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Extractables & Leachables: SupplierApproach to Regulatory and End-UserRequirements2019 BPSA International TION

Understanding the Suitability of USP 665 and BPOG Solvents In 2016 VR Analytical was asked by USP to compare the BPOG solvents with the draft USP 665 solvents Teamed up with a vendor who provided the test articles Study design Process Filter – Hydrophilic polyethersulfone capsule filter Manufactured on March 25, 2016 Other Materials of Construction Polypropylene capsule and internal supports Thermally sealed Gamma irradiated at 24.8 to 27.8 kGy on March 26, 2016USP extracting solutions and BPOG extracting solutions (no PS 80)One lot in duplicate40oC for 1 day and 7 days2019 BPSA International TION

Extractables from PES Filter600500Other knowns400t-butanolµg/mLHTPE - rel atedAcet one300IPAUnknownsAcet aldehyde200PVPCaprolactam10000.1 M H3PO 4pH 35 M NaCl2019 BPSA International SummitDI WaterpH 100.5 M NaOH50% ON

Unique Peaks vs Unique CompoundsRT (min)0.1 M H3PO4pH 35 M NaClDI WaterpH 100.5 MNaOH50% 41.01.90.37Total NumberofCompoundsTotal Conc(µg/mL)HTPE Oligomers2019 BPSA International TION

Conclusions from PES Filter Both low pH solutions extract similarly – no clear preference 50% EtOH extracts the most compounds at the highest concentration – asexpected 0.5 M NaOH had fewer extractables that pH 10 – contrary to expectations 5 M NaCl had the fewest extractables and lowest concentration of extractablesDecided to investigate the effect of pH and ionic strength on extractables withother test articles2019 BPSA International TION

Silicone Tubing Set and PE-based Multilayer BiocontainerTest SolutionsTest ObjectiveLowMedHighD.I. Water1 M NaCl5 M NaClpH 10 (USP)pH 12 : 0.01 M NaOHpH 13 : 0.1 M NaOH (only for bag)pH 13.7(0.5 M NaOH)Ionic StrengthpHOrganic Content50% EthanolAnalytical LC-UV-MSGC-MS/FIDHeadspace GC-MS/FID2019 BPSA International TION

TMSTubingSetResults120BPAUnknown100Aromatic UnknownTotal Extractables μg/mLBenzoic acid80μg/mLBPA structural canoic acid40EthanolPhenol, 4-(1,1dimethylethyl)-20CaprolactamOther below 0.2 mg/mL05 M NaCl1 M NaCl2019 BPSA International SummitDI Water50% EtOHpH 100.01 M NaOH 0.5 M ON

GC-MS/FID ID’s for High pHIncreasing pH correlates with increased polycarbonate degradationPolycarbonate is hydrolyzed under basic conditionsHigh pH PolycarbonateBPACompoundpH 100.01 M NaOH(pH 12)0.5 M NaOH(pH 13.7)BPA0.211.5792019 BPSA International TION

HS-GC-MS/FID ID’sfor High pHEstimated Concentration(µg/mL)0.01 M0.5 MNaOHNaOH(pH 12) (pH 13.7)Name or Classification(Synonym)CAS RNpH Propanol67-63-00.390.320.41Silanol, 1,1,1-trimethyl-1066-40-62.23.431Disiloxane, 1,1,1,3,3,3-hexamethyl-107-46-0--0.181-Hexanol, 2-ethyl-104-76-7--0.10Increasing pH correlates with increased silicone degradationSilicone is hydrolyzed under basic conditionsHigh pH silicone2019 BPSA International SummitSilanol, TCOLLABORATION

7.06.0Summary of ResultsAcet ic acidHydrocarbonStorage BagMethanone, 8-dione, 7,9-bis(1,1dimethylethyl)Pentanoic acid5.0PropanalTotal Extractables Above 0.1 µg/mL (ppm)4.0Hexanalµg/mLPentanalCyclopentane, methyl-3.0Hexanoic acid2-Propanol, 2-methy lSilanol, 1,1,1-tri methyl-2.0ButanalAcet aldehydeHexane1.0Phenol, 2,4-bis(1,1-dimethylethyl)Benzene, 1,3-bis(1,1-dimethylethyl)-0.0DI Water1 M NaCl5 M NaCl2019 BPSA International SummitpH 100.01 MNaOH0.1 MNaOH0.5 MNaOH50% EtOHPhenol, 2,4-bis(1,1-dimethylethyl)-, 1,1'-(hydrogenphosphate) (Irgafos 168 BORATION

Ionic Strength – 5 M NaCl had the fewest extractablesTotal Concentration of Extractables, µg/mLDI Water1 M NaCl5 M NaClPES Filter181Not Tested58Tubing Set8.74.81.3Bag1.680.140.17Salting Out Effect “Practical guidance on salting-out extraction in the context of organic synthesis was first described insome detail within Ludwig Gattermann’s influential 1894 monograph entitled “Die Praxis desOrganischen Chemikers”” “In a simplistic model, dissolved anions of high charge density cause salting out through combinationof electronic repulsion and enhancement of hydrophobic effect”(Hyde et. al., Org. Process Res. Dev. 2017, 21, 1355 1370)2019 BPSA International TION

ConclusionsIonic Strength Increasing ionic strength by adding NaCldecreases the number of detectedextractables as well the concentration. Bracketed by high pH and low pH Salt is difficult on instruments2019 BPSA International SummitpH Material compatibility needs to be consideredwhen selecting a high pH solution Polymer degradation can occur beforemechanical integrity is affected leading to highextractable concentrations USP – recommended pH 10 is compatible withcommonly used polymers in bioprocessingtherefore is a better choice for a RATION

Who Are Influencing the RequirementsEstablishing the Regulatory LandscapeBIOTHERAPEUTICS2019 BPSA International Summit13PRODUCTIONDEPLOYMENTCOLLABORATION

Next Steps} Expert Panel will start the process of reviewing and discussingcomments July 24th, 2019General Comments1. Chapters will result in numerous change control and document updates within the pharmaceutical industry, so USP shouldwork with stakeholders to ensure adequate timeUSP Decision: USP acknowledge’ s this comment and will work to addressDetailed commentsSection1.TitleParagraph/SentenceComment / RationaleProposed change /suggested textIf we are definingChange to:PHARMACEUTICAL as pharmaceutical andsmall molecule, andbiopharmaceuticalbiopharmaceutical aslarge molecule, weprobably need to sayso.2019 BPSA International SummitUSP DecisionAgreed make the necessaryedits} Every comment that isreceived is added to aspread sheet andreviewed, discussed anddecision made as towhether a revision to thechapter is BORATION

BPOG and USP 665 AlignmentAlignmentScopePurposeBPOG ApproachUSP 665 / 1665 Approachü Finalized end-user requirementintended to bracket a wide range ofapplications, supporting qualificationü Draft standard intended to aid in componentselectionALICü Upgrade of 661 establishing baseline FFIOquality requirements for plasticNUcomponents in pharmaceutical processingü Focuses on Bracketing Worst Cases(48 extracts for biocontainer)ü Aim for the middle (85%)(3 extracts for biocontainer)ü Can Always do moreüüüqorfcts Gatr POxBE49 P USTimepoints: Fully Overlapping50% EtOH/water: SameLow pH: Either BPOG pH 1.6 or USP pH 3.0 okay per 665 High pH: Depends (0.5N NaOH okay if process fluid 10, otherwise pH 10)BIOTHERAPEUTICS2019 BPSA International Summit15PRODUCTIONDEPLOYMENTCOLLABORATION

The 665 SEP Extraction Solvents2019 D. Jenke. PharmaEd Extractables, Leachables & Elemental Boston 20119; Boston, April 10, 2019BIOTHERAPEUTICS2019 BPSA International Summit16PRODUCTIONDEPLOYMENTCOLLABORATION

USP 665 Testing to Align With RiskTesting to Align with RiskCritical to DrugManufacturingProcess ( )vSingle campaign may involve 100’s ofpolymeric componentsLow\Medium RiskvMany components associated with lowerrisks (small surface area exposed to largevolumes, or upstream of process clearancesteps)vStrong, compound-specific extractables profilesnot available today for all componentsvEnd-Users have different approaches andrequirements for Low and Medium riskcomponentsFinalClearanceStepCritical to Patient Safety (CQAs) – High RiskBIOTHERAPEUTICS2019 BPSA International Summit17PRODUCTIONDEPLOYMENTCOLLABORATION

Do I Need Low, Medium, or High Risk Data?BIOTHERAPEUTICS2019 BPSA International Summit18PRODUCTIONDEPLOYMENTCOLLABORATION

What Testing is Required for Low, Medium, High Risks?Component Test RequirementLow50% EtOHMed50% EtOHHigh50% EtOHLow pHpH 10* Less animal testingBIOTHERAPEUTICS2019 BPSA International Summit19PRODUCTIONDEPLOYMENTCOLLABORATION

Suppliers Have Historically Performed 661 2019 BPSA International TION

USP 665 & BPOG Key Points to Considerü 661.1 for raw polymers not technically required, but expected forQbD component designü 665 baseline testing in 50% EtOH/water required for ALLcomponents (replace historical 661 ) (NVR, pH shift, UV)ü 665 Medium-risk testing offers cost-effective solution forcomponent that are not high risk. Will drive data to market!ü 665 High-risk compliance requires single timepoint and single lotat pH 10 (and not BPOG 0.5N NaOH).ü Additional data can be generated to support end user qualificationü Timepoints: Intermediate, Long, 30 minü Solvents: 50%EtOH, Low pH, pH 10, 0.5N NaOH, Water, PS80, NaClü USP component risk-level needs to be clearly communicated to endusers (addresses concern that suppliers may not know theapplication)BIOTHERAPEUTICS2019 BPSA International Summit21PRODUCTIONDEPLOYMENTCOLLABORATION

ü NaCl, WFI, PS80 under reviewDatasetsBPOG Extractables Updateü Published data reporting templateand report guidelines50% EtOHuniqueü Assembly family templateü Data sharing ‘rules of the road’.ü Numerous FAQs (some not finalized)Number of Peaksü Component family template0.5N NaOHPS80WFIpH 1.6NaClü Expectation for suppliers to listreports on supplier’s websiteBIOTHERAPEUTICS2019 BPSA International SummitBPOG EXT 05 Extractables Workshop: Data review team22PRODUCTIONDEPLOYMENTCOLLABORATION

Reporting GuidelinesBPOG Extractables Updateü NaCl, WFI, PS80 under reviewü Published data reporting templateand report guidelinesü Component family templateü Assembly family templateü Data sharing ‘rules of the road’.ü Numerous FAQs (some not finalized)ü Expectation for suppliers to listreports on supplier’s ntation/BIOTHERAPEUTICS2019 BPSA International Summit23PRODUCTIONDEPLOYMENTCOLLABORATION

BPOG Extractables UpdateReport IDü NaCl, WFI, PS80 under reviewü Component family templateü Assembly family templateTested Part IDü Published data reporting templateand report guidelinesü Data sharing ‘rules of the road’.ü Numerous FAQs (some not finalized)Part numbers for whichreport is applicableü Expectation for suppliers to listreports on supplier’s ntation/Surface areas for whichreport is applicableBIOTHERAPEUTICS2019 BPSA International Summit24PRODUCTIONDEPLOYMENTCOLLABORATION

BPOG Extractables UpdateAssembly PNsü NaCl, WFI, PS80 under reviewü Published data reporting templateand report guidelinesü Component family templateü Assembly family templateü Data sharing ‘rules of the road’.ComponentPart numbersin systemü Numerous FAQs (some not finalized)ComponentExtractablesReport IDComponentSurfaceAreaü Expectation for suppliers to listreports on supplier’s ntation/2019 BPSA International ORATION

BPOG Extractables UpdateData Pass throughIn order to make the system as efficient as possiblethe intention is that integrators will not need to retestcomponents that have been tested by componentmanufacturers. The simplest way to achieve this isto allow integrators to pass on data provided bytheir component manufacturers to their customers.The goal of the team is to make this as frictionlessas possible and remove the need for a 3 wayconfidentiality agreement (CDA / NDA) to be set upbetween supplier integrator and end user. The teamis currently working on developing a set ofguidelines or ‘Rules of the Road’ for howextractables data can be made easily available tobiomanufacturers by their direct supplier withoutneed for multiway legal agreements.ü NaCl, WFI, PS80 under reviewü Published data reporting templateand report guidelinesü Component family templateü Assembly family templateü Data sharing ‘rules of the road’.ü Numerous FAQs (some not finalized)ü Expectation for suppliers to listreports on supplier’s ntation/BIOTHERAPEUTICS2019 BPSA International Summit26PRODUCTIONDEPLOYMENTCOLLABORATION

Standardize –Extractable Data e-Location2019 BPSA International Summit BioPhorum Operations Group ION

FDA Presentation- Highlights Team of BPOG members (end users) presented information to the FDA onthe topic of E&L End users proposed that the FDA include FEP as GRAS – GenerallyRecognized As Safe – Material2019 BPSA International Summit BioPhorum Operations Group ION