Science behind Trust & Confidence
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A tutorial used to teach professionals on Regulatory Expectations for Supplier Qualification in Pharmaceutical Manufacturing (16 March 2019)
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Science behind Trust & Confidence
- 1. Supplier Qualification, Contract Agreements & their Integration in Pharmaceutical Manufacturing Operations Roohi B. Obaid Mar 16th 2019
- 3. It reflects the views and understanding of presenter & may not be construed to represent the views or policies of organization or association to which speaker has ties Documents of US-FDA & Review Scientific Articles are used to construct presentation Disclaimer Reference
- 4. The top most important constituent
- 5. The top most important constituent Active Pharmaceutical Ingredient
- 6. API
- 7. Its traveling track & speed API
- 8. Its traveling track & speed Delivery to Destination API
- 20. API Poor development Poor Control Poor UnderstandingInconsistency
- 21. Some excipients are critical too Remember Please
- 22. Potential Tragedies Anything that goes wrong, it may reflect in finished product & may end up to damage patient All your controls & GMP go into vain
- 24. How difficult it is to differentiate the taste on the basis of chemical testing of tea?
- 25. We are purchasing paracetamol from X of China. Why do you need to review DMF? 1
- 26. Purchasing paracetamol from X of China since years without any complaint. Why are you interested to inspect the facility? 2
- 27. Searching for source of new product (under development) Why are you interested to see the DMF? What purpose you are looking for? 3
- 28. Searching for source of new product (under development) Why are you interested to see the facility? What purpose you are looking for? 4
- 29. How do you maintain your trust that the material is coming from same facility you have qualified & comply all the attributes that are promised & not narrated in COA? 5
- 31. Supplier includes Services, Materials, Machinery, Consultancy etc. 6
- 32. Supplier includes Services, Materials, Machinery, Consultancy etc. 6
- 33. Supplier includes Services, Materials, Machinery, Consultancy etc. 6
- 34. Supplier includes Services, Materials, Machinery, Consultancy etc. 6
- 36. It is indeed not supplier qualification but security of supply chain too
- 39. Site Master File Drug Master File Supplier Material
- 40. Melamine Case Study > 8000 pets died > 5 infants died Intentionally added to boost proteins
- 41. Melamine Case Study No direct impact on pharmaceutical industry Potential of similar fraud or devastating results No margin of error like heparin tragedy
- 42. Blind trust … started testing
- 44. GMP Supply Chain Influence & Qualify
- 45. Development GMP Supply Chain Influence & Qualify
- 46. Lets have a sketch how things will move
- 47. Frame, Strategy and Progressive Initiatives
- 48. Assess Risk Conduct a comprehensive risk assessment to determine the appropriate controls for the supplier based on the products or services they provide & their criticality to your product 1
- 50. How do you know that this bag is clean. Remember it will be in contact of materials
- 51. Audit Perform a supplier audit to assess the company ability to deliver product or services of desired quality and strength of its GMP compliance 2
- 53. How do you know that product can be consistently produced without contamination & mix up
- 54. How do you know that product is pure & of required strength
- 55. How do you know that data generated for product knowledge & shelf life is of integrity
- 57. Performance Monitor, document & review supplier performance on a regular basis 3
- 59. CAPA, Investigations, Deviations, Change Management, Failures, Salvaged, Recalls, Returns, Complaints
- 60. Agreement Establish appropriate written Quality Agreements regarding responsibility for GMP activities. Make every responsibility simple & clear 4
- 62. Who is responsible for what, Where is ambiguity, Where is mutual responsibility Make simple & clear
- 63. Development & Qualification of Suppliers
- 65. Science, Trust & their Verification
- 66. Independent Pre- Audit Assessment Site Inspection Post Audit Assessment 1 2 3
- 67. Insight Flow diagram(s) of manufacturing processes
- 68. Insight Manufacturer(s) & their Quality Management
- 69. Insight Building, Facilities Site & Process Equipment
- 73. Insight Packaging & Identification labeling of Ingredients and Intermediates
- 74. Insight Storage & Distribution
- 75. Insight Laboratory Control & its Data Integrity
- 76. Insight Rejection & Re-use of Materials
- 78. Insight Complaints, Returns, Recalls & Rejection
- 79. Insight Contract Manufacturers & Laboratories (Quality Agreements)
- 80. Insight Agents, Brokers, Traders, Distributors, Re-packers & Re-labelers
- 81. Audits are not required Sample testing is sufficient Only questionnaire is sufficient Virtual audit is sufficientNO YES Let’s participate 1
- 82. Audits are not required Sample testing is sufficient Only questionnaire is sufficient Virtual audit is sufficientNO YES Let’s participate 1 2
- 83. Audits are not required Sample testing is sufficient questionnaire is sufficient Virtual audit is sufficientNO YES Let’s participate 1 2 3
- 84. Audits are not required Sample testing is sufficient questionnaire is sufficient Virtual audit is sufficientNO YES Let’s participate 1 2 3 4
- 86. Paper Tiger otherwise invites and promotes • Negligence/slopiness • Cutting corners • Deliberate non-compliance • Cheating • Counterfeiting • Crime
- 88. Patient Safety
- 89. Why Audit is necessary? Detects GMP non- compliance Detects Fraud and Counterfeiting A system based on trusting on audits only does not work!
- 90. Why Audit is necessary? Because patient safety is of paramount importance Detects GMP non- compliance Detects Fraud and Counterfeiting A system based on trusting on audits only does not work!
- 91. Global Radar navigates Mandatory API GMP Certification Prioritization of API inspections Focus on fraud & counterfeiting Sanctions & penalties Legal liability of Qualified Persons
- 92. Incidences that receive attention & emerge with more strong control strategy Case Studies
- 94. Ciprofloxacin Regulatory result 42% via HPLC UV gave compliance result ??? Look Analyze Predict
- 95. Gelatin for soft gelatin capsules Material source changed Appropriately not studied Result: Disintegration failure after 1 - 3 month upon exposure to temperature Regulatory action Consumption of 100s of batches of substandard product Look Analyze Predict
- 96. Heparin Heart surgery, kidney dialysis, angioplasty Early 2008: In USA 149 patients reported dead …. due to contaminated heparin Manufacturer in China was never inspected Contaminated heparin detected in 11 countries Massive recalls but trapped in availability vs. risk! Look Analyze Predict
- 97. Heparin FDA identifies contaminant: 5% - 45% Oversulfated chondroitin sulfate (OSCS) OSCS molecular structure closely resembles heparin OSCS mimics heparin in standard testing OSCS is not a natural compound => synthesized! Chondroitin sulfate origin: animal cartilage OSCS is cheap (< $80 vs. heparin $500-1500) OSCS most likely added deliberately Contaminated heparin comes from 12 different sources located all throughout China
- 98. “These APIs are a string of ticking time bombs. Heparin has gone off and there will be more until we fix the problem” “We’re inspecting where the drugs aren’t being made and not where the drugs are being made”
- 99. Do not give guarantees for safe APIs Do not give guarantees against counterfeit & fraud But the more frequent and the more deterrent they are, the smaller the chance for health catastrophes Otherwise doors are wide open to… anything
- 100. Diethylene Glycol (Haiti incidence 1996) Found in glycerin used in manufacturing of acetaminophen syrups More than 88 children died as a result of acute renal failure Look Analyze Predict
- 101. Illegitimate material … Legitimate product … Consumption ??? 49 deaths … Endotoxin contaminated Gentamicin Injection Gentamicin Sulfate manufactured by Fujisawa supplied by China, 1989-94 Look Analyze Predict
- 103. Ireland-Paroxetine, Oct 2013 Contaminated with waste tank Did not give attention, kept continuance of distribution Recall … RA Look Analyze Predict
- 104. Look Analyze Predict Cadila 2014
- 105. Oct 2011-concluded, A known impurity responsible for the odor detected. No data provided to support conclusion Can implemented change in manufacturing process in response to the complaint assure established correlation to the odor detected ??? Cadila 2014, Investigation of complaint & extension of investigation to other potential batches ??? Sep 2011, unpleasant odor in a batch of API
- 106. The data used was basically was reintegrated multiple chromatogram to determine levels Investigation concluded the reason of impurity for unpleasant odor in March 2014 Subsequently in Aug 2012, a similar complaint along failure of batch for max. unknown impurity reported
- 107. Commercial batches within expiry are under question Controls implemented to prevent recurrence were not there Scientific justification for setting of specifications was not specified Parameters for re-integration of chromatogram were not retained
- 108. Subsequent OOS investigation concluded the carryover of impurity from a raw material used in API manufacturing process Investigation did not address the failure of quality unit to recognize this impurity prior to release No one came to evaluate during the review
- 109. Where is adequate assurance of appropriate control to mitigate recurrence of contamination? Subsequent to complaint, your investigation identified the unknown peak and found that it was a result of contamination occurred during manufacturing process
- 110. Where is assessment of contamination risk for batches within expiry? Where is corrective action resulting from the assessment? Where is assessment of cross-contamination risk associated with current practice of material/ solvent flow?
- 111. Explain unauthorized access or changes to data & where is adequate control to prevent omission of data? Why unauthorized manipulation (re- integration) of electronic raw data?
- 112. Look Analyze Predict Apotex 2010
- 113. Apotex , Canada March 2010, Inadequate investigation March 31, 2008-Yellow powder identified as residue of API May 2008, yellow contaminant found during production of Ranitidine HCl Rejected the batch Why investigation was not extended to other batches Other lots were manufactured in same equipment prior to March 31, 2008
- 114. Apotex , Canada March 2010, Inadequate investigation Metformin HCl API found contaminated Did not assess finished product manufactured with this contaminated API Why was it released w/o evaluation of potential impact to product quality
- 115. Look Analyze Predict Novacyl Wuxi China 2014
- 116. Novacyl Wuxi, China Dec 2014, Missing raw data Additional chromatographic peak when compared to standard Discarded chromatograms Over-written chromatograms Changes in integrating parameters Absence of documentation & justification
- 117. Tips & TricksHow to Audit 11th APIC/CEFIC European Conference on APIs
- 118. At the API Manufacturer
- 119. Howtoaudit??? Check location and details of site up front on Google Earth
- 120. Howtoaudit??? Check for large discrepancies between annual output and sales (Indicates purchase API elsewhere and re-labeling)
- 121. Check the label book for labels from other manufacturers (Indicates labeling own API as if produced by others) Howtoaudit???
- 122. Check if any API is shipped in neutrally labeled packaging (Indicates illegitimate re-labeling at receiving end) Howtoaudit???
- 123. Check if API warehouse inventory is lower than theoretically (Indicates hidden API may be stored in other warehouses) Howtoaudit???
- 124. Do not only check first rows of drums (Other rows may be unlabeled) Howtoaudit???
- 125. Do not follow the company’s agenda; ask to see things that were not expected by the company Howtoaudit???
- 126. Only inspect when manufacture of the API is running Howtoaudit???
- 127. Check for compliance of all data included within the API registration documents (e.g. DMF) Howtoaudit???
- 128. Check any reports of inspections of the site performed by other reputed authorities Howtoaudit???
- 129. Check purchasing records and sales records for illicit transactions Howtoaudit???
- 130. Take API samples and have them analytically fingerprinted vs. an original sample from the company and/or compare with registered API quality in dossier or DMF Howtoaudit???
- 131. Obtain a list of shipped batches, dates and clients and later cross- check these during audits of clients’ sites Howtoaudit???
- 132. At the Exporting API Trader
- 133. Check for discrepancies between volumes of API purchased from companies vs. volumes sold under the labels of those companies Check for traces of activities of replacing original labels by different labels (e.g. equipment to remove labels: e.g. a burner) Howtoaudit???
- 134. Check for the presence of API in warehouses with labels from producers not included in official documentation Scrutinize entire labels production, management and reconciliation system for irregularities Take API samples for analytical fingerprinting as above Howtoaudit???
- 135. At the Importing API Trader
- 136. Same points as for Exporting API trader Check information on the origin of the API material at customs vs. data on file at the importing trader Howtoaudit???
- 137. At the API User/ Dosage Form Manufacturer
- 138. Howtoaudit??? Check for fraudulent actions with documentation aimed at hiding the true origin of the material Check the purchasing records on sourced APIs from specific companies vs. the volumes of API from these specific companies actually used in production of the dosage forms
- 139. Check if API with labels from producers not included in official documentation is present in warehouses Take API samples for analytical fingerprinting vs. authentic samples of the approved API supplier and check fingerprint vs. registered API quality Howtoaudit???
- 140. Compare information obtained from the approved API supplier on the API volume sold annually to the inspected dosage form manufacturer and compare vs. volume used annually in production of the dosage forms Verify also that batch numbers and dates match those of the ones obtained from the API manufacturer Howtoaudit???
- 141. DMF & Impurity
- 142. Drug Master File An Outline
- 143. Drug Master File It is a document containing confidential information related to: Manufacturing of drug substance Specification and test method Stability and re- test period
- 144. DMFs – FDA Position DMFs are not to be submitted as substitutes of IND, NDA or Supplemental applications No regulatory requirement that a DMF be submitted Provide confidential information concerning CMC Reviewed only in connection with drug application Information treated as confidential
- 145. Types of DMFs Type I • Manufacturing site, facilities, operating procedures and personnel Type II • Drug substance, intermediate material used in the preparation of drug product Type III • Packaging materials Type IV • Excipient, colorant, flavour Type V • FDA- accepted reference information (clinical / preclinical data)
- 146. Impurities in API An Outline
- 147. What is an Impurity and what it can be? Impurities are unwanted chemicals present in the API or FPP arising from normal manufacture. They are not chemicals accidently or maliciously introduced. Impurities have no therapeutic value and are potentially harmful. Therefore they need to be controlled.
- 149. Organic Impurities May arise during manufacturing process and storage Starting materials By products Intermediates Degradation products Reagents, ligands and catalysts
- 150. May be from manufacturing process and are normally known and identified: In Organic Impurities Reagents, ligands and catalysts Heavy metals Inorganic salts other materials (e.g. filter aids, charcoal)
- 151. Limits to be based on pharmacopoeial standards or known safety data Toxicity generally known, therefore controls achievable Organic or inorganic liquids used during the manufacturing process Residual Solvents
- 152. Progress but do not pursue profit at the expense of consumer safety. It will not favor every time Closing Message
- 153. Your product is your child. Please take care because some time damages of uncertainty are irreversible Closing Message
- 154. Please make zero tolerance as a habit ... “But no one came. Because no one ever does” (Thomas Hardy .. Jude the Obscure) Closing Message
- 155. Thank You