[Federal Register Volume 61, Number 54 (Tuesday, March 19, 1996)]
[Notices]
[Pages 11268-11272]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-6580]



      

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Part IV





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 Products; Availability; Notice

  Federal Register / Vol. 61, No. 54 / Tuesday, March 19, 1996 / 
Notices  
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

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


International Conference on Harmonisation; Draft 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 draft 
guideline entitled ``Impurities in New Drug Products.'' The draft 
guideline was prepared under the auspices of the International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). The draft 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 draft guideline is an annex to the ICH 
guideline entitled ``Impurities in New Drug Substances.''

DATES: Written comments by June 17, 1996.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft 
guideline are available from the Division of Communications Management 
(HFD-210), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1012. 
An electronic version of this guideline is also available via Internet 
by connecting to the CDER file transfer protocol (FTP) server 
(CDVS2.CDER.FDA.GOV).

FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Allen Rudman, Center for Drug Evaluation 
and Research (HFD-645), Food and Drug Administration, 7500 Standish 
Pl., Rockville, MD 20855, 301-594-0375.
    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.
    At a meeting held on November 29, 1995, the ICH Steering Committee 
agreed that a draft guideline entitled ``Impurities in New Drug 
Products'' should be made available for public comment. The draft 
guideline 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. Ultimately, FDA intends to adopt the ICH 
Steering Committee's guideline.
    -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 draft 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 draft 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 
draft guideline.
    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 are acceptable to FDA. The agency 
is now in the process of revising 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 impurities in new drug products.
    Interested persons may, on or before June 17, 1996, submit to the 
Dockets Management Branch (address above) 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 Products

1. Introduction

1.1 -Objective of the Guideline

    -This document 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 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.

 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

[[Page 11269]]
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 exceeded. 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 need 
not 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. Levels of degradation products 
greater than or equal to more than one half the identification 
threshold should be reported. 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 from representative batches should be 
provided showing 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 define 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. 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 development 
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 establish the biological safety of an individual degradation 
product or a given degradation profile at the level(s) specified. 
The applicant should provide a rationale for selecting degradation 
product limits based on safety considerations. The level of any 
degradation product present in a new drug product that has been 
adequately tested and found safe in safety and/or clinical studies 
is considered qualified. Therefore, it is useful to include any 
available information on the actual content of degradation products 
in the relevant batches at the time of use in safety and/or clinical 
studies. Degradation products that are also significant metabolites, 
present in animal and/or human studies, do not need further 
qualification. It may be possible to justify a higher level of a 
degradation product than the level administered in safety studies. 
The justification should include consideration of factors such as: 
(1) The amount of degradation product administered in previous 
safety 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 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

[[Page 11270]]
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 will 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 exceeded. Alternatively, adequate data may be available in the 
scientific literature 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 are acceptable.

2.6 New Impurities

    -During the course of a drug development program the qualitative 
degradation profile of a new drug product may change resulting in 
new degradation products which exceed the identification and/or 
qualification threshold and, 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 exceeds the threshold, the 
``Decision Tree for Safety Studies'' should be consulted. Safety 
studies should provide a comparison of results of safety testing of 
the drug product or drug substance containing a representative level 
of the degradation product with previously qualified material, 
although studies using the isolated degradation products are also 
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 substance or 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 establish 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 Products: A degradation product which 
is not recurring and is not defined by qualitative analytical 
properties. -

                              ATTACHMENT I                              
------------------------------------------------------------------------
    THRESHOLDS FOR IDENTIFICATION OF DEGRADATION PRODUCTS IN NEW DRUG   
                                PRODUCTS                                
-------------------------------------------------------------------------
           Maximum daily dose1--                      Threshold         
------------------------------------------------------------------------
< 1 mg--..................................  1.0% or 5 g TDI2   
                                             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%                        
------------------------------------------------------------------------
\1\ The amount of drug substance administered per day.                  
\2\ Total Daily Intake.                                                 


                                                                        
------------------------------------------------------------------------
    THRESHOLDS FOR QUALIFICATION OF DEGRADATION PRODUCTS IN NEW DRUG    
                                PRODUCTS                                
-------------------------------------------------------------------------
           Maximum daily dose--                       Threshold         
------------------------------------------------------------------------
<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%                        
------------------------------------------------------------------------

BILLING CODE 4160-01-F

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[GRAPHIC] [TIFF OMITTED] TN19MR96.000


BILLING CODE 4160-01-C

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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 will 
be acceptable.

    Dated: March 7, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-6580 Filed 3-18-96; 8:45 am]
BILLING CODE 4160-01-F