Federal Register / Vol. 76, No. 71 / Wednesday, April 13, 2011 / Rules and Regulations 20513 

1Although specific examples for use of 

extraneous protein and antibiotics are not provided, 

the final rule also allows for flexibility in applying 

the existing standards for extraneous proteins and 

antibiotics (§ 610.15(b) and (c)); provided that each 

request for an alternative or exception to these 

requirements is supported by data that establish the 

safety, purity, and potency of the biological 

product. 

1. Thayer, D. W., G. Boyd, W.S. Muller, et al. 

‘‘Radiation resistance of Salmonella,’’ 

Journal of Industrial Microbiology, 5: 

383–390, 1990. 

2. Memorandum for FAP 8M4584 from V. K. 

Bunning, FDA, to W. Trotter, FDA, April 

4, 2000. 

3. Memorandum for FAP 8M4584 from K. 

Morehouse, FDA, to W. Trotter, FDA, 

April 11, 2000. 

4. Memorandum for FAP 8M4584 from K. 

Morehouse, FDA, to W. Trotter, FDA, 

May 14, 1999. 

5. Memorandum for FAP 8M4584 from I. 

Chen, FDA, to W. Trotter, FDA, 

December 11, 1998. 

6. Memorandum for FAP 8M4584 from I. 

Chen, FDA, to W. Trotter, FDA, March 

31, 2000. 

7. U.S. Department of Agriculture, 

Agricultural Research Service, USDA 

National Nutrient Database for Standard 

Reference, Release 23, Nutrient Data 

Laboratory Home Page (http:// 

www.ars.usda.gov/ba/bhnrc/ndl), 2010. 

8. Bureau of Foods Irradiated Foods 

Committee, Recommendations for 

Evaluating the Safety of Irradiated Food, 

Prepared for the Director, Bureau of 

Foods, FDA, July 1980. 

Dated: April 8, 2011. 

Leslie Kux, 

Acting Assistant Commissioner for Policy. 

[FR Doc. 2011–8815 Filed 4–12–11; 8:45 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 610 

[Docket No. FDA–2010–N–0099] 

Revision of the Requirements for 

Constituent Materials 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is amending the 

biologics regulations to permit the 

Director of the Center for Biologics 

Evaluation and Research (CBER) or the 

Director of the Center for Drug 

Evaluation and Research (CDER), as 

appropriate, to approve exceptions or 

alternatives to the regulation for 

constituent materials. A request for an 

exception or alternative will be 

considered for approval when the data 

submitted in support of such a request 

establish the safety, purity, and potency 

of the biological product for the 

conditions of use, including indication 

and patient population, for which the 

applicant is seeking approval. FDA is 

taking this action due to advances in 

developing and manufacturing safe, 

pure, and potent biological products 

licensed under the Public Health 

Service Act (the PHS Act) that, in some 

instances, render the existing 

constituent materials regulation too 

prescriptive and unnecessarily 

restrictive. This 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. 

DATES: This rule is effective May 13, 

2011. 

FOR FURTHER INFORMATION CONTACT: Paul 

E. Levine, Jr., Center for Biologics 

Evaluation and Research 

(HFM–17), Food and Drug 

Administration, 1401 Rockville Pike, 

Suite 200N, Rockville, MD 20852–1448, 

301–827–6210. 

SUPPLEMENTARY INFORMATION: 

I. Background 

In the Federal Register of March 30, 

2010 (75 FR 15639), FDA published a 

proposed rule to amend the regulations 

for constituent materials under § 610.15 

(21 CFR 610.15). Constituent materials 

include ingredients, preservatives, 

diluents, adjuvants, extraneous protein 

and antibiotics that are contained in a 

biological product. FDA is amending the 

regulation for constituent materials 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. An 

exception or alternative will be 

considered for approval when the data 

submitted in support of such a request 

establish the safety, purity, and potency 

of the biological product for the 

conditions for which the applicant is 

seeking approval. Under the final rule, 

the Director of CBER or CDER would not 

approve an exception or alternative 

when the data or the conditions of use, 

including indication and patient 

population, for which the applicant is 

seeking approval, do not provide a 

sufficient scientific and regulatory basis 

for such an approval. 

The final rule provides manufacturers 

of biological products with flexibility, as 

appropriate, to employ advances in 

science and technology, as they become 

available. However, the final rule does 

not diminish public health protections 

that are provided by existing laws and 

regulations. The final rule gives 

manufacturers the potential to employ 

advances in science and technology if 

the data provide a sufficient regulatory 

basis for approval of the product. This 

means that each manufacturer’s request 

for an exception or alternative will be 

considered on a case-by-case basis to 

determine whether the product at issue 

meets the statutory and regulatory 

criteria for safety, purity, and potency 

for use in the intended population. The 

Director of CBER or CDER will only 

approve a request for an exception or 

alternative after determining that the 

particular request meets this prescribed 

criteria for the intended population. 

Examples of how the final rule provides 

flexibility (such as alternatives to the 

use of preservatives and modifications 

to the amount of aluminum permitted in 

certain biological products), without 

diminishing public health protections, 

are provided in the paragraphs that 

follow.1

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 must 

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 must 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 

must 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 (v/v) glycerin. 

Furthermore, under § 610.15, an 

adjuvant must not be introduced into a 

product unless there is satisfactory 

evidence that it does not affect 

adversely the safety or potency of the 

product. 

Section 610.15(a) also requires that 

the amount of aluminum in the 

recommended individual dose of a 

biological product not exceed: 

1. 0.85 milligrams if determined by 

assay; 


emcdonald on DSK2BSOYB1PROD with RULES
20514 Federal Register / Vol. 76, No. 71 / Wednesday, April 13, 2011 / Rules and Regulations 

2See ‘‘The National Vaccine Advisory Committee 

Sponsored Workshop on Thimerosal Vaccines,’’ pp. 

21–25, August 11, 1999. See also Wilson, Graham 

S., Hazards of Immunization, 1967. 

3With the creation of NIH, NIH had regulatory 

authority over biological products until 1972, at 

which time they were transferred to FDA. NIH 

issued the precursor regulation to constituent 

materials, § 610.15, in the Federal Register of 

January 10, 1968 (33 FR 367 at 369). See the Federal 

Register notice of June 29, 1972 (37 FR 12865) and 

the Federal Register notice of August 9, 1972 (37 

FR 15993), for more information concerning the 

transfer of authority from NIH to FDA and how the 

regulations pertaining to biological products under 

21 CFR part 73 were transferred to the then newly 

established 21 CFR part 273. 

4Biological products had contained preservatives 

prior to 1968. ‘‘The National Vaccine Advisory 

Committee Sponsored Workshop on Thimerosal 

Vaccines,’’ p. 24, August 11, 1999. 

5More specifically, the amendment permitted the 

use of up to 1.25 mg per dose of aluminum 

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, 

Bureau of Biologics. ‘‘General Biological Products 

Standards; Aluminum in Biological Products,’’ (46 

FR 51903, October 23, 1981). 

6NIH, Minimum Requirements for Diphtheria 

Toxoid, 4th Revision, 1947. 

7NIH, Minimum Requirements for Tetanus 

Toxoid, 4th Revision, 1952. 

2. 1.14 milligrams if determined by 

calculation on the basis of the amount 

of aluminum compound added; or 

3. 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. 

Section 610.15 establishes standards 

for the presence of certain constituent 

materials in licensed, biological 

products and/or strictly limits the 

amount of certain constituent materials 

present in licensed biological products. 

However, in order to employ 

advancements in science and 

technology to benefit the public health, 

flexibility in applying these regulatory 

standards is needed. 

For example, § 610.15 contains 

specific requirements as to 

preservatives. Preservatives are 

compounds that kill or prevent the 

growth of micro-organisms, particularly 

bacteria and fungi. The current 

requirements for preservatives were 

based, at least in part, on reports from 

scientific literature concerning serious 

injuries and deaths associated with 

bacterial contamination of multipledose containers of vaccines that did not 

contain a preservative.2 As discussed 

previously, § 610.15 provides for limited 

exceptions from the preservative 

requirement. These exceptions include 

live viral vaccines that had been 

licensed under section 351 of the PHS 

Act (42 U.S.C. 262) and that were in 

production when the National Institutes 

of Health (NIH) issued the 1968 

regulation.3 4

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 

a multiple-dose container. Even though 

the use of preservatives has significantly 

declined in recent years with the use of 

products filled in single-dose containers 

that do not require addition of a 

preservative, some biological products 

such as inactivated influenza virus 

vaccines are still presented in multidose containers with a preservative. The 

use of preservatives could also decline 

further as manufacturers develop and 

employ new technologies, such as 

multi-dose adaptors to prevent 

contamination of products in multipledose containers, without the use of 

preservative. 

However, 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. It 

is necessary for FDA to have flexibility 

in applying the regulatory requirements 

for preservatives when, for example, 

state-of-the art technologies, such as the 

development of devices to ensure 

aseptic withdrawing offer a safe 

alternative to the use of preservatives in 

multiple-dose containers. The final rule 

permits the Director of CBER or the 

Director of CDER to approve a request 

to market a biological product in 

multiple-dose containers without the 

use of a preservative, if the 

manufacturer demonstrates that 

sufficient measures, such as an aseptic 

withdrawing technique through the use 

of an appropriate device, ensure that the 

product continues to meet the statutory 

and regulatory requirements for safety, 

purity, and potency. Thus, the final rule 

allows flexibility in the use of 

advancements in technology to provide 

a public benefit, while continuing to 

ensure the safety, purity, and potency of 

the product. 

Another example where it is 

necessary for FDA to have flexibility in 

applying current regulatory 

requirements 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 1981, FDA amended 

§ 610.15(a) to increase the permissible 

level of aluminum per dose to 1.25 mg 

both to make the regulation consistent 

with World Health Organization 

standards,5 and because it appeared that 

certain groups (such as renal dialysis 

patients), who were understood to be at 

high risk of contracting hepatitis, might 

require a higher dosage of the hepatitis 

B vaccine, which would in turn, require 

amounts of aluminum as high as 1.25 

mg per dose. (See ‘‘General Biological 

Products Standards; Aluminum in 

Biological Products,’’ 46 FR 51903, 

October 23, 1981. See also ‘‘General 

Biological Products Standards for 

Aluminum in Biological Products,’’ 46 

FR 23765, April 28, 1981). 

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) 6 and Tetanus Toxoid (1952).7

The final rule does not alter the existing 

requirements regarding the amount of 

aluminum in a biological product. 

Instead, in a change that is analogous to 

the one FDA issued in 1981, involving 

the groups who were at high risk of 

contracting hepatitis, the final rule 

allows either the Director of CBER or the 

Director of CDER to approve an 

exception or alternative when the 

Director determines that a biological 

product meets the requirements for 

safety, purity, and potency for the 

conditions for which the applicant is 

seeking approval, but contains an 

amount of aluminum that is higher than 

currently permitted by § 610.15. For 

example, the final rule permits the 

Director of CBER or CDER to approve a 

manufacturer’s request for an exception 

to use a proposed therapeutic vaccine 

for treating individuals with cancer, 

when the proposed vaccine contains 

aluminum levels higher than currently 

allowed but still meets the requirements 

of safety, purity, and potency. 

II. Clarifications to the Preamble of the 

Proposed Rule 

FDA received comments on the rule 

from manufacturers, private and public 

interest groups, and the general public. 

In response to comments expressing 

concerns about the safety of a licensed 

product for which FDA grants an 

exception or alternative to current 

regulations, FDA emphasizes that a 

manufacturer’s request for an exception 

or alternative will not be approved 

unless the submitted data meet the 


emcdonald on DSK2BSOYB1PROD with RULES
Federal Register / Vol. 76, No. 71 / Wednesday, April 13, 2011 / Rules and Regulations 20515 

statutory and regulatory criteria for 

safety, purity, and potency for use in the 

intended population. FDA also 

emphasizes that the product at issue 

must be shown to be safe, pure, and 

potent for the conditions of use, 

including proposed indication and 

patient population, for which the 

applicant is seeking approval, in 

determining whether the product may 

be approved. FDA further clarifies that 

consideration for approval of a request 

will be done case-by-case and will be 

based on review of the data submitted 

in support of a request. 

In addition, in response to comments, 

FDA clarifies that there is both a need 

for FDA to have flexibility in applying 

the regulatory standards in § 610.15, and 

a need for manufacturers to have 

flexibility in employing advancements 

in science and technology for 

developing new safe, pure, and potent 

alternatives to current products. FDA 

provides more discussion on the need 

for flexibility in the responses to 

comments on the proposed rule. 

FDA considered all comments 

received in response to the proposed 

rule and has determined that the 

proposed rule should be issued as a 

final rule. Accordingly, FDA is issuing 

as a final rule the amendment to 

§ 610.15 under paragraph (d) to permit 

the Director of CBER or the Director of 

CDER, as appropriate, to approve an 

exception or alternative to the 

regulatory requirements for constituent 

materials, when the data submitted with 

the request for approval of an exception 

or alternative establish the safety, 

purity, and potency of the biological 

product, and is acceptable for use in the 

intended population. All requirements 

under § 610.15 remain in effect, except 

those for which the Director approves 

an exception or alternative. FDA 

approval of an exception or alternative 

will be done case-by-case, based on the 

data submitted for a specific product. 

Manufacturers seeking approval of an 

exception or alternative must submit a 

request in writing. The request may be 

submitted as part of the original 

biologics license application (BLA) or as 

an amendment to the original, pending 

application or as a prior approval 

supplement to an approved application. 

III. Comments on the Proposed Rule 

FDA received 15 letters of comment 

on the proposed rule, not including 1 

duplicate letter from the same 

commenter. As stated previously, these 

comments were received from 

manufacturers, private and public 

interest groups, and the general public. 

Several of the comments supported the 

proposed rule and several comments 

disagreed with the proposed rule. Some 

of the comments on the proposed rule 

were similar to or duplicates of other 

comments received, and have been 

grouped together, where appropriate, to 

facilitate a uniform response. 

To make it easier to identify the 

comments and our corresponding 

responses, the word ‘‘Comment’’ 

followed by a number is placed in 

parentheses and is used to indicate a 

particular comment or set of similar 

comments, as appropriate. The word 

‘‘Response’’ in parentheses precedes 

FDA’s response to a comment. The 

order of comments and responses, as 

listed, do not represent a value assigned 

to the comment but is used for 

organizational purposes only. 

(Comment 1) Several comments 

supported the proposed rule. One such 

comment praised the rule for 

broadening the potential capacity for 

biologics manufacturers to provide 

medicines to the public without 

compromising the high level 

expectation of demonstrating safety, 

purity, and potency. Another comment 

supported the proposed rule for 

providing a means to advance 

‘‘innovative science’’ and applications of 

use. Yet another comment expressed 

interest in seeing the ‘‘reasonable 

flexibility’’ provided in the proposed 

rule extended to other 

biopharmaceutical fields. Still another 

comment found the conditions and 

recommendations in the proposed rule 

to be comprehensible and useful. 

(Response) FDA acknowledges and 

appreciates the supportive comments. 

As previously stated, the rule allows 

FDA the flexibility to approve an 

exception or alternative to the 

constituent materials regulation, 

without diminishing public health 

protections. As such, the final rule 

provides patients safe access to 

important products resulting from 

advances in science and technology. 

FDA continues to review existing 

regulations and may propose 

modification of these regulations as 

appropriate for public health and safety. 

(Comment 2) One comment requests 

clarification as to whether a request for 

an exception or alternative to the 

requirements under § 610.15 can be 

made earlier in clinical development 

rather than waiting until submitting the 

original BLA. 

(Response) FDA clarifies that 

although a manufacturer may submit a 

request for an exception or alternative 

early in the clinical development of a 

biological product, FDA considers such 

a request to be timely when the data 

intended to support the request 

establish the safety, purity, and potency 

of the biological product for its intended 

use. In developing data necessary to 

support a request for an exception or 

alternative, manufacturers must comply 

with all applicable laws and regulations, 

including the procedures and 

requirements for investigational new 

drug applications (INDs) and BLAs 

under parts 312 and 601 (21 CFR parts 

312 and 601). Only after FDA 

determines that the biological product 

meets the statutory and regulatory 

criteria for safety, purity, and potency, 

and is acceptable for use in the intended 

population, may the Director of CBER or 

CDER approve a request for an 

exception or alternative. 

However, FDA strongly encourages 

early communication from 

manufacturers intending to submit a 

request for an exception or alternative to 

the requirements under § 610.15. This 

includes pre-IND and IND 

communications by which 

manufacturers may seek FDA advice 

concerning issues such as data needed 

to support the rationale for testing a 

biological product in humans, the 

design of nonclinical pharmacology, 

toxicology, and drug activity studies, 

initial development plans for the 

biological product, and regulatory 

requirements for demonstrating safety, 

purity, and potency. Early 

communications between FDA and 

manufacturers, as described previously, 

are intended to be advisory and are not 

to be interpreted as approval of a 

request for an exception or alternative. 

(Comment 3) One comment requests 

agreement from FDA that sponsors may 

administer multiple doses taken from 

individual preservative-free multi-dose 

vials in clinical trials prior to licensure, 

as long as the sponsor follows preapproved aseptic procedures in defined 

time periods to support this format as 

part of the original license application. 

(Response) FDA does not agree with 

the comment. The current regulation for 

preservatives requires that products in 

multiple-dose containers contain a 

preservative, with listed exceptions. The 

final rule provides the Director of CBER 

or CDER with flexibility to approve a 

request for an exception or alternative to 

this requirement. However, FDA will 

consider each request for an exception 

or alternative on a case-by-case basis 

and approval of such a request will be 

based on the determination that the data 

submitted with the request establishes a 

regulatory basis for approval. Sponsors 

seeking to investigate the use of a new 

biological product in humans must 

follow the procedures and requirements 

for investigational drugs under part 312. 

(See also Response to Comment 4). 


emcdonald on DSK2BSOYB1PROD with RULES
20516 Federal Register / Vol. 76, No. 71 / Wednesday, April 13, 2011 / Rules and Regulations 

8 Delegations of authority give certain officials in 

CBER and CDER the legal authority to take 

substantive actions and perform certain functions of 

the Commissioner of Food and Drugs. Staff Manual 

Guide 1410.702 available on the Internet at 

http://www.fda.gov/AboutFDA/ 

ReportsManualsForms/StaffManualGuides/ 

ucm049563.htm (accessed October 22, 2010); ‘‘Drug 

and Biological Product Consolidation,’’ (68 FR 

38067, June 26, 2003). 

(Comment 4) Several comments 

opposed the proposed rule because the 

commenters understood the rule to give 

the Director of CBER or CDER sole 

authority in the decisionmaking process 

to approve a request for an exception or 

alternative. Another comment stated 

that the proposed rule does not allow 

for a deliberative process for vaccine 

ingredient changes. Other comments 

stated that the drug industry had too 

much influence upon government 

agencies including FDA, and that all 

decisions about additives should reside 

with many experts, in order to avoid the 

potential of undue influence. One 

comment seeks greater transparency 

from FDA and manufacturers for all 

aspects of biologics. Another comment 

states that all changes to medicine, 

particularly those ‘‘which are proscribed 

by some government entities, should be 

subject to a public review.’’ 

(Response) FDA acknowledges and 

appreciates all comments on the 

proposed rule. FDA agrees with 

comments supporting public review and 

transparency. However, FDA disagrees 

with the comments opposing the 

authority of the Director of CBER or 

CDER to approve a biologic product. 

FDA also disagrees with the comments 

that the rule places the decisionmaking 

process in the hands of one person, does 

not allow for a deliberative process for 

vaccine ingredient changes, and that 

manufacturers will have an undue 

influence in the approval process. 

Under the provisions of the PHS Act, 

and the Federal Food, Drug, and 

Cosmetic Act (the FD&C Act), FDA has 

the authority to issue and enforce 

regulations designed to ensure that 

biological products are safe, pure, and 

potent. Through delegations of 

authority,8 the Directors of CBER and 

CDER have been given the authority to 

approve biological products. Thus, the 

Directors of CBER and CDER may 

approve a biologic product determined 

to be safe, pure, and potent, based on 

factors that include review of data, and 

in some cases, taking into account 

recommendations and input from 

independent experts (e.g., advisory 

committees), input from interested 

parties, and public comments. 

The PHS Act and the FD&C Act 

provide FDA with the authority to issue 

regulations that not only establish the 

requirements for product approvals but 

also establish the requirements for 

clinical investigations of unapproved 

biologics (21 U.S.C. 355(i) and 42 U.S.C. 

262(a)(2)(A)). In accordance with part 

312, manufacturers seeking to 

investigate the use of a new biological 

product in humans must follow 

specified procedures and requirements 

for investigational biological products. 

During the IND process, manufacturers 

must submit, for FDA review, data and 

proposals for additional studies 

intended to support the safety, purity, 

and potency of a biological product. 

Manufacturers also are required to 

provide information on patient 

outcomes and adverse events observed 

during this investigation. FDA reviews 

the submitted data and, upon 

determining that the biological product 

does not represent an unreasonable risk 

to the safety of the persons who are the 

subjects of the clinical investigation, 

will allow a manufacturer to proceed 

with the investigational use of a 

biological product. A manufacturer, 

after developing data to support 

approval, may submit a BLA to FDA for 

review and approval. 

Under § 601.2, the Director of CBER or 

CDER may approve a manufacturer’s 

application for a biologics license only 

after a manufacturer submits an 

application accompanied by data 

derived from nonclinical laboratory and 

clinical studies that demonstrate that 

the manufactured product meets 

requirements of safety, purity, and 

potency. These data are reviewed by 

appropriate experts to determine 

whether the application meets the 

statutory and regulatory requirements. 

In addition to the recommendations 

made by these experts, the Director of 

CBER or CDER may seek input from 

other sources within and outside of FDA 

to determine whether the application 

should be approved. Further, FDA 

closely monitors the safety of a 

biological product during its preapproval and post-approval 

development, and may take corrective 

action, as necessary to protect the 

public. 

In addition to the review process 

described previously, a sponsor, 

applicant, or manufacturer of a 

biological product regulated under the 

PHS Act (42 U.S.C. 262), may request 

review of a scientific controversy by an 

appropriate scientific advisory panel 

(§ 10.75(b)(2) (21 CFR 10.75(b)(2)). Also, 

under § 10.75(c), interested persons 

outside of FDA may request internal 

review of a decision through established 

FDA channels of supervision or review. 

Thus, the current regulations establish 

procedures for review and evaluation of 

biological products, which include 

review by appropriate internal and 

external experts. In addition, the current 

regulations allow for public and private 

entities to participate in FDA’s review 

process, as appropriate. This process 

serves to increase transparency and 

helps ensure that the public health is 

protected. The final rule maintains these 

important regulatory procedures and 

requirements while increasing FDA’s 

flexibility in employing advances in 

science and technology. 

(Comment 5) Several comments 

opposed the proposed rule because the 

commenters believe the rule would 

make the use of vaccines less safe. One 

commenter stated that FDA is ignoring 

its mandate to make vaccines safer by 

any and all means at its disposal; that 

FDA is making vaccines less safe by 

removing the certainty as to the 

minimum standards that a biological 

product must meet; and that the 

proposed rule does not require that the 

written requests for such exemptions or 

alternatives include the appropriate 

proofs (toxicological and 

immunological) of the short-term and 

long-term safety to the most susceptible 

humans. A few comments stated that an 

increase in the amount of aluminum 

may compromise the safety of vaccines. 

Another comment stated that families 

do not feel that the current regulations 

are ‘‘too prescriptive and unnecessarily 

restrictive,’’ and that families would 

prefer more stringent rules. Other 

comments discussed specific concerns 

with already-approved vaccines. 

(Response) FDA acknowledges these 

comments, as many of the issues were 

considered in drafting the proposed 

rule. However, FDA disagrees with the 

assertion that the rule will result in a 

decrease in the safety of vaccines and 

other biological products for which a 

request for an exception or alternative to 

any requirement under § 610.15 is made 

and approved. These regulations will 

continue to be the criteria by which all 

license applications will be evaluated. 

However, in order to employ 

advancements in treatment for certain 

populations, such as treatment for 

individuals suffering from lifethreatening conditions (e.g., cancer), 

FDA needs flexibility in applying the 

regulations. By analogy, as is stated in 

the drug regulations at 21 CFR 

314.105(c): 

While the statutory standards apply to all 

drugs, the many kinds of drugs that are 

subject to statutory standards, and the wide 

range of uses for those drugs demand 

flexibility in applying the standards. Thus 

FDA is required to exercise its scientific 

judgment to determine the kind and quantity 

of data and information an applicant is 


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Federal Register / Vol. 76, No. 71 / Wednesday, April 13, 2011 / Rules and Regulations 20517 

required to provide for a particular drug to 

meet the statutory standards. 

The final rule is consistent with this 

CDER regulation as it allows the 

Directors of CBER and CDER flexibility 

in applying current standards for the 

approval of an exception or alternative 

to § 610.15, when data submitted with 

the request for an exception or 

alternative, establish the safety, purity, 

and potency of the biological product. 

Further, consistent with existing 

statutory and regulatory requirements, 

the Directors of CBER and CDER will 

not approve a biological product that is 

unsafe for the intended population. The 

final rule does not alter these statutory 

and regulatory requirements nor does it 

guarantee that a request for an exception 

or alternative will be approved. The 

final rule only allows the Director of 

CBER or CDER the flexibility to approve 

a manufacturer’s request for an 

exception or alternative if the 

manufacturer demonstrates that the 

biological product is safe, pure, and 

potent for use in the intended 

population. 

With regard to comments expressing 

concern about the safety of previously 

licensed vaccines or specific ingredients 

in previously licensed vaccines, FDA 

notes that those comments concerning 

previously licensed vaccines are outside 

the scope of this rulemaking action 

because the rule only allows the 

Director of CBER or CDER to approve a 

manufacturer’s request for an exception 

or alternative to any requirement in 

§ 610.15, when the data submitted in 

support of such a request establish the 

safety, purity, and potency of the 

biological product. 

(Comment 6) One comment opposed 

the proposed rule because the 

commenter did not know how FDA 

would monitor or enforce requirements 

for adequate storage, aseptic 

withdrawing techniques, and timely use 

of vaccines in multiple-dose containers 

without preservative or if additional 

training would be given to health care 

providers. 

(Response) In addressing this 

comment, FDA clarifies that all requests 

for an exception or alternative are 

subject to FDA regulations regarding the 

monitoring and enforcement of 

regulatory standards. These regulations 

were established to assure the quality 

and integrity of data submitted to FDA 

in support of new product approvals 

and to protect the rights and welfare of 

the public. FDA accomplishes this 

through various means, including 

conducting onsite inspections, data 

audits, product testing, and report 

monitoring. FDA also provides advice 

through guidances and other 

communications which are provided to 

assist interested parties in complying 

with regulatory standards for the safety, 

purity, and potency of a product. 

(Comment 7) One comment provided 

alternative revisions to the proposed 

rule and other subsections within 

§ 610.15. Specifically, the commenter 

proposed that FDA revise the proposed 

rule to read as follows: 

Alternatives. Except for the generally 

accepted standards of purity and quality, in 

keeping with the vaccine safening mandates 

set forth in 42 U.S.C. 300aa–27’’; * * * ‘‘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, provided the 

manufacturer proves that the exception or 

alternative would improve the safety of the 

biological drug product or, failing that, 

improves the effectiveness, not efficacy, or 

reduces the per dose cost, of the biological 

drug product without reducing the safety of 

said product’’; and * * * ‘‘include the 

findings, pro and con, of and the data from 

all of the studies conducted to support the 

request. 

(Response) FDA acknowledges the 

comment and appreciates the 

suggestions for revising § 610.15. 

However, in accordance with the 

regulations, FDA is seeking public 

comment only on the proposed rule to 

permit the Director of CBER or the 

Director of CDER, as appropriate, to 

approve exceptions or alternatives to the 

regulation for constituent materials. 

FDA’s response to the comments 

requesting revisions to the proposed 

rule are discussed in the paragraphs that 

follow. 

FDA disagrees with the commenter’s 

suggested revisions to the proposed rule 

because the revisions inappropriately 

limit the application of the rule to 

vaccines; allow more flexibility than is 

intended for approving a manufacturer’s 

request for an exception or alternative; 

may lead to confusion about the rule; 

and are unnecessary. As discussed 

previously, the final rule allows the 

Director of CBER or CDER flexibility to 

approve a request for an exception or 

alternative to a requirement under 

§ 610.15 provided that data are 

submitted that establish the safety, 

purity, and potency of the specific 

biological product. These statutory and 

regulatory requirements apply to the use 

of constituent materials in all biological 

products and not just to vaccines as the 

comment suggests. In addition, FDA 

may only approve a BLA for a vaccine 

or other biological product if it has been 

demonstrated to be ‘‘safe, pure, and 

potent.’’ The commenter’s suggestions 

that FDA should take cost 

considerations into account when 

making a decision to approve a vaccine 

are inconsistent with FDA’s regulatory 

authority. Although FDA is sensitive to 

issues of cost, current statutory 

standards for constituent materials are 

based on the safety, purity, and potency 

of the product. Furthermore, the 

suggested revisions to the proposed rule 

inappropriately limit what FDA may 

consider with respect to a request for an 

exception or alternative. Manufacturers 

are required by current regulations to 

submit all available data, including 

adverse event reports, with a BLA. FDA 

reviews the data to determine whether 

an application should be approved. The 

final rule, as consistent with current 

regulations, does not allow the Director 

of CBER or CDER to approve an 

application if the data are not sufficient 

to establish that the biological product 

is safe, pure, and potent in relation to 

the manufacturer’s intended use of the 

product. 

IV. Legal Authority 

FDA is issuing this regulation under 

the biological products provisions of the 

PHS Act (42 U.S.C. 262 and 264) and 

the drugs and general administrative 

provisions of the FD&C 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 PHS Act and the 

FD&C 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. 

V. Analysis of Impacts 

A. Review Under Executive Order 

12866, the Regulatory Flexibility Act, 

and the Unfunded Mandates Reform 

Act of 1995 

FDA has examined the impacts of the 

final rule under Executive Order 12866 

and the Regulatory Flexibility Act 

(5 U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Pub. L. 

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 final rule is 

not a significant regulatory action under 

the Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 


emcdonald on DSK2BSOYB1PROD with RULES
20518 Federal Register / Vol. 76, No. 71 / Wednesday, April 13, 2011 / Rules and Regulations 

options that would minimize any 

significant impact of a rule on small 

entities. Because the final rule allows 

the Director of CBER or the Director of 

CDER, as appropriate, to approve 

exceptions or alternatives to the 

regulations for constituent materials, 

this action increases the flexibility and 

reduces the regulatory burden for 

affected entities. Therefore, FDA 

certifies that the final rule will not have 

a significant economic impact on a 

substantial number of small entities. 

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 $135 

million, using the most current (2009) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this final rule to result in any 1-year 

expenditure that would meet or exceed 

this amount. 

The benefit of this regulatory action is 

its reduction, through greater flexibility 

in the regulatory requirements, of 

burdens on the biological products 

industry. These issues are discussed in 

greater detail in section I of this 

document. Industry cost reductions may 

result in consumers being offered lower 

prices or wider availability of existing 

and new biological products; this would 

have a positive effect on patients’ 

welfare. 

Any administrative and paperwork 

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 each such 

request. 

We received comments expressing 

concern that this rule would generate 

additional costs in the form of negative 

public health effects. FDA has 

considered the potential for adverse 

consequences, including increased 

morbidity and mortality, associated 

with allowing deviations from the 

constituent materials regulations set 

forth in § 610.15(a) through (c), and will 

grant exemptions only in cases where 

data indicate that biological products in 

their exempted forms will be safe, pure, 

and potent for the conditions for which 

the applicant is seeking approval. As 

experience with the October 1981 rule 

has shown, FDA is able to conduct a 

constituent materials exemption process 

in a manner that is consistent with its 

public health mandate. For all these 

reasons, we believe the final rule will 

impose no overall public health cost. 

B. Environmental Impact 

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. 

C. Federalism 

FDA has analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that the final 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 final 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. 

VI. Paperwork Reduction Act of 1995 

Section 610.15(d) of this final rule 

contains reporting requirements that 

were submitted for review and approval 

to the Director of the Office of 

Management and Budget (OMB), as 

required by section 3507(d) of the 

Paperwork Reduction Act of 1995. The 

requirements were approved and 

assigned OMB control number 0910– 

0666. 

List of Subjects in 21 CFR Part 610 

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, 21 CFR part 610 is amended 

as follows: 

PART 610—GENERAL BIOLOGICAL 

PRODUCTS STANDARDS 

■ 1. The authority citation for 21 CFR 

part 610 continues to read as follows: 

Authority: 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 

paragraph (d) to read as follows: 

§ 610.15 Constituent materials. 

* * * * * 

(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. 

Dated: April 7, 2011. 

Leslie Kux, 

Acting Assistant Commissioner for Policy. 

[FR Doc. 2011–8885 Filed 4–12–11; 8:45 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1314 

[Docket No. DEA–347I] 

RIN 1117–AB30 

Self-Certification and Employee 

Training of Mail-Order Distributors of 

Scheduled Listed Chemical Products 

AGENCY: Drug Enforcement 

Administration (DEA), Department of 

Justice. 

ACTION: Interim final rule with request 

for comment. 

SUMMARY: On October 12, 2010, the 

President signed the Combat 

Methamphetamine Enhancement Act of 

2010 (MEA). It establishes new 

requirements for mail-order distributors 

of scheduled listed chemical products. 

Mail-order distributors must now selfcertify to DEA in order to sell scheduled 

listed chemical products at retail. Sales 

at retail are those sales intended for 

personal use; mail-order distributors 

that sell scheduled listed chemical 

products not intended for personal use, 

e.g., sale to a university, are not affected 

by the new law. This self-certification 

must include a statement that the mailorder distributor understands each of 

the requirements that apply under part 

1314 and agrees to comply with these 

requirements. Additionally, mail-order 

distributors are now required to train 

their employees prior to self 

certification. DEA is promulgating this 

rule to incorporate the statutory 

provisions and make its regulations 

consistent with the new requirements 


emcdonald on DSK2BSOYB1PROD with RULES