[Federal Register Volume 59, Number 183 (Thursday, September 22, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-23378]


[[Page Unknown]]

[Federal Register: September 22, 1994]


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Part VIII





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Draft Guideline on 
Impurities in New Drug Substances; Availability; Notice
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
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[Docket No. 94D-0325]

 
International Conference on Harmonisation; Draft Guideline on 
Impurities in New Drug Substances; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
guideline entitled ``Impurities in New Drug Substances.'' The draft 
guideline was prepared by the Quality Expert Working Group of the 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH). The draft 
guideline is intended to provide guidance to applicants for drug 
marketing registration on the content and qualification of impurities 
in new drug substances produced by chemical syntheses and not 
previously registered in a country, region, or member State.

DATES: Written comments by December 6, 1994.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 
1-23, 12420 Parklawn Dr., Rockville, MD 20857. Copies of the guideline 
are available from the CDER Executive Secretariat Staff (HFD-8), Center 
for Drug Evaluation and Research, Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:
    Regarding the draft guideline: Charles S. Kumkumian, Center for 
Drug Evaluation and Research (HFD-102), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, 301-594-6758.
    Regarding the ICH: Janet Showalter, Office of Health Affairs (HFY-
50), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-443-1382.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives 
have been undertaken by regulatory authorities and industry 
associations to promote Harmonisation of regulatory requirements. FDA 
has participated in many meetings designed to enhance Harmonisation and 
is committed to seeking scientifically based harmonized technical 
procedures for pharmaceutical development. One of the goals of 
Harmonisation is to identify and then reduce differences in technical 
requirements for drug development.
    ICH was organized to provide an opportunity for tripartite 
Harmonisation initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
consumer representatives and others. ICH is concerned with 
Harmonisation of technical requirements for the registration of 
pharmaceutical products among three regions: the European Union, Japan, 
and the United States. The six ICH sponsors are the European 
Commission, the European Federation of Pharmaceutical Industry 
Associations, the Japanese Ministry of Health and Welfare, the Japanese 
Pharmaceutical Manufacturers Association, FDA, and the Pharmaceutical 
Research and Manufacturers of America. The ICH Secretariat, which 
coordinates the preparation of documentation, is provided by the 
International Federation of Pharmaceutical Manufacturers Associations 
(IFPMA).
    The ICH Steering Committee includes representatives from each of 
the ICH sponsors and IFPMA, as well as observers from the World Health 
Organization, the Canadian Health Protection Branch, and the European 
Free Trade Area.
    On March 15, 1994, the ICH Steering Committee agreed that a 
consensus draft guideline entitled ``Impurities In New Drug 
Substances,'' which was developed by the Quality Expert Working Group 
of the ICH, should be made available for public comment. The draft 
guideline will be made available for comment by the European Commission 
and Japanese Ministry of Health and Welfare, as well as by FDA, in 
accordance with their respective consultation procedures. Comments 
about this draft will be considered by FDA and the Expert Working 
Group. Ultimately, FDA intends to adopt the ICH Steering Committee's 
final guideline.
    The draft guideline is intended to provide guidance to applicants 
for drug marketing registration on the content and qualification of 
impurities in new drug substances produced by chemical syntheses and 
not previously registered in a country, region, or member State. The 
draft guideline is not intended to apply to new drug substances used 
during the clinical research stage of development or clinical trials. 
The draft guideline also does not apply to biological/biotechnological 
substances, peptides, radiopharmaceuticals, fermentation and 
semisynthetic products derived from that process, herbal products, and 
crude products of animal or plant origin. Impurities in new drug 
substances are addressed in the draft guideline from two perspectives: 
(1) Chemistry aspects--classification and identification of impurities, 
report generation, setting specifications, and a brief discussion of 
analytical procedures; and (2) safety aspects--guidance for qualifying 
impurities that were not present in batches of the new drug substance 
used in safety and clinical studies and/or impurity levels 
substantially higher than in those batches.
    In the past, guidelines have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidelines to state procedures or standards of general applicability 
that are not legal requirements but that are acceptable to FDA. The 
agency is now in the process of revising Sec. 10.90(b). Therefore, if 
the agency issues this guideline in final form, the guideline would not 
be issued under the authority of current Sec. 10.90(b), and would not 
create or confer any rights, privileges, or benefits for or on any 
person, nor would it operate to bind FDA in any way.
    Interested persons may, on or before December 6, 1994, to the 
Dockets Management Branch (address above) submit written comments on 
the draft guideline . Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. The draft guideline and received comments may be seen in 
the office above between 9 a.m. and 4 p.m., Monday through Friday.
    The text of the draft guideline follows:

Impurities in New Drug Substances

1. Preamble

    This document is intended to provide guidance for registration 
applications on the content and qualification of impurities in new 
drug substances produced by chemical syntheses and not previously 
registered in a region or member State. It is not intended to apply 
to the regulation of new drug substances used during the clinical 
research stage of development, e.g., investigational new drugs or 
clinical trials exemptions. Biological/biotechnological, peptide, 
radiopharmaceutical, fermentation, and semisynthetic products 
derived therefrom, herbal products, and crude products of animal or 
plant origin are not covered. Impurities in new drug substances are 
addressed from two perspectives:
    Chemistry aspects include classification and identification of 
impurities, report generation, setting specifications, and a brief 
discussion of analytical procedures; and
    Safety aspects include specific guidance for qualifying 
impurities which were not present in batches of new drug substance 
used in safety and clinical studies and/or impurity levels 
substantially higher than in those batches. Threshold limits are 
described below which qualification should not be necessary.

2. Classification of Impurities

    Impurities may be classified into the following categories:
    Organic Impurities (Process and Drug Related)
    Inorganic Impurities
    Residual Solvents
    Organic impurities may arise during the manufacturing process 
and/or storage of the new drug substance. They may be identified or 
unidentified, volatile or nonvolatile, and include:
    Starting Materials
    By-Products
    Intermediates
    Degradation Products
    Reagents, Ligands, and Catalysts
    Inorganic impurities may derive from the manufacturing process. 
They are normally known and identified and include:
    Reagents, Ligands, and Catalysts
    Heavy Metals
    Inorganic Salts
    Other Materials (e.g., Filter Aids, Charcoal, etc.)
    Solvents are organic or inorganic liquids used during the 
manufacturing process. Since these are generally of known toxicity, 
the selection of appropriate controls is easily accomplished.
    Excluded from this document are: Extraneous contaminants which 
should not occur in new drug substances and are more appropriately 
addressed as good manufacturing practice issues; polymorphic form, a 
solid state property of the new drug substance; and enantiomeric 
impurities.

3. Rationale for the Reporting and Control of Impurities

3.1 Organic Impurities

    The applicant should summarize those actual and potential 
impurities most likely to arise during the synthesis, purification, 
and storage of the new drug substance. This summary should be based 
on sound scientific appraisal of the chemical reactions involved in 
the synthesis, impurities associated with raw materials which could 
contribute to the impurity profile of the new drug substance, and 
possible degradation products. This discussion need only include 
those impurities that may reasonably be expected based on knowledge 
of the chemical reactions and conditions involved.
    In addition, the applicant should summarize the laboratory 
studies conducted to detect impurities in the new drug substance. 
This summary should include test results of batches manufactured 
during the development process and batches from the proposed 
commercial process, as well as results of intentional degradation 
studies used to identify potential impurities arising during 
storage. Assessment of the proposed commercial process may be 
deferred until the first batch is produced for marketing. The 
impurity profile of the drug substance lots intended for marketing 
should be compared with those used in development and any 
differences discussed.
    The studies conducted to characterize the structure of actual 
impurities present in the new drug substance at or above an apparent 
level of 0.1 percent (e.g., calculated using the response factor of 
the drug substance) should be described. Note that, identification 
of all recurring impurities at or above the 0.1 percent level is 
expected in batches manufactured by the proposed commercial process. 
Degradation products observed in stability studies at labelled 
storage temperatures should be similarly identified. When 
identification of an impurity is not feasible, a summary of the 
laboratory studies demonstrating the unsuccessful effort should be 
included in the application. Where attempts have been made to 
identify impurities below the 0.1 percent level, it is useful also 
to report the results of these studies.
    Identification of impurities below apparent levels of 0.1 
percent is generally not considered necessary. However, 
identification should be attempted for those potential impurities 
that are expected to be unusually potent, producing toxic or 
pharmacologic effects at a level lower than 0.1 percent. In all 
cases, impurities should be qualified as described later in this 
guideline. Although it is common practice to round analytical 
results of between 0.05 and 0.09 percent to the nearest number 
(i.e., 0.1 percent), for the purpose of these guidelines, such 
values would not be rounded to 0.1 percent and these impurities 
would not require identification.

3.2 Inorganic Impurities

    Inorganic impurities are normally detected and quantitated using 
pharmacopeial or other appropriate procedures. Carry over of 
catalysts to the new drug substance should be evaluated during 
development. The need for inclusion or exclusion of inorganic 
impurities in the new drug substance specifications should be 
discussed. Limits are based on pharmacopeial standards of known 
safety data.

3.3 Solvents

    The control of residues of the solvents used in the 
manufacturing process for the new drug substance should be 
discussed. Any solvents which may appear in the drug substance 
should be quantified using analytical procedures with an appropriate 
level of sensitivity. Pharmacopeial or other appropriate procedures 
should be utilized. Limits are based on pharmacopeial standards or 
known safety data taking into consideration dose, duration of 
treatment, and route of administration. Particular attention should 
be given to quantitation of toxic solvents used in the manufacturing 
process.

4. Analytical Procedures

    The registration application should include documented evidence 
that the analytical procedures are validated and suitable for the 
detection and quantitation of impurities. Differences in the 
analytical procedures used during development and proposed for the 
commercial product should be discussed in the registration 
application.
    Organic impurity levels can be measured by a variety of 
techniques, including those which compare an analytical response for 
an impurity to that of an appropriate reference standard or to the 
response of the new drug substance itself. Reference standards used 
in the analytical procedures for control of impurities should be 
evaluated and characterized according to their intended use. It is 
considered acceptable to use the drug substance to estimate the 
levels of impurities. In cases where the response factors are not 
close, this practice may still be acceptable, provided a correction 
factor is applied or the impurities are, in fact, being 
overestimated. Specifications and analytical procedures used to 
estimate identified or unidentified impurities are often based on 
analytical assumptions (e.g., equivalent detector response, etc.). 
The assumptions should be discussed in the registration application.

5. Reporting Impurity Content of Batches

    Analytical results should be provided for all batches of the new 
drug substance used for clinical, safety, and stability testing, as 
well as batches representative of the proposed commercial process. 
The content of individual identified and unidentified and total 
impurities, observed in these batches of the new drug substance, 
should be reported with the analytical procedures indicated. A 
tabulation (e.g., spreadsheet) of the data is recommended. 
Impurities should be designated by code number or by an appropriate 
descriptor, e.g., retention time. Levels of impurities which are 
present but below the validated limit of quantitation need not be 
reported. When analytical procedures change during development, 
reported results should be linked with the procedure used, with 
appropriate validation information provided. Representative 
chromatograms should be provided. Chromatograms of such 
representative batches, from methods validation studies showing 
separation and detectability of impurities (e.g., on spiked 
samples), along with any other impurity tests routinely performed, 
can serve as the representative impurity profiles. The applicant 
should ensure that complete impurity profiles (i.e., chromatograms) 
of individual batches are available if requested. A tabulation 
should be provided which links the specific new drug substance batch 
to each safety study and each clinical study in which it has been 
used.
    For each batch of the new drug substance, the report should 
include:
    Batch Identity and Size
    Date of Manufacture
    Site of Manufacture
    Manufacturing Process
    Impurity Content, Individual and Total
    Use of Batches
    Reference to Analytical Procedure Used

6. Specification Limits for Impurities

    The specifications for a new drug substance should include 
limits for impurities. Stability studies, chemical development 
studies, and routine batch analyses can be used to predict those 
impurities likely to occur in the commercial product. The selection 
of impurities to include in the new drug substance specifications 
should be based on the impurities found in batches manufactured by 
the proposed commercial process. Those impurities selected for 
inclusion in the specifications for the new drug substance are 
referred to as ``specified impurities'' in these guidelines. 
Specified impurities may be identified or unidentified and are 
individually listed in the new drug substance specifications.
    A rationale for the inclusion or exclusion of impurities in the 
specifications should be presented. This rationale should include a 
discussion of the impurity profiles observed in the safety and 
clinical development batches together with a consideration of the 
impurity profile of material manufactured by the proposed commercial 
process. Specific identified impurities should be included along 
with recurring unidentified impurities estimated to be at or above 
0.1 percent. For impurities known to be unusually potent or to 
produce toxic or unexpected pharmacological effects, the sensitivity 
of the analytical methods should be commensurate with the level at 
which the impurities are to be controlled. For unidentified 
impurities, the procedure used and assumptions made in establishing 
the level of the impurity should be clearly stated. Unidentified 
impurities included in the specifications should be referred to by 
some appropriate qualitative analytical descriptive label (e.g., 
``unidentified A,'' ``unidentified with relative retention of 0.9,'' 
etc.). Finally, a general specification limit of not more than 0.1 
percent for any unspecified impurity should be included.
    Limits should be set no higher than the level which can be 
justified by safety data, and, unless safety data indicate 
otherwise, no lower than the level achievable by the manufacturing 
process and the analytical capability. In other words, where there 
is no safety concern, impurity specifications are based on data 
generated on actual batches of the new drug substance allowing 
sufficient latitude to deal with normal manufacturing and analytical 
variation, and the stability characteristics of the new drug 
substance. Although normal manufacturing variations are expected, 
significant variation in batch-to-batch impurity levels may indicate 
that the manufacturing process of the new drug substance is not 
adequately controlled and validated.
    In summary, the new drug substance specifications should 
include, where applicable, limits for:
    Each Specified Identified Impurity
    Each Specified Unidentified Impurity at or above 0.1 
percent
    Any Unspecified Impurity, with a limit of not more than 
0.1 percent
    Total Impurities
    Residual Solvents
    Inorganic Impurities
    A summation of assay value and impurity levels can be used to 
obtain mass balance for the test sample. The mass balance need not 
add to exactly 100 percent because of the analytical error 
associated with each analytical procedure. The summation of impurity 
levels plus the assay value may be misleading, e.g., when the assay 
procedure is nonspecific (e.g., potentiometric titrimetry) and the 
impurity level is relatively high.

7. Qualification of Impurities

    Qualification is the process of acquiring and evaluating data 
which establishes the biological safety of an individual impurity or 
a given impurity profile at the level(s) specified. The applicant 
should provide a rationale for selecting impurity limits based on 
safety considerations. The level of any impurity present in a new 
drug substance which has been adequately tested in safety and/or 
clinical studies is considered qualified. Impurities which are also 
significant metabolites present in animal and/or human studies do 
not need further qualification. A level of a qualified impurity 
higher than that present in a new drug substance can also be 
justified based on an analysis of the actual amount of impurity 
administered in previous safety studies.
    If data are not available to qualify the proposed specification 
level of an impurity, studies to obtain such data may be needed when 
the usual qualification threshold limits given below are exceeded:

------------------------------------------------------------------------
         Maximum daily dose                Qualification threshold      
------------------------------------------------------------------------
 2 g/day................  0.1 percent or 1 milligram per day 
                                      intake (whichever is lower).      
> 2 g/day..........................  0.05 percent.                      
------------------------------------------------------------------------

    Higher or lower threshold limits for qualification of impurities 
may be appropriate for some individual drugs based on scientific 
rationale and level of concern, including drug class effects and 
clinical experience. For example, qualification may be especially 
important when there is evidence that such impurities in certain 
drugs or therapeutic classes have previously been associated with 
adverse reactions in patients. In these instances, a lower 
qualification threshold limit may be appropriate. Conversely, a 
higher qualification threshold limit may be appropriate for 
individual drugs when the level of concern for safety is less than 
usual based on similar considerations (patient population, drug 
class effects, clinical considerations, etc.). Technical factors 
(manufacturing capability and control methodology) may be considered 
as part of the justification for selection of alternative threshold 
limits. Proposals for alternative threshold limits are considered on 
a case-by-case basis.
    The ``Decision Tree for Safety Studies'' (Attachment I) 
describes considerations for the qualification of impurities when 
thresholds are exceeded. In some cases, decreasing the level of 
impurity below the threshold may be simpler than providing safety 
data. Alternatively, adequate data may be available in the 
scientific literature to qualify an impurity. If neither is the 
case, additional safety testing should be considered. The studies 
desired to qualify an impurity will depend on a number of factors, 
including the patient population, daily dose, route, and duration of 
drug administration. Such studies are normally conducted on the new 
drug substance containing the impurities to be controlled, although 
studies using isolated impurities are acceptable.

BILLING CODE 4160-01-F

TN22SE94.000

BILLING CODE 4160-01-C

     a If considered desirable, a minimum screen for genotoxic 
potential should be conducted. A study to detect point mutations and 
one to detect chromosomal aberrations, both in vitro, are seen as an 
acceptable minimum screen.
     b If general toxicity studies are desirable, study(ies) 
should be designed to allow comparison of unqualified to qualified 
material. The study duration should be based on available relevant 
information and performed in the species most likely to maximize the 
potential to detect the toxicity of an impurity. In general, a 
minimum duration of 14 days and a maximum duration of 90 days will 
be acceptable.

8. New Impurities

    During the course of a drug development program, the qualitative 
impurity profile of the new drug substance may change, or a new 
impurity may appear as a result of synthetic route changes, process 
optimization, scale-up, etc. New impurities may be identified or 
unidentified. Such changes call for consideration of the need for 
qualification of the level of the impurity unless it is below the 
threshold values as noted above. When a new impurity exceeds the 
threshold, the ``Decision Tree for Safety Studies'' should be 
consulted. Safety studies should compare the new drug substance 
containing a representative level of the new impurity with 
previously qualified material, although studies using the isolated 
impurity are also acceptable (these studies may not always have 
clinical relevance).

9. Glossary

    Chemical Development Studies: Studies conducted to scale-up, 
optimize, and validate the manufacturing process for a new drug 
substance.
    Enantiomers: Compounds with the same molecular formula as the 
drug substance, which differ in the spatial arrangement of atoms 
within the molecule and are nonsuperimposable mirror images.
    Extraneous Substance: An impurity arising from any source 
extraneous to the manufacturing process.
    Herbal Products: Medicinal products containing, exclusively, 
plant material and/or vegetable drug preparations as active 
ingredients.
    Identified Impurity: An impurity for which a structural 
characterization has been achieved.
    Impurity: Any component of the new drug substance which is not 
the chemical entity defined as the new drug substance.
    Impurity Profile: A description of the identified and 
unidentified impurities present in a new drug substance.
    Intermediate: A material produced during steps of the synthesis 
of a new drug substance which must undergo further molecular change 
before it becomes a new drug substance.
    Ligand: An agent with a strong affinity to a metal ion.
    Manufacture: All operations related to the new drug substance, 
including purchase of materials, production, quality control, 
release, storage, and distribution of the new drug substance.
    New Drug Substance: The designated therapeutic moiety which has 
not been previously registered in a region or member state (also 
referred to as a new molecular entity or new chemical entity). It 
may be a complex, simple ester, or salt of a previously approved 
drug substance.
    Polymorphism: The occurrence of different crystalline forms of 
the same drug substance.
    Potential Impurity: An impurity which, from theoretical 
considerations, may arise from or during manufacture. It may or may 
not actually appear in the new drug substance.
    Qualification: The process of acquiring and evaluating data 
which establishes the biological safety of an individual impurity or 
a given impurity profile at the level(s) specified.
    Reagent: A substance, other than a starting material or solvent, 
which is used in the manufacture of a new drug substance.
    Safety Information: The body of information that establishes the 
biological safety of an individual impurity or a given impurity 
profile at the level(s) specified.
    Solvent: An inorganic or an organic liquid used as a vehicle for 
the preparation of solutions or suspensions in the synthesis of a 
new drug substance.
    Specified Impurity: Identified or unidentified impurity that is 
selected for inclusion in the new drug substance specifications and 
is individually listed and limited in order to assure the safety and 
quality of the new drug substance.
    Starting Material: A material used in the synthesis of a new 
drug substance which is incorporated as an element into the 
structure of an intermediate and/or of the new drug substance. 
Starting materials are normally commercially available and of 
defined chemical and physical properties and structure.
    Toxic Impurity: Impurities having significant undesirable 
biological activity.
    Unidentified Impurity: An impurity which is defined solely by 
qualitative analytical properties (e.g., chromatographic retention 
time).
    Validated Limit of Quantitation: For impurities at a level of 
0.1 percent, the validated limit of quantitation should be less than 
or equal to 0.05 percent. Impurities limited at higher levels may 
have higher limits of quantitation.

    Dated: September 15, 1994.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 94-23378 Filed 9-21-94; 8:45 am]
BILLING CODE 4160-01-F