Guidelines for Investigating & Assessing Product Endotoxin Failures Richard Fitzpatrick & Aoife Brady 1
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
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 • Over 180 medical device companies base in Ireland Lotus Synergy Cardiology • Eleven of the of the top fifteen largest medical device companies base in Ireland • € 8 billion industry supplying cardiovascular, orthopaedic & diagnostic devices Wallstent Mustang • Peripheral Employs over 27,000 people directly Intervention Employs over 100,000 people indirectly 3
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
Physiological effect of endotoxin exposure 5
Implications of product endotoxin failures • • Patient Perspective Business Perspective • Upon entering the body endotoxins • Endotoxin failures including can induce….. inadvertent release of contaminated product for human use or inadequate investigations can lead to ….. – Septic shock – Product Recall – Fever – Back Orders – Organ Failure – Lost of earnings from scrappage of – Death impacted batches – Penalties from competent authorities 6
Examples of FDA 483s for Product Endotoxin Issues Case Study 1 Case Study 2 Company: Sanquin: Holland Company: Sanofi Pasteur: France Plasma Products Vaccine Products 44 Batches Rejected 13 batches rejected Reason Reason • Insufficient Investigation • 13 batches failed over a 4 year period and no root cause identified • Investigation concluded alteration in • A component was identified as the root cleaning process was source of endotoxin cause but was only used in 4 of the impacted batches • All tests on equip were negative for both • The impacted component was endotoxin and bioburden continually used in subsequent batches • 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 7
Regulatory Requirements for endotoxin testing • All companies have a Neuromodulation Interventional responsibility to access their Cardiology products for routine endotoxin testing Electrophysiology • As per AMI ST72 Products Cardiac Rhythm that have direct or indirect Management Urology contact with vascular, neurological or ophthalmic tissue require routine endotoxin testing Endoscopy . Peripheral Intervention . Watchout: FDA update to its 510(k) Sterility Review Guidance document 2016 calls out for endotoxin testing for all implants 8
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 Batch Size # of samples <30 2 30-100 3 • Routine product endotoxin sampling plan: AMI-ST72 3% of lot, up to >101 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
Responding to Product Endotoxin Failures “Production” Release the batch? HELP We havent even started the investigation !! The batch needs to be released today !! “Product Release” We are going into back order ! Do we have an Investigation Plan…..???????????? 10
Investigative Endotoxin Testing to Identify Root Cause 11
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
BET Assay Assessment Flow Chart Test Passes Assay Criteria met Endotoxin Sample criteria met %CV standard (<10%) %CV of sample <20% result within Slope/R2 >0.98 Spike recovery 50-200% specification Blank reaction< Lowest standard Result OOs Test Fails OOS investigation 13
Laboratory Error – Potential Causes Negative Controls Ok Contamination during dilution Correct procedure? • Retest originals • Retest new samples Training Records OOS Result Sample • Correct sample? Any unusual events • Sampled correctly during testing? • Condition Contamination in other test? Test equipment Glucans? Test reagents Technician Error ? Test consumables Change in product formulation? 14
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
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
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
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 • 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 18
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