[Federal Register Volume 59, Number 183 (Thursday, September 22, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-23378]
[[Page Unknown]]
[Federal Register: September 22, 1994]
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Part VIII
Department of Health and Human Services
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Food and Drug Administration
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International Conference on Harmonisation; Draft Guideline on
Impurities in New Drug Substances; Availability; Notice
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
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[Docket No. 94D-0325]
International Conference on Harmonisation; Draft 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 draft
guideline entitled ``Impurities in New Drug Substances.'' The draft
guideline was prepared by the Quality Expert Working Group of the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). The draft
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: Written comments by December 6, 1994.
ADDRESSES: Submit written comments on the draft 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 CDER Executive Secretariat Staff (HFD-8), Center
for Drug Evaluation and Research, Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855.
FOR FURTHER INFORMATION CONTACT:
Regarding the draft guideline: Charles S. Kumkumian, Center for
Drug Evaluation and Research (HFD-102), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-594-6758.
Regarding the ICH: Janet Showalter, Office of Health Affairs (HFY-
50), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, 301-443-1382.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote Harmonisation of regulatory requirements. FDA
has participated in many meetings designed to enhance Harmonisation and
is committed to seeking scientifically based harmonized technical
procedures for pharmaceutical development. One of the goals of
Harmonisation is to identify and then reduce differences in technical
requirements for drug development.
ICH was organized to provide an opportunity for tripartite
Harmonisation 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
Harmonisation 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 Industry
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, 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 IFPMA, as well as observers from the World Health
Organization, the Canadian Health Protection Branch, and the European
Free Trade Area.
On March 15, 1994, the ICH Steering Committee agreed that a
consensus draft guideline entitled ``Impurities In New Drug
Substances,'' which was developed by the Quality Expert Working Group
of the ICH, should be made available for public comment. The draft
guideline will be made available for comment by the European Commission
and Japanese Ministry of Health and Welfare, as well as by FDA, in
accordance with their respective consultation procedures. Comments
about this draft will be considered by FDA and the Expert Working
Group. Ultimately, FDA intends to adopt the ICH Steering Committee's
final guideline.
The draft 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
draft guideline is not intended to apply to new drug substances used
during the clinical research stage of development or clinical trials.
The draft guideline also does not apply to biological/biotechnological
substances, peptides, 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 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, if
the agency issues this guideline in final form, the guideline would not
be issued under the authority of current Sec. 10.90(b), and would not
create or confer any rights, privileges, or benefits for or on any
person, nor would it operate to bind FDA in any way.
Interested persons may, on or before December 6, 1994, to the
Dockets Management Branch (address above) submit written comments on
the draft 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 draft 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 draft 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 stage of development, e.g., investigational new drugs or
clinical trials exemptions. Biological/biotechnological, peptide,
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
described below which qualification should not be necessary.
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 need 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 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 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, identification
of all recurring impurities at or above the 0.1 percent level is
expected in batches manufactured by the proposed commercial process.
Degradation products observed in stability studies at labelled
storage temperatures 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 also
to 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
guideline. 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 are normally 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 are based on pharmacopeial standards of 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 are 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 use. It is
considered acceptable to use the drug substance 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, 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 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
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 these guidelines.
Specified impurities may be identified or unidentified and are
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 sensitivity
of the analytical methods should be commensurate with the level at
which the impurities are to 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,''
etc.). 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 which 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 are 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:
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 can 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, e.g., 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 which has been adequately tested in safety and/or
clinical studies is considered qualified. Impurities which 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 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 (patient population, drug
class effects, clinical considerations, etc.). 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 acceptable.
BILLING CODE 4160-01-F
TN22SE94.000
BILLING CODE 4160-01-C
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 will
be 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 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 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.
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.
Manufacture: All operations related to the new drug substance,
including purchase of materials, production, quality control,
release, storage, and distribution of the new drug substance.
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 are normally 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: September 15, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-23378 Filed 9-21-94; 8:45 am]
BILLING CODE 4160-01-F
