corresponding increase in impurity content (sometimes referred to as 'mass balance'). Where the assay methods for the active and related substances differ it may be necessary to investigate both assays within the forced degradation study, in order to demonstrate that the degradation products can be detected using the related substance assay.