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M. Pharm Sem-I Presentations
Title-Quality Systems
SUBMITTED TO
SAVITRIBAI PHULE, PUNE UNIVERSITY , PUNE
FOR
PARTIAL FULFILMENT OF REQUIREMENTS FOR THE AWARD OF
MASTER OF PHARMACY
IN THE SUBJECT
Quality Management Systems
IN THE FACULTY OF SCIENCE AND TECHNOLOGY
Bhujbal Knowledge City,
MET’s Institute of Pharmacy,
Adgaon, Nashik, 422003.
Maharashtra, India
Academic Year-2021-22 1
Presented By-
Rohit Koli
Shubham Chikhale
Guided By:-
Dr.Sapna Ahirrao
Quality Systems
Change control, Out of specifications (OOS), Out of
Trend (OOT)
Content
• Concept of Change control
• Procedure of change control
• Management of change control
• Conditions of change control
• Out of specifications (OOS)
• Out of trends (OOT)
3
Concept of Change Control
Change:
Change means any modification to product, document,
process, equipment, instrument, system, facility etc.
Change control:
Change control means procedure reviews, verifies, regulates,
manages, approves and controls changes made to the existing
operating system or facility or process or procedure or document
or product of any combination
4
Management of Change Control
Written procedures should be established and maintained to
control changes for:
• Processes, Facilities, Utilities
• Methods, Validation, Computer systems
• Training and training materials
• Regulatory filings and Quality systems
• Changes should be justified and documented
• All changes that have the potential to impact the quality, safety
and efficacy should be evaluated, reviewed and approved
5
Change Control cycle
6
Need for
Change
Closure Plan for
change
Change
control
Implement/
reject solution
Procedure for Change control
7
1. Change request
identification
4. Change request approval
5. Change request
implementation
2. Change request assessment
3. Change request analysis
6. Reject or Defer of change
request
Conditions for Change control
• Revalidation
• Requalification
• Increased testing
• Stability analysis
• Document change
• Regulatory action / variation application
8
Out Of Specifications (OOS)
Out of Specification (OOS) means the test result that falls
outside the specifications or acceptance criteria which has been
specified in the official compendia monographs or the finished
product specification in registration dossiers.
OOS is observed in the analysis of –
• Stability study
• Finished products
• In-process
• Raw materials
• Packing materials
9
US FDA: GUIDELINE FOR INDUSTRY INVESTIGATING
OOS TESTING RESULTS FOR PHARMACEUTICAL
PRODUCTION
• PHASE I:
LABORATORY INVESTIGATION should include an initial
assessment of the accuracy of the laboratory's data.
• PHASE II:
FULL-SCALE OOS INVESTIGATION consist of a
production process review and/or additional laboratory work
10
Laboratory error
Laboratory error is the cause of OOS result which may
occur from instrument, reagent, reference standard, environment
condition, test method, analyst and calculation within laboratory.
Types of laboratory errors –
• Method of analysis
• Error in calculation
• Use of non-calibrated instruments
• Analyst error
• Instrument failure
11
Procedure for OOS
12
1. Reporting to laboratory supervisor
2. Recording and numbering of OOS
3. Investigation by analyst
4. Laboratory testing
5. Approval by laboratory supervisor
6. Testing by analyst
7. Preparation of test reports
8. Evaluation of subject results
9. Investigation by technical management team
10. Conclusion and Report of Data
11. Evaluation by quality manager
OOS INVESTIGATION
Re-testing:
The analysis of original sample at the time of phase- I
laboratory investigation.
Re-sampling:
The original batch is sampled by QA second time after QA
head authorization for re-analysis.
Re-analysis:
The analysis of re-sampled material for the verification of
results, if manufacturing investigation does not have root cause.
13
Tools for OOS Investigation
Problem
6M Method For cause and effectAnalysis-
Cause Effect
Equipment Process
People
Material
Environment
Measurement
Root Cause Analysis
Identify
problem
Identify root
cause
Define
problem
Understand
problem
Monitor
system
Corrective
measures
Corrective and Preventive Action
(CAPA)
• Draw appropriate root cause.
• Root cause should be logical and scientific.
• Collect the historical evidence if any with same
process or any other process in theplant.
• Identify the need for extend the investigation to past
or future batches.Provide corrective action with
evidence.
• Suggest preventive action.
• Conclude the activity in timely manner.
Regulatory impacts on OOS
17
Stabilitystudies required
OOS Shouldbe reportedto
RegulatoryAuthorities
OOS Batch shouldnot be sold
in regulatedmarket
OOS Batch connot be blend
with fresh approvedbatch
OOS Batch cannot be directly
soldin market
Out Of Trend (OOT)
A result that does not follow the expected trend, either in
comparison with other stability batches or with respect to previous
results collected during a stability study.
• More complicated than a comparison to specification limits.
Criteria to consider a result as OOT –
• For assay-
5% change in initial value of assay.
• For impurities-
Between 0.1 to 0.2 % increase or decrease as per initial reports
18
Method for identifying OOT
1. For the purpose of this study, data from ongoing stability
studies of a final drug product with a shelf life of 36 months
is used.
2. The ongoing studies were conducted on 10 batches of Product
X. (solid dosage form).
3. The ongoing studies were conducted for 36 months in
stability chambers at a constant temperature of 25 °C ± 2 °C
and relative humidity of 60% ± 5% in accordance with the
ICH guideline Q1A.
4. Analyst should carry out a assay at a time point of
0,3,6,9,12,18,24 and 36 months for all batches.
19
Types of OOT Determination
For determination of OOT Three methods are used-
1. Regression control chart method
2. By time point method
3. Slope control chart method
1.Regression-control-chart-method-
The regression-control-chart method is used to compare the
results within the batch and detect present OOT results. For the
purpose of this method, the tenth batch is examined.
20
2.By-time-point method-
The by-time-point method is used to determine
whether a result is within expectations on the basis of
experiences from other batches measured at the same
stability time point.
3.Slope-control-chart method-
The slope-control-chart method is commonly used
when it is necessary to compare the results between
several tested batches or between the currently tested
batch and other batches from the historical database.
OOT CYCLE
22
OOT
Determination
OOT Verification
OOT
Identification
New time point
data
Stability
Prediction
Case Study
The following case study, which describes an actual OOS
investigation, demonstrates the right way to approach the
challenge of determining root cause and taking
appropriate corrective action.
Situation -
According to procedure, the specification for the final fill
load sample had been set at ≤1 colony forming units
(CFU)/10 mL. However, 3 CFU/10 mL was observed in
the trypticase soy agar media incubated in an anaerobic
condition. The microorganism was identified
as Propionibacterium sp.
Pinpointing root causes-
A laboratory investigation report was initiated, and
the investigational tests and retest were performed
using remaining sample and retained sample. There
was no microbial growth in either sample. To
confirm that results of the retest were credible (the
retest had been performed more than 195 hours after
sampling), a hold-time study for 195 hours was
performed. However, this study failed to recover
results, and was declared invalid. Because there
were no confirmed laboratory errors and the
investigational test result was not valid due to hold-
time study failure, a deviation was initiated.
Simulating the sample-hold condition study to
reproduce the stored conditions before the sample
was tested. In this case, recovery of the
microorganism was maintained. The microbial hold-
time study (168 h in 2–8 °C conditions) did not
allow the recovery of contaminated
microorganisms, but in a short period of
storage, Propionibacterium sp. could be found
through the bioburden tests.
Performing a QC operator monitoring study to test
three QC analysts, including the first tester to
determine whether microorganisms could have been
introduced during the test
The usual checklist and analyst interview failed to
identify the root cause. QA does not typically
conduct routine oversight of laboratory operations
as they do for aseptic manufacturing operations. QA
internal audits had not identified this deficiency
either. Phase II of the investigation involved more,
and a more diverse group of, specialists, who
brought their knowledge to the investigation. They
reviewed the manufacturing process and event,
which led to the hypothesis that the most likely root
cause was sample contamination. Lab procedures
were reviewed again with the additional
investigational staff involved, and the root cause
identified.
Conclusion-
A number of lessons were learned from this
event. For one thing, supervisors and QA should
spend time watching critical operations in the lab
just as they do in production. It was also
determined that multi-disciplinary teams should
be used for investigations and internal audits and
QA staff included in Phase I investigation for
OOS investigations. The use of isolators should
also be considered, to further reduce the
likelihood of sample contamination occurring in
the future.
Reference
• Frank M. Gryna, Richar Chua, Joseph Defeo, Juran’s Quality
planning and analysis For enterprise quality, 5th edition, Tata
Mc-graw Education pvt ltd., New Delhi, Pg. No.340-356
• MHRA, Guidance for Out Of SecificationInvestigation, online
presentation, (2010), www.mhra.gov.uk/home/groups/comms
con/documents/website resources/con088215.pdf , accessed
May 13, 2013.
• FDA, Guidance for Industry: Investigating Out-Of
Specification (OOS) Test Results for Pharmaceutical
Production (Rockville, MD, 2006).
28
29

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Quality management system

  • 1. M. Pharm Sem-I Presentations Title-Quality Systems SUBMITTED TO SAVITRIBAI PHULE, PUNE UNIVERSITY , PUNE FOR PARTIAL FULFILMENT OF REQUIREMENTS FOR THE AWARD OF MASTER OF PHARMACY IN THE SUBJECT Quality Management Systems IN THE FACULTY OF SCIENCE AND TECHNOLOGY Bhujbal Knowledge City, MET’s Institute of Pharmacy, Adgaon, Nashik, 422003. Maharashtra, India Academic Year-2021-22 1 Presented By- Rohit Koli Shubham Chikhale Guided By:- Dr.Sapna Ahirrao
  • 2. Quality Systems Change control, Out of specifications (OOS), Out of Trend (OOT)
  • 3. Content • Concept of Change control • Procedure of change control • Management of change control • Conditions of change control • Out of specifications (OOS) • Out of trends (OOT) 3
  • 4. Concept of Change Control Change: Change means any modification to product, document, process, equipment, instrument, system, facility etc. Change control: Change control means procedure reviews, verifies, regulates, manages, approves and controls changes made to the existing operating system or facility or process or procedure or document or product of any combination 4
  • 5. Management of Change Control Written procedures should be established and maintained to control changes for: • Processes, Facilities, Utilities • Methods, Validation, Computer systems • Training and training materials • Regulatory filings and Quality systems • Changes should be justified and documented • All changes that have the potential to impact the quality, safety and efficacy should be evaluated, reviewed and approved 5
  • 6. Change Control cycle 6 Need for Change Closure Plan for change Change control Implement/ reject solution
  • 7. Procedure for Change control 7 1. Change request identification 4. Change request approval 5. Change request implementation 2. Change request assessment 3. Change request analysis 6. Reject or Defer of change request
  • 8. Conditions for Change control • Revalidation • Requalification • Increased testing • Stability analysis • Document change • Regulatory action / variation application 8
  • 9. Out Of Specifications (OOS) Out of Specification (OOS) means the test result that falls outside the specifications or acceptance criteria which has been specified in the official compendia monographs or the finished product specification in registration dossiers. OOS is observed in the analysis of – • Stability study • Finished products • In-process • Raw materials • Packing materials 9
  • 10. US FDA: GUIDELINE FOR INDUSTRY INVESTIGATING OOS TESTING RESULTS FOR PHARMACEUTICAL PRODUCTION • PHASE I: LABORATORY INVESTIGATION should include an initial assessment of the accuracy of the laboratory's data. • PHASE II: FULL-SCALE OOS INVESTIGATION consist of a production process review and/or additional laboratory work 10
  • 11. Laboratory error Laboratory error is the cause of OOS result which may occur from instrument, reagent, reference standard, environment condition, test method, analyst and calculation within laboratory. Types of laboratory errors – • Method of analysis • Error in calculation • Use of non-calibrated instruments • Analyst error • Instrument failure 11
  • 12. Procedure for OOS 12 1. Reporting to laboratory supervisor 2. Recording and numbering of OOS 3. Investigation by analyst 4. Laboratory testing 5. Approval by laboratory supervisor 6. Testing by analyst 7. Preparation of test reports 8. Evaluation of subject results 9. Investigation by technical management team 10. Conclusion and Report of Data 11. Evaluation by quality manager
  • 13. OOS INVESTIGATION Re-testing: The analysis of original sample at the time of phase- I laboratory investigation. Re-sampling: The original batch is sampled by QA second time after QA head authorization for re-analysis. Re-analysis: The analysis of re-sampled material for the verification of results, if manufacturing investigation does not have root cause. 13
  • 14. Tools for OOS Investigation Problem 6M Method For cause and effectAnalysis- Cause Effect Equipment Process People Material Environment Measurement
  • 15. Root Cause Analysis Identify problem Identify root cause Define problem Understand problem Monitor system Corrective measures
  • 16. Corrective and Preventive Action (CAPA) • Draw appropriate root cause. • Root cause should be logical and scientific. • Collect the historical evidence if any with same process or any other process in theplant. • Identify the need for extend the investigation to past or future batches.Provide corrective action with evidence. • Suggest preventive action. • Conclude the activity in timely manner.
  • 17. Regulatory impacts on OOS 17 Stabilitystudies required OOS Shouldbe reportedto RegulatoryAuthorities OOS Batch shouldnot be sold in regulatedmarket OOS Batch connot be blend with fresh approvedbatch OOS Batch cannot be directly soldin market
  • 18. Out Of Trend (OOT) A result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. • More complicated than a comparison to specification limits. Criteria to consider a result as OOT – • For assay- 5% change in initial value of assay. • For impurities- Between 0.1 to 0.2 % increase or decrease as per initial reports 18
  • 19. Method for identifying OOT 1. For the purpose of this study, data from ongoing stability studies of a final drug product with a shelf life of 36 months is used. 2. The ongoing studies were conducted on 10 batches of Product X. (solid dosage form). 3. The ongoing studies were conducted for 36 months in stability chambers at a constant temperature of 25 °C ± 2 °C and relative humidity of 60% ± 5% in accordance with the ICH guideline Q1A. 4. Analyst should carry out a assay at a time point of 0,3,6,9,12,18,24 and 36 months for all batches. 19
  • 20. Types of OOT Determination For determination of OOT Three methods are used- 1. Regression control chart method 2. By time point method 3. Slope control chart method 1.Regression-control-chart-method- The regression-control-chart method is used to compare the results within the batch and detect present OOT results. For the purpose of this method, the tenth batch is examined. 20
  • 21. 2.By-time-point method- The by-time-point method is used to determine whether a result is within expectations on the basis of experiences from other batches measured at the same stability time point. 3.Slope-control-chart method- The slope-control-chart method is commonly used when it is necessary to compare the results between several tested batches or between the currently tested batch and other batches from the historical database.
  • 23. Case Study The following case study, which describes an actual OOS investigation, demonstrates the right way to approach the challenge of determining root cause and taking appropriate corrective action. Situation - According to procedure, the specification for the final fill load sample had been set at ≤1 colony forming units (CFU)/10 mL. However, 3 CFU/10 mL was observed in the trypticase soy agar media incubated in an anaerobic condition. The microorganism was identified as Propionibacterium sp.
  • 24. Pinpointing root causes- A laboratory investigation report was initiated, and the investigational tests and retest were performed using remaining sample and retained sample. There was no microbial growth in either sample. To confirm that results of the retest were credible (the retest had been performed more than 195 hours after sampling), a hold-time study for 195 hours was performed. However, this study failed to recover results, and was declared invalid. Because there were no confirmed laboratory errors and the investigational test result was not valid due to hold- time study failure, a deviation was initiated.
  • 25. Simulating the sample-hold condition study to reproduce the stored conditions before the sample was tested. In this case, recovery of the microorganism was maintained. The microbial hold- time study (168 h in 2–8 °C conditions) did not allow the recovery of contaminated microorganisms, but in a short period of storage, Propionibacterium sp. could be found through the bioburden tests. Performing a QC operator monitoring study to test three QC analysts, including the first tester to determine whether microorganisms could have been introduced during the test
  • 26. The usual checklist and analyst interview failed to identify the root cause. QA does not typically conduct routine oversight of laboratory operations as they do for aseptic manufacturing operations. QA internal audits had not identified this deficiency either. Phase II of the investigation involved more, and a more diverse group of, specialists, who brought their knowledge to the investigation. They reviewed the manufacturing process and event, which led to the hypothesis that the most likely root cause was sample contamination. Lab procedures were reviewed again with the additional investigational staff involved, and the root cause identified.
  • 27. Conclusion- A number of lessons were learned from this event. For one thing, supervisors and QA should spend time watching critical operations in the lab just as they do in production. It was also determined that multi-disciplinary teams should be used for investigations and internal audits and QA staff included in Phase I investigation for OOS investigations. The use of isolators should also be considered, to further reduce the likelihood of sample contamination occurring in the future.
  • 28. Reference • Frank M. Gryna, Richar Chua, Joseph Defeo, Juran’s Quality planning and analysis For enterprise quality, 5th edition, Tata Mc-graw Education pvt ltd., New Delhi, Pg. No.340-356 • MHRA, Guidance for Out Of SecificationInvestigation, online presentation, (2010), www.mhra.gov.uk/home/groups/comms con/documents/website resources/con088215.pdf , accessed May 13, 2013. • FDA, Guidance for Industry: Investigating Out-Of Specification (OOS) Test Results for Pharmaceutical Production (Rockville, MD, 2006). 28
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