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Constituent materials regulated under § 610.15 (21 CFR 610.15) include ingredients, preservatives, diluents, adjuvants, extraneous protein and antibiotics that are contained in a biological product. FDA is proposing to amend the regulation for constituent materials at § 610.15 to allow the Director of CBER or the Director of CDER, as appropriate, to approve an exception or alternative to the requirements under § 610.15, when data submitted with the exception or alternative establish the safety, purity, and potency of the biological product. This proposed rule provides manufacturers of biological products with flexibility, as appropriate, to employ advances in science and technology as they become available, without diminishing public health protections. Examples of how the proposed rule would provide flexibility to manufacturers in the use of preservatives and aluminum in biological products are provided below. However, the proposed rule would also provide flexibility to the existing requirements regarding extraneous protein and antibiotics (§ 610.15(b) and (c)), provided that each request for an alternative or exception to these requirements is submitted with data that establish the safety, purity, and potency of the biological product.
Standards for certain constituent materials present in biological products are provided under § 610.15. Section 610.15(a) requires that all ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, 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, and in the combination used it shall not denature the specific substances in the product to result in a decrease below the minimum acceptable potency within the dating period when stored at the recommended temperature. Products in multiple-dose containers shall contain a preservative, except that a preservative need not be added to Yellow Fever Vaccine; Poliovirus Vaccine Live Oral; viral vaccines labeled for use with the jet injector; dried vaccines when the accompanying diluent contains a preservative; or to an Allergenic Product in 50 percent or more volume in volume glycerin. 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.
These regulations also require that the amount of aluminum in the recommended individual dose of a biological product not exceed the following:
• 0.85 milligrams if determined by assay;
• 1.14 milligrams if determined by calculation on the basis of the amount of aluminum compound added; or
• 1.25 milligrams determined by assay provided that data demonstrating that the amount of aluminum used is safe and necessary to produce the intended effect are submitted to and approved by the Director of CBER or the Director of CDER.
This regulation establishes requirements for the presence of certain constituent materials in final licensed, biological products and/or strictly limits the amount of certain constituent materials present in licensed biological products. For example, the regulation contains requirements as to preservatives. Preservatives are compounds that kill or prevent the growth of microorganisms, particularly bacteria and fungi. In the
Preservatives in multiple-dose containers have a long record of safe and effective use in preventing microbial growth in the event that the vaccine is accidentally contaminated, as might occur with repeated punctures of multiple-dose containers. The use of preservatives has significantly declined in recent years with the development of new products presented in single-dose containers. However, some biological products, such as inactivated influenza virus vaccines, are still presented in multi-dose containers and contain a preservative.
However, the requirements in connection with preservatives are too prescriptive and unnecessarily restrictive because, for example, state-of-the art technologies, such as the development of devices to ensure aseptic withdrawing, offer an alternative to the use of preservatives in multiple-dose containers. FDA believes that providing the option to manufacture vaccine in multiple-dose containers without use of a preservative would be acceptable, provided that appropriate safeguards, such as adequate storage, aseptic withdrawing techniques and timely use of the product (e.g., use of the vaccine within a defined period of time) are followed to ensure that the safety, purity, and potency of the product are not compromised. Furthermore, the current regulation under § 610.15(a) does not provide FDA with flexibility to consider situations (outside of the listed exceptions) in which to allow the use of preservative-free vaccines in multiple-dose containers. The proposed rule would permit the Director of CBER or the Director of CDER, as appropriate, to approve a request to market a biological product in multiple-dose containers without use of a preservative, if the manufacturer demonstrates the safety, purity, and potency of the product.
Another example where the current requirements are too prescriptive and unnecessarily restrictive pertains to the amount of aluminum permitted under § 610.15(a) in the recommended single human dose of a biological product. Aluminum, in the form of an aluminum salt, is used as an adjuvant in certain biological products. The existing regulation limits the amount of aluminum per dose to no more than 0.85 milligrams (mg) if determined by assay or 1.14 mg if determined by calculation on the basis of the amount of aluminum compound added. In the
The aluminum content per dose in the formulation of a licensed biological product, as specified in § 610.15(a), reflects the NIH Minimum Requirements for Diphtheria Toxoid (1947)
The proposed rule enables FDA to assess the constituent materials in these and other products and provides sufficient flexibility for FDA to employ advances in science and technology as they become available, without diminishing public health protection.
Manufacturers seeking approval of an exception or alternative to a requirement under § 610.15 would be required to submit a request in writing.
FDA is proposing to amend § 610.15 by adding new paragraph (d) that would permit the Director of CBER or the Director of CDER, as appropriate, to approve exceptions or alternatives to the regulatory requirements for constituent materials, when the data submitted with the exception or alternative establish the safety, purity, and potency of the biological product. All requirements under § 610.15 would remain in effect, except those for which the Director approves an exception or alternative. Manufacturers seeking approval of an exception or alternative must submit a request in writing, as described in section I of this document.
FDA is proposing this rule to permit the Director of CBER or the Director of CDER, as appropriate, to approve exceptions or alternatives to the regulations for constituent materials, when the data submitted with the exception or alternative establish the safety, purity, and potency of the biological product. All requirements under § 610.15 would remain in effect, except those for which the Director approves an exception or alternative. Manufacturers seeking approval of an exception or alternative must submit a request in writing, as described in section I of this document.
FDA is issuing this regulation under the biological products provisions of the Public Health Service Act (42 U.S.C. 262 and 264) and the drugs and general administrative provisions of the Federal Food, Drug, and Cosmetic Act (sections 201, 301, 501, 502, 503, 505, 510, 701, and 704 (21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 371, and 374)). Under these provisions of the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act, we have the authority to issue and enforce regulations designed to ensure that biological products are safe, pure, and potent; and prevent the introduction, transmission, and spread of communicable disease.
FDA has examined the impacts of the proposed rule under Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive Order 12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). The agency believes that this proposed rule is not a significant regulatory action under the Executive order.
The Regulatory Flexibility Act requires agencies to analyze regulatory options that would minimize any significant impact of a rule on small entities. Because the proposed rule would allow the Director of CBER or the Director of CDER, as appropriate, to approve exceptions or alternatives to the regulations for constituent materials, this action would increase flexibility and reduce the regulatory burden for affected entities. Therefore, the agency proposes to certify that the proposed rule will not have a significant economic impact on a substantial number of small entities. We request detailed comment regarding any potential economic impact of this proposed rule.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires that agencies prepare a written statement, which includes an assessment of anticipated costs and benefits, before proposing “any rule that includes any Federal mandate that may result in the expenditure by State, local, and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted annually for inflation) in any one year.” The current threshold after adjustment for inflation is $133 million, using the most current (2008) Implicit Price Deflator for the Gross Domestic Product. FDA does not expect this proposed rule to result in any 1-year expenditure that would meet or exceed this amount.
The benefits of this regulatory action are that the proposed rule would reduce burdens on industry (e.g., developers of biological products) due to greater flexibility and reduced regulatory requirements. These issues are discussed in greater detail in section I of this document.
Any costs associated with this regulatory action are expected to be minimal and widely dispersed among affected entities. Based on FDA experience, we estimate that we would receive a total of approximately three requests annually for an exception or alternative under § 610.15. FDA experience with similar information collection requirements suggests that approximately 1 hour would be required to prepare and submit such a request.
The agency has determined under 21 CFR 25.31(h) that this action is of a type that does not individually or cumulatively have a significant adverse effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.
FDA has analyzed this proposed rule in accordance with the principles set forth in Executive Order 13132. FDA has determined that the proposed rule does not contain policies that have substantial direct effects on the States, on the relationship between the National Government and the States, or on the distribution of power and responsibilities among the various levels of government. Accordingly, the agency has concluded that the proposed rule does not contain policies that have federalism implications as defined in the Executive order and, consequently, a federalism summary impact statement is not required.
This proposed rule contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-3520). A description of these provisions is given below with an estimate of the annual reporting burden. Included in the estimate is the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing each collection of information.
FDA invites comments on the following topics: (1) Whether the proposed collection of information is necessary for the proper performance of FDA's functions, including whether the information will have practical utility; (2) the accuracy of FDA's estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.
Based on FDA experience, we estimate that we will receive a total of approximately 3 requests annually for an exception or alternative under § 610.15. The hours per response are based on FDA experience with similar information collection requirements.
In compliance with the PRA (44 U.S.C. 3507(d)), the agency has submitted the information collection provisions of this proposed rule to OMB for review. Interested persons are requested to send comments regarding information collection to OMB (see
Interested persons may submit to the Division of Dockets Management (see
Biologics, Labeling, Reporting and Recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, and under authority delegated to the Commissioner of Food and Drugs, it is proposed that 21 CFR part 610 be amended as follows:
1. The authority citation for 21 CFR part 610 continues to read as follows:
21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 264.
2. Amend § 610.15 by adding new paragraph (d) to read as follows:
(d) The Director of the Center for Biologics Evaluation and Research or the Director of the Center for Drug Evaluation and Research may approve an exception or alternative to any requirement in this section. Requests for such exceptions or alternatives must be in writing.