[Federal Register Volume 60, Number 161 (Monday, August 21, 1995)]
[Notices]
[Pages 43501-43505]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20608]
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[Docket No. 93D-0139]
International Conference on Harmonisation; Draft Guideline on
Stability Testing of Biotechnological/Biological 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 ``Quality of Biotechnological Products: Stability
Testing of Biotechnological/Biological Products.'' This 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 is intended to
give guidance to applicants regarding the type of stability studies
that should be provided in support of marketing applications for
biotechnological/biological products.
DATES: Written comments by October 5, 1995.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857. Copies of the draft
guideline are available from the CDER Executive Secretariat Staff (HFD-
8), Center for Drug Evaluation and Research, Food and Drug
Administration, 7500 Standish Pl., Rockville, MD 20855, as well as the
CBER Congressional and Consumer Affairs Branch (HFM-12), Center for
Biologics Evaluation and Research,
[[Page 43502]]
Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Kenneth Seamon, Center for Biologics
Evaluation and Research (HFM-20), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852, 301-827-0375.
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 March 29, 1995, the ICH Steering Committee
agreed that a draft guideline entitled ``Quality of Biotechnological
Products: Stability Testing of Biotechnological/Biological 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 Expert Working Group.
Ultimately, FDA intends to adopt the ICH Steering Committee's final
guideline.
This draft 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, etc. In order to ensure
maintenance of biological activity and to avoid degradation, stringent
conditions for their storage are usually necessary. This draft
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). Therefore, this
guideline is not being issued under the authority of Sec. 10.90(b), and
it does not create or confer any rights, privileges, or benefits for or
on any person, nor does it operate to bind FDA in any way.
Interested persons may, on or before October 5, 1995, submit
written comments on the draft 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 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:
Quality of Biotechnological Products: Stability Testing of
Biotechnological/Biological Products (Q5C)
ICH Expert Working Group on Quality of Biotechnology Products
Annex to the Tripartite ICH Guideline for the Stability Testing of New
Drug Substances and Products
Introduction
The principles established in the ICH harmonized tripartite
guideline ``Stability Testing of New Drug Substances and Products''
(27 October 1993) apply in general to biotechnological/biological
products. However, biotechnological/biological products do 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, shear, etc. In order 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, are
an essential 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 the above concerns in mind, the applicant should develop
the proper supporting stability data for a biotechnological/
biological product and consider many external conditions which 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.
Scope of the Annex
The principles adopted and explained in this annex apply 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 rDNA
technology. Thus, the document covers the
[[Page 43503]]
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 principles 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, or whole blood.
Terminology
For the basic terms used in this annex the reader is referred
to the ``Glossary'' in the ICH harmonized tripartite guideline
``Stability Testing of New Drug Substances and Products'' (27
October 1993). However, since traditional terminology used by
manufacturers of biotechnological/biological products does not
always conform to that of the tripartite guideline mentioned above,
traditional terms are specified in brackets to assist the reader. A
supplemental glossary is also included that defines certain of the
traditional terms used in the biologics field.
Selection of Batches
Drug Substance (Bulk Material)
Where bulk material is to be stored after manufacture but prior
to 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 will be determined on a case-by-case basis. Data from
pilot-plant-scale batches of a well-characterized drug substance
(bulk material) 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
full-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 which
properly represent the actual holding containers used during
manufacture. Scaled-down containers may be acceptable for drug
substance stability monitoring assuming that they are constructed of
the same material and make use of the same type of container/closure
system that is routinely used during the manufacture.
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. While the use of pilot-plant-scale data is permissible, the
manufacturer should establish the suitability of such data using the
manufacturing-scale process.
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 will be reviewed on a case-
by-case basis. Product expiration dating will be based upon the
actual data submitted in support of the application. Since dating is
based upon the real-time/real-temperature data submitted for review,
it is expected that continuing updates of initial stability data
will occur during the review and evaluation process. Where pilot-
scale batches were submitted to establish the dating for a product
and, in the event that 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 sponsor/applicant should
notify the appropriate regulatory authorities to determine a
suitable course of action.
Sample Selection Criteria
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 applicant 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
extremes. In certain cases, it may be necessary to provide data that
demonstrate that all samples are properly represented by data
collected for the extremes.
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.
It is also expected that, at the time of submission, applicant/
firms have validated the methods that comprise the stability-
indicating profile and that the data are 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.
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 claimed storage conditions and expiration dating periods. The
protocol should include all necessary information, including well-
defined specifications, test intervals, etc., which taken as a
whole, demonstrates the stability of the biotechnological/biological
product throughout the claimed expiration dating period. The
statistical methods to be used are described in the tripartite
guideline. It is assumed that the manufacturer of the product will
strictly adhere to this protocol.
Potency
Wherever 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. 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 agreement
has been reached on units of potency, the assay results may be
reported in in-house derived units using an appropriately
characterized reference preparation.
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
[[Page 43504]]
should be examined in real-time/real-temperature studies (including
conditions encountered during shipment). The assessment of the
stability of such products may be associated with difficulties
since, in some cases, in vitro tests for biological activity and
physicochemical characterisation are impractical or provide
inaccurate results. Appropriate strategies (e.g., testing the
product prior to conjugation/binding, release of the active compound
from the second moiety, in vivo assays, etc.) or the use of an
appropriate surrogate test should be considered to overcome the
inadequacies of in vitro testing.
Purity and Molecular Characterization
The degree of purity, as well as individual and total upper
limits for 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.
For physicochemically well-defined drug substances and/or drug
products, the use of relevant physicochemical, biochemical, and
immunochemical analytical methodologies should permit a
comprehensive characterisation of the active ingredient (e.g.,
molecular size, charge, hydrophobicity, etc.) 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 (reversed-phase
chromatography, gel filtration, ion exchange, affinity
chromatography, etc.), 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 level cannot be
meaningfully determined through routine analytical methods, the
applicant should propose and justify alternative testing procedures.
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 (colour and opacity for
solutions/suspensions; colour, 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 (stabilizers, preservatives, etc.) 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 adversely affect the
product and should be carefully evaluated. Closure configurations,
vial liners seal-types should also be considered (see below).
Storage Conditions
Temperature
Since 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 recommended storage temperature.
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.
Accelerated and Stress Conditions
As previously noted, the expiration dating generally is based
upon the 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 for future product development (e.g., preliminary
assessment of proposed manufacturing changes such as change in
formulation, scale-up, etc.), assist in validation of analytical
methods for the stability program, or generate information which 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 conditions other than
those recommended (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 recommended storage conditions. While the
tripartite guideline 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.
Light
Applicants should consult the appropriate regulatory
authorities on a case-by-case basis to determine guidance for
testing.
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.
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.
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 recommendations
that follow are based upon expected shelf-lives in that range, and
take account of the fact that, frequently, degradation of
biotechnological/biological products is not 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 generally 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.
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While the testing intervals listed above are 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.
Specifications
Although biotechnological/biological products may be subject to
significant losses of activity and to physicochemical 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 or limits for physicochemical changes (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 clinical
performance is not affected. The proposals should be in accordance
with the principles outlined in the appropriate section of the
tripartite guideline.
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/regional requirements.
Glossary
Conjugated Product
A conjugated product is made up of an active ingredient
(peptide, carbohydrate, etc.) bound covalently or noncovalently to a
carrier (protein, peptide, inorganic mineral, etc.) with the
objective of improving the efficacy or stability of the product.
Degradation Product
Any material resulting from modification of the active
ingredients, additives, and/or excipients present in a drug
substance or drug product which occurs due to processing or storage
(e.g., by deamidation, oxidation, aggregation, proteolysis, etc.).
Degradation products are considered impurities, although some
degradation products may be active.
Impurity
Any process-generated substance present in raw materials, drug
substance, or drug product that is not considered to be active
ingredient, additives, or excipients.
Intermediate
A material produced during a manufacturing process that is not
the drug substance or the drug product but whose 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 prior to continuation of the
manufacturing process. This includes material that may undergo
further molecular modification or be held for an extended period of
time prior to further processing.
Manufacturing-Scale Production
Manufacture at the scale typically encountered in a facility at
the largest capacity 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.
Potency
Expression of the predicted capacity of a product to achieve
its intended role; it is based on the measurement of some attribute
of the product and is determined by a suitable quantitative
laboratory 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 is included in the
assay. The reference material should have some known relationship
with the product, the therapeutic, preventive, or diagnostic
capacity of which has been studied in humans.
Purity
Purity is a relative term with respect to biotechnological/
biological products. The purity may be expressed as the amount
(weight/weight) of the desired protein of a homogeneous amino acid
sequence usually expressed on a percentage basis. However, due to
the effects of glycosylation, deamidation, etc., the absolute purity
of a biotechnological/biological product is extremely difficult to
determine. Therefore, the purity of biotechnological/biological
products may be evaluated by determining the amounts of known
impurities, such as host cell proteins, DNA, other impurities, and/
or degradation products. Thus, the purity of a biotechnological/
biological product is typically assessed by more than one method and
the purity value derived is method-dependent. For example, the
purity values derived from a chromatographic and by an
electrophoretic method may be different but equally valid for a
given batch of biotechnological/biological product because each
method focuses on a different aspect of this biological entity.
Well-Characterized (Biotechnological/Biological) Product
A product whose structural features (including amino acid
sequences, as well as physicochemical, biochemical, biological and/
or immunochemical properties) have been elucidated using a set of
modern, bioanalytical, and testing methods.
Dated: August 14, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-20608 Filed 8-18-95; 8:45 am]
BILLING CODE 4160-01-F
