[Federal Register Volume 68, Number 81 (Monday, April 28, 2003)]
[Proposed Rules]
[Pages 22341-22343]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-10301]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 106 and 107

[Docket No. 95N-0309]
RIN 0910-AA04


Current Good Manufacturing Practice, Quality Control Procedures, 
Quality Factors, Notification Requirements, and Records and Reports for 
the Production of Infant Formula; Reopening of the Comment Period

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; reopening of the comment period.

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SUMMARY: The Food and Drug Administration (FDA) is reopening until June 
27, 2003, the comment period for the proposed rule, published in the 
Federal Register of July 9, 1996 (61 FR 36154), revising its infant 
formula regulations in 21 CFR parts 106 and 107. The proposed rule 
would establish requirements for current good manufacturing practice 
(CGMP) and audits, establish requirements for quality factors, and 
amend its quality control procedures, notification, and records and 
reports requirements for infant formula. FDA is reopening the comment 
period to update comments and to receive any new information.

DATES: Submit written or electronic comments by June 27, 2003.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Shellee Anderson, Center for Food 
Safety and Applied Nutrition (HFS-800), Food and Drug Administration, 
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1491, or e-
mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Reopening of Comment Period

    In the Federal Register of July 9, 1996 (61 FR 36154), FDA proposed 
regulations (the 1996 proposal) to revise its infant formula 
regulations to establish requirements for quality factors and CGMP; to 
amend its quality control procedure, notification, and records and 
report requirements for infant formulas; to require that infant 
formulas contain, and be tested for, required nutrients and for any 
nutrient added by the manufacturer throughout their shelf life, and 
that they be produced under strict microbiological controls; and to 
require that manufacturers implement the CGMP and quality control 
procedure requirements by establishing a production and in-process 
control system of their own design. The agency proposed these 
requirements to implement provisions of the Drug Enforcement, Education 
and Control Act of 1986 (Public Law 99-570) that amended section 412 of 
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 350a).
    Interested persons were originally given until October 7, 1996, to 
comment on the 1996 proposal. However, at the request of a trade 
organization, the comment period was extended to December 6, 1996 (61 
FR 49714, September 23, 1996).
    FDA's Food Advisory Committee (FAC) met on April 4 and 5, 2002, to 
discuss general scientific principles related to quality factors for 
infant formula. The committee was also asked to discuss the scientific 
issues related to the generalization of findings from a clinical study 
using preterm infant formula consumed by preterm infants to a term 
infant formula intended for use by term infants. On November 18 and 19, 
2002, the Infant Formula Subcommittee (IFS) of the FAC met to discuss 
the scientific issues and principles involved in assessing and 
evaluating whether a ``new'' infant formula supports normal physical 
growth in infants when consumed as a sole source of nutrition. The 
Contaminants and Natural Toxicants Subcommittee (CNTS) of the FAC met 
on March 18 and 19, 2003, to discuss the scientific issues and 
principles involved in assessing and evaluating Enterobacter sakazakii 
contamination in powdered infant formula, risk reduction strategies 
based on available data, and research questions and priorities. 
Information on these three meetings, including the agenda, questions 
asked, guest speakers, committee roster, briefing information, and 
transcripts of the meetings can be found at http://www.fda.gov/ohrms/dockets/ac/cfsan02.htm.

II. Request for Comments

    Because of the length of time that has elapsed since publication of 
the 1996 proposal and the occurrence of the FAC, IFS, and CNTS 
meetings, FDA is interested in updating comments and receiving any new 
information before issuing a final rule. Accordingly, the agency is 
requesting comments on all

[[Page 22342]]

issues in the proposed rule. Comments previously submitted to the 
Dockets Management Branch do not need to be resubmitted because all 
comments submitted to the docket number will be considered in any final 
rule to the 1996 proposal. Since the 1996 proposal was published, 
several issues within the scope of that proposal have come to the 
agency's attention and are set forth in this document for comment.
    (Issue 1) In April 2001, an outbreak of E. sakazakii occurred in 10 
infants in the neonatal intensive care unit of a hospital in Tennessee 
(Ref. 1). One of these infants died. The ill infants had consumed 
formula that was made from sterile water and a specific batch of 
powdered infant formula. Samples from both opened and unopened cans of 
the implicated brand of powdered infant formula were cultured. E. 
sakazakii was found in all samples from one particular batch of the 
product. Because of its concerns with E. sakazakii, FDA requests 
comment on whether there is a need to include a microbiological 
requirement for E. sakazakii and, if so, what requirement the agency 
should consider to ensure the safety of powdered infant formula and 
prevent future outbreaks. The agency requests comment on what other 
changes, if any, in the proposed microbiological requirements would be 
appropriate to ensure the safety of powdered infant formula and to 
prevent outbreaks of illness. FDA also requests comment on whether 
powdered infant formula to be consumed by premature and newborn infants 
should meet stricter microbiological requirements than formula intended 
for older infants. The agency specifically requests comments on issues 
discussed at the CNTS meeting that are relevant to this rulemaking.
    (Issue 2) On March 19, 2002, FDA issued a letter (Ref. 2) in 
response to a notice of a manufacturer's conclusion that 
Bifidobacterium lactis strain Bb12 and Streptococcus thermophilus 
strain Th4 are generally recognized as safe (GRAS) for their intended 
use as ingredients in milk based infant formula that is intended for 
consumption by infants 4 months and older, at levels not to exceed 
CGMP. The agency has no questions about the manufacturer's conclusion 
at this time. In the 1996 proposal, FDA provided controls in proposed 
Sec.  106.55 for powdered infant formula to prevent adulteration from 
microorganisms, including a proposed limit on the maximum allowable 
number of microorganisms in the aerobic plate count. The agency 
requests comment on what changes, if any, in the proposed 
microbiological requirements would be appropriate to provide for 
powdered infant formula and to ensure its safety if microorganisms are 
intentionally added to infant formulas. Would infant formula containing 
these added microorganisms exceed the maximum allowable number in the 
aerobic plate count? How can manufacturers ensure that a high aerobic 
plate count is due to the intentional addition of microorganisms and 
not contamination?
    (Issue 3) The agency requests comments on which provisions of the 
proposed rule would require manufacturers to change their current 
activities. What new activities would manufacturers have to undertake 
to comply with the proposed regulations? What activities would 
manufacturers have to discontinue to comply with the proposed 
regulations? What are the costs of these changes? For example:
    (Issue 3a) Proposed Sec.  106.20(a) requires that buildings used in 
the manufacture of infant formula allot space for the separation of 
incompatible operations, such as the handling of raw materials, the 
manufacture of the product, and packaging and labeling operations. FDA 
requests comment on the types of control systems that manufacturers use 
to separate raw, in-process, and finished materials and the costs of 
making changes.
    (Issue 3b) Proposed Sec.  106.20(d) would require manufacturers to 
use air filtration systems, including prefilters and particulate matter 
air filters, on air supplies to production areas where ingredients or 
infant formula are directly exposed to the atmosphere. FDA requests 
comment on the types and costs of air filtration systems used by infant 
formula manufacturers and the costs of making changes.
    (Issue 4) One comment to the 1996 proposal stated that the 
validation section in proposed Sec.  106.35 is so vague and the impact 
so enormous that implementing it would be counterproductive. In 
proposed Sec.  106.35(a)(4) the agency proposed that, for purposes of 
the section, ``validation'' means establishing documented evidence that 
provides a high degree of assurance that a system will consistently 
produce a product meeting its predetermined specifications and quality 
characteristics. In proposed Sec.  106.35(b)(1), FDA proposed that all 
automatic systems be designed, installed, tested, and maintained in a 
manner that will ensure that they are capable of performing their 
intended function. The agency proposed in proposed Sec.  106.35(b)(4) 
that automatic systems be validated before their first use to 
manufacture commercial product. Proposed Sec.  106.35(b)(5) states that 
the infant formula manufacturer shall ensure that any automatic system 
that is modified be validated after the modification and before use of 
the modified system to manufacture commercial product. FDA requests 
comments on the proposed validation requirements. The agency 
specifically requests comments on current validation activities of 
infant formula facilities and how often manufacturers validate their 
systems.
    (Issue 5) Several provisions of the 1996 proposal (e.g., Sec. Sec.  
106.30(d)(1) and 106.35(b)(2)) would require that manufacturers 
calibrate instruments and controls. In these proposed provisions the 
agency specifies that calibration occur at routine intervals. FDA 
requests comments on how often and under what conditions manufacturers 
now calibrate instruments and controls against a known standard and the 
adequacy of current procedures.
    (Issue 6) FDA proposed to establish two quality factor measures for 
infant formula, protein quality and normal physical growth. Quality 
factors are those factors necessary to demonstrate that the infant 
formula, as prepared for market, provides nutrients in a form that is 
bioavailable and safe as shown by evidence that demonstrates that the 
formula supports healthy growth when fed as a sole source of nutrition. 
The agency requests comments on the appropriateness of these quality 
factors and any information on other quality factors that could be 
implemented to be consistent with current scientific knowledge as 
required under section 412(b)(1) of the act. FDA specifically requests 
comments on issues relevant to this rulemaking that were discussed at 
the two FAC meetings and on the following quality factor issues:
    (Issue 6a) What requirements should the agency establish to 
determine when manufacturers must conduct clinical growth studies for a 
new or reformulated infant formula?
    (Issue 6b) In proposed Sec.  106.97, FDA would require that 
manufacturers compare their clinical study growth data with the 
National Center for Health Statistics (NCHS) growth charts. The IFS of 
the FAC considered other sources of reference data in addition to the 
NCHS and recommended the Iowa reference data as the most appropriate 
reference data for comparison because they are longitudinal, collected 
over the time period of interest for clinical studies of infant growth, 
and collected in a research setting. FDA requests comments on whether 
the Iowa reference data should be the standard

[[Page 22343]]

for clinical study growth data rather than the NCHS growth charts.
    (Issue 6c) In proposed Sec.  106.97(a)(1)(i)(A), the agency would 
require that manufacturers conduct clinical studies that are no less 
than 4 months in duration, enrolling infants no more than 1 month old 
at time of entry into the study. The IFS of the FAC recommended that 
infants be enrolled by 14 days of age. FDA requests comments on the 
appropriate age for infants enrollment into clinical studies and on the 
duration of the studies.
    (Issue 7) In proposed Sec.  106.97(a)(1)(ii), the agency states 
provisions that it recommends manufacturers include in a clinical study 
protocol. Proposed Sec.  106.97(a)(1)(ii)(C) discusses review and 
approval by an Institutional Review Board (IRB) in accordance with part 
56 (21 CFR part 56), and the need for obtaining written informed 
consent from parents or legal representatives of the infants in 
accordance with part 50 (21 CFR part 50). Subsequent to the publication 
of the 1996 proposal, the agency issued an interim final rule entitled 
``Additional Safeguards for Children in Clinical Investigations of FDA-
Regulated Products'' (66 FR 20589, April 24, 2001), which amended parts 
50 and 56 to include, within the scope of that rule, data and 
information about a clinical study of an infant formula when submitted 
as part of an infant formula notification under section 412(c) of the 
act. Thus, requirements related to IRB review and informed consent for 
such clinical studies are dealt with in that interim final rule, and 
therefore, reference to IRB review and informed consent will be removed 
from the 1996 proposal. With respect to the other clinical study 
protocol provisions in proposed Sec.  106.97(a)(1)(ii), the agency 
intends to remove them from the proposed rule and develop a guidance 
document on what it recommends be included in a clinical study protocol 
for infant formula that is submitted as part of an infant formula 
notification under section 412(c) of the act.

III. How to Submit Comments

    Interested persons may submit to the Dockets Management Branch (see 
ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments to http://www.fda.gov/dockets/ecomments or two paper copies of any mailed comments, except 
that individuals may submit one paper copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Docket Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday.

IV. References

    FDA has placed the following references on display in the Dockets 
Management Branch (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Centers for Disease Control and Prevention, ``Enterobacter 
sakazakii Infections Associated With the Use of Powdered Infant 
Formula-Tennessee, 2001,'' 51(14):297, Morbidity and Mortality 
Weekly Report, April 12, 2002.
    2. FDA, Agency response letter to GRAS notice number GRN 00049, 
March 19, 2002.

    Dated: April 15, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-10301 Filed 4-25-03; 8:45 am]
BILLING CODE 4160-01-S