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FDA Requirements

Regulatory Requirements

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 distribution of the final product for widespread use.

Even in a pandemic, the regulatory framework for developing, manufacturing, and distributing a vaccine remain a barrier for production of desperately needed vaccines. 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.

In the U.S., Section 351 of the Public Health Service Act (P.L 78-410) requires a manufacturer to first obtain a license to ship or import the vaccine. To obtain a license, manufacturers must make the vaccine by approved procedures, in approved facilities, and by approved staff. Requirements for vaccine licensure in the U.S. published in the Code of Federal Regulations, Title 21, Part 600, are generated and enforced by the Center for Biologics Evaluation and Research (CBER) at the U.S. Food and Drug Administration (FDA).

After licensure, the vaccine is subject to lot-by-lot release by CBER. Samples and a summary of testing may be required for each lot. The license becomes the standard that a manufacturer must follow, and any departure from the approved procedure is a potential basis for regulatory action.


Vaccine must be designed to withstand handling and storage in transit; therefore, the manufacturer must take appropriate steps to control the means and routes of shipment. Destination records of the vaccine must be maintained to initiate any needed recall. The manufacturer is responsible to ensure that only approved labeling is used.

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 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.

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