Guidance for Industry
ANDAs: Impurities in Drug Products
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draft guidance, when finalized, will represent the Food and Drug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to submit comments on this draft guidance, to expedite FDA review
of your comments, please:
- Clearly
explain each issue/concern and, when appropriate, include a
proposed revision and the rationale and/or justification for the
proposed revision.
- Identify
specific comments by line numbers; use the pdf version of the
document whenever possible.
- If
possible, e-mail an electronic copy (Word) of the comments you
have submitted to the docket to cummingsd@cder.fda.gov.
I.
INTRODUCTION
This guidance
provides recommendations on what chemistry, manufacturing and
controls (CMC) information sponsors should include regarding the
reporting, identification, and qualification of impurities that
are classified as degradation products in drug products
when submitting:
- Original
abbreviated new drug applications (ANDAs)
- ANDA
supplements for changes that may affect the quantitative or
qualitative degradation product profile
The guidance
also provides recommendations for establishing acceptance criteria
for degradation products (specifically, degradation products
of the active ingredient or reaction products of the
active ingredient with an excipient(s) and/or immediate
container/closure system) in generic drug products. The guidance
will replace an existing 1998 draft guidance of the same name.
This guidance
does not apply to an ANDA or ANDA supplement that has been
reviewed prior to the publication of the final guidance.
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the draft guidance for industry titled ANDAs: Impurities in
Drug Products, issued in December 1998, for the following
reasons:
1. To update information on
listing of degradation products, setting acceptance criteria, and
qualifying degradation products (thresholds and procedures) in
ANDAs in conformance with the revision of the guidance for
industry (November 2003) on Q3B(R) Impurities in New Drug
Products.
2.
To remove those sections of the 1998 draft guidance
containing recommendations that are no longer needed because they
are addressed in the more recent Q3B(R) (see the list
below).
The Q3B(R)
was developed by the International Conference on Harmonisation (ICH)
to provide guidance on impurities in drug products for new drug
applications (NDAs). However, the Agency believes that many of
the recommendations provided on impurities in drug products also
apply to ANDAs. Please refer to the following specific sections
in the Q3B(R) for these recommendations:
- Section I,
Introduction
- Section II,
Rationale for the Reporting and Control of Degradation Products
- Section III,
Analytical Procedures
- Section IV,
Reporting Degradation Products, Content of Batches
- Attachment
1, Thresholds for Degradation Products
We recommend that the specification for a drug product include a
list of degradation products. Stability studies, chemical
development studies, and routine batch analyses can be used to
predict the degradation profile for the commercial product.
It is important that the list of degradation products for the drug
product specification be based on degradation products 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
degradation products in the drug product specification. It is
important that the rationale include a discussion of the
degradation profiles observed in stability studies and in the
degradation profiles observed in the batch(es) under consideration
together with a consideration of the degradation profile of the
batch(es) manufactured by the proposed commercial process.
Individual degradation products with specific
acceptance criteria that are included in the specification for the
drug product are referred to as "specified degradation products"
in this guidance. Specified degradation products can be
identified or unidentified.
We recommend that specified identified
degradation products be included in the list of degradation
products along with specified unidentified degradation products
that are estimated to be present at a level greater than the
identification threshold given in Q3B(R). For degradation
products 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 degradation products are
expected to be controlled.
For unidentified degradation products to be
listed in the drug product specification, we recommend that you
clearly state the procedure used and assumptions made in
establishing the level of the degradation product. It is
important that specified unidentified degradation products
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 Q3B(R), Attachment 1) for any unspecified
degradation product and acceptance criteria for total degradation
products.
We recommend that the drug product specification include, where
applicable, a list of the following types of degradation products:
-
Each specified identified
degradation product
-
Each specified unidentified
degradation product
-
Any unspecified degradation
product with an acceptance criterion of not more than (£)
the figure in the identification threshold in Attachment 1,
Q3B(R)
-
Total degradation products
We recommend
that the acceptance criterion be set no higher than the qualified
level (see section IV, Qualification of Degradation Products). In
establishing degradation product acceptance criteria, the first
critical consideration is whether a degradation product is
specified in the United States Pharmacopeia (USP). If there is a
monograph in the USP that includes a limit for a specified
identified degradation product, we recommend that the acceptance
criterion be set no higher than the official compendial limit.
If the level of
the degradation product 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 degradation product’s acceptance criterion.
If the
acceptance criterion for a specified degradation product does not
exist in the USP and this degradation product can be qualified by
comparison to an FDA-approved human drug product, the acceptance
criterion should 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 product 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 degradation product 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 degradation product levels or an unusually high
level of degradation products may indicate that the manufacturing
process of the drug product is not adequately controlled or
designed.
IV. Qualification of Degradation Products
Qualification is the
process of acquiring and evaluating data that establish the
biological safety of an individual degradation product or a given
degradation profile at the level(s) being considered. When
appropriate, we recommend that applicants provide a rationale for
establishing degradation product acceptance criteria that includes
safety considerations.
A
degradation product is considered qualified when it meets one or
more of the following conditions:
·
When the observed level and
proposed acceptance criterion for the degradation product do not
exceed the level observed in an FDA-approved human drug product.
·
When the degradation product is a
significant metabolite of the drug substance.
-
When the observed level and the
proposed acceptance criterion for the degradation product are
adequately justified by the scientific literature.
-
When the observed level and
proposed acceptance criterion for the degradation product do not
exceed the level that has been adequately evaluated in
toxicology studies.
Although Quantitative Structure Activity Relationships (QSAR)
programs may be used for prediction of toxicity of an individual
degradation product or a given degradation profile, the
results are not generally
considered conclusive for qualification purposes.
Recommended
qualification thresholds
for degradation products based on the maximum daily dose of the
drug are provided in ICH Q3B(R). When these qualification
thresholds are exceeded, we recommend that degradation product
levels be qualified. In some cases, it may be appropriate to
increase or decrease the qualification threshold for qualifying
degradation products. For example, when there is evidence that a
degradation product 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 degradation products 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 degradation products when the usual qualification
threshold recommended in ICH Q3B(R) is exceeded.
In some cases, decreasing the level of the degradation product
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
degradation product. The studies considered appropriate to
qualify the degradation product 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 product containing the degradation product
to be controlled, although studies using isolated degradation
products can sometimes be appropriate. The following are
descriptions of methods for qualifying degradation products.
A degradation product present in a
drug product covered by an ANDA can be qualified by comparing the
analytical profiles of a generic drug product 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 in the case of an ANDA submitted pursuant to a suitability
petition. It is essential
that maximum daily doses of the degradation product and routes of
administration should be taken into account for qualification by
comparative analytical studies. The qualified threshold of a
degradation product in a dosage form may not be applicable to all
drug products containing that degradation product if the maximum
daily doses or the routes of administration are different.
We recommend that you
conduct the stability studies on comparable samples (e.g., age of
samples) to get a meaningful comparison of degradation profiles.
A degradation
product present in the generic drug product is considered
qualified if the amount of identified degradation product in the
generic drug product reflects the levels observed in the
corresponding approved human drug product.
If the level of
the specified identified degradation product is adequately
justified by the scientific literature, no further qualification
is considered necessary. In addition, a degradation product that
is also a significant metabolite of the drug substance is
generally considered qualified.
If the level of
the specified identified degradation product is adequately
justified by the scientific literature, no further qualification
is considered necessary. In addition, a degradation product that
is also a significant metabolite of the drug substance is
generally considered qualified.
Toxicity tests
are the least preferred method to qualify degradation products.
We recommend the tests be used only when degradation products
cannot be qualified by either of the above procedures (section
IV.B.1 or 2). The tests are designed to detect compounds that
induce general toxic or genotoxic effects in experimental
systems. If performed, such studies should be conducted on the
drug product or drug substance containing the degradation products
to be controlled, although studies using isolated degradation
products may also be used.
Notes on Attachment 1
a Lower thresholds can be appropriate if the
degradation product is unusually toxic.
b For example, do known safety data for this
degradation product 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 A degradation product 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
degradation product do not exceed the level justified by an
FDA-approved human drug product.
·
When the
degradation product is a significant metabolite of the drug
substance.
-
When the observed level and the proposed acceptance criterion
for the degradation product are adequately justified by the
scientific literature.
·
When the observed level and proposed acceptance
criterion for the degradation product do not exceed the level that
has been adequately evaluated in toxicity studies.
e 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 considered an appropriate minimum screen for
genotoxicity.
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 a degradation product. 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.
