[Federal Register Volume 75, Number 244 (Tuesday, December 21, 2010)]
[Proposed Rules]
[Pages 80011-80013]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-31888]



Food and Drug Administration

21 CFR Part 58

[Docket No. FDA-2010-N-0548]

Good Laboratory Practice for Nonclinical Laboratory Studies

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.


SUMMARY: The Food and Drug Administration (FDA) is seeking comment on 
whether to amend the regulations governing good laboratory practices 
(GLPs). The Agency decided that to require a GLP quality system for all 
facilities/laboratories, as well as to more completely address 
nonclinical studies as they are presently conducted, the Agency would 
need to modify the existing regulations.

DATES: Submit either electronic or written comments by February 22, 

ADDRESSES: You may submit comments, identified by the Docket No. FDA-
2010-N-0548, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Fax: 301-827-6870.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and docket number for this rulemaking. All comments received may be 
posted without change to http://www.regulations.gov, including any 
personal information provided. For additional information on submitting 
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in the brackets in the heading of this document, 
into the ``Search'' box and follow the prompts

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and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 
1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: C. T. Viswanathan, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 5346, Silver Spring, MD 20993-0002, 301-


I. Background

    FDA's GLP regulations, part 58 (21 CFR part 58), were finalized on 
December 22, 1978 (43 FR 60013). As stated in its scope (Sec.  58.1), 
this regulation prescribes good laboratory practices for conducting 
nonclinical laboratory studies that support or are intended to support 
applications for research or marketing permits for products regulated 
by FDA, including food and color additives, animal food additives, 
human and animal drugs, medical devices for human use, biological 
products, and electronic products. A nonclinical laboratory study, as 
defined in Sec.  58.3(d), is an * * * in vivo or in vitro experiment in 
which test articles are studied prospectively in test systems under 
laboratory conditions to determine their safety. The term does not 
include studies utilizing human subjects or clinical studies or field 
trials in animals. [It also] does not include basic exploratory studies 
carried out to determine whether a test article has any potential 
utility or to determine physical or chemical characteristics of a test 
    The conduct of nonclinical laboratory studies has changed markedly 
since issuance of this regulation in 1978. For example, it is presently 
common for nonclinical laboratory studies to be conducted across 
multiple testing facilities, or sites (multisite studies). When the 
regulation was originally finalized, however, most studies were 
conducted within a single facility. In addition, laboratories have 
expanded the use of electronic technology, both for laboratory 
instrumentation and as a means for collecting, storing, and reporting 
study data. Current part 58 does not specifically describe these modern 
arrangements and advances.
    In 2006, FDA announced its Human Subject Protection/Bioresearch 
Monitoring (HSP/BIMO) initiative aimed at modernizing the Agency's 
regulations and policies governing the conduct of studies used to 
support submissions to FDA. In response to the announcement of the HSP/
BIMO initiative, FDA received stakeholder recommendations that included 
suggestions for the revision of part 58. In 2007, FDA established an 
Agency-wide GLP working group (WG) to evaluate the existing regulation 
and determine if regulatory revision and/or guidance should be pursued. 
The WG gathered information as to the needs of each FDA center with 
regard to nonclinical laboratory studies, reviewed suggestions from 
external sources, conferred with the Environmental Protection Agency 
(EPA) which has a similar regulation, and performed a thorough 
evaluation of the existing regulations. The WG concluded that to ensure 
the integrity of the data in all nonclinical laboratory studies 
submitted to FDA, nonclinical laboratory facilities that conduct these 
studies need to follow a GLP quality system approach. Currently, the 
regulations governing nonclinical laboratory studies do not use such an 
approach consistently throughout part 58. A GLP quality system would 
allow nonclinical laboratories to develop standard operating procedures 
consistent with their specific operational needs as long as they 
satisfy regulatory requirements aimed at ensuring data integrity. The 
WG decided that to require a GLP quality system for all facilities/
laboratories, as well as to more completely address nonclinical studies 
as they are presently conducted, the Agency would need to modify the 
existing regulations.

II. Agency Request for Information

    FDA is soliciting public comments about whether to modify the 
existing regulations, and in particular about the areas FDA has 
identified as potentially appropriate for revision, as follows:

1. GLP Quality System

    While many of the requirements of the existing regulation are 
consistent with a GLP quality system, FDA believes that modifications 
may be necessary to incorporate all basic elements needed for a 
comprehensive GLP quality system, such as that set forth in the 
internationally recognized standard, Quality management systems--
Requirements ISO 9001, available from the International Organization 
for Standardization (ISO) at: http://www.iso.org/iso/home.html. 
Ultimately, any GLP quality system proposed for a facility must be 
capable of ensuring the integrity of resulting data. FDA is considering 
whether to include in the regulations a core set of essential elements 
for such a GLP quality system, including specifically mentioning 
management responsibility for all activities at the facility and 
specifying a requirement for standard operating procedures for all 
essential functions.

2. Multisite Studies

    It is currently common practice for nonclinical laboratory studies 
to be performed across multiple sites (multisite studies), rather than 
for a single facility to conduct all aspects/phases of a study. FDA is 
considering revising the GLP regulations to specifically address the 
use of multisite studies through the addition of specific definitions 
to describe personnel and study aspects specific to multisite studies, 
e.g., by requiring that an individual be designated as the responsible 
person for each site of a multisite study. Such an individual would be 
responsible for any phase(s) of the study conducted at the site and 
would report to the study director.

3. Electronic/Computerized Systems

    Since the regulation was finalized, many laboratory systems have 
become fully automated. In addition, many facilities now employ 
computerized systems for managing general laboratory functions as well 
as for instrumentation in which such systems are integral components. 
While the present regulation does not preclude such electronic systems, 
several of the current regulatory requirements are more consistent with 
paper-based systems (e.g., an individual as archivist Sec.  58.190(c)); 
maintenance of copies of study protocols and the Master Schedule by the 
quality assurance unit (Sec.  58.35(b)(1) and (b)(2))). FDA is 
considering updating the regulation to reflect the use of electronic 
and computerized systems. FDA believes that any modifications to the 
regulation to reference electronic/computerized systems should be 
general, to accommodate changes and advances in technology.

4. Sponsor Responsibilities

    Whether nonclinical laboratory studies are conducted by a sponsor 
or at a contracted facility, FDA believes that the study sponsor should 
clearly have responsibilities that the present regulation does not 
specifically mention, such as development and/or approval of study 
protocols. FDA is therefore considering amending the regulations to 
include additional specific responsibilities of sponsors of nonclinical 
laboratory studies.

5. Animal Welfare

    In the United States, the Animal Welfare Act (7 U.S.C 2131-2159) 
governs the treatment and use of

[[Page 80013]]

animals, including their use for research purposes. FDA is soliciting 
comments regarding whether and how to receive documentation of 
compliance with these existing statutory provisions or comparable 
international standards governing the ethical and humane use of 
laboratory animals in nonclinical laboratory studies. This issue is not 
specifically addressed in the present regulation.

6. Information on Quality Assurance Inspectional Findings

    When an FDA bioresearch monitoring (BIMO) inspection of a 
nonclinical study identifies problems, FDA often finds it difficult to 
determine whether the quality assurance unit (QAU) failed to adequately 
inspect the study, or whether the QAU made recommendations for 
corrective actions and management did not adequately respond. FDA is 
considering the addition of a requirement that the QAU prepare a yearly 
summary of general inspectional findings that would reveal problems 
that are not necessarily study-specific and that includes the 
recommendations made to management to resolve those problems. Such a 
report would be maintained at the facility and be made available to FDA 
upon request, usually during the course of a BIMO inspection.

7. Process-Based Systems Inspections

    A number of procedures used in conducting a particular nonclinical 
laboratory study are common across many or even most studies conducted 
at the facility. Facilities often find it more resourceful to 
periodically inspect such procedures during systems inspections rather 
than repetitively as part of each study-specific inspection, as 
currently required in Sec.  58.35(b). For example, it may be 
appropriate to periodically inspect procedures such as slide 
preparation for pathology studies as part of a facility's process-based 
systems inspections rather than for each study. FDA therefore is 
considering permitting a combination of systems inspections and study-
specific inspections. The results of the appropriate systems 
inspection(s) would be referenced in the study-specific inspection 
reports relevant to those aspects of the procedures for the study under 

8. Test and Control Article Information

    When reviewing and inspecting nonclinical laboratory studies, 
particularly those submitted for new drugs (human and animal), basic 
information about the test article, such as strength, purity, 
stability, and for mixtures thereof, concentration and uniformity, is 
often absent from the laboratory's records, therefore precluding 
appropriate interpretation of the study results. Although the current 
regulations require that these parameters be determined (Sec.  
58.105(a) and (b) and Sec.  58.113(a)), the regulations do not specify 
who is to receive this information or include a timeframe for delivery 
of the information to the facility performing the nonclinical testing. 
FDA is therefore considering additional requirements under the sections 
in the regulations discussing test and control characterization (Sec.  
58.105) and mixtures of articles with carriers (Sec.  58.113), 
including timeframes for provision of this information to the study 
    In addition, sponsors have requested the ability to cite compliance 
with the applicable good manufacturing requirements (i.e, parts 210 and 
211, etc. as relevant) regarding the specifications, quality, and 
integrity of the test article. FDA is considering whether to accept 
compliance with either the specifics that would be required under a 
revised part 58, subpart F or the relevant good manufacturing 

9. Sample Storage Container Retention

    FDA's regulations currently require that facilities maintain test 
article storage containers for the duration of the study (21 CFR 
58.105(c)). FDA believes that compliance with the regulatory 
requirements for the handling of test and control articles, which 
include documentation of receipt, distribution, and use of each batch 
(Sec.  58.107(d)) provides adequate information about the use and 
integrity of study samples. Therefore, FDA is considering eliminating 
the requirement at Sec.  58.105(c).
    FDA welcomes comments from all interested persons on these issues 
and any other concerns related to the current GLP regulations, 
including recommendations as to the best method(s) for addressing such 

III. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.
    This advance notice of proposed rulemaking is issued under section 
201 et al. of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321 
et al.) and under authority of the Commissioner of Food and Drugs.

    Dated: December 15, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-31888 Filed 12-20-10; 8:45 am]