[Federal Register: July 19, 2000 (Volume 65, Number 139)]
[Notices]
[Page 44791-44797]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19jy00-91]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0009]
International Conference on Harmonisation; Draft Revised Guidance
on Impurities in New Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
revised guidance entitled ``Q3B(R) Impurities in New Drug Products.''
The draft revised guidance, which updates a guidance on the same topic
published in the Federal Register of May 19, 1997 (the 1997 guidance),
was prepared under the auspices of the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). The draft revised guidance
clarifies the 1997 guidance, adds information, and provides consistency
with more recently published ICH guidances. The draft revised guidance
is intended to provide guidance for registration or marketing
applications on the content and qualification of impurities in new drug
products produced from chemically synthesized new drug substances not
previously registered in a region or member State. The draft revised
guidance is a complement to the ICH guidance entitled ``Q3A Impurities
in new Drug Substances,'' which is being revised also.
DATES: Submit written comments by September 18, 2000.
ADDRESSES: Submit written comments on the draft revised guidance to the
Dockets Management Branch (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. Copies of the draft
revised guidance are available from the Drug Information Branch (HFD-
210), Center for Drug Evaluation and Research, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4573.
Single copies of the draft revised guidance may be obtained by mail
from the Office of Communication, Training, and Manufacturers
Assistance (HFM-40), Center for Biologics Evaluation and Research
(CBER), 1401 Rockville Pike, Rockville, MD 20852, or by calling the
CBER Voice Information System at 1-800-835-4709 or 301-827-1800. Copies
may be obtained from CBER's FAX
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Information System at 1-888-CBER-FAX or 301-827-3844.
FOR FURTHER INFORMATION CONTACT:
Regarding the guidance: Charles P. Hoiberg, Center for Drug Evaluation
and Research (HFD-800), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-5169.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs (HFY-
20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, 301-827-0864.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
In October 1999, the ICH Steering Committee agreed that a draft
revised guidance entitled ``Q3B(R) Impurities in New Drug Products''
should be made available for public comment. The draft revised guidance
is a revision of a guidance on the same topic published in the Federal
Register of May 19, 1997 (62 FR 27454). The draft revised guidance is
the product of the Quality Expert Working Group of the ICH. Comments
about this draft will be considered by FDA and the Quality Expert
Working Group.
In accordance with FDA's good guidance practices (62 FR 8961,
February 27, 1997), this document is now being called a guidance,
rather than a guideline.
In the Federal Register of January 4, 1996 (61 FR 372), the agency
published an ICH guidance entitled ``Q3A Impurities in New Drug
Substances.'' ICH Q3A, which is being revised also, provides guidance
to applicants for drug marketing registration on the content and
qualification of impurities in new drug substances produced by chemical
synthesis and not previously registered in a country, region, or member
State.
This draft revised guidance is a complement to the ICH Q3A guidance
and provides guidance for registration or marketing applications on the
content and qualification of impurities in new drug products produced
from chemically synthesized new drug substances not previously
registered in a region or member State. The draft revised guidance
addresses only those impurities in drug products classified as
degradation products of the active ingredient or reaction products of
the active ingredient with an excipient and/or immediate container/
closure system. Impurities arising from excipients present in the drug
product are not addressed in this draft revised guidance.
The draft revised guidance includes revised text on threshold
limits, revised text on degradation products, and new guidance on
rounding. Additions to the glossary include definitions for the terms
``identification threshold,'' ``qualification threshold,'' ``reporting
threshold,'' and ``rounding.'' The draft revised guidance was updated
to include references to ICH guidances on analytical validation and
specifications. Minor editorial changes were made to improve the
clarity and consistency of the document.
This draft revised guidance represents the agency's current
thinking on impurities in new drug products. It does not create or
confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statute, regulations, or
both.
Interested persons may submit to the Dockets Management Branch
(address above) written comments on the draft revised guidance by
September 18, 2000. Two copies of any comments are to be submitted,
except that individuals may submit one copy. Comments are to be
identified with the docket number found in brackets in the heading of
this document. A copy of the draft revised guidance and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. An electronic version of this guidance is
available on the Internet at http://www.fda.gov/cder/guidance/index.htm
or http://www.fda.gov/cber/publications.htm.
The text of the draft revised guidance follows:
Q3B(R) Impurities in New Drug Products \1\
1. Introduction
1.1 Objective of the Guidance
This document provides guidance recommendations for registration
or applications for marketing on the content and qualification of
impurities in new drug products produced from chemically synthesized
new drug substances not previously registered in a region or member
State.
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\1\ This draft revised guidance represents the agency's current
thinking on impurities in new drug products. It does not create or
confer any rights for or on any person and does not operate to bind
FDA or the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statute,
regulations, or both.
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1.2 Background
This guidance is a complement to the ICH Q3A guidance on
impurities in new drug substances, which should be consulted for
basic principles.
1.3 Scope of the Guidance
This guidance addresses only those impurities in drug products
classified as degradation products of the drug substance or reaction
products of the drug substance with an excipient and/or immediate
container/closure system (collectively referred to as ``degradation
products'' in this guidance). Impurities arising from excipients
present in the product are not covered by this guidance. This
guidance also does not address the regulation of products used
during the clinical research stages of development. Biological/
biotechnological products, peptides, oligonucleotides,
radiopharmaceuticals, fermentation and semisynthetic products
derived therefrom, herbal products, and crude products of animal or
plant origin are not covered. Also excluded from this guidance are:
Extraneous contaminants that should not occur in drug products and
are more appropriately addressed as good manufacturing practice
issues, polymorphic form, a solid state property of the new drug
substance, and enantiomeric impurities. Impurities present in the
new drug substance need not be monitored or specified in drug
products unless they are also degradation products (see ICH Q6A
guidance for specifications).
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2. Guidance
2.1 Analytical Procedures
The application for a marketing authorization should include
documented evidence that the analytical procedures have been
validated and are suitable for the detection and quantitation of
degradation products. Analytical methods should be validated to
demonstrate that impurities unique to the new drug substance do not
interfere with, or are separated from, specified and unspecified
degradation products in the product (see ICH Q2A and Q2B guidances
for analytical validation).
Degradation product levels can be measured by a variety of
techniques, including those which compare an analytical response for
a degradation product to that of an appropriate reference standard
or to the response of the new drug substance itself. Reference
standards used in the analytical procedures for control of
degradation products should be evaluated and characterized according
to their intended uses. The drug substance may be used to estimate
the levels of degradation products. In cases where the response
factors are not close, this practice may still be used if a
correction factor is applied or the degradation products are, in
fact, being overestimated. Specifications and analytical procedures
used to estimate identified or unidentified degradation products are
often based on analytical assumptions (e.g., equivalent detector
response). These assumptions should be discussed in the application
for marketing authorization. Differences in the analytical
procedures used during development and those proposed for the
commercial product should be discussed.
2.2 Rationale for the Reporting and Control of Impurities
The applicant should summarize those degradation products
observed during stability studies of the drug product. This summary
should be based on sound scientific appraisal of potential
degradation pathways in the drug product and impurities arising from
the interaction with excipients and/or the immediate container/
closure system. In addition, the applicant should summarize any
laboratory studies conducted to detect degradation products in the
drug product. This summary should include test results of batches
manufactured during the development process and batches
representative of the proposed commercial process. A rationale
should be provided for exclusion of those impurities that are not
degradation products, e.g., process impurities from the drug
substance and excipients and their related impurities. The impurity
profile of the batches representative of the proposed commercial
process should be compared with the profiles of batches used in
development, and any differences discussed.
Degradation products observed in stability studies conducted at
recommended storage conditions should be identified when present at
a level greater than (>) the identification thresholds given in
Attachment 1. When identification of a degradation product is not
feasible, a summary of the laboratory studies demonstrating the
unsuccessful effort should be included in the application for
marketing authorization.
Degradation products present at a level of not more than
(<ls-thn-eq>) the threshold generally would not need to be
identified. However, analytical procedures should be developed for
those degradation products that are suspected to be unusually
potent, producing toxic or significant pharmacologic effects at
levels lower than indicated. Conventional rounding rules should be
applied, and the results presented with the same number of decimals
as given in the limit.
2.3 Reporting Impurity Content of Batches
Analytical results should be provided in tabular format for all
relevant batches of new drug product used for clinical, safety, and
stability testing, as well as batches that are representative of the
proposed commercial process. Because the degradation test procedure
can be an important support tool for monitoring the manufacturing
quality as well as for deciding the expiration dating period of the
product, the reporting level should be set below the identification
threshold. The recommended target value for the reporting threshold
(expressed as a percentage of the drug substance) is found in
Attachment I. A higher reporting threshold should only be proposed,
with justification, if the target reporting threshold cannot be
achieved.
In addition, where an analytical method reveals the presence of
impurities in addition to the degradation products (e.g., impurities
arising from the synthesis of the drug substance), the origin of
these impurities should be discussed. Chromatograms or equivalent
data (if other methods are used) from representative batches
including long-term and accelerated stability conditions should be
provided. The procedure should be capable of quantifying at least at
the reporting threshold, and the chromatograms should show the
location of the observed degradation products and impurities from
the new drug substance.
The following information should be provided:
<bullet> Batch identity, strength, and size
<bullet> Date of manufacture
<bullet> Site of manufacture
<bullet> Manufacturing process, where applicable
<bullet> Immediate container/closure
<bullet> Degradation product content, individual and total
<bullet> Use of batch
<bullet> Reference to analytical procedure(s) used
<bullet> Batch number of the drug substance used in the drug
product
<bullet> Storage conditions
2.4 Specification Limits for Degradation Products
The specifications for a new drug product should include limits
for degradation products expected to occur during manufacture and
under recommended storage conditions. Stability studies, knowledge
of degradation pathways, product development studies, and laboratory
studies should be used to characterize the degradation profile.
Specifications should be set taking into account the qualification
of the degradation products, the stability data, the content arising
from the drug substance specification, the expected expiry period,
and the recommended storage conditions for the product, allowing
sufficient latitude to deal with normal manufacturing, analytical,
and stability profile variation. The specifications for the product
should include, where applicable, limits for:
<bullet> Each specified degradation product
<bullet> Any unspecified degradation product
<bullet> Total degradation products
Although some variation is expected, significant variation in
batch to batch degradation profiles may indicate that the
manufacturing process of the new drug product is not adequately
controlled and validated. A rationale for the inclusion or exclusion
of impurities in the specifications should be presented. This
rationale should include a discussion of the impurity profiles
observed in the safety and clinical studies, together with a
consideration of the impurity profile of the product manufactured by
the proposed commercial process. All impurities at a level greater
than (>) the reporting threshold should be summed and reported as
Total Impurities. The summation should be performed on the unrounded
individual values, and the total value should be rounded and
reported as described in section 2.2.
2.5 Qualification of Degradation Products
Qualification is the process of acquiring and evaluating data
that establishes the biological safety of an individual degradation
product or a given degradation profile at the level(s) specified.
The applicant should provide a rationale for selecting degradation
product limits based on safety considerations. The level of any
degradation product present in a new drug product that has been
adequately tested and found safe in safety and/or clinical studies
is considered qualified. Therefore, it is useful to include any
available information on the actual content of degradation products
in the relevant batches at the time of use in safety and/or clinical
studies. Degradation products that are also significant metabolites,
present in animal and/or human studies, do not need further
qualification. It may be possible to justify a higher level of a
degradation product than the level administered in safety studies.
The justification should include consideration of factors such as:
The amount of degradation product administered in previous safety
and/or clinical studies and found to be safe; the percentage change
in the degradation product; and other safety factors, as
appropriate.
If data are not available to qualify the proposed specification
level of a degradation product, studies to obtain such data may be
needed (see Attachment 2) when the usual qualification thresholds
set out in Attachment 1 are exceeded. Higher or lower thresholds for
qualification of degradation products may be appropriate for some
individual products based on scientific rationale and level of
concern, including drug class effects and clinical experience. For
example, qualification may be especially important when there is
evidence that such degradation products in certain drug products or
therapeutic classes have previously been associated with adverse
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reactions in patients. In these instances, a lower qualification
threshold may be appropriate. Conversely, a higher qualification
threshold may be appropriate for individual products when the level
of concern for safety is less than usual based on similar
considerations (e.g., patient population, drug class effects, and
clinical considerations). In unusual circumstances, technical
factors (e.g., manufacturing capability, a low drug substance to
excipient ratio, or the use of excipients that are also crude
products of animal or plant origin) may be considered as part of the
justification for selection of alternative threshold limits based
upon manufacturing experience with the proposed commercial process.
Proposals for alternative thresholds would be considered on a case-
by-case basis.
The ``Decision Tree for Safety Studies'' (Attachment 2)
describes considerations for the qualification of impurities when
thresholds are exceeded. Alternatively, if data are available in the
scientific literature, then such data may be submitted for
consideration to qualify a degradation product. If neither is the
case, additional safety testing should be considered. The studies
desired to qualify a degradation product will depend on a number of
factors, including the patient population, daily dose, and route and
duration of product administration. Such studies should normally be
conducted on the product or substance containing the degradation
products to be controlled, although studies using isolated
degradation products are considered acceptable.
2.6 New Degradation Products
During the course of drug development studies, the qualitative
degradation profile of a new drug product may change, resulting in
new degradation products that exceed the identification and/or
qualification threshold. In this event, these new degradation
products should be identified and/or qualified. Such changes call
for qualification of the level of the degradation product unless it
is present at a level of not more than (<ls-thn-eq>) the threshold
values as set out in Attachment 1.
When a new degradation product exceeds the threshold, the
``Decision Tree for Safety Studies'' should be consulted. Safety
studies should provide a comparison of results of safety testing of
the product or substance containing a representative level of the
degradation product with previously qualified material, although
studies using the isolated degradation products are also considered
acceptable (these studies may not always have clinical
significance).
3. Glossary
Degradation product: A molecule resulting from a chemical change
in the substance brought about over time and/or by the action of,
e.g., light, temperature, pH, or water or by reaction with an
excipient and/or the immediate container/closure system (also called
decomposition product).
Degradation profile: A description of the degradation products
observed in the drug substance or drug product.
Development studies: Studies conducted to scale-up, optimize,
and validate the manufacturing process for a drug product.
Identification threshold: A limit above which (>) an impurity
needs identification.
Identified degradation product: A degradation product for which
a structural characterization has been achieved.
Impurity: Any component of the drug product that is not the
chemical entity defined as the drug substance or an excipient in the
product.
Impurity profile: A description of the identified and
unidentified impurities present in a drug product.
New drug substance: The designated therapeutic moiety that has
not been previously registered in a region or member State (also
referred to as a new molecular entity or new chemical entity). It
may be a complex, simple ester, or salt of a previously approved
substance.
Potential degradation product: An impurity that, from
theoretical considerations, may arise during or after manufacture or
storage of the drug product. It may or may not actually appear in
the substance or product.
Qualification: The process of acquiring and evaluating data that
establishes the biological safety of an individual impurity or a
given impurity profile at the level(s) specified.
Qualification threshold: A limit above which (>) an impurity
needs to be qualified.
Reaction product: Product arising from the reaction of a
substance with an excipient in the drug product or immediate
container/closure system.
Reporting threshold: A limit above which (>) an impurity needs
to be reported.
Rounding: The process of reducing a result to the number of
significant figures or number of decimal places as dictated by the
appropriate limit. For example, a result greater than or equal to
(<gr-thn-eq>) 0.05 and less than () 0.15 is rounded to 0.1.
Safety information: The body of information that establishes the
biological safety of an individual impurity or a given impurity
profile at the level(s) specified.
Specified degradation product: An identified or unidentified
degradation product that is selected for inclusion in the new drug
product specifications and is individually listed and limited in
order to ensure the safety and quality of the new drug product.
Toxic impurity: An impurity having significant undesirable
biological activity.
Unidentified degradation product: A degradation product that is
defined solely by qualitative analytical properties, e.g.,
chromatographic retention time.
Unspecified degradation product: A degradation product that is
not included in the list of specified degradation products.
Attachment 1.
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Thresholds for Reporting of Degradation Products in New Drug Products
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Maximum Daily Dose \1\ Threshold \2\
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<ls-thn-eq> 1 gram (g).................... 0.1%
> 1 g..................................... 0.05%
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Thresholds for Identification of Degradation Products in New Drug
Products
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Maximum Daily Dose \1\ Threshold \2\
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1 milligram (mg)......................... 1% or 5 micrograms (<greek-
m>g) TDI,\3\ whichever is
lower
1 mg-10 mg................................ 0.5% or 20 <greek-m>g TDI,
whichever is lower
>10 mg-2 g................................ 0.2% or 2 mg TDI, whichever
is lower
> 2 g..................................... 0.1%
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Thresholds for Qualification of Degradation Products in New Drug
Products
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Maximum Daily Dose \1\ Threshold \2\
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10 mg.................................... 1% or 50 <greek-m>g TDI,
whichever is lower
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10 mg-100 mg.............................. 0.5% or 200 <greek-m>g TDI,
whichever is lower
>100 mg-2 g............................... 0.2% or 2 mg TDI, whichever
is lower
> 2 g..................................... 0.1%
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\1\ The amount of substance administered per day.
\2\ Threshold is based on percent of the substance. Higher reporting
thresholds should be scientifically justified.
\3\ Total daily intake.
BILLING CODE 4160-01-F
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[GRAPHIC] [TIFF OMITTED] TN19JY00.012
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[GRAPHIC] [TIFF OMITTED] TN19JY00.013
<SUP>a</SUP> If considered desirable, a minimum screen, e.g.,
genotoxic potential, should be conducted. A study to detect point
mutations and one to detect chromosomal aberrations, both in vitro,
are recommended as an acceptable minimum screen, as discussed in the
ICH guidances: ``S2A Specific Aspects of Regulatory Genotoxicity
Tests for Pharmaceuticals'' and ``S2B Genotoxicity: A Standard
Battery for Genotoxicity Testing of Pharmaceuticals.''
<SUP>b</SUP> If general toxicity studies are desirable,
study(ies) should be designed to allow comparison of unqualified to
qualified material. The study duration should be based on available
relevant information and performed in the species most likely to
maximize the potential to detect the toxicity of an impurity. In
general, a minimum duration of 14 days and a maximum duration of 90
days would be acceptable.
<SUP>c</SUP> On a case-by-case basis, single-dose studies may be
acceptable, especially for single-dose drugs. If repeat-dose studies
are desirable, a maximum duration of 90 days would be acceptable.
Dated: July 10, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-18150 Filed 7-18-00; 8:45 am]
BILLING CODE 4160-01-C