2 - Dashboard (Clarifications & Updates)
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This document provides a summary of a dashboard and reflective review presentation from 2019. It discusses various quality topics related to pharmaceutical manufacturing including assay testing of APIs, use of preservatives, microbial limits, process validation, cleaning validation, API testing responsibilities, and more. Key points emphasized include using a risk-based approach to assessing changes and product holds, ensuring sampling methods are scientifically sound, and the importance of evaluating cleaning procedures to maintain ability to clean. Recent regulatory guidance from EMA regarding evaluation of nitrosamines is also summarized.
2 - Dashboard (Clarifications & Updates)
- 1. Dashboard & Reflective Review 2019 Clarifications & Updates Roohi B. Obaid & Obaid Ali 22 Dec 2019, Technology Park, ICCBS, University of Karachi
- 3. It reflects the views and understanding of presenter & may not be construed to represent the views or policies of organization or association to which speaker has ties Documents of US-FDA & Review Scientific Articles are used to construct presentation
- 5. We Know Assay of API is a mandatory test before release of product. Preservatives are added to save formulation from microbial growth Some microbes degrade some APIs in formulation
- 6. If Preservative is used in your formulation, would it be required to test for its effectiveness every time before release of every batch?
- 7. Remember Parametric Release Periodic Testing Real time Testing1 2 3
- 8. Remember Parametric Release Periodic Testing Real time Testing1 2 3
- 9. Remember Parametric Release Periodic Testing Real time Testing1 2 3
- 10. Remember Parametric Release Periodic Testing Real time Testing1 2 3
- 11. Remember Antimicrobial preservatives should not be used as a substitute for GMP, solely to reduce the viable microbial population or control the pre-sterilization bio-burden of a multi dose formulation during manufacturing.
- 12. If An oral formulation that was out of specification initially in terms of microbial count. However, It came within specifications after two weeks Can it be released?
- 13. If An oral formulation that was out of specification initially in terms of microbial count. However, It came within specifications after two weeks Can it be released? No
- 16. 18 Dec 2019 Recall Don’t miss the opportunity to recall. We are dealing with life Be vigilant please
- 18. Objectionable Known human pathogen Adversely affect product stability Interfere with analytical method/bioavailability Potentially damage the integrity of container
- 19. Objectionable Microbial specie, its count Dosage form and its intended use Patient population & route of administration Potential to affect product safety
- 20. Second Part of Lecture
- 22. Validation Sound rationale is expected for process validation Minimum number of conformance batches necessary to validate is no longer specified
- 23. Validation Successful completion of initial conformance batches would normally be expected before commencement of commercial distribution with few exceptions. Exceptions include short supply situations, orphan drugs
- 24. Validation Large sample size & testing of additional attributes are required for exceptions
- 26. Is it enough You test rinse solution to support residue determination in performing cleaning validation.
- 27. Is it enough • Use direct method • Solvent and solubility matters • Assess risk How do you ensure process is not losing its ability to clean No
- 28. Is it enough The purpose of cleaning validation is to demonstrate that a particular cleaning process will consistently clean the equipment to a predetermined standard Remember
- 29. Is it enough Both sampling method & analytical test method should be scientifically sound enough to provide adequate rationale to support the validation. Remember
- 31. API Testing Analytical testing of API to ensure its compliance with their specifications (approved for the purpose by the Regulatory Authority or referring any compendial specifications) Who is Responsible?
- 32. API Testing Lets Resolve All applicable specifications established for release All established specifications are complied API FG
- 33. API Testing Lets Resolve All applicable specifications established for release All established specifications are complied API FG
- 34. API Testing Lets Resolve All applicable specifications established for release All established specifications are complied API FG
- 35. API Testing Validate the reliability of API supplier
- 37. Analytical Procedure Is it necessary to use compendial method/procedure as it is, while testing API or product?
- 38. Analytical Procedure Alternate method, fully validated, suitable for use and giving equivalent result or better result than the compendia may be used No
- 39. API If API is found compliant with all specifications approved for the purpose either in pharmacopeia or …. While manufactured in non-GMP compliant facility Can it be used?
- 41. Quality Defects If drug has been recalled due to any quality defect, and discarded. Would it be necessary to investigate? Can this investigation expand to other batches that are not available in market?
- 43. Dedicated Cleaning procedures and environmental controls may not be used to manufacture penicillin with other products in multidrug manufacturing facility? Why?
- 44. Dedicated There is no established safe level of penicillin residue in non-penicillin drug product. There is no qualified trace levels that is proven safe and cannot sensitize anaphylactic reactions Because
- 46. Bulk Hold In process material, Sustained release pellets, Tablet core, may be stored? How long?
- 47. Bulk Hold Lets think
- 48. Bulk Hold A Risk & Science based ASSESSMENT process can help identify which material attributes & process parameters might affect the critical quality attributes of the finished drug product Chemically & Physically Stable In-process
- 49. Bulk Hold Assessment should be designed to ensure that material stored under controlled conditions for a specified period are appropriate for use in manufacturing the finished product without having formal stability study to verify the holding period. Remember
- 50. Bulk Hold This assessment may include sampling and testing the material being held to verify the manufacturing holding period. Risk ….
- 51. Bulk Hold You cannot hold more than period established in the risk assessment. One needs to conduct stability studies according to approved stability protocol to verify holding period. Unstable Material
- 52. Bulk Hold The stability studies should include evaluation of in-process materials up to the time of their use in manufacturing a finished drug product Batch will be monitored long term if the same in-process material is used Unstable Material
- 54. Sampling Be opened, sampled and sealed in a manner designed to prevent contamination of their content Warehouse
- 55. Sampling Is there any harm to sample from warehouse? Container Closure
- 56. Sampling What about sterile or depyrogenated? Container Closure
- 57. Sampling Sampling should be under conditions equivalent to the purported quality of material. This is to preserve the fitness for use of remaining units as well as to ensure sample integrity if they are to be examined for microbial contamination Container Closure
- 59. Blend Proper sampling of powder blend is a matter of concern? Why?
- 60. Blend Demonstration of adequacy of mixing is the requirement Scientifically sound
- 61. Blend Between & within location variability in the powder blend is a critical component of finished product quality and therefore should be evaluated. Scientifically sound
- 62. Blend Adequacy of blend mixing and that sampling of the blend is done at the suitable juncture in the manufacturing process Science and Risk based Sampling Approach to ensure
- 63. Blend No difference exist between locations in a blend that could aversely affect finished product quality Need to ensure
- 64. Blend Is a reliable & most widely used sampling tool but It may have draw backs & limitations causing disturbance to the powder bed, powder segregation .. Towards PAT Traditional Powder Thief
- 65. Blend Reliability of the sampling method should be evaluated as a part of analytical method development Traditional Powder Thief
- 66. Blend PAT, Real time monitoring Statistical Process Control tools Sample size of powder, number of probes, their justification of locations. (variability across locations, over time of one location and potential correlation b/w sample and unit dosage form) Innovative Approaches
- 68. 7 Steps – EMA Guidance Sep 2019
- 69. Oct 2019 Evaluate possibility of nitrosamines being present in every concerned medicine within 6 months by 26 March 2020 EMA & Nitrosamines 1
- 70. Oct 2019 Prioritize evaluation starting with medicine more likely to be at risk of containing nitrosamine EMA & Nitrosamines 2
- 71. Oct 2019 Prior knowledge: take into account finding from EMA Committee (CHMP) EMA & Nitrosamines 3
- 72. Oct 2019 Notify authorities of the outcome of risk evaluation EMA & Nitrosamines 4
- 73. Oct 2019 Immediately report reduction of nitrosamine to authorities EMA & Nitrosamines 5
- 74. Oct 2019 Apply necessary change to market authorization to address nitrosamine risk by 26 Sep 2022 EMA & Nitrosamines 6
- 75. Oct 2019 Complete all steps within 3 years, prioritizing high risk products EMA & Nitrosamines 7
- 78. Nov 2019 ICH Q12 Approved and in queue of implementation Q12 –Lifecycle Management
- 79. Dec 2019 on effective Change Management Some changes do not require regulatory approval due to movement towards established conditions. Inspections will be of more importance PIC/S Draft Recommendation
- 80. Dec 2019 How to Evaluate/ Demonstrate the Effectiveness of Pharmaceutical Quality System in relation to risk based change management PIC/S Draft Recommendation
- 81. Dec 2019 6 months trial on GMP inspections 1. Change proposal 2. Risk assessment of change 3. Planning & implementation of change 4. Review & effectiveness of change PIC/S Draft Recommendation
- 83. July 2019 Improve collaboration & knowledge sharing Exchange program MoU b/w BP & USP
- 84. Thanks