[Federal Register Volume 62, Number 96 (Monday, May 19, 1997)]
[Notices]
[Pages 27454-27461]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-13019]
[[Page 27453]]
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Part IV
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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International Conference on Harmonisation; Guideline on Impurities in
New Drug Products; Availability; Notice
Federal Register / Vol. 62, No. 96 / Monday, May 19, 1997 / Notices
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0009]
International Conference on Harmonisation; Guideline on
Impurities in New Drug Products; 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 Products.'' 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 provides guidance
for registration or marketing applications on the content and
qualification of impurities in new drug products produced from
chemically synthesized new drug substances not previously registered in
a region or member State. The guideline is an annex to the ICH
guideline entitled ``Impurities in New Drug Substances.''
DATES: Effective May 19, 1997. Submit written comments at any time.
ADDRESSES: Submit written comments on the guideline to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline
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.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Albinus M. D'Sa, Center for Drug
Evaluation and Research (HFD-170), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-443-3741.
Regarding 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 March 19, 1996 (61 FR 11268), FDA
published a draft tripartite guideline entitled ``Impurities in New
Drug Products.'' The notice gave interested persons an opportunity to
submit comments by June 17, 1996.
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 on November 6, 1996.
In the Federal Register of January 4, 1996 (61 FR 372), the agency
published a guideline entitled ``Impurities in New Drug Substances.''
The guideline provides guidance to applicants for drug marketing
registration on the content and qualification of impurities in new drug
substances produced by chemical synthesis and not previously registered
in a country, region, or member state.
This guideline is an annex to that guideline and provides guidance
for registration or marketing applications on the content and
qualification of impurities in new drug products produced from
chemically synthesized new drug substances not previously registered in
a region or member State. The guideline addresses only those impurities
in drug products classified as degradation products of the active
ingredient or reaction products of the active ingredient with an
excipient and/or immediate container/closure system. Impurities arising
from excipients present in the drug product are not addressed in this
guideline.
This guideline represents the agency's current thinking on
impurities in new drug products. 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.
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 written comments on the
guideline to the Dockets Management Branch (address above). 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. An electronic version of this guideline is
available on the Internet using the World Wide Web (WWW) (http://
www.fda.gov/cder/guidance.htm).
The text of the guideline follows:
Impurities in New Drug Products
1. Introduction
1.1 Objective of the Guideline
This document provides guidance recommendations for registration
or marketing applications on the content and qualification of
impurities in new drug products produced from chemically synthesized
new drug substances not previously registered or approved for
marketing in a region or member State.
1.2 Background
This guideline is an annex to the Guideline on Impurities in New
Drug Substances, which should be consulted for basic principles.
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1.3 Scope of the Guideline
This guideline addresses only those impurities in drug products
classified as degradation products of the active ingredient or
reaction products of the active ingredient with an excipient and/or
immediate container/closure system (collectively referred to in this
guideline as degradation products). Impurities arising from
excipients present in the drug product are not covered in this
document. This guideline also does not address the regulation of
drug products used during the clinical research stages of
development. Biological/biotechnological products, peptides,
oligonucleotides, radiopharmaceuticals, fermentation products and
semisynthetic products derived therefrom, herbal products, and crude
products of animal or plant origin are not covered. Also excluded
from this document are: Extraneous contaminants, which should not
occur in drug products and are more appropriately addressed as good
manufacturing practice issues, polymorphic form, a solid state
property of the new drug substance, and enantiomeric impurities.
Impurities present in the new drug substance need not be monitored
in drug products unless they are also degradation products.
2. Guidelines
2.1 Analytical Procedures
The registration or marketing application should include
documented evidence that the analytical procedures are validated and
suitable for the detection and quantitation of degradation products.
Analytical methods should be validated to demonstrate that
impurities unique to the new drug substance do not interfere with or
are separated from specified and unspecified degradation products in
the drug product.
Degradation product levels can be measured by a variety of
techniques, including those which compare an analytical response for
a degradation product 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
degradation products should be evaluated and characterized according
to their intended uses. The drug substance may be used to estimate
the levels of degradation products. In cases where the response
factors are not close, this practice may still be used if a
correction factor is applied or the degradation products are, in
fact, being overestimated. Specifications and analytical procedures
used to estimate identified or unidentified degradation products are
often based on analytical assumptions (e.g., equivalent detector
response). These assumptions should be discussed in the registration
or marketing application. Differences in the analytical procedures
used during development and those proposed for the commercial
product should be discussed.
2.2 Rationale for the Reporting and Control of Impurities
The applicant should summarize those degradation products
observed during stability studies of the drug product. This summary
should be based on sound scientific appraisal of potential
degradation pathways in the drug product and impurities arising from
the interaction with excipients and/or the immediate container/
closure system. In addition, the applicant should summarize any
laboratory studies conducted to detect degradation products in the
drug product. This summary should include test results of batches
manufactured during the development process and batches
representative of the proposed commercial process. A rationale
should be provided for exclusion of those impurities which are not
degradation products, e.g., process impurities from the drug
substance and excipients and their related impurities. The impurity
profile of the drug product batches representative of the proposed
commercial process should be compared with the profiles of drug
product batches used in development and any differences discussed.
Degradation products observed in stability studies conducted at
recommended storage conditions should be identified when the
identification thresholds given in ATTACHMENT I are equaled or
exceeded (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). When identification of a degradation
product is not feasible, a summary of the laboratory studies
demonstrating the unsuccessful effort should be included in the
registration or marketing application.
Degradation products below the indicated levels generally would
not need to be identified. However, identification should be
attempted for those degradation products that are suspected to be
unusually potent, producing toxic or significant pharmacologic
effects at levels lower than indicated.
2.3 Reporting Impurity Content of Batches
Analytical results should be provided in tabular format for all
relevant batches of new drug product used for clinical, safety, and
stability testing, as well as batches which are representative of
the proposed commercial process. Because the degradation test
procedure can be an important support tool for monitoring the
manufacturing quality as well as for deciding the expiration dating
period of the drug product, the reporting level should be set below
the identification threshold. The recommended target value for the
reporting threshold (as a percentage of the drug substance) can be
found in ATTACHMENT 1. A higher reporting threshold should only be
proposed, with justification, if the target reporting threshold
cannot be achieved.
In addition, where an analytical method reveals the presence of
impurities in addition to the degradation products (e.g., impurities
arising from the synthesis of the drug substance), the origin of
these impurities should be discussed. Chromatograms, or equivalent
data (if other methods are used), from representative batches
including long-term and accelerated stability conditions should be
provided. The procedure should be capable of quantifying at least at
the reporting threshold and the chromatograms should show the
location of the observed degradation products and impurities from
the new drug substance.
The following information should be provided:
Batch identity, strength, and size
Date of manufacture
Site of manufacture
Manufacturing process, where applicable
Immediate container/closure
Degradation product content, individual and total
Use of batch
Reference to analytical procedure(s) used
Batch number of the drug substance used in the drug
product
Storage conditions
2.4 Specification Limits for Impurities
The specifications for a new drug product should include limits
for degradation products expected to occur under recommended storage
conditions. Stability studies, knowledge of degradation pathways,
product development studies, and laboratory studies should be used
to characterize the degradation profile. Specifications should be
set taking into account the qualification of the degradation
products, the stability data, the expected expiry period, and the
recommended storage conditions for the new drug product, allowing
sufficient latitude to deal with normal manufacturing, analytical,
and stability profile variation. The specification for the drug
product should include, where applicable, limits for:
Each specified degradation product
Any unspecified degradation product
Total degradation products
Although some variation is expected, significant variation in
batch-to-batch degradation profiles may indicate that the
manufacturing process of the new drug product is not adequately
controlled and validated. 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 studies, together with a
consideration of the impurity profile of the product manufactured by
the proposed commercial process.
2.5 Qualification of Impurities
Qualification is the process of acquiring and evaluating data
that establishes the biological safety of an individual degradation
product or a given degradation profile at the level(s) specified.
The applicant should provide a rationale for selecting degradation
product limits based on safety considerations. The level of any
degradation product present in a new drug product that has been
adequately tested and found safe in safety and/or clinical studies
is considered qualified. Therefore, it is useful to include any
available information on the actual content of degradation products
in the relevant batches at the time of use in safety and/or clinical
studies. Degradation products that are also significant metabolites,
present in animal and/or human studies, would not need further
qualification. It may be possible to justify a higher level of a
degradation product than the level administered in safety studies.
The justification should include consideration of factors such as:
(1) The
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amount of degradation product administered in previous safety and/or
clinical studies and found to be safe; (2) the percentage change in
the degradation product; and (3) other safety factors as
appropriate.
If data are not available to qualify the proposed specification
level of a degradation product, studies to obtain such data may be
needed (see ATTACHMENT II) when the usual qualification thresholds
given in ATTACHMENT I are equaled or exceeded. Higher or lower
thresholds for qualification of degradation products may be
appropriate for some individual drug products 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 degradation products in
certain drugs or therapeutic classes have previously been associated
with adverse reactions in patients. In these instances, a lower
qualification threshold may be appropriate. Conversely, a higher
qualification threshold 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, and
clinical considerations). In unusual circumstances, technical
factors (e.g., manufacturing capability, a low drug substance to
excipient ratio, or the use of excipients that are also crude
products of animal or plant origin) may be considered as part of the
justification for selection of alternative thresholds. Proposals for
alternative thresholds would be considered on a case-by-case basis.
The ``Decision Tree for Safety Studies'' (See Guideline on
Impurities in New Drug Substances and ATTACHMENT II) describes
considerations for the qualification of impurities when thresholds
are equaled or exceeded. Alternatively, if data are available in the
scientific literature, then such data may be submitted for
consideration to qualify a degradation product. If neither is the
case, additional safety testing should be considered. The studies
desired to qualify a degradation product will depend on a number of
factors, including the patient population, daily dose, route and
duration of drug administration. Such studies should normally be
conducted on the drug product or drug substance containing the
degradation products to be controlled, although studies using
isolated degradation products may be considered acceptable.
2.6 New Impurities
During the course of drug development studies, the qualitative
degradation profile of a new drug product may change, resulting in
new degradation products that exceed the identification and/or
qualification threshold. In this event, these new degradation
products should be identified and/or qualified. 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 in
ATTACHMENT I.
When a new degradation product equals or exceeds the threshold
(for rounding, see section 2.2), the ``Decision Tree for Safety
Studies'' should be consulted. Safety studies should provide a
comparison of results of safety testing of the drug product or drug
substance containing a representative level of the degradation
product with previously qualified material, although studies using
the isolated degradation products also may be considered acceptable
(these studies may not always have clinical significance).
3. Glossary
Degradation Product: A molecule resulting from a chemical change
in the drug molecule brought about over time and/or by the action
of, e.g., light, temperature, pH, or water, or by reaction with an
excipient and/or the immediate container/closure system (also called
decomposition product).
Degradation Profile: A description of the degradation products
observed in the drug substance or drug product.
Development Studies: Studies conducted to scale-up, optimize,
and validate the manufacturing process for a drug product.
Identified Impurity: An impurity for which a structural
characterization has been achieved.
Impurity: Any component of the drug product that is not the
chemical entity defined as the drug substance or an excipient in the
drug product.
Impurity Profile: A description of the identified and
unidentified impurities present in a drug product.
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.
Potential Degradation Product: An impurity which, from
theoretical considerations, may arise during or after manufacture or
storage of the drug product. It may or may not actually appear in
the drug substance or drug product.
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.
Reaction Product: Product arising from the reaction of a drug
substance with an excipient in the drug product or immediate
container/closure system.
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.
Specified Degradation Product: Identified or unidentified
degradation product that is selected for inclusion in the new drug
product specifications and is individually listed and limited in
order to assure the safety and quality of the new drug product.
Toxic Impurity: An impurity having significant undesirable
biological activity.
Unidentified Degradation Product: An impurity which is defined
solely by qualitative analytical properties, e.g., chromatographic
retention time.
Unspecified Degradation Product: A degradation product which is
not recurring from batch to batch.
Attachment I
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Thresholds for Reporting of Degradation Products in New Drug Products
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Maximum daily dose\1\ Threshold\3\
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1 g...................................... 0.1%
> 1 g..................................... 0.05%
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Thresholds for Identification of Degradation Products in New Drug
Products
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Maximum daily dose\1\ Threshold\3\
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< 1="" mg....................................="" 1.0%="" or="" 5="">g TDI\2\
whichever is lower
1 mg - 10 mg.............................. 0.5% or 20 g TDI
whichever is lower
> 10 mg - 2 g............................. 0.2% or 2 mg TDI whichever
is lower
> 2 g..................................... 0.1%
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------------------------------------------------------------------------
Thresholds for Qualification of Degradation Products in New Drug
Products
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Maximum daily dose\1\ Threshold\3\
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< 10="" mg...................................="" 1.0%="" or="" 50="">g TDI
whichever is lower
10 mg - 100 mg............................ 0.5% or 200 g TDI
whichever is lower
> 100 mg - 2 g............................ 0.2% or 2 mg TDI whichever
is lower
> 2 g..................................... 0.1%
------------------------------------------------------------------------
\1\ The amount of drug substance administered per day
\2\ Total Daily Intake
\3\ Threshold is based on percent of the drug substance
BILLING CODE 4160-01-F
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BILLING CODE 4160-01-C
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a 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 seen as an acceptable minimum screen, as discussed in the ICH
guidelines: ``Genotoxicity: Specific Aspects of Regulatory Tests''
and ``Genotoxicity: A Standard Battery for Genotoxicity Testing of
Pharmaceuticals.''
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 would be acceptable.
c On a case-by-case basis, single-dose studies may be
acceptable, especially for single-dose drugs, and when such studies
are conducted using an isolated impurity. If repeat-dose studies are
desirable, a maximum duration of 90 days would be acceptable.
Dated: May 6, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-13019 Filed 5-16-97; 8:45 am]
BILLING CODE 4160-01-F
