Table 4 List of FPP common deficiencies in the 3.2.P section of the CTD recommended by SAHPRA for sterile products finalised by the pre-registration Unit between 2011 and 2017
Section/subsection | Deficiency | Amount | % overall |
|---|---|---|---|
3.2.P.1 Description and composition of the FPP | |||
3.2.P.1 | Nitrogen is used as pressure source for filtration it must be indicated in the list of excipients and controlled in 3.2.P.5 | 74 | 3.1 |
Other | 12 | ||
86 | |||
3.2.P.2 Pharmaceutical development | |||
3.2.P.2.2 Final pharmaceutical product | |||
3.2.P.2.2 | The product development report is insufficient. It does not address the development of the buffered blend for filling, neither does it address aspects such as choice of container closure system, filter media, sterilisation methods | 39 | 13 |
3.2.P.2.2 | It is stated that sterile filtration is chosen as method of sterilisation without justification. The choice of sterilisation by filtration as the method of sterilisation must be scientifically justified in terms of the decision tree for sterilisation choices for aqueous products (CPMP/QWP/054/98). Terminal sterilisation should normally be the method of choice if the product is expected to be heat stable | 106 | |
3.2.P.2.2 | Discuss the selection and effectiveness of preservative | 34 | |
3.2.P.2.2 | Include the pore size of the filter used for the method of sterilisation | 67 | |
3.2.P.2.2 | The volume of overfills were unjustified in pharmaceutical development. Provide data to support that the indicated total fill volume sufficient to administer nominal dose | 34 | |
3.2.P.2.2 | Provide results of tests on extractable volume and the API content after reconstitution of the FPP with the selected solvent | 76 | |
3.2.P.2.3 Manufacturing process development | |||
3.2.P.2.3 | Justify sterilisation by filtration. Heat instability during autoclaving has been determined at 121 °C/20 min. Have studies been done at reduced Fo – values to confirm that terminal sterilisation is not possible | 45 | 1.6 |
3.2.P.2.4 Container closure system | |||
3.2.P.2.4 | Submit in-use stability testing method and results in this section to confirm integrity of the container closure system to prevent microbial contamination | 32 | 1.9 |
3.2.P.2.4 | The consistency for droplet size for the dropper used should be conducted to ensure that the same API/FPP is ejected at each drop | 21 | |
3.2.P.2.6 Compatibility | |||
3.2.P.2.6 | Extractability and leaching studies of the selected filter should be submitted | 45 | 6.3 |
3.2.P.2.6 | The studies to confirm the compatibility of the product with the recommended intravenous (IV) solutions was not conducted | 54 | |
3.2.P.2.6 | Provide compatibility studies of the formulation with the equipment used in the manufacturing process | 31 | |
3.2.P.2.6 | Compatibility and leaching studies of the formulation with the coated rubber stoppers to demonstrate that these do not cause leaching should be submitted | 23 | |
Other | 19 | ||
626 | |||
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 information must include an inspection flow diagram describing both processes, the batch manufacturing formulae, a comprehensive flow diagram and a comprehensive description detailing the various stages of both steps in the manufacturing process including environmental classification of areas, sterilisation methods and conditions of containers and equipment | 54 | 13 |
3.2.P.3.3 | Nitrogen is used as pressure source for filtration, it must be indicated in 3.2.P.3.3 and should be indicated in the formula and controlled in 3.2.P.5. In addition, the method of sterilisation used for nitrogen should be stated | 43 | |
3.2.P.3.3 | Confirm that the filter integrity is confirmed before and after filtration. Reference to the process procedure only to conduct filter integrity test is inadequate | 23 | |
3.2.P.3.3 | State the type and size (porosity) of the filters used for filtration of the solution | 45 | |
3.2.P.3.3 | Describe the grades of clean areas for manufacture and filling process of water for injection/diluent | 82 | |
3.2.P.3.3 | Provide lyophilisation conditions of the cycle used and confirm that the lyophiliser is sterilised after each cycle | 68 | |
3.2.P.3.3 | Proof of efficacy of the sterilisation of the dead space in the connecting tube and twist off ports of the bags must be provided | 27 | |
3.2.P.3.4 Control of critical steps and intermediates | |||
3.2.P.3.4 | Bioburden testing and the acceptance criteria for bioburden must be included as an in-process control measure | 59 | 2.2 |
3.2.P.3.5 Process validation and/or evaluation | |||
3.2.P.3.5 | Provide summary reports on the validations for the sterilisation of the rubber closures and for the lyophilised powder | 76 | 17 |
3.2.P.3.5 | The validation of sterilisation and depyrogenation processes with conditions and determination of maximum holding/processing times must also be included | 83 | |
3.2.P.3.5 | The hold time validation data should include hold time before and after filtration of final product bulk or hold time within lyophiliser chamber after cycle completion | 34 | |
3.2.P.3.5 | Provide summary reports on the validations of depyrogenation of the glass vials and sterilisation of the rubber closures and for the water for injection/diluent | 23 | |
3.2.P.3.5 | Submit a summary report of the validation (qualification) of the sterilisation cycle of the final product including the loading patterns | 23 | |
3.2.P.3.5 | Submit a summary report of the validation of the selected filter | 16 | |
3.2.P.3.5 | Provide a protocol or report of the validation of autoclaves and sterilisation/depyrogenation tunnels | 23 | |
3.2.P.3.5 | Provide a protocol or summary report of the media fill procedures and validation of holding times | 43 | |
3.2.P.3.5 | Include a summary report on autoclaving of production equipment | 45 | |
3.2.P.3.5 | A number of issues on the media fill validation including; Media fill validation not covering all product volumes and container types, details of the media fill conditions were not described, Aseptic process not validated by media fill to name a few | 65 | |
3.2.P.3.5 | The validation process should contain storage and shipping conditions linked to process validation results | 25 | |
Other | 16 | ||
873 | |||
3.2.P.4 Control of inactive pharmaceutical ingredients | |||
3.2.P.4.1 Specifications | |||
3.2.P.4.1 | Nitrogen is used as pressure source for filtration. Provide specifications and control procedures | 56 | 4.5 |
3.2.P.4.1 | Indicate the leak test performed on the container closure system during filling | 45 | |
Other | 23 | ||
124 | |||
3.2.P.5 Control of FPP | |||
3.2.P.5.1 Specifications | |||
3.2.P.5.1 | Seal integrity testing (leak testing) of ampoules must be included as a final product control | 23 | 11 |
3.2.P.5.1 | Visible particulate matter should be included as a specification either as final product release specification or as in-process control | 54 | |
3.2.P.5.1 | Bacterial endotoxin test (BET) should be included as a specification either as final product release specification or as an in-process control | 80 | |
3.2.P.5.1 | In view of the batch release data and stability data provided for related substances the justification of the specifications for total impurities based on batch release data is not accepted and should be reconsidered | 34 | |
3.2.P.5.1 | Include a specification for preservative effectiveness. The test is not required for routine analysis provided that the preservative effectiveness has been established at the lowest limit specified, however, the specification should be retained as a skip test | 43 | |
3.2.P.5.1 | The following were missing from the specifications and should be submitted: preservative efficiency testing at the end of shelf life; active content in reconstituted solution; product-related impurities in specifications considered as too wide; acceptance and extractable volume after reconstitution as well as uniformity of mass | 22 | |
3.2.P.5.3 Validation of analytical procedures | |||
3.2.P.5.3 | Provide validation data for the sterility test method. If a pharmacopoeial method from a recognised pharmacopoeia is used partial validation data will suffice | 23 | 2.5 |
3.2.P.5.3 | Provide validation data for the bacterial endotoxin test method | 45 | |
3.2.P.5.6 Justification of specifications | |||
3.2.P.5.6 | There were unjustified items: bacterial endotoxin limits; pH specification limits; active salt selection; omission of impurities in specifications and missing container closure test | 54 | 2.8 |
Other | 22 | ||
400 | |||
3.2.P.7 Container closure system of the FPP | |||
3.2.P.7 | Consistency of the droplet size should be confirmed | 45 | 7.2 |
3.2.P.7 | Coating composition of the stoppers used was not included | 27 | |
3.2.P.7 | The CoAs for glass and rubber stoppers used were not provided | 17 | |
3.2.P.7 | Sterilisation of primary packaging components was not satisfactorily described | 13 | |
3.2.P.7 | Compatibility of the stopper material with the final product was not demonstrated on potential extractables. Extractability and leaching study is therefore requested | 39 | |
3.2.P.7 | Leachability study of the leachables originating from the container closure system should be investigated | 34 | |
Other | 21 | ||
196 | |||
3.2.P.8 Stability of the FPP | |||
3.2.P.8.3 Stability data | |||
3.2.P.8.3 | Provide results of the stability studies on the diluted solution in selected diluent for infusion confirming the recommendations in the PI | 28 | 13 |
3.2.P.8.3 | The results of the photo stability studies showing no effect to impurity values and thus no requirement for protection from light during storage of the product should be provided | 45 | |
3.2.P.8.3 | The results of the in-use stability study confirming stability of the product at a specific temperature for specified amount of time as indicated in the PI and in accordance with the guidelines should be provided | 38 | |
3.2.P.8.3 | The results of the transportation stability test at specified elevated storage condition for a sufficient amount of time should be submitted | 23 | |
3.2.P.8.3 | Provide stability results to confirm the effectiveness of the preservative | 43 | |
3.2.P.8.3 | Stability studies should be conducted in upright and inverted positions, the results were only submitted for samples stored in an upright position. Submit for the inverted position | 34 | |
3.2.P.8.3 | There were missing tests during stability studies, for example, volume in container, sterility and BET. This should be conducted in the next testing and submitted | 44 | |
3.2.P.8.3 | Missing or insufficient data for aspects such as vacuum stress for container closure ingress testing; supporting storage out of Refrigeration; potency test performance during stability control; chromatograms from final product long-term, accelerated, and stressed stability studies and sterility tests on preservative efficiency | 38 | |
3.2.P.8.3 | Stability studies for temperature excursions at the end of the shelf-life should be submitted | 36 | |
Other | 15 | ||
344 | |||
3.2.R.1 Pharmaceutical and biological availability | |||
3.2.R.1* | Data to substantiate efficacy have been provided in Module 3.2.P.2 where essential similarity of the innovator and test product was proven however, a request for exemption from submitting proof of Biological availability based on the Biostudies Guidelines was not stipulated. Exemption will only be considered when motivation and comparative data have been submitted in Module 3.2.R.1 | 93 | 3.4 |
93 | |||