Supplies and Reagents

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Supplies and Reagents

Supplies and ReagentsPACT Workshop: Design &Operation of GMP Cell TherapyFacilitiesApril 4 th /5 th , 2006NHLBI-sponsored PACT Group


Guidance for IndustryINDs – Approaches to Complyingwith CGMP During Phase ISOP for handling, review, acceptance andcontrol of componentsComponents to be controlled (segregated,labeled) until examined (and tested) andreleased for productionKeep record with relevant information


Guidance for IndustryRelevant Information:– Receipt date– Quantity in shipment– Supplier name– Lot #– IND batch #– Storage conditions– Expiration date


Guidance for IndustryEstablish acceptance criteria for specifiedattributes if possible; attributes andacceptance criteria reviewed in INDapplicationCertificate of Analysis and/or otherdocumentation on each lot reviewed toensure it meets acceptance criteria forspecified attributes


21 CFR Part 1271.210Supplies and ReagentsVerification:– Verification by establishment that uses thesupply or reagent OR– Verification by the vendorReagents: must be sterileIn-house reagents: validate or verifyproduction process


Records21 CFR 1271.210Supplies and Reagents– Receipt: type, quantity, manufacturer, lot #,date of receipt, expiration date– Records of verification:Include test results if appropriateC of A (if vendor verification)– Record of lot # used in manufacture


Careful scrutiny of the materials used inmanufacturing is necessary to prevent theintroduction of adventitious agents or toxicimpurities, as well as to ensure theultimate safety, effectiveness, andconsistency of the final product.– U.S.P. Ancillary Materials for Cell, Gene, andTissue-Engineered Products


General RequirementsSterileNon-pyrogenicWhen possible, items approved forhuman use, injectable/infusable, , USPgrade, manufactured under U.S. License


When possible, it is preferable to usematerials/reagents that are approved orlicensed therapeutic products:– well characterized– have an established toxicological profile– manufactured according to controlled anddocumented proceduresChoices may be driven by production protocol– unique functional contributions or biologicaleffectse.g. FBS, cell culture media, DMSO


SpecificationsComplete Specification FormEach item identified by unique part #– CHxxxxxx– MAxxxxxxChemicals/reagentsMaterialsCurrently approx. 820 specsDatabase/paper copyTreated as a controlled document


VendorsAcceptable Vendor(s)/Suppliers– Specific vendor– Multiple vendors– Vendor history


Vendor QualificationIs it possible/practical/cost effective?MCT Facility – approx. 280 vendorsHow?– Audits/site visits may be possible if local– Survey (phone, mail)– Prior history with manufacturer: complaints,C of A– Determined by other, e.g. hospital contract,pharmacy– Licensed products


Materials RequirementsPlanning Matrix (MRP)Planning document used during productdevelopment; completed and approved prior toclinical productionMeans to identify critical supplies and reagentsused in productionProvides means to review how items are used,identify qualification requirementsMaterials and inventory planning document


Tier System (USP)General Chapters: AncillaryMaterials for Cell, Gene, and Tissue-Engineered Products (USP 29 NF 24 –official 4-1-06) 44 TiersDefinitionsExamplesQualification or Risk Reduction Activities


Tier 1Definition: low-risk, highly qualified materials thatare well-suited for use in manufacturing andhave a strong safety profile.– Licensed biologic, an approved drug, an approved orcleared medical device, or intended for use as animplantable biomaterial.– Obtained as a sterile packaging system or dosageform.– Items may be used according to the manufacturer’sinstructions or may be utilized “off label” in themanufacturing process.Examples: Human Albumin, Insulin, Pulmozyme,Saline, Dextran 40, Isolex reagents, etc.


Tier 2Definition: low-risk, well-characterized materialsthat are well-suited for use in manufacturing.– Intended use is for drug, biologic, or medical devicemanufacture, including cell, gene, and tissue-engineered products as materials or reagents, andthey are produced under relevant cGMPs.– Most animal-derived materials are excluded from thiscategory.Examples: Human AB serum, itemsmanufactured under IDE such as cell selectionbeads, etc.


Tier 3Definition: moderate risk materials that willrequire a higher level of qualification thanprevious tier materials.– Frequently, these materials are produced for in vitrodiagnostic use and are not intended for use in theproduction of cell, gene, or tissue-engineered engineered clinicalproducts– In some cases, upgrade of manufacturing processesmay be necessary in order to employ the material inmanufacturing of these productsExamples: cell/tissue culture media such asAIM-V, Ex-vivo, MEM, HBSS, RPMI, etc.


Tier 4Definition: the highest risk level for materials or reagents.Extensive qualification is necessary prior to use inmanufacturing.– The material is generally not produced in compliance withcGMPs.– Tier 4 materials and reagents are not intended for use in theproduction of cell, gene, or tissue-engineered engineered products.– This risk level includes highly toxic substances with knownbiological mechanisms of action, and also includes mostcomplex, animal-derived fluid materials not subjected toadventitious viral removal or inactivation procedures.– In the early stages of development the necessity of thesematerials should be evaluated and alternative substances orsources explored.Examples: Fetal Bovine Serum, Animal or human cellsused as feeder layers


Qualification or Risk ReductionActivities – Tier 1– DMF cross reference (when possible orpractical)– Certificate of Analysis– Assess lot-toto-lot effect on performance– Assess removal from final product– Stability assessment on materials as storedfor use in manufacturing


Qualification or Risk ReductionActivities – Tier 2Same as Tier 1 plus:– When relevant, confirm certificate ofanalysis test results critical to product(could include functional assay)– Vendor audit


Qualification or Risk ReductionActivities – Tier 3Same as Tier 2 plus:– Work with manufacturer to upgrademanufacturing process for material toGMP– Develop stringent internal specifications– Determine if lot-toto-lot biocompatibility,cytotoxicity, , or adventitious agent testingare needed


Qualification or Risk ReductionActivities – Tier 4Qualification or Risk Reduction Activities – sameas Tier 3 plus:– Verify traceability to country of origin– Assure country of origin is qualified as safewith respect to source-relevant relevant animaldiseases, including TSE– Adventitious agent testing for animal source-relevant viruses


Current Practice SOPs for handling materials and reagents Critical supplies/reagents listed in CMC Specifications Systems to record information Segregation/inspection/labeling prior torelease QA Review of C of A at receipt In-house reagents: perform validation,verification


Needs ImprovementVendor audits – very limitedAdditional Qualifications:– Compare lot to lot variability (FBS)– Reserve one lot for clinical trial– Additional testing on a few items (cell lines,DMSO when vendor changed)


Sources:Guidance for Industry INDs – Approaches toComplying with CGMP During Phase I; FDAJanuary 200621 CFR Part 1271; FDA, 2005U.S.P. Ancillary Materials for Cell,Gene, and Tissue-Engineered Products; 29 NF24 – official 4-1-064

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