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U.S. Department of Health and Human Services

Animal & Veterinary

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QUALITY STANDARDS FOR THE MANUFACTURE OF ANIMAL DRUGS -- A REPORT FROM VMAC

by Richard E. Geyer, Esq. Deputy Director, CVM Office of Surveillance and Compliance, Executive Secretary, VMAC
FDA Veterinarian Newsletter January/February 1998 Volume XIII, No I

INTRODUCTION

In recent years, FDA's Center for Veterinary Medicine has engaged in extensive discussions with the animal drug industry and the veterinary profession regarding the Agency's drug manufacturing requirements. Some have contended that those requirements unnecessarily limit the availability of approved animal drugs because of their effect on the cost of manufacturing the drugs. Concern has also been expressed about the procedures the Agency follows in establishing, communicating, and applying the requirements. The issues relate to drug quality standards, which are implemented through chemistry, manufacturing and control (CMC) information submitted in new animal drug applications. The issues also involve interpretation of the Agency's current good manufacturing practice (CGMP) regulations, which are pertinent prior to approval but become especially significant in the post-approval context.

Drug quality issues have a pivotal role in CVM's mission. Because of this, and because this area has been characterized by controversy, the Center decided to obtain independent advice from the Veterinary Medicine Advisory Committee (VMAC). The committee and several consultants met in May, 1997 to listen to presentations from the Center for Veterinary Medicine and other FDA components, the Animal Drug Alliance, the Animal Health Institute, the American Veterinary Medical Association, and other organizations. The committee and consultants met again in November, 1997 to make recommendations on five specific issues related to animal drug manufacturing standards.

Summary of VMAC Comments

Following is a brief summary of the committee's comments on each of the issues. A more complete summary will appear in the official minutes of the November meeting, which will be available on CVM's Internet Home Page (http://www.cvm.fda.gov/) and through FDA's Freedom of Information Office (FDA, FOIA Staff, 5600 Fishers Lane, HFI-35, Rockville, MD 20855.)

ISSUE: When CVM decides whether to adopt a particular drug quality standard, should it weigh the benefits against the costs of adopting, or not adopting, the standard? If so, how should such benefits and costs be assessed? What factors should be considered?

The committee consensus was that CVM should weigh the benefits against the costs when it makes decisions on drug quality standards, but that in doing so it should not reduce drug safety, effectiveness and quality. The committee also concurred that drug availability should be considered when the Center makes drug manufacturing decisions. The committee emphasized that use of FDA-approved drugs is preferred over use of unapproved drugs. Several members stated that when CVM decides whether to adopt a particular drug quality standard, there should be an internal process for consideration of information that reflects costs and benefits related to that standard. Several members also stated their understanding that CVM is currently making an effort to consider costs and benefits, especially concerning the availability of a drug to treat a disease for which no approved drug exists.

ISSUE: Should CVM tailor its interpretation and application of quality standards in the regulation of drugs for minor uses and minor species? If so, what are the factors that most directly impact on the decision as to how to tailor the interpretation or application?

The committee generally agreed that CVM should tailor its interpretation and application of quality standards in the regulation of drugs for minor uses and minor species. The factors that most directly impact on the decision as to how to tailor the interpretation or application should include: species or species involved, e.g., human food safety needs to be considered in the case of drugs for use in food animal species; the availability of alternative drugs; the effects of applying current or alternative standards on cost, quality, and safety; availability of sponsors to manufacture and market the drug; size of the population of animals involved, and the likely percentage of the population to receive the drug; economic importance to the producer and consumer groups; and potential extralabel use of the drugs.

ISSUE: Can sterility validation be reduced without increasing the risk of microbiological contamination?

This is an important issue because of the belief by some that current sterility validation requirements establish higher standards than necessary to assure that drugs are not contaminated during the manufacturing process. On the other hand, CVM representatives told the committee that it has already substantially reduced the validation data required for the manufacture of animal drugs; that the Center currently relies on minimal data for such products; but that the Center is willing to review data that would support further reduction in the requirements.

Generally, the committee concluded that it did not have enough information, e.g., on the incidence of problems occurring as a result of different levels of sterility validation, to provide a basis for specific advice as to changes. However, several members concluded that CVM's current direction and standards are acceptable. Others suggested that requirements could be reduced somewhat in light of drug availability needs and the absence of reported problems due to lack of sterility. Several members stated that CVM should provide the maximum flexibility in evaluating the validation processes, accepting new data from firms which show that they can meet or exceed the current standards.

ISSUE: Should CVM change its administrative review process for adopting new drug quality standards to provide for review by the Center Director?

The committee supported the concept that CVM's following the Agency's Good Guidance Practices would alleviate concern about adoption of policy without review at the highest levels in CVM. Most committee members stated the opinion that review at the Office level in CVM would be sufficient. Additional views expressed included the following: The Center Director is expected to be aware of sensitive issues in policy that are under development and, in any event, should have the right to review any given policy document; the review process within CVM should provide for careful and thoughtful review of proposed policies; and the policy review process should not be so cumbersome that approvals are held up.

ISSUE: Should a process be developed that would involve representatives from the animal health industry and its regulators, to review and identify inconsistencies in the application and interpretation of quality standards for animal drug manufacturing and to prioritize the identified issues? Or are current mechanisms sufficient to meet the need for communication between FDA (headquarters and field) and industry?

CVM personnel listed a number of CVM initiatives in recent years involving communication with the drug industry on manufacturing issues. Industry representatives stated that they believe that there is now adequate means for communication between industry and CVM. Based on these statements and the adoption of the Good Guidance Practices, the committee concluded that existing mechanisms are adequate to provide for communication, and that a new process is not needed.

One of the committee members summarized his view of the November meeting as follows: The committee does not expect to see any lowering of the quality standards, or reinterpretation of what is required by the CGMPs in the manufacture of animal drugs. FDA will communicate more, both internally and externally. And the Agency will be more flexible in its interpretation of methods and processes. But, the committee still expects that safety, quality and effectiveness will be the highest points of the Center's considerations.

Additional Issues Raised in May, 1997

Additional issues, besides the five addressed by VMAC in the November meeting, were raised in the May meeting. At the November meeting, Dr. Stephen F. Sundlof, CVM Director, presented an overview of all the issues raised in the May meeting. He also summarized CVM's response to issues raised in May but not included in November's discussion. Among the topics he addressed were:

  • The contention that a number of animal drugs have been removed from the market due to the application of increased (and presumably unnecessary) CGMP requirements. Little evidence has been provided that a change in manufacturing requirements would significantly increase the number of approved drugs, and several veterinary practitioners noted at the May meeting that there has been an improvement in drug quality in recent years. CVM's review indicates that several drugs were removed from the market because of CGMP difficulties, but that others were removed from the market for business reasons and in most cases acceptable substitutes were available.
  • CVM will communicate with the Center for Drug Evaluation and Research (CDER) with regard to changes in the requirements for in-process controls and finished product testing that were suggested in the May meeting.
  • A concern was raised in May as to whether there is a potential disincentive for manufacturers to upgrade their facilities, because the Agency may impose new requirements in the process. CVM's staff will investigate this matter and make recommendations. CVM does not want to be seen as an impediment to desired upgrades to manufacturing facilities.
  • Internal communication within FDA regarding drug manufacturing issues is an ongoing concern, and steps will be taken in the near future that will be intended to bring about improvement in this regard. Dr. Sundlof also encouraged increased communication on drug manufacturing issues between CVM and its partners in the animal drug industry.

Conclusion

CVM will take VMAC's advice, and the entire record of the May and November meetings, into consideration as it makes decisions in the drug manufacturing area. The outcome of future deliberations, within the Center and the Agency, could include changes in policy, new guidance documents, new partnership arrangements with industry, positions on proposed legislative changes and the like. The Center intends to respond as fully as it can to the significant drug manufacturing issues that the animal drug industry, and the veterinary profession, have raised in recent years.

Dr. Sundlof stated that CVM places great importance on the availability of approved animal drugs to meet the needs of veterinary medicine. At the same time, CVM is very conscious of the need to meet statutory standards for drug quality.