5 
 
Guidance for Industry 
 
Drug Stability Guidelines 
 
(This version of the guidance replaces the version that was made available in December 1990. This guidance 
document has been revised to correct the contact information, address formatting issues and to add missing text 
linked to the table of contents.  
 
For questions regarding this guidance document, contact Dr. Dennis M. Bensley, Jr., Center for 
Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 Standish Place, 
Rockville, MD 20855, (240) 276-8268. 
 
Additional copies of this guidance document may be requested from the Communications Staff, 
HFV-12, Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, 
Rockville, MD  20855, and may be viewed on the Internet at 
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry.  
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
December 9, 2008 
 
 
 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................1 
III.  GENERAL CONSIDERATIONS...................................................................................2 
A.  PROTOCOLS.......................................................................................................2 
B.  GENERAL STABILITY CONSIDERATIONS.................................................2 
1.  Definition of Active Ingredient.........................................................................2 
2.  Strength (Potency)............................................................................................3 
3.  Drug Preparation...............................................................................................3 
i  4.  Chemical and Physical Properties.....................................................................4 
5.  Added Substances.............................................................................................4 
6.  Product Changes...............................................................................................4 
7.  Correlation with Efficacy and Toxicity Studies................................................4 
8.  Degradation Products........................................................................................5 
9.  Product Stability Parameters.............................................................................5 
C.  STORAGE CONDITIONS..................................................................................5 
1.  Shelf-Life Duration of Studies..........................................................................5 
2.  Expiration Dates................................................................................................5 
3.  Temperature......................................................................................................7 
4.  Environmental Factors......................................................................................8 
5.  Special Labeling Restrictions...........................................................................8 
D.  CONTAINERS......................................................................................................8 
1.  Intended Market Container...............................................................................9 
2.  Container Material Integrity.............................................................................9 
3.  Containers for Liquids:  Special Considerations..............................................9 
4.  Physical Observations.......................................................................................9 
5.  Sealed Containers..............................................................................................9 
6.  Adhesive/Glue.................................................................................................10 
7.  Container Changes..........................................................................................10 
E.  STABILITY SAMPLES.....................................................................................10 
1.  Samples...........................................................................................................10 
2.  Sampling Plan.................................................................................................11 
3.  Handling and Analysis of Samples.................................................................11 
F.  STABILITY SCHEDULE..................................................................................11 
1.  General............................................................................................................11 
2.  Test Schedule Information..............................................................................13 
3.  Table of Suggested Test Schedules.................................................................16 
G.  ANALYTICAL METHODS..............................................................................18 
1.  Quality Control/Release Methods...................................................................18 
2.  Method Attributes...........................................................................................18 
3.  Method Controls and Conditions....................................................................20 
4.  Standards Curves............................................................................................20 
5.  Stability Method References...........................................................................20 
H.  STATISTICAL EVALUATION........................................................................23 
1.  Design Considerations....................................................................................23 
2.  Data Analysis..................................................................................................23 
3.  Expiration Date Determination.......................................................................23 
I.  REPORTING OF DATA...................................................................................24 
J.  STABILITY STUDY COMMITMENTS.........................................................25 
1.  Initial Study Commitments.............................................................................25 
2.  Product/Container Changes/Alternate Drug Substance Suppliers..................26 
3.  Analysis of Distribution Samples...................................................................26 
4.  Post-Approval Studies....................................................................................26 
K.  STABILITY STUDY COMMITMENT FORMAT.........................................26 
1.  Samples of Testing..........................................................................................26 
ii  2.  Control Tests...................................................................................................27 
3.  Container.........................................................................................................27 
4.  Product Storage Conditions............................................................................27 
5.  Frequency or Interval of Testing.....................................................................27 
6.  Result Reporting.............................................................................................27 
7.  Withdrawal Provisions....................................................................................27 
IV.  SPECIFIC CONSIDERATIONS..................................................................................28 
A.  PHARMACEUTICAL DOSAGE FORMS......................................................28 
B.  STERILE PREPARATIONS.............................................................................29 
C.  TYPE A, B, AND C MEDICATED PRODUCTS............................................30 
1.  Expiration Dating Requirements.....................................................................30 
2.  Study Temperature and Length.......................................................................31 
3.  Product Composition......................................................................................32 
4.  Lots for Stability Study...................................................................................33 
5.  Testing Levels.................................................................................................33 
6.  Pelleted Products.............................................................................................33 
7.  Moisture Content............................................................................................34 
8.  Test Results.....................................................................................................34 
9.  Additional Studies...........................................................................................34 
10.  Pilot vs. Production Samples..........................................................................35 
D.  TYPE B AND C MEDICATED LIQUID FEED SUPPLEMENTS...............35 
1.  Protocols.........................................................................................................36 
2.  Stability Test Information...............................................................................36 
3.  Types of Stability Testing...............................................................................38 
4.  Stability Testing Studies.................................................................................38 
5.  Recommended Labeling.................................................................................41 
E.  MEDICATED BLOCKS....................................................................................43 
1.  Stability Study.................................................................................................43 
2.  Label Statement for Usage..............................................................................44 
F.  SOLUBLE POWDERS AND DRINKING WATER.......................................44 
1.  Soluble Powders..............................................................................................44 
2.  Drinking Water...............................................................................................45 
G.  ORAL DRENCHES............................................................................................45 
H.  MILK REPLACERS..........................................................................................46 
I.  MASTITIS PREPARATIONS..........................................................................46 
J.  SUSTAINED  RELEASE PRODUCTS..........................................................47 
K.  MICROENCAPSULATED PRODUCTS.........................................................47 
L.  VAT DIPS............................................................................................................47 
M.  rDNA PRODUCTS.............................................................................................47 
N.  DRUG SUBSTANCES........................................................................................48 
iii  Guidance for Industry 
 
Drug Stability Guidelines 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
 
I.  INTRODUCTION 
The guideline is to be used as an aid in designing and conducting studies to establish drug 
stability in support of original, abbreviated or supplements to new animal drug applications 
(NADAs/ANADAs).  The guideline will provide a framework within which stability studies can 
be conducted to provide meaningful and sufficient data.  The concept of the guidelines is 
applicable to studies on drug substances and the actual dosage form.  The guideline is not 
intended to restrict experimentation.  The guideline applies to pharmaceutical dosage forms and 
medicated feed products. 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs current thinking on a topic and should be 
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
Section 512(b) of the Federal Food, Drug and Cosmetic Act (21 U.S.C. 360b) establishes the 
requirements for new animal drug approval.  21 CFR 514.1 specifies the proper form and the 
information required to be submitted. Included is a requirement under section 514.1(b)(5)(x) that 
an applicant submit data from stability studies completed as well as information about studies 
that are underway to substantiate the request for a specific expiration date and provide 
information on the stability of the drug products. 
CGMP regulations under 21 CFR Part 200 also require stability testing for pharmaceutical 
dosage forms (21 CFR 211) and Type A Medicated Articles (medicated premixes) (21 CFR 
226).  This guideline can be used as an aid to conduct the required stability testing. 
The agency advises that this final guideline represents its current position on the development of 
stability studies to meet the requirements of the submission of original or abbreviated new 
1  animal drug applications and the corresponding CGMP regulations.  The guideline may be useful 
to manufacturers of new animal drug products.  A person may follow the guideline or may 
choose to use alternate procedures even though they are not provided for in the guideline.  If a 
person chooses to use alternate procedures, that person may wish to discuss the matter further 
with the agency to prevent an expenditure of money and effort on activities that may later be 
determined to be unacceptable by FDA.  This guideline does not bind the agency, and it does not 
create or confer any rights, privileges, or benefits for or on any person. 
III.  GENERAL CONSIDERATIONS 
 
A.  PROTOCOLS 
Prior to the submission of an original or supplemental NADA, an applicant may wish to 
submit a stability protocol for comment before committing to studies that will become a 
permanent part of the NADA. 
The protocol should contain an outline of the proposed plan to be used in generating 
stability data.  The protocol should describe the type of product being tested, sampling 
process, duration and frequency of testing, number of samples and replicates per time 
interval, storage conditions (length of storage, type of storage, temperatures and 
packaging), methods of analysis (description or reference of published methods) with 
accompanying support data, if available, and other tests.  The information listed in these 
guidelines should be incorporated as appropriate in the development of a plan. 
The Center's review scientists will evaluate and comment on the proposed protocols or 
assist an applicant (upon request) in the design of a study. 
It should be noted that the Center for Veterinary Medicine does not approve protocols. 
Applicants or drug firms proposing to conduct stability studies should refer to the 
following texts: 
  "Chemical Stability of Pharmaceuticals" by K. Connors, G. Amidon and L. 
Kennon, John Wiley & Sons (1979). 
and 
  "Formulation of Veterinary Dosage Forms", vol. 17, Drugs and The 
Pharmaceutical Sciences, Blodinger, J., Marcel Dekker Inc., NY. (1983). Chapter 
5.  
These texts provide information on the various aspects of establishing a stability 
program. 
B.  GENERAL STABILITY CONSIDERATIONS 
 
1.  Definition of Active Ingredient 
 
2  The active ingredient of an animal drug preparation is defined as that 
chemical whose biological, physiological, pharmacological, or chemical 
activities are claimed on the label to be beneficial for animals in normal or 
pathological conditions (diagnosis, prognosis, treatment, prophylaxis, 
therapy) or for animal production. 
2.  Strength (Potency) 
The strength of a drug substance may be its concentration (quantity of the 
drug per unit measure), its potency, or both.  The potency of a drug is a 
measurable (quantitative) extent of the biological, physiological, 
pharmacological, or chemical activities of the drug per unit weight or 
volume of the drug preparation. 
Drug preparations are considered stable if the active ingredient can 
maintain its strength at the level specified on the label for the maximum 
anticipated shelf-life (the time period from the date of manufacture until 
administration to the animal) under environmental conditions likely to be 
encountered in actual use.  However, few, if any, drug preparations 
maintain their full label-claimed strength under specified conditions. 
Therefore, allowances are made for some unavoidable deviations from 
drug levels declared on the label by designating specific limits for 
tolerable deviations. 
A drug product is considered unstable when the drug substance (active 
ingredient) loses sufficient potency to adversely affect the safety or 
efficacy of the drug or falls outside labeled specifications as shown by 
stability-indicating methods. 
To properly evaluate the stability of a drug product, it is essential to 
determine the storage conditions under which the drug strength can be 
maintained in order to provide a safe and efficacious drug product. 
As a guide in determining drug strength in pharmaceutical dosage forms, 
the following is recognized by the scientific community: 
  "Although there are exceptions, 90% of the labeled potency is 
generally recognized as the minimum acceptable potency level.1 
 3.  Drug Preparation 
The active ingredient should be formulated in any drug preparation at 
100% of label claim.  An overage of the active ingredient may be 
permitted in a product should the need exist.  All overages should be 
                                                 
1 Remingtons Pharmaceutical Sciences, Sixteenth Edition, Pg. 284 (1985). 
3  justified.  The assay limits must account for the overage.  The overage 
should not exceed the limits of 5% for antibiotics and 3% for nonantibiotic 
chemicals as established by the Center for Veterinary Medicine. 
4.  Chemical and Physical Properties 
Strength is not the only criterion of drug product stability. Maintenance of 
various chemical and physical properties to preserve the effectiveness and 
safety of the drug is also important.  Properties, such as physical 
appearance, crystalline form, particle size, solubility, disintegration rate, 
pH, sterility, viscosity, palatability (taste and odor), may be stability 
related and thus require testing and the setting of specific storage 
conditions and limits.  In addition, tests may also be needed to determine 
the absence or presence of harmful degradation products. 
5.  Added Substances 
Stability data on substances that are added to a drug preparation to 
enhance its stability, usefulness, physical or chemical properties or as an 
aid in manufacturing may be required.  The type of substance(s) used, its 
purpose, and its relationship to the active drug ingredient(s) and total drug 
preparation will determine if testing for the substance is required. 
Examples of added substances that may commonly be used are 
antioxidants, antibacterials, absorbants (bentonite), etc. 
6.  Product Changes 
Changes made in the composition (formulation) or dosage form of the 
original or succeeding product(s) present a new drug product and will 
require generation of new stability data.  Data requirements will depend on 
the nature and degree of change. 
Any change requires an evaluation as to the effect on the stability of the 
products. 
7.  Correlation with Efficacy and Toxicity Studies 
Stability studies supporting an application should be performed on the 
drug preparation in its final formulation whose efficacy and safety has 
been demonstrated.  Any change made in an approved preparation requires 
consideration of the effects on the efficacy and safety of the "changed" 
drug product. 
4  8.  Degradation Products 
Degradation products that occur during storage (under shelf-life testing) 
should be identified.  These products should be thoroughly investigated 
and evaluated for safety and toxicology purposes.  The presence of 
degradation products may require additional safety and efficacy studies. 
9.  Product Stability Parameters 
The established regulatory registration (NADA or NDA) specifications or 
Compendial standards are to be used for determining the stability of the 
products.  There can be only one set of standards. Samples of products 
(from production lots) on stability should be representative of those in the 
market place.  Expiration dating is based on the ability of the product to be 
measured over a certain period of time against the established 
specifications or standards. 
C.  STORAGE CONDITIONS 
In setting up the environmental conditions under which the stability of the drug 
preparation will be studied, the end use of the product should be kept in mind. 
Consideration should be given to simulating conditions to which the preparation will be 
exposed during shelf-life and expiration periods.  These conditions should include stock 
storage and transportation conditions under proposed label directions. 
1.  Shelf-Life Duration of Studies 
Stability studies should be designed to provide enough useful information 
to determine the anticipated shelf-life of a drug product, when stored 
under conditions set forth on the labeling. 
The duration of stability studies should extend at least to the usual shelf-
life for that type of product or beyond the recall specification limits, 
whichever is shorter. 
Shelf-life is defined as the time period from the date of manufacture of the 
product until it is administered to the animal. 
2.  Expiration Dates 
The applicant should propose a tentative expiration date on the basis of 
available stability data.  This expiration date may be based on analysis of 
pilot-lot data. 
The accumulation of stability data from production lot samples will justify 
any adjustment (reduction, extension or removal) of the proposed tentative 
5  expiration date.  The requirement for expiration dates is found under 21 
CFR 211.137 and 211.166 for pharmaceutical dosage forms and 226.58(d) 
for Type A medicated articles of the good manufacturing practice 
regulations. 
In addition, 21 CFR 514.1(b)(5)(x) lists the basic requirement of an 
expiration date for all veterinary products: 
a.  Pharmaceutical Dosage Forms: 
Expiration dates are required. 
b.  Medicated Feed Products: 
 
i.  Premixes [Type A medicated articles]  
 
Expiration dates are required. 
 
ii.  Supplements/Intermediates [Type B medicated products] 
 
The need for an expiration date will be determined on a 
case-by-case basis (depending on the proposed uses, etc.). 
 
iii.  Complete Feeds [Type C medicated products] 
 
The need for an expiration date will be determined on 
available stability data submitted and the proposed uses. 
 
Experience indicates that the following periods are the maximum time 
periods commonly used in determining product expiration periods: 
 
PRODUCT TYPE MAX. TIME PERIOD
Dosage forms:                                  5 years 
Implants, injectables, tablets, capsules,   
soluble powders, etc. 
   
Medicated Products:   
Liquid feed supplements                    60 days1
Type A Medicated Articles [Premixes]         * 
Type B Medicated Feeds         ** 
Type C Medicated Feeds [Finished Feeds]     * 
Type C Medicated Feeds [Blocks]         180 days2
   
Medicated drinking water                   Label Directions3
 
6  Each dosage form or medicated feed preparation will have its own unique 
shelf-life.  
 
 NOTE: The expiration date period should begin at the time of 
manufacture of the lot. 
____________________________________________________________
       
1 Shelf-life figures less than or greater than this figure may be proposed or 
be necessary.  Based on the stability data presented and the proposed use, 
acceptability will be determined on a case by case basis for the product. 
 
2 The shelf-life of blocks should be determined according to label 
directions, consumption data, range (open field) stability studies combined 
with the warehouse shelf-life (180 days). 
 
3 The shelf-life of medicated drinking water should be determined by 
stability studies based on label directions for use.  (See section F for 
additional information.) 
 
* Sufficient historical data/information is not available to list a maximum 
time period for this type product.  Expiration date assignment will be 
based on data submitted. 
 
** Depending on type (intermediate, supplement, etc.), the level and/or 
proposed use of this product, the time period can fall under the Type A 
(premix) or Type C (medicated feed) categories.  The need for an 
expiration date will be determined on a case-by-case basis. 
____________________________________________________________ 
 
3.  Temperature 
     
It is recommended that in order to study the stability profile of the active 
ingredient(s) and drug preparation, samples should be stored at 
temperatures of 25C and 37-40C, although in some instances, higher or 
lower temperatures may be required. 
Those preparations labeled for storage at freezing or refrigerator 
conditions are to be studied at these temperatures. 
On occasion, studies at elevated temperatures, i.e., greater than 40C may 
be necessary. 
Non-isothermal studies may also be utilized where advisable or considered 
necessary to determine a tentative expiration date. 
7  Comparison of data obtained at different storage temperatures provides 
useful information about the temperature-drug relationship and the need 
for any special storage conditions. 
4.  Environmental Factors 
 The following conditions are some of the factors that should be 
considered in determining stability during storage: 
a.  Effect of exposure to extremes of temperature. 
 
b.  Effect of exposure to air, sunlight, ultraviolet light and other 
artificial light. 
 
c.  Effect of exposure to humidity (normal or exaggerated conditions). 
  
5.  Special Labeling Restrictions 
Drug products that may be expected to be exposed to extremes of 
temperature, humidity, air, light, etc., may require special label 
restrictions.  The restrictions should be practical and such that they can 
reasonably be expected to be followed under actual conditions. 
All recommended restrictions must be supported by appropriate data. 
D.  CONTAINERS 
Regulation 21 CFR 211.94 of the current good manufacturing practice (CGMP) 
regulations for pharmaceutical dosage forms provides information that is to be used when 
considering containers for drug products.  The regulation is published below: 
211.94 Drug product containers and closures. 
(a) Drug product containers and closures 
shall not be  reactive, additive, or absorptive  
so as to alter the safety, identity, strength,  
quality, or purity of the drug beyond the   
official or established requirements. 
 (b) Container closure systems shall provide 
  adequate  protection against foreseeable  
  external factors in storage and use that can  
  cause deterioration or contamination of the  
  drug product. 
(c) Drug product containers and closures 
shall be clean and,  where indicated by the 
nature of the drug, sterilized and processed to  
remove pyrogenic properties to assure that 
they  are suitable for their intended use. 
(d) Standards or specifications, methods of  
  testing, and,  where indicated, methods of  
  cleaning, sterilizing, and processing to remove 
8    pyrogenic properties shall be written  and  
  followed for drug product containers and closures. 
Even though this regulation is for pharmaceutical dosage forms, it is used as a guide for 
containers for all other veterinary products, e.g., Type A medicated articles, complete 
feeds, blocks, etc.  The text and concepts embodied in the regulation can be applied to all 
types of packaging for veterinary products.  It is used in assessing the usefulness of the 
proposed container and the stability of the product in the proposed container.  It should be 
noted that sections (c) and (d) of the above regulation are not applicable for all veterinary 
product packages. 
1.  Intended Market Container 
In order to demonstrate stability of the drug product under actual or 
simulated storage conditions, the product must be studied in its intended 
market container(s).  This is required under 21 CFR 211.166 (a)(4). 
2.  Container Material Integrity 
The container should be capable of preventing physical dissipation of the 
drug substance or other excipients by means of evaporation, permeation, 
absorption, adsorption or leaching through the container wall.  Container 
materials should not interact with the product. 
In some instances, the use of containers smaller in volume than the market 
container but identical in composition and construction may be permitted. 
Proper justification must be provided. 
3.  Containers for Liquids:  Special Considerations 
Container/closure systems which hold liquid products - injections, 
solutions, suspensions - should be stored in both upright and inverted 
positions.  This type of storage is necessary to provide information on any 
possible reaction between the product and the cap, seal, stopper, etc.  Tests 
should be performed for integrity of seal, torque fit (if necessary), leaching 
from liner or closure, leaking, etc. 
4.  Physical Observations 
Physical observations of the container and contents should always be 
made and reported during any stability testing period.  Tests should be 
conducted as needed to confirm any unusual findings and be reported. 
5.  Sealed Containers 
Products that are hermetically sealed should be tested for integrity of seal. 
9  6.  Adhesive/Glue 
High temperature studies may be needed to study the stress of adhesive 
properties of any glue used. 
7.  Container Changes 
The following information is applicable to pharmaceutical dosage forms 
and medicated feed products as appropriate. 
a.         Container Material Change 
A change in the type of container material used in the composition 
of the container (unless it is considered comparable, i.e., in the 
same generic chemical class to that as approved), will require new 
stability studies to be conducted with the drug product. 
b.         Container Size/Shape Change 
A change in the size or shape of the original container may not 
necessitate the initiation of a new stability study.  The decision will 
be made at the time of the review of the NADA supplement. 
c.         Introduction of New Containers or Closure Systems 
Whenever new containers or closure systems are introduced for 
use with a product, the first three (3) production lots of product 
using the new container or closure system should be placed into 
study using the approved ongoing stability program. 
E.  STABILITY SAMPLES 
 
1.  Samples 
Samples from production-size batches are preferred and should be used for 
stability studies.  These type samples provide for approximate actual use 
conditions.  The applicant should use real world conditions as much as 
possible.  If pilot scale samples are used, this fact should be reported. 
Laboratory scale samples provide for optimum control of all factors. 
Therefore, it should be kept in mind that changes may be needed in 
specifications once the drug is approved for use and the "real" or "actual" 
use situations are monitored and evaluated.  Such changes may be 
provided by the applicant or be requested by the Agency. 
10  2.  Sampling Plan 
A description of the sampling plan should be submitted to show how 
samples are representative of the lot or batch.  In addition, the frequency 
of sampling and the number of samples taken per time period should be 
reported.  Certain information on which to make these decisions should be 
given, for example, the variability of the assay method at the 
concentrations being determined should be considered.  Greater variability 
may necessitate an increase in the number of samples needed at each time 
period. 
3.  Handling and Analysis of Samples 
To establish the initial data point, samples should be analyzed as soon as 
possible after they are manufactured. The same day is highly desirable. 
This is recommended in order to make sound and valid conclusions about 
the stability of the active drug ingredient(s) and the preparation.  If the 
initial analysis cannot be performed on the same day, the samples should 
be placed in moisture-proof, air-tight containers and sealed with as little 
air as possible inside.  They should be stored at 0F or at some 
temperature chosen to reduce the chance of degradation, mold growth and 
chemical action. 
Storage of frozen samples for an extended period of time should be 
avoided.  Those preparations that cannot be stored at freezing 
temperatures should be analyzed as soon as possible to establish an initial 
analysis point and then be placed in their appropriate stability testing 
environment.  Samples that are shipped to sites other than the 
manufacturing site for stability testing should be properly packaged and 
labeled.  These samples should be tested upon receipt prior to their 
introduction into the respective stability program. an initial analysis should 
be conducted as soon as possible, at release or upon receipt. 
F.  STABILITY SCHEDULE 
Suggested Schedules for conducting Stability Studies          
1.  General 
 
In general, a schedule for conducting stability testing should be 
established which represents the conditions under which the preparation 
will most likely be stored.  The schedule in conjunction with a stability 
commitment should be designed to establish a stability profile for the 
product.          
 
a.        Pre-Approval Studies      
11  Prior to approval of the drug product for use, the applicant should 
propose a stability schedule.  The schedule should be submitted 
with the stability commitment for review.    
 
Acceptability of the schedule and commitment will be based on the 
information received, past history of the drug substance, related 
drug preparation(s), storage conditions and accompanying 
commitments.  Discussions with the applicant will be held when 
necessary.       
 
The information may be submitted during the investigational drug 
stage as a protocol for review or with the submission of a new 
animal drug application.    
 
At least 3 lots of product of a typical batch size should be tested for 
stability.          
 
b.         Post-Approval Studies          
 
Post approval commitments and studies should be designed to 
insure and verify the adequacy of pre-approval data and that the 
change from pilot to production lot has not introduced any 
unknown variable or been influenced by any unforeseen problems.          
 
After sufficient stability information has been accumulated, revised 
commitments may be submitted to adjust the suggested schedule.          
 
c.         Stability Tests          
 
Under any particular schedule, all the pertinent stability tests - 
physical, chemical or microbiological - which have been designed 
for the study must be conducted.  Results are to be reported as per 
the stability reporting commitment.          
 
d.        Reformulated Products          
 
Reformulated products are considered as new products and should, 
therefore, be subjected to the ongoing original product stability 
schedule and commitment.          
 
e.         Accelerated Temperature Studies          
 
Accelerated temperature studies should be conducted when 
necessary to provide information for stability prediction or 
tentative expiration date period.          
 
12  2.  Test Schedule Information 
 
The information discussed in the section below is related to the table of 
suggested schedule.           
 
a.         Temperatures          
 
i.          Room Temperature         
 
1.         Pharmaceutical Dosage Forms          
 
All pharmaceutical dosage forms should be studied 
at 25C (77F) which is considered the normal 
room temperature.  If another "normal room" 
temperature is studied or required for storage, the 
study should then follow the schedule at that 
temperature.          
 
2.         Feed Preparations          
 
Feed preparations should be studied under the 
following schedules:          
 
a.         Type A Medicated Articles  
(Medicated Premixes)          
 
Type A medicated articles should be studied 
at room temperature (25F or 77F) under 
the same schedule intervals as 
Pharmaceutical Dosage Forms.  
                     
b.         Type B & C Medicated Products          
 
Type B and C medicated feed products 
should be studied at ambient temperatures. 
(Ambient temperatures are those that 
actually occur during a certain time period.)          
 
Type B products should be studied for the 
appropriate period depending upon what 
category it is judged to belong, e.g., as an 
intermediate premix or a supplement.   
 
Type C products should be tested as follows:          
Complete, finished feed - 0(initial), 1, 2, 3 
mos. 
13  Blocks - 0(initial), 2, 4, 6 mos.  
Liquid feeds (field storage) - 0(initial), 2, 4, 
6, 8 weeks.          
 
NOTE: See section F for the definition of 
ambient temperatures.          
 
ii.         Elevated Temperatures          
 
Simultaneous to the normal room temperature stability 
study, a study should be run for a shorter period of time at a 
higher temperature.          
 
1.         Pharmaceutical Dosage Forms         
 
The period should be for at least one year at 37 to 
40C. See "Table of Suggested Test 
Schedule" for the appropriate schedule.          
 
2.         Type A Medicated Articles (medicated premixes)          
 
The period should extend for at least 6 months at 
37 to 40C. "Table of Suggested Test 
Schedule" for the appropriate schedule.          
 
3.         Type B Medicated Feed Products          
 
Type B products should be studied for the 
appropriate period depending upon what category it 
is judged to belong, e.g., as an intermediate premix 
or a supplement.          
 
4.         Type C Medicated Feed products          
 
The period should be studied at 37 to 40C.          
       
Complete, finished feeds - 1 month 
Blocks - up to 6 months 
Liquid feeds - 8 weeks 
 
Periods less than stated times should be justified.          
 
Under actual real life environmental conditions, the higher 
temperatures are not expected to exist for long periods.  
However, in order to study the stress placed on the 
14  preparation by possible higher temperatures data from 
elevated studies must be provided.          
 
iii.        Refrigeration          
 
Those preparations that may require refrigeration either in 
the intact, unopened container or after opening or after 
reconstitution should be studied within the schedule for the 
length of anticipated storage period or expiration date.  The 
study should include tests on unused portions in opened           
containers after initial use, when appropriate.  Preparations 
that may come under this category are liquids, solutions, 
injections, suspensions, creams, ointments, pastes, and 
some solid dosage forms, e.g., powders, suppositories and 
reconstituted solutions.          
 
vi.        Freezing          
 
All liquid preparations - injections, solutions, suspensions, 
and semi-solid preparations (creams, ointments and pastes), 
medicated liquid feeds, etc. - should be subjected to a short 
term stability study at freezing temperatures.  This short 
term period should cover at least 7 days.          
 
1.  Physical observations should be made daily to 
determine if precipitates or other abnormal 
occurrences are evident.       
    
2.         If the preparation is frozen, procedures for thawing 
should be recommended.          
 
3.         If a precipitate remains after thawing, the precipitate 
should be identified. The toxicity and safety of the 
identified precipitate should be determined, if 
necessary.  Procedures for dissolving the 
precipitate, if possible, should be recommended.  
Proper product labeling directions should be 
provided.          
 
4.         If separation of layers in suspensions occur, 
procedures for thawing frozen material and 
reconstituting the product to its original state, 
should be recommended.   
 
15  At the end of the freeze test period, the normal stability 
tests should be conducted to insure that the product has 
maintained its standards and degradation has not occurred.   
 
If the results of the above studies indicate any 
abnormalities, proper warnings may need to be appended to 
the label and be placed in the insert.          
 
v.         Ambient Temperatures          
 
Certain types of products may need to be studied under 
natural environmental conditions.  The existing weather 
conditions should be reported.  Temperatures (minimum 
and maximum) should be reported at the time of sampling 
and testing.  Products that may be studied under these 
conditions are medicated feeds, blocks or liquid feeds 
which are used outdoors and, therefore, are expected to be 
exposed to natural, existing temperatures.          
 
b.         Special Humidity Considerations          
 
Those preparations requiring a special humidity environment 
should include that factor (amount of humidity) with the 
temperature schedule under study.          
 
3.  Table of Suggested Test Schedules 
 
a.         Solid Dosage Forms Including Medicated Feed Products          
 
i.          All products should be subjected to both room temperature 
and elevated temperature studies (length depending on the 
proposed expiration date).          
 
1.         Room Temperature: 25C (ca 77F); or other2          
 
             
Proposed   
 
Expiration Date  Test Schedule 
             
6 months  0 (Initial),2,4,6 mos. 
 
1 year  0 (Initial),3,6,9,12 mos.  
   
18 months  0 (Initial),3,6,9,12,18 mos. 
 
2 years  0 (Initial),3,6,9,12,18,24 mos. 
 
3 years  0 (Initial),3,6,9,12,18,24,36 mos. 
             
4 years  0 (Initial),3,6,9,12,18,24,36,48 mos. 
 
5 years  0 (Initial),3,6,9,12,18,24,36,48,60 mos. 
 
                                                 
2 When a temperature other than that specified above is to be used, it should be specified in the protocol or study.          
16  2.         Elevated Temperatures: 37-40C (98-104F)          
 
                Proposed Expiration Date  Test Schedule 
  6 months  0 (Initial),2,4,6 mos. 
  1 year or greater  0 (Initial),3,6,9,12 mos. 
 
3.         Ambient Temperatures          
 
Actual temperature existing at location of stored 
product.  (This level does not represent "controlled" 
temperatures.)          
 
ii.         Those products requiring refrigeration must be subjected to 
the appropriate study at the respective temperature station.          
 
Normal refrigeration temperatures: 2-8 (36 - 46F)          
 
Schedule and length of anticipated storage period 
(expiration date) under these conditions will depend on 
nature of the product, active ingredient and/or other related 
factors.   
 
Note: If possible, samples should be studied at both 
temperature settings.                    
 
b.         Liquid and Semi-Solid Type Products          
 
In addition to the schedules in a. (above), all liquid and semi-solid 
products (e.g. pastes, ointments, liquid feeds, etc.), should be 
subjected to a freeze-thaw-freeze cycle study.          
 
Freezing temperature should be 0C (32F) or below.     
          
Test schedule:           0(initial).......7 days          
 
c.         Reconstituted Products          
 
Time element and schedule will depend upon nature of product, 
active ingredient, proposed expiration date and/or other related 
factors.          
 
Example:   A powder dissolved in a solvent to be held for 14 days 
should be tested at the recommended storage 
temperature (room, elevated and/or refrigerated 
temperature stations) according to the following 
schedule:          
17   
0(initial),3,7,11,14 days.          
 
NOTE:      Extension of the period schedule may be necessary and 
will depend on review of the data obtained.  A 
significant loss in potency is an example that may cause 
an extension of the time schedule.  Other examples may 
include, appearance of degradation products, aberrant 
physical observations, etc.  The decision to extend the 
period will be made on the evaluation of data submitted 
to the Center or by the firm on its own initiative.          
 
G.  ANALYTICAL METHODS 
A key factor in a stability study is the use of an analytical method which will provide 
meaningful and reliable data.  In all cases, the method should be capable of providing 
proper information for each test conducted. 
Stability assay methods should be sufficiently specific to differentiate between the 
unaltered drug and any possible degradation products.  The method should be described 
in detail. 
All assay methods should be supported by accuracy and precision information and be 
properly validated. 
All analyses should be conducted in replicate, preferably in duplicate.  The raw data 
should be reported. 
1.  Quality Control/Release Methods 
Official (USP, NF, AOAC, et. al.) or other control methods may be used 
for assaying the finished products.  Theses same methods or in-house 
quality control tests may serve as stability methods if they can be shown to 
be stability-indicating. 
In any case, it is the responsibility of the applicant to provide sufficient 
data to demonstrate the method's suitability as stability-indicating for the 
product being tested. 
2.  Method Attributes 
A stability-indicating method should address the following attributes: 
accuracy, precision, specificity and limit of detection.  The mechanisms 
for determining these attributes can be found in appropriate textbooks and 
the scientific literature. 
18  a.         Accuracy 
The accuracy of an assay method is a statistical measurement 
which relates to the difference between the average test results and 
the true value when the latter is known. 
At a minimum, the average mean recovery of the active 
ingredient(s) from the preparation should be determined at the 
label claim (assumed to be 100%) and at two additional points, 
each bracketing the label claim irrespective of the presence of an 
allowable manufacturing overage. 
The percent recovery from fortified (spiked) samples or synthetic 
mixtures containing a known amount of drug is the usual way of 
measuring accuracy. 
b.         Precision 
Precision involves the statistical measurement that is related to the 
repeatability of the method.  Precision is measured by the standard 
deviation or coefficient of variation of the method at the levels of 
interest. 
c.         Specificity 
The method should be specific enough to determine the active 
ingredient(s) as the intact molecule in the presence of other 
substances, such as: closely related drugs, intermediates, 
impurities, degradation or by-products, or the drug preparation 
excipients that could reasonably be expected to mask or simulate 
the analytical behavior of the ingredient. 
As part of the specificity test for a stability-indicating method, the 
product should be tested with acid and base to determine if 
decomposition occurs with the active ingredient.  Decomposition 
testing with sunlight or artificial light should also be performed. 
In some cases, confirmatory techniques may be necessary to 
determine the specificity of a method. 
Copies of actual spectra, chromatograms, photographs of TLC 
plates or other data/information should be submitted to substantiate 
this attribute. 
d.         Limit of Detection 
19  The method must be able to respond to the least amount of the 
chemical under analysis. 
3.  Method Controls and Conditions 
a.         Method Blanks 
i.          Control (Reagent) Blank  
A control (or reagent) blank should always be run 
whenever the method is performed unless the method does 
not require one, such as, with the use of an internal 
standard.  A method control blank is a solution made of 
solvents used in the method prepared according to the 
method procedures.  This control is necessary to assure 
proper validation and to show noninterference of the 
sample with the method solvents (reagents), proper 
functioning of the equipment, and that proper analytical 
techniques are being exercised. 
ii.         Sample Blank  
When a sample blank is used, it should consist of all 
excipients of the drug product less the active ingredient. 
This sample blank should normally be used only during 
product and method development stages. 
Sample blanks are not acceptable for a product release of 
regulatory or stability testing method. 
b.         Method Conditions  
Parameters (or conditions) under which the method is conducted 
should be properly documented and reported. 
4.  Standards Curves 
For those methods requiring the use of a standard curve, the curve should 
be prepared on the day the method is run.  At least 3 points must be 
plotted to provide meaningful data and interpretation. 
5.  Stability Method References 
The following articles may be referenced as guides for analytical method 
validation: 
20    Guidelines for Assay Validation 
Pharmaceutical Technology, March 1982, pg. 66  
  Submitting HPLC methods to the compendia and regulatory agencies 
Pharmaceutical Technology, September 1982, pg. 120  
  Practical applications of cGMPs to gas and high-performance liquid 
chromatographic systems 
Pharmaceutical Technology, March, 1984, pg. 81  
  Validating alternate laboratory assay methods 
Pharmaceutical Technology, May 1979, pg. 60  
  Standard Additions: Uses and limitations in spectrophotometric 
analysis 
American Laboratory, July 1977, pg. 21  
  GMP - method validation procedures in an OTC firm 
Pharmaceutical Technology, August 1980, pg. 45  
  Stability of Pharmaceutical Products 
Remington's Pharmaceutical Sciences, 1985  
  Stability of Pharmaceuticals 
J. Pharm. Sci. 67, 443, 1978  
  Stability Studies of Veterinary Formulations 
Formulations of Veterinary Dosage Forms, J. Blodinger, Marcel 
Dekker, 1983, Chapter 5  
NOTE:  The above list is not meant to be all inclusive. Articles are 
constantly being made available for scientific use.  The above articles are 
referenced here only as an aid or guide for use in developing stability 
methods and conducting the validation process. 
The format for the presentation of analytical methods should be one that is 
clear and contains all necessary information.  The following format is 
suggested: 
 
TITLE OF METHOD 
 
I.         SCOPE/PRINCIPLE OF METHOD 
 
This section should briefly describe the physical process 
and chemical principle of the method. 
 
II.        APPARATUS 
 
This section should provide all information for the use of 
the equipment or other apparatus necessary to conduct all 
aspects of the method. 
 
III.      REAGENTS 
 
21  This section should list all the reagents and their 
preparation (where necessary) used to conduct the method. 
 
IV.      PROCEDURE 
 
This section should contain all information applicable and 
relative to the sample, standard and blank preparation 
(extraction, clean-up, dilution, etc.,) instrument parameters, 
determination and calculations. 
 
(a)       Sample Preparation 
(i)        Extraction 
(ii)       Clean-up 
(iii)      Dilution 
(iv)      Other 
(b)       Standard Preparation 
(i)        Extraction 
(ii)       Clean-up 
(iii)      Dilution 
(iv)      Other 
(c)       Blank (Reagent) Preparation 
(d)       Instrument Operating Parameters 
(i)        Instrument 
(ii)       Ancillary units 
(iii)      Operating conditions 
Columns 
Temperatures 
Special calibration 
Other 
(e)       Determinative Step 
(f)       Calculations (all dilution factors and calculation 
parameters should be clearly explained.) 
(g)       Raw data; Summary of results 
(h)       Chromatograms, spectra, etc. 
(i)        System Suitability information, if necessary 
 
V. VALIDATION INFORMATION 
 
(a)       Accuracy 
(b)       Precision 
(c)       Specificity 
(d)       Sensitivity 
(e)       Reproducibility 
(f)        Ruggedness 
 
VI.       OTHER RELATED INFORMATION 
22   
This section should contain information to ensure the 
method is being properly controlled 
 
H.  STATISTICAL EVALUATION 
It is the responsibility of the applicant to design the stability study and then apply the 
proper statistical techniques.  The information listed below includes items felt necessary 
and important to the stability study.  The type or depth of statistical approach to be used 
should be sufficient to accurately define and interpret the results obtained. 
1.  Design Considerations 
The first point to be examined in the design of a stability study is the 
population to which inference is to be made.  This means, for example, 
that if the stability of different batches (or lots) is to be inferred, then 
samples from more than one batch must be put on test.  Furthermore, 
research or pilot batches should be comparable to production batches.  The 
sources of variation should be identified and quantified in order to 
estimate the number of batches, samples per batch, assays per sample, etc., 
needed in the study.  These variance estimates should be made from 
preliminary studies or previous experience with the drug.  Batches may be 
manufactured and assays measured at staggered intervals in order to 
minimize the [5~influence of day to day variations in the assay method. 
2.  Data Analysis 
The data may be modeled using regression techniques, with "goodness of 
fit" tests used to assess the adequacy of the model.  The expiration date is 
defined so that at least 90% of all samples will be above the stability limit 
(e.g., 90% of label claim) throughout the shelf-life of the drug.  This 
expiration date will be determined from the fitted model and the estimated 
batch to batch and/or sample to sample variation. 
Data should be presented in a form that is amendable to statistical analysis 
and readily understood by the reviewer.  Statistical evaluations are 
strongly recommended.  The procedures employed should be described or 
relevant references given.  When appropriate, graphs and other visual aids 
may be provided. 
3.  Expiration Date Determination 
The method for determining the expiration date should be described. 
References to Journals or text books are acceptable.  Information 
described in Journal of Pharmaceutical Sciences, 65, 311, Feb. 1976 can 
23  be used as a guide.  There is no specific method that is accepted as the 
method of choice.  Each applicant must provide the information needed. 
I.  REPORTING OF DATA 
When reporting stability data, the following information should be included:  
1.  Name and type of product 
2.         Lot number and size of lot under test  
3.         Formulation  
NOTE:  For a medicated feed, report the formulation of base feed used as 
a diluent. 
2.  Label Claim  
5.         Conditions of storage  
4.  Type of container(s)  
7.         Analytical and Physical data:  
a.         Assay and identity tests 
  component (ingredient(s)) tested for.  
  individual data with appropriate units.  
  description of tests or references.  
  specifications (limits) - +% label claim.  
  sample of calculations, where necessary.  
b.         Other tests (pH, disintegration, etc.)  
8.  Statistical presentation, if available  
9.         Names and addresses of testing facilities  
Spectra, chromatograms, charts, or other pertinent information should be 
submitted to support and clarify any submitted data.  The applicant must 
make the determination when this information is necessary. 
Those applicants utilizing computers may submit data in computer-
readable form.  Explanations should be presented along with the computer 
information to clarify the format, nomenclature, etc., used. 
24  J.  STABILITY STUDY COMMITMENTS 
 
1.  Initial Study Commitments 
a.         Purpose 
Since stability data submitted as part of a new animal drug 
application are almost invariably based on laboratory or pilot-scale 
batches, the problems associated with the scale-up to full-size 
production batches must be considered.  In order to demonstrate 
that the transition can be made from pilot-scale to full-scale 
production without encountering stability problems, a stability-
testing protocol with corresponding commitments should be 
developed and submitted. 
b.         Protocol and Commitments 
The protocol for a stability study with necessary commitments 
should include the following information: 
i.          The number and/or frequency of production batches to be 
placed in a continuing stability study.  
ii.         Description of the chemical, microbiological, and physical 
tests to be used to monitor the stability of the drug product.  
iii.        Description of the containers to be used.  
iv.        The proposed environmental and storage conditions under 
which the drug product will be studied and then marketed.  
v.         Frequency or intervals of testing.  
vi.        Frequency at which results will be reported.  
vii.       Provisions to test batches manufactured immediately before 
and after a production batch which is found to be out-of-
specifications.  
viii.      Provisions for withdrawal from the market of any 
production batch found to be out-of-specifications and, if 
necessary, those batches immediately before and after the 
batch in question.  
25  2.  Product/Container Changes/Alternate Drug Substance Suppliers 
Whenever changes in formulation (changes in drug concentration or 
inactive ingredients), use of new containers, alternate sources, etc., are 
made, the product manufactured under the new conditions should be 
placed into the ongoing approved stability study. 
A commitment should specify all conditions relative to the new change 
and a statement to perform any additional studies needed for the changes 
in the application. 
In most cases, the approved expiration date may be used.  However, this 
will be determined at the time of the review of the supplemental 
submission and requested action. 
3.  Analysis of Distribution Samples 
Although not mandatory, it may be desirable to obtain samples from 
distributed batches for stability testing.  Ideally, these samples should 
obtained from geographical areas which represent extremes of temperature 
and humidity. 
It should be noted that the above voluntary activity does not relieve the 
applicant from the requirements for stability testing as established under 
cGMPs. 
4.  Post-Approval Studies 
After approval, the sponsor may make a request to liberalize or remove 
storage condition restrictions, to adjust (extend, reduce or remove) an 
expiration dating period, remove or provide a storage temperature 
restriction, provide for use of a different container, or amend existing 
commitments.  In these cases, adequate stability data should be presented 
to justify the request. 
K.  STABILITY STUDY COMMITMENT FORMAT 
A commitment to assure stability of a product should specifically define the following 
items. 
1.  Samples of Testing 
The first three (3) production lots should be tested followed by 3 to 10% 
of annual production lots (with a minimum of 1 lot per year). 
26  The number and/or frequency of production batches to be placed on a 
continuing stability study should be based on a consideration of the 
anticipated annual production and known stability profile. 
2.  Control Tests 
The chemical, microbiological, and physical tests to be used to monitor 
the stability of the drug product should be described. 
Tests and methods must be appropriate and adequate for the study. 
Assay methods must be stability-indicating, i.e., they must accurately 
differentiate between the intact drug molecule(s), any possible degradation 
products and product excipients.  Methods must be adequately validated. 
3.  Container 
The container to be used should be described. 
The container and closure system should be those proposed for use in 
marketing the product. 
4.  Product Storage Conditions 
Product storage conditions must specify type of storage, temperature and 
humidity conditions, light, etc.  These conditions must be applicable to the 
drug product in the market container and label requirements. 
5.  Frequency or Interval of Testing 
The schedule of testing samples relative to the proposed expiration date 
period at the recommended temperatures should be described. 
6.  Result Reporting 
Prior to approval for marketing, all available data should be submitted 
with the original applications and any amendments.  Post-approval data 
may be reported in the Drug Experience Report (DER) or in supplemental 
applications. 
7.  Withdrawal Provisions 
Provisions to test batches manufactured immediately before and after a 
batch which is found to be out-of-specifications should be provided. 
27  Provisions for withdrawal from the market of any production batch found 
to be out-of-specifications and, if necessary, those batches immediately 
before and after the batch in question should be provided. 
  
IV.  SPECIFIC CONSIDERATIONS 
 
A.  PHARMACEUTICAL DOSAGE FORMS 
The section on General Considerations addressed the general aspects for determining the 
stability of drug components in finished drug preparations.  However, it is also 
appropriate to note that some specific tests are often indicated for certain pharmaceutical 
dosage forms in addition to those normally conducted.  The tests listed below, although 
not conclusive, should be considered as stability tests of the product. 
DOSAGE FORMS                             SPECIFIC TESTS INDICATED 
 
Tablets                                                Hardness measurements 
                                                            Disintegration rate 
                                                            Dissolution rates, where appropriate 
 
Capsules                                              Dissolution rates, where appropriate 
     a.   Soft-gelatin                              Inspection for leaks 
     b.   Hard-gelatin                             Visual Examination for brittleness 
 
Suspensions                                        Viscosity, where appropriate 
                                                            Resuspendability 
                                                            Effects of freezing 
                                                            pH 
                              
Ointments, creams, gels                      Homogeneity 
and pastes                                           Viscosity, where appropriate 
                                                            Effects of freezing 
                         
Oral Powders                                      Completeness of solution/or dispersion 
                              
Powders for injections                        Completeness of solution/or dispersion 
 
Implants                                              Hardness 
                                                            Dissolution rate 
                                                            Friability 
 
Injections                                            Sterility 
                                                            Syringeability, where appropriate 
                                                            Effects of freezing 
                                                            Multiple insertions/withdrawals 
28                                                              pH 
                                                            Testing inverted containers 
                              
 Solutions                                            Sterility, where appropriate 
                                                            Effects of freezing 
pH 
 
Aerosols                                              Delivered dose 
                        Particle size distribution 
                        Valve corrosion 
                        Spray pattern 
 
B.  STERILE PREPARATIONS 
Sterility is to be considered as part of the stability profile (shelf-life) of a drug preparation 
stated to be sterile.  Because of storage requirements and the number of samples 
necessary for sterility testing, the frequency of testing for stability studies should be on 
the initial date and at the proposed expiration date.  The test for sterility that is conducted 
at the release of a lot is to be considered as the initial date test.  If the proposed expiration 
date is extended, sufficient samples should be anticipated for retention to provide for tests 
at the extended date. 
If methods other than USP are used to test sterility, their adequacy should be 
demonstrated.  The method should be properly referenced.  The specific UPS method 
should be delineated. Non-USP methods should be described in detail. 
Ophthalmic Preparations 
Sterility is to be demonstrated for all ophthalmic preparations.  Specific details for 
ophthalmic preparations are given in 21 CFR 200.50. 
Ampules 
Sterility is to be demonstrated on sealed ampules only on the date of manufacture. Since 
the type of containers is hermetically sealed, this type of seal prevents microbial 
contamination.  The product will be opened only once and used. 
Sterile Preparations with Microbial Inhibitors 
Sterile preparations whose formulations include added substances (used to prevent 
microbial growth) to maintain a sterile environment during the product's shelf-life are to 
be tested for sterility and for levels of the added substances on the initial date of 
manufacture.  After the initial analysis, only levels of inhibitors need be tested for during 
the regular testing schedules.  If a lack of or low levels are found, tests for sterility must 
be initiated and continued as per the suggested schedule until the expiration date. 
29  Multiple Dose Containers 
Those products that are to be marketed in multi-dose containers require special testing to 
assure that sterility and potency are maintained.  In order to properly conduct the test for 
multiple entry, the container stopper must be entered with a needle and withdrawn the 
maximum number of times the dosage on the label states.  Under these conditions, 
sterility and potency must be maintained.  The bottle contents should be checked for 
visual stopper particles.  The latter may occur upon penetration of the needle into the 
stopper.  Although, the ideal test period should be over the life of the proposed expiration 
period, the penetration study need only be conducted once and prior to the start of 
stability studies. 
C.  TYPE A, B, AND C MEDICATED PRODUCTS 
This section provides information for conducting stability studies for medicated feed 
products, premixes and complete feeds.  This section applies only to dry feed products. 
Liquid feed products and blocks are covered under separate sections elsewhere in the 
guidelines. 
Under the Second Generation regulation published March 3, 1986, two new concepts in 
the area of medicated feeds were presented.  The new concepts consisted of the renaming 
of feed products in general and adding the requirement of an expiration date. 
Under this regulation, the following classifications were provided: 
  Medicated premixes are now called Type A Medicated Articles.  
  Medicated finished feeds are now divided into two (2) different types, viz.,- 
o  Type B Medicated Feeds (Supplements, Intermediates, etc.) which must 
be diluted with feed material or can be fed top-dressed prior to feeding.  
o  Type C Medicated Feeds (Complete feeds, blocks, free-choice, etc). 
(which can be fed "as is" without the need of further dilution)  
NOTE:  In this guideline, the terms "premixes" and "medicated feeds" and their 
corresponding types will be used. 
1.  Expiration Dating Requirements  
(Reference: 21 CFR 514.1(b)(5)(x)) 
a.         Type A Medicated Articles (Medicated Premixes) 
Expiration date periods are required for all Type A Medicated 
articles (Premixes). (cGMP: 21 CFR 226.58) 
b.         Type B Medicated Feed Products 
30  The need for an expiration date for Type B medicated feeds will be 
evaluated on a case-by-case basis. 
c.         Type C Medicated Feed Products 
The need for or absence of an expiration date for Type C 
medicated feeds will need to be justified with stability data. 
2.  Study Temperature and Length 
a.         Room Temperature 
i.  Type A Medicated Articles (Premixes)  
All medicated premixes should be subjected to a room 
temperature study. The test schedule will be dependent on 
the proposed expiration date.  Section "Table of Suggested 
Test Schedule" for Test Schedule. 
ii.  Type B Medicate Feed Products  
Type B products, if prepared and sold as intermediate 
premixes, should follow the guides for a Type A Medicated 
(Premix) Articles. 
Those Type B products used as Type C products should 
follow the guides for Type C Medicated Product. 
iii.  Type C Medicated Products (Complete feeds)  
Stability studies for Type C products should be carried out 
at ambient temperature and RH for a least 90 days.  All 
existing weather conditions must be recorded. (See Section 
F.2.(v) for definition of ambient temperatures.  If 
temperatures other than ambient are used, then they should 
be specified. 
Test schedule:  0 (initial) 1, 2, 3 months 
b.         Elevated Temperatures  
i.  Type A Medicated Articles (Premixes)  
All medicated premixes (Type A Medicated Articles) 
should be studied at an elevated temperature station, 
(usually 37C) to at least 6 months. 
31  Test schedule:  0 (initial), 2, 4, 6 months 
ii.  Type B Medicated Feed Products  
Type B products, if prepared and sold as intermediate 
premixes, should follow the guides for a Type A Medicated 
Article. 
Those Type B product used as Type C products should 
follow the guides for Type C Medicated Products. 
iii.  Type C Medicated Feed Products (complete feeds)  
When Type C medicated products are studied at elevated 
temperatures, the study need not be carried beyond a one 
(1) month period, since feed products at elevated 
temperatures are likely to become moldy and, therefore, 
unusable. 
Test schedule:  0 (initial), 2, 3, 4 weeks 
NOTE:  Any testing can be carried to a longer period of 
time if the usage or data dictates or the sponsor wishes. The 
Center reserves the right to request longer periods of study 
if the data so indicate.  
If the stability data indicate a shorter period is necessary 
than that listed above or proposed, then the shorter time 
period will be required on the label. This action is to alert 
the user that the product will remain stable for the time 
period designated. Adjustment or removal of an expiration 
date for those products not required to have one may be 
accomplished through the submission of additional data 
requesting and justifying such action. 
3.  Product Composition 
The stability study should include a study of the medicated premix and the 
medicated feed product consisting of the active drug ingredient (from the 
medicated premix) and typical non-medicated feed components. This 
latter may contain vitamins, minerals, etc. A commercially available feed 
may be used. The exact formula for the premix and complete feed should 
be available for the study. 
If the exact formula cannot be obtained, the bag or label attached to the 
bag or available with the bulk product may be submitted. 
32  4.  Lots for Stability Study 
In order to produce meaningful results, samples from at least 3 production 
size lots should be tested. Data obtained from pilot size lots will provide 
only "Tentative" information on which to make an expiration/stability 
decision. 
5.  Testing Levels  
a.         Premixes (Type A Medicated Articles) 
The active drug ingredient(s) present must be tested at the labeled 
level(s). 
b.         Feeds (Type B and/or C Medicated Products) 
Complete feed products must be tested at the appropriate use level 
or levels of the active ingredient(s) listed on the label. 
c.         Multiple Drug Ingredients 
Where multiple drugs ingredients are proposed for use, the highest 
and lowest use levels for each proposed ingredient must be tested. 
Depending on the number of active ingredients in the feeds and 
recommended use ranges (levels), tests must be conducted at the 
high-low, low-low and low-high levels. 
6.  Pelleted Products 
The results of analysis of the mash product from with the pellets are 
prepared must be submitted along with the data/information from pelleted 
products. 
A description of the pelleting conditions should be submitted. Pressures 
and temperatures at the beginning and end of the pelleting process should 
be reported. The type of equipment should also be listed. 
Analyses of samples should be performed before and after pelleting to 
obtain an indication of what effect the pelleting has on concentration 
(potency) and the physical product. The assay schedule should be 
provided. 
33  7.  Moisture Content 
Moisture determinations, where necessary, should be made at the time of 
individual analyses and submitted with assay results. Corrections in 
calculations should be applied where necessary. 
8.  Test Results  
The following types of information, as a minimum, should be provided for 
each testing station: 
a.         Moisture content, if necessary. 
b.         Assay results (adjusted for moisture, if necessary). 
NOTE:  The initial assay results must always be reported.  This is 
the starting point for all studies. 
c.         Any other information relative to the stability study or product. 
d.         All raw data including representative spectra or chromatogram of 
sample and standards related to the method. 
NOTE:  Assay limits should be determined based on recovery data 
using sufficient numbers of spiked and actual samples. 
9.  Additional Studies 
The following one-time studies should also be conducted on samples of 
medicated premixes and feeds: 
a.         Interference studies - Combination of Drugs 
When two or more active drug ingredients are present these studies 
are necessary to determine if any interference occurs that will 
hinder the proper assay of either ingredient.  These studies should 
also be conducted when it is known that similar drug products 
approved for use in the species under proposal will be encountered 
in marketing and/or use. 
b.         Segregation studies 
Where necessary for bulk or bagged materials, analysis of top, 
middle and bottom samples should be conducted.  These studies 
should be conducted to assure the drug component does not 
concentrate in one portion of the product or container.  The sample 
34  should be transported at least 50 miles (round trip) to simulate 
actual conditions. 
c.         Homogeneity studies 
Homogeneity studies should be performed on all proposed premix 
and finished feed products. 
For these studies, analysis of top, middle and bottom of bagged or 
stored bulk samples should be conducted.  Bags should be stored in 
position most commonly used in commercial outlets/storage 
facilities. 
When label directions call for very small quantities (e.g. 2.5 oz.) of 
the premix to be added to unmedicated feed to make a ton, 
homogeneity is especially important. 
10.  Pilot vs. Production Samples 
Samples from production-size batches should be used for stability studies.  
These samples provide for approximate actual use conditions.  However, if 
pilot scale samples are used, this fact should be reported.  Laboratory scale 
samples provide for optimum control of all factors.  Therefore, it should 
be kept in mind that changes may be needed in limits once the drug is 
approved for use and the "real" or "actual" use situations are monitored 
and evaluated.  Such changes may be provided by the applicant or 
requested by the Agency.  The applicant should use real world conditions 
as much as possible. 
D.  TYPE B AND C MEDICATED LIQUID FEED SUPPLEMENTS 
The approval of a medicated premix for use in formulating liquid feed supplements calls 
for different types of stability studies than those indicated for use in dry feeds. 
The purpose of stability testing a medicated premix in liquid feed supplements (LFS) is 
twofold: 
  to ensure that the drug substance is chemically stable in general in LFS matrices  
  to ensure the drug substance is homogeneously distributed or positionally stable 
(in general) in LFS matrices during on-site storage before and at the time of use.  
Drug stability in a LFS may be tested in specifically developed formulations or in 
formulas containing ingredients typical of those in current use in the liquid feed industry. 
See Appendix B. 
35  A drug sponsor under a new application should establish the chemical stability of the 
drug to be used in a liquid feed matrix.  The sponsor may establish whether or not the 
drug is positionally stable in the matrix or how that stability must be maintained by 
agitation. 
Approval of the use of a specific drug (in a medicated premix) in a LFS will be published 
in a regulation (21 CFR 558) for use in a matrix with specific parameters. 
Manufacturers of liquid feed supplements may use the approved premix for a LFS by 
submitting data for a formula they wish to produce and use.  The data may be submitted 
under a master file. Approval for use of the LFS will be granted by an agency approval 
letter under a supplement to the sponsor's NADA. 
Appendix A provides information relative to current commonly found physical/chemical 
parameters used in the liquid feed industry. 
Appendix B lists common ingredients generally used in liquid feeds under current 
practices in the liquid feed industry. 
Appendixes A and B are for the drug sponsor's use in obtaining approval for use of the 
drug premix in all liquid feed supplements with no further need for the liquid feed 
supplement manufacturer to develop data unless the LFS manufacturer wants to claim 
that the drug is positionally stable in his liquid feed matrix and no agitation is needed. 
1.  Protocols 
Prior to initiation of any studies for testing a premix containing a drug 
chemical in a LFS, it is strongly suggested a testing protocol requesting 
the Center's comments be submitted. 
2.  Stability Test Information 
The following information should be provided to study the stability of any 
medicated liquid feed formulation: 
a.         A complete description of the proposed formulations 
This description should provide complete information on the 
composition of the actual formulation(s) to be used including the 
potency of the drug ingredients, identification of all other 
ingredients and the approximate ranges of their use levels. 
The description should also provide information on the physical 
and chemical parameters of the formulation and manufacturing 
conditions.  The latter should include, where appropriate, mixing 
times, temperatures, etc. 
36  NOTE:  The LFS sponsor/manufacturer is responsible to assure 
that and LFS produced falls within the stability parameters of the 
matrix. 
b.         Finished Product Specifications 
The specifications should describe: 
i.  The physical characteristics of the formulation  
  appearance  
  color  
  odor  
ii.  The chemical characteristics of the formulation 
  viscosity data, if applicable  
  pH data  
  other properties or characteristics  
  identification of the active ingredient  
  quantitative assay of the active ingredient  
NOTE:  The data should provide maximum/minimum 
limits (based on data to verify same), where necessary, 
unless the actual use or stability data warrants the 
observance of fixed conditions.  
c.         Analytical Method Information 
The method(s) used to determine the specifications for the active 
ingredient(s) or other chemical characteristics should be provided. 
The method(s) should be provided in detail or be properly 
referenced to a master file, actual NADA, or appropriate journal. 
The assay limits proposed or already established for the LFS 
product and determined to be appropriate (by data) should be 
provided.  Proper validation data should be provided to support the 
performance of the method and the proposed assay limits. 
d.         Conditions of Testing 
A complete description of the testing conditions involved in the 
studies should be provided.  Containers, temperatures, intervals for 
stability testing, sampling techniques, and mixing and storage 
equipment should be reported. 
37  e.         Results of Stability Tests 
The raw data should be analyzed and reported.  Statistical analysis 
may be required. 
3.  Types of Stability Testing 
a.         Chemical Stability 
Applicable to all medicated premix products intended for use in a 
LFS. 
The drug ingredient must be stable, that is, it does not degrade in 
the matrix proposed.  If the drug chemical remains stable but fails 
to show uniform dispersion in the matrix (in either laboratory or 
field trials), testing will be expected to show that upon mixing or 
agitation the drug chemical remains stable and uniformly dispersed 
in the proposed matrix. 
If the sponsor of the application recommends agitation in advance 
of any use, chemical stability testing may only be necessary. 
Laboratory testing will be required. 
b.         Positional Stability 
Applicable to those medicated premix products in a LFS matrix not 
requiring agitation. 
A proposed LFS formulation will be considered as positionally 
stable if appropriate laboratory studies demonstrate that the active 
ingredient(s) remain dispersed throughout (no significant 
stratification or layering) the LFS after 8 weeks storage without 
agitation at 30C and under refrigeration (2 to 8C).  Stability in 
the same product must be verified by one field study in which there 
is no agitation. 
If stratification occurs, agitation may be needed to disperse the 
active ingredient. 
4.  Stability Testing Studies 
a.         Laboratory Study 
The design of the laboratory studies for both chemical and 
positional stability should include the following factors as standard 
requirements: 
38  iii.  Samples from at least 3 pilot batches manufactured under 
production conditions.  
ii.         An appropriate container for storage of samples.  The 
container should be described.  
iii.        Samples should be stored undisturbed (i.e., unagitated) at 
the designated storage temperature of 30C, and under 
refrigeration (2 to 8C).  
iv.  Samples should be taken from the top, middle and bottom 
of the container contents for analysis.  Analysis of the 
container contents should be performed in duplicate at 0, 2, 
4, 6 and 8 weeks.  The physical condition/appearance of the 
container contents should be observed and reported at each 
time of sampling.  
v.         A short freeze-thaw study for period of at least 5 days 
should be conducted to indicate the effect of freezing, if 
any, and the subsequent thawing.  Samples should be taken 
from the top, middle and bottom of container contents for 
analysis at the end of the 5 day cycle.  The condition of the 
sample should be observed and recorded throughout the 
study.  
vi.  Other stability tests may be added as deemed necessary to 
better describe the stability parameters and the stability of 
the product.  
vii.       If agitation is to be used, the equipment, mixing sequence 
and time intervals should be described.  
b.         Field Study  
The purpose of the field study is to verify the results of the 
laboratory studies and to demonstrate if any temperature layering 
effect may take place when using large, outside storage tanks.  In 
any case, the stability of the product must not be adversely 
affected. 
The field study should include the following: 
i.          Use of an actual batch of the formulation  
Only one lot need be studied.  
39  iv.  Analysis of the storage container contents  
1.         A one (1) pint sample should be removed when the 
tank is full, approximately half-full (50% of 
capacity) and again at 25% and 10% of capacity.  In 
the case of a positionally stable product, samples 
should be taken from the top 20% of the storage 
container, if possible.  If not, sample from the 
delivery pipe.  In the case of a product being 
agitated, remove the sample by the delivery pipe. 
Any sample removed by the delivery pipe should be 
taken after discarding any material in the delivery 
pipe. 
2.         Samples should be analyzed in duplicate. 
3.         Analytical results should be within the established 
assay limits for the labeled active ingredient(s). 
4.         The physical condition/appearance of the product 
should be observed and reported when sampling is 
performed. 
iii.        Length of the study  
The length of the study should be commensurate with the 
anticipated time interval of storage and use, i.e., intervals 
when supplies of the LFS are to be renewed, generally not 
less than 2 weeks and not more than 8 weeks.  
iv.        Reporting of weather conditions  
Existing weather conditions (temperature, wind, rain, etc.) 
should be described when the tank in filled (full) and when 
samples are taken.  
v.  Type of mixing equipment  
If the drug fails to show positional stability in laboratory 
studies, storage tanks with mixing equipment should be 
used.  The equipment, mixing sequence and time intervals 
should be reported.  
c.         Lick-Tank Operation 
40  If a user plans to use a lick-wheel system to deliver a LF product, 
the type of stability testing to be conducted should simulate those 
conditions to be used in field storage and use, including mixing. 
5.  Recommended Labeling 
Information relative to proper use and mixing and equipment, where 
necessary to maintain stability of the LFS product should be provided so 
that proper labeling can be attached to the premix container. 
If agitation is necessary for the LFS formulation or if the LFS 
formulations if found to be positionally unstable, appropriate directions 
are recommended for placement on the premix container label (which is to 
be used in preparing the LFS) and any LFS labeling. 
a.         For liquid supplements stored in recirculating tank systems: 
"Because the drug product is not positionally stable in this liquid 
supplement, recirculate immediately prior to use for no less than 
10 minutes, moving not less than 1% of the tank contents per 
minute from the bottom of the tank to the top. 
Recirculate daily as directed in this paragraph, even when the 
supplement is not used." 
b.         For liquid supplements stored in mechanical, air or other agitation-
type tank systems: 
"Because the drug product is not positionally stable in this liquid 
supplement, agitate immediately prior to use for not less than 10 
minutes, creating a turbulence at the bottom of the tank that is 
visible at the top. 
Agitate daily as directed in this paragraph, even when the 
supplement is not used." 
c.         If the medicate LFS is found to be chemically and positionally 
stable in both laboratory and field studies, no agitation instructions 
will be required on the labels for such LFS products. 
______________________________________________________________________________ 
 
 
 
 
41  APPENDIX A 
 
In survey undertaken by AFMA (now the AFIA) in 1980 which covered about 75% of 
actual production, a set of physical/chemical parameters (listed below) was found that 
can be used as guidelines for a typical liquid feed supplement. 
 
Parameter  Low High  Average
pH  3.8 7.5  5
Total Moisture  27 40  35
Mixing Temp., F  63 96  81
                       (C)  (17) (36)  (27)
Mixing Time, Min.  17 37  27
Time of Days*  10 45  27
*(Manufacture to Consumption)   
______________________________________________________________________________ 
 
APPENDIX B 
 
The 1980 survey indicated the ingredients below commonly compose a "liquid 
supplement matrix." 
 
The ratios of ingredients in the formula matrix as listed below may be adjusted to arrive 
at a typical formulation with a pH of about 5.0 and moisture of about 35%.   
 
Sample formula for testing drug stability in Liquid Supplements: 
 
Ingredient  Percent (%) In Formula 
 
Molasses  47 
Lignin Sulfonate  10 
Condensed Molasses Fermentation Solubles  15 
Urea, Dry  8 
Corn Steep Liquor  3 
Ammonium Sulfate  2 
Ammonium Polyphosphate  3 
Phosphoric Acid  2 
Salt  2 
Typical Vitamin/Trace Mineral Premix  8 
   
TOTAL  100.0% 
 
NOTE:  The appendices should be used as a guide in the development of a liquid feed 
matrix.  Ingredients other than those listed in Appendix B may be used because of 
availability, convenience, research, new technology or proposed use.  Users should be 
aware that use of such new ingredients may cause a change in parameters listed in 
Appendix A.  In any case, the liquid feed supplement will be evaluated as presented. 
42  ______________________________________________________________________________ 
 
E.  MEDICATED BLOCKS 
Medicated blocks are compressed feed material (which contain medication) that is shaped 
into a cubic form for animal free-choice use. Medicated blocks are considered as Type C 
medicated products. 
1.  Stability Study 
The most meaningful stability data will be that obtained on field samples 
stored under the same conditions as those blocks consumed by cattle.  The 
data can be obtained from samples used during efficacy trials or the 
development of consumption data. These blocks should be stored so that 
animals do not disturb them. 
The information should include: 
a.         The formulation representative of the product to be marketed. 
b.         Components and composition of the various formulations on which 
the study is to be conducted. 
c.         Description of procedures used in preparation of the blocks, 
including temperatures, pressures and other parameters used. 
d.         Data developed on blocks stored under warehouse conditions since 
blocks may be stored for some time before being placed on the 
range. Under simulated warehouse conditions, samples should be 
stored at 25C and 37-40C for six months. 
e.         Data developed on blocks placed on the range for consumption. 
Actual weather conditions should be provided, e.g., temperature, 
cloud cover, rain, snow, etc. 
Since consumption rates vary, it is not possible to state the length 
of time that a stability study should be conducted under range 
conditions.  As a general rule, the blocks should be in the field at 
least for 14 days but not more than 90 days. 
f.         The schedule of testing stations. 
g.         The method of sampling the blocks for tests.  Basically, all 
samples should be taken from the surface and from a core of the 
block.  However, an applicant may propose a different technique. 
43  h.         A stability-indicating and validated analytical method. 
NOTE:  Samples of the mash product used to manufacture the 
block should be retained for analysis.  The results of the analysis 
should be reported with the block results. 
2.  Label Statement for Usage 
A procedure for determining the type of label statement that will provide 
added assurance that blocks do not remain on the range beyond the period 
of satisfactory stability is as follows: 
a.         The available stability data should be reviewed and the time 
interval should be determined over which the drug(s) exhibits 
satisfactory stability. 
b.         On the basis of stability data, daily consumption, and size of the 
block, a label statement should be developed that will indicate how 
blocks are to be used and when new blocks should be placed for 
use. 
c.         Formula to determine label statement: 
        
No. of cattle (per block) =      __A__                    
                 B x C 
 
Where: 
A = weight of block (lb) 
B = lbs/animal/day 
C = number of days 
 
For example: 
 
If the drug has exhibited satisfactory stability for 2 weeks (14 
days), the average daily consumption is 1/4 lbs and the  block 
weighs 28 lbs, the label should say, "Use one block for every eight 
(8) cattle.  NEW BLOCKS SHOULD BE PLACED OUT IN 
APPROXIMATELY FOURTEEN (14) DAYS." 
 
F.  SOLUBLE POWDERS AND DRINKING WATER 
 
1.  Soluble Powders 
Medicated soluble powders for the preparation of drinking water are 
expected to remain stable for the projected shelf-life of the product. 
44  Samples should be stored both at 25C and at 37-40C.  In addition, to 
testing for drug strength, storage samples should also be tested for 
moisture content, solubility (dissolution of the powder in a solvent), 
caking, and pH of solution. 
Soluble powders are considered pharmaceutical dosage forms and, 
therefore, must be manufactured according to the cGMPs under 21 CFR 
211. 
Stability studies should be run on the solution containing the dissolved 
powder over the labeled storage period.  Appropriate restrictions should be 
stated on the label where necessary. 
2.  Drinking Water 
Medicated drinking water should exhibit adequate stability for the time 
period(s) indicated on the label. 
Medicated drinking water should be prepared using both soft and hard 
water and stored both at temperatures of 25C and at 37-40C in metal 
troughs, including rusty troughs, for stability testing.  For concentrated 
solutions stored at both temperatures in representative metering devices, 
the storage period should correspond to the maximum time during which 
the concentrate remains efficacious and safe. 
If ambient temperatures or those other than that stated above for the above 
studies are used, all existing condition must be described. 
Proportioner concentrate assays and use level assays should be provided. 
NOTE:  In conducting the above tests, local drinking water (whether well 
or municipal) should be used.  It is not necessary to develop "specially" 
prepared water for testing, since it will not reflect the "real world" use. 
G.  ORAL DRENCHES 
 
Drenches for oral administration may be available either as powders or as concentrated 
solutions or suspensions.  They may also appear as solutions or suspensions ready for 
use. 
Drenches are considered pharmaceutical dosage forms and must be manufactured 
according to the cGMPs under 21 CFR 211. 
45  In all cases, the product, at the time of use, should meet the general requirements for 
chemical stability and maintain, under expected storage conditions, a reasonable degree 
of physical integrity, such as, absence of caking, sticking, gross discoloration or 
irreversible loss of suspension or solution of the product. 
Maintenance of adequate physical and chemical stability of partially used liquid products 
is necessary.  If this product shows degradation, then a label restriction against reuse may 
be required. 
NOTE:  In conducting the above tests, local drinking water (whether well or municipal) 
should be used.  It is not necessary to develop "specially" prepared water for testing, 
since it will not reflect the "real world" use. 
H.  MILK REPLACERS 
 
In addition to the data requested in the general guidelines for the stability of the product 
as a drug dosage form, recovery data should be submitted to show that the drug to be 
used as a milk replacer is stable in solution for the length of time stated on the label. 
Medicated milk replacers should be prepared using both hard and soft water.  They 
should be stored at temperatures of 25C and 37-40C in their market containers (metal, 
synthetic rubber and/or plastic) for the length of time stated on the label.  If temperatures 
other than 25C are used, e.g., ambient temperature, that temperature plus weather 
conditions must be described and reported. 
Data must also be developed to show that the drug is homogenously mixed and 
distributed in the milk replacer solution. 
NOTE:  In conducting the above tests, local drinking water (whether well or municipal) 
should be used.  It is not necessary to develop "specially" prepared water for testing, 
since it will not reflect the "real world" use. 
I.  MASTITIS PREPARATIONS 
 
The stability tests for mastitis preparations are basically the same as for solutions listed 
under pharmaceutical dosage forms. 
Tests for stability should include: 
  Appearance  
  Potency  
  Suspendability  
46    Syringeability  
  Leaching data for syringes  
  Freezing  
  pH Measurement  
J.  SUSTAINED  RELEASE PRODUCTS 
In addition to the specific stability tests that are required for the particular dosage form, 
the stability study should include assays for the release pattern of the active ingredient. 
Because of the nature of these types of drugs, drug release patterns or rates should be 
measured by dissolution tests.  When microencapsulated sustained-release dosage forms 
are to be studied, measurement of the capsule particle size range distribution, including 
ratios of core to wall thickness, may be necessary. 
K.  MICROENCAPSULATED PRODUCTS 
Microencapsulated drug products offer specialized drug delivery systems and dosage 
form characteristics that may prolong the shelf-life of the drug.  In addition to the specific 
stability tests that are recommended for the particular dosage form, the measurements 
during the course of the stability study should demonstrate that properties claimed for the 
microencapsulated product have not been diminished or destroyed during storage. 
Maintenance of the integrity of the wall material should be demonstrated. 
L.  VAT DIPS 
In addition to the specific stability information recommended for the particular marketed 
dosage form, stability studies of vat dips, i.e., the dosage form dissolved in the 
recommended solvent system for use should include active ingredient assays and pH.  
Such tests should be conducted at intervals to the period proposed on the label of field 
storage. 
M.  rDNA PRODUCTS 
rDNA derived or "genetically engineered" active ingredients will be administered to 
animals using available conventional delivery systems, e.g., tablets, capsules, solutions, 
etc.  Stability studies for products containing drug chemicals derived from rDNA 
techniques should be the same as those conducted for the particular dosage form.  Other 
tests related to the manufacture of the product may be necessary and will be determined 
on a case-by-case basis. 
NOTE:  rDNA type products are often called "Bio-Tech" products. 
47  N.  DRUG SUBSTANCES 
Even though the Stability Guidelines are mainly related to finished dosage forms or 
medicated products (Type A, B or C), the concepts are applicable for performing studies 
on drug substances or raw materials used in the manufacture of the final dosage form. 
 
 
 
48