Deviations Permissibility & Handling in GMP
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This document discusses deviations in manufacturing processes and their proper handling according to GMP regulations. It defines what constitutes a deviation and differentiates between planned and unplanned deviations. It outlines the obligations to properly document, investigate, and report on deviations to determine their impact. The proper steps for investigating deviations are provided, including determining what happened, who was involved, and identifying the root cause. The importance of corrective and preventive actions is emphasized to prevent future deviations and ensure product quality.
![Deviations Permissibility & Handling in GMP
(Tutorial-4)
Roohi B. Obaid
19 May 2018 at Karachi
[143 slides]](https://image.slidesharecdn.com/deviationspermissibilityhandlingingmp-180520064358/85/Deviations-Permissibility-Handling-in-GMP-1-320.jpg)
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Deviations Permissibility & Handling in GMP
- 1. Deviations Permissibility & Handling in GMP (Tutorial-4) Roohi B. Obaid 19 May 2018 at Karachi [143 slides]
- 3. Knowledge Sharing Exercise To Learn through Debate, Discussion & Experience of others
- 4. This presentation discusses Regulatory Science, nothing more & nothing less Reference: US-FDA Documents / Scientific Articles/ Real time hands on experience of Compliance & Enforcement Personal point of view & nothing to disclose Disclaimer
- 5. Deviation
- 7. Deviation Departure from an approved instruction or established standards
- 9. Absolute Fact The drug which is tested is not used & the drug which is used is not tested
- 10. Absolute Fact Certainty Probability Control on Manufacturing Process Q
- 11. Absolute Fact Product quality depends on each step in manufacturing process must be controlled to maximize the probability and enhance certainty that the FPP will meet its quality, design specifications, perform well & uphold promise
- 12. Quality System OOS Deviations Recall & Returns Complaints Risk Management Change Management
- 13. Deviation GMP Mistakes or Error Reprocessing or Rework Unapproved changes Performing an activity without proper training Outside of operating parameter or in-process control limit Failure to follow SOP or approved batch record instructions
- 14. Departure from an approved instruction or established standard
- 15. Departure from an approved instruction or established standard e.g. Soaking
- 16. Departure from an approved instruction or established standard Departure from approved procedure or established specifications e.g. Soaking
- 17. Departure from an approved instruction or established standard Departure from approved procedure or established specifications e.g. Soaking e.g. Water bath
- 18. Obligation ANY deviation from established procedure should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusion should be documented [ICH]
- 20. Obligation Written procedure should be established & followed for investigating critical deviations or the failure of a batch … the investigation should extend to other batches that may have been associated with the specific failure or deviation [ICH]
- 22. Obligation Deviation in yield associated with critical process should be investigated to determine their impact or potential impact on the resulting quality of affected batches
- 23. Obligation Any deviation should be evaluated to ensure that there is no detrimental effect upon the fitness for the purpose of material (intermediate, API, etc.)
- 24. Obligation Deviation from approved standard of calibration on critical instrument should be investigated to determine if these could have had an impact on quality of …. Manufactured using this equipment since last successful calibration
- 25. Obligation
- 26. Obligation All deviation, investigation and OOS reports should be reviewed as part of the batch record review before the batch is released
- 27. Obligation Evaluation report that cross refers the validation protocol should be prepared, summarizing the results obtained, commenting on any deviation observed & drawing the appropriate conclusion, including recommending changes to correct deficiencies
- 28. Types ? Activity performed differently and or modified than that specified in an approved document
- 29. Types ? Activity performed differently and or modified than that specified in an approved document Planned Un-planned
- 31. Planned Deviation Pre-described, Pre-approved for specified period for specific number of batches
- 32. Planned Deviation Pre-described, Pre-approved for specified period for specific number of batches Feb 2016 Annual Maintenance 60 Batches .. One batch per day Jan 2016 Mfg .. Schedule 5 to 10 Feb
- 33. Planned Deviation Pre-described, Pre-approved for specified period for specific number of batches Approved well before execution Handled through approved change control procedure Changes should be evaluated for product impact significance
- 34. Planned Deviation Unintentional Pre-described, Pre-approved for specified period for specific number of batches Un-planned Unexpected
- 35. Un-Planned Deviation Uncontrolled event in the form of non- compliance at any stage of manufacturing etc. Incident
- 36. Quality impacting (purity, strength, release, delivery etc.) Non-quality impacting Sec. packaging, out of trend, yield etc.)
- 37. Major Critical Minor Quality impacting (purity, strength, release, delivery etc.) Non-quality impacting Sec. packaging, out of trend, yield etc.)
- 38. Typical examples Temperature, humidity, air pressure Breakdown of process equipment Equipment out of calibration
- 39. Typical examples Alternative equipment used Process done but not documented In-process control limit went out
- 40. Take Home Message Your corrective action must not be Biased & must Match with potential root cause
- 41. Take Home Message The purpose of conducting investigation must not be to release the batch
- 42. Take Home Message … It is to determine the root cause for the deviation
- 43. Take Home Message … It is to implement appropriate & meaningful CA
- 44. Take Home Message … It is to evaluate the implicated system
- 46. Investigating Steps Discovery of deviation Documentation of events Immediate corrective action Investigation of root cause Casual analysis Corrective action Preventive action Effectiveness evaluation Review & reshape the policy
- 47. Investigation
- 48. Investigation What was discovered Who was involved When did the event occur Where did the deviation occur How was the deviation discovered How frequently does the process occur
- 49. Investigation Remember, there is a big difference b/w What happened & Why happened -OR- What happened & How happened What was discovered Who was involved When did the event occur Where did the deviation occur How was the deviation discovered How frequently does the process occur
- 51. What Happened Why How Why eg. Dissolution failure
- 52. Remember Deviation is a beauty It evolves knowledge and science, but …
- 53. Remember Deviation is a beauty It evolves knowledge and science, but … Don’t let it affect your product quality, performance & promise
- 54. Obligations & Emerging Expectations
- 56. Every deviation is fully recorded
- 57. Assessment of deviations from specified procedures
- 59. Focus deviations on Periodical Quality Reviews
- 60. Authorization for deviations from manufacturing formula, process, packaging & testing instructions
- 61. Policies, procedures, records of actions that took part in construction of decision for deviation
- 62. Policies, procedures, records of actions that took part in construction of decision for deviation DOCUMENT
- 63. What have been done to avoid it? Why it was unavoidable
- 64. What have been done to avoid it? Why it was unavoidable REASON?
- 65. Any signal deviating from trend will be investigated
- 66. Deviations in stability programs, no matter it is authorized
- 67. Quality System staff are effectively integrated into manufacturing & involved in non-conformance investigation
- 68. Investigation, conclusion & follow up must be documented
- 69. Justify deviations from the written procedures
- 70. Don’t leave any failure uninvestigated, no matter, batch is destroyed or already been consumed
- 71. Investigation will always be extended to other batches & reason of limit will justify
- 72. Let’s Recap through discussion
- 73. Deviations
- 75. Deviations 1 2 3 4 Use of Tray Dryer instead of FBD
- 76. Deviations 1 2 3 4 Exceeded the time specified for boiling a liquid e.g. > 10 min
- 77. Deviations 1 2 3 4 Used the wrong sieve no. for sieving
- 78. Deviations 1 2 3 4 Changed the mixing order of ingredients during batch processing
- 79. Non- Conformance
- 81. 1 2 3 4 Work done but not recorded Non- Conformance
- 82. 1 2 3 4 Line clearance not done, another batch started Non- Conformance
- 83. 1 2 3 4 Change in size of packaging by supplier Non- Conformance
- 84. 1 2 3 4 Testing by a person who is not qualified for the purpose Non- Conformance
- 85. Incident
- 86. 1 2 3 4 Incident
- 87. 1 2 3 4 Sieve break during operation Incident
- 88. 1 2 3 4 Material dropped on the floor while shifting to hopper Incident
- 89. 1 2 3 4 Mix up of 40 mg & 240 mg label Incident
- 90. 1 2 3 4 Blister machine suddenly malfunctioned Incident
- 91. Discrepancy
- 97. … A multiple injection manufacturing facility Injection X 500 mg / 10 ml always found with yield 103 to 104% Assay trend moves in between 101 to 103% Process loss of 3 to 6% for other injection products Lets think what is going on … ?
- 99. System Tools: Policy, SOP, Forms, Register, Process Flow Incorporate risk assessment into process Train staff in whole process including risk ..
- 100. System Ensure procedure is understood & followed Track progress of each deviation Ensure timely closure
- 101. System Periodical review of deviations Trend & pattern of repeat events Strategy to move forward
- 102. Process
- 103. Process Raise ASAP Complete initial detail Assess criticality Corrections Investigation Assess risk Corrections Conclusion Corrective action Preventive action Close Reviews
- 104. Closing Deviations 8
- 105. 1 Write up the investigation in detail 2 Explain what happened & why 3 Identify & document root cause(s) 4 Detail corrections & corrective actions
- 106. 5 Ensure CAPA are raised 6 Reviewed by Quality Assurance 7 Final closure by Quality Assurance 8 Record closure & maintain register
- 107. Take Home Message Make sure that policy, procedures, forms, process flow are well understood & aligned to walk and talk together
- 108. Take Home Message Appropriate training & trained staff for investigations is inevitable to reach logical decisions that satisfy regulatory expectations
- 109. Take Home Message Be simple Don’t make the process unreasonably complicated or over complicated
- 110. Take Home Message Don’t expect that everyone can be a good investigator
- 111. Common Problems
- 112. 1 Poor investigation 2 Not addressing facts/ignoring evidence 3 Only considering one root cause 4 Poor scientific basis
- 113. 5 Making & stucking on assumptions 6 Not raising CAPA 7 Repeat deviations 8 Leave assessment of impact on other batches
- 114. … Tablet 400 mg instead of 200 mg Same product of two different strengths … Proportionality in granulation was same … Batch was compressed for 400 mg tablet Packaging jar was labeled for 200 mg … All documents were prepared for 200 mg except compression … Lets think what can be done … ?
- 115. … Evaluation of supplier competence Glass bottles We have to monitor and review the performance as per QMS Lets think what can be done … ?
- 116. Remember Deviation is not allowed if not justified in Quality System Document to ensure that history of the product can be traced back with regard to concerning personnel, equipment, materials, process etc.
- 117. Remember Handling of non-conformance or deviations are key component of Quality System Document investigation, conclusion and follow up to ensure that product confirms to the required expectations. It is inevitable to measure process & product attributes
- 118. Remember Investigation of discrepancy is critical esp. when affect product quality It may be detected at any stage of manufacturing & testing process, it should be handled appropriately, sometime it may not have an impact on product
- 119. Remember Responsive deviation & investigation system is a front burner attribute of Quality System Implementation of Quality System facilitates compliance and assures consistent production for safe, effective product under a sustainable and productive environment
- 120. Remember Deviation may be acceptable if Does not compromise the quality of drug product, it is justified, documented & comes under microscope for review on regular basis
- 121. Remember Sufficient rigorous scientific evidence & statistical measures
- 122. Remember Sufficient Rigorous Scientific Evidence & Statistical Measures Product and process deviation can be explained scientifically with identifiable root cause to keep aligned goal of process validation
- 123. A closer look at inspection (MHRA) Deviations were not fully recorded and investigated
- 124. A closer look at inspection (MHRA) Deviation investigations did not include an appropriate level of investigations and did not capture all relevant information
- 125. A closer look at inspection (MHRA) Quality impact of deviations and CAPAs implemented were not appropriately assessed
- 126. A B Approved for particular purpose NOT Approved for particular purpose
- 127. A B Weighed on B, but not recorded Approved for particular purpose NOT Approved for particular purpose
- 128. A B Approved for particular purpose NOT Approved for particular purpose Weighed on B, but not recorded Impact?
- 129. Escape from investigation Trapped in investigation Unreasonable
- 130. If B goes out of calibration & investigated for all the weighing done on it, the particular batch will escape from investigation due to non-recording If A goes out of calibration & investigated for all the weighing done on it, the particular batch will be added for no reason in the investigation
- 131. A • XXX B • YYY C • ZZZ
- 132. A • XXX B • YYY C • ZZZ A • XXX C • ZZZ B • YYY
- 133. Lets imagine a product/ process/ procedure and think of an instance where a minimum deviation can greatly impact the product quality Processing Parameter Equipment Testing Procedure
- 134. Paracetamol suspension Millions of bottles rejected PHC Program Xanthan gum Process time
- 135. Paracetamol tablet Millions of packs recalled Product discontinuation for > year RB Gelatin Source Mixer?
- 136. Soft gelatin Formulation Millions of capsules recalled Manufacturing site closed for > year MK Gelatin Source Stability study?
- 137. XXX HC Cream Product discontinued RB toll mfg GZ Testing method Interpretation w/o scientific support
- 138. Paracetamol suspension Millions of bottles rejected PHC Program Particle size change Stability study?
- 139. Benzyl Benzoate Lotion Millions of bottles rejected ?????? Order of mixing? Processing temperature?
- 140. PVP Solution Thousands of bottles rejected ?????? Cap change? Potency loss?
- 141. Salbutamol SR/ Cetrizine tablet Stop manufacturing ?????? Release w/o dissolution? Critical deviation?
- 142. 2X mg X mg 1/2X mg
- 143. Thank You