[Federal Register Volume 61, Number 3 (Thursday, January 4, 1996)]
[Notices]
[Pages 372-376]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-64]
[[Page 371]]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation, Guidelines Availability:
Impurities in New Drug Substances; Notice
Federal Register / Vol. 61, No. 3 / Thursday, January 4, 1996 /
Notices
[[Page 372]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 94D-0325]
International Conference on Harmonisation; Guideline on
Impurities in New Drug Substances; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a
guideline entitled ``Impurities in New Drug Substances.'' The guideline
was prepared under the auspices of the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). The guideline 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: Effective January 4, 1996. Submit written comments at any time.
ADDRESSES: Submit written comments on the guideline to the Dockets
Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,
12420 Parklawn Dr., Rockville, MD 20857. Copies of the guideline are
available from the Consumer Affairs Branch (previously the CDER
Executive Secretariat Staff) (HFD-210), Center for Drug Evaluation and
Research, Food and Drug Administration, 7500 Standish Pl., Rockville,
MD 20855.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Robert W. Trimmer, Center for Drug
Evaluation and Research (HFD-625), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-0370.
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 the Federal Register of September 22, 1994 (59 FR 48740), FDA
published a draft tripartite guideline entitled ``Impurities in New
Drug Substances.'' The notice gave interested persons an opportunity to
submit comments by December 6, 1994.
After consideration of the comments received and revisions to the
guideline, a final draft of the guideline was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies at the ICH meeting held in March 1995.
The guideline 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
guideline is not intended to apply to new drug substances used during
the clinical research stage of development or clinical trials. The
guideline also does not apply to biological/biotechnological
substances, peptides, oligonucleotides, 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 guideline from
two 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.
In the past, guidelines have generally been issued under
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of
guidelines to state procedures or standards of general applicability
that are not legal requirements but that are acceptable to FDA. The
agency is now in the process of revising Sec. 10.90(b). Therefore, the
guideline is not being issued under the authority of Sec. 10.90(b).
Although this guideline does not create or confer any rights on or for
any person, and does not operate to bind FDA in any way, it does
represent the agency's current thinking 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.
As with all of FDA's guidelines, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guideline. The comments in the docket will be periodically
reviewed, and, where appropriate, the guideline will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit to the Docket
Management Branch (address above) written comments on the guideline.
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. The guideline
and received comments may be seen in the office above between 9 a.m.
and 4 p.m., Monday through Friday.
The text of the guideline follows:
Impurities in New Drug Substances
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
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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 which 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, below which, qualification is not needed.
2. Classification of Impurities
Impurities may be classified into the following categories:
Organic Impurities (Process and Drug Related)
Inorganic Impurities
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:
Starting Materials
By-Products
Intermediates
Degradation Products
Reagents, Ligands, and Catalysts
Inorganic impurities may derive from the manufacturing process.
They are normally known and identified, and include:
Reagents, Ligands, and Catalysts
Heavy Metals
Inorganic Salts
Other Materials (e.g., Filter Aids, Charcoal, etc.)
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.
Excluded from this document are: Extraneous contaminants which
should not occur in new drug substances and are more appropriately
addressed as good manufacturing practice 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 which could
contribute to the impurity profile of the new drug substance, and
possible degradation products. This discussion may only include
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 that arise 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 or above an apparent
level of 0.1 percent (e.g., calculated using the response factor of
the drug substance) should be described. Note that all recurring
impurities at or above the 0.1 percent level 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
below the 0.1 percent level, it is useful to also report the results
of these studies.
Identification of impurities below apparent levels of 0.1
percent is generally not considered necessary. However,
identification should be attempted for those potential impurities
that are expected to be unusually potent, producing toxic or
pharmacologic effects at a level lower than 0.1 percent. In all
cases, impurities should be qualified as described later in this
guide. Although it is common practice to round analytical results of
between 0.05 and 0.09 percent to the nearest number (i.e., 0.1
percent), for the purpose of these guidelines, such values would not
be rounded to 0.1 percent and these impurities would not require
identification.
3.2 Inorganic Impurities
Inorganic impurities normally are detected and quantitated using
pharmacopeial or other appropriate procedures. Carry over of
catalysts to the new drug substance should be evaluated during
development. The need for inclusion or exclusion of inorganic
impurities in the new drug substance specifications should be
discussed. Limits should be based on pharmacopeial 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. Any solvents which may appear in the drug substance
should be quantified using analytical procedures with an appropriate
level of sensitivity. Pharmacopeial or other appropriate procedures
should be utilized. Limits should be based on pharmacopeial
standards or known safety data taking into consideration dose,
duration of treatment, and route of administration. Particular
attention should be given to quantitation of toxic solvents used in
the manufacturing process.
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. Differences in the
analytical procedures used during development and 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. The
drug substance may be used 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 often are based on analytical assumptions (e.g.,
equivalent detector response, etc.). The 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 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 which are
present but are below the validated limit of quantitation need not
be reported. When analytical procedures change during development,
reported results should be linked with 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 which 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:
Batch Identity and Size
Date of Manufacture
Site of Manufacture
Manufacturing Process
Impurity Content, Individual and Total
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Use of Batches
Reference to Analytical Procedure Used
6. Specification Limits 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 guideline. 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 recurring unidentified impurities estimated to be at or above
0.1 percent. 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. Unidentified impurities included in the
specifications should be referred to by some 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 0.1 percent for any unspecified
impurity should be included.
Limits should be set no higher than the level that can be
justified by safety data, and, unless safety data indicate
otherwise, no lower than the level achievable by the manufacturing
process and the analytical capability. In other words, where there
is no safety concern, impurity specifications should be based on
data generated on actual batches of the new drug substance 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.
In summary, the new drug substance specifications should
include, where applicable, limits for:
Organic Impurities:
Each Specified Identified Impurity
Each Specified Unidentified Impurity at or above 0.1
percent
Any Unspecified Impurity, with a limit of not more
than 0.1 percent
Total Impurities
Residual Solvents
Inorganic Impurities
A summation of assay value and impurity levels generally may be
used to obtain mass balance for the test sample. The mass balance
need not add to exactly 100 percent because of the analytical error
associated with each analytical procedure. The summation of impurity
levels plus the assay value may be misleading, for example, when the
assay procedure is nonspecific (e.g., potentiometric titrimetry) and
the impurity level is relatively high.
7. Qualification of Impurities
Qualification is the process of acquiring and evaluating data
which 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 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 below are exceeded:
------------------------------------------------------------------------
Maximum daily dose Qualification threshold
------------------------------------------------------------------------
2 grams (g)/day............... 0.1 percent or 1 milligram
per day intake (whichever
is lower)
> 2 g/day................................. 0.05 percent
------------------------------------------------------------------------
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 methodology) may be considered
as part of the justification for selection of alternative threshold
limits. Proposals for alternative threshold limits are considered on
a case-by-case basis.
The ``Decision Tree for Safety Studies'' (Attachment I)
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, 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 seen as acceptable.
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a 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 seen as an
acceptable minimum screen.
b 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
seen as 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, for example, synthetic route
changes, process optimization, or scale-up. New impurities may be
identified or unidentified. Such changes call for consideration of
the need for qualification of the level of the impurity, unless it
is below the threshold values as noted above. 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 seen as 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.
Identified Impurity: An impurity for which a structural
characterization has been achieved.
Impurity: Any component of the new drug substance which 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 which 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 which 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 which, 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
which establishes the biological safety of an individual impurity or
a given impurity profile at the level(s) specified.
Reagent: A substance, other than a starting material or solvent,
which is used in the manufacture of a new drug substance.
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 assure the safety and
quality of the new drug substance.
Starting Material: A material used in the synthesis of a new
drug substance which is incorporated as an element into the
structure of an intermediate and/or of the new drug substance.
Starting materials normally are commercially available and of
defined chemical and physical properties and structure.
Toxic Impurity: Impurities having significant undesirable
biological activity.
Unidentified Impurity: An impurity which is defined solely by
qualitative analytical properties (e.g., chromatographic retention
time).
Validated Limit of Quantitation: For impurities at a level of
0.1 percent, the validated limit of quantitation should be less than
or equal to 0.05 percent. Impurities limited at higher levels may
have higher limits of quantitation.
Dated: December 21, 1995.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-64 Filed 1-3-96; 8:45 am]
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