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
`BACKGROUND ............................................................................................................... 1
`II.
`III. GENERAL CONSIDERATIONS ................................................................................... 2
`A.
`PROTOCOLS ....................................................................................................... 2
`B.
`GENERAL STABILITY CONSIDERATIONS................................................. 2
`Definition of Active Ingredient......................................................................... 2
`Strength (Potency) ............................................................................................ 3
`Drug Preparation............................................................................................... 3
`
`1.
`2.
`3.
`
`i
`
`Hospira, Exh. 2008, p. 1
`
`

`
`4.
`5.
`6.
`7.
`8.
`9.
`
`1.
`2.
`3.
`4.
`5.
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`
`1.
`2.
`3.
`
`1.
`2.
`3.
`
`1.
`2.
`3.
`4.
`5.
`
`1.
`2.
`3.
`
`1.
`2.
`3.
`4.
`
`1.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`I.
`J.
`
`K.
`
`Chemical and Physical Properties..................................................................... 4
`Added Substances ............................................................................................. 4
`Product Changes ............................................................................................... 4
`Correlation with Efficacy and Toxicity Studies................................................ 4
`Degradation Products........................................................................................ 5
`Product Stability Parameters............................................................................. 5
`STORAGE CONDITIONS .................................................................................. 5
`Shelf-Life Duration of Studies.......................................................................... 5
`Expiration Dates................................................................................................ 5
`Temperature ...................................................................................................... 7
`Environmental Factors...................................................................................... 8
`Special Labeling Restrictions ........................................................................... 8
`CONTAINERS...................................................................................................... 8
`Intended Market Container ............................................................................... 9
`Container Material Integrity ............................................................................. 9
`Containers for Liquids: Special Considerations .............................................. 9
`Physical Observations....................................................................................... 9
`Sealed Containers.............................................................................................. 9
`Adhesive/Glue................................................................................................. 10
`Container Changes.......................................................................................... 10
`STABILITY SAMPLES..................................................................................... 10
`Samples........................................................................................................... 10
`Sampling Plan ................................................................................................. 11
`Handling and Analysis of Samples................................................................. 11
`STABILITY SCHEDULE.................................................................................. 11
`General............................................................................................................ 11
`Test Schedule Information.............................................................................. 13
`Table of Suggested Test Schedules................................................................. 16
`ANALYTICAL METHODS .............................................................................. 18
`Quality Control/Release Methods................................................................... 18
`Method Attributes ........................................................................................... 18
`Method Controls and Conditions.................................................................... 20
`Standards Curves ............................................................................................ 20
`Stability Method References........................................................................... 20
`STATISTICAL EVALUATION........................................................................ 23
`Design Considerations .................................................................................... 23
`Data Analysis.................................................................................................. 23
`Expiration Date Determination....................................................................... 23
`REPORTING OF DATA ................................................................................... 24
`STABILITY STUDY COMMITMENTS ......................................................... 25
`Initial Study Commitments............................................................................. 25
`Product/Container Changes/Alternate Drug Substance Suppliers.................. 26
`Analysis of Distribution Samples ................................................................... 26
`Post-Approval Studies .................................................................................... 26
`STABILITY STUDY COMMITMENT FORMAT......................................... 26
`Samples of Testing.......................................................................................... 26
`
`ii
`
`Hospira, Exh. 2008, p. 2
`
`

`
`IV.
`
`D.
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`10.
`
`Control Tests................................................................................................... 27
`2.
`Container......................................................................................................... 27
`3.
`Product Storage Conditions ............................................................................ 27
`4.
`Frequency or Interval of Testing..................................................................... 27
`5.
`Result Reporting ............................................................................................. 27
`6.
`Withdrawal Provisions.................................................................................... 27
`7.
`SPECIFIC CONSIDERATIONS .................................................................................. 28
`A.
`PHARMACEUTICAL DOSAGE FORMS ...................................................... 28
`B.
`STERILE PREPARATIONS............................................................................. 29
`C.
`TYPE A, B, AND C MEDICATED PRODUCTS............................................ 30
`Expiration Dating Requirements..................................................................... 30
`Study Temperature and Length....................................................................... 31
`Product Composition ...................................................................................... 32
`Lots for Stability Study................................................................................... 33
`Testing Levels................................................................................................. 33
`Pelleted Products............................................................................................. 33
`Moisture Content ............................................................................................ 34
`Test Results..................................................................................................... 34
`Additional Studies........................................................................................... 34
`Pilot vs. Production Samples .......................................................................... 35
`TYPE B AND C MEDICATED LIQUID FEED SUPPLEMENTS............... 35
`Protocols ......................................................................................................... 36
`1.
`Stability Test Information............................................................................... 36
`2.
`Types of Stability Testing............................................................................... 38
`3.
`Stability Testing Studies ................................................................................. 38
`4.
`Recommended Labeling ................................................................................. 41
`5.
`E. MEDICATED BLOCKS.................................................................................... 43
`1.
`Stability Study................................................................................................. 43
`Label Statement for Usage.............................................................................. 44
`2.
`SOLUBLE POWDERS AND DRINKING WATER....................................... 44
`Soluble Powders.............................................................................................. 44
`Drinking Water ............................................................................................... 45
`ORAL DRENCHES............................................................................................ 45
`G.
`H. MILK REPLACERS .......................................................................................... 46
`MASTITIS PREPARATIONS .......................................................................... 46
`I.
`J.
`SUSTAINED – RELEASE PRODUCTS.......................................................... 47
`K. MICROENCAPSULATED PRODUCTS......................................................... 47
`L.
`VAT DIPS............................................................................................................ 47
`M.
`rDNA PRODUCTS ............................................................................................. 47
`DRUG SUBSTANCES........................................................................................ 48
`N.
`
`F.
`
`1.
`2.
`
`iii
`
`Hospira, Exh. 2008, p. 3
`
`

`
`Guidance for Industry
`
`Drug Stability Guidelines
`
`
`
`This guidance represents the Food and Drug Administration’s (FDA’s) 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.
`
`INTRODUCTION
`
`
`
`I.
`
`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.
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities. Instead, guidances describe the FDA’s 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 FDA’s 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
`
`Hospira, Exh. 2008, p. 4
`
`

`
`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
`
`Hospira, Exh. 2008, p. 5
`
`

`
`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 Remington’s Pharmaceutical Sciences, Sixteenth Edition, Pg. 284 (1985).
`
`3
`
`Hospira, Exh. 2008, p. 6
`
`

`
`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
`
`Hospira, Exh. 2008, p. 7
`
`

`
`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
`
`Hospira, Exh. 2008, p. 8
`
`

`
`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:
`
`b.
`
`
`Expiration dates are required.
`
`Medicated Feed Products:
`
`i.
`
`ii.
`
`iii.
`
`
`Premixes [Type A medicated articles]
`
`Expiration dates are required.
`
`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.).
`
`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
`Dosage forms:
`Implants, injectables, tablets, capsules,
`soluble powders, etc.
`
`MAX. TIME PERIOD
`5 years
`
`
`
`
`
`Medicated Products:
`60 days1
`Liquid feed supplements
`Type A Medicated Articles [Premixes] *
`Type B Medicated Feeds
`**
`Type C Medicated Feeds [Finished Feeds] *
`180 days2
`Type C Medicated Feeds [Blocks]
`
`
`
`Medicated drinking water
`
`
`
`Label Directions3
`
`6
`
`Hospira, Exh. 2008, p. 9
`
`

`
`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 25°C and 37°-40°C, 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 40°C may
`be necessary.
`
`Non-isothermal studies may also be utilized where advisable or considered
`necessary to determine a tentative expiration date.
`
`7
`
`
`
`
`
`
`
`Hospira, Exh. 2008, p. 10
`
`

`
`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.
`
`b.
`
`
`c.
`
`Effect of exposure to extremes of temperature.
`
`Effect of exposure to air, sunlight, ultraviolet light and other
`artificial light.
`
`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
`
`Hospira, Exh. 2008, p. 11
`
`

`
` 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
`
`Hospira, Exh. 2008, p. 12
`
`

`
`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