1. 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

2. 2 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 FDA Organization

3. 3 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 CBER Organization

4. 4 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

5. 5 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.

6. Vaccine Manufacturing & Characterization

7. 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

8. 8 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…

9. 9 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…

10. Vaccine Production Quality and Control Detailed manufacturing procedures: –Defined compatible components Product characterization –specifications with defined ranges Cell substrates Consistency of Production In Process Tests for Product Quality/Safety –viral yields, inactivation validation, amino acid analysis Source and quality of starting materials

11. 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

12. 12 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)

13. Vaccine Ingredients & Excipients

14. 14 Vaccine Ingredients Antigen –Component of vaccine that illicits an immune response and is typically a weakened or fragmented portion of the disease pathogen

15. 15 Vaccine Ingredients Adjuvant –Helps promote a stronger immune response to the antigen Aluminum Salts MF59

16. 16 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.

17. 17 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

18. 18 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

19. 19 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.

20. 20 Vaccine Excipients Inert substances other than the active ingredient included in a finalized vaccine product

21. 21 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

22. 22 Examples of Vaccine Content

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27. 27 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 of all vaccines after they are licensed.

28. 28 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

29. Thank you!

30. 30 BACKUP SLIDES

31. 31 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)

32. 32 CMC Content - Source Material (cont’d ) Evaluation –Risk assessment of parent cells - history, potential exposure to viral agents –Screening donors for risk factors, absence of disease markers Testing for viruses –Endogenous virus testing –Donors, animals, host cells, cell banks, EPC –General and Species specific tests –FDA-approved tests if available Control –Establishing & maintaining cell banks, viral seeds under cGMP’s –Closed herds & flocks, sentinel animals –Quarantine until testing and control assures and establishes safety

33. 33 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.htmhttp://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.htmhttp://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.htmhttp://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 www.who.int/biologicals/publications/nonclinical_evaluation_v accines_nov_2003.pdf