Pharmacovigilance role in Investigating OOS for Finished Product on the Stability Program through Health Hazard Assessment & Post monitoring and effectiveness check.
How to succeed when you get a FDA 483 form letter. What to do and how to handle your FDA 483. For more information go to http://compliance-insight.com/fda-483-warning-letters/fda-483-observations/
ICH Q3D - Elemental impurities in pharmaceutical productspi
The ICH has developed the Q3D guideline on elemental impurities. Both the FDA and the EMA encourage the ICH Q3D guideline implementation. All companies will have to be compliant for already authorised and marketed products as of December 2017.
OOS and OOT investigation is always a challenging task. This slide may help for a better understanding of investigation procedure according to regulatory requrement.
Development safety update report (dsur) pharmacovigilance and safetyAzierta
According to ICH guideline E2F (Step 5) on Development Safety Update Reports (DSURs) already implemented since 2011, companies must submit DSURs on a yearly basis for medicinal products involved in clinical trials. The focus of the DSUR is on data and findings from clinical trials of drugs and biologicals, whether they are authorized or not.
DSURs are internationally-harmonized, safety documents covering the safety summary of medicinal products during their development or clinical trial phase.
They are based heavily on the PSUR format already used for updating the safety record of drugs in their marketing phase.
A DSUR should be prepared after the first authorization of a clinical trial worldwide. A copy of the DSUR should be submitted to each concerned European Member State (MS) if a clinical trial is authorized in this MS for this investigational drug (still using the DIBD). Therefore, the first DSUR can be submitted to a concerned MS earlier than 1 year, but the covered reporting period should not be longer than 1 year.
The DSUR presents an annual review & evaluation of safety information:
• Information reported during the current review period and analysis based on previous knowledge of the products’ safety
• Description of new issues that may impact the overall program or specific clinical trials.
• Summarization of current understanding and management of known and potential safety risks to exposed patients.
• Provide an update on the status of the clinical development program.
In Azierta, scientific and healthcare consulting, we are experts in Pharmacovigilance and we have a team of highly qualified drug safety experts who support our clients to manage pharmacovigilance in an optimal way. Our work covers all areas of pharmacovigilance, both at the level of medicines, as well as medical devices and cosmetic products.
If you are interested in the contents of the good practices of pharmacovigilance (GVPs), as well as in other products related to pharmacovigilance visit our safety reports website for more details and feel free to contact us, we will be pleased to help you.
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceutic
How to succeed when you get a FDA 483 form letter. What to do and how to handle your FDA 483. For more information go to http://compliance-insight.com/fda-483-warning-letters/fda-483-observations/
ICH Q3D - Elemental impurities in pharmaceutical productspi
The ICH has developed the Q3D guideline on elemental impurities. Both the FDA and the EMA encourage the ICH Q3D guideline implementation. All companies will have to be compliant for already authorised and marketed products as of December 2017.
OOS and OOT investigation is always a challenging task. This slide may help for a better understanding of investigation procedure according to regulatory requrement.
Development safety update report (dsur) pharmacovigilance and safetyAzierta
According to ICH guideline E2F (Step 5) on Development Safety Update Reports (DSURs) already implemented since 2011, companies must submit DSURs on a yearly basis for medicinal products involved in clinical trials. The focus of the DSUR is on data and findings from clinical trials of drugs and biologicals, whether they are authorized or not.
DSURs are internationally-harmonized, safety documents covering the safety summary of medicinal products during their development or clinical trial phase.
They are based heavily on the PSUR format already used for updating the safety record of drugs in their marketing phase.
A DSUR should be prepared after the first authorization of a clinical trial worldwide. A copy of the DSUR should be submitted to each concerned European Member State (MS) if a clinical trial is authorized in this MS for this investigational drug (still using the DIBD). Therefore, the first DSUR can be submitted to a concerned MS earlier than 1 year, but the covered reporting period should not be longer than 1 year.
The DSUR presents an annual review & evaluation of safety information:
• Information reported during the current review period and analysis based on previous knowledge of the products’ safety
• Description of new issues that may impact the overall program or specific clinical trials.
• Summarization of current understanding and management of known and potential safety risks to exposed patients.
• Provide an update on the status of the clinical development program.
In Azierta, scientific and healthcare consulting, we are experts in Pharmacovigilance and we have a team of highly qualified drug safety experts who support our clients to manage pharmacovigilance in an optimal way. Our work covers all areas of pharmacovigilance, both at the level of medicines, as well as medical devices and cosmetic products.
If you are interested in the contents of the good practices of pharmacovigilance (GVPs), as well as in other products related to pharmacovigilance visit our safety reports website for more details and feel free to contact us, we will be pleased to help you.
Presentation complied by Drug Regulations – a not for profit organization from publicly available material form FDA , EMA, EDQM . WHO and similar organizations.
Visit www.drugregulations.org for the latest in Pharmaceutic
GOOD MANUFACTURING PROCESS Provides a high level assurance that medicines are manufactured in a way that ensures their safety, efficacy and quality
Medicines are manufactured to comply with their marketing authorization
Quality is built in
Testing is part of GMP, but alone does not provide a good level of quality assurance
Effective handling of OOS investigations involves adhering to OOS investigation guidelines to ensure thorough analysis and resolution. Following robust protocols and regulatory standards in OOS investigation processes is crucial for maintaining product quality and compliance.
Read more here https://www.ipa-india.org/wp-content/uploads/2023/05/Presentation-on-Handling-OOS-Investigations-Regulatory-Expectations-Dipesh-Shah-Comsumer-Safety-Officer-USFDA.pdf
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
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Macroeconomics- Movie Location
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Objective:
Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
June 3, 2024 Anti-Semitism Letter Sent to MIT President Kornbluth and MIT Cor...Levi Shapiro
Letter from the Congress of the United States regarding Anti-Semitism sent June 3rd to MIT President Sally Kornbluth, MIT Corp Chair, Mark Gorenberg
Dear Dr. Kornbluth and Mr. Gorenberg,
The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
harassment and intimidation at the Massachusetts Institute of Technology (MIT). Failing to act decisively to ensure a safe learning environment for all students would be a grave dereliction of your responsibilities as President of MIT and Chair of the MIT Corporation.
This Congress will not stand idly by and allow an environment hostile to Jewish students to persist. The House believes that your institution is in violation of Title VI of the Civil Rights Act, and the inability or
unwillingness to rectify this violation through action requires accountability.
Postsecondary education is a unique opportunity for students to learn and have their ideas and beliefs challenged. However, universities receiving hundreds of millions of federal funds annually have denied
students that opportunity and have been hijacked to become venues for the promotion of terrorism, antisemitic harassment and intimidation, unlawful encampments, and in some cases, assaults and riots.
The House of Representatives will not countenance the use of federal funds to indoctrinate students into hateful, antisemitic, anti-American supporters of terrorism. Investigations into campus antisemitism by the Committee on Education and the Workforce and the Committee on Ways and Means have been expanded into a Congress-wide probe across all relevant jurisdictions to address this national crisis. The undersigned Committees will conduct oversight into the use of federal funds at MIT and its learning environment under authorities granted to each Committee.
• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
• The Committee on Oversight and Accountability is investigating the sources of funding and other support flowing to groups espousing pro-Hamas propaganda and engaged in antisemitic harassment and intimidation of students. The Committee on Oversight and Accountability is the principal oversight committee of the US House of Representatives and has broad authority to investigate “any matter” at “any time” under House Rule X.
• The Committee on Ways and Means has been investigating several universities since November 15, 2023, when the Committee held a hearing entitled From Ivory Towers to Dark Corners: Investigating the Nexus Between Antisemitism, Tax-Exempt Universities, and Terror Financing. The Committee followed the hearing with letters to those institutions on January 10, 202
Pharmacovigilance role through investigating Out of Specification (OOS) for Finished Product on the Stability Program
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