Guidelines for Investigating & Assessing Product Endotoxin Failures Richard Fitzpatrick & Aoife Brady

Transcription

1 Guidelines for Investigating & Assessing Product Endotoxin Failures Richard Fitzpatrick & Aoife Brady 1

2 Content Summary of Irish Pharmaceutical/Medical Device Industry Background on Endotoxin What are endotoxins Where endotoxins are found Physiological effect of endotoxin on the body Regulatory requirements for endotoxin testing of medical devices AMI-ST72, USP 85, USP 161 Implications of endotoxin Failures Patient Perspective Business Perspective Guidelines for Investigating Product Endotoxin Failures 5 Step guide for conducting product endotoxin investigations Examples of Product Endotoxin Root Causes 2

3 Summary of Irish Pharmaceutical/Medical Device Industry Over 120 pharma companies base in Ireland Nine of the top 10 largest pharma companies base in Ireland Pharma sector worth 50.8 billion Employs over 25,000 people directly, 100,000 people indirectly Cardiology Synergy Lotus Over 180 medical device companies base in Ireland Eleven of the of the top fifteen largest medical device companies base in Ireland Peripheral Intervention Mustang Wallstent 8 billion industry supplying cardiovascular, orthopaedic & diagnostic devices Employs over 27,000 people directly Employs over 100,000 people indirectly 3

4 Summary on Bacterial Endotoxins Endotoxins are components of the cell wall of Gram negative bacteria Specifically endotoxins are the lipopolysaccharides in the outer membrane of Gram negative bacteria The primary source of Gram negative bacteria for medical devices is water to which the product is exposed Upon entering the body endotoxins can induce septic shock and can be fatal Endotoxins are not destroyed by sterilization therefore control & prevention of endotoxin contamination is central to advoiding endotoxin issues Estimated that 1 x10 5 Gram negative bacteria equivalent to 1 EU To exceed 20 EU in excess of 2 x10 7 Gram negative bacteria would have to contaminate the device 4

5 Physiological effect of endotoxin exposure 5

6 Implications of product endotoxin failures Patient Perspective Upon entering the body endotoxins can induce.. Septic shock Fever Organ Failure Death Business Perspective Endotoxin failures including inadvertent release of contaminated product for human use or inadequate investigations can lead to.. Product Recall Back Orders Lost of earnings from scrappage of impacted batches Penalties from competent authorities 6

7 Examples of FDA 483s for Product Endotoxin Issues Case Study 1 Company: Sanquin: Holland Plasma Products 44 Batches Rejected Reason Insufficient Investigation Investigation concluded alteration in cleaning process was source of endotoxin All tests on equip were negative for both endotoxin and bioburden Investigation failed to link a leak as the possible source of the endotoxin contamination No additional investigation for subsequent batches that had endotoxin alert levels Case Study 2 Company: Sanofi Pasteur: France Vaccine Products 13 batches rejected Reason 13 batches failed over a 4 year period and no root cause identified A component was identified as the root cause but was only used in 4 of the impacted batches The impacted component was continually used in subsequent batches 7

8 Regulatory Requirements for endotoxin testing Interventional Cardiology Neuromodulation Electrophysiology All companies have a responsibility to access their products for routine endotoxin testing Cardiac Rhythm Management Endoscopy. Urology Peripheral Intervention. As per AMI ST72 Products that have direct or indirect contact with vascular, neurological or ophthalmic tissue require routine endotoxin testing 8 Watchout: FDA update to its 510(k) Sterility Review Guidance document 2016 calls out for endotoxin testing for all implants

9 Regulatory Requirements for Endotoxin Sampling Plan Validated method for product endotoxin testing: AMI-ST72, USP161, USP85 Rational for endotoxin testing of product Pre vs Post sterilization: AMI-ST72, USP161 Batch Definition: AMI-ST72 Routine product endotoxin sampling plan: AMI-ST72 Batch Size # of samples < >101 3% of lot, up to maximum of 10 Control/Link Batch Release with Product Endotoxin Results AMI-ST72 Conduct an adequate & timely investigation AMI-ST72 What scale of investigation satisfies an adequate investigation??? 9

10 Responding to Product Endotoxin Failures Production The batch needs to be released today!! HELP Release the batch? We havent even started the investigation!! Product Release We are going into back order! Do we have an Investigation Plan..???????????? 10

11 Investigative Endotoxin Testing to Identify Root Cause 11

12 Five Step Guide for Investigating Endotoxin Failures 1. Conduct Lab OOS and confirm endotoxin result 2. Conduct initial investigation Assemble investigation team Contain product Assess impact to subsequent batches Conduct a line walk of the production process Apply Investigation tools such as Is/Is Not Helps define the scope of the problem Fish bone diagram helps to identify root causes of the endotoxin failure 3.Conduct review of endotoxin controls Product Bioburden Trends Product Endotoxin Trends Cleanroom Environmental Trends Process solutions that come in contact with product Change of suppliers/production staff or manufacturing process People behaviour/gmp/cleaning 4. Conduct investigative endotoxin testing to identify root cause 5. Evaluate investigative results and determine product disposition strategy 12

13 BET Assay Assessment Flow Chart Test Passes Assay Criteria met %CV standard (<10%) Slope/R2 >0.98 Blank reaction< Lowest standard Sample criteria met %CV of sample <20% Spike recovery % Endotoxin result within specification Result OOs Test Fails OOS investigation 13

14 Laboratory Error Potential Causes Negative Controls Ok Contamination during dilution Retest originals Retest new samples Sample Correct sample? Sampled correctly Condition OOS Result Correct procedure? Training Records Any unusual events during testing? Test equipment Test reagents Test consumables Contamination in other test? Glucans? Technician Error? Change in product formulation? 14

15 Five Step Guide for Investigating Endotoxin Failures 1. Conduct Lab OOS and confirm endotoxin result 2. Conduct initial investigation Assemble investigation team Contain product Assess impact to subsequent batches Conduct a line walk of the production process Apply Investigation tools such as Is/Is Not Helps define the scope of the problem Fish bone diagram helps to identify root causes of the endotoxin failure 3.Conduct review of endotoxin controls Product Bioburden Trends Product Endotoxin Trends Cleanroom Environmental Trends Process solutions that come in contact with product Change of suppliers/production staff or manufacturing process People behaviour/gmp/cleaning 4. Conduct investigative endotoxin testing to identify root cause 5. Evaluate investigative results and determine product disposition strategy 15

16 Schematic representation of production batch where all test units pass endotoxin testing and batch is released Batch consist of 60 lot Each lot consist of 20 units Batch period is defined as a weeks production Mon-Fri Batch consist of 1200 units estimated value 250K As per AMI ST72 ten units are required for endotoxin testing and batch release (batch>100 units) 2 units are randomly pulled on each day of production. Randomly selecting 2 units from each day of production improves the power of the sampling plan In this scenario all units passed endotoxin testing and batch can be released 16

17 Schematic representation of production batch where two units selected from Wednesday production failed endotoxin testing and batch is contained Two units selected from Wednesday s production failed endotoxin testing. Batch is contained All other units selected throughout the batch passed endotoxin testing Initial assessment of results suggests endotoxin failure is not systemic throughout the batch 17

18 Guidelines for conducting investigative endotoxin testing to determine root cause Hypothetical situation: 2 units from lot 32 failed batch release endotoxin testing Step1: Test 10 additional units for endotoxin from the impacted lot to determine if the root cause of the endotoxin failure is systemic within the lot Step 2: Test 10 additional units for endotoxin from lots either side of the impacted lot ie lot 31 and lot 33 to determine if root cause is confined to lot 32 or is more systemic in nature Step 3: Test 2 units from each of the 60 lots to determine if root cause is systemic throughout the batch or is confined to a specific process/component batch 18 Note test results obtained from investigative testing can not be used for batch release. Pending investigation outcome a 2 nd round of batch release testing is required to enable batch release

19 Case Study 1. All units selected for investigative endotoxin testing throughout the batch failed All units selected for endotoxin testing failed Root cause for endotoxin testing is systemic throughout the batch Manufacturing process is not in control Impacted batch should be scrapped and manufacturing ceased until root cause is identified 19

20 Case Study 2. All units selected from a specific days production failed endotoxin testing All units selected from a Wednesdays production failed endotoxin testing All other units selected from the weeks production passed endotoxin testing This indicates that root cause for the failure is confined to a specific process / component lot unique to Wednesday. Test 10 additional units derived from Monday, Tuesday, Thursday & Fridays production lots for batch release testing If the 2 nd round of batch release testing passes all units manufactured on Monday, Tuesday, Thursday & Friday can be released. All units manufactured on Wednesday should be scrapped 20

21 Case Study 3. All units selected for investigative endotoxin testing throughout the batch passed All units selected for investigative endotoxin testing throughout the batch passed Consideration should be give to whether the two units that failed endotoxin testing in lot 32 are Atypical to lot 32 Atypical to Wednesday production Atypical to the entire batch production Review all investigative results to establish if the batch can be released on the basis that the two failed units are atypical to the batch Conduct 2 nd round of batch release testing to disposition batch 21

22 Examples Product Endotoxin Root Causes Contaminated Coating soln Inproper storage of glassware following washing facilitated formation of Gram negative biofilim Contaminated Component Supply by external vendor Water used in the manufacturing process highly contaminated with endotoxin Labels used to identify units for endotoxin testing Labels manufactured using recycled paper which was highly contaminated with endotoxin Saliva Saliva contains high amounts of endotoxin 800 EU/ml Hand mouth contact absolutely avoided in cleanroom 22

23 Conclusion Five Step Guide for Investigating Endotoxin Failures: 1. Conduct Lab OOS and confirm endotoxin result 2. Conduct initial investigation 3. Conduct review of endotoxin controls 4. Conduct investigative endotoxin testing to identify root cause 5. Evaluate investigative results and determine product disposition strategy The goal of this 5 step guide is to facilitate an informed, structured and timely conclusion to the endotoxin OOS investigation and the fate of the impacted batch 23

24 Responding to Product Endotoxin failures Where do I start?! An informed & structured Investigation Plan will facilitate a timely conclusion to the endotoxin OOS investigation and the fate of the impacted batch 24