SPECIAL INSTRUCTIONS for STABILITY TESTING of SPECIFIC DRUG PRODUCTS

SPECIAL INSTRUCTIONS for STABILITY TESTING of SPECIFIC DRUG PRODUCTS


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.

PHARMACEUTICAL DOSAGE FORMS
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
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.
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
MEDICATED PREMIXES AND FINISHED FEEDS- DRY FEED 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.,-
Type B Medicated Feeds (Supplements, Intermediates, etc.) which must be diluted with feed material or can be fed top-dressed prior to feeding.
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.
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.
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.
Study Temperature and Length
a. Room Temperature
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.
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.
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
Type A Medicated Articles (Premixes)
All medicated premixes (Type A Medicated Articles) should be studied at an elevated temperature station, (usually 37°C) to at least 6 months.
Test schedule: 0 (initial), 2, 4, 6 months
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.
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: (1) 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.
NOTE: (2) 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.
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.
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.
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.
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.
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.
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.
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 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.
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
and
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.
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.
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.
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.
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:
The physical characteristics of the formulation:
appearance
color
odor
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.
e. Results of Stability Tests.
The raw data should be analyzed and reported. Statistical analysis may be required.
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 30°C and under refrigeration (2° to 8°C). 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.
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:
Samples from at least 3 pilot batches manufactured under production conditions.
An appropriate container for storage of samples. The container should be described.
Samples should be stored undisturbed (i.e., unagitated) at the designated storage temperature of 30°C, and under refrigeration (2° to 8°C).
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.
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.
Other stability tests may be added as deemed necessary to better describe the stability parameters and the stability of the product.
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 include the following:
Use of an actual batch of the formulation. Only one lot need be studied.
Analysis of the storage container contents.
a) 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.
b) Samples should be analyzed in duplicate.
c) Analytical results should be within the established assay limits for the labeled active ingredient(s).
d) The physical condition/appearance of the product should be observed and reported when sampling is performed.
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.
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.
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
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.
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.
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 in 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:
____________________________________________________________

Percent (%)
Ingredient 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.
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.
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 25°C and 37-40°C 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.
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.
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:
A
No. of cattle (per block) = _________
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
SOLUBLE POWDERS
Medicated soluble powders for the preparation of drinking water are expected to remain stable for the projected shelf-life of the product. Samples should be stored both at 25°C and at 37-40°C. 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.
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 25°C and at 37-40°C 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.
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 25°C and 37-40°C in their market containers (metal, synthetic rubber and/or plastic) for the length of time stated on the label. If temperatures other than 25°C 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 homogeously 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
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.
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.


ALPHABETICAL LISTING
- A - Acid/Base Decomposition Tests Section 2 - G.3.a.(i) Active Ingredient Section 2 - B.1. Added Substances Section 2 - B.5. Adhesive/Glue Section 2 - D.6. Aerosols Section 3 - A. Alternate Drug Suppliers Section 2 - J.2. Analysis of Samples Section 2 - E.3. Analytical Methods Section 2 - G.2. - B - Base Decomposition Test Section 2 - G.2.c. Blocks, Medicated Section 3 - G.3.a.(i) - C - Capsules Section 3 - A. Chemical and Physical Properties Section 2 - B.4. Chemical Stability (LFS) Section 3 - D.3.a. Commitment Format Section 2 - K. Commitment, Stability Section 2 - K.(b) Container Changes Section 2 - D.7. Containers Section 2 - D. Containers for liquids Section 2 - D.3. Containers Material Integrity Section 2 - D.2. Correlation with Efficacy/Toxicity Section 2 - B.7. Cream Section 3 - A. - D - Data Analysis (Statistics) Section 2 - H. Data Reporting Section 2 - I. Definition of Active Ingredient Section 2 - B.1. Degradation Products Section 2 - B.8. Design Considerations (Statistics) Section 2 - H.1. Dip, Vat Section 3 - L. DNA Products Section 3 - M. Dosage Forms (Pharmaceutical) Section 3 - A. Drenches, Oral Section 3 - G. Drinking Water Section 3 - F.2. Drug Preparation Section 2 - B.3. Drug Substances Section 3 - N. - E - Efficacy and Stability Section 2 - B.7. Emulsion Section 3 - A. Environmental Factors Section 2 - C.4. Expiration Date Determination Section 2 - H.3. Expiration Date Periods Section 2 - C.2. Expiration Dates Section 2 - C.2. Expiration Dating (Feeds) Section 3 - C.2.a.(1) - F - Feeds Section 3 - C. Feeds, Liquid Section 3 - D. Field Study (Liquid Feeds) Section 3 - D.4.b. Format - Method Section 2 - G. Format - Stability Commitment Section 2 - K. - G - Gel Section 3 - A. General Stability Section 2 - B. Glue (containers) Section 2 - D.6. - H - Handling of Samples Section 2 - E.3. Homogeneity (Premixes/Feeds) Section 3 - C.9.c. - I - Implants Section 3 - A. Initial Study Commitments Section 2 - J.1. Injections Section 3 - A. Intended Market Container Section 2 - D.1. Inteference (Premix/Feeds) Section 3 - C.9.a. - J - - K - - L - Label Restrictions, (Storage) Section 2 - C.5. Label Statement (Blocks) Section 3 - E.2.c. Labeling Statements (Liq Feeds) Section 3 - D.3. Laboratory Studies (Liq Feeds) Section 3 - D.4.a. Lick Tank Operation (Liq Feeds) Section 3 - D.4.c. Light degradation tests Section 2 - G.2.c. Liquid Feeds Section 3 - D. Liquids, Containers for Section 2 - D.3.. Lots for Stability (Feeds) Section 3 - C.4. - M - Market Container Section 2 - D.1. Mastitis Preparations Section 3 - I. Material (Container) Integrity Section 2 - D.2. Medicated Blocks Section 3 - E. Medicated Finished Feeds Section 3 - C. Medicated Liquid Feeds Section 3 - D. Medicated Premixes Section 3 - C. Method Attributes Section 2 - G.2. Method Conditions Section 2 - G.3. Method Control Section 2 - G.3. Method Format Section 2 - G. Method References Section 2 - G.5. Methods (Release) Section 2 - G.1. Microencapsulated Products Section 3 - K. Milk Replacers Section 3 - H. Moisture Content Section 3 - C.7. Multiple Dose Container Section 3 - B. - N - New Drug Substances Section 3 - N. - O - Observations, Physical Section 2 - D.4. Ointments Section 3 - A. Oral Drenches Section 3 - G. - P - Pastes Section 3 - A. Pelleted Product Section 3 - C.6. Periods, Expiration date Section 2 - C.2. Pharmaceutical Dosage Forms Section 3 - A. Physical Observations (containers) Section 2 - D.4. Physical Properties (general) Section 2 - B.4. Pilot Samples Section 3 - C.10 Positional Stability Section 3 - D.3.b. Post-Approval Studies Section 2 - J.4. Potency (general product) Section 2 - B.2. Powder for Injection Section 3 - A. Powders, Oral Section 3 - A. Powders, Soluble Section 3 - F.1. Premixes, Expiration Dating Section 3 - C.1. Premixes, Homogeneity Section 3 - C.9.c. Premixes, Interference Section 3 - C.4. Premixes, Lots for Stability Section 3 - C.4. Premixes, Medicated Section 3 - C. Premixes, Product Composition Section 3 - C.3. Premixes, Test results Section 3 - C.8. Premixes, Testing level Section 3 - C.5. Preparations, Sterile Section 3 - B. Production Samples Section 3 - C.10 Product Changes Section 2 - B.6. Product Changes (Commitment) Section 2 - J.2. Product Composition Premixes/Feeds Section 3 - C.3. Product Specifications Section 2 - B.9. Product Stability Parameters Section 2 - B.9. Product, Stress of Section 2 - G.2.c. Protocols, general Section 2 - A. Protocols, Medicated Liquid Feeds Section 3 - D.1. - Q - Quality Control Methods Section 2 - G.1. - R - Reconstituted Products Section 2 - F.3.C. Release Methods Section 2 - G.2.a. Reporting of Data Section 2 - I. Restrictions, Labeling (Storage) Section 2 - C.4. Results, Test (Premixes/Feeds) Section 3 - C.8. - S - Samples Section 2 - E.1. Samples (Premixes/Feeds) Section 3 - C.10. Sampling Plan Section 2 - E.2. Sealed Containers Section 2 - D.5. Segregation (Premixes/Feeds) Section 3 - C.9.b. Shelf Life Section 2 - C.1. Soluble Powders Section 3 - F.1. Solution Section 3 - A. Stability, Chemical (Liquid Feeds) Section 3 - C.3.a. Stability, Field (Liquid Feeds) Section 3 - C.4.b. Stability, Laboratory (Liquid Feeds) Section 3 - C.4. Stability, Lots (Premixes Feeds) Section 3 - C.4. Stability, Medicated Blocks Section 3 - E.1. Stability Method References Section 2 - G.5. Stability, Positional (Liquid Feeds) Section 3 - C.3.b. Stability Samples Section 2 - E.1. Stability Schedule Section 2 - F. Stability, Standards for Section 2 - B.9. Stability Study Commitment Section 2 - J. Stability Study Format Section 2 - K. Stability Tests, Information (Liq) Section 3 - D.2. Standard Curve Section 2 - G.4. Sterile Operations Section 3 - B. Sterile Preparations Section 3 - B. Strength (potency-general) Section 2 - B.2. Study Temperatures (Premixes/Feeds) Section 3 - C.2. Study Temperatures, general Section 2 - F.2.(A). Sustained Release Products Section 3 - J. Substances, Drug Section 3 - N. Supplements, Liquid Feeds Section 3 - D. Suspensions Section 3 - A. - T - Tablets Section 3 - A. Temperature, Storage Condition Section 2 - C.3. Temperature, Test Schedule Section 2 - F.2.(A). Test Information (Liquid) Section 3 - D. Test Results Section 3 - C.8. Test Schedule Section 2 - F.2. Test Schedule Table Section 2 - F.2.(B) Testing Levels (Premixes/Feeds) Section 3 - C.5. Toxicity Studies Section 2 - B.7. Type A Medicated Article Section 3 - C. Type B Medicated Feed Product Section 3 - C. Type C Medicated Feed Product Section 3 - C. Type of Stability Testing (Liquid) Section 3 - C.3. - U - - V - Vat dips Section 3 - L. - W - Water, Drinking Section 3 - F.2.