Transcript Regulatory Challenges for Vaccines of the Future

Vaccine Ingredients
Norman W. Baylor, Ph.D.
Director, Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
Food and Drug Administration
National Immunization Conference
March 31, 2009
FDA Organization
Office of the Commissioner
Office of Regulatory Affairs
Center for Biologics
Evaluation and Research
Center for Drug
Evaluation and Research
Center for Devices and
Radiological Health
Center for Food Safety
And Applied Nutrition
Center for Veterinary
Medicine
National Center for
Toxicological Research
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CBER Organization
Office of the Director
Office of Biostatistics
& Epidemiology
Office of Information
Technology
Office of Management
Office of Communication,
Outreach and Development
Office of Compliance
and Biologics Quality
Office of Blood Research
and Review
Office of Vaccine Research
and Review
Office of Cellular, Tissue
and Gene Therapies
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Licensed vaccines, must be:
• Safe: “Relatively free from harmful effect… when
prudently administered, taking into account the
character of the product in relation to the condition of
the recipient at the time.”
• Pure: “Relatively free from extraneous matter in the
finished product,…”
• Potent: “Specific ability of the product … to effect a
given result.”
• Manufactured consistently according to current Good
Manufacturing Practices
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How does FDA evaluate vaccines to
make sure they are safe?
• Prior to licensure new vaccines are tested
extensively for safety in the laboratory, in
animals, and in successive stages of human
clinical trials.
• Prior to going into humans, sponsors must first
submit an Investigational New Drug Application
(IND) to FDA.
• If data at any stage of clinical development raise
significant concerns regarding the safety of the
product, FDA may request additional information
or may halt ongoing or planned studies.
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Vaccine Manufacturing &
Characterization
Vaccine Development and Characterization
• Sterility (21 CFR 610.12)
• General Safety (21 CFR
610.11)
– test on final container
product
– detection of
extraneous toxic
contaminants
• Purity (21 CFR 610.13)
– pyrogenicity
– moisture content
• Identity (21 CFR 610.14)
– on final container, e.g.
SDS-PAGE, Western
blot,
• Other release tests
– in process testing
critical for safety and
manufacturing
consistency
21 CFR 610.15: Constituent Materials.
• (a) Ingredients, preservatives, diluents,
adjuvants. All ingredients used in a licensed
product, and any diluent provided as an aid in
the administration of the product, shall meet
generally accepted standards of purity and
quality.
• Any preservative used shall be sufficiently
nontoxic so that the amount present in the
recommended dose of the product will not be
toxic to the recipient…
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21 CFR 610.15: Constituent materials.
• An adjuvant shall not be introduced into a product unless
there is satisfactory evidence that it does not affect
adversely the safety or potency of the product.
• The amount of aluminum in the recommended individual
dose of a biological product shall not exceed:
– (1) 0.85 milligrams if determined by assay;
– (2) 1.14 milligrams if determined by calculation on the
basis of the amount of aluminum compound added; or
– (3) 1.25 milligrams determined by assay provided that
data demonstrating that the amount of aluminum used is
safe…
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Vaccine Production Quality and Control
• Consistency of Production
• Detailed manufacturing
• In Process Tests for Product
procedures:
Quality/Safety
– Defined compatible
– viral yields, inactivation
components
validation, amino acid
– Defined compatible
analysis
components
• Source and quality of
• Product characterization
starting materials
– specifications with defined
ranges
• Cell substrates
Vaccine Production and Quality
Control (cont’d)
• Purification: reagents, pyrogens, contaminants
– validation of removal of testing or testing of
residual levels in final product
– adventitious agent testing
• Examination of extraneous materials
• Knowledge of stability
• Facility inspection
Vaccine Nonclinical Studies
• Product Characterization
• Attenuation (Live Organisms)
• Inactivation/Reversion
• Absence of Adventitious Agents
• Pyrogenicity
• Potency, Immunogenicity
• Challenge/Protection Studies
• GLP toxicity study (novel
products)
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Vaccine Ingredients &
Excipients
Vaccine Ingredients
• Antigen
– Component of vaccine that illicits an immune
response and is typically a weakened or
fragmented portion of the disease pathogen
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Vaccine Ingredients
• Adjuvant
– Helps promote a stronger immune response
to the antigen
• Aluminum Salts
• MF59
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Vaccine Ingredients
• Preservatives are compounds that kill or
prevent the growth of microorganisms,
particularly bacteria and fungi.
– They are used in vaccines to prevent
microbial growth in the event that the vaccine
is accidentally contaminated, as might occur
with repeated puncture of multi-dose vials.
– In some cases, preservatives are added
during manufacture to prevent microbial
growth.
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U. S. Pharmacopeia (USP) Antimicrobial
Preservative Effectiveness Test (PET)
• Demonstration that the effectiveness of a substance
when used as a preservative or additive prevents the
growth of pathogenic organisms
• Inoculation with the following:
– Bacteria:
• Staphylococcus aureus
• Pseudomonas aeruginosa
• Escherichia coli
– Fungi
• Aspergillus niger
• Candida albicans
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Thimerosal
• Used as a preservative in some vaccines since the
1930's
– 49.6% mercury by weight and is metabolized or
degraded into ethylmercury and thiosalicylate.
– At concentrations found in vaccines, it meets the
requirements for a preservative as set forth by the
United States Pharmacopeia; that is, it kills the
specified challenge organisms and is able to prevent
the growth of the challenge fungi.
– No longer used in routinely recommended pediatric
vaccines, with the exception of some influenza
vaccines
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Thimerosal
• As a vaccine preservative, used in
concentrations of 0.003% to 0.01%.
– A vaccine containing 0.01% thimerosal as a
preservative contained 50 micrograms of
thimerosal per 0.5 ml dose or approximately
25 micrograms of mercury per 0.5 mL dose.
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Vaccine Excipients
• Inert substances other than the active
ingredient included in a finalized vaccine
product
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Vaccine Excipients
• Buffers
– Resist Changes in pH
• Sodium Chloride
• Stabilizers
– Inhibit chemical reactions
• Amino acids
• Sugars (Lactose/sucrose)
• Diluents
– Used to dilute vaccines to proper concentration prior
to administration
• Phosphate buffered saline
• Surfactants
– Used to alter surface tension
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Examples of Vaccine Content
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Ingredients
Quantity/dose
(0.5 mL)
Function
25 Lf
10 Lf
25 μg
25 μg
Immunogen
Immunogen
Immunogen
Immunogen
8 μg
10 μg
40 D-antigen Units (DU)
8 DU
32 DU
Immunogen
Immunogen
Immunogen
Immunogen
Immunogen
Active Ingredients
Diphtheria toxoid
Tetanus toxoid
Inactivated Pertussis Toxoid
Filamentous hemagglutinin
(FHA)
Pertactin
Hepatitis B surface antigen
Type 1 poliovirus
Type 2 poliovirus
Type 3 poliovirus
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Ingredients
Quantity/dose
(0.5 mL)
Function
0.85 mg
Adjuvant
NaCl
Residual formaldehyde
4.5 mg
≤100 μg
Polysorbate 80 (Tween 80)
Neomycin sulfate
Polymyxin B
Yeast Protein
≤100 μg
≤0.05 ng
≤0.01 ng
≤5%
For Isotonicity
Virus
Inactivation
Surfactant
Antimicrobial
Antimicrobial
Process
Residual
Adjuvants
Aluminum
Excipients
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Ingredients
Quantity/dose
(0.5 mL)
Function
15 Lf
5 Lf
20 μg
20 μg
3 μg
5 μg
40 D-antigen Units
(DU)
8 DU
32 DU
10 μg
Immunogen
Immunogen
Immunogen
Immunogen
Immunogen
Active Ingredients
Diphtheria toxoid
Tetanus toxoid
Pertussis Toxin (PT) detoxified
Filamentous hemagglutinin (FHA)
Pertactin
Fimbriae types 2 and 3 (FIM)
Type 1 poliovirus, inactivated
Type 2 poliovirus, inactivated
Type 3 poliovirus, inactivated
Haemophilus influenzae type b capsular
polysaccharide (polyribosyl-ribitolphosphate [PRP]) covalently bound to 24 μg
tetanus toxoid (PRP-T)
Immunogen
Immunogen
Immunogen
Immunogen
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Adjuvant
Aluminum phosphate
(0.33 mg aluminum)
1.5 mg
Adjuvant
Residual formaldehyde
Residual glutaraldehyde
Residual bovine serum albumin
≤5 μg
≤50 ng
≤50 ng
Virus Inactivation
Detoxifying Agent
Component of
Growth Material
2-phenoxyethanol (0.6 % v/v)
3.3 mg
10 ppm
≤4 pg
≤4 pg
Excipients
Polysorbate 80 (Tween 80)
Neomycin
Polymyxin B Sulfate
Surfactant
Antimicrobial
Antimicrobial
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Summary
• Licensed vaccines undergo rigorous safety testing
before released, and manufacturers are required to list
the contents of the vaccine in the package insert
• Vaccines in general require a more stringent regulatory
oversight partly because of the complexities of the
manufacturing process
• Tests in the vaccine production process are done to
ensure that vaccines are free from contamination by
viruses, bacteria, fungi, and parasites and are screened
for known infections of humans and animals.
• High demand for safety emphasizes the importance of a
well characterized manufacturing process to ensure safe
vaccines.
• FDA continuously monitors the safety and effectiveness
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of all vaccines after they are licensed.
Available Resources
• FDA documents /Federal Register (FR)
notices /FDA regulations
– http://www.fda.gov/cber/publications.ht
m
– 1-800-835-4709 or 301-827-1800
• International Conference on
Harmonisation (ICH) Documents (U.S.,
E.U. and Japan)
• Baylor N, Midthun K: Regulation & Testing
of Vaccines. Vaccines 5th ed, 2008, WB
Saunders
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Thank you!
BACKUP SLIDES
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CMC Content - Source Material
• Cells, Viruses, Banking
•
Systems
– Origin/ Method of collection
– History (potential
exposure)
– Manipulation,
establishment of banks,
cryopreservation
– Testing – Source/ source
material
Genetic material
– Origin
– Gene
modification,
construction of
vector,
purification
– Testing (e.g.,
sequencing)
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CMC Content - Source Material (cont’d)
• Evaluation
• Control
– Risk assessment of parent cells
– Establishing &
- history, potential exposure to
maintaining cell banks,
viral agents
viral seeds under
– Screening donors for risk
cGMP’s
factors, absence of disease
– Closed herds & flocks,
markers
sentinel animals
• Testing for viruses
– Quarantine until
– Endogenous virus testing
testing and control
– Donors, animals, host cells, cell
assures and
banks, EPC
establishes safety
– General and Species specific
tests
– FDA-approved tests if available
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Nonclinical Safety Evaluation:
Guidance Documents
• Draft 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 diseases” (2006)
– http://www.fda.gov/cber/gdlns/vaccsubstrates.htm
• Guidance for Industry: “Considerations for plasmid DNA vaccines
for infectious disease indications” (2007)
– http://www.fda.gov/cber/gdlns/plasdnavac.htm
• Guidance for Industry: “Considerations for developmental toxicity
studies for preventive and therapeutic vaccines for infectious
disease indications” (2006)
– http://www.fda.gov/cber/gdlns/reprotox.htm
• WHO document entitled “WHO guideline on nonclinical evaluation
of vaccines”
www.who.int/biologicals/publications/nonclinical_evaluation_v
accines_nov_2003.pdf
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