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Vaccine clinical trial -Quality, include control of cell substrate


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Title: Vaccine clinical trial -Quality, include control of cell substrate

Vaccine clinical trial-Quality, include control
of cell substrate
  • Ywan-Feng Li
  • Center for Drug Evaluation
  • 4-7-2011
  • ????????????(I)

The views expressed in this presentation are not
necessary those of Center for Drug
The views offered here do not necessarily reflect
official positions of TFDA 
Heterogenicity of the biological/biotechnological
Peptides (20-30 a,a,)
Tissue engineering P.
rDNA proteins (Mab, fusion protein)
Gene/cell therapy P.
Blood/plasma products
rDNA-derived vaccines
Traditional vaccines
Process defines product
  • 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

Type of vaccine
  • Vaccines represent the most diverse type of
  • 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)

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
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 However, quality and assessment of the vaccine (Ag and adjuvant) is the same for either type of vaccine However, quality and assessment of the vaccine (Ag and adjuvant) is the same for either type of vaccine
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

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

Vaccines in development/trial, Taiwan, 2011
  • Ag type
  • Virus vaccine
  • Polysaccharide conjugate vaccine
  • rDNA protein vaccine
  • Indication
  • Infectious disease
  • Cancer

  • 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
  • WHO Biologicals TRS
  • Japan NIID Minimum requirements for biological
  • Pharmacopeia Ph. Eur, USP

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..

A clinical trialStarts 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

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

  • Vaccine
  • Information from research stage
  • Clinical trial-IND
  • Collaboration from all parties makes a trial going

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
  • Raw materials, starting materials, solvents,
    reagents, catalysts, e.g.,
  • Source, history of the cell substrate
  • History of construction of the expression plasmid

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.
  • 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

Control of materials
  • Documents, starting from research stage
  • Origin, lineage
  • History of passage, testing
  • Media component, e.g., FBS, trypsin
  • All of the documents be transferable to R D
  • Establishment of a cell bank or virus bank
  • GMP
  • Storage, inventory, identification, handling, GMP
  • Qualification of cell and virus bank
  • Contract lab
  • GLP/GMP status

History of a virus strain
  • Example (FDA, Review of Vero cell banks for
    Rotarix, 2008)
  • The Serotype G1 HRV strain (genotype P8) 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 --------.

Raw material of animal sourceCOA of FBS
(partially shown)
Raw material of animal sourceCOA of porcine
  • 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

Biosafety control Combination of testings
(starting material, UPB, intermediates..) and
demonstrating production process to remove a wide
variety of potential infectious viruses
  • Control of materials (before phase 1)
  • Raw materials, starting materials, solvents,
    reagents, catalysts
  • Biologically-sourced materials, TSE concern
  • Source, history, and generating of cell substrate
  • Expression construct
  • Cell banking system, characterization, and
  • Non-viral agent
  • Endogenous and adventitious viruses
  • Tumorigenicity, case dependent

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,
  • 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

Risk classification of AMsUSPlt1043gt
  • 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

Risk classification of AMs USPlt1043gt
  • Risk tier 2
  • Low-risk, well-characterized materials with
    intended use as AMs, produced in compliance with
  • For use in drug, biologic, or medical device
    manufacture, e.g., growth factor, proteolytic
    enzymes, density gradient media (Exclude most
    animal-derived materials)
  • COA
  • Assess removal from final product
  • Vendor audit

Risk classification of AMs USPlt1043gt
  • Risk tier 3
  • Moderate-risk materials not intended for use as
  • For in vitro diagnostic use or reagent grade
    materials, e.g, growth factors, culture media,
  • COA
  • Confirm critical test result shown in COA
  • Develop internal specifications, eventually
  • Assess removal from final product
  • Vendor audit

Risk classification of AMs USPlt1043gt
  • Risk tier 4
  • High-risk materials
  • Toxin, most animal-derived materials
  • Feeder cells, ascites-derived Ab, cholera toxin,
    animal-derived additives (e.g., FBS)
  • COA
  • Confirm critical test result shown in COA
  • Develop internal specifications, eventually
  • Assess removal from final product
  • Vendor audit
  • Source animal, country of origin, adventitious
    agent testing

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

Ideal substrate to produce biological/biotechnolog
ical 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
  • Incidence of misidentification in 1977 was 16,
    1999 was 18
  • ATCC working group ASN-0002 (BOX), currently
    developing a standard for human cell line

Cell substrateFrom embryonic egg for Flu vaccine
Harvest allantoic fluid, manual or automated
Inoculation into allantoic cavity, manually or
automated system
Cell lines for the production of vaccines
  • Licensed vaccine

Cell substrate Cell substrate Vaccine 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)
Qualification of the cell bank-Biosafety tests
  • Non-viral agent
  • Sterility, Mycoplasma, (Mycobacteria,
  • Adventitious or endogenous viruses
  • General (in vitro and in vivo test, retrovirus)
  • Specific (cell line dependent)
  • Tumorigenicity, case dependent

Qualification of the cell bank-Virus tests
  • 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.
  • 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
  • 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)

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
  • Porcine circovirus types 1 and 2 are both small
    sscDNA viruses and common in pigs. 
  • Neither PCV1 nor PCV2 are known to infect or
    cause illness in humans, however PCV2 may cause
    illness in pigs.
  • Detecting PCV1 DNA in Rotarix and PCV1/PCV2 DNA
    in RotaTeq vaccine products
  • 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)
  • 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
  • A live, oral vaccine derived from human 89-12
    strain (G1P8 type)
  • Package insert (2010)

FDA actionsAdditional testings are required
  • FDA (Dec., 2010) requested information regarding
  • 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.

Validation of viral clearance steps
  • For rDNA vaccine produced from mammalian/insect
    cell lines, why virus testing alone is not
  • Due to limitations of testing methods
  • Sensitivity, susceptibility (indicator cell,
    animal model)
  • Sampling of test material
  • Reference Validation of Biopharmaceutical
    purification processes for virus clearance
    evaluation, Allan Darling, Mol. Biotec. Vol. 21,

Allan Darling, Molecular Biotechnology, vol. 21,
  • Besides DL of test method, ability to detect low
    concentrations of virus is also limited by
    statistical sampling
  • Probability that a sample v does not contain
    virus is
  • p(0) ((V-v)/V)n
  • If Vgtgtv, above equation be simplified by Poisson
  • p(0) e-cv, c (In p)/-v
  • If v1 mL, c10-1000 virus particles/L
  • Probability of 1 mL will not contain a virus
  • c 10 100 1000
  • p(0) 0.99 0.90 0.37

  • 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

A clinical trial-IND dossier
  • Biological/biotechnological products
  • 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

  • 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
  • After phase 1, any change such as cell line,
    process, manufacture site, will require

CTD M3 (partially shown)
  • 3.2.S DRUG SUBSTANCE (???)
  • 3.2.S.1 General Information (????)
  • 3.2.S.1.1 Nomenclature (??)
  • 3.2.S.1.2 Structure (???)
  • 3.2.S.1.3 General Properties (????)
  • 3.2.S.2.Manufacture (??)
  • 3.2.S.2.1 Manufacturer(s) (???)
  • 3.2.S.2.2 Description of manufacturing process
    and process controls (?????????)
  • 3.2.S.2.3 Control of materials (????)
  • 3.2.S.2.4 Controls of critical steps and
    intermediates (??????????)
  • 3.2.S.2.5 Process validation and/or evaluation
  • 3.2.S.2.6 Manufacturing process development
  • 3.2.S.3 Characterization (??)

3.2.S.2.2 Description of manufacturing process and process controls ???????????????????,????????? ??????? (??????)??
3.2.S.2.3 Control of materials ??????????,?????,???? ????????????/??????? ??????????????????????????? ???(Cell bank)?????(Virus seed lot)?????????? ???????????identity?viability?purity????????????? ?????? Unprocessed bulk?????? ????????????,??expression construct ?????
3.2.S.2.4 Controls of critical steps and intermediates ???????????????,??DNA/?????? ????????????(conjugation)???????
3.2.S.2.5 Process validation and/or evaluation ??????????????/??,?????????????????????????
?? (?????)
CMC summary-Phase 1
  • Manufacturer ad manufacturing process
  • 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

CMC summary-Phase 1
  • Control of materials
  • Raw materials, starting materials, solvents,
    reagents, catalysts
  • Biologically-sourced materials, TSE concern
  • Source, history, and generating of cell substrate
    and viral/bacterial seed
  • Expression construct
  • Cell/virus/bacteria banking system,
    characterization, and testing
  • Non-viral agent
  • Adventitious and endogenous viruses
  • Tumorigenicity, case dependent

CMC summary-Phase 1
  • Analytical method
  • Pharmacopeia
  • Non pharmacopeia
  • A brief description
  • Qualification of safety related method
  • E.g., HCP, host cell DNA, residual reagent

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
  • Adjuvant, excipients, diluents
  • Dosage form, composition
  • Premix, on-site mix (adjuvant, dilution,
  • Specification (preliminary)

CMC summaryPhase 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
  • Batch for animal and clinical studies
  • Same batch/formulation is recommended for vaccine
  • If not, describe (to compare)
  • CMC
  • Animal study might be useful

Phase-in of validation
  • Validation of manufacturing processes and
    analytical methods goes along with the clinical
  • In phase 1, safety related method requires
    certain extent of validation
  • E.g., Host cell DNA, protein, viral test (e.g.,
  • Limit - specificity and LOD
  • Quantitation- more extensive validation

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

Phase-in of validation Bioassay (potency)
  • No need for LOD, LOQ
  • At phase 1/2
  • Specificity
  • Precision
  • Repeatability, e.g.,
  • Samples from several independent preparations of
    the same stock
  • Same sample, well to well, CVlt15-20
  • (Linearity/range/accuracy)

Phase-in of validation Bioassay (potency)
  • At phase 3 and NDA
  • Precision
  • Intermediate precision, e.g.,
  • plate to plate, day to day, analyst to analyst
  • Reproducibility, inter-laboratory
  • Robustness
  • Apply changes that probably will not happen
    (e.g., increase in Rx time, temperature change)
  • Pushing the system
  • Linearity/range/accuracy

USPlt1226gt 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
  • Drug substance from different suppliers may have
    different impurity profiles
  • Drug product contains different excipients,

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
  • To maintain stability during trial
  • Enable use in animal Tox and FIH study
  • Bioanalytical assays, to monitor immune response
    in vivo
  • Vaccine-specific parameters
  • Identify infections

After Phase 1
  • Formulation for next clinical studies
  • Develop/optimize manufacturing processes
  • Optimize analytical test methods
  • Update CMC section of IND

Phase 2
  • 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

Phase 3
  • Select commercial manufacturing and packaging
  • Prepare pharmaceutical development report
  • Scale up
  • Process validation
  • Establish stability studies
  • Prepare CMC section of NDA

Lot release, in general
Marion Gruber, FDA-vaccine review , 2008
Tests after mixing, an example
Marie-Chantal Uwamwezi, GSK-malaria vaccine, 2010
Product development-a reference to check
  • US National Institute of Allergy and Infectious
  • Instruction and advise to HIV vaccine researchers
  • Information regarding (HIV) vaccines in all
  • Preclinical master contract (HIV vaccines)
  • Manufacture GMP pilot lots of vaccine for testing
    in humans, or lots for testing in nonhuman
  • Perform tests for safety, immunogenicity and
    other preclinical testing of vaccine candidates
  • Preparation of FDA submissions leading up to
    human trials

Overview of product development of a vaccine
  • Thank you!

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,
  • 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)

Phase 1 3- incremental requirement
Phase 1 3- incremental requirement
Phase 1 3- incremental requirement
Different role and thus point of view
Contract manufacturer
Regulatory agency
Concentration of test drug
Scientist If only the purified protein is potent, as expected. Concentration is not a major issue.
Sponsor 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.
Contract manufacturer Concentration be clarified before agreement. It depends on the capacity of the production. Process improvement or modification Timeline, cost
Regulation If only the stability of product is demonstrated, concentration is not a major issue.
Lot and quantity of the test material
Regulation Different lots can be used for animal and clinical study, if only they are comparable
Sponsor 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
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 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
Estimate cost of the test materialsExamples
Manufacturer 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
Sponsor 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
Thank you