[Federal Register Volume 62, Number 96 (Monday, May 19, 1997)]
[Notices]
[Pages 27454-27461]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-13019]


      

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Part IV





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Guideline on Impurities in 
New Drug Products; Availability; Notice

  Federal Register / Vol. 62, No. 96 / Monday, May 19, 1997 / Notices  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 96D-0009]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a 
guideline entitled ``Impurities in New Drug Products.'' 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 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 guideline is an annex to the ICH 
guideline entitled ``Impurities in New Drug Substances.''

DATES: Effective May 19, 1997. Submit written comments at any time.

ADDRESSES: Submit written comments on the guideline to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline 
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.

FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Albinus M. D'Sa, Center for Drug 
Evaluation and Research (HFD-170), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-3741.
    Regarding 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 March 19, 1996 (61 FR 11268), FDA 
published a draft tripartite guideline entitled ``Impurities in New 
Drug Products.'' The notice gave interested persons an opportunity to 
submit comments by June 17, 1996.
    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 on November 6, 1996.
    In the Federal Register of January 4, 1996 (61 FR 372), the agency 
published a guideline entitled ``Impurities in New Drug Substances.'' 
The guideline provides guidance to applicants for drug marketing 
registration on the content and qualification of impurities in new drug 
substances produced by chemical synthesis and not previously registered 
in a country, region, or member state.
    This guideline is an annex to that guideline and provides guidance 
for registration or marketing applications on the content and 
qualification of impurities in new drug products produced from 
chemically synthesized new drug substances not previously registered in 
a region or member State. The guideline addresses only those impurities 
in drug products classified as degradation products of the active 
ingredient or reaction products of the active ingredient with an 
excipient and/or immediate container/closure system. Impurities arising 
from excipients present in the drug product are not addressed in this 
guideline.
    This guideline 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.
    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 written comments on the 
guideline to the Dockets Management Branch (address above). 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. An electronic version of this guideline is 
available on the Internet using the World Wide Web (WWW) (http://
www.fda.gov/cder/guidance.htm).
    The text of the guideline follows:

Impurities in New Drug Products

1. Introduction

1.1 Objective of the Guideline

    This document provides guidance recommendations for registration 
or marketing applications on the content and qualification of 
impurities in new drug products produced from chemically synthesized 
new drug substances not previously registered or approved for 
marketing in a region or member State.

1.2 Background

    This guideline is an annex to the Guideline on Impurities in New 
Drug Substances, which should be consulted for basic principles.

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1.3 Scope of the Guideline

    This guideline addresses only those impurities in drug products 
classified as degradation products of the active ingredient or 
reaction products of the active ingredient with an excipient and/or 
immediate container/closure system (collectively referred to in this 
guideline as degradation products). Impurities arising from 
excipients present in the drug product are not covered in this 
document. This guideline also does not address the regulation of 
drug products used during the clinical research stages of 
development. Biological/biotechnological products, peptides, 
oligonucleotides, radiopharmaceuticals, fermentation products and 
semisynthetic products derived therefrom, herbal products, and crude 
products of animal or plant origin are not covered. Also excluded 
from this document are: Extraneous contaminants, which should not 
occur in drug products and are more appropriately addressed as good 
manufacturing practice issues, polymorphic form, a solid state 
property of the new drug substance, and enantiomeric impurities. 
Impurities present in the new drug substance need not be monitored 
in drug products unless they are also degradation products.

2. Guidelines

2.1 Analytical Procedures

    The registration or marketing application should include 
documented evidence that the analytical procedures are validated and 
suitable for the detection and quantitation of degradation products. 
Analytical methods should be validated to demonstrate that 
impurities unique to the new drug substance do not interfere with or 
are separated from specified and unspecified degradation products in 
the drug product.
    Degradation product levels can be measured by a variety of 
techniques, including those which compare an analytical response for 
a degradation product to that of an appropriate reference standard 
or to the response of the new drug substance itself. Reference 
standards used in the analytical procedures for control of 
degradation products should be evaluated and characterized according 
to their intended uses. The drug substance may be used to estimate 
the levels of degradation products. In cases where the response 
factors are not close, this practice may still be used if a 
correction factor is applied or the degradation products are, in 
fact, being overestimated. Specifications and analytical procedures 
used to estimate identified or unidentified degradation products are 
often based on analytical assumptions (e.g., equivalent detector 
response). These assumptions should be discussed in the registration 
or marketing application. Differences in the analytical procedures 
used during development and those proposed for the commercial 
product should be discussed.

2.2 Rationale for the Reporting and Control of Impurities

    The applicant should summarize those degradation products 
observed during stability studies of the drug product. This summary 
should be based on sound scientific appraisal of potential 
degradation pathways in the drug product and impurities arising from 
the interaction with excipients and/or the immediate container/
closure system. In addition, the applicant should summarize any 
laboratory studies conducted to detect degradation products in the 
drug product. This summary should include test results of batches 
manufactured during the development process and batches 
representative of the proposed commercial process. A rationale 
should be provided for exclusion of those impurities which are not 
degradation products, e.g., process impurities from the drug 
substance and excipients and their related impurities. The impurity 
profile of the drug product batches representative of the proposed 
commercial process should be compared with the profiles of drug 
product batches used in development and any differences discussed.
    Degradation products observed in stability studies conducted at 
recommended storage conditions should be identified when the 
identification thresholds given in ATTACHMENT I are equaled or 
exceeded (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). When identification of a degradation 
product is not feasible, a summary of the laboratory studies 
demonstrating the unsuccessful effort should be included in the 
registration or marketing application.
    Degradation products below the indicated levels generally would 
not need to be identified. However, identification should be 
attempted for those degradation products that are suspected to be 
unusually potent, producing toxic or significant pharmacologic 
effects at levels lower than indicated.

2.3 Reporting Impurity Content of Batches

    Analytical results should be provided in tabular format for all 
relevant batches of new drug product used for clinical, safety, and 
stability testing, as well as batches which are representative of 
the proposed commercial process. 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 drug product, the reporting level should be set below 
the identification threshold. The recommended target value for the 
reporting threshold (as a percentage of the drug substance) can be 
found in ATTACHMENT 1. 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 Impurities

    The specifications for a new drug product should include limits 
for degradation products expected to occur under recommended storage 
conditions. Stability studies, knowledge of degradation pathways, 
product development studies, and laboratory studies should be used 
to characterize the degradation profile. Specifications should be 
set taking into account the qualification of the degradation 
products, the stability data, the expected expiry period, and the 
recommended storage conditions for the new drug product, allowing 
sufficient latitude to deal with normal manufacturing, analytical, 
and stability profile variation. The specification for the drug 
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.

2.5 Qualification of Impurities

    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, would not need further 
qualification. It may be possible to justify a higher level of a 
degradation product than the level administered in safety studies. 
The justification should include consideration of factors such as: 
(1) The

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amount of degradation product administered in previous safety and/or 
clinical studies and found to be safe; (2) the percentage change in 
the degradation product; and (3) other safety factors as 
appropriate.
    If data are not available to qualify the proposed specification 
level of a degradation product, studies to obtain such data may be 
needed (see ATTACHMENT II) when the usual qualification thresholds 
given in ATTACHMENT I are equaled or exceeded. Higher or lower 
thresholds for qualification of degradation products may be 
appropriate for some individual drug products based on scientific 
rationale and level of concern, including drug class effects and 
clinical experience. For example, qualification may be especially 
important when there is evidence that such degradation products in 
certain drugs or therapeutic classes have previously been associated 
with adverse reactions in patients. In these instances, a lower 
qualification threshold may be appropriate. Conversely, a higher 
qualification threshold may be appropriate for individual drugs when 
the level of concern for safety is less than usual based on similar 
considerations (e.g., patient population, drug class effects, and 
clinical considerations). In unusual circumstances, technical 
factors (e.g., manufacturing capability, a low drug substance to 
excipient ratio, or the use of excipients that are also crude 
products of animal or plant origin) may be considered as part of the 
justification for selection of alternative thresholds. Proposals for 
alternative thresholds would be considered on a case-by-case basis.
    The ``Decision Tree for Safety Studies'' (See Guideline on 
Impurities in New Drug Substances and ATTACHMENT II) describes 
considerations for the qualification of impurities when thresholds 
are equaled or 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, route and 
duration of drug administration. Such studies should normally be 
conducted on the drug product or drug substance containing the 
degradation products to be controlled, although studies using 
isolated degradation products may be considered acceptable.

2.6 New Impurities

    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 consideration of the need for qualification of the level of the 
impurity unless it is below the threshold values as noted in 
ATTACHMENT I.
    When a new degradation product equals or exceeds the threshold 
(for rounding, see section 2.2), the ``Decision Tree for Safety 
Studies'' should be consulted. Safety studies should provide a 
comparison of results of safety testing of the drug product or drug 
substance containing a representative level of the degradation 
product with previously qualified material, although studies using 
the isolated degradation products also may be considered acceptable 
(these studies may not always have clinical significance).

3. Glossary

    Degradation Product: A molecule resulting from a chemical change 
in the drug molecule brought about over time and/or by the action 
of, e.g., light, temperature, pH, or water, or by reaction with an 
excipient and/or the immediate container/closure system (also called 
decomposition product).
    Degradation Profile: A description of the degradation products 
observed in the drug substance or drug product.
    Development Studies: Studies conducted to scale-up, optimize, 
and validate the manufacturing process for a drug product.
    Identified Impurity: An impurity for which a structural 
characterization has been achieved.
    Impurity: Any component of the drug product that is not the 
chemical entity defined as the drug substance or an excipient in the 
drug product.
    Impurity Profile: A description of the identified and 
unidentified impurities present in a drug product.
    New Drug Substance: The designated therapeutic moiety which has 
not been previously registered in a region or member State (also 
referred to as a new molecular entity or new chemical entity). It 
may be a complex, simple ester, or salt of a previously approved 
drug substance.
    Potential Degradation Product: An impurity which, from 
theoretical considerations, may arise during or after manufacture or 
storage of the drug product. It may or may not actually appear in 
the drug substance or drug product.
    Qualification: The process of acquiring and evaluating data that 
establishes the biological safety of an individual impurity or a 
given impurity profile at the level(s) specified.
    Reaction Product: Product arising from the reaction of a drug 
substance with an excipient in the drug product or immediate 
container/closure system.
    Safety Information: The body of information that establishes the 
biological safety of an individual impurity or a given impurity 
profile at the level(s) specified.
    Specified Degradation Product: Identified or unidentified 
degradation product that is selected for inclusion in the new drug 
product specifications and is individually listed and limited in 
order to assure the safety and quality of the new drug product.
    Toxic Impurity: An impurity having significant undesirable 
biological activity.
    Unidentified Degradation Product: An impurity which is defined 
solely by qualitative analytical properties, e.g., chromatographic 
retention time.
    Unspecified Degradation Product: A degradation product which is 
not recurring from batch to batch.

                              Attachment I                              
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  Thresholds for Reporting of Degradation Products in New Drug Products 
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           Maximum daily dose\1\                    Threshold\3\        
------------------------------------------------------------------------
 1 g......................................  0.1%                        
> 1 g.....................................  0.05%                       
------------------------------------------------------------------------



                                                                        
------------------------------------------------------------------------
    Thresholds for Identification of Degradation Products in New Drug   
                                Products                                
-------------------------------------------------------------------------
           Maximum daily dose\1\                    Threshold\3\        
------------------------------------------------------------------------
< 1 mg....................................  1.0% or 5 g TDI\2\ 
                                             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%                        
------------------------------------------------------------------------



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------------------------------------------------------------------------
    Thresholds for Qualification of Degradation Products in New Drug    
                                Products                                
-------------------------------------------------------------------------
           Maximum daily dose\1\                    Threshold\3\        
------------------------------------------------------------------------
< 10 mg...................................  1.0% or 50 g TDI   
                                             whichever is lower         
10 mg - 100 mg............................  0.5% or 200 g TDI  
                                             whichever is lower         
> 100 mg - 2 g............................  0.2% or 2 mg TDI whichever  
                                             is lower                   
> 2 g.....................................  0.1%                        
------------------------------------------------------------------------
\1\ The amount of drug substance administered per day                   
\2\ Total Daily Intake                                                  
\3\ Threshold is based on percent of the drug substance                 

BILLING CODE 4160-01-F

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BILLING CODE 4160-01-C

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    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 seen as an acceptable minimum screen, as discussed in the ICH 
guidelines: ``Genotoxicity: Specific Aspects of Regulatory Tests'' 
and ``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, and when such studies 
are conducted using an isolated impurity. If repeat-dose studies are 
desirable, a maximum duration of 90 days would be acceptable.

    Dated: May 6, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-13019 Filed 5-16-97; 8:45 am]
BILLING CODE 4160-01-F