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USP 665 Polymeric Components and SystemsUsed in the Manufacturing of Drug ProductsBPSA International Single-Use SummitJuly 13, 2017, Washington, DCMichael N. Eakins B.Sc., Ph.D.Member, USP Packaging & Distribution ExpertCommitteePrincipal Consultant, Eakins & Associates

United States Pharmacopeia Scientific, independent, volunteer-driven, nonprofitorganization– Established in 1820– Headquartered in Rockville, MD– Facilities in Africa, Brazil, China, India, Switzerland Set public quality standards for prescription and over-thecounter medicines, excipients (inactive ingredients),dietary supplements, and food ingredients Worked closely with FDA and predecessors for 100 years,developing and revising drug quality standards Translated into Chinese and Spanish Legally recognized in 39 and standards used in 140 countries2

USP General ChaptersUSP General Chapters Chapters 1 to 999 are enforceable in the USAUSP General Information Chapters Chapters 1000 to 1999 Chapters provide information – they contain nostandards, tests, assays, nor other mandatoryspecifications, with respect to any Pharmacopeialarticles3

Plastic Components and Packaging Materials 1661 Evaluation of Plastic Packaging Systems and their Materialsof Construction with Respect to Their User Safety Impact 661 Plastic Packaging Systems and Their Materials of Construction 661.1 PlasticMaterials ofConstruction 661.2 PlasticPackaging Systemsfor PharmaceuticalUse 661.3 PlasticComponents andSystems Used inPharmaceuticalManufacturing4

USP Revision BulletinIssued May 1, 2017USP General Chapters: 659 , 661 , 661.1 , 661.2 Reason: Compliance Provides a three-year period for implementation of therequirements specified in General Chapters 661.1 and 661.2 ,which otherwise will become applicable on May 1, 2017 throughGeneral Chapter 659 Reinstates requirements previously expressed in General Chapter 661 during this three-year period Enables early adoption of the requirements in General Chapters 661.1 and 661.2 at any time during the three-year period inlieu of meeting the reinstated 661 requirements Removes the exemption to General Chapters 661.1 and 661.2 for previously approved plastic materials andpackaging systems by a regulatory authority5

Plastic Components and Packaging Systems 661.3 Plastic Components and Systems Used inPharmaceutical Manufacturing Published in Pharmacopeial Forum 42 (3), May 1, 2016 665 Polymeric Components and Systems Used toManufacture Pharmaceutical and Biopharmaceutical DrugProducts Published Pharmacopeial Forum 43 (3), May 1, 2017 1661 Evaluation of Plastic Packaging Systems and TheirMaterials of Construction with Respect to their User SafetyImpact Published in Pharmacopeial Forum 42 (3), May 1, 2016 1665 Characterization of Polymeric Components andSystems Used to Manufacture Pharmaceutical andBiopharmaceutical Drug Products Published Pharmacopeial Forum 43 (3), May 1, 20176

New Chapters 665 and 1665 1665 Characterization of Polymeric Components andSystems Used to Manufacture Pharmaceutical andBiopharmaceutical Drug Products 665 Polymeric Components and Systems Used toManufacture Pharmaceutical and BiopharmaceuticalDrug Products7

Publication Timeline Chapters 665 and 1665 have beenpublished in the Pharmacopeial Forum (PF) PF 43 (3) May 1, 2017Comment Deadline: July 31, 2017Comments will be reviewedTarget Official Publication: USP 41 FirstSupplement (February, 2018) Target Official Date: August 1, 20188

665 Polymeric Components and Systems Used toManufacture Pharmaceutical and BiopharmaceuticalDrug ProductsScope: Parameters covered Active pharmaceutical ingredients and drug products Pharmaceuticals, Small Molecules, Biopharmaceuticalsand Biologics Single-Use Systems and Multi-Use SystemsAssessment Process Initial Assessment (detailed explanation in 1665 ) Risk Assessment (detailed explanation in 1665 )Polymeric Materials of ConstructionPolymeric Components & Systems9

1665 Characterization of Polymeric Componentsand Systems Used to Manufacture Pharmaceuticaland Biopharmaceutical Drug ProductsAssessment Process Initial Assessment Risk Assessment: Application and Use of the RiskAssessment MatrixEstablishing the Level of Characterization Baseline: Expanded; Full testing (extractables profiling)Standard Extraction Protocol Selection of Solvents Extraction Temperature, Duration and MethodologyTesting the ExtractsEvaluation of Extractables ProfileSafety Qualification10

665 Polymeric Components and Systems Used toManufacture Pharmaceutical and BiopharmaceuticalDrug Products It is likely that one or more polymeric components will comeinto contact with the manufacturing process from rawmaterials to drug product Such an interaction could result in Process EquipmentRelated Leachables (PERLs) which have the potential to altera key quality attribute of drug substances and drug productsshould the PERLs persist through the manufacturingprocess Therefore PERLs should be assessed for polymericmanufacturing components and systems, but should ALLpolymeric manufacturing components or systems beevaluated to the same degree?11

665 Polymeric Components and Systems Used toManufacture Pharmaceutical and BiopharmaceuticalDrug Products If we can find a science-based way to differentiate thosemanufacturing components or systems that should be fullyevaluated for organic extractables from those which requireminimum testing, then the overall amount of testing and costcan be reduced One approach to achieve this is by using an InitialAssessment followed by a Risk Assessment The outcome of the Risk Assessment will determine the levelof testing required for organic leachables12

The Initial Assessment of a Component 665 Is the component isolated from theprocess stream?YesNo material or component testingNoIs the component in contact with a liquidprocess stream?NoNo material or component testingYesIs the component used in an establishedmanufacturing operation or used tomanufacture an established API or DP?YesJustify No material or componenttestingNoYesCan a Comparator component or systembe established?Justify No material or componenttestingNoProceed to Risk Assessment13

The Concept of a Comparator 1665 A comparator is a component or system that is used to producean approved and marketed drug product. As the comparator isused to produce an approved and marketed drug product, thenthe comparator has been established and deemed to be suitablefor its intended purpose Areas to consider in establishing equivalence: Equivalence in intended use, Equivalence in component or system composition, Equivalence in composition of the drug product(s), Equivalence in the processing conditions of use, and Equivalence in the drug product dosage form.If a comparator has been established for a component orsystem under assessment, further characterization is notrequired providing a justification is presented14

Risk Assessment 1665 Application of the Risk Evaluation Matrix The Risk Evaluation Matrix considers four dimensionswhich address the risk that a plastic component will beleached by a process stream to such an extent thatprocess streams could contain potentially impactfulextractables. These dimensions include: The duration of contact,The temperature of contact,The chemical composition of the process stream, andThe nature of the component’s materials of construction. The matrix then considers each dimension separatelyand assigns a level of risk associated with certainmeasures relevant to each dimension. Three levels ofrisk are established (A, B or C).15

Testing Requirements for Three Risk LevelsRiskLevelA(LowerRisk)AssessmentTesting RequirementsMaterials of Construction 661.1 Component or System 665 LevelBaseline All individual materials of construction comply with 661.1 : Biocompatibility 87 IdentityTesting Biocompatibility 87 BExpandedBaselineTestingPhysicochemical characteristics (TOC, UV, Acidity/alkalinityExtractable metalsAdditives by proper reference to 21 CFR 174-179Indirect Food Additive regulationsAll individual materials of construction comply with 661.1 : IdentityBiocompatibility 87 and Class VI 88 Physicochemical characteristics (TOC, UV, Acidity/alkalinityExtractable metalsAdditives determined by testingFull Testing Same as Expanded Baseline TestingC(HigherRisk) Biocompatibility 87 andClass VI 88 Extractable metals in SolutionC1Biocompatibility 87 and Class VI 88 Full Organic ExtractablesProfiling via Standard ExtractionProtocol (Solutions C1, C2 and C3)Bold entries represent testing required in addition to the testing required in the lower risk levels. 16

Steps Involved in Generating a Risk EvaluationMatrix1. Identification of the factors of contact that contributeto the leachables risk,2. Identification of the factors of production and use thatmitigate or exacerbate the leachables risk,3. Risk scoring the factors individually,4. Combining the scores for the individual factors into acomposite or total risk score,5. Comparing the score for a particular circumstance to ascale that links certain scores to specific testinglevels.16

Risk Evaluation Matrix 1665 The Risk Evaluation Matrix considers four dimensions: The duration of contact: 24 hr; 1 - 7 days; 7 days The temperature of contact: 0 C; 2 - 25 C; 30 C The chemical composition of the process stream:– “Aqueous” ( 5% organic)– “Somewhat Organic” (5% - 40% organic)– “Highly Organic” ( 40% organic) The nature of the component’s materials of construction:– “Inert” (level of additives is 0.1% by weight)– “Intermediate” (level of additives is 0.1% to 1% by weight)– “Reactive” (level of additives is 1% by weight) The matrix then considers each dimension separately and assigns alevel of risk associated with certain measures relevant to eachdimension. Three levels of risk are established (1, 2 or 3).18

The Risk Evaluation Matrix 1665 The matrix considers each dimension separately andassigns a level of risk associated with certainmeasures relevant to each dimension.RiskDimensionDurationLevel 1 24hoursLevel 21 – 7 daysTemperatureaSolventMaterialReactivityFrozen ( -10 C)AqueouspH 3 and pH 9InertRefrigerated (2 - 8 C)Somewhat organicIntermediateHighly organic orextreme pH(pH 3 or pH 9)ReactiveAmbient (15 - 25 C)Level 3 7 daysElevated ( 30 C)aThe gaps in temperature ranges reflect temperature ranges that are rarelyexperienced in manufacturing processes19

Applying the Risk Evaluation Matrix 1665 Step 1: Establish values for each risk dimension The 4 dimensions for each component being assessed is “rated” aseither 1, 2, or 3. A numerical risk sequence can be generated basedon these assignments. Although the numerical order of the risk sequence values is largelyinconsequential, the proper use of the numerical risk sequencerequires that the sequence be given in order of decreasing digitvalues. A component that is rated as highest risk in all four dimensionsgenerates a numerical risk sequence of 3333– 7 days (3); 30 C (3); Highly organic or extreme pH (3); Reactive (3) A component that is rated as different risk levels in the fourdimensions could generate a numerical risk sequence of 3221– 7 days (3); refrigerated (2); Somewhat organic (2); Inert (1)20

Applying of the Risk Evaluation Matrix 1665 Step 2: Linking the numerical risk sequence with a levelof characterizationDimensional ScoresExampleThree or four dimensionsscore Level 33333 or 3332 or 3331Two dimensions score Level 3332233213311One dimension scores Level 3 3222 or 322132113111No dimension scores Level 322222221 or 2211 or 2111 or 1111Characterization LevelLevel CLevel CLevel B or C*Level A or B**Level BLevel A or B**Level ALevel BLevel A* If the dimensional score 2 is material reactivity, Level B; if not Level C** If the dimensional score 1 is material reactivity, Level A; if not Level B21