[Federal Register Volume 65, Number 139 (Wednesday, July 19, 2000)]
[Notices]
[Pages 44791-44797]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 00-18150]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 96D-0009]


International Conference on Harmonisation; Draft Revised Guidance 
on Impurities in New Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
revised guidance entitled ``Q3B(R) Impurities in New Drug Products.'' 
The draft revised guidance, which updates a guidance on the same topic 
published in the Federal Register of May 19, 1997 (the 1997 guidance), 
was prepared under the auspices of the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The draft revised guidance 
clarifies the 1997 guidance, adds information, and provides consistency 
with more recently published ICH guidances. The draft revised guidance 
is intended to provide 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 revised 
guidance is a complement to the ICH guidance entitled ``Q3A Impurities 
in new Drug Substances,'' which is being revised also.

DATES: Submit written comments by September 18, 2000.

ADDRESSES: Submit written comments on the draft revised guidance to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852. Copies of the draft 
revised guidance are available from the Drug Information Branch (HFD-
210), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-4573. 
Single copies of the draft revised guidance may be obtained by mail 
from the Office of Communication, Training, and Manufacturers 
Assistance (HFM-40), Center for Biologics Evaluation and Research 
(CBER), 1401 Rockville Pike, Rockville, MD 20852, or by calling the 
CBER Voice Information System at 1-800-835-4709 or 301-827-1800. Copies 
may be obtained from CBER's FAX

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Information System at 1-888-CBER-FAX or 301-827-3844.

FOR FURTHER INFORMATION CONTACT:
Regarding the guidance: Charles P. Hoiberg, Center for Drug Evaluation 
and Research (HFD-800), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, 301-827-5169.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs (HFY-
20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-827-0864.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote international harmonization of regulatory 
requirements. FDA has participated in many meetings designed to enhance 
harmonization and is committed to seeking scientifically based 
harmonized technical procedures for pharmaceutical development. One of 
the goals of harmonization is to identify and then reduce differences 
in technical requirements for drug development among regulatory 
agencies.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
consumer representatives and others. ICH is concerned with 
harmonization of technical requirements for the registration of 
pharmaceutical products among three regions: The European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission, the European Federation of Pharmaceutical Industries 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, the Centers for Drug 
Evaluation and Research and Biologics Evaluation and Research, FDA, and 
the Pharmaceutical Research and Manufacturers of America. The ICH 
Secretariat, which coordinates the preparation of documentation, is 
provided by the International Federation of Pharmaceutical 
Manufacturers Associations (IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and the IFPMA, as well as observers from the World 
Health Organization, the Canadian Health Protection Branch, and the 
European Free Trade Area.
    In October 1999, the ICH Steering Committee agreed that a draft 
revised guidance entitled ``Q3B(R) Impurities in New Drug Products'' 
should be made available for public comment. The draft revised guidance 
is a revision of a guidance on the same topic published in the Federal 
Register of May 19, 1997 (62 FR 27454). The draft revised guidance is 
the product of the Quality Expert Working Group of the ICH. Comments 
about this draft will be considered by FDA and the Quality Expert 
Working Group.
    In accordance with FDA's good guidance practices (62 FR 8961, 
February 27, 1997), this document is now being called a guidance, 
rather than a guideline.
    In the Federal Register of January 4, 1996 (61 FR 372), the agency 
published an ICH guidance entitled ``Q3A Impurities in New Drug 
Substances.'' ICH Q3A, which is being revised also, 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 revised guidance is a complement to the ICH Q3A guidance 
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 revised guidance 
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 revised guidance.
    The draft revised guidance includes revised text on threshold 
limits, revised text on degradation products, and new guidance on 
rounding. Additions to the glossary include definitions for the terms 
``identification threshold,'' ``qualification threshold,'' ``reporting 
threshold,'' and ``rounding.'' The draft revised guidance was updated 
to include references to ICH guidances on analytical validation and 
specifications. Minor editorial changes were made to improve the 
clarity and consistency of the document.
    This draft revised guidance represents the agency's current 
thinking on impurities in new drug 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.
    Interested persons may submit to the Dockets Management Branch 
(address above) written comments on the draft revised guidance by 
September 18, 2000. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. A copy of the draft revised guidance and received 
comments may be seen in the office above between 9 a.m. and 4 p.m., 
Monday through Friday. An electronic version of this guidance is 
available on the Internet at http://www.fda.gov/cder/guidance/index.htm 
or http://www.fda.gov/cber/publications.htm.
    The text of the draft revised guidance follows:

Q3B(R) Impurities in New Drug Products \1\

1. Introduction

1.1 Objective of the Guidance

    This document provides guidance recommendations for registration 
or applications for marketing 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.
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    \1\ This draft revised guidance 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.
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1.2 Background

    This guidance is a complement to the ICH Q3A guidance on 
impurities in new drug substances, which should be consulted for 
basic principles.

1.3 Scope of the Guidance

    This guidance addresses only those impurities in drug products 
classified as degradation products of the drug substance or reaction 
products of the drug substance with an excipient and/or immediate 
container/closure system (collectively referred to as ``degradation 
products'' in this guidance). Impurities arising from excipients 
present in the product are not covered by this guidance. This 
guidance also does not address the regulation of products used 
during the clinical research stages of development. Biological/
biotechnological products, peptides, oligonucleotides, 
radiopharmaceuticals, fermentation and semisynthetic products 
derived therefrom, herbal products, and crude products of animal or 
plant origin are not covered. Also excluded from this guidance are: 
Extraneous contaminants that 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 or specified in drug 
products unless they are also degradation products (see ICH Q6A 
guidance for specifications).

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2. Guidance

2.1 Analytical Procedures

    The application for a marketing authorization should include 
documented evidence that the analytical procedures have been 
validated and are 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 product (see ICH Q2A and Q2B guidances 
for analytical validation).
    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 application 
for marketing authorization. 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 that are not 
degradation products, e.g., process impurities from the drug 
substance and excipients and their related impurities. The impurity 
profile of the batches representative of the proposed commercial 
process should be compared with the profiles of batches used in 
development, and any differences discussed.
    Degradation products observed in stability studies conducted at 
recommended storage conditions should be identified when present at 
a level greater than (>) the identification thresholds given in 
Attachment 1. When identification of a degradation product is not 
feasible, a summary of the laboratory studies demonstrating the 
unsuccessful effort should be included in the application for 
marketing authorization.
    Degradation products present at a level of not more than 
() the threshold generally would not need to be 
identified. However, analytical procedures should be developed for 
those degradation products that are suspected to be unusually 
potent, producing toxic or significant pharmacologic effects at 
levels lower than indicated. Conventional rounding rules should be 
applied, and the results presented with the same number of decimals 
as given in the limit.

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 that 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 
product, the reporting level should be set below the identification 
threshold. The recommended target value for the reporting threshold 
(expressed as a percentage of the drug substance) is found in 
Attachment I. 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 Degradation Products

    The specifications for a new drug product should include limits 
for degradation products expected to occur during manufacture and 
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 content arising 
from the drug substance specification, the expected expiry period, 
and the recommended storage conditions for the product, allowing 
sufficient latitude to deal with normal manufacturing, analytical, 
and stability profile variation. The specifications for the 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. All impurities at a level greater 
than (>) the reporting threshold should be summed and reported as 
Total Impurities. The summation should be performed on the unrounded 
individual values, and the total value should be rounded and 
reported as described in section 2.2.

2.5 Qualification of Degradation Products

    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, 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: 
The amount of degradation product administered in previous safety 
and/or clinical studies and found to be safe; the percentage change 
in the degradation product; and 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 2) when the usual qualification thresholds 
set out in Attachment 1 are exceeded. Higher or lower thresholds for 
qualification of degradation products may be appropriate for some 
individual 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 drug products or 
therapeutic classes have previously been associated with adverse

[[Page 44794]]

reactions in patients. In these instances, a lower qualification 
threshold may be appropriate. Conversely, a higher qualification 
threshold may be appropriate for individual products 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 threshold limits based 
upon manufacturing experience with the proposed commercial process. 
Proposals for alternative thresholds would be considered on a case-
by-case basis.
    The ``Decision Tree for Safety Studies'' (Attachment 2) 
describes considerations for the qualification of impurities when 
thresholds are exceeded. 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, and route and 
duration of product administration. Such studies should normally be 
conducted on the product or substance containing the degradation 
products to be controlled, although studies using isolated 
degradation products are considered acceptable.

2.6 New Degradation Products

    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 qualification of the level of the degradation product unless it 
is present at a level of not more than () the threshold 
values as set out in Attachment 1.
    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 product or substance containing a representative level of the 
degradation product with previously qualified material, although 
studies using the isolated degradation products are also considered 
acceptable (these studies may not always have clinical 
significance).

3. Glossary

    Degradation product: A molecule resulting from a chemical change 
in the substance 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.
    Identification threshold: A limit above which (>) an impurity 
needs identification.
    Identified degradation product: A degradation product 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 
product.
    Impurity profile: A description of the identified and 
unidentified impurities present in a drug product.
    New drug substance: The designated therapeutic moiety that has 
not been previously registered in a region or member State (also 
referred to as a new molecular entity or new chemical entity). It 
may be a complex, simple ester, or salt of a previously approved 
substance.
    Potential degradation product: An impurity that, from 
theoretical considerations, may arise during or after manufacture or 
storage of the drug product. It may or may not actually appear in 
the substance or 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.
    Qualification threshold: A limit above which (>) an impurity 
needs to be qualified.
    Reaction product: Product arising from the reaction of a 
substance with an excipient in the drug product or immediate 
container/closure system.
    Reporting threshold: A limit above which (>) an impurity needs 
to be reported.
    Rounding: The process of reducing a result to the number of 
significant figures or number of decimal places as dictated by the 
appropriate limit. For example, a result greater than or equal to 
() 0.05 and less than () 0.15 is rounded to 0.1.
    Safety information: The body of information that establishes the 
biological safety of an individual impurity or a given impurity 
profile at the level(s) specified.
    Specified degradation product: An 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 ensure the safety and quality of the new drug product.
    Toxic impurity: An impurity having significant undesirable 
biological activity.
    Unidentified degradation product: A degradation product that is 
defined solely by qualitative analytical properties, e.g., 
chromatographic retention time.
    Unspecified degradation product: A degradation product that is 
not included in the list of specified degradation products.

                              Attachment 1.
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  Thresholds for Reporting of Degradation Products in New Drug Products
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          Maximum Daily Dose \1\                    Threshold \2\
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 1 gram (g)....................  0.1%
> 1 g.....................................  0.05%
------------------------------------------------------------------------


 
------------------------------------------------------------------------
    Thresholds for Identification of Degradation Products in New Drug
                                Products
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          Maximum Daily Dose \1\                    Threshold \2\
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 1 milligram (mg).........................  1% or 5 micrograms (g) TDI,\3\ 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%
------------------------------------------------------------------------


 
------------------------------------------------------------------------
    Thresholds for Qualification of Degradation Products in New Drug
                                Products
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          Maximum Daily Dose \1\                    Threshold \2\
------------------------------------------------------------------------
 10 mg....................................  1% or 50 g TDI,
                                             whichever is lower

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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 substance administered per day.
\2\ Threshold is based on percent of the substance. Higher reporting
  thresholds should be scientifically justified.
\3\ Total daily intake.

BILLING CODE 4160-01-F

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[GRAPHIC] [TIFF OMITTED] TN19JY00.013

    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 recommended as an acceptable minimum screen, as discussed in the 
ICH guidances: ``S2A Specific Aspects of Regulatory Genotoxicity 
Tests for Pharmaceuticals'' and ``S2B 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. If repeat-dose studies 
are desirable, a maximum duration of 90 days would be acceptable.

    Dated: July 10, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-18150 Filed 7-18-00; 8:45 am]
BILLING CODE 4160-01-C