[Federal Register Volume 61, Number 133 (Wednesday, July 10, 1996)]
[Notices]
[Pages 36466-36469]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-17471]



[[Page 36465]]


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Part VI





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



International Conference on Harmonisation; Final Guidelines on 
Stability Testing of Biotechnological/Biological Products; 
Availability; Notice

  Federal Register / Vol. 61, No. 133 / Wednesday, July 10, 1996 / 
Notices  

[[Page 36466]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 93D-0139]


International Conference on Harmonisation; Final Guideline on 
Stability Testing of Biotechnological/Biological Products; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA) is publishing a final 
guideline entitled ``Quality of Biotechnological Products: Stability 
Testing of Biotechnological/Biological 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 is intended to 
provide guidance to applicants regarding the type of stability studies 
that should be provided in support of marketing applications for 
biotechnological/biological products.

DATES: Effective July 10, 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, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the 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: -Nga Y. Nguyen, Center for Biologics 
Evaluation and Research (HFM-18), Food and Drug Administration, 1401 
Rockville Pike, -Rockville, MD 20852, 301-402-4996.
    Regarding ICH: -Janet Jenkins-Showalter, Office of Health Affairs 
(HFY-1), -Food and Drug Administration, 5600 Fishers Lane, Rockville, 
MD 20857, 301-827-0865.

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 August 21, 1995 (60 FR 43501), FDA 
published a draft tripartite guideline entitled ``Quality of 
Biotechnological Products: Stability Testing of Biotechnological/
Biological Products.'' The notice gave interested persons an 
opportunity to submit comments by October 5, 1995.
    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 29, 1995.
    The guideline is intended to supplement the tripartite ICH 
guideline entitled ``Stability Testing of New Drug Substances and 
Products'' published in the Federal Register of September 22, 1994 (59 
FR 48754). Biotechnological/biological products have distinguishing 
characteristics to which consideration should be given in any well-
defined testing program designed to confirm their stability during the 
intended storage period. For such products, in which the active 
components are typically proteins and/or polypeptides, maintenance of 
molecular conformation and biological activity is dependent on 
noncovalent as well as covalent forces. The products are particularly 
sensitive to environmental factors such as temperature changes, 
oxidation, light, ionic content, shear, and so forth. In order to 
ensure maintenance of biological activity and to avoid degradation, 
stringent conditions for their storage are usually necessary. This 
guideline is intended to assist the applicant in developing appropriate 
supporting stability data for a biotechnological/biological product.
    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 for or on any person, 
and does not operate to bind FDA, it does represent the agency's 
current thinking on stability testing of biotechnological/biological 
products.
    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 review, 
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 
final 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.
    The text of the guideline follows:

Quality of Biotechnological Products: Stability Testing of 
Biotechnological/Biological Products

1. Preamble

    The guidance stated in the ICH harmonized tripartite guideline 
entitled ``Stability Testing of New Drug Substances and Products'' 
(issued by ICH on October 27, 1993) applies in general to 
biotechnological/biological products. However, biotechnological/

[[Page 36467]]

biological products have distinguishing characteristics to which 
consideration should be given in any well-defined testing program 
designed to confirm their stability during the intended storage 
period. For such products in which the active components are 
typically proteins and/or polypeptides, maintenance of molecular 
conformation and, hence, of biological activity, is dependent on 
noncovalent as well as covalent forces. The products are 
particularly sensitive to environmental factors such as temperature 
changes, oxidation, light, ionic content, and shear. To ensure 
maintenance of biological activity and to avoid degradation, 
stringent conditions for their storage are usually necessary.
    The evaluation of stability may necessitate complex analytical 
methodologies. Assays for biological activity, where applicable, 
should be part of the pivotal stability studies. Appropriate 
physicochemical, biochemical, and immunochemical methods for the 
analysis of the molecular entity and the quantitative detection of 
degradation products should also be part of the stability program 
whenever purity and molecular characteristics of the product permit 
use of these methodologies.
    With these concerns in mind, the applicant should develop the 
proper supporting stability data for a biotechnological/biological 
product and consider many external conditions that can affect the 
product's potency, purity, and quality. Primary data to support a 
requested storage period for either drug substance or drug product 
should be based on long-term, real-time, real-condition stability 
studies. Thus, the development of a proper long-term stability 
program becomes critical to the successful development of a 
commercial product. The purpose of this document is to give guidance 
to applicants regarding the type of stability studies that should be 
provided in support of marketing applications. It is understood that 
during the review and evaluation process, continuing updates of 
initial stability data may occur.

2. Scope of the Annex

    The guidance stated in this annex to ``Stability Testing of New 
Drug Substances and Products'' applies to well-characterized 
proteins and polypeptides, their derivatives and products of which 
they are components, and which are isolated from tissues, body 
fluids, cell cultures, or produced using recombinant 
deoxyribonucleic acid (r-DNA) technology. Thus, the document covers 
the generation and submission of stability data for products such as 
cytokines (interferons, interleukins, colony-stimulating factors, 
tumor necrosis factors), erythropoietins, plasminogen activators, 
blood plasma factors, growth hormones and growth factors, insulins, 
monoclonal antibodies, and vaccines consisting of well-characterized 
proteins or polypeptides. In addition, the guidance outlined in the 
following sections may apply to other types of products, such as 
conventional vaccines, after consultation with the appropriate 
regulatory authorities. The document does not cover antibiotics, 
allergenic extracts, heparins, vitamins, whole blood, or cellular 
blood components.

3. Terminology

    For the basic terms used in this annex, the reader is referred 
to the ``Glossary'' in ``Stability Testing of New Drug Substances 
and Products.'' However, because manufacturers of biotechnological/
biological products sometimes use traditional terminology, 
traditional terms are specified in parentheses to assist the reader. 
A supplemental glossary is also included that explains certain terms 
used in the production of biotechnological/biological products.

4. Selection of Batches

3.1 Drug Substance (Bulk Material)

    Where bulk material is to be stored after manufacture, but 
before formulation and final manufacturing, stability data should be 
provided on at least three batches for which manufacture and storage 
are representative of the manufacturing scale of production. A 
minimum of 6 months stability data at the time of submission should 
be submitted in cases where storage periods greater than 6 months 
are requested. For drug substances with storage periods of less than 
6 months, the minimum amount of stability data in the initial 
submission should be determined on a case-by-case basis. Data from 
pilot-plant scale batches of drug substance produced at a reduced 
scale of fermentation and purification may be provided at the time 
the dossier is submitted to the regulatory agencies with a 
commitment to place the first three manufacturing scale batches into 
the long-term stability program after approval.
    The quality of the batches of drug substance placed into the 
stability program should be representative of the quality of the 
material used in preclinical and clinical studies and of the quality 
of the material to be made at manufacturing scale. In addition, the 
drug substance (bulk material) made at pilot-plant scale should be 
produced by a process and stored under conditions representative of 
that used for the manufacturing scale. The drug substance entered 
into the stability program should be stored in containers that 
properly represent the actual holding containers used during 
manufacture. Containers of reduced size may be acceptable for drug 
substance stability testing provided that they are constructed of 
the same material and use the same type of container/closure system 
that is intended to be used during manufacture.

3.2 Intermediates

    During manufacture of biotechnological/biological products, the 
quality and control of certain intermediates may be critical to the 
production of the final product. In general, the manufacturer should 
identify intermediates and generate in-house data and process limits 
that assure their stability within the bounds of the developed 
process. Although the use of pilot-plant scale data is permissible, 
the manufacturer should establish the suitability of such data using 
the manufacturing scale process.

3.3 Drug Product (Final Container Product)

    Stability information should be provided on at least three 
batches of final container product representative of that which will 
be used at manufacturing scale. Where possible, batches of final 
container product included in stability testing should be derived 
from different batches of bulk material. A minimum of 6 months data 
at the time of submission should be submitted in cases where storage 
periods greater than 6 months are requested. For drug products with 
storage periods of less than 6 months, the minimum amount of 
stability data in the initial submission should be determined on a 
case-by-case basis. Product expiration dating should be based upon 
the actual data submitted in support of the application. Because 
dating is based upon the real-time/real-temperature data submitted 
for review, continuing updates of initial stability data should 
occur during the review and evaluation process. The quality of the 
final container product placed on stability studies should be 
representative of the quality of the material used in the 
preclinical and clinical studies. Data from pilot-plant scale 
batches of drug product may be provided at the time the dossier is 
submitted to the regulatory agencies with a commitment to place the 
first three manufacturing scale batches into the long-term stability 
program after approval. Where pilot-plant scale batches were 
submitted to establish the dating for a product and, in the event 
that the product produced at manufacturing scale does not meet those 
long-term stability specifications throughout the dating period or 
is not representative of the material used in preclinical and 
clinical studies, the applicant should notify the appropriate 
regulatory authorities to determine a suitable course of action.

4.4 Sample Selection

    Where one product is distributed in batches differing in fill 
volume (e.g., 1 milliliter (mL), 2 mL, or 10 mL), unitage (e.g., 10 
units, 20 units, or 50 units), or mass (e.g., 1 milligram (mg), 2 
mg, or 5 mg), samples to be entered into the stability program may 
be selected on the basis of a matrix system and/or by bracketing.
    Matrixing, i.e., the statistical design of a stability study in 
which different fractions of samples are tested at different 
sampling points, should only be applied when appropriate 
documentation is provided that confirms that the stability of the 
samples tested represents the stability of all samples. The 
differences in the samples for the same drug product should be 
identified as, for example, covering different batches, different 
strengths, different sizes of the same closure, and, possibly, in 
some cases, different container/closure systems. Matrixing should 
not be applied to samples with differences that may affect 
stability, such as different strengths and different containers/
closures, where it cannot be confirmed that the products respond 
similarly under storage conditions.
    Where the same strength and exact container/closure system is 
used for three or more fill contents, the manufacturer may elect to 
place only the smallest and largest container size into the 
stability program, i.e., bracketing. The design of a protocol that 
incorporates bracketing assumes that the stability of the 
intermediate condition samples are represented by those at the

[[Page 36468]]

extremes. In certain cases, data may be needed to demonstrate that 
all samples are properly represented by data collected for the 
extremes.

5. Stability-Indicating Profile

    On the whole, there is no single stability-indicating assay or 
parameter that profiles the stability characteristics of a 
biotechnological/biological product. Consequently, the manufacturer 
should propose a stability-indicating profile that provides 
assurance that changes in the identity, purity, and potency of the 
product will be detected.
    At the time of submission, applicants should have validated the 
methods that comprise the stability-indicating profile, and the data 
should be available for review. The determination of which tests 
should be included will be product-specific. The items emphasized in 
the following subsections are not intended to be all-inclusive, but 
represent product characteristics that should typically be 
documented to demonstrate product stability adequately.

5.1 Protocol

    The dossier accompanying the application for marketing 
authorization should include a detailed protocol for the assessment 
of the stability of both drug substance and drug product in support 
of the proposed storage conditions and expiration dating periods. 
The protocol should include all necessary information that 
demonstrates the stability of the biotechnological/biological 
product throughout the proposed expiration dating period including, 
for example, well-defined specifications and test intervals. The 
statistical methods that should be used are described in the 
tripartite guideline on stability.

5.2 Potency

    When the intended use of a product is linked to a definable and 
measurable biological activity, testing for potency should be part 
of the stability studies. For the purpose of stability testing of 
the products described in this guideline, potency is the specific 
ability or capacity of a product to achieve its intended effect. It 
is based on the measurement of some attribute of the product and is 
determined by a suitable in vivo or in vitro quantitative method. In 
general, potencies of biotechnological/biological products tested by 
different laboratories can be compared in a meaningful way only if 
expressed in relation to that of an appropriate reference material. 
For that purpose, a reference material calibrated directly or 
indirectly against the corresponding national or international 
reference material should be included in the assay.
    Potency studies should be performed at appropriate intervals as 
defined in the stability protocol and the results should be reported 
in units of biological activity calibrated, whenever possible, 
against nationally or internationally recognized standards. Where no 
national or international reference standards exist, the assay 
results may be reported in in-house derived units using a 
characterized reference material.
    In some biotechnological/biological products, potency is 
dependent upon the conjugation of the active ingredient(s) to a 
second moiety or binding to an adjuvant. Dissociation of the active 
ingredient(s) from the carrier used in conjugates or adjuvants 
should be examined in real-time/real-temperature studies (including 
conditions encountered during shipment). The assessment of the 
stability of such products may be difficult because, in some cases, 
in vitro tests for biological activity and physicochemical 
characterization are impractical or provide inaccurate results. 
Appropriate strategies (e.g., testing the product before 
conjugation/binding, assessing the release of the active compound 
from the second moiety, in vivo assays) or the use of an appropriate 
surrogate test should be considered to overcome the inadequacies of 
in vitro testing.

5.3 Purity and Molecular Characterization

    For the purpose of stability testing of the products described 
in this guideline, purity is a relative term. Because of the effect 
of glycosylation, deamidation, or other heterogeneities, the 
absolute purity of a biotechnological/biological product is 
extremely difficult to determine. Thus, the purity of a 
biotechnological/biological product should be typically assessed by 
more than one method and the purity value derived is method-
dependent. For the purpose of stability testing, tests for purity 
should focus on methods for determination of degradation products.
    The degree of purity, as well as the individual and total 
amounts of degradation products of the biotechnological/biological 
product entered into the stability studies, should be reported and 
documented whenever possible. Limits of acceptable degradation 
should be derived from the analytical profiles of batches of the 
drug substance and drug product used in the preclinical and clinical 
studies.
    The use of relevant physicochemical, biochemical, and 
immunochemical analytical methodologies should permit a 
comprehensive characterization of the drug substance and/or drug 
product (e.g., molecular size, charge, hydrophobicity) and the 
accurate detection of degradation changes that may result from 
deamidation, oxidation, sulfoxidation, aggregation, or fragmentation 
during storage. As examples, methods that may contribute to this 
include electrophoresis (SDS-PAGE, immunoelectrophoresis, Western 
blot, isoelectrofocusing), high-resolution chromatography (e.g., 
reversed-phase chromatography, gel filtration, ion exchange, 
affinity chromatography), and peptide mapping.
    Wherever significant qualitative or quantitative changes 
indicative of degradation product formation are detected during 
long-term, accelerated, and/or stress stability studies, 
consideration should be given to potential hazards and to the need 
for characterization and quantification of degradation products 
within the long-term stability program. Acceptable limits should be 
proposed and justified, taking into account the levels observed in 
material used in preclinical and clinical studies.
    For substances that cannot be properly characterized or products 
for which an exact analysis of the purity cannot be determined 
through routine analytical methods, the applicant should propose and 
justify alternative testing procedures.

5.4 Other Product Characteristics

    The following product characteristics, though not specifically 
relating to biotechnological/biological products, should be 
monitored and reported for the drug product in its final container:
    Visual appearance of the product (color and opacity for 
solutions/suspensions; color, texture, and dissolution time for 
powders), visible particulates in solutions or after the 
reconstitution of powders or lyophilized cakes, pH, and moisture 
level of powders and lyophilized products.
    Sterility testing or alternatives (e.g., container/closure 
integrity testing) should be performed at a minimum initially and at 
the end of the proposed shelf life.
    Additives (e.g., stabilizers, preservatives) or excipients may 
degrade during the dating period of the drug product. If there is 
any indication during preliminary stability studies that reaction or 
degradation of such materials adversely affect the quality of the 
drug product, these items may need to be monitored during the 
stability program.
    The container/closure has the potential to affect the product 
adversely and should be carefully evaluated (see below).

6. Storage Conditions

6.1 Temperature

    Because most finished biotechnological/biological products need 
precisely defined storage temperatures, the storage conditions for 
the real-time/real-temperature stability studies may be confined to 
the proposed storage temperature.

6.2 Humidity

    Biotechnological/biological products are generally distributed 
in containers protecting them against humidity. Therefore, where it 
can be demonstrated that the proposed containers (and conditions of 
storage) afford sufficient protection against high and low humidity, 
stability tests at different relative humidities can usually be 
omitted. Where humidity-protecting containers are not used, 
appropriate stability data should be provided.

6.3 Accelerated and Stress Conditions

    As previously noted, the expiration dating should be based on 
real-time/real-temperature data. However, it is strongly suggested 
that studies be conducted on the drug substance and drug product 
under accelerated and stress conditions. Studies under accelerated 
conditions may provide useful support data for establishing the 
expiration date, provide product stability information or future 
product development (e.g., preliminary assessment of proposed 
manufacturing changes such as change in formulation, scale-up), 
assist in validation of analytical methods for the stability 
program, or generate information that may help elucidate the 
degradation profile of the drug substance or drug product. Studies 
under stress conditions may be useful in determining whether 
accidental exposures to

[[Page 36469]]

conditions other than those proposed (e.g., during transportation) 
are deleterious to the product and also for evaluating which 
specific test parameters may be the best indicators of product 
stability. Studies of the exposure of the drug substance or drug 
product to extreme conditions may help to reveal patterns of 
degradation; if so, such changes should be monitored under proposed 
storage conditions. Although the tripartite guideline on stability 
describes the conditions of the accelerated and stress study, the 
applicant should note that those conditions may not be appropriate 
for biotechnological/biological products. Conditions should be 
carefully selected on a case-by-case basis.

6.4 Light

    Applicants should consult the appropriate regulatory authorities 
on a case-by-case basis to determine guidance for testing.

6.5 Container/Closure

    Changes in the quality of the product may occur due to the 
interactions between the formulated biotechnological/biological 
product and container/closure. Where the lack of interactions cannot 
be excluded in liquid products (other than sealed ampules), 
stability studies should include samples maintained in the inverted 
or horizontal position (i.e., in contact with the closure), as well 
as in the upright position, to determine the effects of the closure 
on product quality. Data should be supplied for all different 
container/closure combinations that will be marketed.
    In addition to the standard data necessary for a conventional 
single-use vial, the applicant should demonstrate that the closure 
used with a multiple-dose vial is capable of withstanding the 
conditions of repeated insertions and withdrawals so that the 
product retains its full potency, purity, and quality for the 
maximum period specified in the instructions-for-use on containers, 
packages, and/or package inserts. Such labeling should be in 
accordance with relevant national/regional requirements.

6.6 Stability after Reconstitution of Freeze-Dried Product

    The stability of freeze-dried products after their 
reconstitution should be demonstrated for the conditions and the 
maximum storage period specified on containers, packages, and/or 
package inserts. Such labeling should be in accordance with relevant 
national/regional requirements.

7. Testing Frequency

    The shelf lives of biotechnological/biological products may vary 
from days to several years. Thus, it is difficult to draft uniform 
guidelines regarding the stability study duration and testing 
frequency that would be applicable to all types of biotechnological/
biological products. With only a few exceptions, however, the shelf 
lives for existing products and potential future products will be 
within the range of 0.5 to 5 years. Therefore, the guidance is based 
upon expected shelf lives in that range. This takes into account the 
fact that degradation of biotechnological/biological products may 
not be governed by the same factors during different intervals of a 
long storage period.
    When shelf lives of 1 year or less are proposed, the real-time 
stability studies should be conducted monthly for the first 3 months 
and at 3 month intervals thereafter.
    For products with proposed shelf lives of greater than 1 year, 
the studies should be conducted every 3 months during the first year 
of storage, every 6 months during the second year, and annually 
thereafter.
    While the testing intervals listed above may be appropriate in 
the preapproval or prelicense stage, reduced testing may be 
appropriate after approval or licensure where data are available 
that demonstrate adequate stability. Where data exist that indicate 
the stability of a product is not compromised, the applicant is 
encouraged to submit a protocol that supports elimination of 
specific test intervals (e.g., 9-month testing) for postapproval/
postlicensure, long-term studies.

8. Specifications

    Although biotechnological/biological products may be subject to 
significant losses of activity, physicochemical changes, or 
degradation during storage, international and national regulations 
have provided little guidance with respect to distinct release and 
end of shelf life specifications. Recommendations for maximum 
acceptable losses of activity, limits for physicochemical changes, 
or degradation during the proposed shelf life have not been 
developed for individual types or groups of biotechnological/
biological products but are considered on a case-by-case basis. Each 
product should retain its specifications within established limits 
for safety, purity, and potency throughout its proposed shelf life. 
These specifications and limits should be derived from all available 
information using the appropriate statistical methods. The use of 
different specifications for release and expiration should be 
supported by sufficient data to demonstrate that the clinical 
performance is not affected, as discussed in the tripartite 
guideline on stability.

9. Labeling

    For most biotechnological/biological drug substances and drug 
products, precisely defined storage temperatures are recommended. 
Specific recommendations should be stated, particularly for drug 
substances and drug products that cannot tolerate freezing. These 
conditions, and where appropriate, recommendations for protection 
against light and/or humidity, should appear on containers, 
packages, and/or package inserts. Such labeling should be in 
accordance with relevant national and regional requirements.

10. Glossary

Conjugated Product

    A conjugated product is made up of an active ingredient (e.g., 
peptide, carbohydrate) bound covalently or noncovalently to a 
carrier (e.g., protein, peptide, inorganic mineral) with the 
objective of improving the efficacy or stability of the product.

Degradation Product

    A molecule resulting from a change in the drug substance (bulk 
material) brought about over time. For the purpose of stability 
testing of the products described in this guideline, such changes 
could occur as a result of processing or storage (e.g., by 
deamidation, oxidation, aggregation, proteolysis). For 
biotechnological/biological products, some degradation products may 
be active.

Impurity

    Any component of the drug substance (bulk material) or drug 
product (final container product) that is not the chemical entity 
defined as the drug substance, an excipient, or other additives to 
the drug product.

Intermediate

    For biotechnological/biological products, a material produced 
during a manufacturing process that is not the drug substance or the 
drug product but for which manufacture is critical to the successful 
production of the drug substance or the drug product. Generally, an 
intermediate will be quantifiable and specifications will be 
established to determine the successful completion of the 
manufacturing step before continuation of the manufacturing process. 
This includes material that may undergo further molecular 
modification or be held for an extended period before further 
processing.

Manufacturing Scale Production

    Manufacture at the scale typically encountered in a facility 
intended for product production for marketing.

Pilot-Plant Scale

    The production of the drug substance or drug product by a 
procedure fully representative of and simulating that to be applied 
at manufacturing scale. The methods of cell expansion, harvest, and 
product purification should be identical except for the scale of 
production.

    Dated: July 1, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-17471 Filed 7-9-96; 8:45 am]
BILLING CODE 4160-01-F