Investigating OOS for Finished Product on the Stability Program. Presented by: Nicole Chang, QA Manager, Apotex Pty Ltd

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1 Investigating OOS for Finished Product on the Stability Program Presented by: Nicole Chang, QA Manager, Apotex Pty Ltd

2 Overview 1. Requirements of the commercial stability program 2. Out of Specification and atypical results 3. Phases of investigation Phase I: Laboratory investigation Phase II: Full scale investigation Phase III: Review of product development 4. Health Hazard Assessment 5. Assessing the Impact of OOS/OOT 6. Monitoring and Effectiveness Check 7. Testing to Proactively Identify Issues 8. Conclusion

3 Requirements of the Commercial Stability Program Medicinal Products The program should permit the detection of any stability issues associated with the formulation in the marketed package. The purpose of the program is to monitor the product over its shelflife and to determine that the product remains and can be expected to remain, within specifications under the labelled storage conditions. 1 batch per year, in every strength & every primary packaging type The principle of bracketing may be applied if scientifically justified & recorded Should be considered for any reworking, reprocessing or recovery operation. Out of specification or significant atypical trends should be investigated. Any confirmed OOS result or significant negative trend should be reported to the relevant competent authorities.

4 Out of Specification & Atypical Results Out of specification (OOS): Any result that falls outside of the registered specification. Ex. Assay result = 94.6%. Limit: %. Atypical result (i.e. OOT) Any result that is within the registered limit, but appears irregular or outside the trend of previous results. Or routine trending shows that it will not meet specification at expiry. OOS/OOT within a stability study This issue is more complex than an OOS within release Product on the market could be affected This may lead to a recall % Ass say Months (expiry = 24)

5 Phase I: Laboratory Investigation Upon observation of an OOS/OOT result, the Analyst should immediately inform the Supervisor. Together, they should determine if an assignable cause for the result exists by reviewing the following: Raw data Review chromatograms and print outs Compare results to historical data or trends Sample Was the correct sample tested? considerations Is there evidence of contamination or improper sample appearance, storage, handling, labelling or damage. Inspect the sample in the original container and all sample preparations to determine if samples have been compromised or may not have been fully extracted Equipment Was the correct equipment used and were the settings correct? Are there any indications of equipment malfunction? Is the calibration/maintenance current? Were system suitability parameters met? Test execution & analyst training Was the correct method used? Was the raw data properly documented? Was the analyst trained on the technique? Standard & sample preparations Review other test results within the run Check the standards, solvents and reagents to determine if they are correct and have been preconditioned properly Were correct standards/chemicals used? Was the sample powder homogenous? Were all solutions prepared correctly? Are the results acceptable? Is there a clear bias to the run?

6 Phase I: Laboratory Investigation Party Responsibilities Analyst Achieve accurate laboratory testing results Ensure that only those instruments meeting established performance specifications are used and that all instruments are properly calibrated Ensure system suitability requirements are met Check data for compliance to test specifications prior to discarding of sample preparations Immediately document any deviations that have occurred during testing (i.e. spills, incomplete transfer of sample composite, OOS/OOT) Supervisor Contract Laboratory Manufacturer s QCU Provide an objective and timely assessment once an OOS has been identified Convey its data, findings and supporting documentation to the manufacturing firm s quality control unit (QCU) Initiate full scale OOS investigation

7 Phase II: Full Scale Investigation Review Production Records Perform complete review of batch records for the impacted batch and identify the following: Dates manufacturing, packaging, expiry and stability study initiation Any deviations issued during manufacturing or packaging Raw material batches used in the manufacturing of the impacted batch including capsule shells for encapsulated product. Consider other batches that may have used those materials. Compare these results/parameters to other released batches of the product. In process testing results. E.g. hardness, thickness, average weight, and if applicable disintegration, LOD, release testing of intermediates Production parameters, e.g. compression/encapsulation speed, coating. Any process or formulation changes including new excipient or raw material suppliers.

8 Phase II: Full Scale Investigation Review Stability Data Review the stability data for the impacted batch and for the product. Make note of any relevant trends. Confirm if there was any previous laboratory investigations or OOT results Review forced degradation or accelerated stability data to determine stability of the product under stress conditions. Confirm and summarize if there are any previous stability OOS or OOT events for the batch and/or product. Consider all stability study types (i.e. conditions, pack format, etc.) Review complaint/ade history for the batch and product Identify any reports that may be related to the investigation.

9 Phase III: Review of Product Development May be necessary when further evaluation is required to be performed on the formulation, method or if additional studies are required. Studies may be required to isolate, identify and qualify impurities Change and re-validation of analytical methods may be required Changes to specifications may be necessary based on evaluation of the stability data Widening of specifications Tightening of release specifications Proposal for changes in the container closure system may be necessary if there is a reaction of the product with components of the container closure system. Proposal for changes in the formulation of the product or termination of the formulation if instability of the product is related to the formulation. Note: Changes listed above may require TGA approval in order to implement.

10 Health Hazard Assessment Responsibilities of sponsors All sponsors of products must ensure that it has an appropriate system of pharmacovigilance (PV) in place in order to assure responsibility and liability for its products on the market and to ensure that appropriate action can be taken when necessary. A sponsor should have a permanent and qualified person for PV who has experience in all aspects of PV and if not medically qualified should report or have access to a medically qualified person. The following information is required in order to make a proper assessment: Thorough description of the problem Clear identification of the impurity, if relevant. Quantitative estimate of the levels of active, impurity, etc.

11 Health Hazard Assessment (cont d) The assessment should consider the following: Have any illnesses or injury resulted from the use of the product? What population is most affected by this hazard? How serious is the health hazard? How likely will illness be the result of this hazard? Are the consequences from this hazard short or long term? Assessments should conclude if the impact of the OOS/OOT to the patient is: Potentially life-threatening or could cause serious risk to health (Class I) Could cause illness or mistreatment (Class II) Non safety related (Class III)

12 Assessing the Impact of OOS/OOT Upon confirmation of an OOS or OOT result, determine the impact to marketed products. Identify all impacted customers Block remaining inventory if there is evidence to suggest that the OOS result is isolated to the specific batch or the product. Consider whether there is a common active raw material or common blend. If there is evidence to suggest that the OOS result obtained is related to issues with formulation, process or packaging, consider placing production/packaging documents on hold to prevent further production Perform a health hazard assessment (for safety/efficacy), if applicable Perform risk assessment and provide proposal(s) to the relevant authorities Ensure timely investigation and set targets for completion.

13 Post Monitoring & Effectiveness Check Once the investigation has been completed consider: Continue reviewing reports of ADEs and LOEs for the impact batch/product. Review stability data for other batches of the impacted product. If changes to the product/packaging were required as a result of the investigation, review stability of post-change batches to confirm that the change is effective. Monitor batches under worse case conditions. If no cause was determined for the OOS/OOT, consider additional time point testing within or after expiry or initiation of worse case studies.

14 Testing to Proactively Identify Issues Worse case testing should be considered to identify any issues with the stability. Involves: Storage of samples under relevant climatic conditions (i.e. long-term: 25 & 30 C.) Only the sample stored under stricter conditions is analysed (thus covers the lower conditions) In case of OOS results, the sample stored under lower conditions will be analysed too. Example: Protocol for product labelled as, Store below 25 C. Testing under accelerated conditions should be considered for: validation batches, after a major change to the process/formulation/packaging.

15 Conclusions Ensure that you have the following procedures in place: Laboratory investigation Full scale investigation Health Hazard Assessment Post monitoring and effectiveness check Good practice to store and test samples under the worse case condition. Consider initiating accelerated studies for batches where there have been major changes to the process/formulation/packaging Routine trending is necessary to proactively identify any potential failures. Any confirmed OOS, or significant negative trends should be reported to the competent authorities

16 Relevant Standards & Guidance Documents PIC/S Guide for Good Manufacturing Practice for Medicinal Products,15 Jan 2009 ICH Q9 Quality Risk Management, 9 Nov, 2005 Uniform recall procedure for therapeutic goods (URPTG), 2004 edition Guidance for Industry - Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, U.S. Dept of Health & Human Services, Food & Drug Administration Centre for Drug Evaluation and Research (CDER), Oct 2006 ICH Q1A(R2) Stability Testing of new Drug Substances and Products, Aug 2003

17 Thank you! QUESTIONS?

Laboratory OOS Investigations The Missing Link

Laboratory OOS Investigations The Missing Link India Pharmaceutical Alliance Carmelo Rosa, Psy.D Director Division of Drug Quality I November 6-17, 2017 Indian Pharmaceutical Alliance DISCLAIMER: The views