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Supply Chain – Elastomers Elastomers for Parenteral Products–Components for Container-Closure Systems – e.g., stoppers for vials, bottles, plastic bag ports–Components for Injection Systems – e.g., plungers, tip caps, needle shields–Components for Medical Devices – e.g., parts for Metered Dose Inhalers29 2020 USPSupply Chain – Elastomers Formulations: Ingredients and RolesIngredientRoleElastomerBase material: bromobutyl, chlorobutyl, halobutylFillerInfluences physical properties: clay, talc, carbonatesPlasticizerProcessing aidCuring AgentForms cross-links: Sulfur, S-donors, phenol-formaldehydeAcceleratorCross-link type and rate: carbamates, sulfenamidesActivatorGive onset of vulcanization: ZnO stearic acidAnti-oxidantStabilizer: BHT, Irganox 1010PigmentColor30 2020 USP

Supply Chain – Elastomers Thermoset Rubber Formulation: ThenIngredientChlorobutyl Rubber% by Weight52.7%AdditivesCalcined Clay39.5%Paraffinic Oil4.2%Zinc Oxide1.6%Thiuram0.1%Hindered Phenol Anti-Oxidant0.5%Titanium Oxide/Carbon Black1.3%31 2020 USPSupply Chain – ElastomersThermoset Rubber Formulation: NowIngredient% by WeightAdditivesMineral Fillers34.4%Butylated hydroxytoluene0.3%Antioxidant0.3%Peroxide1.0%32 2020 USP

Supply Chain – Elastomers Elastomers for pharmaceuticals have become much cleaner over the lastdecades:–Lower number of ingredients–Cleaner ingredients–Coating of stoppers/plungers Composition of Elastomers is still very complex Extractables from:–Formulation ingredients–Impurities in ingredients (solvents, halides, oligomers)–Reaction/degradation products during elastomer manufacturing33 2020 USPSupply Chain – Elastomers Modern Rubber Formulations–Alternative fillers (lower levels of PAHs ornone)–Peroxide cured (no nitrosamines)–Levels of curing agents and additivesoptimized (lower levels of extractables) Older Rubber Formulations–Carbon Black Fillers (PAHs)–Sulfur Cured (Nitrosamines)–Excess levels of curing agents andadditives34 2020 USP

Supply Chain – ElastomersExtractable profile of a modernMDI elastomeric valvecomponentExtractable profile of an oldMDI elastomeric valvecomponent35 2020 USPCoated Elastomers for Vials & Pre-filled SyringesUncoated Topof PlugPiston Partially CoatedUncoatedSide and TopPiston Fully Coated36 2020 USP

Extractables: Coated Versus Non-Coated ElastomersExtraction of Organic Components into n-Heptane (GC)Uncoated PlungerCoated Plunger37 2020 USPCase Study: Elastomers Problem: Particles (10 to 200 µm) observed in diluent vials containing aphosphate buffer at 6 months Source: Particles identified as zinc phosphate. Zinc oxide is present in thebromobutyl stopper. Leached [zinc ion] required to form precipitate was only 224ppb Resolution: Switch to a chlorobutyl stopper that does not contain zincCastner J. et al. American Pharmaceutical Review Pages 70 – 75, March –April 200438 2020 USP

Case Study: Elastomers FDA Case Study:–Problem: Butylated hydroxytoluene (BHT) was observed in a lyophilized product at 12 monthsafter switching from latex to a chlorobutyl stopper–Source: BHT, a common food additive, was found at very low levels and has very low toxicity.Its source was the butyl rubber stopper–Resolution: Set acceptance level for BHT and continue to monitor BHT levelsIngrid Markovic, FDA CDER American Pharmaceutical Review Pages 96 – 101, May-June 200939 2020 USPCase Study: Elastomers FDA Case Study:–Problem: Iron leachables catalyzed oxidation of the preservative and other excipientstriggering formation of protein-preservative adducts. Decrease in potency.–Source: months. Uncoated stoppers released iron at levels 1 ppm and the shelf life datinghad been extended from 15 to 18 months–Resolution: Recall affected lots, return to 15 month shelf life, and implement coated stoppers.Eventual removal of product from marketIngrid Markovic, FDA PQRI Workshop on Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products 201140 2020 USP

MODULE 3: Extractables andLeachables Evaluation:General ConsiderationsExtractables and Leachables – Introduction Key Questions:–Why?–When?–How?42 2020 USP

Extractables and Leachables – Why?The expectation by regulatory authorities, globally, is that E&Lstudies be preformed for high risk dosage forms43 2020 USPExtractables and Leachables – When? When should extractable testing start? When should extractable testing be completed? When should leachable testing start?–Packaging for Drug Products:44 2020 USP

Evaluation of Packaging E&L (NDA) – When?PhaseIIIComponents: ExtractablesSurvey of information(consider all components)System (drug mfg. process package):LeachablesWhat is the level of concern?Analytical characterizationControl alcompoundsToxopinionControlcomponentsMonitor leachablesOptimize methodsIIIE L: Validated methodsStability testing45 2020 USPEvaluation of Packaging E&L (ANDA) – When?ProjectStartComponents: ExtractablesSystem (drug mfg. process package):LeachablesSurvey of information(consider all components)What is the level of concern?Analytical characterizationControl alcompoundsToxopinionControlcomponentsMonitor leachablesOptimize methodsE L: Validated methodsStability testing46 2020 USP

Evaluation of Packaging E&L – When? Packaging Platform Approach–Conduct Extractable studies on a specific container-closure system (CCS), e.g., glassvial/stopper, plastic pre-filled syringe/plunger combination, plastic bags Use a specific CCS for a number of products with similar extracting power Advantage is that extractable data is available and methods are devised and validated Stability studies can start immediately looking for leachables47 2020 USPExtractables & Leachables – How ? Guidance in USP General Information Chapter 1663 Assessment ofExtractables Associated with Pharmaceutical Packaging/Delivery Systems –Module 8 Evaluation of Extractables – Module 9 Guidance in USP General Information Chapter 1664 Assessment of DrugProduct Leachables Associated with Pharmaceutical Packaging/DeliverySystems – Module 1048 2020 USP

MODULE 4: MaterialsSelection and EarlyAssessmentMaterials Selection and Early Assessment Understanding:–Nature of the manufacturing components–Nature of the packaging system–Packaging component supply-chain(s) –Packaging system material composition –Supplier InformationSupplier InformationDrug product risk level50 2020 USP

Dosage Form “Risk”: USP 1664 Table 1. Modified FDA/CDER/CBER Risk-Based Approach toConsideration of LeachablesExamples of Packaging Concerns for Common Classes of Drug ProductsDegree of ConcernAssociated with theRoute of AdministrationLikelihood of Packaging Component-Dosage Form InteractionHighMediumLowHighestInhalation Aerosols andSpraysInjections and InjectableSuspensions; InhalationSolutionsSterile Powders and PowdersforInjection; Inhalation PowdersHighTransdermal Ointments andPatchesOphthalmic Solutions andSuspensions; NasalAerosols and SpraysLowTopical Solutions andSuspensions; Topical andLingual Aerosols; OralSolutions and Suspensions——Oral Tablets and Oral (Hardand Soft Gelatin) Capsules;Topical Powders; OralPowders51 2020 USPMaterials Selection and Early Assessment High-Risk Dosage Forms–Safety assessment recommended during container closure system component selection–Controlled Extraction Studies required for all “critical components”–Drug product leachables studies required–Extractables/leachables correlation required–Extractables and leachables specifications and acceptance criteria required52 2020 USP

Materials Selection and Early Assessment Low-Risk Dosage Forms–Low Risk does not No Risk–Chemical Composition of all plastics, elastomers and adhesives–Appropriate references to indirect food additive regulations–For glass and plastic containers, data from USP containers is required (testing should be onthe packaging component not the unformed resin)–Method(s) to monitor consistency of composition, as appropriate53 2020 USPMaterials Selection and Early Assessment Desirable Information to Obtain from Suppliers–The base elastomeric/polymeric material (e.g., high density polyethylene, butyl rubber, stainless steel)–The additive composition of the component Reaction/degradation chemistry–Polymerization process plus associated polymerization/curing agents–Fabrication process, including additives designed to assist in fabrication–Cleaning/washing processes for finished components–Storage/shipping environment for components–Technical Data Sheets–Confidential Information on Qualitative Composition–Since Plastic & Rubber formulations are proprietary, it is difficult to obtain information on the formulation–Vendors may supply list of “potential” Extractables observed with common solvents e.g., water–Results may confirm vendors list and/or find new Extractables54 2020 USP

Materials Selection and Early AssessmentConsiderations in Component Selection For all dosage forms:–Components containing sources of known potent carcinogens or mutagens should beavoided/minimized, e.g.: Polynuclear Aromatic Hydrocarbons (PNAs) N-nitrosamines 2-Mercaptobenzothiozole (2-MBT)55 2020 USPMaterials Selection and Early Assessment What Role Does the Toxicologist Play?Resource can be in-house or outsourcedProduct PhaseDesign PhaseDevelopment PhasePost-Market MaterialChangesObjectiveDesign out undesirablesubstances; design in safe andfunctional materialsPerform ISO, Toxicology,E&L studies to fullyevaluate material safetyPerform difference studiesand appropriate ISO,Toxicology, E&L studies asneededToxicologist RoleQualitative or semi-qualitativestatement of general safety risksQuantitative andcomprehensive safetyrisk assessmentQuantitative safety riskassessment focusing on thechanges56 2020 USP

Safety Assessment of LeachablesThere are currently no regulatory guidelines in place for how to assess therisk of leachables and extractables Generally:–Comprehensive assessments are performed for each chemical compound (above sciencebased thresholds)–Assessments are based upon Available animal and human toxicology data (i.e., literature) Chemical structure – activity analysis (i.e., databases)57 2020 USPRisk Assessment of Leachables – What is NeededToxicologists Need to know Identity of extractable Dose – under conditions of maximum daily use of the drug, how much of a totaldaily dose in ppm of the leachable will be administered to humans? –If Drug A is given at 1 gram/day, the dose of a leachable present @ 1 ppm is 1 μg–If Drug B is given at 10 mg/day, the dose of a leachable present @ 100 ppm is also 1 μgDuration – How long will the patient be exposed to the leachable?–Chronic, daily exposure to a potential toxin always carries a higher theoretical risk of eliciting anadverse effect than short-term exposure–Greater scrutiny of safety data supporting a leachable will be paid to those in chronic use drugsRoute of Administration – Can affect the toxicological profile of any toxin–If not absorbed, may not be toxic via the oral route, but very toxic intravenously!–Different metabolites can form from exposure to the body via different routes (i.e., oral versusintravenous)58 2020 USP

Risk Assessment of Leachables – What is Needed Patient population – Are patients with a disease receiving the drug containingleachable(s); health status can influence the risk assessment Indication –What is being treated by the drug has great influence on a riskassessment; greater risk is tolerated if the drug is to treat a life-threatening illness! “Special” populations – factors such as a potential pediatric indication,administration to an elderly population, need to be understood to better assesspotential risk59 2020 USPRisk Assessment of Extractables Irgafos 168 Phosphate (Di-tertiary butyl phenyl phosphate)–Irgafos 168 phosphate extractable wasobserved–This is an oxidized reaction product ofIrgafos 168 phosphite (contains additionaloxygen atom)–Could likely present as a leachable;observed in a solvent extraction conditiondeemed “highly relevant” to the clinical formulation–Highest IV “extractable dose” is 50 µg/day (1.0 µg/kg/day)–Data on compound is not available!OOPOO60 2020 USP

Risk Assessment of Extractables Neither structure (Irgafos 168 phosphite or phosphate) gave concern formutagenicity, carcinogenicity, or systemic toxicity in humans– Irgafos 168 phosphite has sufficient safety data available to enable a riskassessment of Irgafos 168 phosphate– Identical results obtained for both compoundsEven assuming the unlikely scenario that the extractable dose is the same as the leachabledose (“worst case” situation)Proceed with confidence with migration studies knowing that if Irgafos 168phosphate presents as a leachable, its risk can be assessed61 2020 USPRisk Assessment of propanol – like nucleus (CAS #55956-25-7)H 2C–I only have a partial structure–“Several” unidentified extractables were likely to sharethis nucleusOCH3––They might present as leachables; observed in morethan 1 solvent extraction conditions collectivelydeeming them “possibly relevant” to the clinicalformulationOHOCH3No safety data available for the base structure62 2020 USP

Risk Assessment of Extractables DEREK structural analysis yielded no alerts for mutagenicity, carcinogenicity, orsystemic toxicity matters of concern to humans Nevertheless, the additional chemical constituents in the unidentified chemicalscontaining this nucleus may posses concerning toxicophores–Potentially problematic if not characterized prior to conducting migration study Recommended further clarification of structures sharing this nucleus beforeproceeding with migration work Once structures are characterized, do a toxicological re-evaluation to determineif safety could be supported if these were to go on to become leachables63 2020 USPMODULE 5: USP Chapter 1663 – Principles ofExtractable Assessment

Extractable Assessment Best PracticesStudiesKey CharacteristicsMaterial Characterization(Tentative Leachables) Screening of packaging candidates Establish composition of extractable materials Broad Based/Screening extraction and testing(Semi-quantitative) Toxicological AlertsSimulation Study(Probable Leachables) Leachables Study(Confirmed Leachables) Establish the actual accumulation of target leachables Drug product under actual conditions of use Toxicological assessment of all targeted leachablesOutcome: Negligible or unacceptable safety riskEstablish worst case accumulation of leachablesConditions to mimic worst case (accelerated)Justified simulating solventsAssessment of all extractables above the AETIdentify Leachable TargetsSource: Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products (PODP) Workshop Houston/ Egert/Hendricker February 22-23, 201165 2020 USPPurpose of an Extraction Study Material characterization of the packaging components Compare supplier information with empirical data – Confirmation “Impurities profiling” of the materials–Identify as many potential “Bad Actors” as possible Early risk evaluation Identify compounds that may need to be monitored as leachable –Concentration in the materials–Risk for migration–ToxicityNOT a Final Step in a Safety Assessment!66 2020 USP

Parameters to be Considered in an Extraction Study Extraction Study: what are the scientific principles and best demonstratedpractices under which it should be accomplished? Extraction Study: consists of two critical dimensions:–Laboratory generation of the extract (Extraction)–Testing the extract (Characterization)67 2020 USPParameters to be Considered in an Extraction Study An extraction process is accomplished by steps that are based on themanipulation of several experimental parameters, including:–The chemical nature of the extracting media–The time duration of the extraction process–The temperature at which the extraction is performed–The stoichiometry of the extraction process (extracted surface area per unit volume ofextracting solution)–The phase equilibrium of the material–The mechanism or process by which the extraction is accomplished68 2020 USP

Drug Product (Vehicle) Extraction SolventExtracting Medium Tactics A critical parameter – ideally it would be the final formulation:–Final formulation may not be available–The final formulation might complicate the extract characterization to such an extent that it isimpractical–If the use of the drug product as the extracting solvent is not feasible then the drug productvehicle, or placebo, could be used as an effective extracting medium69 2020 USPDrug Product (Vehicle) Extraction Solvent Advantage– The extraction propensity is the sameDisadvantage–Risk of missing the presence of compound –Risk of misinterpretation of analytical data –Matrix interference of drug product (vehicle)Drug product (vehicle) matrix degradants may be misinterpreted as extractableRisk of underestimating compound concentrations Extraction conditions – may potentially be too mild Difficult to select the right set of extraction conditions (e.g., extraction time, temperature)70 2020 USP

Extraction TechniquePreferred: Use of “old”, low cost extraction techniques which can be implementedin every lab Exhaustive extractions: Reflux or Soxhlet–Similar extraction yields–Reflux has shown - in limited cases - to introduce artifacts in extraction profile–Soxhlet has more practical implications Takes longer (24h) to have the same extraction yields as reflux (8h) Safety implications in Lab (24h extraction) Less practical for solvents with high boiling points Less practical for aqueous extraction vehicles71 2020 USPExtraction Technique Sonication–Less exhaustive than Reflux & Soxhlet (PQRI)–However, it may be less detrimental to certain materials–Often used as the extraction technique for Labels Avoids disintegration of Label, while extracting most relevant compoundsClosed Vessel–Amount of material is extracted with Extraction Solution–Closed vessel avoids loss of volatile organic compounds–Typically ISO 10993-12 Conditions are used (e.g., 50 C, 72h)72 2020 USP

Extraction Technique Headspace Enrichment (Non-solvent Mediated)–Direct analysis of the material using Headspace GC/MS–Complete profile of volatile organic co

5 2020 USP Module 1. Quality Concepts Module 2. Importance of Material Quality Module 3. Extractables and Leachables Evaluation: General Considerations