[Federal Register Volume 61, Number 129 (Wednesday, July 3, 1996)]
[Notices]
[Pages 34849-34852]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-16973]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 96D-0159]


Compounding of Drugs for Use in Animals; Compliance Policy Guide; 
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a Compliance Policy Guide (CPG) section 608.400 
entitled ``Compounding of Drugs for Use in Animals.'' The purpose of 
this CPG is to provide guidance to FDA's field and headquarters staff 
with regard to the compounding of animal drugs by veterinarians and 
pharmacists for use in animals. The CPG contains information that may 
be useful to industry and the public. The text of the CPG is included 
in this notice. This CPG does not bind FDA, nor does it create or 
confer any rights, privileges, benefits, or immunities on or for any 
person.

DATES: Written comments may be submitted at any time.

ADDRESSES: Submit written requests for single copies of CPG section 
608.400 entitled ``Compounding of Drugs for Use in Animals'' to the 
Industry Information Staff (HFV-12), Center for Veterinary Medicine, 
Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. 
Send two self-addressed adhesive labels to assist that office in 
processing your requests. Submit written comments on CPG section 
608.400 entitled ``Compounding of Drugs for Use in Animals'' to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Two copies of any 
comments are to be submitted, except that individuals may submit one 
copy. Requests and comments should be identified with the docket number 
found in brackets in the heading of this document. A copy of CPG 
section 608.400 and received comments are available for public 
examination in the Dockets Management Branch between 9 a.m. and 4 p.m., 
Monday through Friday.
FOR FURTHER INFORMATION CONTACT: Richard E. Geyer, Center for 
Veterinary Medicine (HFV-200), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1764.

SUPPLEMENTARY INFORMATION: FDA is announcing the availability of CPG 
section 608.400 entitled ``Compounding of Drugs for Use in Animals.'' 
The purpose of this CPG is to provide clear policy and regulatory 
guidelines to FDA's field and headquarters staff with regard to the 
compounding of animal drugs by veterinarians and pharmacists for use in 
animals. It also contains information that may be useful to industry 
and to the public.
    The Federal Food, Drug, and Cosmetic Act (the act) does not 
distinguish compounding from manufacturing or other processing of drugs 
for use in animals. However, veterinarians and pharmacists do 
manipulate drugs (e.g., combine or dilute finished dosage forms, 
prepare finished dosage forms from bulk drug substances, or prepare 
injectables from powdered oral dosage forms) to obtain products that 
differ from the starting materials.
    FDA acknowledges the use of compounding within certain areas of 
veterinary practice. The current state of veterinary medicine requires 
products to treat many conditions in a number of different species, 
some of which are known to have unique physiological characteristics. 
While the agency acknowledges the need for compounding under certain 
circumstances, it is also aware of recent adverse reactions and animal 
deaths caused by compounded drug products and is concerned about the 
risks associated with compounding practices in veterinary medicine. In 
addition, the agency is greatly concerned about pharmacies that produce 
large quantities of unapproved new animal drugs that are essentially 
copies of FDA-approved products. These pharmacy products are actively 
advertised and promoted, and sometimes are priced lower than the 
approved product. The firms claim that they are practicing within the 
scope of their State licenses. However, it is apparent that some of 
these firms use their pharmacy licenses to circumvent the entire drug 
approval process, and are mass marketing products that have been 
produced under little or no quality control, manufacturing standards to 
ensure purity, potency, and stability.
    When the Animal Medicinal Drug Use Clarification Act of 1994 
(AMDUCA) is implemented and becomes effective, it will allow 
compounding from approved drugs because it will permit the extralabel 
use of approved animal and human drugs. Extralabel use, including 
compounding, under AMDUCA will be subject to conditions specified by 
the implementing regulations. The scope of compounding made legal upon 
the effective date of AMDUCA will be addressed by those regulations.
    CPG section 608.400 represents FDA's current position and 
interpretation of the act. The CPG is intended to provide clear 
guidance to FDA field and headquarters staff and also could

[[Page 34850]]

provide information to the animal health industry. However, this 
document, which is intended merely for internal FDA guidance, does not 
bind FDA, nor does it create or confer any rights, privileges, 
benefits, or immunities on or for any persons. FDA may reconsider its 
position at a later date in light of comments received or other data or 
information which comes to the attention of the agency.

COMPLIANCE POLICY GUIDE \1\
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    \1\ This Update to the Compliance Policy Guides Manual (March 
1995 edition) is a new CPG. This update will be included in the next 
printing of the Compliance Policy Guides Manual. The statements made 
in the CPG are not intended to create or confer any rights, 
privileges, or benefits on or any private person, but are intended 
for internal guidance.
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CHAPTER - 6

SUB CHAPTER - 600

Sec. 608.400 Compounding of Drugs for Use in Animals

Background:

    The Federal Food, Drug, and Cosmetic Act (the Act) does not 
distinguish compounding from manufacturing or other processing of 
drugs for use in animals. However, veterinarians and pharmacists do 
manipulate drugs (e.g., combine or dilute finished dosage forms, 
prepare finished dosage forms from bulk drug substances, or prepare 
injectables from powdered oral dosage forms) to obtain products that 
differ from the starting materials.
    There is a potential for causing harm to public health and to 
animals when drug products are compounded, distributed, and used in 
the absence of adequate and well-controlled safety and efficacy 
data, adherence to the principles of contemporary pharmaceutical 
chemistry and current good manufacturing practices.
    The Agency acknowledges the use of compounding within certain 
areas of veterinary practice. The practice of veterinary medicine 
requires products to treat many conditions in a number of different 
species, some of which have unique physiological characteristics. 
FDA, other federal, state agencies, and producer groups encourage 
drug sponsors to obtain approvals for all new animal drugs.
    While the Agency acknowledges the use of compounding under 
certain circumstances, it is also aware of adverse reactions and 
animal deaths caused by compounded drug products and is concerned 
about the risks associated with compounding practices in veterinary 
medicine. An example is the recent death of cattle due to the 
presence of endotoxin in a parenteral product prepared from 
spectinomycin approved for oral use. In addition, the Agency is 
greatly concerned about pharmacies that produce large quantities of 
unapproved new animal drugs that are essentially copies of FDA-
approved products. These pharmacy products are actively advertised 
and promoted, and sometimes are priced lower than the approved 
product. The firms claim that they are practicing within the scope 
of their state licenses. However, it is apparent that some of these 
firms use their pharmacy licenses to circumvent the entire drug 
approval process, and are mass marketing products which have been 
produced with little or no quality control, manufacturing standards 
to ensure purity, potency and stability.
    The pharmacokinetics and depletion times for residues from 
compounded products are not known and the assigning of 
extemporaneous withdrawal times may result in potentially harmful 
residues in food. Excipients and vehicles from unapproved or unknown 
origins may pose additional risks.
    Section 510(g)(1) of the Act exempts from the registration 
requirements licensed pharmacies which do not compound drugs except 
exclusively within the regular course of their business of 
dispensing or selling drugs at retail. Section 510(g)(2) exempts 
from the registration requirements licensed practitioners who 
manufacture, prepare, propagate, compound, or process drugs during 
the regular course of business of dispensing drugs at retail. The 
Act and regulations do not, however, exempt such practitioners or 
pharmacists from the approval requirements in the new animal drug 
provisions of Sections 501(a)(5) and 512. Therefore, compounding 
allowed under the Act is limited to the preparation of drug products 
which do not meet the definition of new animal drugs. In the absence 
of an approved new animal drug application (NADA), the compounding 
of a new animal drug from any article, including an approved or 
unapproved finished human or animal drug, or a bulk drug, results in 
an adulterated new animal drug in violation of section 501(a)(5).
    Compounding from Approved Dosage Form Drugs: When the Animal 
Medicinal Drug Use Clarification Act of 1994 (AMDUCA) goes into 
effect, it will allow the ``extra-label'' use of approved animal and 
human drugs. It will also allow compounding from those approved 
drugs. Under AMDUCA ``extra-label'' use, including compounding, will 
be subject to conditions specified by regulation. AMDUCA will become 
effective upon promulgation of the regulations. The scope of 
compounding made legal upon the effective date of AMDUCA will also 
be addressed by the regulations. The proposed regulations were 
published in the Federal Register on May 17, 1996. They have no 
effect until finalized.
    Compounding from Bulk Drugs: Two Federal Appeals Court 
decisions, United States v. Algon Chemical Inc., 879 F.2d 1154 (3d 
Cir. 1989), United States v. 9/1 Kg. Containers, 854 F.2d 173 (7th 
Cir. 1988), affirmed the FDA position that the Act does not permit 
veterinarians to compound unapproved finished drug products from 
bulk drugs, unless the finished drug is not a new animal drug. The 
principle established by the court applies equally to compounding by 
pharmacists. However, one of the courts acknowledged the Agency's 
policy that, if the need is great and the risk small, the Agency may 
exercise regulatory discretion with respect to veterinarians 
compounding from approved drugs under Compliance Policy Guide (CPG) 
615.100, Extra-label Use of New Animal Drugs in Food-Producing 
Animals.

Definitions:

    The Act and accompanying regulations do not define compounding 
as different from other processing of drug compounds.
    Bulk drug is an active ingredient (in unfinished form) intended 
for manufacture into finished dosage form drug products (from United 
States v. Algon Chemical Inc., 879 F.2d 1154 (3d Cir. 1989)). See 
also 21 CFR 207.3(a)(4). Bulk drugs (or ``bulk drug substances'') 
may be supplied in various size containers and may or may not meet 
USP standards.
    Compounding is defined, for the purposes of this CPG, as any 
manipulation to produce a dosage form drug other than that 
manipulation that is provided for in the directions for use on the 
labeling of the approved drug product, for example, the 
reconstitution of a sterile powder with sterile water for injection.
    Compounding ordinarily not subject to regulatory action, is 
defined as compounding by a licensed pharmacist or veterinary 
practitioner, when the criteria described in this document are met, 
within the confines of a legitimate practice. However, this document 
shall not be construed to bind the FDA or otherwise constrain its 
enforcement discretion. In addition, this document imposes no new 
obligations.
    Compounding subject to regulatory action, is defined as 
compounding by a licensed pharmacist or other practitioner, when the 
criteria described in this document are not met, even if it is 
otherwise within the confines of a legitimate practice. Compounding 
outside the confines of a legitimate pharmacy or veterinary 
practice, whether by a pharmacist, veterinarian or other party, is 
subject to regulatory action.
    ``Legitimate practice'' is defined as follows:
    (a) Pharmacist: A person licensed and operating in conformity 
with state law, and dispensing in response to a valid prescription.
    (b) Veterinarian: A person licensed and operating in conformity 
with state law, and prescribing or dispensing in response to a valid 
Veterinarian-Client-Patient Relationship (VCPR.)
    Valid Veterinarian-Client-Patient Relationship (VCPR)
    A valid VCPR exists when: (1) the veterinarian assumes the 
responsibility for making medical judgments regarding the health of 
the animal(s) and the need for medical treatment, and the client 
(owner or other caretaker) agrees to follow the instructions of the 
veterinarian; and (2) the veterinarian has sufficient knowledge of 
the circumstances to initiate at least a general or preliminary 
diagnosis of the medical condition of the animal(s), i.e., the 
veterinarian has recently seen and is personally acquainted with the 
keeping and care of the animal(s) by virtue of an examination of the 
animal(s), and/or by medically appropriate and timely visits to the 
premises where the animal(s) are kept; and (3) the practicing 
veterinarian is readily available for follow-up in case of adverse 
reactions or failure of the regimen of therapy. Source: American 
Veterinary Medical Association.

[[Page 34851]]

Policy:

    Circumstances exist when it may be necessary for a veterinarian 
to compound, or direct for a pharmacist to compound, an article that 
will result in an unapproved new animal drug. There is occasionally 
a need to utilize drugs labeled for human use, and much less 
commonly, bulk drug substances, for compounding into an appropriate 
dosage form. Some examples of these situations include: combinations 
of anesthetic drugs for titrated administration; preparation of 
dilute dosage forms for small, young, or exotic species patients; 
and usage of some antidote preparations. The Agency will exercise 
regulatory discretion and ordinarily would not take regulatory 
action against violations of the Act resulting from compounding an 
unapproved new animal drug if a determination is made that, in order 
to provide appropriate medical therapy, it is necessary to compound 
a new animal drug when the following conditions are met:
    (1) A legitimate medical need is identified (the health of 
animals is threatened and suffering or death would result from 
failure to treat the affected animals),
    (2) There is a need for an appropriate dosage regimen for the 
species, age, size, or medical condition of the patient, and
    (3) There is no marketed approved animal drug which, when used 
as labeled or in an ``extra-label'' manner in conformity with 
criteria listed in CPG 615.100, or human-label drug, when used in 
conformity with criteria listed in CPG 608.100, may treat the 
condition diagnosed in the available dosage form, or there is some 
other rare extenuating circumstance. (For example, the approved drug 
cannot be obtained in time to treat the animal(s) in a timely 
manner, or there is a medical need for different excipients.)
    After making the above determinations, the following criteria 
should be met and precautions observed:
    (1) Dispensing by a licensed veterinarian; or the receipt of a 
valid prescription of a licensed veterinarian by a pharmacist. 
Dispensing should be within the confines of a valid veterinarian-
client-patient relationship. Veterinarians should exercise 
professional judgment to determine when compounding requires the 
services of a pharmacist. Professional assistance is appropriate 
when the complexity of compounding exceeds the veterinarian's 
knowledge, skill, facilities, or available equipment.
    (2) The veterinarian takes measures to ensure that:
    (a) When used in food-producing animals: no illegal residues 
occur; a significantly extended time period is assigned for drug 
withdrawal; and steps are taken to assure that the assigned time 
frames are observed;
    (b) The safety and efficacy of the compounded new animal drug is 
consistent with current standards of pharmaceutical and 
pharmacological practices, e.g., known incompatibilities are 
avoided;
    (c) Appropriate steps are taken to minimize risk of personnel 
exposure to potentially harmful ingredients in the preparation 
process; and
    (d) Procedures are instituted to assure that appropriate patient 
records for the treated animals are maintained.
    (3) All drugs dispensed to the animal owner by the veterinarian 
or a pharmacist, bear labeling information which is adequate to 
assure proper use of the product. The following label information 
should be included:
    (a) Name and address of the veterinary practitioner;
    (b) the active ingredient or ingredients;
    (c) the date dispensed and the expiration date, which should not 
exceed the length of the prescribed treatment except in cases where 
the veterinarian can establish a rationale for a later expiration 
date;
    (d) directions for use specified by the practitioner, including 
the class/species or identification of the animals; and the dosage, 
frequency, route of administration, and duration of therapy;
    (e) cautionary statements specified by the veterinarian and/or 
pharmacist (this would include all appropriate warnings necessary to 
ensure safety of human operators handling the finished drug, 
especially if there are potential hazards of exposure to any 
components);
    (f) the veterinarian's specified withdrawal/discard time(s) for 
meat, milk, eggs, or any food which might be derived from the 
treated animal(s) (while the veterinarian must set the withdrawal 
time, the veterinarian in doing so may use relevant information 
provided by a dispensing pharmacist although the veterinarian 
retains ultimate responsibility);
    (g) if dispensed by a licensed pharmacist, the name and address 
of the dispenser, serial number and date of order or its filing;
    (h) if dispensed by a veterinarian, the serial number; and
    (i) any other applicable requirements of state or federal law.
    (4) The pharmacist adheres to the National Association of Boards 
of Pharmacy Good Compounding Practices (GCP), or to equivalent state 
good compounding practice regulations, except where provisions 
conflict with this CPG. Among other practices, pharmacists should 
keep records of compounding formulas, logs of compounded items and 
specific ingredients, record of assurance of quality of raw 
materials; and information on adverse effects and product failures. 
Pharmacists should label compounded products with expiration dates 
that do not exceed the prescribed period of treatment, and with 
withdrawal times furnished by the prescribing veterinarian.
    Veterinarians and pharmacists who compound or prescribe 
compounded medicaments and pharmacists who compound medicaments 
according to these guidelines criteria set out above would be 
considered to be engaged in extemporaneous compounding not 
ordinarily subject to regulatory action.

Regulatory Action Guidance:

    Investigations will be conducted in coordination with state 
officials as specified in the October 26, 1995 letter from Associate 
Commissioner for Regulatory Affairs (FDA) and Executive Director, 
National Boards of Pharmacy, to state pharmacy and drug regulatory 
officials, and FDA officials.
    FDA actions based on violative conditions will be consistent 
with state laws and regulations to the extent possible. Deviations 
from GCP may be deferred to state authorities for action.
    In general, the agency will place its highest regulatory 
priority on compounding products for use in food animals.
    A. The following situations would likely indicate compounding 
subject to regulatory action and the existence of one or more would 
ordinarily be of high regulatory priority.
    -Preparation for sale of large quantities of unapproved new 
animal drugs on an ongoing basis and where no valid medical need or 
VCPR exists. Compounding very limited quantities in anticipation of 
future need is acceptable provided that a history of past need can 
be documented;
    -Compounding of medicaments that are essentially similar to FDA-
approved products except in rare instances where a legitimate need 
can be established, for example, to treat animals on a timely basis 
or to avoid problems caused by certain excipients.
    -Substitution or recommendation by a pharmacist of a compounded 
medicament for a prescription instead of using an FDA-approved 
product;
    -Compounding from bulk drugs for use in food animals, with the 
rare exception of those medicaments that are permitted to be 
compounded by the Center for Veterinary Medicine (CVM) through 
compassionate regulatory discretion or other means (such as certain 
antidotes, large volume electrolyte products and other substances). 
Because these items may be revised, an official contact office at 
CVM has been designated to provide current information. That contact 
office is HFV-236, Case Guidance Branch, Division of Compliance, 
(301) 594-1785.
    -Preparation for sale of unapproved new animal drugs on any 
scale which employ fanciful or trade names, colorings or other 
additives, or in any way imply that the products have some unique 
effectiveness or composition;
    -Advertising, promotion, display, sale, or other means of 
marketing, prepared unapproved new animal drugs; and soliciting 
business to compound specific drug products, product classes or 
therapeutic classes of drug products;
    -Offering compounded medicaments at wholesale to other state 
licensed veterinarians or pharmacists or other commercial entities 
for resale;
    -Offering financial incentives such as rebates and consulting 
fees; and
    -Dispensing of large quantities of compounded medicaments, where 
questions of stability of the finished product would arise;
    -Failing to follow good compounding practices, including current 
standards of pharmaceutical and pharmacological practices, as 
described above;
    -Labeling a product with an expiration date that exceeds the 
prescribed treatment period;
    -Labeling a product with a withdrawal time established by the 
pharmacist instead of the veterinarian;
    -Dispensing a disproportionate amount of compounded products out 
of state. The primary concern is the difficulty of maintaining 
proper relationships, for

[[Page 34852]]

example, pharmacist/veterinarian/client and VCPR. Rare instances of 
specialized compounding to meet emergency needs would not be 
considered disproportionate.
    B. The following situations would indicate excessive risk to 
public health or to animals, or an otherwise adverse risk/benefit 
ratio, of high regulatory priority:
    -Instances where illegal residues occur in meat, milk, eggs, 
honey, or aquaculture products and the residues were caused by the 
use of a compounded drug in association with the violation being 
investigated;
    -Compounding of medicaments for food-producing animals, 
especially those used in lactating dairy animals, which cause a 
significant risk of illegal residues because, for example, 
withholding times have not been established by the veterinarian 
using adequate scientific information; and
    -Preparation of drug products that are essentially similar to 
products that have been removed from the market due to regulatory 
concerns, for example, chloramphenicol, dimetridazole, DES in food 
animals.
    C. The following activities would indicate compounding subject 
to regulatory action, and possibly of high regulatory priority. 
However, guidance from CVM should be solicited to assess the 
potential public health threat and/or animal safety (i. e., risk vs 
benefits).
    -Instances where animals have been harmed or their safety 
unnecessarily compromised, such as compounding a nonsterile product 
for parenteral or ophthalmic administration where a sterile product 
is indicated, or other instances of not adhering to good compounding 
practices.
    -Compounded substances that do not bear the required label 
information, including the name of the authorizing veterinarian, the 
active ingredients, directions for use, cautionary statements, and 
withdrawal times.
    D. The following compounding situations would not ordinarily be 
considered for regulatory action. Appropriate state and local 
practice and pharmacy laws must be adhered to, however.
    -Compounding for non-food animals and minor food animal uses 
where public health and animal safety have not been threatened, and 
are of great need and small risk. This would include such common 
practices as: veterinarians' combining agents for anesthesia, large 
volume parenterals, preparing appropriate dosage-forms for the size 
of the patient in question, ``animal-side'' compounding, and other 
similar common practices that are widely accepted in the day to day 
treatment of animal patients.
    -Compounding from bulk drug substances for use in nonfood 
animals, including animals in public and private aquaria, when 
animal health is not threatened, and there is not a significant risk 
of diversion of the bulk drugs or compounded drugs for use in food 
animals. Bulk drug substances would ordinarily be expected to be in 
small packages that meet or exceed USP standards; see definition of 
``bulk drugs'' above. Compounding should be performed in accordance 
with current standards of pharmaceutical practice (including 
referral to compendial monographs or established pharmacy 
textbooks).
    If circumstances exist on a case-by-case basis that indicate 
otherwise, the Field should request guidance from CVM before 
considering regulatory action. The preceding is not intended to be a 
complete list of activities relating to compounding; there may be 
other factors which are appropriate when assessing an individual 
case.

Guidance for Charging Violations:

    A warning letter is ordinarily the first choice of action, when 
referral to state authorities is not appropriate. Injunction would 
be the usual choice of court action, although seizure should be 
considered in the case of high priority drugs such as 
chloramphenicol or DES intended for use in food animals. Criminal 
action can be considered in egregious situations.
    Compounded drugs subject to regulatory action under this policy 
will ordinarily be charged as unapproved new animal drugs, violative 
under Section 501(a)(5). Deviations from GCP, if not subject of 
state action will ordinarily be charged under Section 501(a)(2)(b). 
The tissue residue violations are covered under Section 
402(a)(2)(D).

    Dated: June 26, 1996.
Gary Dykstra,
Acting Associate Commissioner for Regulatory Affairs.
[FR Doc. 96-16973 Filed 7-2-96; 8:45 am]
BILLING CODE 4160-01-F