Guidance for Industry
ANDAs: Impurities in Drug Substances
(PDF
version of this document)
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes
only.
Comments and suggestions regarding this draft
document should be submitted within 90 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to Dockets Management
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852. All comments should be identified
with the docket number listed in the notice of availability that
publishes in the Federal Register.
For questions regarding this draft document,
contact M. Scott Furness, (301) 827-5845.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
January 2005
OGD
Revision 1
Additional copies are available
from:
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
Guidance for Industry
ANDAs: Impurities in Drug
Substances
This
draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It does
not create or confer any rights for or on any person and does not
operate to bind FDA or the public. You can use an alternative
approach if the approach satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an
alternate approach, contact the appropriate FDA staff. If you
cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this document.
If you plan to submit comments on this
draft guidance, we recommend that you note the following
suggestions to help expedite FDA review of your comments:
·
Clearly explain
each issue/concern. You may include a proposed revision for FDA
consideration, along with a rationale or justification for the
revision.
·
Identify specific comments by line numbers.
·
If possible, use the pdf version of the document.
·
If possible, e-mail an electronic copy (Word) of
the comments you have submitted to the docket to
cummingsd@cder.fda.gov.
This guidance provides revised recommendations
on what chemistry, manufacturing and controls (CMC) information to
include regarding the reporting, identification, and qualification
of impurities in drug substances produced by chemical synthesis when
submitting:
·
Original abbreviated new drug applications (ANDAs)
·
Drug master files (DMFs) including type II DMFs
·
ANDA supplements for changes in drug substance
synthesis or process
The guidance also provides recommendations for
establishing acceptance criteria for impurities in drug substances.
The guidance, when finalized, will replace a 1999 guidance of the
same name.
This guidance does not apply to DMFs referenced
in ANDAs or ANDA supplements if the FDA has already accepted a DMF
for that dosage form, route of administration, and daily intake
prior to publication of the final version of this guidance. This
guidance also does not apply to applications for peptide,
oligonucleotide, radiopharmaceutical, fermentation, and
semisynthetic products derived from herbal products or crude
products of animal or plant origin.
FDA’s guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
We are revising the guidance for
industry titled ANDAs: Impurities in Drug Substances,
published in November 1999, for the following reasons:
1. To update information on listing of
impurities, setting acceptance criteria, and qualifying impurities
(thresholds and procedures) in ANDAs in conformance with the
revision of the guidance for industry (February 2003) on Q3A
Impurities in New Drug Substances (Q3A)(R).
2.
To remove those sections of the 1999 guidance containing
recommendations that are no longer needed because they are addressed
in the more recent Q3A(R) (See the list below).
The Q3A(R) was developed by the International Conference
on Harmonisation (ICH) to provide guidance on impurities in drug
substances for new drug applications (NDAs). However, the Agency
believes that many of the recommendations provided on impurities in
drug substances also apply to ANDAs. Please refer to the following
specific sections in the Q3A(R) for these recommendations:
·
Section I, Introduction
·
Section II, Classification of Impurities
·
Section III, Rationale for the Reporting and Control
of Impurities
·
Section IV, Analytical Procedures
·
Section V, Reporting Impurity Content of Batches
·
Attachment 1, Threshold Levels (for reporting,
identification, and qualification)
We recommend that the specifications for a drug
substance include a list of impurities. Stability studies, chemical
development studies, and routine batch analyses can be used to
predict those impurities likely to occur in the commercial product.
It is important that the list of impurities for the drug substance
specification be based on impurities found in the batch(es)
manufactured by the proposed commercial process.
We recommend that you include in your
submission a rationale for the inclusion or exclusion of impurities
in the drug substance specification. It is important that the
rationale include a discussion of the impurity profiles observed in
the batch(es) under consideration together with a consideration of
the impurity profile of the batch(es) manufactured by the proposed
commercial process.
Individual impurities with a specific
acceptance criterion that are included in the specification for a
drug substance are referred to as specified impurities in
this guidance. Specified impurities can be identified or
unidentified.
We recommend that identified specified
impurities be included in the list of impurities along with
unidentified specified impurities that are estimated to be
present at a level greater than the identification threshold given
in Q3A(R). For impurities known to be unusually potent or to
produce toxic or unexpected pharmacological effects, we recommend
that the quantitation and/or detection limit of the analytical
procedures correspond to the level at which the impurities are
expected to be controlled.
For unidentified impurities to be listed
in the drug substance specification, we recommend that you clearly
state the procedure used and assumptions made in establishing the
level of the impurity. It is important that unidentified
specified impurities be referred to by an appropriate
qualitative analytical descriptive label (e.g., unidentified A,
unidentified with relative retention of 0.9). We recommend that you
also include general acceptance criteria of not more than the
identification threshold (see Q3A(R) in Attachment 1) for any
unidentified impurity and acceptance criteria for total impurities.
We recommend that the drug substance specification include, where
applicable, a list of the following types of impurities:
- Each identified specified impurity
- Each unidentified specified impurity
- Any unspecified impurity with an
acceptance criterion of not more than (£)
the figure in the identification threshold in Attachment 1,
Q3A(R)
- Total impurities
·
Residual solvents
·
Inorganic impurities
We recommend that
the acceptance criterion be set no higher than the qualified level
(see section IV, Qualification of Impurities). In establishing
impurity acceptance criteria, the first critical consideration is
whether an impurity is specified in the United States Pharmacopeia (USP).
If there is a monograph in the USP that includes a limit for an
identified specified impurity, we recommend that the acceptance
criterion be set no higher than the official compendial limit.
However, if the
level of the impurity is above the level specified in the USP, we
recommend qualification. Then, if appropriate qualification has
been achieved, an applicant may wish to petition the USP for
revision of the impurity’s acceptance criterion.
If the acceptance criterion for a drug
substance impurity does not exist in the USP and this impurity can
be qualified by comparison with an FDA-approved human drug product,
it is important that the acceptance criterion be consistent with the
level observed in the approved human drug product. In other
circumstances, the acceptance criterion may need to be set lower
than the qualified level to ensure drug substance quality. For
example, if the level of the metabolite impurity is too high, other
quality attributes, like potency, could be seriously affected. In
this case, we would recommend that the impurity acceptance criterion
be set lower than the qualified level.
We recommend that ANDA sponsors develop robust
formulations and manufacturing processes that are based on sound
state-of-the-art scientific and engineering principles and
knowledge. Although routine manufacturing variations are expected,
significant variation in batch-to-batch impurity levels or an
unusually high level of impurity may indicate that the manufacturing
process of the drug substance is not adequately controlled or
designed.
Qualification is 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)
being considered. When appropriate, we recommend that applicants
provide a rationale for establishing impurity acceptance criteria
that includes safety considerations.
An impurity is considered qualified when it
meets one or more of the following conditions:
-
When the observed level and proposed acceptance criterion for the
impurity do not exceed the level observed in an FDA-approved human
drug product.
-
When the impurity is a significant metabolite of the drug
substance.
-
When the observed level and the proposed acceptance criterion for
the impurity are adequately justified by the scientific
literature.
-
When the observed level and proposed acceptance criterion for the
impurity do not exceed the level that has been adequately
evaluated in comparative in vitro genotoxicity studies.
Although Quantitative Structure Activity Relationships (QSAR)
programs may be used for prediction of toxicity of an individual
impurity or a given impurity profile, the
results are not generally considered conclusive for
qualification purposes.
Recommended
qualification thresholds
based on the maximum daily dose of the drug substance are provided
in ICH Q3A(R). When these qualification thresholds are
exceeded, we recommend that impurity levels be qualified. In some
cases, it may be appropriate to increase or decrease the threshold
for qualifying impurities. For example, when there is evidence that
an impurity in certain drug classes or therapeutic classes has
previously been associated with adverse reactions in patients, it
may be important to establish a lower qualification threshold.
Conversely, when the concern for safety is low, a higher threshold
for qualifying impurities may be appropriate. The FDA will consider
proposals for applications for alternative qualification thresholds
on a case-by-case basis after considering issues such as patient
population, drug class effects, and historical safety data.
The decision tree in Attachment 1 describes
considerations for the qualification of an impurity when the usual
qualification threshold recommended in ICH Q3A(R) is exceeded.
In some cases, decreasing the level of the impurity below the
threshold rather than providing additional data can be the simplest
course of action. Alternatively, adequate data could be available
in the scientific literature to qualify the impurity. The studies
considered appropriate to qualify the impurity will depend on a
number of factors, including the patient population, daily dose, and
route and duration of drug administration. Such studies can be
conducted on the drug substance containing the impurities to be
controlled, although studies using isolated impurities can sometimes
be appropriate. The following are descriptions of methods for
qualifying impurities.
An impurity present in a drug substance covered
by an ANDA can be qualified by comparing the analytical profiles of
the drug substance with those in an approved human drug product
using the same validated, stability-indicating analytical procedure
(e.g. comparative HPLC studies). This approved human drug product
is generally the reference listed drug (RLD). However, you may also
compare the profile to a different drug product with the same route
of administration and similar characteristics (e.g., tablet versus
capsule) if samples of the reference listed drug are unavailable or
for an ANDA submitted pursuant to a suitability petition. We
recommend that you conduct the stability studies on comparable
samples (e.g., age of samples) to get a meaningful comparison of the
impurity profiles.
An impurity present in the ANDA drug substance
is considered qualified if the amount of identified impurity in the
ANDA drug substance reflects the levels observed in the
corresponding approved human drug product.
If the level of the identified specified
impurity is adequately justified by the scientific literature, no
further qualification is considered necessary. In addition, an
impurity that is also a significant metabolite of the drug substance
is generally considered qualified.
Comparative in vitro genotoxicity tests
are the least preferred method to qualify impurities because they
are the most time consuming and costly of the methods described. We
recommend the tests be used only when impurities cannot be qualified
by either of the above procedures (section IV.B.1 or 2). The tests
are designed to detect compounds that induce genetic damage directly
or indirectly by various mechanisms. If performed, such studies
should be conducted on the drug product or drug substance containing
the impurities to be controlled, although studies using the isolated
impurities may also be used.
Notes on Attachment 1
a
Lower thresholds can be appropriate
if the impurity is unusually toxic.
b
For example, do known safety data for
this impurity or its structural class preclude human exposure at the
observed level?
c
In this context, an FDA-approved
human drug product generally refers to the reference listed drug.
It may also include a different drug product with the same route of
administration and similar characteristics such as tablet versus
capsule.
d
An impurity is considered qualified for ANDAs when one or more of
the following conditions are met:
-
When the observed level and
proposed acceptance criterion for the impurity do not exceed the
level justified by an FDA-approved human drug product.
-
When the impurity is a significant
metabolite of the drug substance.
-
When the observed level and the
proposed acceptance criterion for the impurity are adequately
justified by the scientific literature.
-
When the observed level and
proposed acceptance criterion for the impurity do not exceed the
level that has been adequately evaluated in comparative in
vitro genotoxicity studies.
e
If appropriate, 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 considered an
appropriate minimum screen.
f
If general toxicity studies are appropriate, one or more studies
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 for detecting the toxicity of an impurity. On a
case-by-case basis, single dose studies can be appropriate,
especially for single dose drugs. In general, a minimum duration of
14 days and a maximum duration of 90 days would be considered
appropriate.
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Date created: January 27, 2005 |