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Vaccine clinical trial -Quality, include control of cell substrate Ywan-Feng Li Center for Drug Evaluation 4-7-2011 新醫藥品法規人才培訓課程(I) The views expressed in this presentation are not necessary those of Center for Drug Evaluation-Taiwan 本次內容僅代表查驗中心之觀點及 經驗分享 凡涉及政策方向及法規解釋適用, 應依衛生主管機關之指示為準 The views offered here do not necessarily reflect official positions of TFDA 4-7-2011 2 Heterogenicity of the biological/biotechnological products Tissue engineering P. Gene/cell therapy P. Blood/plasma products Peptides (20-30 a,a,) rDNA proteins (Mab, fusion protein) rDNA-derived vaccines Allergens 4-7-2011 Traditional vaccines 3 Scope Vaccine Information from research stage Clinical trial-IND Cell substrate-Testing for adventitious agents Quality, starts from phase 1 Quality, (almost) finalizes at phase 3 and continues through product life span Collaboration from all parties makes a trial going 4-7-2011 4 Type of vaccine Vaccines represent the most diverse type of products 4-7-2011 Attenuated or killed pathogens (bacteria, virus, parasites) (~traditional vaccine) Purified and recombinant protein Synthetic peptides Polysaccharide (free or conjugate to carrier) DNA, viral vectors (Cell-based product) 5 Preventive versus therapeutic vaccines In general: Characteristic Preventive Therapeutic Population Healthy subject Usually patient Clinical outcome Decrease microbial infection and/or transmission Cure or postpone disease progression (usually as a 2nd line strategy) Regimen Low dose, episodic Usually high dose, continual (more like a drug) Evaluations in early trial Safety, immunogenicity Safety, immunogenicity 4-7-2011 6 Preventive versus therapeutic vaccines Characteristic Preventive Therapeutic Regulatory evaluation Emphasis on safety Efficacy Benefit/risk assessment Efficacy Public expectation Highly concern and sensitive to the potential risks Less concern regarding the potential risks However, quality and assessment of the vaccine (Ag and adjuvant) is the same for either type of vaccine 4-7-2011 7 First licensed cancer therapeutic vaccine-Provenge (FDA) Autologous dendritic cells, activated by prostatic acid phosphatase (plus GM-CSF) 2010, approved by FDA to treat asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer 2011, FDA approved Dendreon's request to increase production capacity FDA approved "36 additional workstations at the company's New Jersey facility, adding to the 12 already approved" 2011 (Mar.), US Medicare proposed to cover the cost of $93,000/patient prostate cancer vaccine 4-7-2011 8 Type of vaccine IND New vaccines Include addition or change of adjuvant Modification of original product Formulation (e.g., lyophilized vs. liquid) Strength Route of administration Change in indication, age group, schedule, etc. Concomitant administration with other vaccine 4-7-2011 9 Vaccines in development/trial, Taiwan, 2011 4-7-2011 Ag type Virus vaccine Polysaccharide conjugate vaccine rDNA protein vaccine Indication Infectious disease Cancer 10 Reference In general Guideline on the requirements for quality documentation concerning biological IMP in clinical trials, draft, EMA, 2010 Guideline on strategies to identify and mitigate risks for FIH clinical trials with investigational medicinal products, EMA, 2007 Vaccines 4-7-2011 WHO: Biologicals TRS Japan NIID: Minimum requirements for biological products Pharmacopeia: Ph. Eur, USP 11 Quality of a product (EMA) NDA, to ensure a consistent, state-of-the art quality of a product IMP, quality attributes related to safety aspects Nature of product, clinical phase, patient population, nature/severity of illness, duration of trial. IMP documentation, M3 of CTD “IMP should be produced in accordance with the principles and the detailed guidelines of GMP…..” 4-7-2011 12 A clinical trial Starts with the quality/control of the test drug Quality of a biological/biotechnological product Include safety issues, e.g., impurity, adventitious agent (e.g., bacteria/fungi, mycoplasma, virus) Test drug used in animal toxicity studies be representative of the material for human study So as to support a phase 1 study with end points of safety and preliminary immunogenicity 4-7-2011 13 Characterization -Ag vs. therapeutic drug For Ag, immunogenicity is the desired effect, therefore, concept of certain characteristics is different (e.g., product-related impurity, which would otherwise cause undesired immunogenicity for protein drug) In general, extent of characterization is less for an Ag (e.g., product-related impurity) Thus, “Process = quality” is more likely to be the case for Ag. Therefore, the approach to establish a “design space” or platform technology is less likely to apply to vaccine product 4-7-2011 14 Scope Vaccine Information from research stage Clinical trial-IND Collaboration from all parties makes a trial going 4-7-2011 15 Information from research stage Science A vast amount of information has generated from basic research However, most information is yet to be interpreted and thus transferable to development Provide rationale based on disease pathogenesis, and identify Ag candidate Control of materials 4-7-2011 Raw materials, starting materials, solvents, reagents, catalysts, e.g., Source, history of the cell substrate History of construction of the expression plasmid 16 Information from research stage Safety information Plan to obtain and document relevant safety data from research studies even they are designed to assess biologic effects. 4-7-2011 This is an effective approach to lunch preclinical safety evaluation Extent and design of toxicity studies could depend on how much prior info exist Especially for vaccine product 17 Control of materials Documents, starting from research stage Establishment of a cell bank or virus bank ~GMP Storage, inventory, identification, handling, GMP Qualification of cell and virus bank 4-7-2011 Origin, lineage History of passage, testing Media component, e.g., FBS, trypsin All of the documents be transferable to R& D stage Contract lab GLP/GMP status 18 History of a virus strain Example (FDA, Review of Vero cell banks for Rotarix, 2008) The Serotype G1 HRV strain (genotype P[8]) which GSK used to make vaccine product is designated RIX4414. It was derived from strain 89-12, initially developed by Avant Therapeutics, Inc. ---------------. The virus was isolated in ------------ from a child in Cincinnati with a natural case of rotavirus with mild diarrhea. This original isolate was passaged 26 times in primary African Green monkey kidney cells (AGMK) by Avant for use as seed material. The P26 virus was ------- passaged by -- --------------- AVANT, -------, which passaged the seed virus an additional 7 passages to P33. This was the material that was clinically tested ---------------. The additional 7 passages were performed in an AGMK cell line that ------- characterized in --------. 4-7-2011 19 Raw material of animal source COA of FBS (partially shown) 4-7-2011 20 Raw material of animal source COA of porcine trypsin 4-7-2011 21 Scope Vaccine Information from research stage Clinical trial-IND Cell substrate-Testing for adventitious agents Quality, starts from phase 1 Quality, (almost) finalizes at phase 3 and continues through product life span Collaboration from all parties makes a trial going 4-7-2011 22 Biosafety control Combination of testings (starting material, UPB, intermediates..) and demonstrating production process to remove a wide variety of potential infectious viruses Research stage Contract lab Contract lab Cell/virus seed & raw material Cell/virus bank and unprocessed bulk Viral clearance steps Purified bulk (Calculation of estimated particles/dose) 4-7-2011 23 CMC Control of materials (before phase 1) Raw materials, starting materials, solvents, reagents, catalysts Source, history, and generating of cell substrate Expression construct Cell banking system, characterization, and testing 4-7-2011 Biologically-sourced materials, TSE concern Non-viral agent Endogenous and adventitious viruses Tumorigenicity, case dependent 24 A reference - Ancillary materials (AMs) for cell-based product Reagent and materials that are NOT intended to be present in the final product, e.g., FBS, digestion enzymes, GF, cytokines, antibiotics, media Vendor qualification (cGMP), audit/inspection record Quality control testing program Documentation Grade, traceability, or country of origin/source ( animal-derived AMs) Batch analytical results Stability assessment during use 4-7-2011 25 Risk classification of AMs USP<1043> Risk tier 1 Low-risk, highly qualified materials with intended use as therapeutic drug or biologic, medical device, or implantable material Therapeutic grade E.g, HSA, insulin, IL-12, antibiotics Certificate of analysis (COA) Assess removal from final product 4-7-2011 26 Risk classification of AMs USP<1043> Risk tier 2 Low-risk, well-characterized materials with intended use as AMs, produced in compliance with GMPs For use in drug, biologic, or medical device manufacture, e.g., growth factor, proteolytic enzymes, density gradient media (Exclude most animal-derived materials) 4-7-2011 COA Assess removal from final product Vendor audit 27 Risk classification of AMs USP<1043> Risk tier 3 Moderate-risk materials not intended for use as AMs For in vitro diagnostic use or reagent grade materials, e.g, growth factors, culture media, chemicals COA Confirm critical test result shown in COA Develop internal specifications, eventually Assess removal from final product Vendor audit 4-7-2011 28 Risk classification of AMs USP<1043> Risk tier 4 High-risk materials Toxin, most animal-derived materials COA Confirm critical test result shown in COA Feeder cells, ascites-derived Ab, cholera toxin, animal-derived additives (e.g., FBS) Develop internal specifications, eventually Assess removal from final product Vendor audit Source animal, country of origin, adventitious agent testing 4-7-2011 29 Recent guidance - Cell substrate Guidance for industry: Characterization and qualification of cell substrates and other biological starting materials used in the production of viral vaccines for the prevention and treatment of infectious disease, FDA, 2010 Recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products and for the characterization of cell banks, draft, WHO, 2010 4-7-2011 30 Ideal substrate to produce biological/biotechnological products WHO Technical report series, No. 878, 1998 Permanent/continuous cell line MCB, WCB Quality controlled Serum-free and/or protein-free media Nature Reviews, June 2010, vol.10, p.441 Cell line identification 4-7-2011 Incidence of misidentification in 1977 was 16%, 1999 was 18% ATCC working group ASN-0002 (BOX), currently developing a standard for human cell line authentication 31 Cell substrate From embryonic egg for Flu vaccine Inoculation: into allantoic cavity, manually or automated system 4-7-2011 Harvest: allantoic fluid, manual or automated systems 32 Cell lines for the production of vaccines Licensed vaccine Cell substrate Vaccine Type Origin Live attenuated Inactivated Primary tissues or cells Calf lymph, mouse brain, chicken egg, chicken embryo cell Small pox, Influenza, Measles, Mumps JEV, Influenza, Rabies Diploid cells Human (MRC-5, WI-38) Rubella, Varicella/Zoster Poliovirus, HAV, Rabies Continuous cells (Non-tumorigenic) Monkey (Vero) Small pox, Rotavirus Poliovirus, JEV, Rabies Continuous cells (Tumorigenic ±) Canine (MDCK) - Influenza Non-mammalian cells Yeast (S. cerevisiae) Insect (Hi-5) - HBV, HPV (rDNA product) 4-7-2011 33 Qualification of the cell bank -Biosafety tests Non-viral agent Sterility, Mycoplasma, (Mycobacteria, Spiroplasma) Adventitious or endogenous viruses General (in vitro and in vivo test, retrovirus) Specific (cell line dependent) Tumorigenicity, case dependent 4-7-2011 34 Qualification of the cell bank -Virus tests MCB Tests for Retroviruses and Other Endogenous Viruses Infectivity + WCB EPC + Electron microscopy + + Reverse transcriptase Case dependent Case dependent Other virus-specific tests Case dependent Case dependent Tests for Nonendogenous or Adventitious Viruses In vitro Assays + In vivo Assays + Antibody production tests Case dependent (e.g., MAP, RAP, HAP—for rodent cell lines) Other virus-specific tests Case dependent Case dependent Case dependent + + Case dependent Case dependent Specific tests for : Cell lines derived from human, NHP, or other cell lines as appropriate. Culture media using animal-derived components ( e.g., bovine or porcine) USP, Ph. Eur. 35 Tumorigenicity Tumorigenicity (when not known, test on EPC) Cells form tumor in animal (nude mice), Hela as + control, medium/2n cells as – control, 12 wks, ≧4 months Oncogenicity (when T+ and for product of prophylactic use) Agents (e.g., virus, DNA) induce host cell to form tumor (newborn animal), negative control, ≧4 months Cell substrate w/ or w/o tumorigenicity (in trial or licensed) 4-7-2011 Traditional vaccine rDNA protein product (drug or vaccine) T- O- Yes (inactivated, attenuated) Yes T+ O- Yes (Inactivated) Yes T+ (O+) e.g., rodent cells No Yes 36 PCV Porcine circovirus types 1 and 2 are both small sscDNA viruses and common in pigs. Detecting PCV1 DNA in Rotarix and PCV1/PCV2 DNA in RotaTeq vaccine products Neither PCV1 nor PCV2 are known to infect or cause illness in humans, however PCV2 may cause illness in pigs. Viruses derived from Vero MCB and carried through manufacture process to products PCV1 DNA is present in poliovirus harvests, but not in final bulk or container (due to inactivation step) Source: FDA vaccine advisor committee meeting (May 7, ’10) 4-7-2011 37 PCV RotaTeq (Merck) A live, oral pentavalent vaccine that contains 5 live reassortant rotaviruses, parent strains were isolated from human and bovine hosts Package insert (Sep. 2010) Rotarix 4-7-2011 A live, oral vaccine derived from human 89-12 strain (G1P[8] type) Package insert (2010) 38 FDA actions Additional testings are required FDA (Dec., 2010) requested information regarding 4-7-2011 Plans that the manufacturers may have to implement additional adventitious agent testing methods as part of their manufacturing process as these methods become available including, but not limited to, screening for PCV and PCV DNA, and Any additional in-process testing for adventitious agents that they may have recently added, but not reported to FDA. 39 Validation of viral clearance steps For rDNA vaccine produced from mammalian/insect cell lines, why virus testing alone is not enough? Due to limitations of testing methods Sampling of test material 4-7-2011 Sensitivity, susceptibility (indicator cell, animal model) Reference: “Validation of Biopharmaceutical purification processes for virus clearance evaluation”, Allan Darling, Mol. Biotec. Vol. 21, 2002 40 Allan Darling, Molecular Biotechnology, vol. 21, 2002 Besides DL of test method, ability to detect low concentrations of virus is also limited by statistical sampling If V>>v, above equation be simplified by Poisson distribution Probability that a sample v does not contain virus is p(0) = ((V-v)/V)n p(0) = e-cv, c = (In p)/-v If v=1 mL, c=10-1000 virus particles/L Probability of 1 mL will not contain a virus particle c 10 100 1000 p(0) 0.99 0.90 0.37 4-7-2011 41 Scope Vaccine Information from research stage Clinical trial-IND Cell substrate-Testing for adventitious agents Quality, starts from phase 1 Quality, (almost) finalizes at phase 3 and continues through product life span Collaboration from all parties makes a trial going 4-7-2011 42 A clinical trial -IND dossier Biological/biotechnological products 4-7-2011 Poorly characterized, e.g., virus vaccine, cell-based vaccine Well-characterized, e.g., rDNA protein vaccine, DNA vaccine Technical related document Clinical study proposal Investigator brochure CMC Pharmacology and toxicology (PK, when appropriate) Clinical 43 CMC A summary report with supporting documents, e.g., batch analysis, stability data A valid description which reveals all necessary components to demonstrate the quality and control of the test drug Present data in tabular form with brief narrative highlighting the main points CTD format is a valid reference to organize the dossier After phase 1, any change such as cell line, process, manufacture site, will require comparability 4-7-2011 44 CTD M3 (partially shown) 3.2.S DRUG SUBSTANCE (原料藥) 3.2.S.1 General Information (一般資料) 3.2.S.2.Manufacture (製造) 4-7-2011 3.2.S.1.1 Nomenclature (命名) 3.2.S.1.2 Structure (結構式) 3.2.S.1.3 General Properties (一般性質) 3.2.S.2.1 Manufacturer(s) (製造者) 3.2.S.2.2 Description of manufacturing process and process controls (製程敍述及製程管制) 3.2.S.2.3 Control of materials (物質管制) 3.2.S.2.4 Controls of critical steps and intermediates (關鍵步驟及中間 體管制) 3.2.S.2.5 Process validation and/or evaluation (製程確效及/或評估) 3.2.S.2.6 Manufacturing process development (製造程序的發展) 3.2.S.3 Characterization (特性) 45 舉 例 ( ) 原 料 藥 部 分 3.2.S.2.Manufacture 3.2.S.2.2 流程圖並簡要敘述製程及製程管控關鍵步驟,包括批量大小、物料 Description of 、起始物、試劑 (來源及供應商)等。 manufacturing process and process controls 表列製程所使用的物料,例如培養基,酵素等。 如果抗原的生產來自細胞及/或病毒種批系統: 說明種細胞或病毒的來源、分離、識別、及培養過程、特性。 細胞庫(Cell bank)及病毒種批(Virus seed lot)系統的建立 過程及管控 3.2.S.2.3 Control of 細胞庫或病毒種批系統的identity、viability、purity及培 materials 養過程中的基因穩定性`。 病源的檢測。 Unprocessed bulk的病源檢測。 如果是基因重組製造的抗原,提供expression construct 相關的資料 3.2.S.2.4 Controls of critical steps and intermediates 3.2.S.2.5 Process validation and/or evaluation 4-7-2011 簡要敘述安全性相關的步驟及管控,例如DNA/蛋白質清除步 驟、不活化反應、嵌合反應(conjugation)、無菌過濾等。 敘述安全性相關步驟的評估數據/結果,例如無菌過濾、不活化、病毒 清除、減毒、凍乾等步驟。 46 CMC summary -Phase 1 Manufacturer ad manufacturing process 4-7-2011 Flow diagram and description, batch size Controls which relate to product safety For rDNA products derived from cell lines of human or animal origin, validation of the viral clearance procedure For inactivated vaccines, a validation of the inactivation process For live vaccines, a demonstration of the attenuating characteristics 47 CMC summary -Phase 1 Control of materials Raw materials, starting materials, solvents, reagents, catalysts Source, history, and generating of cell substrate and viral/bacterial seed Expression construct Cell/virus/bacteria banking system, characterization, and testing 4-7-2011 Biologically-sourced materials, TSE concern Non-viral agent Adventitious and endogenous viruses Tumorigenicity, case dependent 48 CMC summary -Phase 1 Analytical method Pharmacopeia Non pharmacopeia 4-7-2011 A brief description Qualification of safety related method E.g., HCP, host cell DNA, residual reagent 49 CMC summary -Phase 1 Drug substance (Ag, adjuvant, novel excipient) Characterization Specification (preliminary), e.g., identity, strength, potency, and purity (& impurity) E.g., HCP, DNA, residual reagents Drug product 4-7-2011 Adjuvant, excipients, diluents Dosage form, composition Premix, on-site mix (adjuvant, dilution, reconstitution) Specification (preliminary) 50 CMC summary Phase 1 Stability At least cover the duration of trial In-use stability information, e.g., after mixing, dilution, reconstitution, multiple withdrawing Batch analytical result, DS and DP 4-7-2011 Batch for animal and clinical studies Same batch/formulation is recommended for vaccine products If not, describe (to compare) CMC Animal study might be useful 51 Phase-in of validation Validation of manufacturing processes and analytical methods goes along with the clinical development In phase 1, safety related method requires certain extent of validation 4-7-2011 E.g., Host cell DNA, protein, viral test (e.g., PCR) “Limit” - specificity and LOD “Quantitation”- more extensive validation 52 Potency assay Correlation to in-vivo biological activity should be justified Potency should be in the stability study, even it is not proven to be stability-indicating in the early trial 4-7-2011 53 Phase-in of validation Bioassay (potency) No need for LOD, LOQ At phase 1/2 Specificity Precision Repeatability, e.g., 4-7-2011 Samples from several independent preparations of the same stock Same sample, well to well, %CV<15-20% (Linearity/range/accuracy) 54 Phase-in of validation Bioassay (potency) At phase 3 and NDA Precision Intermediate precision, e.g., 4-7-2011 Reproducibility, inter-laboratory Robustness plate to plate, day to day, analyst to analyst Apply changes that probably will not happen (e.g., increase in Rx time, temperature change) Pushing the system Linearity/range/accuracy 55 USP<1226> Verification of compendial procedures Users of compendial analytical procedures are not required to validate procedure, but documented evidence of “suitability” should be established under actual conditions of use Not for microbiological procedures Some of the analytical performance characteristics for “validation” study, may be used for verification process E.g., “specificity” is a key parameter, potential interference from 4-7-2011 Drug substance from different suppliers may have different impurity profiles Drug product contains different excipients, additives 56 Pre-clinical preparation Ag (and adjuvant) Analytical methods, to characterize Ag/adjuvant, specification set up, and stability indicating Formulation, delay optimization until beyond phase 1 and achieves proof of concept Bioanalytical assays, to monitor immune response in vivo 4-7-2011 To maintain stability during trial Enable use in animal Tox and FIH study Vaccine-specific parameters Identify infections 57 After Phase 1 Formulation for next clinical studies Develop/optimize manufacturing processes Optimize analytical test methods Update CMC section of IND 4-7-2011 58 Phase 2 4-7-2011 Update clinical supplies Identify critical process parameters Optimize manufacturing process Select doses for phase 3 studies Establish formulation and container/closure Update phase 2 package 59 Phase 3 Select commercial manufacturing and packaging sites Prepare pharmaceutical development report Scale up Process validation Establish stability studies Prepare CMC section of NDA 4-7-2011 60 Lot release, in general Marion Gruber, FDA-vaccine review , 2008 4-7-2011 61 Tests after mixing, an example Marie-Chantal Uwamwezi, GSK-malaria vaccine, 2010 4-7-2011 62 Product development -a reference to check US National Institute of Allergy and Infectious Diseases-Vaccines Instruction and advise to HIV vaccine researchers Information regarding (HIV) vaccines in all aspects Preclinical master contract (HIV vaccines) 4-7-2011 Manufacture GMP pilot lots of vaccine for testing in humans, or lots for testing in nonhuman primates Perform tests for safety, immunogenicity and other preclinical testing of vaccine candidates Preparation of FDA submissions leading up to human trials 63 Overview of product development of a vaccine Source: US NIAID 4-7-2011 64 Thank you! 4-7-2011 65 SPARE SLIDES 4-7-2011 66 Phase 2 & 3 - incremental requirement PC characterization, to more detail Character(s) affected by manufacture process Batch information Comparability due to changes such as process, scale Stability data, update Manufacturing and controls, update Specification, update Phase-in validation Process validation (phase 3 or NDA) Analytical method validation (phase 3 or NDA) 4-7-2011 67 Phase 1 3 - incremental requirement Paul-Ehrlich-Institut 4-7-2011 68 Phase 1 3 - incremental requirement Paul-Ehrlich-Institut 4-7-2011 69 Phase 1 3 - incremental requirement Paul-Ehrlich-Institut 4-7-2011 70 Different role and thus point of view Scientist Contract manufacturer Sponsor Regulatory agency Concentration of test drug Scientist If only the purified protein is potent, as expected. Concentration is not a major issue. Sponsor Contract manufacturer Concentration affects injection volume, either for animal study or clinical trial. Volume/dose for sc, id, im is less than iv, thus more concentrate formulation is required for route other than iv. Concentration affects the vaccine formulation, if adjuvant is to be used. Concentration be clarified before agreement. It depends on the capacity of the production. Process improvement or modification Timeline, cost Regulation 4-7-2011 If only the stability of product is demonstrated, concentration is not a major issue. 72 Lot and quantity of the test material Regulation Different lots can be used for animal and clinical study, if only they are comparable Sponsor 4-7-2011 Same or different lot for toxicity and clinical study Timeline, contract, cost Quantity for pharmacology studies (may be research grade) Quantity for toxicity studies Overage of 15-20%, plus consideration of formulation and vialing (e.g., 10 dose/vial, last 2 doses will use 1 vial) (Quantity for specification and stability testings, retention samples) Quantity for clinical trial 73 On site mixing -Ag and adjuvant come from different manufacturer Regulation In-use stability At least potency and sterility tests are required…. Robustness of the method of on-site mixing During trial, if no change in the CMC (manufacture, specification…..), tests are done on one representative lot. Sponsor 4-7-2011 Design the method of mixing What are the test items required at this condition Who/where would be able to perform the in-use stability tests 74 Estimate cost of the test materials Examples Manufacturer Sponsor 4-7-2011 If there is no DMF already in place, additional cost is needed to prepare document Any test/study by contract lab (e.g., viral clearance, cell bank qualification) is at additional cost ~10% overage for each filling/mixing step or each component. Usually 30-40% of the total quantity are used for clinical trial, the rest of the products are used in animal studies (e.g., immunogenicity, toxicity) and tests (e.g, in-use stability) Final quantity ordered need to take all experiments, tests, and reserve samples into consideration 75 Thank you