[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.

[[Page 43505]]

     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