[Federal Register Volume 61, Number 54 (Tuesday, March 19, 1996)]
[Notices]
[Pages 11268-11272]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-6580]
[[Page 11267]]
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Part IV
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guideline on
Impurities in New Drug Products; Availability; Notice
Federal Register / Vol. 61, No. 54 / Tuesday, March 19, 1996 /
Notices
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 96D-0009]
International Conference on Harmonisation; Draft 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 draft
guideline entitled ``Impurities in New Drug Products.'' The draft
guideline was prepared under the auspices of the International
Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). The draft 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 draft guideline is an annex to the ICH
guideline entitled ``Impurities in New Drug Substances.''
DATES: Written comments by June 17, 1996.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft
guideline are available from the Division of Communications Management
(HFD-210), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1012.
An electronic version of this guideline is also available via Internet
by connecting to the CDER file transfer protocol (FTP) server
(CDVS2.CDER.FDA.GOV).
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Allen Rudman, Center for Drug Evaluation
and Research (HFD-645), Food and Drug Administration, 7500 Standish
Pl., Rockville, MD 20855, 301-594-0375.
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.
At a meeting held on November 29, 1995, the ICH Steering Committee
agreed that a draft guideline entitled ``Impurities in New Drug
Products'' should be made available for public comment. The draft
guideline 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. Ultimately, FDA intends to adopt the ICH
Steering Committee's guideline.
-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 draft 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 draft 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
draft guideline.
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 are acceptable to FDA. The agency
is now in the process of revising 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 impurities in new drug products.
Interested persons may, on or before June 17, 1996, submit to the
Dockets Management Branch (address above) 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 Products
1. Introduction
1.1 -Objective of the Guideline
-This document 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 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.
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
[[Page 11269]]
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 exceeded. 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 need
not 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. Levels of degradation products
greater than or equal to more than one half the identification
threshold should be reported. 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 from representative batches should be
provided showing 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 define 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. 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 development
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 establish 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, do 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 amount of degradation product administered in previous
safety 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 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
[[Page 11270]]
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 will 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 exceeded. Alternatively, adequate data may be available in the
scientific literature 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 are acceptable.
2.6 New Impurities
-During the course of a drug development program the qualitative
degradation profile of a new drug product may change resulting in
new degradation products which exceed the identification and/or
qualification threshold and, 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 exceeds the threshold, 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 are also
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 substance or 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 establish 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 Products: A degradation product which
is not recurring and is not defined by qualitative analytical
properties. -
ATTACHMENT I
------------------------------------------------------------------------
THRESHOLDS FOR IDENTIFICATION OF DEGRADATION PRODUCTS IN NEW DRUG
PRODUCTS
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Maximum daily dose1-- Threshold
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< 1 mg--.................................. 1.0% or 5 g TDI2
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%
------------------------------------------------------------------------
\1\ The amount of drug substance administered per day.
\2\ Total Daily Intake.
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THRESHOLDS FOR QUALIFICATION OF DEGRADATION PRODUCTS IN NEW DRUG
PRODUCTS
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Maximum daily dose-- Threshold
------------------------------------------------------------------------
<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%
------------------------------------------------------------------------
BILLING CODE 4160-01-F
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[GRAPHIC] [TIFF OMITTED] TN19MR96.000
BILLING CODE 4160-01-C
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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 will
be acceptable.
Dated: March 7, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-6580 Filed 3-18-96; 8:45 am]
BILLING CODE 4160-01-F