[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]]
_______________________________________________________________________
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.
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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