Documentation: First & Last Exit in GMP
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The document discusses documentation and standard operating procedures (SOPs) for GMP compliance. It describes issues found at a pharmaceutical company (Goran Pharma) regarding inadequate testing of glycerin lots for impurities. The FDA found the company's responses to be inadequate. The document also discusses how to properly write SOPs, including getting appropriate reviews and authorization. It provides examples of documentation issues found during an FDA inspection at another company (Lupin) regarding inadequate cleaning processes and validation. The FDA requested extensive corrective and preventative actions from Lupin to address their cleaning validation program and ensure proper documentation and process controls.
Documentation: First & Last Exit in GMP
- 1. Roohi B. Obaid 07 March 2020 2nd Version Documentation The First & Last Exit in GMP
- 3. Documents of US-FDA, Papers from Pharmaceutical Technology & Review Scientific Articles are used to construct presentation Reference
- 4. Opening Case Documentation The First & Last Exit in GMP
- 5. A 10 year old child experiencing 101℃ fever was administered 1 TSP full Paracetamol Suspension at home by his mother. He died
- 7. Goran Pharma April 2018 Identification of DEG or EG was not done on each lot of glycerin
- 8. Goran Pharma April 2018 Identification of DEG or EG was not done on each lot of glycerin
- 9. Glycerin Why it (excipient) requires testing for each lot
- 10. Glycerin Impurities Why these (DEG or EG) requires testing for each lot
- 11. DEG Death Tragedies 1938 … 1995 … going on Suicide … dosage incidence
- 12. Goran Pharma April 2018 Identification of DEG or EG was not done on each lot of glycerin Failed to assure acceptability of lots
- 13. Goran Pharma April 2018 Laboratory results will be compared with supplier’s COA to confirm the reliability of testing for all lots Revised SOP
- 14. Goran Pharma April 2018 Not clear whether testing on each incoming component lot for all attributes to verify the accuracy of supplier’s COA will be done OR Supplier’s test results will be qualified through an initial round of testing as well as ongoing testing at appropriate intervals FDA: Inadequate Response
- 15. Goran Pharma April 2018 Not clear whether testing on each incoming component lot for all attributes to verify the accuracy of supplier’s COA will be done OR Supplier’s test results will be qualified through an initial round of testing as well as ongoing testing at appropriate intervals FDA: Inadequate Response
- 16. Goran Pharma April 2018 Not clear whether testing on each incoming component lot for all attributes to verify the accuracy of supplier’s COA will be done OR Supplier’s test results will be qualified through an initial round of testing as well as ongoing testing at appropriate intervals FDA: Inadequate Response
- 17. Laboratory results will be compared with supplier’s COA to confirm the reliability of testing for all lots
- 18. Laboratory results will be compared with supplier’s COA to confirm the reliability of testing for all lots Not clear whether testing on each incoming component lot for all attributes to verify the accuracy of supplier’s OR Supplier’s test results will be qualified through an initial round of testing as well as ongoing testing at appropriate intervals
- 19. Goran Pharma April 2018 Provide an Improved Procedure FDA: Inadequate Response
- 20. Compliance Finished dosage form will be subject to end product testing before release from the GMP zone for the market Write an instruction that may diminish the regulatory intent if written in SOP Group Working
- 21. Compliance Finished dosage form will be subject to end product testing before release from the GMP zone for the market Write an instruction that may diminish the regulatory intent if written in SOP Group Working
- 22. Compliance E.g. In case of Injectables Sterility test: Product may be released after 12 days upon observing no growth. Two days are consumed in distribution or to reach market. Group Working
- 23. Compliance E.g. In case of Tablets Every 5th batch of oral solid dosage form will be subject to dissolution test Group Working
- 24. Compliance E.g. In case of Tablets Every 3rd batch of oral solid dosage form will be subject to microbial testing Group Working
- 25. Compliance E.g. In case of Oral Liquid Solution Assay will be performed before filling of every solution and not after packaging Group Working
- 26. Documentation The First & Last Exit in GMP
- 29. 1 2 Regulatory Expectations Policies and Procedures
- 30. 1 3 2 Regulatory Expectations Document Integrity Policies and Procedures
- 31. 1 3 2 4 Regulatory Expectations Document Integrity Policies and Procedures Batch Documentation
- 33. If someone reads detail procedure to swim Can he swim independently? Opening Question 100% 50% 10% 0% 1
- 34. If someone reads detail procedure to swim Can he swim independently? Opening Question 100% 50% 10% 0% 1
- 35. How much you are sure that someone can manufacture tablets if he follows the written SOP and these tablets will be of desired quality? Opening Question 100% 50% 10% 0% 2
- 36. How much you are sure that someone can manufacture tablets if he follows the written SOP and these tablets will be of desired quality? Opening Question 100% 50% 10% 0% 2
- 41. Procedure Execution Recording Documentation Documentation
- 42. Procedure Execution Recording Documentation Documentation Operations Record that describes how an activity, event or process was actually performed
- 43. Procedure Execution Recording Documentation Documentation
- 44. Procedure Execution Recording Documentation Documentation Operations Record for describing activity, event or process (i.e. recordkeeping)
- 45. Procedure Execution Recording Documentation Documentation
- 46. 2 Policies and Procedures
- 47. Policies • Documents used to influence and dictate actions / decisions • Broad in scope and affect typically different organizational/ business/ geographical units • Describes requirements but NOT specifics on how to accomplish tasks
- 48. Policies • Documents used to influence and dictate actions / decisions • Broad in scope and affect typically different organizational/ business/ geographical units • Describes requirements but NOT specifics on how to accomplish tasks
- 49. Policies • Documents used to influence and dictate actions / decisions • Broad in scope and affect typically different organizational/ business/ geographical units • Describes requirements but NOT specifics on how to accomplish tasks
- 50. Policies Directions reflecting vision ……Where to go …… How to go? … How to execute? … How to move ? … What not to do? …
- 51. Procedure Set of instructions that describes a task or process. A specified way to perform an activity
- 52. Instructions The specific, detailed requirements for performing a particular task
- 53. Governance
- 59. Consistent Construct Continuous What, Why and How
- 60. Consistent Construct Continuous Clear CompleteCorrect
- 64. Question A company has a Cleaning Policy in place but don’t have a procedure to execute for cleaning of water tank inside GMP zone It is outsourced & performed by 3rd party, company is unaware about the procedure of cleaning used by them. You are Inspector. Please write detail what are your concerns with regard to Quality (Q) & Compliance (C) 3
- 65. Question If a mixer is run for 15 minutes, it mixes the materials because it is repeated 3 times and validated, Is it logical to waive in-process tests? 4
- 66. Workshop Write instruction how to clean a pipe piece used in filling of water in manufacturing unit Write instructions to hang a wall clock, adjust its time, change of its battery periodically, and its monitoring OR
- 67. Workshop What others aspects should be included in SOP other than instructions
- 68. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 69. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 70. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 71. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 72. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 73. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 74. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 75. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 76. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 77. Workshop How to write SOP • Concept …begin with the end in mind • Select a format (approved) • Collect the inputs • Define scope • Identify the audience • Write SOP • Send for review • Answer the questions • Get it authorized
- 78. Written By • Performer Reviewed By • Supervisor Approved By • Operational Head Authorized By • Mgmt. Representative SOP Writing
- 79. Written By • Performer Reviewed By • Supervisor Approved By • Operational Head Authorized By • Mgmt. Representative SOP Writing Development & Approval of Training Plan & Training Material
- 80. Development & Approval of Training Plan & Training Material
- 81. Effectiveness of Training Material – Identified Development & Approval of Training Plan & Training Material
- 82. Effectiveness of Training Material – Identified Performance Indicators of Trainer - Developed Development & Approval of Training Plan & Training Material
- 84. Implementation of SOP following Authorization Monitored … Amendment or Modification
- 85. Standard Operating Procedure enables Uniform working among different individuals for a Consistent output
- 86. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 87. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 88. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 89. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 90. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 91. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 92. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 93. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 94. Workshop Write Cleaning Policy (An outline) • Statement • Principle, values, philosophy • Detail objectives • Strategy to achieve objectives • Specific actions when required • Desired outcome of specific actions • Performance indicators • Review program
- 95. Lupin 2019 Cleaning process for manufacturing equipment was inadequate FDA Observation
- 96. Lupin 2019 Cleaned as per label But dirt was visible
- 97. Lupin 2019 Non-dedicated tablet press labeled as “cleaned,” observed with unknown XXX residues on multiple product contact surfaces. FDA explained
- 98. Lupin 2019 Procedure was not followed or the required post-cleaning checks were inadequate Firm’s Response - 1
- 99. Lupin 2019 Tablet press was re-cleaned, and operators were retrained. Firm’s Response - 2
- 100. Lupin 2019 Inadequate Response FDA Stance
- 101. Lupin 2019 A comprehensive, independent retrospective assessment of your cleaning processes, practices, and validation studies to evaluate the scope of cross-contamination hazards. FDA asked for
- 102. Lupin 2019 Identity of residues FDA asked for
- 103. Lupin 2019 Other manufacturing equipment that may have been improperly cleaned FDA asked for
- 104. Lupin 2019 An assessment whether cross- contaminated products may have been released for distribution. FDA asked for
- 105. Lupin 2019 The assessment should cover each piece of equipment used to manufacture more than one product, including API and finished products. FDA asked for
- 106. Lupin 2019 A CAPA plan, based on the retrospective assessment, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. FDA asked for
- 107. Lupin 2019 A detailed summary of your process for lifecycle management of equipment cleaning FDA asked for
- 108. Lupin 2019 Describe provisions for ongoing verification that proper cleaning is consistently executed for all products, and any improvements to be implemented FDA asked for
- 109. Lupin 2019 Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. FDA asked for
- 110. Lupin 2019 This should include but not be limited to identification and evaluation of all worst- case: 1. drugs with higher toxicities 2. drugs with higher drug potencies FDA asked for
- 111. Lupin 2019 3. Drugs of lower solubility in their cleaning solvents 4. Drugs with characteristics that make them difficult to clean FDA asked for
- 112. Lupin 2019 5. Swabbing locations for areas that are most difficult to clean 6. Maximum hold times before cleaning FDA asked for
- 113. Lupin 2019 Describe the steps that must be taken in change management system before introducing new mfg equipment or a new product FDA asked for
- 114. Lupin 2019 A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment. FDA asked for
- 115. 3 Document Integrity
- 118. Complete
- 119. Complete Accurate
- 124. Attributable Legible Contemporaneously Original Accurate Traceable to a unique individual
- 125. Attributable Legible Contemporaneously Original Accurate Data must be recorded permanently and be readable
- 126. Attributable Legible Contemporaneously Original Accurate Activities must be recorded at the time they occur
- 127. Attributable Legible Contemporaneously Original Accurate First capture of data (not transcribed data), must review the original record, must retain the original or certified copy of the original record
- 128. Attributable Legible Contemporaneously Original Accurate Records must be accurate, which is achieved through the Quality Management System
- 129. Attributable Legible Contemporaneous AccurateOriginal A L AOC Explanation was recorded by pencil
- 130. Attributable Legible Contemporaneous AccurateOriginal A L AOC Explanation was recorded by pencil
- 131. Attributable Legible Contemporaneous AccurateOriginal A L AOC No editing performed without documented amendment
- 132. Attributable Legible Contemporaneous AccurateOriginal A L AOC No editing performed without documented amendment
- 133. Attributable Legible Contemporaneous AccurateOriginal A L AOC True copy was not sent to the Regulatory Agency
- 134. Attributable Legible Contemporaneous AccurateOriginal A L AOC True copy was not sent to the Regulatory Agency
- 135. Attributable Legible Contemporaneous AccurateOriginal A L AOC QA performed particular activity as documented
- 136. Attributable Legible Contemporaneous AccurateOriginal A L AOC QA performed particular activity as documented
- 137. Attributable Legible Contemporaneous AccurateOriginal A L AOC Real time was recoded in raw data, while this raw data is not kept as a metadata
- 138. Attributable Legible Contemporaneous AccurateOriginal A L AOC Real time was recoded in raw data, while this raw data is not kept as a metadata
- 139. Lets review and have a grip on ALCOA
- 140. AttributableA Attributable means information is captured in the record So that it is uniquely identified as executed by the originator of the data (e.g. a person or a computer system).
- 141. LegibleL The terms legible, traceable and permanent refer to the requirements that data are readable, understandable, and allow a clear picture of the sequencing of steps or events in the record so that all activities conducted can be fully reconstructed by the people reviewing these records at any point during the records retention period. Traceable Permanent
- 142. ContemporaneousC Contemporaneous data are data recorded at the time they are generated or observed.
- 143. OriginalO Original data include the first or source capture of data or information and all subsequent data required to fully reconstruct the conduct of the activity.
- 144. OriginalO Original data original data should be original data and/or true and verified copies that preserve the content and meaning of the original data should be as such, original records should be complete, enduring & readily retrievable & readable throughout the records retention period. reviewed retained
- 145. AccurateA The term “accurate” means data are correct, truthful, complete, valid and reliable.
- 146. Lets have an insight on ALCOA & understand ALCOA+
- 147. Complete All data are available, nothing has been deleted (evidence: audit trail) Available in order one by one & traceable
- 149. Consistent Data are recorded chronologically with date and time (evidence: audit trail)
- 151. Enduring Data are accessible for an extended period of time – after 20 years.
- 152. Available Data are accessible over the lifetime of the product.
- 153. Static Dynamic
- 154. Static Dynamic Fix data document such as paper record or an electronic image
- 155. Static Dynamic Record format allows interaction b/w the user & record content
- 156. Question Please write 9 different expectations of regulators from your documents 5
- 159. Batch history is imperative to tracking, sustaining product quality, viability & safety It’s a high risk data It’s a matter of life & lives
- 161. Check Verify Review
- 162. Why do we review Batch Record?
- 163. Why we do not believe on real time data? Why do we review Batch Record?
- 164. Why we do not believe on real time data? Why do we review Batch Record? What we expect from Batch Record Review?
- 165. How it is performed?
- 166. Lets have a hypothesis outline to make decision clear & consistent
- 167. Minor health or regulatory suffering Reversible life crisis Irreversible life crisis Limited to discussion on today’s session 2 1 3
- 168. Certificate of Analysis of API Review
- 183. Handwritten change but date of change was not traceable
- 184. Use of ditto mark
- 185. Use of signature stamp
- 186. Ink color is not specified & multi color is used without reason
- 187. Log book correction failed to identify the person who made the change
- 188. Use of pencil
- 189. Traces of erasing pencil marks
- 191. Meta data not available for verification
- 192. Correction of documentation error should include
- 193. Correction of documentation error should include Draw a single line through the error1
- 194. Correction of documentation error should include Draw a single line through the error Make the correction next to the error2 1
- 195. Correction of documentation error should include Draw a single line through the error Make the correction next to the error Write an explanation for the error 2 1 3
- 196. Correction of documentation error should include Draw a single line through the error Signature & date the correction Make the correction next to the error Write an explanation for the error 2 1 4 3
- 197. Check Verify Review
- 198. Question What are the 3 basic intents of Batch Document Review 6
- 200. Manual recording are inherently slow & prone to error
- 201. Manual recording are inherently slow & prone to error Incorrect data entry
- 202. Manual recording are inherently slow & prone to error Blindness & failure to recognize OOS Incorrect data entry
- 203. Manual recording are inherently slow & prone to error Blindness & failure to recognize OOS Missing signatures Incorrect data entry
- 204. Manual recording are inherently slow & prone to error Blindness & failure to recognize OOS Missing signatures Used incorrect form Incorrect data entry
- 205. Manual recording are inherently slow & prone to error Blindness & failure to recognize OOS Sending wrong form to wrong person Missing signatures Used incorrect form Incorrect data entry
- 206. Manual recording are inherently slow & prone to error Blindness & failure to recognize OOS Sending wrong form to wrong person Missing signatures Used incorrect form Incorrect data entry Form left incomplete
- 207. Data located in separate positions
- 208. What documentation was missed & what reviews missed. List the deficiencies Pakistan 150 deaths case
- 209. Thank You