EXTRACTABLE LEACHABLES OVERVIEW, INDUSTRY REQUIREMENTS & AVECIA APPROACH BY ARYO NIKOPOUR 12/1
OUTLINE • Definition • Industry Guidance • Extractables Method Development • Extractables Method Validation • Leachables Method Development • Leachables Method Validation • Extractables & Leachables Experience • Case Studies
WHAT DOES DRUG PACKAGING DO? Store and Protect The Drug Product
SUITABILITY OF CONTAINER CLOSURE SYSTEM Safety Suitability Protection Performance for Use Compatibility
EXTRACTABLES • Extractable: A chemical compound (volatile, semi-volatiles non-volatile and elemental impurities) that gets extracted from a packaging component in a suitable solvent by utilizing optimum extraction conditions (time and temperature). • Extractable profile for a given packaging component, typically can be a chromatogram (GC- MS, LC-MS and ICP-MS) representing all possible extractables. • Extractable profile is established for all packaging components (resin, vial, foil-laminate) for their consistent quality assurance. FDA DSaRMAC, May 2004
LEACHABLES • Leachable is any chemical compound (volatile, non-volatile and inorganics ) that leaches into the drug product formulation either from a packaging component or local environment on storage (time and temperature) through expiry of the drug product. An extractable can be a leachable. Extractables Leachables Migrants
LEACHABLES • The identity and concentration of recurring leachables in the drug product or placebo formulation should be determined through the end of the drug products shelf life. • In general, the levels of extractables should be greater than the levels of leachables for the correlation to be considered valid. • Evaluation of leachables in the drug product formulation in future routine stability studies may not be needed when such a correlation exists. Guidance for Industry: Container Closure System for Packaging Human Drugs and Biologics. May 1999
PHARMA/BIOPHARMA SUPPLY CHAIN Raw Material Manufacturer Packagers & Distributor Retailer Supplier Flow of Information and Traceability across
APPROACHES TO E&L STUDIES • Form a Team Toxicologist • Role of Analytical Chemist – Risk based approach DOE Analytical – Established study protocol RA/QA Chemist – Execute experiments – Analyze data, determine AET – Identify E&L ≥AET – Submit report to team members for review Manufacturing Formulators
REGULATORY BODIES AND ORGANIZATIONS
USP Requirements: Guidelines: Elastomeric Closures <381> Extractables <1663> Glass Containers <660> Leachables <1664> Plastic Containers <661> Biocompatibility of Materials <1031> Biological Reactivity Tests – in vitro<87> Biological Reactivity Tests- in vivo <88>
MEDICAL DEVICE: ISO 10993 BIOCOMPATABILITY • ISO 10993-1: Evaluation and testing in the risk management process • ISO 10993-7: Ethylene oxide sterilization residuals • ISO 10993-9 : Framework for identification and quantification of potential degradation products • ISO 10993-12: Sample preparation and reference materials • ISO 10993-13: Identification and quantification of degradation products from polymeric medical devices • ISO 10993-14: Identification and quantification of degradation products from ceramics • ISO 10993-15: Identification and quantification of degradation products from metals and alloys • ISO 10993-18: Chemical characterization of materials
FDA GUIDANCE FOR INDUSTRY MDI and DPI Drug Products: Chemistry, manufacturing, and controls documentation. Suggested Testing: “The drug product should be evaluated for compounds that leach from elastomeric, plastic components or the coating of the container and closure system, such as…………. “…polynuclear aromatics , nitrosamines, monomers, plasticizers, accelerators, antioxidants and vulcanizing agents”
FDA GUIDANCE FOR INDUSTRY • Determine the identification and concentration profile through the end of the drug product shelf life. • Correlate with the extractables profile of the container and closure components (determined under the various control extraction conditions).
FDA GUIDANCE FOR INDUSTRY(USP) Likelihood of Packaging Component-Dosage Form Interaction Degree of Concern Associate with Route of Administration High Medium Low Sterile Powders and Inhalation Aerosols Highest Powders for Injection Injections and injectable Suspension Inhalation Powder Ophthalmic Solutions High Transdermal Ointments and Patches Nasal Aerosols and Sprays Topical Solutions and Suspensions Topical Powders; Oral Oral Tablets Topical and Lingual Aerosols Low Powders Oral Capsules Oral Solution and Suspensions
STEP 1. LITERATURE SEARCH • Review DMF (Type III) • Review CDER “Guidance for Container Closure Systems for Packaging of Human Drug and Biologics” • Review Leachables and Extractables Testing Points to Consider form ITFG/IPAC-RS • Review Guidance for MDI/DPI • Leachables and Extractables Handbook, Wiley 2012 • OINDP/OPDP
STEP 2A. WHAT ARE THE CRITICAL COMPONENTS? • Is the container closure in contact with the formulation? Identify Material (i.e., HDPE, LDPE, etc.) • Is the container closure in contact the patient’s mouth or mucosa? • Secondary Container/Closure? • Extractables/Leachables Potential?
STEP 2B. TOXICITY EVALUATION • Consult with a toxicologist for the Toxicity Evaluation of the major extractable. • Determine the Permitted Daily Exposure (PDE). • Finalize the target leachable compounds based on the quantitative data of extractable and PDE data. Risk Assessments: • Dose • Duration • Route of Administration • Patient Population & Indication • Special Population • Women of Childbearing Potential
RISK BASED APPROACH TO E&L • Safety – Immunogenicity and toxicity • Efficacy – Leachable may cause lose of activity – Leachable may interact with product • Quality – Quality Attribute may change due to presence of leachables – May impact product stability
MDI DEVICE Canister Actuator Contaminan t
TYPICAL FOIL-LAMINATE COMPONENTS E = Adhesive2 A = Exterior layer Polyester/PP/PE F = Nylon/Polyester/ PP/PE(0.001 inch) (0.00048 inch) D = Aluminum Foil G = Adhesive3 B = Inks (0.00035 inch) H = Interior layer Polyester/PP/PE (0.003 C = Adhesive1 inch) DSaRMAC, May 05,2004
SINGLE USE SYSTEMS (SUS) • SUS Components includes: – Filters – Processing Containers (bags) – Tubing – Connectors – Gaskets – Valves All Product Contact surfaces have the potential to release extractables material into a process, In a biopharmaceutical process, a risk assessment for E&L should be make . Following Factors will affect the assessment: – Nature of Extractables – Process Fluid – Contact Time – Contact Temperature – Down Stream processes
EXTRACTABLES & LEACHABLES USP Nomenclature PQRI-PODP Outcome Extractables Study Controlled Extraction Identify Extractables as Tentative Leachables USP<1663> Studies Simulation Study Simulation Study Extractables as probable Leachables (fewer (Model Extraction Study) extractables). Assessing Safety Risk from Contamination Leachables Study Migration Study Confirmed Leachables in support of Shelf Life USP <1664> Studies in Final CCS Leachables Extractables Simulation Study Material Toxicological Study Study Assessment Assessment AET, SCT, TTC, AET AET QT
SOURCES OF EXTRACTABLES & LEACHABLES Materials Drug Substance Water, Excipients Manufacturing SUS (Tubing, Filters , Bags) Leachables Environment Stability Container/ Method(s) Migrants Closure
STEP 3. ESTABLISH EXTRACTABLE PROFILE (CONTROL EXTRACTION STUDIES) • A controlled extraction study, is a qualitative and quantitative investigation of critical components of CCS. • Establish a basis for development and validation of analytical method in support of routine QC testing. • Establish a basis for development of Leachable studies. • Allow for the “Correlation” of extractables and leachables. Reference: Leachables and Extractables Handbook, Wiley 2012
STEP 3. ESTABLISH EXTRACTABLE PROFILE (CONTROL EXTRACTION STUDIES) 1. Extraction studies of critical component using solvents with different strengths: IPA (Soxhlet, Reflux) Water (Pressurized Vessel) Heptane (Soxhlet, Reflux) For semi permeable CCS, evaluate secondary CCS too. What factors have impact on Diffusion: Time Solvent Temperature Physical properties of the polymer
STEP 3: CONTROLLED EXTRACTION STUDIES (CONT.) NVOC Inorganics VOC SVOC Elemental Low Molecular Weight Mid Molecular Weight High Molecular weight -Monomers -Lubricants -Plasticizers -Metals -Solvent Residues -Plasticizers -Antioxidants Alkali Earth Metals -Residues from polymer -Antioxidants -Anti-Slip Agents treatment -Solvents -Fillers -Polymer Breakdown ICP/MS , ICP-OICES AAS, Direct Injection GC/MS LC/MS, LC-PDA HS-GC/MS, HS-GC-FID GC-FID Screening, Target Analysis, Screening, Target Analysis, Screening, Target Analysis, Identification and Identification and Screening, Target Analysis, Identification and Quantification Quantification Quantification Identification and Quantification
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