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120th Training Session - Unfortunate Wave of DEG Tragedy.pdf

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120th Training Session - Unfortunate Wave of DEG Tragedy.pdf

  1. 1. GMP & Control of DEG – 13 Nov 2022, Hotel Marriott, Karachi
  2. 2. Disclaimer We discuss science with reproducible evidence nothing more, nothing less It is experience based learning expression received during last 25 years while dealing hundreds of foreign & domestic inspections, regulatory compliance & enforcements, dozen of meetings with international experts (FDA, EU, Japan, Canada, MHRA) etc. etc. Thoughts represent the current thinking of Centre for Quality Sciences Obaid Ali & Roohi B. Obaid
  3. 3. Indonesia Paracetamol DEG - Contamination Kidney Failures 195 Deaths so far Is it GMP failure or something else? Understand to Control before it happens here Professional Development is the key Centre for Quality Sciences Sunday, 13 Nov, 2022 Ambassador – 1, Hotel Marriott, Karachi
  4. 4. • Awareness & Magnitude in Pakistan • Waves of Global Outbreaks • Supply Chain Integrity • Strength of bond b/w safety & testing? • Capacity to construct wall • Catch the signal from noises • What can we do?
  5. 5. Impurity & Contamination Is it important to control .. Is it not important to control.. Why it is important & Why it is not.. How it is important What is limitation & What is residual level .. What is meaningful & What is meaningless ..
  6. 6. GMP What is the purpose? What is the intent? Consistency Contamination Mix up
  7. 7. Benzene N. D. M. A. Di Ethylene Glycol
  8. 8. Impurity & Contamination From where it comes in the finished drug product?
  9. 9. Example Microbial contamination, Chemical contamination or dirt etc. Meningococcal outbreak
  10. 10. Are we aware & can we assess the magnitude of impurity & contamination
  11. 11. Systems … Tissues … Cell … Genetic information Human body Harmonized, Collaborated and well integrated Integrated Respond to keep life moving on with its best Immunity
  12. 12. Uncontrolled growth of abnormal cell in the body Cancer Substance that promote Cancer (Carcinogensis) Carcinogen Chemical agent harms Genetic information Genotoxic
  13. 13. All genotoxic are not mutagen But All Mutagens are genotoxic
  14. 14. Mutation can cause cancer But Not always necessary so ..
  15. 15. Carcinogen can promote Carcinogenesis It is indeed formation of Cancer
  16. 16. As many mutation can cause cancer therefore Also likely to be carcinogen
  17. 17. A genotoxic agent damages cellular DNA, resulting in mutations or cancer. Genotoxic are known to be potentially mutagenic or carcinogenic when inhaled, ingested or penetrate the skin. Genomics
  18. 18. AFLATOXIN Most carcinogenic substance
  19. 19. API Transformation Starting material
  20. 20. Transformation Multiple Reactions Reagent Intermediate Catalyst Solvents
  21. 21. Reagent Intermediate Catalyst Solvents Impurity Byproducts
  22. 22. Impurity Genotoxic Carcinogenic May be
  23. 23. US 1937 107 deaths South Africa 1969 7 deaths Nigeria 1990 2008 40 deaths 84 deaths Bangladesh 1990 2009 364 deaths 24 deaths Haiti 1995 85 deaths India 1986 14 deaths
  24. 24. Acetic acid increase pH • 2 Hydroxy ethoxy acetaldehyde • 2 Hydroxy ethoxy acetic acid What will happen?
  25. 25. Acetic acid increase pH • 2 Hydroxy ethoxy acetaldehyde • 2 Hydroxy ethoxy acetic acid What will happen?
  26. 26. Benzene
  27. 27. Benzene 108 unique lots from 30 different brands analyzed.
  28. 28. Benzene 108 unique lots from 30 different brands analyzed. 24 lots from 8 brands 2.24 – 17.7 ppm of benzene
  29. 29. Benzene 108 unique lots from 30 different brands analyzed. 24 lots from 8 brands 2.24 – 17.7 ppm of benzene 14 lots from 8 brands 0.20 – 1.89 ppm of benzene
  30. 30. Benzene 108 unique lots from 30 different brands analyzed. 24 lots from 8 brands 2.24 – 17.7 ppm of benzene 14 lots from 8 brands 0.20 – 1.89 ppm of benzene 21 lots Detectable benzene
  31. 31. Benzene 108 unique lots from 30 different brands analyzed. 24 lots from 8 brands 2.24 – 17.7 ppm of benzene 14 lots from 8 brands 0.20 – 1.89 ppm of benzene 21 lots Detectable benzene Recalls Procter & Gamble’s Old Spice, Secret, Pantene, Aussie, Herbal Essences, & Waterl<ss products, and Sure & Brut products
  32. 32. Methyl diazonium RAS Oncogenes N D M A
  33. 33. Methyl diazonium RAS Oncogenes N D M A Gastric Liver Bladder Prostate Leukemia Myeloma
  34. 34. Impurity & Contamination Is it important to control .. Is it not important to control.. Why it is important & Why it is not.. How it is important What is limitation & What is residual level .. What is meaningful & What is meaningless ..
  35. 35. Heparin Case Study
  36. 36. Pig Heparin Chondroitin Sulfate Tragedy
  37. 37. Anticoagulant 1916 – Dog liver to 1930 – Bovine lungs 1939 – First approved – Bovine lungs 1942 – Porcine source got approval 1996 – BSE crisis – UK 2007 – Heparin adulteration crisis Often used in dialysis or heart surgery What is heparin? From where?
  38. 38. How heparin is formulated as drug? 3000 pigs for 1 kg heparin Extraction Separation Purification Porcine intestine Polysaccharides complex with resin or ammonium salt Acid – base wash etc. etc. Natural peptide, lipids Bacterial endotoxin related glycosaminoglycans
  39. 39. A pig highly pathogenic disease … Prolonged high fever, Red discoloration of the body & Blue ears, Reproductive failure, Pneumonia and increased susceptibility to secondary bacterial infection. It is caused by a virus classified as a member of the genus Arterivirus. PRRS (Porcine reproductive and respiratory syndrome) Blue Ear Disease
  40. 40. 2 million kills /day • 1,000 – 20,000 kg intestine processed for heparin • 15 – 300 kg per month • Supplied through brokers to the pharmaceuticals Economically Motivated Adulteration (EMA) Quantum
  41. 41. • Crisis of availability – Blue Ear Disease in pigs • Shortage of crude heparin • OSCS – derived from animal cartilage • Similar structure to heparin • Cannot be identified with test used for heparin What happened & why people died?
  42. 42. • Baxter International & China • Over sulfated chondroitin sulfate • Severe allergic reaction & low blood pressure What happened & why people died?
  43. 43. • High charge density • Strong anti factor IIa activity • Test not capable to catch difference Why OSCS cause allergy?
  44. 44. • Don’t rely on opaque supply chain • Crude material with natural impurities • Don’t use weak method • Catch signals & real world observations • Listen from noises to synchronize Take Home Message
  45. 45. Simple bioassay can help in protecting the global supply chain of heparin Screening for the presence of poly sulfated contaminants Be vigilant
  46. 46. Tea Break
  47. 47. Contamination - A challenging issue Reference: US-FDA
  48. 48. Inspections Progress Deep Sleep
  49. 49. No regulation before 2012 for Foreign inspections in FDA Inspections of domestic sites every 2 years Deep Sleep
  50. 50. Inspect domestic & foreign sites in accordance with risk based schedule Thousand drug manufacturing facilities with no inspection history They completed the task FDASIA - 2012
  51. 51. • Inadequate control on cross-contamination • Data integrity • Poor investigation • Inadequate control for sterile manufacturing Top Concern
  52. 52. • From industrial chemicals • Di Ethylene Glycol • Benzene • Pesticides – Ciprofloxacin tragedy • Etc. Dangerous Cross-contamination
  53. 53. Can an API firm make multiple potent drugs including hormones on shared equipment? Challenge Question
  54. 54. Can operators share same dining where people gather from cosmetics and penicillin area both? Challenge Question
  55. 55. Please see & note in your notebook what’s wrong
  56. 56. 1. Passed through filter bag at the top of fluid bed 2. Vertical drop in duct by pass – re- enter 3. Another stay to contaminate next batch 1 2 3
  57. 57. Case Study Reference: Redica
  58. 58. Beta Lactam Packaging Non-Beta Lactam Packaging Common Area of personnel
  59. 59. Product was recalled Manufacturing was stopped Decontamination & renovation of facility Warning was issued Take Home Message
  60. 60. Case Study Contamination due to inadequate cleaning
  61. 61. Process equipment duct are usually contaminated with residue from multiple drugs Visible residue of fluid bed dryer and tablet coaters often ring alarm From Inspector’s Diary
  62. 62. Don’t assume that cross-contamination or contamination is uniformly distributed Don’t do wrong risk assessment on the basis of testing From Inspector’s Diary
  63. 63. Rust on product contact surfaces Water traps during mantling without allowing drying From Inspector’s Diary
  64. 64. Equipment erroneously labeled clean Equipment use and cleaning log book deficiencies Documentation of failed visual inspection From Inspector’s Diary
  65. 65. Failure to follow cleaning procedure Availability of cleaning SOPs Incomplete equipment dis-assembly From Inspector’s Diary
  66. 66. Inadequate cleaning validation Incorrect preparation of detergent Improper equipment storage From Inspector’s Diary
  67. 67. Incorrect performance of surface swabbing Monitoring of cleaning effectiveness From Inspector’s Diary
  68. 68. Have you identified all cross-contamination hazards (chemical, microbiological, physical) Are cleaning procedures detailed enough? Are they easy to follow? Do it contain pictures to help operators? Self – evaluation for cleaning
  69. 69. How do you ensure personnel are properly trained & always follow the validated cleaning procedure? How do you know that they are rinsing the equipment for the correct number of minutes? How do you control the human variability? Self – evaluation for cleaning
  70. 70. How do you monitor equipment cleaning effectiveness? How often do you have justification for the frequency of your cleaning effectiveness or cleaning monitoring program? Self – evaluation for cleaning
  71. 71. How often do you validate your cleaning process based on data that you are gathering? Do you have any cleaning program? Self – evaluation for cleaning
  72. 72. Why do these deficiencies continue to emerge? How can companies evaluate their cleaning practices? How do you know that drug will not harm? Assure Yourself
  73. 73. The filling machine and HEPA filter located directly above the filling machine in the filling room were significantly discolored with an unknown substance Read & share what you understood It was due to fumigation agent. Discolored HEPA filters are now recolored FDA Firm
  74. 74. The filling machine and HEPA filter located directly above the filling machine in the filling room were significantly discolored with an unknown substance Read & share what you understood It was due to fumigation agent. Discolored HEPA filters are now recolored FDA Firm Evidence & justification demonstrating the source of staining was missing Assessment of the impact of the residue on the performance of HEPA was missing Impact of contamination hazard on drug product and patient was missing
  75. 75. DIDP Case Study
  76. 76. Dibutyl phthalate (DBP) & Di(2-ethylhexyl) phthalate (DEHP) Avoid the use of these two specific phthalates as excipients Phthalates FDA Point of View
  77. 77. As a plasticizer in enteric-coatings of solid oral drug products to maintain flexibility As softeners of plastics, solvents in perfumes, Additives to nail polish, as well as in lubricants and insect repellents Phthalates Uses
  78. 78. Epidemiological studies suggest that certain phthalates may affect reproductive and developmental outcomes. Other studies have confirmed the presence of DBP and DEHP in amniotic fluid, breast milk, urine, and serum Phthalates Till date data in humans are less clear
  79. 79. Plasticizer DIDP & DINP Di-iso Decyl Phthalate – 5.5 ppm & Nonyl Phthalate – 5.7 ppm Recalled Augmentin found contaminated that was manufactured in GSK Worthing, England, 2011 Abrasion of poly vinyl chloride plastic tubing used to transfer powder & granules during tablet production
  80. 80. Phthalates are endocrine disruptors – may disrupt hormonal system and cause cancer including breast cancer Can damage liver, kidney, lungs & reproductive system Phthalates
  81. 81. • Short shelf life • Metabolize and removed through urine and stool in 24 hours (Anderson – 2001) Phthalates – Removal from body
  82. 82. Drinking straws, sealants used in food packaging, toys, flooring, gloves, garden hoses Phthalates (DINP) From where it comes in

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