the registration of veterinary pharmaceuticals john w. hallberg, d.v.m., ph.d. director, us...

The Registration of Veterinary Pharmaceuticals

John W. Hallberg, D.V.M., Ph.D.

Director, US Regulatory Affairs

Pharmacia Animal Health

Curriculum VitaeJohn W. Hallberg

• Director, US Animal Health Regulatory Affairs

• EDUCATION

– Bachelor of Science, Animal Science, Iowa State University, 1976

– Masters of Science, Meat Science, ISU, 1978– Thesis: Creatine Phosphokinase

Isoenzymes in Stress-Susceptible and Stress-Resistant Pigs

– Doctor of Veterinary Medicine, ISU, 1982– Doctor of Philosophy, ISU, 1984

– Dissertation: Neural and Pulmonary Aspects of the Porcine Stress Syndrome

– Licensed veterinarian in the states of Iowa and Michigan

Curriculum Vitae John W. Hallberg

• EMPLOYMENT HISTORY – 1974-1976: Meat Lab Employee and Foreman, Iowa State University

(ISU)

– 1976-1977: Meat Lab Manager, ISU

– 1976-1978: Graduate Research Assistant, ISU

– 1978-1981: Graduate Research Assistant (summers), ISU– 1982-1983: Veterinarian, General Food Animal Practice with Dr. McGory,

Cascade,IA– 1983-1990: Veterinarian, General Food Animal Practice at Drs. White,

Jedlicka and Hallberg, PC, Cascade, IA– 1990-1997: Clinical Research Scientist II, The Upjohn Company,

Kalamazoo, MI– 1998-1999: Clinical Research Scientist III, Pharmacia and Upjohn Animal

Health

– 2000-2001: Manager, US Animal Health Regulatory Affairs, Pharmacia Animal Health

– 2001-Present: Director, US Animal Health Regulatory Affairs, Pharmacia Animal Health

Development of Pharmaceutics

• The Law:– Pure Food and Drugs Act of 1906

• Prevented interstate commerce in misbranded or adulterated drugs

– Federal Food, Drug and Cosmetic Act of 1938 (FFDAC)

• Drugs must be proven safe• Strict liability statute


• The Law: FFDCA– 1962 Amendments

• “Safe and Effective”

– Orphan Drug Act 1983• Minor Use

– Hatch-Waxman Act 1984• “Generic Drugs”

– Food and Drug Administration Modernization Act of 1997


• Animal Medicinal Drug Clarification Act (AMDUCA) of 1994– Allow extra-label drug use– Codifies responsibility

• Animal Drug Availability Act of 1996 (ADAA)– Vet. Feed Directive: 21CFR 207, 225, 510, 514, 558– Efficacy: 21 CFR 514.111, 415.117– Minor Species: draft proposal– Drug Combinations: pending


• Key Definitions from the “Act”– Drug

• Articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals.

– New Drug• A drug that is not generally regarded as

safe and effective under the conditions prescribed and recommended or suggested in the labeling.


• Key Definitions from the “Act”– Adulterated

• Something is wrong with the product: Contaminated, wrong ingredients, missing ingredients, incorrect proportions, not made under cGMP

– Misbranded• Something is wrong with the label: false

and misleading in any particular


• Violations of the FFDCA– Misdemeanors – no criminal intent < 1

year in prison, fine $100,000 for person, $200,000 for corporation

– Felony – repeat offender, not more that 3 years in prison, fine $250,000 for person, $500,000 for corporation


• The Regulations:– The Code of Federal Regulations -

21 CFR• Further expands on the act and the previous

four definitions


• The Guidelines:– Help the Sponsor interpret the “Code”– Many of these by activity and species


• Investigational New Animal Drug Application

• New Animal Drug Application


• Safe – Target Animal Safety– Human Food Safety– Environmental Safety

• Effective– Target Animal


• The Project Team at Pharmacia– Microbiology: S. Salmon, MS– Pharmaceutic Development: A. Cooper, Ph.D.; B. Re– Manufacturing: B. Burleigh, E. Behie, R. Blalock– Drug Safety: B. Seaman, D.V.M.– Residue Metabolism: R. Hornish, Ph.D; J. Caputo, Ph.D.; S. Brown,

D.V.M., Ph.D.– Regulatory: J. Hallberg, D.V.M., Ph.D.; C. Donovan, MS; M. Steele– Information Management/Biostatistics: K. Dame, T. Chester, Ph.D.– Clinical Development: Mike Moseley, Ph.D. (Project Leader); H.

Deluyker, D.V.M., Ph.D., M. Wachowski– Marketing: D. Ricke, C. Roeder, J. Luchsinger, D.V.M.– Technical Service: B. Beachnau, D.V.M.; A. Belschner, D.V.M.; G.

Neubauer, D.V.M.; J. Ver Steeg, D.V.M.; R. Saltman, D.V.M.; J. Olson, D.V.M.


• Example of Pirlimycin Hydrochloride– Lincosaminide antibiotic– “Upjohn” discovery– Replacement for clindamycin on the human

side

Development of Pharmaceutics Pirlimycin, continued

• 1980: Formed Project Team• 1981: Established product criteria for

efficacy, milk discard, and product stability

• 1982: Formulation development• 1983: Established an INAD• 1984: Initial field efficacy study• 1986-1987: Field dose determination and

confirmation


• 1988: Initiated pivotal metabolism, toxicology and environmental safety studies

• 1989: Phased review submissions for Tox, EA, Target Animal Safety and Efficacy

• 1990-1992: Phased review submissions for residue metabolism, residue decline, residue method, label, Freedom of Information Summary


• Tox Studies:– 90 Day Rat and Dog Studies– Segment II Teratology– Two Generation Repro Study in Rats– Genotox

• Unscheduled DNA Synthesis• Ames Test• CHO Mammalian Cell Forward Mutation Assay• Micro Nucleus Test


• Tox Studies Results– NOEL = 10 mg/kg/day– ADI = 0.01 mg/kg/day, 0.6 mg pirlimycin

per day for a 60 kg adult– Safe Concentration

• Muscle = 1.2 ppm• Fat = 4.8 ppm• Liver = 2.4 ppm• Kidney = 3.6 ppm• Milk = 0.4 ppm


• Residue/Metabolism Studies– C14 Rat metabolism study– 2- C14 metabolism studies in the cow– 3 cold tissue residue declines studies– 4 cold milk residue decline studies– Residue method validation– Tolerances for pirlimycin in milk 0.40

ppm and liver (0.50 ppm)


• Residue/Metabolism Studies• Results:

– Tolerances in Milk (0.40 ppm) and Liver (0.50 ppm)

– Approved Residue Methods– Determination of Milk Discard Period (36

hours)– Determination of Pre-Slaughter Withdrawal

Period (28 days)


• Efficacy Studies– Multi-location field efficacy study– Staph. aureus model efficacy study– Results: Indication

• PIRSUEAqueous Gel (pirlimycin hydrochloride) is indicated for the treatment of clinical and subclinical mastitis in lactating dairy cattle. PIRSUE has been proven effective only against Staphylococcus species such as Staphylococcus aureus and Streptococcus species such as Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis.


• Target Animal Safety– Two pivotal GLP udder irritation studies– Results: The formulation was safe and non-

irritating

• Environmental Assessment– Studies on environmental degradation– Studies on adverse effects on algae, fish,

earthworms, and plants– Results: A finding of “No Significant Impact”


• 1990: CVM accepts Tox, Efficacy, TAS and Metabolism

• 1991: CVM accepts 36 hour milk discard

• 1992: CVM accepts residue methods• 1993: CVM accepts EA and CMC

section


• 1993: P&U submits summary NADA• 10 September 1993: CVM Approval• Activities to present: worldwide approvals

for Pirsue Aqueous Gel, upgrade to a sterile product


• Necessary Activities for Sterile– Submission of the MRL document in the

EU– CMC: New formulation, package,

manufacturing facility– Bioequivalence study, new udder

irritation study, new milk and tissue residue decline study, two new efficacy studies for the EU, new EA studies for EU


• EU Approval of the MRL 1999• US Sterile Approval 7 September 2000• EU Sterile Approval January 2001• Total Time Summary Inception to

Completion

20 Years


• What’s New– www.cvm.fda.gov “Important News”

Development of Biologics

• Regulation: Vaccine-Serum-Toxins Act– USDA regulates through APHIS with the CFR,

Veterinary Service Memos and Veterinary Service Notices

– USDA Vaccine Groups• Veterinary Biologics Staff - Hyattsville, MD• National Veterinary Services Lab - Ames, IA• Veterinary Biologics Field Office - Ames, IA

Development of Biologics

• Product Licensure:– Purity, Safety, Potency and Efficacy

Development of Pharmaceutics and Biologics

• Conclusion

• Thank you• Questions

the registration of veterinary pharmaceuticals john w. hallberg, d.v.m., ph.d. director, us...

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