**#171**

**Guidance for Industry**

**Waivers of *In Vivo* Demonstration of Bioequivalence of Animal Drugs
in Soluble Powder Oral Dosage Form Products and Type A Medicated
Articles**

Draft Guidance

*This draft guidance is being distributed for comment purposes only.*

Comments and suggestions regarding this draft guidance should be sent to
the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. All
comments should be identified with the Docket No. 2004D-0283. Comments
also may be submitted electronically on the Internet at
<http://www.fda.gov/dockets/ecomments>.

For questions regarding the draft guidance document, contact Marilyn
Martinez, Center for Veterinary Medicine (HFV-130), Food and Drug
Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-7577,
e-mail: [mmartin1@cvm.fda.gov](mailto:mleadbet@cvm.fda.gov).

Additional copies of this draft guidance document may be requested from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/cvm>.

**U.S. Department of Health and Human Services\
Food and Drug Administration\
Center for Veterinary Medicine (CVM)\
August 2004**

Draft Guidance for Industry

**Waivers of *In Vivo* Demonstration of Bioequivalence of Animal Drugs
in Soluble Powder Oral Dosage Form Products and Type A Medicated
Articles**[^1]

> **This draft guidance, when finalized, will represent the agency's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 statute(s) and regulation(s). If
> you want to discuss an alternative approach, contact the FDA staff
> responsible for implementing this guidance. If you cannot identify the
> appropriate FDA staff, call the appropriate number listed on the title
> page of this guidance.**

**I. PURPOSE**

This document describes how the Center for Veterinary Medicine (CVM)
intends to evaluate requests for waiving the requirement for submitting
*in vivo* data demonstrating the bioequivalence of animal drugs in
soluble powder oral dosage form products and Type A medicated articles.
It expands upon CVM's Bioequivalence Guidance,[^2] particularly the
section on Criteria for Waiver of *In Vivo* Bioequivalence Study.

**II. BACKGROUND**

In general, an abbreviated new animal drug application (ANADA) must
include information to show that the generic product and pioneer product
are bioequivalent.[^3] This requirement is patterned very closely on the
human generic drug provision.[^4]

The Center for Drug Evaluation and Research's (CDER) regulations
implementing the bioequivalence requirement are at 21 CFR part 320. In
most cases, there must be an *in vivo* demonstration of no significant
differences in the rate and extent of drug availability associated with
the generic and pioneer drug products when administered at the same
molar dose under similar conditions.[^5] In certain circumstances,
however, the demonstration of bioequivalence does not need to be
established on the basis of *in vivo* studies.[^6] For several
categories of drugs, including oral solutions, bioequivalence is
considered self-evident under specified conditions.[^7] In certain
circumstances, the bioequivalence of solid oral dosage forms can be
documented using *in vitro* approaches.[^8] For highly soluble, highly
permeable, rapidly dissolving, and orally administered drug products,
documentation of bioequivalence using an *in vitro* approach is
appropriate based on a biopharmaceutics classification system.[^9]

CVM has not issued regulations regarding the bioequivalence requirement
for generic products. It has issued guidance on *in vivo* bioequivalence
studies, which includes a list of some of the product categories,
including oral solutions and other solubilized forms, that may be
eligible for an *in vivo* bioequivalence waiver.[^10] The guidance
states that: "in general, the generic product being considered for a
waiver contains the same active and inactive ingredients in the same
dosage form and concentration and has the same pH and physico-chemical
characteristics as an approved pioneer product."[^11] This guidance
provides additional information and recommendations regarding
bioequivalence waivers for soluble powder oral dosage form products
intended for use in animal drinking water and Type A medicated articles
intended for use in animal feed.

**FDA's guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory requirements are cited. The
use of the word "should" in Agency guidances means that something is
suggested or recommended, but not required.**

**III. DISCUSSION**

This guidance describes how CVM intends to evaluate requests to waive
the requirements for conducting an *in vivo* bioequivalence study,
hereafter referred to in this guidance as "biowaivers," for certain
categories of animal drugs.

A. **Waivers for soluble powder oral dosage form products*.*** CVM
believes it will usually be appropriate to grant biowaivers for oral
dosage forms known as "soluble powders." Such products are intended for
administration to animals via the drinking water that, under most
husbandry systems, is provided on an *ad libitum* basis.

The conceptual basis for granting biowaivers for "soluble powders" is
that once a drug is in solution prior to administration, the product\'s
formulation will usually not influence the bioavailability of the active
pharmaceutical ingredient (API). This is because, from a mechanistic
perspective, the rate-limiting step in systemic drug absorption will be
its permeability across the GI mucosal membranes, which is a drug
dependent rather than formulation dependent event. Similarly, if a drug
acts locally within the GI tract (not systemically absorbed), the local
exposure to the dissolved drug in the generic and pioneer formulations
will be equivalent if the drug is already in solution because the
rate-limiting step is drug movement down the GI tract and its lateral
diffusion across the viscous intestinal contents. The only exceptions of
which CVM is aware are when the formulation contains substances that
could cause adverse pharmacologic effects (e.g., altered
gastrointestinal (GI) transit time, membrane permeability, or drug
metabolism), or when there is inactivation of the API by, for example, a
chelating agent. Therefore, in making waiver decisions for soluble
powders, CVM intends to evaluate 1) solubility data provided by the
sponsor to ensure that, prior to administration, the product will go
into solution under the range of physical conditions that a user of the
product would typically encounter when adding the soluble powder to
animal drinking water in the field; and 2) the product\'s formulation to
ensure that there are no ingredients in the generic formulation likely
to cause adverse pharmacologic effects.

B. **Waivers for Type A medicated articles*. ***With respect to
eligibility for a biowaiver, CVM believes there is no reasonable basis
for drawing a distinction between APIs intended for administration to
animals via drinking water and APIs intended to be administered via
feed, provided these drug substances have similar physico-chemical
properties, particularly solubility. A soluble drug, present in a Type A
medicated article and mixed into a feed matrix, rapidly dissolves when
exposed to the fluids of the GI tract. From a mechanistic perspective,
if such a drug readily goes into solution across the range of
physiological pH values, it will likely go rapidly into solution when
exposed to the fluids in the GI tract. Accordingly, such medicated feeds
will effectively behave as oral solutions shortly after administration.
As such, CVM also intends to review biowaiver requests that involve APIs
in Type A medicated articles on the basis of a demonstration of
solubility and the product\'s formulation to ensure that there are no
ingredients in the generic formulation likely to cause adverse
pharmacologic effects. Determining appropriate methods for ascertaining
product bioequivalence for Type A medicated articles that contain APIs
that are not classified as water soluble may prove more challenging and
are not the subject of this guidance.

> 1***. Type A medicated articles and feed formulation effects.*** Feed
> constituents may affect the bioavailability of the APIs in a Type A
> medicated article. CVM believes, however, that this should not be a
> factor in considering a biowaiver request since the variability in
> feed constituents between the pioneer and generic Type A medicated
> articles should not be greater than the natural variations that can
> occur in the final feed to which the animal will be exposed, whether
> that feed contains the generic product or the pioneer product.
>
> 2\. ***Type A medicated articles containing biomass products.*** Many
> antimicrobials, and some drugs in other pharmacologic classes, that
> may become the active ingredients of soluble powder oral dosage form
> products and Type A medicated articles are produced through
> fermentation processes. In soluble powder oral dosage form products,
> the APIs typically are subjected to substantial extraction and
> purification following the fermentation process. While the APIs in
> some Type A medicated articles are virtually identical in purity to
> these soluble powder oral dosage form products, the APIs in others may
> contain significant quantities, or even all, of the fermenting
> microorganisms and nutrient substrate (biomass) associated with the
> fermentation process.
>
> Because dried fermentation biomass derived from a number of different
> fermentation processes is a well-accepted and routinely used feed
> ingredient, CVM will consider the potential for the biomass component
> of a Type A article to cause adverse pharmacologic effects in the same
> manner that it considers these effects with respect to other feed
> ingredients. Generally, CVM would deny a biowaiver on the basis of
> such potential feed ingredient effects only when it has information
> indicating that a specific feed ingredient may have such an effect.

C. **Effect of a grant of a bioequivalence waiver*.*** The granting of a
waiver of the need to submit *in vivo* bioequivalence study data does
not imply that a product is approvable. For product approval, all of the
applicable legal requirements must be met. For example, products
containing a biomass may raise animal, food, or environmental safety
issues that would have to be addressed.

If a waiver of the need to submit *in vivo* bioequivalence studies is
granted, the sponsor may request a waiver for the need to submit tissue
residue depletion data.[^12] If CVM waives the requirement to submit a
tissue residue depletion study, it will assign the withdrawal time
established for the pioneer product to the generic product.

**IV. GUIDANCE**

For soluble powder oral dosage form products and Type A medicated
articles, CVM recommends that requests to waive the requirement to
establish bioequivalence through *in vivo* studies (blood level
bioequivalence or clinical endpoint bioequivalence) be made either by a
comparison of formulations or a demonstration of solubility. Sponsors
may make these waiver requests prior to submitting an ANADA.

A. **Comparison of Formulations:** For both soluble powder oral dosage
form products and Type A medicated articles, CVM is likely to grant a
biowaiver if the sponsor can show that the generic soluble powder oral
dosage form product or Type A medicated article contains the same active
and inactive ingredient(s) and is produced using the same manufacturing
processes as the approved comparator product or article. If this
approach is selected, CVM recommends that the generic sponsor
provide: 1) sufficient evidence that the generic product contains the
same active and inactive ingredient(s) as the pioneer product, 2)
composition statements for both the generic product and the pioneer
product and 3) a description of the generic and pioneer products'
manufacturing process.

B. **Demonstration of Solubility:** For soluble powder oral dosage form
products, a biowaiver may be granted if the generic product contains the
same API(s) as the pioneer product, the product is soluble under the
range of physical conditions that a user of the product would typically
encounter when adding the soluble powder to animal drinking water in the
field; and there are no ingredients in the generic product\'s
formulation likely to cause adverse pharmacologic effects.

For Type A medicated articles, a biowaiver may be granted without direct
comparison to the pioneer product's formulation and manufacturing
process if the generic product contains the same API(s) as the pioneer
product, the API is soluble, and there are no ingredients in the generic
product\'s formulation likely to cause adverse pharmacologic effects.
CVM recommends that the sponsor demonstrate solubility using one of the
following two methods:

> 1\. *"USP definition" approach**:*** CVM believes that for an API to
> be considered "soluble" with respect to a biowaiver request, it should
> be "very soluble," "freely soluble," or "soluble" as these terms are
> defined in Table 1.[^13] In using this table, the product should be
> tested in a pH range of 1.2 (0.1N HCl) to 7.5.
>
> ^**Table\ 1.**\ Values\ for\ estimating\ drug\ solubility\ based\ upon\ "USP\ definition"^

+---------------+------------------------------------------------------+
| **Descriptive | > **Appropriate Volume of Solvent In Milliliters Per |
| Term**        | > Gram of Solute**                                   |
+---------------+------------------------------------------------------+
| Very soluble  | > Less than 1 part solvent needed to dissolve 1 part |
|               | > solute                                             |
+---------------+------------------------------------------------------+
| Freely        | > From 1 to 10 parts solvent needed to dissolve 1    |
| soluble       | > part solute                                        |
+---------------+------------------------------------------------------+
| Soluble       | > From 10 to 30 parts solvent needed to dissolve 1   |
|               | > part solute                                        |
+---------------+------------------------------------------------------+
| Sparingly     | > From 30 to 100 parts solvent needed to dissolve 1  |
| soluble       | > part solute                                        |
+---------------+------------------------------------------------------+
| Slightly      | > From 100 to 1000 parts solvent needed to dissolve  |
| soluble       | > 1 part solute                                      |
+---------------+------------------------------------------------------+
| Very slightly | > From 1000 to 10,000 parts solvent needed to        |
| soluble       | > dissolve 1 part solute                             |
+---------------+------------------------------------------------------+
| Practically   | > More than 10,000 parts solvent needed to dissolve  |
| insoluble     | > 1 part solute                                      |
+---------------+------------------------------------------------------+

> 2\. *"Dosage adjusted" approach:* In this approach, the aqueous
> solubility (across a pH range of 1.2 to 7.5) should be evaluated
> according to the highest expected mg/kg daily intake of a drug and the
> "gastric fluid volume" of the target animal species. If the daily dose
> can be shown to be soluble in the gastric volume under the most
> conservative intended conditions of use (largest dose to fluid volume
> ratio), CVM believes the drug should be considered soluble. This
> method of defining drug solubility is similar to that described for
> categorizing compounds when using the Biopharmaceutics Classification
> System (BCS)[^14] and to the BCS-based approach described in CDER
> guidance.[^15] In this case, the appropriate fluid volume for testing
> drug solubility depends upon the target animal species for which this
> medicated feed is intended.[^16] If the Type A medicated article is to
> be used in the manufacture of medicated feeds across several animal
> species, the most conservative condition (largest dose to fluid volume
> ratio) should provide the basis for determining whether the drug is
> "soluble." The sponsor should provide the estimated daily drug intake
> (mg/kg body weight) based on the labeled drug concentration (e.g.,
> grams of drug per ton) in the feed administered to the animal (e.g., a
> Type C medicated feed) and the amount of feed (kg/day) expected to be
> consumed by an individual animal. When using this approach, we
> recommend using the species-specific animal weight and fluid volume
> estimates summarized in Table 2.
>
> ^**Table\ 2.**\ Values\ for\ estimating\ drug\ solubility\ based\ upon\ "dosage\ adjusted"\ method^a,b,c

+---------------+-------------------------+----------------------------+
| > **\         | **Body weight\          | **"Gastric" volume\        |
| > Species**   | (for estimating drug    | (to be used as volume of   |
|               | intake)**               | solvent)**                 |
+---------------+-------------------------+----------------------------+
| Cattle        | 400 kg                  | 200 Liters (rumen)         |
+---------------+-------------------------+----------------------------+
| P             | 60 kg                   | 2 Liters                   |
| re-ruminating |                         |                            |
| calf          |                         |                            |
+---------------+-------------------------+----------------------------+
| Swine         | 200 kg                  | 8 Liters                   |
+---------------+-------------------------+----------------------------+
| Horse         | 450 kg                  | 18 Liters                  |
+---------------+-------------------------+----------------------------+
| Chicken       | 2.5 kg                  | 0.1 Liters                 |
+---------------+-------------------------+----------------------------+
| Turkey        | 10 kg                   | 0.4 Liters                 |
+---------------+-------------------------+----------------------------+

> ^a^Gastric volume estimate for cattle, swine and horses are based upon
> values reported in, ME Ensminger, JE Oldfield and WW Heinemann, *Feeds
> and Nutrition*, 1990, Ensminger Publishing Company, California, p 53.
>
> ^b^Volume, based upon daily water consumption, is based upon values
> reported in GD Goldstein and E Skadhauge, Renal and extrarenal
> regulation of body fluid composition, In: *Avian Physiology*, 2000, GC
> Whittow, ed., Academic Press, Florida, pp 265-291 and Average Daily
> and Annual Water Requirements, Government of Alberta Canada,
> <http://www1.agric.gov.ab.ca/app19/calc/livestock/waterreq_dataentry2.jsp>
>
> ^c^Animal weights are based upon the following references: NRC,
> Nutrient Requirements of Swine 1988), poultry (NRC, Nutrient
> Requirements of Poultry 1994), and beef cattle (NRC, Nutrient
> Requirements of Beef Cattle 1984).
>
> CVM assumes the amount of medicated feed consumed per day and the
> "gastric volume" will vary proportionally with animal age. Therefore,
> we recommend that the solubility assessment within a given target
> animal species be based upon only one solute/solvent ratio. If the
> daily dose can be shown to be soluble in the gastric volume under the
> most conservative intended conditions of use, the drug should be
> determined to be soluble.

When establishing solubility of the API under either the USP definition
or dosage adjusted approach, we recommend that the following test
conditions be followed:

The pH-solubility profile of the test drug substance should be
determined at 37 ± 1 ^o^C in aqueous media with pHs of approximately
1.2, 4.6 and 7.5. A minimum of three replicate determinations of
solubility in each pH condition is recommended. Depending on study
variability, additional replication may be necessary to provide a
reliable estimate of solubility. Standard buffer solutions described in
the USP are considered appropriate for use in solubility studies. If
these buffers are not suitable for physical or chemical reasons, other
buffer solutions can be used after consultation with CVM. Solution pH
should be verified after addition of the drug substance to a buffer.
Methods other than the traditional shake-flask method, such as acid or
base titration methods, can also be used with justification to support
the ability of such methods to predict equilibrium solubility of the
test drug substance. It is recommended that concentration of the drug
substance in selected buffers (or pH conditions) be determined using a
validated stability-indicating assay that can distinguish the drug
substance from its degradation products. If degradation of the drug
substance is observed as a function of buffer composition and/or pH, it
should be reported along with other stability data.[^17]

As part of a waiver request based on API solubility, CVM also recommends
that the generic sponsor include: 1) sufficient evidence that the
generic product contains the same active ingredient(s) as the pioneer
product; and 2) a composition statement for the proposed generic
product.

[^1]: This draft guidance has been prepared by the Office of New Animal
    Drug Evaluation in the Center for Veterinary Medicine at the Food
    and Drug Administration.

[^2]: CVM Guidance for Industry \# 35, "Bioequivalence Guidance,"
    October 9, 2002.

[^3]: Section 512(n)(1)(E) of the Federal Food, Drug, and Cosmetic Act
    (the Act).

[^4]: Section 505(j)(2)(A)(iv) of the Act.

[^5]: ^?^ 21 CFR 320.1(e) and 320.21(b). CDER\'s guidance on how to meet
    the bioequivalence requirements set forth in 21 CFR part 320 is
    contained in: CDER Guidance for Industry: Bioavailability and
    Bioequivalence Studies for Orally Administered Drug Products ---
    General Considerations, March 2003.

[^6]: 21 CFR 320.21(b),(f) and 320.22.

[^7]: 21 CFR 320.22(b)(3).

[^8]: CDER Guidance for Industry: Bioavailability and Bioequivalence
    Studies for Orally Administered Drug Products --- General
    Considerations, March 2003, Page 10.

[^9]: [Id]{.underline}. Additional information about these waivers and
    the biopharmaceutics classification system CDER uses are in: CDER
    Guidance for Industry: Waiver of *In Vivo* Bioavailability and
    Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms
    Based on a Biopharmaceutics Classification System, August 2000.

[^10]: CVM Guidance for Industry \# 35, "Bioequivalence Guidance",
    October 9, 2002.

[^11]: [Id]{.underline}., Page 7.

[^12]: As described in the CVM guidance #35, "Bioequivalence Guidance,"
    October 9, 2002, Pages 24-26.

[^13]: ^?^ The United Stated Pharmacopeia, USP 26, NF 21, 2003.

[^14]: ^?^ GL Amidon, H Lennernas, VP Shah, JR Crison, A theoretical
    basis for a biopharmaceutics drug classification: the correlation of
    *in vitro* drug product dissolution and *in vivo* bioavailability.
    *Pharm. Res.*, 12 (1995), 413-420.

[^15]: ^?^ CDER Guidance for Industry: Waiver of In Vivo Bioavailability
    and Bioequivalence Studies for Immediate-Release Solid Oral Dosage
    Forms Based on a Biopharmaceutics Classification System, August
    2000.

[^16]: CVM assumes that most or all soluble powder oral dosage form
    products would use the USP definition approach. While the dosage
    adjusted approach is described in terms of Type A medicated
    articles, it is technically applicable to soluble powder oral dosage
    form products as well.

[^17]: These recommendations are based on CDER Guidance for Industry:
    Waiver of *In Vivo* Bioavailability and Bioequivalence Studies for
    Immediate-Release Solid Oral Dosage Forms Based on a
    Biopharmaceutics Classification System, August 2000, section titled
    "Determining Drug Substance Solubility Class" (page 3). CVM has
    modified CDER\'s recommendations to take into account the unique
    conditions associated with the use of animal drugs in drinking water
    and feed.