Current Good Manufacturing Practice Regulation and Investigational New Drugs, 2458-2462 [06-353]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 71, Number 10 (Tuesday, January 17, 2006)]
[Rules and Regulations]
[Pages 2458-2462]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 06-353]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 210

[Docket No. 2005N-0285]


Current Good Manufacturing Practice Regulation and 
Investigational New Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending its current 
good manufacturing practice (CGMP) regulations for human drugs, 
including biological products, to exempt most investigational ``Phase 
1'' drugs from complying with the requirements in FDA's regulations. 
FDA will instead exercise oversight of production of these drugs under 
the agency's general statutory CGMP authority and investigational new 
drug application (IND) authority. In addition, FDA is making available 
simultaneously with the publication of this direct final rule, a 
guidance document setting forth recommendations on approaches to CGMP 
compliance for the exempted Phase 1 drugs.
    Elsewhere in this issue of the Federal Register, FDA is publishing 
a companion proposed rule, under FDA's usual procedure for notice-and-
comment rulemaking, to provide a procedural framework to finalize the 
rule in the event the agency receives any significant adverse comments 
and withdraws this direct final rule. The companion proposed rule and 
direct final rule are substantively identical.
    Elsewhere in this issue of the Federal Register, FDA is announcing 
the availability of a draft guidance for industry entitled ``INDs--
Approaches to Complying With CGMP During Phase 1'' to provide further 
guidance on the subject.

DATES: This rule is effective June 1, 2006. Submit written or 
electronic comments on or before April 3, 2006. If FDA receives no 
significant adverse comments within the specified comment period, the 
agency will publish a document confirming the effective date of the 
final rule in the Federal Register within 30 days after the comment 
period on this direct final rule ends. If timely significant adverse 
comments are received, the agency will publish a notice of significant 
adverse comment in the Federal Register withdrawing this direct final 
rule before May 2, 2006.

[[Page 2459]]


ADDRESSES: Submit written comments on the direct final rule to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic 
comments to https://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Monica Caphart, Center for Drug 
Evaluation and Research (HFD-320), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-9047; or Christopher 
Joneckis, Food and Drug Administration, Center for Biologics Evaluation 
and Research (HFM-1), 1401 Rockville Pike, Rockville, MD 20852, 301-
435-5681.

SUPPLEMENTARY INFORMATION:

I. Discussion

    This action is intended to streamline and promote the drug 
development process while ensuring the safety and quality of the 
earliest stage investigational drug products, those intended for use in 
Phase 1 clinical trials. Together with its companion guidance, this 
rule represents a significant step in the agency's plan to formally lay 
out an approach to aid manufacturers in implementing manufacturing 
controls that are appropriate for this stage of development.
    As defined in 21 CFR 312.21, a Phase 1 clinical trial includes the 
initial introduction of an investigational new drug into humans. Such 
studies are aimed at establishing basic safety and are designed to 
determine the metabolism and pharmacologic actions of the drug in 
humans. The total number of subjects in a Phase 1 study is limited--
generally no more than 80 subjects. This is in contrast to Phase 2 and 
Phase 3 trials, which may involve substantially greater numbers of 
subjects being exposed to the drug product, and which aim to test the 
effectiveness of the drug product. During Phase 2 or 3, drug products 
may be made available for treatment use through one of several 
mechanisms for expanded access to investigational drugs.
    FDA's general CGMP regulations for human drugs are set forth in 
parts 210 and 211 (21 CFR parts 210 and 211). Although the preamble to 
the September 1978 final rule issuing these regulations expressly 
stated that the CGMP regulations applied to investigational drug 
products, it also raised the possibility of proposing an additional 
CGMP regulation to cover drugs being used in research:
    The Commissioner finds that, as stated in Sec.  211.1, these CGMP 
regulations apply to the preparation of any drug product for 
administration to humans or animals, including those still in 
investigational stages. It is appropriate that the process by which a 
drug product is manufactured in the development phase be well 
documented and controlled in order to assure the reproducibility of the 
product for further testing and for ultimate commercial production. The 
Commissioner is considering proposing additional CGMP regulations to 
cover drugs in research stages (43 FR 45014 at 45029, September 29, 
1978).
    Such additional regulations have never been issued.
    In 1991, the agency issued a ``Guideline on the Preparation of 
Investigational New Drug Products (Human and Animal).'' That document, 
however, did not discuss all manufacturing scenarios, and did not 
clearly address small- or laboratory-scale production of drug products 
for use in Phase 1 clinical trials. Additionally, the 1991 guidance did 
not fully discuss the agency's expectations on appropriate approaches 
to manufacturing controls for batches produced during drug development.
    For several reasons, FDA believes that production of human drug 
products, including biological drug products, intended for use in Phase 
1 clinical trials should be exempted from complying with the specific 
regulatory requirements set forth in parts 210 and 211. First, even if 
exempted from the requirements of parts 210 and 211, investigational 
drugs remain subject to the statutory requirement that deems a drug 
adulterated:
    if * * * the facilities or controls used for, its manufacture, 
processing, packing, or holding do not conform to or are not operated 
or administered in conformity with current good manufacturing practice 
to assure that such drug meets the requirements of * * * [the Federal 
Food, Drug, and Cosmetic] Act as to safety and has the identity and 
strength, and meets the quality and purity characteristics, which it 
purports or is represented to possess (21 U.S.C. 351(a)(2)(B)).
    Second, FDA oversees drugs for use in Phase 1 trials through its 
existing IND authority. Every IND must contain, among other things, a 
section on chemistry, manufacturing, and control information that 
describes the composition, manufacture, and control of the 
investigational drug product (21 CFR 312.23(a)(7)). Submission of this 
information, along with other information required in the IND, informs 
the agency of the steps that the manufacturer is taking to ensure the 
safety and quality of the investigational drug. Under this IND 
authority, FDA has the option to place an IND on clinical hold if the 
study subjects would be exposed to an unreasonable and significant risk 
or if the IND does not contain sufficient information to assess the 
risks to subjects (21 CFR 312.42). FDA also may terminate an IND if the 
methods, facilities, and controls used for the manufacturing, 
processing, and packing of the investigational drug are inadequate to 
establish and maintain appropriate standards of identity, strength, 
quality, and purity as needed for subject safety (21 CFR 
312.44(b)(iii)).
    Thus, even though FDA is exempting Phase 1 drug products from 
compliance with the specific requirements of the CGMP regulations, the 
agency retains the ability to take appropriate actions to address 
manufacturing issues. For example, in addition to the authority to put 
an IND on clinical hold or terminate an IND, FDA may initiate an action 
to seize an investigational drug or enjoin its production if its 
production does not occur under conditions sufficient to ensure the 
identity, strength, quality, and purity of the drug, which may 
adversely affect its safety.
    FDA believes this change in the CGMP regulations (parts 210 and 
211) is appropriate because many of the issues presented by the 
production of investigational drugs intended for use in the relatively 
small Phase 1 clinical trials are different from issues presented by 
the production of drug products for use in the larger Phase 2 and Phase 
3 clinical trials or for commercial marketing. We are considering 
additional guidance and regulations to clarify the agency's 
expectations with regard to fulfilling CMGP requirements when producing 
investigational drugs for Phase 2 and Phase 3 clinical studies.
    Additionally, many of the specific requirements in the regulations 
in part 211 do not apply to the conditions under which many drugs for 
use in Phase 1 clinical trials are produced. For example, the concerns 
underlying the regulations' requirement for fully validated 
manufacturing processes, rotation of the stock for drug product 
containers, the repackaging and relabeling of drug products, and 
separate packaging and production areas are generally not concerns for 
these very limited production investigational drug products used in 
Phase 1 clinical trials. Consequently, in this direct final rule, FDA 
is amending the scope section of the drug CGMP regulations in 21 part

[[Page 2460]]

210 to make clear that production of investigational drugs for use in 
Phase 1 studies conducted under an IND does not need to comply with the 
regulations in part 211. However, once an investigational drug product 
has been manufactured by, or for, a sponsor and is available for use in 
a Phase 2 or Phase 3 study thus demonstrating an intent to expose more 
subjects to the investigational drug and requiring that the 
regulations' CGMP requirements be met, the same investigational drug 
product used in any subsequent Phase 1 study by the same sponsor must 
be manufactured in compliance with part 211. In addition to drug 
products that, if eventually approved, would be approved under section 
505 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
355), this rule would apply to investigational biological products that 
are subject to the CGMP requirements of section 501(a)(2)(B) of the act 
(21 U.S.C. 351(a)(2)(B)). Examples of such products include recombinant 
and nonrecombinant therapeutic products, vaccine products, allergenic 
products, in vivo diagnostics, plasma derivative products, blood and 
blood products, gene therapy products, and somatic cellular therapy 
products (including xenotransplantation products) that are subject to 
the CGMP requirements of section 501(a)(2)(B).
    To convey the agency's current thinking on the possible approaches 
to manufacturing controls for the production of Phase 1 drugs, FDA is 
issuing simultaneously with this direct final rule a draft guidance 
titled ``INDs--Approaches to Complying With CGMP During Phase 1,'' 
which sets forth recommendations on approaches to statutory compliance. 
Comments on that guidance can be submitted to the public docket 
identified in that document.

II. Direct Final Rulemaking

    FDA has determined that the subject of this rulemaking is suitable 
for a direct final rule. This direct final rule adds Sec.  210.2(c) to 
make clear that production of an investigational drug for use in a 
Phase 1 study conducted under an IND, when the drug has not yet been, 
or is not being, manufactured for use in Phase 2 or 3 studies or for an 
already approved use, is not subject to the requirements in part 211. 
Additionally, the rule states that once an investigational drug product 
has already been manufactured and is available for use in Phase 2 or 
Phase 3 studies or for an already approved use, the investigational 
drug product used in any subsequent Phase 1 investigational studies 
must comply with part 211.
    Because of the small batch size for these drugs, many of the issues 
implicated in larger scale production, which occurs late in the drug 
development process, or in commercial manufacture are not present 
during production of drugs for use in Phase 1 studies. The action taken 
should be noncontroversial, and the agency does not anticipate 
receiving any significant adverse comment on this rule.
    If FDA does not receive significant adverse comment the agency will 
publish a document in the Federal Register confirming the effective 
date of the final rule. The agency intends to make the direct final 
rule effective 30 days after publication of the confirmation document 
in the Federal Register. A significant adverse comment is one that 
explains why the rule would be inappropriate, including challenges to 
the rule's underlying premise or approach, or would be ineffective or 
unacceptable without a change. A comment recommending a rule change in 
addition to this rule will not be considered a significant adverse 
comment unless the comment also states why this rule would be 
ineffective without the additional change.
    Elsewhere in this issue of the Federal Register, FDA is publishing 
a companion proposed rule, identical in substance to the direct final 
rule, that provides a procedural framework from which to proceed with 
standard notice-and-comment rulemaking should the direct final rule be 
withdrawn because of significant adverse comment. The comment period 
for the direct final rule runs concurrently with that of the companion 
proposed rule. Any comments received under the companion proposed rule 
will be treated as comments regarding this direct final rule and vice 
versa. FDA will not provide additional opportunity for comment on the 
companion proposed rule. A full description of FDA's policy on direct 
final rule procedures may be found in a guidance document published in 
the Federal Register of November 21, 1997 (62 FR 62466).

III. Legal Authority

    Under section 501(a)(2)(B) of the act (21 U.S.C. 201 et seq.) a 
drug is deemed adulterated if the methods used in, or the facilities, 
or controls used for, its manufacture, processing, packing, or holding 
do not conform to or are not operated in conformity with CGMP to ensure 
that such drug meets the requirements of the act as to safety, and has 
the identity and strength, and meets the quality and purity 
characteristics, which it purports or is represented to possess. The 
rulemaking authority conferred on FDA by Congress under the act permits 
the agency to amend its regulations as contemplated by this direct 
final rule. Section 701(a) of the act (21 U.S.C. 371(a)) gives FDA 
general rulemaking authority to issue regulations for the efficient 
enforcement of the act. We refer readers to the legal authority section 
of the preamble of the 1978 CGMP regulations for a fuller discussion 
(43 FR 45014 at 45020-45026).

IV. Environmental Impact

    The agency has determined that under 21 CFR 25.30(h) this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Analysis of Impacts

    FDA has examined the impacts of the direct 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 (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 direct final 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 the 
rule on small entities. Because exempting production of drugs for use 
in Phase 1 studies from compliance with specific regulatory 
requirements does not add any burden, the agency certifies that the 
rule will not have a significant economic impact on a substantial 
number of small entities. Therefore, under the Regulatory Flexibility 
Act, no further analysis is required.
    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

[[Page 2461]]

after adjustment for inflation is $115 million using the most current 
(2003) 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 purpose of this direct final rule is to amend our current CGMP 
regulations to exempt the manufacture of Phase 1 drugs from compliance 
with the regulatory requirements in part 211. The rule will affect drug 
manufacturers, chemical manufacturers, and laboratories that 
manufacture drugs on a small scale for use in Phase 1 clinical trials.
    For drug manufacturers that produce Phase 1 drug products in-house 
and also produce approved drug products, this direct final rule is 
expected to reduce the amount of documentation they produce and 
maintain when they manufacture a Phase 1 drug. In some cases, it should 
also reduce the amount of component and product testing.
    Because they have far less experience with pharmaceutical CGMPs, 
some chemical manufacturers and laboratories may experience a slight 
increase in documentation if they currently do not have written 
standard operating procedures (SOPs), or if they need to modify 
existing methods of documentation. Although formats may be different, 
the rule should not require more information than is already collected 
as part of standard laboratory practices.
    Because the actual SOPs and manufacturing requirements are 
different for each new drug product and manufacturing facility, the 
procedures to comply with the statutory CGMP requirements for Phase 1 
production are generated as part of product development. The savings or 
costs would be incurred on a per-IND and not per-facility basis.
    This rule is intended to clarify requirements of the statutory 
CGMPs that are necessary for Phase 1 products and to exempt certain 
drugs produced under INDs from other CGMP requirements. Some 
manufacturers may realize savings because they no longer must meet 
certain requirements. The savings to drug manufacturers that produce 
the phase 1 drugs in-house will vary greatly from product to product. 
FDA lacks data to estimate the extent of cost savings. Some examples 
where substantial savings may be realized are the level of testing and 
analyzing components and in-process materials. These costs can 
typically range from $50 to $1,200 per component tested. The extent of 
the need for SOPs and methods validation may also be greatly reduced. 
We estimate that large drug manufacturers that produce Phase 1 drugs 
in-house could potentially save between 24 to 40 hours per IND. In 
addition, the clarifications we have made could lead some large firms 
to produce future drugs for Phase 1 trials in-house, rather than 
contracting the work out.
    For chemical manufacturers and laboratories, the requirements in 
this rule may increase the time required for developing SOPs for 
quality, process, and procedural controls and will be incurred on a 
recurring basis for each new product produced. There may also be an 
incremental increase in training costs to educate employees on the CGMP 
requirements. We estimate that an additional 12 to 24 hours may be 
required for these activities depending on the experience of the entity 
and its employees with our current CGMP rule.
    The facility that manufactures the drug for the Phase 1 trials is 
identified in the IND. We do not keep a database of these facilities 
and, therefore, we do not have a precise number of entities that might 
be affected by this final rule. To estimate the economic impact, we 
derived an estimate of the number affected annually based on the number 
of INDs we receive.
    In 2003, we received about 350 research and 500 commercial INDs. 
However, this rule would not apply to the majority of these INDs 
because they are for drug products that already have approvals and thus 
are subject to part 211. To derive an estimate of the percentage of 
INDs that would be affected by this rule, we used the percentage of 
total new drug applications (NDAs) that were for new molecular entities 
(NMEs) and applied that percentage to the number of annual IND 
applications. Historically, about 30 percent of NDAs are for NMEs each 
year. Assuming the relationship would be the same for the INDs and that 
the number of INDs will remain at about 850, this rule would affect 
about 255 INDs per year. A firm may produce multiple drug products for 
Phase 1 trials in a given year and use different companies to produce 
each of these drugs. Therefore, we do not know how many individual 
entities would be affected by this rule each year.
    The Small Business Administration (SBA) defines manufacturers of 
biologic drugs as small entities if they employ fewer than 500 people 
and other drug manufacturers as small if they employ fewer than 750 
people. FDA estimates that about 65 percent of the entities that submit 
NDAs and biologics license applications to the agency meet SBA's 
definition of a small entity. We assume that the distribution of large 
to small entities that submit INDs would be about the same. Although 
many of the entities that produce drug products for Phase 1 trials are 
laboratories, they are usually part of much larger institutions and are 
not considered small under SBA's definition. All of the entities 
affected by this rule have personnel with the skills necessary to 
comply with the requirements.
    Because we do not know the experience levels the affected entities 
have with our current CGMP requirements, we used the midpoint of the 
estimated ranges to estimate the potential recurring savings or costs.
    Savings to large manufacturers from reduced SOP and validation 
requirements for Phase 1 drug production in-house, assuming a time 
savings of 32 hours per application, a fully loaded wage rate of $45 
and 90 INDs per year (approximately 35 percent of 255) would total 
$129,600 per year or $1,440 per IND. This would be in addition to any 
other savings from decreased component testing.
    The incremental average annual cost to chemical manufacturers and 
laboratories, assuming all would incur costs and assuming an average 
increase of 18 hours per application for writing SOPs and training, a 
fully loaded wage rate of $45, and 165 INDs (approximately 65 percent 
of 255) affected per year, would total $133,650 per year or $810 per 
IND.
    Although we do not know the number and size distribution of the 
entities affected by this rule, FDA believes that the impact on them 
will be negligible and should actually reduce the compliance burden for 
some. To clarify the requirements for the manufacture of drugs for 
Phase 1 trials, we have prepared a draft guidance document with 
recommendations for compliance.

VI. Paperwork Reduction Act of 1995

    This direct final rule contains no new information collection 
requirements that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). Under the direct final rule, the production of human drug 
products, including biological drug products, intended for use in Phase 
1 clinical trials will be exempted from complying with the specific 
regulatory requirements set forth in parts 210 and 211. Parts 210 and 
211 contain information collection requirements that have been approved 
by OMB under control number 0910-0139. As explained in the following 
paragraph, the information collection requirements

[[Page 2462]]

in parts 210 and 211 will be reduced under this direct final rule.
    The OMB-approved hourly burden to comply with the information 
collection requirements in parts 210 and 211 (control number 0910-0139) 
is 848,625 hours. FDA estimates that, under the direct final rule, 
approximately 7,315 drugs will be exempted from complying with the 
specific regulatory requirements set forth in parts 210 and 211. Based 
on this number and the total number of drugs that are subject to parts 
210 and 211, FDA estimates that the burden hours approved under control 
number 0910-0139 will be reduced by approximately 50,493 hours. Thus, 
as a result of the direct final rule, the amended burden hours in 
control number 0910-0139 will be approximately 798,132 hours.

VII. Federalism

    FDA has analyzed this direct final rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the 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 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.

VIII. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments 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 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

List of Subjects in 21 CFR Part 210

    Drugs, Packaging and containers.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
210 is amended as follows:

PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, 
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

0
1. The authority citation for 21 CFR part 210 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 360b, 371, 374; 42 U.S.C. 
216, 262, 263a, 264.

0
2. Section 210.2 is amended by adding paragraph (c) to read as follows:


Sec.  210.2  Applicability of current good manufacturing practice 
regulations.

* * * * *
    (c) An investigational drug for use in a Phase 1 study, as defined 
in Sec.  312.21(a) of this chapter, is subject to the statutory 
requirements set forth at 21 U.S.C. 351(a)(2)(B). The production of 
such drug is exempt from compliance with the regulations in part 211 of 
this chapter. However, this exemption does not apply to an 
investigational drug for use in a Phase 1 study once the 
investigational drug has been made available for use by or for the 
sponsor in a Phase 2 or Phase 3 study, as defined in Sec.  312.21(b) 
and (c) of this chapter, or the drug has been lawfully marketed. If the 
investigational drug has been made available in a Phase 2 or 3 study or 
the drug has been lawfully marketed, the drug for use in the Phase 1 
study must comply with part 211.

    Dated: January 9, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 06-353 Filed 1-12-06; 8:45 am]
BILLING CODE 4160-01-S