[Federal Register Volume 61, Number 3 (Thursday, January 4, 1996)]
[Notices]
[Pages 372-376]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-64]




[[Page 371]]

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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation, Guidelines Availability: 
Impurities in New Drug Substances; Notice

  Federal Register / Vol. 61, No. 3 / Thursday, January 4, 1996 / 
Notices  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

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


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is publishing a 
guideline entitled ``Impurities in New Drug Substances.'' The guideline 
was prepared under the auspices of the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The guideline 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: Effective January 4, 1996. Submit written comments at any time.

ADDRESSES: Submit written comments on the 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 Consumer Affairs Branch (previously the CDER 
Executive Secretariat Staff) (HFD-210), Center for Drug Evaluation and 
Research, Food and Drug Administration, 7500 Standish Pl., Rockville, 
MD 20855.
FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Robert W. Trimmer, Center for Drug 
Evaluation and Research (HFD-625), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-0370.
    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 the Federal Register of September 22, 1994 (59 FR 48740), FDA 
published a draft tripartite guideline entitled ``Impurities in New 
Drug Substances.'' The notice gave interested persons an opportunity to 
submit comments by December 6, 1994.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Steering Committee and endorsed by the three participating regulatory 
agencies at the ICH meeting held in March 1995.
    The 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 
guideline is not intended to apply to new drug substances used during 
the clinical research stage of development or clinical trials. The 
guideline also does not apply to biological/biotechnological 
substances, peptides, oligonucleotides, 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 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, the 
guideline is not being issued under the authority of 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 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.
    As with all of FDA's guidelines, the public is encouraged to submit 
written comments with new data or other new information pertinent to 
this guideline. The comments in the docket will be periodically 
reviewed, and, where appropriate, the guideline will be amended. The 
public will be notified of any such amendments through a notice in the 
Federal Register.
    Interested persons may, at any time, submit to the Docket 
Management Branch (address above) written comments on the 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 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 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 

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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 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 
defined, 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
     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 may 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 that arise 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 all recurring 
impurities at or above the 0.1 percent level 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 
below the 0.1 percent level, it is useful to also 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 
guide. 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 normally are 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 should be based on pharmacopeial 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. 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 should be 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 uses. The 
drug substance may be used 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 often are 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 are 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
    
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     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 this guideline. 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 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 
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. 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''). 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 that 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 should be 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:
     Organic Impurities:
      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 generally may 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, for example, 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 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 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 grams (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 (e.g., patient population, 
drug class effects, clinical considerations). 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 seen as acceptable.

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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 are 
seen as 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, for example, synthetic route 
changes, process optimization, or scale-up. 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 seen as 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.
    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.
    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 normally are 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: December 21, 1995.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-64 Filed 1-3-96; 8:45 am]
BILLING CODE 4160-01-F