C Regulatory Aspects of Vaccine Development, Manufacture, and Distribution

Regulatory issues are involved in nearly every aspect of vaccine development, manufacturing, and marketing approval. Regulations come into play from the time of vaccine design and clinical testing, through manufacturing, to when the final product is distributed for widespread use.

Section 351 of the Public Health Service Act (P.L 78-410) requires a manufacturer of biological products to first obtain a license to ship the product (vaccine) in interstate and/or foreign commerce or to import the vaccine into the United States. To obtain a license, manufacturers must make a vaccine by an approved procedure, in approved facilities, and by an approved staff. Standards and requirements for vaccine licensure in the United States are generated and enforced by the Center for Biologics Evaluation and Research (CBER) at the U.S. Food and Drug Administration (FDA). The licensing regulations are published in the Code of Federal Regulations, Title 21, Part 600.

THE LICENSURE PROCESS

The process of obtaining a license to manufacture and distribute a vaccine is complex and time-consuming, both for the manufacturer and the FDA. To obtain permission to conduct a clinical study, the sponsor must have first prepared pilot lots for experimental purposes including preclinical



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The Children's Vaccine Initiative: Achieving the Vision C Regulatory Aspects of Vaccine Development, Manufacture, and Distribution Regulatory issues are involved in nearly every aspect of vaccine development, manufacturing, and marketing approval. Regulations come into play from the time of vaccine design and clinical testing, through manufacturing, to when the final product is distributed for widespread use. Section 351 of the Public Health Service Act (P.L 78-410) requires a manufacturer of biological products to first obtain a license to ship the product (vaccine) in interstate and/or foreign commerce or to import the vaccine into the United States. To obtain a license, manufacturers must make a vaccine by an approved procedure, in approved facilities, and by an approved staff. Standards and requirements for vaccine licensure in the United States are generated and enforced by the Center for Biologics Evaluation and Research (CBER) at the U.S. Food and Drug Administration (FDA). The licensing regulations are published in the Code of Federal Regulations, Title 21, Part 600. THE LICENSURE PROCESS The process of obtaining a license to manufacture and distribute a vaccine is complex and time-consuming, both for the manufacturer and the FDA. To obtain permission to conduct a clinical study, the sponsor must have first prepared pilot lots for experimental purposes including preclinical

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The Children's Vaccine Initiative: Achieving the Vision testing in animals. When the pilot lots are ready for clinical testing in humans, the sponsor submits a Notice of Claimed Investigational Exemption for a New Drug; from that point on, the product is referred to as an investigational new drug (IND). A complete IND application includes (1) descriptions of the composition, source, and manufacturing process of the product; (2) quality control and the methods used to test the vaccine's safety, purity, and potency; (3) a summary of all laboratory and preclinical animal testing; (4) a detailed description of the proposed clinical study; and (5) names and qualifications of each clinical investigator. During a 30-day waiting period, the IND application is reviewed by the FDA to determine whether human subjects will be exposed to unwarranted risks (Hopps et al., 1988). Although an establishment license (described below in more detail) is not required to begin a clinical trial, it is important that the manufacturer produces vaccine lots in a facility meeting current Good Manufacturing Practices. Plants that follow current Good Manufacturing Practices must demonstrate complete control over product components, equipment, manufacturing environment, record-keeping, and personnel. There should be no changes in the facility or manufacturing process that could alter any critical aspects of the product between the time that pivotal lots for clinical trials are prepared to establish vaccine efficacy and the time that lots are prepared for final licensing and distribution (Weber, 1991). If the manufacturer is convinced that the vaccine is safe and effective after having performed clinical trials, an application for a license is made to CBER. The Product License Application (PLA) is an exhaustive document which includes (1) a detailed description of the manufacturing procedures, testing methods, and process controls for the product; (2) results of all laboratory tests performed on a specified number of lots (including stability testing); (3) results of clinical studies; and (4) proposed labeling (Hopps et al., 1988). The newly created Office of Vaccines Research and Review within CBER is now responsible for the review of vaccine IND applications and PLAs. The internal review process entails a detailed examination and analysis of the submitted data for scientific content and accuracy and for compliance with applicable regulations. Individuals from other offices of CBER may also participate in the vaccine review and approval process. The vaccine manufacturer must also submit an Establishment License Application (ELA). The ELA describes (1) the organization and personnel, (2) buildings and work areas, (3) equipment and systems, (4) control of components and containers, (5) production and process controls, (6) packaging and labeling controls, and (7) records and reports to be maintained (Hopps et al., 1988). The manufacturer must satisfy the FDA that it has complied with an extensive body of regulations termed Good Manufac-

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The Children's Vaccine Initiative: Achieving the Vision turing Practices throughout the production process. Validation is a critical component of current Good Manufacturing Practices compliance. Essentially, validation is demonstrating that the manufacturing procedures, tests, equipment, and systems perform as intended and produce the expected and consistent results. The Office of Establishment Licensing and Product Surveillance within CBER is responsible for the review of vaccine ELAs. The internal review consists primarily of determining that (1) the layout of the manufacturing facilities, the equipment, and the systems are adequate for vaccine production and storage; (2) the expert personnel have been properly trained for their assigned duties and functions; and (3) validation of the equipment, systems, and process controls is satisfactory. FDA approval for licensure is based on (1) a satisfactory review of all data indicating that the product is safe and effective for its intended use; (2) review and acceptance of the manufacturer's labeling; (3) a satisfactory review of the manufacturer's protocols that summarize the manufacturing and testing on a specified number of vaccine lots to establish the consistency of the process; (4) confirmatory testing by CBER on product samples received from the manufacturer; and (5) a satisfactory FDA inspection of the manufacturer's vaccine production facilities (Hopps et al., 1988). In November 1992, the FDA published guidelines on cooperative manufacturing for biological products, recognizing four types of manufacturing arrangements: short supply, divided, shared, and contract. Short supply allows a licensed manufacturer to obtain from an unlicensed facility source materials that are declared to be in short supply. Historically, the short supply provisions are provided under an old FDA regulation that is rarely used today by licensed vaccine manufacturers. Divided manufacturing permits two manufacturers, each licensed to produce the biologic in its entirety, to produce such a product together. Approval of this arrangement requires both manufacturers to file PLA amendments that describe what procedures will be performed at each facility, along with copies of the labeling to be used for the intermediate and finished products. This arrangement is not often used by licensed vaccine manufacturers. Under a shared arrangement, two or more manufacturers participate in the manufacture of a biological product, with each manufacturer required to hold both an establishment license and a product license for the ingredient that it contributes to the process. However, none of the manufacturers are required to be licensed to perform all steps in the manufacturing process. To qualify for licensure approval, each manufacturer performs significant steps in the manufacture of the active ingredient of the product. Under a shared arrangement, the manufacturer of the final product also has the ultimate responsibility for providing data that demonstrate the potency,

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The Children's Vaccine Initiative: Achieving the Vision safety, and effectiveness of the product. Licenses are not issued to any manufacturer until the final product has been shown to be safe and effective. Under a contract arrangement, only one of the manufacturers holds a license, while the other performs one or more steps that would not be considered ''significant" to warrant a license. Examples would include filling and labeling of final containers of the product. However, all steps of manufacturing performed at the unlicensed facility must be under the supervision and control of the licensed manufacturer. Contract arrangements are frequently used by biologics manufacturers, including vaccine manufacturers. POSTLICENSING Manufacture After a manufacturer has obtained licensure, the vaccine is subject to lot-by-lot release by CBER. Samples and a summary of testing may be required for each lot presented for release at any time. The approved license application becomes the standard that a manufacturer must follow. Any departure from the approved procedure is a potential basis for regulatory action. During the life of a product, however, changes from the original methods may be necessary. In these cases, the FDA requires that no unauthorized change take place and that the manufacturer has an internal system in place through which proposed changes are reviewed and evaluated. All important changes must be reported to CBER 30 days in advance, and these changes in manufacturing procedures or in labeling may not be implemented until they are approved by CBER. Depending on the nature and extent of the change, CBER will make a determination of whether a new license application would be required or a license amendment to the PLA would suffice. Examples of changes requiring an amendment would be new dosage forms or modifications in the purification process, given that the integrity of the product remains unchanged. Similarly, modifications to manufacturing facilities or equipment would require the manufacturer to file an amendment to the approved ELA. In any case, the manufacturer must demonstrate on a regular basis that the vaccine meets stability requirements. The shipment of licensed bulk vaccines for export is permitted by CBER, provided that the bulk vaccine is prepared in exactly the same way as specified in the manufacturer's approved PLA up to the point of shipment. Approval of bulk shipments requires the manufacturer to file a product license amendment (in addition to the PLA), describing at what step

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The Children's Vaccine Initiative: Achieving the Vision of manufacturing the bulk vaccine will be shipped, as well as the shipping and packaging controls and the labeling that will accompany the shipment. The labeling must specify that the bulk vaccine is "For Further Manufacturing Only." The license amendment must also include a written agreement, signed by the foreign consignee, stating that labeling of the finished filled containers of vaccine will not bear the U.S. license number of the bulk manufacturer nor make such reference in the labeling. Since U.S. Customs will detain a biological product from entering the country without a license number, the agreement effectively bars the product from being returned to the United States. Distribution A vaccine must be packaged to withstand the handling and storage to which it will be subjected in transit; therefore, the manufacturer must, as far as possible, control the route and shipment method. In addition, the manufacturer must maintain destination records of the vaccine, to initiate a rapid and efficient recall should it be necessary. Also, it is the manufacturer's responsibility to ensure that only approved labeling is used in any labeling or packaging operation (Weber, 1991). Finally, through the Vaccine Adverse Events Reporting System (see Chapter 6), the FDA, along with the Centers for Disease Control and Prevention, is responsible for monitoring adverse reactions to vaccines. THE DRUG EXPORT AMENDMENTS ACT OF 1986 In addition to the export of vaccines under the licensing provisions of the Public Health Service Act, the Drug Export Amendments Act of 1986 (P.L. 99–660) permits the export of unlicensed biological products under certain specified conditions. The Drug Export Amendments establish three separate tracks for the export of unapproved drugs and unlicensed biological products. Under track 1, the FDA is authorized to approve the export of finished products that are not approved for marketing in the United States, but that have the same active ingredients as a product for which marketing approval is actively being sought in the United States. Export under track 1 is limited to 21 specified industrialized countries. The FDA is also authorized to approve the export of drugs and biologics intended for the treatment of tropical diseases. Congress drafted this provision to enable the export of drugs and biologics intended for diseases and conditions in developing countries but that do not exist to a

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The Children's Vaccine Initiative: Achieving the Vision significant extent in the United States, and thus would not be likely candidates for market approval in the United States. Export approval permits for track 2 products are not limited to the 21 specified industrialized countries. Normally, the FDA anticipates that approval under track 2 would ordinarily be based on data from two well-controlled clinical trials, but that the trials would not necessarily have to meet the full detail and documentation requirements necessary for approval of a U.S. marketing application. However, there must be evidence that the product is safe and effective for the intended use in the country to which it is to be exported. Finally, the act permits the FDA to approve the export of partially processed human biological products that are intended for further manufacture in one or more of the same set of 21 specified industrialized track 1 countries. These track 3 products must be approved, or be in the process of being approved, in the country of destination (U.S. Food and Drug Administration, 1990). REFERENCES Hopps HE, Meyer BC, Parkman PD. 1988. Regulation and testing of vaccines. Vaccines, Plotkin SA and Mortimer EA. eds. Philadelphia: W.B. Saunders Company. U.S. Food and Drug Administration. 1990. A Review of FDA's Implementation of the Drug Export Amendments of 1986. Rockville, Maryland. Weber JCW. 1991. Regulatory Aspects of Vaccine Development. Vaccines for Fertility Regulation, Ada GL and Griffin PD, eds. Cambridge: Cambridge University Press.