Mohamed, Farahidah

The International Islamic University Malaysia Repository

Good Manufacturing Practice for Clinical Trial of New Anticancer Drugs (Conventional vs New Generation Dosage Form, i.e Stem Cell-Based)Assoc. Prof. Dr. Farahidah MohamedDeputy DirectorInnovation & Commercialisation UnitResearch Management CentreInternational Islamic University MalaysiaThis Photo by Unknown author is licensed under CC BY.OUTLINEIntroduction• Conventional Dosage Form• Next Generation Dosage Form: Advanced Therapy Medicinal Product (ATMP)• Drug R&D timelineIntroduction to Good Manufacturing Practice• Conventional vs ATMPsSummaryIntroduction –Conventional Dosage Form• Chemical or herbal-based, usually a single compound• Non-sterile & sterile manufacturing condition• Common product specifications according to dosage form (tablet, capsule, syrup, suspension, ointment, lotion, cream, capsule)Introduction –Next Generation Dosage Form (NGDF)Asim Ali Yaacob et al. 2020Introduction –NGDF for Advanced Therapy Medicinal ProductsIntroductionAdvanced Therapy Medicinal Products (ATMPs) are innovative and complex• Stem cells for cancer or for regenerative medicinesPose challenges to the DESIGN and CONDUCT of clinical trials• Manufacturing constraint (new design of GMP facility, huge investment, shelf-life, tight control on logistic)• Difficulty in designing placebo, long-term follow-up, not always feasible to provide pre-clinical dataIntroduction4 classes of ATMP• Gene-Therapy Medicinal Products (GTMPs)• Somatic Cell Therapy Medicinal Products (sCTMPs)• Tissue-Engineered Products (TEPs)• Combined ATMPsIntroduction – ATMP for cancer• Gene-Therapy Medicinal Products (GTMP)• Gene silencing• Anti-sense therapy• RNA interference• Gene and genome editing• Somatic gene therapy• Somatic Cell Therapy Medicinal Products (sCTMPs)DRUG R&D TIMELINEhttps://doctortarget.com/machine-learning-applied-drug-discovery/9Start of GMP & GCPIntroductionGood Manufacturing Practice (GMP)Good Clinical Practice (GCP)Good Laboratory Practice (GLP)Introduction to Good Manufacturing Practice (GMP)Is a concept that ensures product are consistently manufactured based on a controlled procedures under a controlled environment to yield consistent product quality based on appropriate quality standardsSource of References:PIC/S ICH GuidelinesISPE Good Engineering PracticeUS cGMP GuidelineEU GMP GuidelineEtc1 11 2PIC/S1 3GMP ScopesQUALITY CONTROLPRODUCTION ENGINEERING QUALITY ASSURANCE1 4GMP- Quality Control+Conduct testings on:+raw materials+packaging materials+finished product+water for manufacturing+air quality inside the plant1 5GMP- Production+Manufacture products according to an approved process+Conduct in-process quality control (IPQC) testing1 6GMP- Engineering+Monitor quality of utilities:+Water Purification System+HVAC System – heating, ventilating & air-conditioning+Monitor quality and status of production equipment+Calibration+Breakdown1 7GMP- Quality Assurance+Managing Risk+Quality Risk Management+Documentation+Regulatory requirement+Product registration+Product complaint+Personnel competency1 8Quality Control for in-coming materials (ikool™ as case example)P R O D U C T I O NP R O C E S SB A S E D  O N A P P R O V E DB M R  A N D B P RQ C  T E S T I N G  F O R  F I N I S H E D  P R O D U C TAssay of active ingredients5 APIsMicrobial Limit testTAMCTYMCS.aureusE.coliMinimum Fill weightGMP for Advanced Therapy Medicinal Product (ATMP)2 2GMP for Advanced Therapy Medicinal Product (ATMP)2 3PIC/S GMP Guide - revised2 4Annex 2A- Manufacture of Advanced Therapy Medicinal Products (ATMP) for Human Use2 5Annex 2A-Manufacture of Advanced Therapy Medicinal Products (ATMP) for Human Use2 6GMP requirement is based on manufacturing method of ATMPs manufacture.For example, for gene therapy ATMPs, genetic modifications can be obtained through a variety of methods (e.g. viral & non-viral vectors, mRNA, ex vivo and in vivo genome-editing tools).Annex 2A-Manufacture of Advanced Therapy Medicinal Products (ATMP) for Human Use2 7The genetically modified cells can be of human origin (autologous or allogeneic) or of animal origin (xenogeneic cells), either primary or established cell lines.In a medicinal product, the genetically modified cells or gene therapy products can be presented alone or combined with medical devices.Appropriate application of Annex 2A2 8Example Products Application of this AnnexGene therapy: mRNALinear DNA template preparationIn vitro cell free transcription mRNA purificationFormulation & fillingGene therapy: in vivo viral vectors Plasmid manufacturingEstablishment of MCB and WCBVector manufacturing and purificationFormulation & fillingGene therapy: in vivo non-viral vectors (naked DNA, lipoplexes, polyplexes etc.Plasmid manufacturingEstablishment of bacterial bankFermentation and purificationFormulation & fillingGene therapy: ex-vivo genetically modified cellsDonation, procurement and testing of starting tissue/cellsPlasmid manufacturingEx-vivo genetic modification of cellsFormulation & fillingVector manufacturingFormulation & fillingSomatic cell therapyDonation, procurement and testing of starting tissue/cellsEstablishment of MBC and WBC or primary cell lot or cell proofCell isolation, culture, purification, combination with non-cellular componentsFormulation, combination and fillingTissue-engineered productsDonation, procurement and testing of starting tissue/cellsInitial processing, isolation and purification, establish MCB, WBC, primary cell lot or cell poolCell isolation, culture, purification, combination with non-cellular componentsFormulation, combination and fillingExample of Approved sCTMP for cancer+PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.+Each dose of PROVENGE contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF+ The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals.+PROVENGE is designed to stimulate the immune system2 9Example of Approved sCTMP for cancer+Confirm Patient Identity - PROVENGE is intended solely for autologous use.+Confirm the proper product has been received according to the label on the outside of the insulated polyurethane container.+Prior to PROVENGE infusion, match the patient’s identity with the patient identifiers on the Cell Product Disposition Form and the PROVENGE infusion bag.3 0Example of Approved sCTMP for cancer+Confirm Product Release - Do not infuse PROVENGE until confirmation of product release has been received from Dendreon (GMP manufacturer of Provenge)+Dendreon will send a Cell Product Disposition Form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), to the infusion site.3 1Simplified Manufacturing Process Flow for ATMP3 2Manufacturing steps requiring GMP status for Gene therapy3 3Quality Control for ATMPs+ATMPs manufactured for exploratory, early phase clinical trials (phase I and phase I/II), are expected to be validatedproportionately with the knowledge and the risk associated with the respective phase.+All aseptic and sterilisation processes as well as virus inactivation or removal for investigational and authorisedATMPs are expected to be validated.+The effectiveness of disinfection methods should be proven.3 4SUMMARY – GMP for conventional medicines vs ATMPs3 55Ps of GMP – applicable for both3 6PeopleComprehend role andresponsibilitiesProductsClear specificationat every stageof productionProcessProperly documentedsimple, and consistentPremiseCleanliness and equipmentwell-maintainedProceduresGuidelines forundertakingcritical processes

Good manufacturing practice for clinical practice of new anticancer drugs (conventional vs new generation dosage form i.e Stem cell-based)

http://irep.iium.edu.my/98666/3/farahidah%20slides%202022.pdf

Good manufacturing practice for clinical practice of new anticancer drugs (conventional vs new generation dosage form i.e Stem cell-based)

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