A Risk-Based Approach To Setting Sterile Filtration .

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A Risk-Based Approach toSetting Sterile Filtration Bioburden LimitsEBE Biomanufacturing Working Group Industry Consortium

Disclaimer:- These slides are intended for educational purposes onlyand for the personal use of the audience. These slides arenot intended for wider distribution outside the intendedpurpose without presenter approval.- The content of this slide deck is accurate to the best ofthe presenter’s knowledge at the time of production.2

Problem and objective statement No clear origin to the rationale behind the EMA* recommended bioburdenlimit before sterile filtration of not more than (NMT) 10 colony-forming units(CFU) / 100 ml. The limit has been taken from the pharmacopoeialspecification for ’water for injection to produce bulk’ and lacks scientificbasis when applied to final drug products. According to the 1996/2016guideline less than 100 ml sampling volume acceptable, if justified. But noguidance on how to “justify” given. EBE BWG position paper and follow-on paper provide a strategy andscientific methodology for justifying alternate bioburden test limits /smaller test volumes as well as a case-by-case risk assessmentapproach for bioburden exceeding a predefined limit.* Draft Guideline of EMA on the sterilization of themedicinal product, active substance, excipient andprimary container, 2016Draft Guideline on the requirements for qualitydocumentation concerning biological investigationalmedicinal products in clinical trials, 2016EMA (1996): CPMP Notes for Guidance on Manufactureof Finished Dosage g-SterileFiltrationBioburdenLimits-quot

The RisksThree major risks identified: Risk 1: Bioburden test method insensitivity(pre-sterile filtration risk due to method)- Risk 2: Process-related risks and microbialbreach across sterile filter (post-sterilefiltration risk due to process)- Risk of false negative or passing a batch withunacceptable bioburdenRisk of 1 CFU in filtered solutionRisk 3: by-products of bioburden-microbial-derived components e.g. proteases,endotoxins and exotoxins4

The Risk-based Approach regarding the sterile filtrationprocess (Risks #1 and #2)Step 1:Acceptable riskassociated withbioburden test Negative binomial (NB)distribution to modelbioburden distribution Establish test such thatprobability of passingbatch with bioburden isbounded by a lower risk(e.g. 1% probability offalse negative) Requires higheracceptable bioburdenconcentrations fordetectionStep 2:Acceptable risk of 1 CFU in sterilefiltered solution Depends on variousprocess design parameters(demonstrated microbialretention, filter area,batch (filtration) volume,number of filters used inseries or use of abioburden reducing prefilter) Set acceptable risk (riskbound) and couple withmethod insensitivity (prefiltration) risk todetermine overallcombined risk5Step 3:Combined RiskTable limit filteredbatch sizeExample: Post-filtration riskof 10-4 risk of microbialbreach in 1 in 10,000batches. For facilitymanufacturing 100 batchesper year, one batch wouldhave 1 CFU (in one vial)every 100 years.

The holistic view: further mitigation of process-related risksin addition to limiting filtered batch size Use of closed systems, aseptic connections, and disposableprocessing componentsDefined hold times qualified by microbial and chemical stabilityMultiple bioburden reduction filtrationsFilter integrity testingSelection of sterile filters with demonstrated microbial retentiongreater than 107 CFU/cm2Larger filter surface area to volume ratio typically used in earlydevelopment productsValidated integrity of container closure systemQualified operators and validated interventions with media fillsValidated CIP/SIP proceduresMonitoring of facility capability (historical bioburden data), trendingand setting of an internal limit6

Bioburden Control Strategy Given the typically low (zero) pre-filtration bioburden, an alertlimit should be defined rather than a fixed limit or acceptancecriterion such as 10 CFU/100 ml. Trends towards morefrequently observed bioburden excursions from historicaldata would trigger search for root cause the facility is in acontrolled stateTable: Pre-sterile filtration bioburden data taken over an extended period of time for 3 productsProductAnalyzed Valuesbatches withoutfinding511Values withbioburden, but 10CFU/100ml6 (5x1, 1x2)Values withbioburden 10CFU/100 ml0Product 1516Product 23183135 (5x1)0Product 375696 (3x1, 1x2,1x4, 1x5)1*Specification applied: 10 CFU/100ml**negative binomial7QuantileCalculated Excludedrecordslevel *) 2 (neg.bin.**)0 1(Poisson) 4 (neg.bin.**)01

Case-by-Case assessment of contamination byproducts (risk #3)What are the risks of bioburden excursions ?Microorganisms might degrade or modify the product (e. g. by extracellularenzymes). Degraded or modified products might lose function or cause a safetyissue. – however product integrity and biochemical purity are usually checked in thefinal drug product. There remains the risk that protein degradation may occur duringstorage.Microorganisms (gram-negative) release endotoxins (lipopolysaccharide LPS),which might contaminate the drug solution and cause a safety issue – howeverendotoxins can be detected and quantified using the Bacterial Endotoxins Test (BET/ LAL-assay). Defined endotoxin limits exist. For certain formulations endotoxinsmight be masked requiring further measures. Demasking strategies and monocyteactivation test [Ph.Eur.] as possible alternative available.Microorganisms release other cellular components like exotoxins, DNA, flagellaand/or lipopeptides / lipoproteins, which might contaminate the drug solution andcause a safety issue. - but potential load of lipopeptides / lipoproteins and exotoxinscan be calculated (total bacteria mass extracellular proteins or total microbialprotein content potential exotoxin as well as potential lipopeptide / lipoproteinload). This includes gram-positive and gram-negative bacteria1. 1F. von Wintzingerode, American Pharmaceutical Review, April 2017, pages 10 - 198

Conclusions/ Position Statement Risk-based approaches are consistent with ICH guidanceRisks involving bioburden test and process can be quantitated andacceptable risk tolerance be utilized- Analogies can be made to AQL testing and acceptable sterility assurance level(SAL)By-products due to bioburden exceeding predefined limits can alsobe calculated and the risk assessed in a case-by-case riskassessment (CCRA or CCAB) and documented in the QMSPosition: Smaller bioburden test volumes (e.g., 10 ml) do not increaserisk significantly for typical processes. Methodology can be used tojustify alternate limits to 10 CFU/100 ml. Batches exceeding predefined bioburden limits pre-sterile filtration may be released followinga systematic CCRA/CCAB (if assessment favourable).9

A Risk-Based Approach to ID Sampling ofBiologics Drug SubstancesEBE Biomanufacturing Working Group Industry Consortium

The Problem100% Containerwise ID Sampling & Testing of Incoming DS EBE survey indicates that 100% containterwise testing (ie thawing, opening, samplingevery bulk DS unit) has been cited by inspectors during on-site inpections as aregulatory requirement and that travel/satellite samples have not been accepted.It appears that a new interpretation is being applied by EU inspectors to cGMP IDtesting of incoming bulk DS shipments of biopharm products- QUESTION: What has caused a change in this EU inspectional interpretation onthe regulatory side?EBE Member Company Survey: Biotech industry has applied various interpretationsof the sampling required for cGMP ID testing of bulk DS shipments:1. No ID testing of the received bulk DS batch (primarily internal site to site DSshipment)2. Testing the received bulk DS shipment for representative DS satellitesample(s) prepared during DS fill at DS manufacturing site3. 100 % Containerwise sampling individual containers of the received bulk DSshipment at DP site11

Current Regulations for cGMP ID TestingEudralex Vol 4 GMP Annex 8: Sampling of Starting Material and PackagingMaterialsIt is permissible to sample only a proportion of the containers where a validated procedure hasbeen established to ensure that no single container of starting material has been incorrectlylabelled . Under such a system, it is possible that a validated procedure exempting identitytesting of each incoming container of starting material could be accepted ”FDA “Questions and Answers on Current Good Manufacturing Practices,Good Guidance Practices, Level 2 Guidance - Control of Components andDrug Product Containers and Closures”“These regulations require representative samples of each shipment of each lot of active andinactive component (or raw materials) to be tested to confirm the identity of the component aslabeled prior to release for use in drug product manufacturing The CGMP regulations do notspecify the number of containers to be sampled from each received shipment. The CGMPspermit each drug product manufacturer to make its own decision as to the number of containersto sample, as long as the sampling plan is scientifically sound, leads to representative samples,and complies with the principles established at 21 CFR 211.84(b).”Both regulations allow less than 100% sampling (ie each container), based ona scientifically sound, validated procedure12

Unique Risks100% sampling of containers of biological products introduces twosignificant risks to product quality: Thawing and re-freezing every bulk DS container introduces more physicalstress on the product that can increase the risk of aggregation in the DSsolution Sampling every aseptically-filled bulk DS container increases the risk ofmicrobial contamination from the sampling operationIn addition, 100% sampling introduces logistical complications tomanufacturing and testing: Large numbers of low volume DS containers must be sampled, processedand tested for ID, increasing time and costs To assure stability, DS units must be re-frozen and held pending ID testresultsORAseptic processing must proceed before results of containerwise ID testingare available to avoid lengthy hold of thawed DS containers prior tosterilizing filtration13

EBE Recommendations for cGMP ID testing of Biologics(Continue to) utilize a scientifically sound, validated, risk-basedapproach for ID verification without mandating 100% container-wisesampling and testing of thawed Drug Substances upon receipt by DrugProduct manufacture. Representative samples may be collected at the time of DS fill (‘satellite’ samples)and can be acceptable where procedural and quality requirements are defined.Suitability of the DS manufacturer quality system must be verified and continuedcompliance to defined quality system procedures is ensured.A program for satellite samples must be procedurally defined at both DS and DPsites. The procedures must be suitably validated and monitored.Sample(s) collected during DS containers fill must be representative of the entire DSbatchSatellite samples must be shipped with DS batch containers as a unit (i.e. not aspre-shipment samples).Appropriate controls must be in place forLabeling, identification and reconciliationSecure shipping and transportAppropriate monitoring of transport and documented chain of custodyReceipt of shipment and verification at DP manufacturing site14

Team Composition Team Bioburden Risk-basedApproach Team ID Testing Risk-basedApproach Karoline Bechtold-Peters, NovartisDavid Roesti, NovartisFriedrich von Wintzingerode; RocheChristian Matz, RocheBenoit Ramond, SanofiAndrew Lennard, AmgenJeanne Mateffy, AmgenHarry Yang, Medimmune - AstraZenecaSteven Chang, Medimmune - AstraZenecaMelvyn Perry, PfizerDonald C. Singer, GSKJulian Kay, GSKPaola Barzi, MerckGroupFrederik Intelmann, Boehringer IngelheimLiesbeth Voeten, JanssenAnette Yan Marcussen, NovonordiskLilly is a consortium member of EBE Karoline Bechtold-Peters, NovartisAldick, Thomas, RocheAndrea Calenne, BiogenHuub Strouken, RocheKaat de Moor, SynthonPhilippe Dupont, BiophytisSaroj Ramdas, GSKJennifer Walraven; GSKWendy Zwolenski-Lambert, NovartisNadine Ritter, consulting 15

Back-up Slides

Systematics of a Case-by-case Risk Assessmentof Bioburden – example calculations Molecular identification of bacteria by 16S rDNA sequencingLiterature search for exotoxins, MALP-2 like lipopeptides/proteins, etc.Calculation of hypothetical toxic load based on-- Cell number (CFU) per mLCell volume, cell mass and hence the total microbial protein content Exotoxins (as % of total microbial protein content) Lipopeptides/proteins (as % of total microbial protein content) Other by-products such as flagellin, DNA, cell wall polysaccharides,.Drug dose per dayAssessment of risk potential---Protein exotoxins: The calculated dose of toxinis noncritical if it is less than theTDLo* of botulinum toxin A (1.2 pg/kg bodyweight).Lipopeptides/proteins: The calculated doseof toxin is non-critical if it is less than theTDLo* of lipopolysaccharide (LPS endotoxin)(4 ng/kg body weight).*Toxic dose low. Based on the RTECS Guideline (US Dept. of Health and Human Services), the lowestdose of a substance which, whatever the dosage form and over an indeterminate time period, causes a17documented toxic effect in humans

Key aspects of CCRA/CCAB approach**F. von Wintzingerode,American Pharmaceutical Review,April 2017, pages 10 - 1918

Endotoxins Endotoxins can be detected and quantified using the Bacterial Endotoxins Test.Defined endotoxin limits exist. Therefore release of endotoxins as a consequence ofexceeding bioburden limits is not a critical issue. However a couple of years ago the masking of endotoxins also referred to as a lowendotoxin recovery effect (LER effect) was detected by one company andcommunicated to FDA. Low endotoxin recovery (LER) can be defined as the failure to detect known amountof endotoxin in a biological product using the compendial bacterial endotoxin test(Limulus Amoebocyte Lysate, LAL) despite the fact that the positive controls showno evidence of inhibition and is typically characterized by a decline in themeasurable endotoxin concentration over time (such as during sample storage). Based on current knowledge the biological products with the highest risk of inducingLER are the ones which contain polysorbate and high molecular weight proteins orchelating agents. Different strategies exist in the industry to deal with LER such as further tightening ofthe endotoxin burden controls, use of demasking procedures or introduction of therabbit pyrogen test as release test. Furthermore the Monocyte Activation Test (MAT)is a possible alternative test (Ph.Eur.) and Naturally Occurring Endoxtoxins may beused instead of LPS (NOE, Reference Standard in development by USP)11However, FDA does not accept NOEs as appropriate LER mitigation strategy16

Process Flow Diagram for Manufacture of a SterileLiquid Drug Product* Multiple bioburdenreduction filtrations andbioburden samples typicallytaken during DS manufacture*pre-sterile filtrationbioburden17

Modeling bioburden distribution in solution to quantitatemethod insensitivity (pre-filtration risk) Negative binomial (NB)distribution used to modelbioburden distributionNB model allows for bacterialclumping with betterrepresentation of“microbiological environment”compared to uniform (Poisson)distributionStatistical analysis showssensitivity (probability) to detect10 CFU/100 mL 41.2%At same 41.2% sensitivity level,corresponding bioburden levelfor different sample test volumescan be calculated18

Limited method sensitivity means risk of passing batcheswith o passbioburdentest)966.6%1058.8%1150.0%

Step 1: Control risk associated with bioburden test Negative binomial (NB) distribution used to model bioburdendistributionEstablish test such that probability of passing batch with bioburdenis bounded by a lower risk, i.e. 5% probability of false negativeRequires higher acceptable bioburden concentrations for detectionStatistical analysisshows probabilityto reject at10 CFU/100 mL 41.2%For anacceptable riskbound at e.g. 5%63 CFU20 CFU32 CFU

Step 2: Assess Risk of 1 CFU in sterile filteredsolution Depends on various process design parameters- Demonstrated microbial retention (filter validation studies), i.e.107 CFU/ cm2 or greater for particular filter typeFilter areaBatch (filtration) volumeNumber of filters used in series or use of a bioburden reducingpre-filterQuantitate risk and couple with method insensitivity(pre-filtration) risk to determine overall combined risk21

Step 3: Combined Risk Table(example for single filter,107 CFU/cm2 retention capability, and 1000 cm2 area)Pre-filtration TestSchemeRisk 10-510-40.10%10-5SampleVolumeV ptanceLimitAL ximumBatch Size Post-filtration risk of 10-4 risk of microbial breach in 1in 10,000 batches. Forfacility manufacturing 100batches per year, one batchwould have 1 CFU (in onevial) every 100 years. Retention of max bioburdenD0 well within typical processand filter retention 04658972146891Pre-filtration risk Probability to pass a batch with a bioburden exceeding the maximum level D0Post filtration risk Probability to have 1 CFU in the final filtered solution3Maximum bioburden D0 Maximum acceptable level of bioburden in the unfiltered solution222

Corresponding risk contour plots(Bound at 5% pre-filtration risk)Probability is strong function ofbatch size at small sample volumes23

Resulting design space within risk tolerance(Bound at 5% pre-filtration risk, 10-4 post-filtration risk)1000 cm2 24Example:Limit of 1 CFU/10 mlfor max batch volumeof 424 L would bewithin stated risktolerance(5% probability of falsenegative and breach in1 in 10,000 batches)

Different design scenarios: Filter area(Bound at 5% pre-filtration risk,10-4 post-filtration risk)200 cm22000 cm2Here:Limit of 1 CFU/10 ml for max batch volume of 85 L (200 cm2) or 849 L(2000 cm2) would be within stated risk tolerance (5%/10-4)25

Different risk tolerance scenarios: Process risk(Bound at 5% pre-filtration risk, varying post-filtration risk)10-410-526

Bioburden Control Strategy Given the typically low (zero) pre-filtration bioburden, an alert limit should be defined rather than a fixed limit or acceptance criterion such as 10 CFU/100 ml. Trends towards more frequently observed bioburden excursions from historical data would trigger search for root cause the facility is in a controlled .

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