[Federal Register: July 20, 2000 (Volume 65, Number 140)]
[Notices]
[Page 45085-45090]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr20jy00-78]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 94D-0325]
International Conference on Harmonisation; Draft Revised Guidance
on Impurities in New Drug Substances
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 ``Q3A(R) Impurities in New Drug Substances.''
The draft revised guidance, which updates a guidance on the same topic
published in the Federal Register of January 4, 1996 (the 1996
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 1996 guidance, adds information, and provides consistency
with more recently published ICH guidances. The draft revised guidance
is intended to provide guidance to applicants for drug marketing
registration on the content and qualification of impurities in new drug
substances produced by chemical syntheses and not previously registered
in a country, region, or member State.
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 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 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 ``Q3A(R) Impurities in New Drug Substances''
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 January 4, 1996 (61 FR 372). 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.
The draft revised guidance is intended to provide guidance to
applicants for drug marketing registration on the content and
qualification of impurities in new drug substances produced by chemical
syntheses and not previously registered in a country, region, or member
State. The draft revised guidance is not intended to apply to new drug
substances used during the clinical research stage of development or
clinical trials. The draft revised guidance also does not apply to
biological/biotechnological substances, peptides, oligonucleotides,
[[Page 45086]]
radiopharmaceuticals, fermentation and semisynthetic products derived
from that process, herbal products, and crude products of animal or
plant origin. Impurities in new drug substances are addressed in the
draft revised guidance from two different perspectives: (1) Chemistry
aspects--classification and identification of impurities, report
generation, setting specifications, and a brief discussion of
analytical procedures; and (2) safety aspects--guidance for qualifying
impurities that were not present in batches of the new drug substance
used in safety and clinical studies and/or impurity levels
substantially higher than in those batches.
The draft revised guidance includes revised text on threshold
limits, revised text on specification limits for impurities, and new
guidance on rounding. Additions to the glossary include definitions for
the terms ``identification threshold,'' ``qualification threshold,''
``reporting threshold,'' and ``rounding.'' References to validated
limit of quantitation were removed. The section on solvents references
a more recently published ICH guidance entitled ``Q3C Impurities:
Residual Solvents.'' 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 substances. 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:
Q3A(R) Impurities in New Drug Substances \1\
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\1\ This draft revised guidance represents the agency's current
thinking on impurities in new drug substances. 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. Preamble
This document is intended to provide guidance for registration
applications on the content and qualification of impurities in new
drug substances produced by chemical syntheses and not previously
registered in a region or member State. It is not intended to apply
to the regulation of new drug substances used during the clinical
research stage of development. Biological/biotechnological, peptide,
oligonucleotide, radiopharmaceutical, fermentation and semisynthetic
products derived therefrom, herbal products, and crude products of
animal or plant origin are not covered.
Impurities in new drug substances are addressed from two
perspectives:
Chemistry aspects include classification and identification of
impurities, report generation, setting specifications, and a brief
discussion of analytical procedures; and
Safety aspects include specific guidance for qualifying
impurities that were not present in batches of new drug substance
used in safety and clinical studies and/or impurity levels
substantially higher than in those batches. Threshold limits are
defined, at or below which qualification is not needed.
2. Classification of Impurities
Impurities may be classified into the following categories:
<bullet> Organic Impurities (Process- and Drug-Related)
<bullet> Inorganic Impurities
<bullet> Residual Solvents
Organic impurities may arise during the manufacturing process
and/or storage of the new drug substance. They may be identified or
unidentified, volatile or nonvolatile, and include:
<bullet> Starting Materials
<bullet> By-Products
<bullet> Intermediates
<bullet> Degradation Products
<bullet> Reagents, Ligands, and Catalysts
Inorganic impurities may derive from the manufacturing process.
They are normally known and identified, and include:
<bullet> Reagents, Ligands, and Catalysts
<bullet> Heavy Metals or Other Residual Metals
<bullet> Inorganic Salts
Solvents are organic or inorganic liquids used during the
manufacturing process. Since these are generally of known toxicity,
the selection of appropriate controls is easily accomplished (see
ICH Q3C Impurities: Residual Solvents).
Excluded from this document are: Extraneous contaminants (other
materials such as filter aids, charcoal) that should not occur in
new drug substances and are more appropriately addressed as good
manufacturing practice (GMP) issues; polymorphic form, a solid state
property of the new drug substance; and enantiomeric impurities.
3. Rationale for the Reporting and Control of Impurities
3.1 Organic Impurities
The applicant should summarize those actual and potential
impurities most likely to arise during the synthesis, purification,
and storage of the new drug substance. This summary should be based
on sound scientific appraisal of the chemical reactions involved in
the synthesis, impurities associated with raw materials that could
contribute to the impurity profile of the new drug substance, and
possible degradation products. This discussion may include only
those impurities that may reasonably be expected based on knowledge
of the chemical reactions and conditions involved.
In addition, the applicant should summarize the laboratory
studies conducted to detect impurities in the new drug substance.
This summary should include test results of batches manufactured
during the development process and batches from the proposed
commercial process, as well as results of intentional degradation
studies used to identify potential impurities arising during
storage. Assessment of the proposed commercial process may be
deferred until the first batch is produced for marketing. The
impurity profile of the drug substance lots intended for marketing
should be compared with those used in development, and any
differences discussed.
The studies conducted to characterize the structure of actual
impurities present in the new drug substance at a level greater than
(>) the threshold given in Attachment 1 (e.g., calculated using the
response factor of the drug substance) should be described. Note
that all specified impurities at a level greater than (>) the
identification threshold in batches manufactured by the proposed
commercial process should be identified. Degradation products
observed in stability studies at recommended storage conditions
should be similarly identified. When identification of an impurity
is not feasible, a summary of the laboratory studies demonstrating
the unsuccessful effort should be included in the application. Where
attempts have been made to identify impurities present at levels of
not more than (<ls-thn-eq>) the identification thresholds, it is
useful to also report the results of these studies.
Identification of impurities present at an apparent level of not
more than (<ls-thn-eq>) the identification threshold is generally
not necessary. However, analytical procedures should be developed
for those potential impurities that are expected to be unusually
potent, producing toxic or pharmacologic effects at a level less
than or equal to (<ls-thn-eq>) the identification threshold. All
impurities should be qualified as described later in this guidance.
Conventional rounding rules should be applied, and the results
presented with the same number of decimals as given in the limit
(see glossary).
3.2 Inorganic Impurities
Inorganic impurities are normally detected and quantitated using
pharmacopoeial or other appropriate procedures. Carryover of
catalysts to the new drug substance should be evaluated during
development. The need for
[[Page 45087]]
inclusion or exclusion of inorganic impurities in the new drug
substance specifications should be discussed. Limits should be based
on pharmacopoeial standards or known safety data.
3.3 Solvents
The control of residues of the solvents used in the
manufacturing process for the new drug substance should be discussed
and presented according to the ICH Q3C guidance for residual
solvents.
4. Analytical Procedures
The registration application should include documented evidence
that the analytical procedures are validated and suitable for the
detection and quantitation of impurities (see ICH Q2A and Q2B
guidances for analytical validation). Differences in the analytical
procedures used during development and those proposed for the
commercial product should be discussed in the registration
application.
Organic impurity levels can be measured by a variety of
techniques, including those which compare an analytical response for
an impurity 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 impurities should be
evaluated and characterized according to their intended uses. It is
considered acceptable to use the drug substance as a standard to
estimate the levels of impurities. In cases where the response
factors are not close, this practice may still be acceptable,
provided a correction factor is applied or the impurities are, in
fact, being overestimated. Specifications and analytical procedures
used to estimate identified or unidentified impurities are often
based on analytical assumptions (e.g., equivalent detector
response). These assumptions should be discussed in the registration
application.
5. Reporting Impurity Content of Batches
Analytical results should be provided for all batches of the new
drug substance used for clinical, safety, and stability testing, as
well as for batches representative of the proposed commercial
process. The content of individual identified and unidentified and
total impurities observed in these batches of the new drug substance
should be reported with the analytical procedures indicated. A
tabulation (e.g., spreadsheet) of the data is recommended.
Impurities should be designated by code number or by an appropriate
descriptor, e.g., retention time. Levels of impurities that are not
more than (>) the reporting threshold given in Attachment 1 need not
be reported. A higher reporting threshold should only be proposed
with justification. 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 3.1. When analytical procedures
change during development, reported results should be linked to the
procedure used, with appropriate validation information provided.
Representative chromatograms should be provided. Chromatograms of
such representative batches from methods validation studies showing
separation and detectability of impurities (e.g., on spiked
samples), along with any other impurity tests routinely performed,
can serve as the representative impurity profiles. The applicant
should ensure that complete impurity profiles (i.e., chromatograms)
of individual batches are available if requested.
A tabulation should be provided that links the specific new drug
substance batch to each safety study and each clinical study in
which it has been used.
For each batch of the new drug substance, the report should
include:
<bullet> Batch Identity and Size
<bullet> Date of Manufacture
<bullet> Site of Manufacture
<bullet> Manufacturing Process
<bullet> Impurity Content, Individual and Total
<bullet> Use of Batches
<bullet> Reference to Analytical Procedure Used
6. Specifications for Impurities
The specifications for a new drug substance should include
limits for impurities. Stability studies, chemical development
studies, and routine batch analyses can be used to predict those
impurities likely to occur in the commercial product. The selection
of impurities to include in the new drug substance specifications
should be based on the impurities found in batches manufactured by
the proposed commercial process. Those impurities selected for
inclusion in the specifications for the new drug substance are
referred to as ``specified impurities'' in this guidance. Specified
impurities may be identified or unidentified and should be
individually listed in the new drug substance specifications.
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 development batches, together with a consideration of the
impurity profile of material manufactured by the proposed commercial
process. Specific identified impurities should be included along
with specified unidentified impurities estimated to be present at a
level greater than (>) the qualification/identification threshold
given in Attachment 1. For impurities known to be unusually potent
or to produce toxic or unexpected pharmacological effects, the
quantitation/detection limit of the analytical methods should be
commensurate with the level at which the impurities must be
controlled. For unidentified impurities, the procedure used and
assumptions made in establishing the level of the impurity should be
clearly stated. Specified unidentified impurities included in the
specifications should be referred to by an appropriate qualitative
analytical descriptive label (e.g., ``unidentified A,''
``unidentified with relative retention of 0.9''). Finally, a general
specification limit of not more than (<ls-thn-eq>) the
qualification/identification threshold (Attachment 1) for any
unspecified impurity should be included.
Limits should be set no higher than the level that can be
justified by safety data and consistent with the level achievable by
the manufacturing process and the analytical capability. Where there
is no safety concern, impurity specifications should be based on
data generated on batches of the new drug substance manufactured by
the proposed commercial process, allowing sufficient latitude to
deal with normal manufacturing and analytical variation, and the
stability characteristics of the new drug substance. Although normal
manufacturing variations are expected, significant variation in
batch-to-batch impurity levels may indicate that the manufacturing
process of the new drug substance is not adequately controlled and
validated (see ICH Q6A guidance on specifications).
In summary, the new drug substance specifications should
include, where applicable, limits for:
Organic Impurities
<bullet> Each Specified Identified Impurity
<bullet> Each Specified Unidentified Impurity at a level greater
than (>) the qualification/identification threshold
<bullet> Any Unspecified Impurity with a limit of not more than
(<ls-thn-eq>) the qualification/identification threshold
<bullet> Total Impurities
Residual Solvents
Inorganic Impurities
7. Qualification of Impurities
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) specified. The applicant
should provide a rationale for selecting impurity limits based on
safety considerations. The level of any impurity present in a new
drug substance that has been adequately tested in safety and/or
clinical studies is considered qualified. Impurities that are also
significant metabolites present in animal and/or human studies do
not need further qualification. A level of a qualified impurity
higher than that present in a new drug substance can also be
justified based on an analysis of the actual amount of impurity
administered in previous relevant safety studies.
If data are not available to qualify the proposed specification
level of an impurity, studies to obtain such data may be needed when
the usual qualification threshold limits given in Attachment 1 are
exceeded.
Higher or lower threshold limits for qualification of impurities
may be appropriate for some individual drugs 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 impurities in certain
drugs or therapeutic classes have previously been associated with
adverse reactions in patients. In these instances, a lower
qualification threshold limit may be appropriate. Conversely, a
higher qualification threshold limit may be appropriate for
individual drugs when the level of concern for safety is less than
usual based on similar considerations (e.g., patient population,
drug class effects, clinical considerations). Technical factors
(manufacturing capability and control
[[Page 45088]]
methodology) may be considered as part of the justification for
selection of alternative threshold limits based on manufacturing
experience with the proposed commercial process. Proposals for
alternative threshold limits are 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. In some cases, decreasing the level of
impurity below the threshold may be simpler than providing safety
data. Alternatively, adequate data may be available in the
scientific literature to qualify an impurity. If neither is the
case, additional safety testing should be considered. The studies
desired to qualify an impurity will depend on a number of factors,
including the patient population, daily dose, and route and duration
of drug administration. Such studies are normally conducted on the
new drug substance containing the impurities to be controlled,
although studies using isolated impurities are acceptable.
8. New Impurities
During the course of a drug development program, the qualitative
impurity profile of the new drug substance may change, or a new
impurity may appear as a result of synthetic route changes, process
optimization, scale-up, etc. New impurities may be identified or
unidentified. Such changes call for qualification of the level of
the impurity unless it is not more than (>) the threshold values as
noted in Attachment 1. When a new impurity exceeds the threshold,
the ``Decision Tree for Safety Studies'' should be consulted. Safety
studies should compare the new drug substance containing a
representative level of the new impurity with previously qualified
material, although studies using the isolated impurity are also
acceptable (these studies may not always have clinical relevance).
9. Glossary
Chemical development studies: Studies conducted to scale-up,
optimize, and validate the manufacturing process for a new drug
substance.
Enantiomers: Compounds with the same molecular formula as the
drug substance, which differ in the spatial arrangement of atoms
within the molecule and are nonsuperimposable mirror images.
Extraneous substance: An impurity arising from any source
extraneous to the manufacturing process.
Herbal products: Medicinal products containing, exclusively,
plant material and/or vegetable drug preparations as active
ingredients. In some traditions, materials of inorganic or animal
origin may also be present.
Identification threshold: A limit above which (>) an impurity
needs identification.
Identified impurity: An impurity for which a structural
characterization has been achieved.
Impurity: Any component of the new drug substance that is not
the chemical entity defined as the new drug substance.
Impurity profile: A description of the identified and
unidentified impurities present in a new drug substance.
Intermediate: A material produced during steps of the synthesis
of a new drug substance that must undergo further molecular change
before it becomes a new drug substance.
Ligand: An agent with a strong affinity to a metal ion.
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
drug substance.
Polymorphism: The occurrence of different crystalline forms of
the same drug substance.
Potential impurity: An impurity that, from theoretical
considerations, may arise from or during manufacture. It may or may
not actually appear in the new drug substance.
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.
Reagent: A substance, other than a starting material or solvent,
that is used in the manufacture of a new drug substance.
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.
Solvent: An inorganic or an organic liquid used as a vehicle for
the preparation of solutions or suspensions in the synthesis of a
new drug substance.
Specified impurity: Identified or unidentified impurity that is
selected for inclusion in the new drug substance specifications and
is individually listed and limited in order to ensure the safety and
quality of the new drug substance.
Starting material: A material used in the synthesis of a new
drug substance that is incorporated as an element into the structure
of an intermediate and/or of the new drug substance. Starting
materials are normally commercially available and of defined
chemical and physical properties and structure.
Toxic impurity: An impurity having significant undesirable
biological activity.
Unidentified impurity: An impurity that is defined solely by
qualitative analytical properties (e.g., chromatographic retention
time).
Unspecified impurity: An impurity that is not included in the
list of specified impurities.
Attachment 1
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Qualification Threshold and
Maximum Daily Dose Identification Threshold Reporting Threshold \1\
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<ls-thn-eq> 2 grams (g)/day 0.1 percent or 1 milligram per day 0.05 percent
intake (whichever is lower)
> 2 g/day 0.05 percent 0.03 percent
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\1\ Higher reporting thresholds should be scientifically justified.
BILLING CODE 4160-01-F
[[Page 45089]]
[GRAPHIC] [TIFF OMITTED] TN20JY00.010
Notes on Attachment 2
<SUP>a</SUP> If considered desirable, a minimum screen for
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.
<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 are recommended.
<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.
[[Page 45090]]
Dated: July 10, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-18151 Filed 7-19-00; 8:45 am]
BILLING CODE 4160-01-C