Table 3 List of FPP common deficiencies in the 3.2.P section of the CTD recommended by SAHPRA for non-sterile products finalised by the pre-registration unit between 2011 and 2017
Subsection | Deficiency | Amount | % overall |
|---|---|---|---|
3.2.P.1 Description and composition of the FPP | |||
3.2.P.1 | Include an indication that water or other solvents are not present in the FPP since they have been eliminated during the manufacturing process | 34 | 14 |
3.2.P.1 | State the polymorphic form of the API(s) used in the unitary batch formula | 52 | |
3.2.P.1 | If a potency adjustment for the API has to be made, a statement to the effect that the actual quantity of the active will depend on the potency and the Pharmaceutical ingredients Inactive (IPI) that will be used to adjust the bulk quantity should be made. The manner in which the adjustment will be made should also be specified | 48 | |
3.2.P.1 | Include the grades of all the IPIs used in the formulation, or the functionality specification of the IPI, if applicable. Indication that it is a pharmaceutical grade is not sufficient | 101 | |
3.2.P.1 | The purpose of each IPI should be stated briefly. If the IPI is used for multiple purposes in the formulation, each purpose should be mentioned | 31 | |
3.2.P.1 | The Colour Index Numbers (Foodstuffs, Cosmetics and Disinfectants Act, 1972 Regulation Food Colourants) or the colourant reference number in accordance with the European directive of colourants for those used in the formulation | 26 | |
3.2.P.1 | The theoretical quantity of the base of the active pharmaceutical ingredient (API) should be stated if a compound, e.g., hydrate, solvate, salt is used | 19 | |
3.2.P.1 | The description of the FPP (including scoring) is incomplete and does not concur with other relevant sections in the dossier such as 3.2.P.5.1 and Module 1.3 | 32 | |
3.2.P.1 | The theoretical mass must be indicated for uncoated tablets. In the case of coated dosage forms, the theoretical mass of the core, coating material, as well as the total mass of the dosage form/unit should be indicated | 48 | |
3.2.P.1 | Fill mass, type of gelatine used as well as the capsule size, composition and mass of the capsule should be indicated | 21 | |
3.2.P.1 | The overage used for the active pharmaceutical ingredient (API) should be indicated as a footnote and justified in 3.2.P.2.2 | 12 | |
Other | 19 | ||
443 | |||
3.2.P.2 Pharmaceutical development | |||
3.2.P.2.1 Components of the pharmaceutical product | |||
3.2.P.2.1 | A Pharmaceutical Development Report (generally of not more than 25 A4 pages) should be submitted with each application | 13 | 3.8 |
3.2.P.2.1 | Provide a brief summary of the synthesis of the API including a brief discussion of the physico-chemical characteristics of the API which are relevant to the final product | 23 | |
3.2.P.2.1 | Include a discussion of the stability of the final product formulation and conclusion on stability and shelf-life allocation in accordance with the P&A CTD guideline | 10 | |
3.2.P.2.1 | Explain the difference in specific excipients between the test and reference product | 11 | |
3.2.P.2.1 | Submit the compatibility studies of the API-IPI used in the formulation to confirm that these are compatible with each other | 23 | |
3.2.P.2.1 | Results from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., bioequivalence) should be discussed | 45 | |
3.2.P.2.2 Final pharmaceutical product | |||
3.2.P.2.2 | The reason for the overage should be stated/justified, e.g., with reference to batch results, in 3.2.P.2.2.2 | 21 | 1.4 |
3.2.P.2.2 | Justify the choice and quantity of excipients used in the formulation | 23 | |
3.2.P.2.3 Manufacturing process development | |||
3.2.P.2.3 | The discriminatory nature of the selected dissolution medium should be illustrated | 32 | 2.0 |
3.2.P.2.3 | Provide justification of the selected dissolution quality control (QC) medium with the inclusion of a surfactant | 34 | |
3.2.P.2.4 Container closure system | |||
3.2.P.2.4 | Submit the discussion on the suitability of the formulation with the primary packaging system to confirm the acceptability of the proposed primary packaging | 34 | 1.2 |
Other | 5 | ||
274 | |||
3.2.P.3 Manufacture of the FPP | |||
3.2.P.3.3 Description of manufacturing process and process controls | |||
3.2.P.3.3 | The description of the manufacturing procedure must include duration of treatment, manufacturing conditions (temperature and humidity) and specifications for machine settings and capacity | 83 | 13 |
3.2.P.3.3 | No provision has been made to bulk storage before packaging. Indicate the nature of the containers and maximum period the core and/or film-coated tablets may be stored (bulk) before final packaging. Submit information and provide supporting data with regard to holding time studies. This includes bulk holding time for cores prior to coating as well as container used | 97 | |
3.2.P.3.3 | The manufacturing process flowchart is inadequate, include the in-process controls, hold times for processing steps and other additional controls to ensure completeness | 23 | |
3.2.P.3.3 | The proposed holding times for intermediate products should to be included in the calculation of the shelf-life; they should not exceed 25% of the shelf life and if more than 30 days stability data should be submitted | 29 | |
3.2.P.3.3 | Describe the tablet compression procedure and compression speed included as well as coating parameters used | 7 | |
3.2.P.3.3 | The leak test, sealing test and adhesiveness for the blister packs must be described | 11 | |
3.2.P.3.3 | Drying time must be indicated and moisture content to which the granules are dried must be stated | 24 | |
3.2.P.3.3 | State the sieve sizes and mixing/blending speed during manufacture of the product as well as duration of stirring and drying temperature | 76 | |
3.2.P.3.3 | A brief description of the packaging procedure must be provided | 33 | |
3.2.P.3.3 | Fluid bed drying conditions must include inlet and outlet air temperature | 6 | |
3.2.P.3.3 | The manufacturing process outlined is inaccurate in comparison to the description and validation report | 17 | |
3.2.P.3.4 Control of critical steps and intermediates | |||
3.2.P.3.4 | The in-process control tests and frequency must be included as well as expansion of specifications for the granulate to include moisture content | 88 | 7.5 |
3.2.P.3.4 | Specification for uniformity of content of the divided tablet must be included and blend uniformity as an in-process test | 41 | |
3.2.P.3.4 | The limit for tablet hardness must be included as an in-process test and limits should be expressed in Newton and inclusion of the friability test | 43 | |
3.2.P.3.4 | Include the test for friability for uncoated tablets as an in-process control or in the final specifications | 24 | |
3.2.P.3.4 | Confirm that Batch Manufacturing records and packaging documents will be available upon request or during inspection | 10 | |
3.2.P.3.4 | Limits proposed on the critical steps were not accepted and further justification is required | 32 | |
Other | 6 | ||
3.2.P.3.5 Process validation and/or evaluation | |||
3.2.P.3.5 | Submit a bulk formula for each batch size for each strength as three master manufacturing batch records were submitted with different batch sizes | 4 | 2.2 |
3.2.P.3.5 | Include validation report for three commercial batches to confirm reproducibility and batch to batch consistency of the manufacturing process | 43 | |
3.2.P.3.5 | Provide validation protocol and/or report for the proposed batch size | 25 | |
722 | |||
3.2.P.4 Control of inactive pharmaceutical ingredients | |||
3.2.P.4.1 Specifications | |||
3.2.P.4.1 | Quantitative and qualitative composition of the colourant must be included | 26 | 6.2 |
3.2.P.4.1 | Provide a declaration that the IPI, e.g., talc is asbestos free | 7 | |
3.2.P.4.1 | Submit the certificate of analysis for each of the IPIs used | 32 | |
3.2.P.4.1 | Include specifications and control procedures of the IPIs used in the formulation for non-pharmacopoeial | 32 | |
3.2.P.4.1 | Provide evidence that the IPIs are transmissible spongiform encephalopathies/bovine spongiform encephalopathies (TSE/BSE) free | 44 | |
3.2.P.4.1 | The related substances controlled in the IPIs should be quantified | 45 | |
3.2.P.4.1 | Provide the identification used for the colourant or dye, for example a UV spectrum | 16 | |
3.2.P.4.1 | Confirm that the colourant complies with purity criteria of the Foodstuffs, Cosmetics and Disinfectants Act, Act 54 of 1972 or with directives of the European countries or the register of the USFDA | 32 | |
3.2.P.4.3 Validation of analytical procedures | |||
3.2.P.4.3 | Validation data were not submitted for analytical testing methods of non-pharmacopoeial substances. Submit | 16 | 0.9 |
Other | 13 | ||
263 | |||
3.2.P.5 Control of FPP | |||
3.2.P.5.1 Specifications | |||
3.2.P.5.1 | The dissolution specification must be brought in line with the profiles of the biostudy and reference products for this parameter. All the strengths of both test and reference products demonstrated very rapid dissolution whereas the specification is not in line with the definition of rapid dissolution | 139 | 15 |
3.2.P.5.1 | The dissolution specification for release and shelf-life must correspond | 16 | |
3.2.P.5.1 | Tighten the assay release and stability specification to 95–105% in accordance with the PA guidelines and include this as a percentage label claim | 80 | |
3.2.P.5.1 | The final product specification must be expanded to include a limit for residual solvents and the relevant validated control procedure must be described | 16 | |
3.2.P.5.1 | The FPP specifications should include an additional identification test | 23 | |
3.2.P.5.1 | Include the leak test to confirm that the product is protected from moisture in the final FPP specifications or as an in-process control | 11 | |
3.2.P.5.1 | Include all the parameters to be controlled for the Final product, i.e. FPP specifications at release and shelf life | 9 | |
3.2.P.5.1 | Tighten the specifications for water content taking into consideration the increased formation of impurities by water hydrolysis and the fact that the stability results do not justify the proposed specification | 22 | |
3.2.P.5.1 | Include authorised documentation code and date of authorisation for release and stability specifications (version control) | 19 | |
3.2.P.5.1 | Bring the degradation/related impurity limits of the FPP in line with the ICH guideline Q3B | 16 | |
3.2.P.5.1 | Tighten specifications for Total impurities to be in line with the stability and batch analyses results | 48 | |
3.2.P.5.1 | Tighten the shelf life specification limits of the specified and unspecified impurities, as they appear to be wider | 45 | |
3.2.P.5.1 | Tighten specifications for disintegration time since the final product is highly soluble | 11 | |
3.2.P.5.1 | Include a test for microbial purity in the FPP specifications | 9 | |
3.2.P.5.1 | Bring the FPP specifications in line with those indicated in a recognised pharmacopoeial monograph | 15 | |
3.2.P.5.2 Analytical procedures | |||
3.2.P.5.2 | The pore size of the filter must be stated in the dissolution method description or justified | 21 | 1.8 |
3.2.P.5.2 | Dissolution method should specify inline filtration or filtered immediately. The method for withdrawal and filtration of samples must ensure that dissolution of undissolved particles does not occur after sampling | 38 | |
3.2.P.5.3 Validation of analytical procedures | |||
3.2.P.5.3 | Submit validation data for the assay method of the API, residual solvents and related substances/degradation products | 28 | 2.9 |
3.2.P.5.3 | The following inconsistencies were observed in the submitted validation data which required clarification: nature of stress used in stress samples used in validation not confirmed, reference standard not calibrated against an internal standard; linearity of potency assay not conducted, detection limit for some specified related substances/residual solvents, acceptance criteria for system suitability tests and other parameters not justified | 32 | |
3.2.P.5.3 | Representative chromatograms should be submitted for validation of analytical methods | 21 | |
3.2.P.5.3 | Submit validation data of forced degradation studies in the assay method | 12 | |
3.2.P.5.4 Batch analysis | |||
3.2.P.5.4 | Submit a complete analysis data of at least two batches | 23 | 0.7 |
3.2.P.5.6 Justification of specifications | |||
3.2.P.5.6 | Justification of specifications was not submitted and requested | 11 | 1.3 |
3.2.P.5.6 | The proposed justification of specifications is inadequate and not accepted. An amendment is proposed in 3.2.P.5.1 | 21 | |
Other | 11 | ||
697 | |||
3.2.P.6 Reference standard or materials | |||
3.2.P.6 | Supply information on the primary reference standard used to confirm traceability if pharmacopoeial and describe how the secondary reference standards were established | 19 | 3.7 |
3.2.P.6 | Provide certificate of analysis (CoAs) of the reference standards used | 32 | |
3.2.P.6 | Provide the CoAs showing the results of the identification, purity and content of the reference standards used | 43 | |
3.2.P.6 | Characterisation of the reference and impurity reference standards not complete or inadequate | 12 | |
Other | 14 | ||
120 | |||
3.2.P.7 Container closure system of the FPP | |||
3.2.P.7 | Include an identification test, e.g., IR of the immediate container closure system | 31 | 7.1 |
3.2.P.7 | Give a specification and demonstrate the integrity for the heat seal bond strength as well chemical nature and identification test for this heat seal lacquer in the aluminium foil | 27 | |
3.2.P.7 | Specify the printing details on blisters and give a control test for the quality of the printing | 7 | |
3.2.P.7 | The chemical nature of the desiccant must be disclosed | 13 | |
3.2.P.7 | Identification, chemical nature and density of the container closure must be included as well as specifications and the relevant control procedure included. This includes colour, dimensions and thickness | 38 | |
3.2.P.7 | The manufacturers of the primary packaging materials should be included | 23 | |
3.2.P.7 | Information included in the packaging insert/patient information leaflet (PI/PIL)/label is not in accordance with the packaging presentations contained in this section. Correct | 21 | |
3.2.P.7 | The certificates of analysis (CoAs) for the immediate container closure(s) used were not provided | 43 | |
Other | 28 | ||
231 | |||
3.2.P.8 Stability of the FPP | |||
3.2.P.8.1 Stability summary and conclusions | |||
3.2.P.8.1 | Provide a justification for the out of trend assay results | 28 | 4.5 |
3.2.P.8.1 | The shelf-life specifications are incomplete or have missing criteria or parameters. Include these or provide a justification for not including the parameters listed in 3.2.P.5.1 | 32 | |
3.2.P.8.1 | Indicate the date of initiation of the stability studies | 15 | |
3.2.P.8.1 | Include the minimum and maximum size of the batches placed under stability study | 32 | |
3.2.P.8.1 | Submit stability data for an alternative local packer for final products manufactured in a different country to the manufacturer, on the product packed in bulk containers over a suitable period covering the relevant transport conditions | 29 | |
3.2.P.8.1 | Indicate the type of batch, e.g., pilot/production/experimental as well as the batch size. For pilot batches, a provisional shelf life of up to 24 months is allocated | 11 | |
3.2.P.8.2 Post-approval stability protocol and stability commitment | |||
3.2.P.8.2 | The proposed post-approval stability study did not include the batches being placed on stability annually or how many batches per strength are annually put on stability testing | 34 | 1.7 |
3.2.P.8.2 | The proposed stability programme commitment is not in accordance with the stability guideline; Summary tables with test results from stability studies conducted under accelerated and stressed conditions were not submitted | 21 | |
3.2.P.8.3 Stability data | |||
3.2.P.8.3 | Correct the container closure system to correspond with that indicated in the container closure section, Module 3.2.P.7 | 36 | 9.3 |
3.2.P.8.3 | Impurity/degradation shelf-life limits should be tightened from a quality perspective in view of the results observed for commercial batches | 56 | |
3.2.P.8.3 | Critical stability indicating parameters such as related substances and dissolution are not included in the stability testing. These should be included | 54 | |
3.2.P.8.3 | The proposed shelf life is not supported by the submitted studies, provide additional data to support the proposed shelf life, which should now be reasonably available | 98 | |
3.2.P.8.3 | Stability studies for different manufacturing sites were not provided, confirming similar stability. Submit | 34 | |
3.2.P.8.3 | Submit photostability data under normal conditions which show that secondary packaging protects the ultra-violet ray (UV)-sensitive API and that unrelated impurities did not increase with exposure to light and UV | 14 | |
Other | 9 | ||
503 | |||