Contains Nonbinding Recommendations 

99 

Guidance for Industry 

STABILITY TESTING OF NEW 

BIOTECHNOLOGICAL/BIOLOGICAL VETERINARY 

MEDICINAL PRODUCTS

VICH GL17 

FINAL GUIDANCE 

This final document provides guidance to applicants regarding the type of stability data that 

should be provided in support of new animal drug applications (referred to as marketing 

applications in the guidance) for approval of veterinary biotechnological/biological products 

submitted to the European Union, Japan and the United States. It is understood that during 

the review and evaluation process, continuing updates of initial stability data may occur. 

Comments and suggestions regarding this document should be submitted to the Division of 

Dockets Management, (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 

1061, Rockville, MD 20852. 

For questions regarding this final document, contact Mai Huynh, Center for Veterinary 

Medicine, (HFV-142), Food and Drug Administration, 7500 Standish Place, Rockville, MD 

20855, 240-276-8273, Mai.huynh@fda.hhs.gov. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

March 26, 2001 
Contains Nonbinding Recommendations 

VICH GL17 (STABILITY 4) 

June 2000 

For implementation at Step 7 

STABILITY TESTING OF 

NEW BIOTECHNOLOGICAL/BIOLOGICAL 

 VETERINARY MEDICINAL PRODUCTS 

Recommended for Implementation 

at Step 7 of the VICH Process 

on 15 June 2000 

by the VICH Steering Committee 

THIS GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING GROUP ON THE 

BASIS OF THE ICH GUIDANCES ON THE SAME SUBJECT AND WAS SUBJECT TO CONSULTATION BY THE 

PARTIES, IN ACCORDANCE WITH THE VICH PROCESS. AT STEP 7 OF THE PROCESS THE FINAL DRAFT 

IS RECOMMENDED FOR ADOPTION TO THE REGULATORY BODIES OF THE EUROPEAN UNION, JAPAN AND

USA. 

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STABILITY TESTING OF

NEW BIOTECHNOLOGICAL/BIOLOGICAL 

VETERINARY MEDICINAL PRODUCTS

I. PREAMBLE (1).......................................................................................... 4 

II. SCOPE OF THE ANNEX (2)...................................................................... 4 

III. TERMINOLOGY (3)................................................................................... 5 

IV. SELECTION OF BATCHES (4)................................................................. 5 

A. Drug Substance (Bulk Material) (4.1).........................................................................5 

B. Intermediates (4.2).....................................................................................................5 

C. Drug Product (Finished Product) (4.3) .......................................................................5 

D. Sample Selection (4.4)...............................................................................................6 

E. Container/Closure (4.5)..............................................................................................6 

V. STABILITY-INDICATING PROFILE (5)..................................................... 6 

A. Protocol (5.1) .............................................................................................................7 

B. Potency (5.2)..............................................................................................................7 

C. Purity and Molecular Characterization (5.3)...............................................................7 

D. Other Product Characteristics (5.4)............................................................................8 

VI. STORAGE CONDITIONS (6) .................................................................... 8 

A. Temperature (6.1) ......................................................................................................8 

B. Humidity (6.2).............................................................................................................9 

C. Accelerated and Stress Conditions (6.3)....................................................................9 

D. Light (6.4)...................................................................................................................9 

VII. USAGE CONDITIONS (7) ......................................................................... 9 

A. Stability after First Opening or Reconstitution of Freeze-Dried Product (7.1) ............9 

B. Multiple-Dose Vials (7.2) ...........................................................................................9 

VIII. TESTING FREQUENCY (8)....................................................................... 9 

IX. SPECIFICATIONS (9).............................................................................. 10 

X. LABELING (10) ....................................................................................... 10 

XI. GLOSSARY (11)...................................................................................... 10 

Conjugated Product...........................................................................................................10

Degradation Product..........................................................................................................10

Impurity..............................................................................................................................11 

Intermediate.......................................................................................................................11 

Manufacturing Scale Production........................................................................................11 

Pilot-Plant Scale ................................................................................................................11 

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STABILITY TESTING OF NEW BIOTECHNOLOGICAL/BIOLOGICAL 

VETERINARY MEDICINAL PRODUCTS 

This final guidance document represents the agency’s current thinking on stability 

testing of new biotechnological/biological veterinary medicinal products. It does not 

create or confer any rights for or on any person and does not operate to bind FDA or 

the public. An alternative approach may be used if such approach satisfies the 

requirements of applicable statutes and regulations. 

I. PREAMBLE (1) 

The guidance stated in the VICH harmonized tripartite guidance entitled "Stability Testing of New 

Veterinary Drug Substances and Medicinal Products" (GL3)1

 applies in general to new 

biotechnological/biological products. However, 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 well-characterized 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 new 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. 

II. SCOPE OF THE ANNEX (2) 

The guidance stated in this annex applies to products composed of well-characterized proteins 

and polypeptides, and their derivatives 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, growth 

hormones and growth factors, insulins, monoclonal antibodies, and those vaccines which consist 

of well-characterized proteins or polypeptides even when chemically synthesized. This document 

 

1

 A copy of the guidance document entitled "Stability Testing of New Veterinary Drug Substances and Medicinal Products" 

(#73) (GL3) may be obtained on the Internet from the CVM Home Page athttp://www.fda.gov/AnimalVeterinary/default.htm. 

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dose not cover antibiotics, heparins, vitamins, cell metabolites, DNA products, allergenic 

extracts, conventional vaccines, cells, whole blood, and cellular blood components. 

III. TERMINOLOGY (3) 

For the basic terms used in this annex, the reader is referred to the "Glossary" in "Stability 

Testing of New Veterinary Drug Substances and Medicinal Products, GL3 (Guidance for Industry 

#73)," (http://www.fda.gov/AnimalVeterinary/default.htm.) 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. 

IV. SELECTION OF BATCHES (4) 

A. Drug Substance (Bulk Material) (4.1) 

 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 manufacture scale of production. A minimum of six months 

stability data at the time of submission should be submitted in cases where storage periods 

greater than six months are requested. For drug substances with storage periods of less than six 

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 should 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 overall quality of the batches of drug substance placed on formal stability studies 

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. 

 B. Intermediates (4.2) 

 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 

products 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. 

 C. Drug Product (Finished Product) (4.3) 

 Stability information should be provided on at least three batches of finished product 

representative of that which will be used at manufacturing scale. Where possible, batches of 

finished product included in stability testing should be derived from different batches of bulk 

material. A minimum of six months data at the time of submission should be submitted in cases 

where storage periods greater than six months are requested. For drug products with storage 

periods of less than six 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 

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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 finished 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 authorities 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. 

 D. Sample Selection (4.4) 

 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 

extremes. In certain cases, data may be needed to demonstrate that all samples are properly 

represented by data collected for the extremes. 

 E. Container/Closure (4.5) 

 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 ampoules), 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. 

V. STABILITY-INDICATING PROFILE (5) 

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 

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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. 

 A. Protocol (5.1) 

 The dossier accompanying the application for marketing authorization should include a 

detailed protocol for the assessment of the stability of both drug substance, when applicable, 

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 guidance on stability. 

 B. Potency (5.2) 

 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 guidance, 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 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 if possible. 

 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. In many cases, the validated in vivo potency test will indicate that there has been 

no significant dissociation. 

 C. Purity and Molecular Characterization (5.3) 

 For the purpose of stability testing of the products described in this guidance, 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 and necessary. Limits of acceptable degradation should be 

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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-polyacrylamide gel electrophoresis, 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. 

 D. Other Product Characteristics (5.4) 

 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 affects 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. 

VI. STORAGE CONDITIONS (6) 

 A. Temperature (6.1) 

 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. 

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 B. Humidity (6.2) 

 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. 

 C. Accelerated and Stress Conditions (6.3) 

 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 for 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 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 guidance 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. 

 D. Light (6.4) 

 Applicants should consult the appropriate regulatory authorities on a case-by-case basis to 

determine guidance for testing. 

VII. USAGE CONDITIONS (7) 

 A. Stability after First Opening or Reconstitution of Freeze-Dried Product 

(7.1) 

 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. 

 B. Multiple-Dose Vials (7.2) 

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, 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. 

VIII. TESTING FREQUENCY (8) 

The shelf-lives of biotechnological/biological products may vary from days to several years. 

Thus, it is difficult to draft uniform guidances regarding the stability study duration and testing 

frequency that would be applicable to all types of biotechnological/biological products. With only 

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a few exceptions, however, the shelf-lives for existing products and potential future products will 

be within the range of 0.5 to five years. Therefore, the guidance is based upon expected shelflives 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 less than one year are expected, the real-time stability studies should be 

conducted monthly for the first three months and at three month intervals thereafter. For 

products with expected shelf-lives of greater than one year, the studies should be conducted 

every three months during the first year of storage, every six months during the second year, 

and annually thereafter. 

While the testing intervals listed above may be appropriate in the pre-approval or pre-license 

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., nine-month testing) for post-approval/post-licensure, long-term 

studies. If in vivo potency tests are part of the stability protocol, the omission of some testing 

points for those tests should be justified. 

IX. SPECIFICATIONS (9) 

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 guidance on stability. 

X. LABELING (10) 

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. 

XI. GLOSSARY (11) 

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 guidance, such 

changes could occur as a result of processing or storage (e.g., by deamidation, oxidation, 

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Page 11 

aggregation, proteolysis). For biotechnological/biological products, some degradation products 

may be active. 

Impurity 

 Any component of the drug substance (bulk material) or drug product (finished 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 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 before the manufacturing process is continued. 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.