Pharmacovigilance role in Investigating OOS for Finished Product on the Stability Program through Health Hazard Assessment & Post monitoring and effectiveness check.

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

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 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 shelf-
life 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: 95.0-105.0%.
100
105
110
115
%Assay
Atypical result (i.e. OOT)
• Any result that is within the registered
limit, but appears “irregular’ or outside
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
80
85
90
95
100
0 5 10 15 20 25 30
%Assay
Months (expiry = 24)
limit, but appears “irregular’ or outside
the trend of previous results.
• Or routine trending shows that it will not
meet specification at expiry.

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
considerations
 Was the correct sample tested?
 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 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
 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?
Review other test
results within the
run
 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• Immediately document any deviations that have occurred during
testing (i.e. spills, incomplete transfer of sample composite, OOS/OOT)
Supervisor Provide an objective and timely assessment once an OOS has been
identified
Contract
Laboratory
Convey its data, findings and supporting documentation to the
manufacturing firm’s quality control unit (QCU)
Manufacturer’s
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 otherincluding 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• 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– 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 shouldhas 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?• 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.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• 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”.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’• 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 edition2004 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?