[Federal Register Volume 65, Number 140 (Thursday, July 20, 2000)]
[Notices]
[Pages 45085-45090]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-18151]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 94D-0325]


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

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 ``Q3A(R) Impurities in New Drug Substances.'' 
The draft revised guidance, which updates a guidance on the same topic 
published in the Federal Register of January 4, 1996 (the 1996 
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 1996 guidance, adds information, and provides consistency 
with more recently published ICH guidances. The draft revised guidance 
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: 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 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 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 ``Q3A(R) Impurities in New Drug Substances'' 
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 January 4, 1996 (61 FR 372). 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.
    The draft revised guidance 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 revised guidance is not intended to apply to new drug 
substances used during the clinical research stage of development or 
clinical trials. The draft revised guidance also does not apply to 
biological/biotechnological substances, peptides, oligonucleotides,

[[Page 45086]]

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 revised guidance from two different 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.
    The draft revised guidance includes revised text on threshold 
limits, revised text on specification limits for impurities, and new 
guidance on rounding. Additions to the glossary include definitions for 
the terms ``identification threshold,'' ``qualification threshold,'' 
``reporting threshold,'' and ``rounding.'' References to validated 
limit of quantitation were removed. The section on solvents references 
a more recently published ICH guidance entitled ``Q3C Impurities: 
Residual Solvents.'' 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 substances. 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:

Q3A(R) Impurities in New Drug Substances \1\
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    \1\ This draft revised guidance represents the agency's current 
thinking on impurities in new drug substances. 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. 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. Biological/biotechnological, peptide, 
oligonucleotide, radiopharmaceutical, fermentation and semisynthetic 
products derived therefrom, herbal products, and crude products of 
animal or plant origin are not covered.
    Impurities in new drug substances are addressed from two 
perspectives:
    Chemistry aspects include classification and identification of 
impurities, report generation, setting specifications, and a brief 
discussion of analytical procedures; and
    Safety aspects include specific guidance for qualifying 
impurities that were not present in batches of new drug substance 
used in safety and clinical studies and/or impurity levels 
substantially higher than in those batches. Threshold limits are 
defined, at or below which qualification is not needed.

2. Classification of Impurities

    Impurities may be classified into the following categories:
     Organic Impurities (Process- and Drug-Related)
     Inorganic Impurities
     Residual Solvents
    Organic impurities may arise during the manufacturing process 
and/or storage of the new drug substance. They may be identified or 
unidentified, volatile or nonvolatile, and include:
     Starting Materials
     By-Products
     Intermediates
     Degradation Products
     Reagents, Ligands, and Catalysts
    Inorganic impurities may derive from the manufacturing process. 
They are normally known and identified, and include:
     Reagents, Ligands, and Catalysts
     Heavy Metals or Other Residual Metals
     Inorganic Salts
    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 (see 
ICH Q3C Impurities: Residual Solvents).
    Excluded from this document are: Extraneous contaminants (other 
materials such as filter aids, charcoal) that should not occur in 
new drug substances and are more appropriately addressed as good 
manufacturing practice (GMP) 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 that could 
contribute to the impurity profile of the new drug substance, and 
possible degradation products. This discussion may include only 
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 a level greater than 
(>) the threshold given in Attachment 1 (e.g., calculated using the 
response factor of the drug substance) should be described. Note 
that all specified impurities at a level greater than (>) the 
identification threshold in batches manufactured by the proposed 
commercial process should be identified. Degradation products 
observed in stability studies at recommended storage conditions 
should be similarly identified. When identification of an impurity 
is not feasible, a summary of the laboratory studies demonstrating 
the unsuccessful effort should be included in the application. Where 
attempts have been made to identify impurities present at levels of 
not more than () the identification thresholds, it is 
useful to also report the results of these studies.
    Identification of impurities present at an apparent level of not 
more than () the identification threshold is generally 
not necessary. However, analytical procedures should be developed 
for those potential impurities that are expected to be unusually 
potent, producing toxic or pharmacologic effects at a level less 
than or equal to () the identification threshold. All 
impurities should be qualified as described later in this guidance. 
Conventional rounding rules should be applied, and the results 
presented with the same number of decimals as given in the limit 
(see glossary).

3.2 Inorganic Impurities

    Inorganic impurities are normally detected and quantitated using 
pharmacopoeial or other appropriate procedures. Carryover of 
catalysts to the new drug substance should be evaluated during 
development. The need for

[[Page 45087]]

inclusion or exclusion of inorganic impurities in the new drug 
substance specifications should be discussed. Limits should be based 
on pharmacopoeial standards or known safety data.

3.3 Solvents

    The control of residues of the solvents used in the 
manufacturing process for the new drug substance should be discussed 
and presented according to the ICH Q3C guidance for residual 
solvents.

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 (see ICH Q2A and Q2B 
guidances for analytical validation). Differences in the analytical 
procedures used during development and those proposed for the 
commercial product should be discussed in the registration 
application.
    Organic impurity levels can be measured by a variety of 
techniques, including those which compare an analytical response for 
an impurity to that of an appropriate reference standard or to the 
response of the new drug substance itself. Reference standards used 
in the analytical procedures for control of impurities should be 
evaluated and characterized according to their intended uses. It is 
considered acceptable to use the drug substance as a standard 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). These 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 for 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 that are not 
more than (>) the reporting threshold given in Attachment 1 need not 
be reported. A higher reporting threshold should only be proposed 
with justification. 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 3.1. When analytical procedures 
change during development, reported results should be linked to 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 that 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. Specifications for Impurities

    The specifications for a new drug substance should include 
limits for impurities. Stability studies, chemical development 
studies, and routine batch analyses can be used to predict those 
impurities likely to occur in the commercial product. The selection 
of impurities to include in the new drug substance specifications 
should be based on the impurities found in batches manufactured by 
the proposed commercial process. Those impurities selected for 
inclusion in the specifications for the new drug substance are 
referred to as ``specified impurities'' in this guidance. Specified 
impurities may be identified or unidentified and should be 
individually listed in the new drug substance specifications.
    A rationale for the inclusion or exclusion of impurities in the 
specifications should be presented. This rationale should include a 
discussion of the impurity profiles observed in the safety and 
clinical development batches, together with a consideration of the 
impurity profile of material manufactured by the proposed commercial 
process. Specific identified impurities should be included along 
with specified unidentified impurities estimated to be present at a 
level greater than (>) the qualification/identification threshold 
given in Attachment 1. For impurities known to be unusually potent 
or to produce toxic or unexpected pharmacological effects, the 
quantitation/detection limit of the analytical methods should be 
commensurate with the level at which the impurities must be 
controlled. For unidentified impurities, the procedure used and 
assumptions made in establishing the level of the impurity should be 
clearly stated. Specified unidentified impurities included in the 
specifications should be referred to by an appropriate qualitative 
analytical descriptive label (e.g., ``unidentified A,'' 
``unidentified with relative retention of 0.9''). Finally, a general 
specification limit of not more than () the 
qualification/identification threshold (Attachment 1) for any 
unspecified impurity should be included.
    Limits should be set no higher than the level that can be 
justified by safety data and consistent with the level achievable by 
the manufacturing process and the analytical capability. Where there 
is no safety concern, impurity specifications should be based on 
data generated on batches of the new drug substance manufactured by 
the proposed commercial process, 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 (see ICH Q6A guidance on specifications).
    In summary, the new drug substance specifications should 
include, where applicable, limits for:
    Organic Impurities
     Each Specified Identified Impurity
     Each Specified Unidentified Impurity at a level greater 
than (>) the qualification/identification threshold
     Any Unspecified Impurity with a limit of not more than 
() the qualification/identification threshold
     Total Impurities
    Residual Solvents
    Inorganic Impurities

7. Qualification of Impurities

    Qualification is 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. The applicant 
should provide a rationale for selecting impurity limits based on 
safety considerations. The level of any impurity present in a new 
drug substance that has been adequately tested in safety and/or 
clinical studies is considered qualified. Impurities that are also 
significant metabolites present in animal and/or human studies do 
not need further qualification. A level of a qualified impurity 
higher than that present in a new drug substance can also be 
justified based on an analysis of the actual amount of impurity 
administered in previous relevant 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 in Attachment 1 are 
exceeded.
    Higher or lower threshold limits for qualification of impurities 
may be appropriate for some individual drugs based on scientific 
rationale and level of concern, including drug class effects and 
clinical experience. For example, qualification may be especially 
important when there is evidence that such impurities in certain 
drugs or therapeutic classes have previously been associated with 
adverse reactions in patients. In these instances, a lower 
qualification threshold limit may be appropriate. Conversely, a 
higher qualification threshold limit may be appropriate for 
individual drugs when the level of concern for safety is less than 
usual based on similar considerations (e.g., patient population, 
drug class effects, clinical considerations). Technical factors 
(manufacturing capability and control

[[Page 45088]]

methodology) may be considered as part of the justification for 
selection of alternative threshold limits based on manufacturing 
experience with the proposed commercial process. Proposals for 
alternative threshold limits are 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. 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, and 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.

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 qualification of the level of 
the impurity unless it is not more than (>) the threshold values as 
noted in Attachment 1. 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. In some traditions, materials of inorganic or animal 
origin may also be present.
    Identification threshold: A limit above which (>) an impurity 
needs identification.
    Identified impurity: An impurity for which a structural 
characterization has been achieved.
    Impurity: Any component of the new drug substance that 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 that must undergo further molecular change 
before it becomes a new drug substance.
    Ligand: An agent with a strong affinity to a metal ion.
    New drug substance: The designated therapeutic moiety 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 
drug substance.
    Polymorphism: The occurrence of different crystalline forms of 
the same drug substance.
    Potential impurity: An impurity that, 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 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.
    Reagent: A substance, other than a starting material or solvent, 
that is used in the manufacture of a new drug substance.
    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.
    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 ensure the safety and 
quality of the new drug substance.
    Starting material: A material used in the synthesis of a new 
drug substance that 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: An impurity having significant undesirable 
biological activity.
    Unidentified impurity: An impurity that is defined solely by 
qualitative analytical properties (e.g., chromatographic retention 
time).
    Unspecified impurity: An impurity that is not included in the 
list of specified impurities.

                                                  Attachment 1
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                                           Qualification Threshold and
         Maximum Daily Dose                 Identification Threshold               Reporting Threshold \1\
----------------------------------------------------------------------------------------------------------------
 2 grams (g)/day           0.1 percent or 1 milligram per day    0.05 percent
                                       intake (whichever is lower)
> 2 g/day                             0.05 percent                          0.03 percent
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\1\ Higher reporting thresholds should be scientifically justified.

BILLING CODE 4160-01-F

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[GRAPHIC] [TIFF OMITTED] TN20JY00.010

    Notes on Attachment 2
    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 recommended as an acceptable minimum screen.
    b If general toxicity studies are desirable, 
study(ies) should be designed to allow comparison of unqualified to 
qualified material. The study duration should be based on available 
relevant information and performed in the species most likely to 
maximize the potential to detect the toxicity of an impurity. In 
general, a minimum duration of 14 days and a maximum duration of 90 
days are recommended.
    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.


[[Page 45090]]


    Dated: July 10, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-18151 Filed 7-19-00; 8:45 am]
BILLING CODE 4160-01-C