Ensure safety of all drugs - Opinion - The Times-Tribune: Congress Needs To Draw Bright Line Between Compounding and Manufacturing

Ensure safety of all drugs - Opinion - The Times-Tribune

Tennessee Board of Pharmacy Reminds Pharmacies of Difference Between Compounding and Manufacturing

Board Rules for Compounding Reemphasized
In the wake of the tragic events causing harm and loss of life across
the country, including several deaths in Tennessee, due to the fungal
meningitis outbreak, it is important to review the current definitions
and rules for Tennessee-licensed pharmacies practicing the art of
compounding. 
To start this discussion, it is important to understand the difference
between compounding and manufacturing. Refer to the following
definitions:
Tennessee Code Ann. §63-10-204 Definitions.
(4) “Compounding” means the preparation, mixing, assembling, packaging or labeling of a drug or device:
(A) As the result of a prescription order or initiative based on
the prescriber-patient-pharmacist relationship in the course
of professional practice;
(B) In anticipation of prescription orders based on routine,
regularly observed prescribing patterns; or
(C) For the purpose of, or as an incident to, research, teaching
or chemical analysis and not for sale or dispensing;
(12) “Dispense” means preparing, packaging, compounding or labeling for delivery and actual delivery of a
prescription drug, nonprescription drug or device in the
course of professional practice to a patient or the patient’s
agent by or pursuant to the lawful order of a prescriber;
(21) “Manufacturer” means any person, except a pharmacist
compounding in the normal course of professional practice,
engaged in the commercial production, preparation, propagation, conversion or processing of a drug, either directly or
indirectly, by extraction from substances of natural origin or
independently by means of chemical synthesis, or both, and
includes any packaging or repackaging of a drug or the labeling
or relabeling of its container and the promotion and marketing
of such drugs or devices;
(13) “Distribute” means the delivery of a drug or device, other
than by administering or dispensing, to persons other than the
patient or the patient’s agent;
Therefore, be advised that the patient-specific prescription via the
prescriber-patient-pharmacist (also known as the three-legged stool)
is required for the pharmacist to prepare and dispense a compounded
prescription.
To sell a manufactured drug without a prescription in Tennessee, (ie, office or hospital use) a wholesaler/manufacturer/distributor
(W/M/D) license, issued by the Tennessee Board of Pharmacy, is
required as discussed in the July 27-28, 2011 Board meeting minutes:
A company with the business model of providing admixture
pharmacy services, appeared before the board to ask for permission to operate as a pharmacy in Tennessee. The representative
explained that the company would compound sterile preparation in anticipation of institutional pharmacies’ prescription
orders and it would be based on the institution prescriber’s
routine prescribing patterns. The compounded admixture is
not patient specific but the company would like to send the
admixture to institutions based on past usage of the product.
After discussion, a member of the Board made the motion that
based on the business model discussed with this company, it
would be necessary that they be licensed in Tennessee as a
manufacturer/wholesaler/distributor. Furthermore, the motion
stated that if they decided to dispense patient specific, they
would have to be licensed as a pharmacy as well. The motion
was seconded and carried.
Currently, there are pharmacies licensed by the Board that carry
both W/M/D and pharmacy licenses. However, be advised that Food
and Drug Administration and Drug Enforcement Administration
(DEA) regulations may require licensure or other certifications to also
manufacture drug products for sale, purchase, or transfer.
For pharmacists practicing the art of sterile compounding under a
pharmacy license for patient-specific prescriptions, it is advised
to review the current Tennessee Board of Pharmacy rules found at
the following Web link: www.state.tn.us/sos/rules/1140/1140-07
.pdf. Board rules require documentation to be completed and readily
available, including flow hood certification, pre-filter records, training,
and policies and procedures
http://health.state.tn.us/Boards/Pharmacy/index.shtml
December  2012

Ohio Board of Pharmacy Discusses Basic Differences Between Manufacturing and Compounding Under Its Rules

Manufacturing Versus Compounding: 

Basic Differences

Manufacturing and compounding are two very different 

practices that are regulated differently as well. Ohio recognizes and 

enforces federal law that states compounding 

is performed by a pharmacist in a pharmacy and pursuant to a 

patient-specific prescription (refer to 21 USCA 

353a). Manufacturing does not require a patient-specific 

prescription, but requires a manufacturing license from

FDA that enables the company to produce and sell manufactured medications 

(typically in bulk) again without a 

patient-specific prescription. To obtain an FDA manufacturing license, 

the manufacturing site must also pass 

stringent quality assurance standards (good manufacturing practice) 

designed to test manufacturing of sterile 

drug product. Thus, there is much more scrutiny placed 

on this type of practice (manufacturing) typically due to 

the large amounts of drug product being made for resale. 

Medication compounding, on the other hand, involves 

the practice of taking commercially available products 

and modifying them to meet the unique needs of an individual

 patient pursuant to a prescription from a licensed 

provider. Our state law defines compounding in Ohio 

Revised Code 4729.01(C). Also, a pharmacy must follow 

the compounding requirements pursuant to Ohio Administrative Code 

(OAC) Rules 4729-5-25, 4729-9-25, 4729-

9-21, and 4729-19; current professional compounding 

standards; and all applicable federal and state laws, rules, 

and regulations. As required by OAC 4729-19-04, for 

compounding sterile injectables, the Board would expect 

to see in your written policies and procedures adherence 

to United States Pharmacopeia (USP) Chapter 797 guidelines. 

These guidelines are differentiated by the severity/

risk of the type of products being compounded. The Board 

expects that you review and understand these guidelines 

to assess your practice prior to compounding sterile injectable

 prescriptions. For more information regarding 

the USP Chapter 797 compounding guidelines, visit www

.usp.org/store/products-services/usp-compounding. 

Compounding in Ohio does not require a special FDA 

manufacturing license and can be performed with no 

extra licenses other than those required by the Board 

for pharmacy practice (RPh license for the pharmacist 

to practice, a terminal distributor of dangerous drugs 

license for the location, and, if needed, a Drug Enforcement 

Administration license for controlled substances). 

No doubt, compounding is a legal and common practice 

in many Ohio pharmacies and brings incredible value to 

Ohio patients. However, make sure that your processes 

meet all standards for compounding and that you are not 

manufacturing as defined above. The Board has created 

a great compounding document for review, which can be 

accessed from the Board’s Web site at www.pharmacy

.ohio.gov. Click on the “Terminal Distributor (TDDD) Licenses”

 tab and then on the “Compounding in Ohio” link. 

Source found here

Factors FDA considers in Deciding Whether to Take Enforcement Action

Importation of Active Pharmaceutical Ingredients (APIs) Requirements CPG 460.200 Pharmacy Compounding Compliance Policy Guides Manual (Tab M), in part provides:


Generally, FDA will continue to defer to state authorities regarding less significant violations of
the Act related to pharmacy compounding of human drugs. FDA anticipates that, in such cases,
cooperative efforts between the states and the Agency will result in coordinated investigations,
referrals, and follow-up actions by the states. 
However, when the scope and nature of a pharmacy's activities raise the kinds of concerns
normally associated with a drug manufacturer and result in significant violations of the new
drug, adulteration, or misbranding provisions of the Act, FDA has determined that it should
seriously consider enforcement action. In determining whether to initiate such an action, the
Agency will consider whether the pharmacy engages in any of the following acts: 
1. Compounding of drugs in anticipation of receiving prescriptions, except in very limited
quantities in relation to the amounts of drugs compounded after receiving valid
prescriptions. 
2. Compounding drugs that were withdrawn or removed from the market for safety reasons.
Appendix A provides a list of such drugs that will be updated in the future, as appropriate. 
3. Compounding finished drugs from bulk active ingredients that are not components of FDA
approved drugs without an FDA sanctioned investigational new drug application (IND) in
accordance with 21 U.S.C. § 355(i) and 21 CFR 312. 
4. Receiving, storing, or using drug substances without first obtaining written assurance from
the supplier that each lot of the drug substance has been made in an FDA-registered facility. 
5. Receiving, storing, or using drug components not guaranteed or otherwise determined to
meet official compendia requirements. 
6. Using commercial scale manufacturing or testing equipment for compounding drug product
7. Compounding drugs for third parties who resell to individual patients or offering
compounded drug products at wholesale to other state licensed persons or commercial
entities for resale. 
8. Compounding drug products that are commercially available in the marketplace or that are
essentially copies of commercially available FDA-approved drug products. In certain
circumstances, it may be appropriate for a pharmacist to compound a small quantity of a
drug that is only slightly different than an FDA-approved drug that is commercially
available. In these circumstances, FDA will consider whether there is documentation of the
medical need for the particular variation of the compound for the particular patient. 
9. Failing to operate in conformance with applicable state law regulating the practice of
pharmacy. 
The foregoing list of factors is not intended to be exhaustive. Other factors may be appropriate
for consideration in a particular case. 

FDA Division of Compliance: Inspecting Businesses that May be Manufacturing Under Guise of Compounding

The Division of Compliance of the United States Food and Drug Administration (FDA) has issued assignments to conduct inspections of firms, including internet pharmacies, who may be engaged in the practice of manufacturing under the guise of pharmacy compounding.  The FDA web site contains the following statement regarding Veterinary Drug Compounding.

Inspections, Compliance, and Criminal Investigations

.9.2 - VETERINARY DRUG ACTIVITIES

CVM is responsible for inspections of therapeutic and production drugs, and Active Pharmaceutical Ingredients (APIs). Therapeutic drugs are used in the diagnosis, cure, mitigation, treatment or prevention of disease. Production drugs are used for economic enhancement of animal productivity. Examples include: growth promotion, feed efficiency and increased milk production.
Preapproval inspections are conducted pursuant to pending NADA or ANADA applications.

Post approval inspections of veterinary drugs are conducted to determine compliance with the Current Good Manufacturing Practices (CGMPs) for Finished Pharmaceuticals under 21 CFR Part 211³. These cGMPs apply to both human and veterinary drugs. Information on veterinary drugs approved can be found in the "Green Book" database accessed through CVM's website.

APIs are active pharmaceutical ingredients. Many of the APIs used to manufacture dosage form drugs are imported from foreign countries. The intended source for an API must be indicated in NADA/ANADA submissions for new animal drug approvals. Any change in a source for an API would require a supplement to the application.

Extra label drug use refers to the regulations in 21 CFR Part 530⁴ codified as a result of the Animal Medicinal Drug Use Clarification Act⁵ (AMDUCA) of 1994. These regulations set forth the requirements that veterinarians must meet to prescribe extra label uses of FDA approved animal and human drugs. The regulations describe what is a valid veterinary-client-patient relationship as well as what is considered illegal extra label use. 21 CFR Part 530 addresses issues regarding extra label use in non-food as well as food producing animals. 21 CFR 530.41⁶ contains a list of drugs that cannot be used in an extra label manner in food-producing animals. During an inspection or investigation if you encounter any situations on suspected illegal extra label use of any FDA approved animal or human drugs or those prohibited for extra label use in food animals, you should contact CVM's Division of Compliance (HFV-230) (240-276-9200).

21 CFR Part 530 also addresses compounding of products from approved animal or human drugs by a pharmacist or veterinarian. The regulations clearly state compounding is not permitted from bulk drugs. This would include APIs. CVM has an existing CPG on Compounding of Drugs for Use in Animals (CPG 608.400⁷). A copy can be found on CVM's website. The Division of Compliance (HFV-230) has issued assignments to conduct inspections of firms, including internet pharmacies, who may be engaged in the practice of manufacturing under the guise of pharmacy compounding. You should contact the Division of Compliance (HFV-230) at 240-276-9200 to report instances of compounding or to seek guidance on inspectional issues, or regulatory and enforcement policies.

Positions taken by Society of Veterinary Hospital Pharmacists and Former FDA Officials in Franck's Appeal

In the amicus brief filed by the Society of Veterinary Hospital Pharmacists (SVHP's), its position is clearly stated:

    Regarding the legality of traditional compounding with bulk chemicals, SVHP has adopted a "Position Statement on Compounding," a complete copy of which is available on SVHP's website. See http:svhp.org/position-statement/.   That statement recognizes that in many circumstances traditional compounding with bulk chemicals is essential to providing high quality pharmaceutical care for sick animal patients.  SVHP supports the ability of veterinary pharmacists, in consultation with veterinarians caring for animal patients in need, to compound medicines from bulk ingredients as follows:   If an FDA approved product is unavailable or not appropriate for treatment, compounding with bulk chemicals (APIs) may become necessary and required for proper treatment. The APIs/bulk ingredients used to compound an appropriate product should be of highest possible chemical grade, and the finished product should be compounded from those bulk ingredients using a formula – preferably a USP formula – with evidence-based documentation of potency and stability.  


     The legal position taken by the United States in this matter, through the Federal Drug Administration (“FDA”), is that any compounding from bulk materials by pharmacists for animals is illegal under the Federal Food Drug and Cosmetic Act (“FDCA”), 21 U.S.C. § 301, et seq., and has been since the statute was first enacted in 1938. SVHP respectfully disagrees, and believes that legal position to be incorrect.


In the amicus brief filed by Former FDA officials, they make a very persuasive argument distinguishing between traditional compounding and manufacturing of drugs.  Their summary of argument provides:

     The Federal Food, Drug, and Cosmetic Act (“FD&C Act”) did not criminalize traditional pharmacy compounding, including compounding animal drugs from bulk ingredients. Instead, the FD&C Act was enacted to regulate drug Case: 11-15350 manufacturing, which is categorically distinct from traditional pharmacy compounding. Additionally, none of the amendments to the FD&C Act reflect Congress’ intent to criminalize traditional pharmacy compounding, including compounding animal drugs from bulk substances. 

    In asserting that any compounding of animal drugs from bulk substances is unlawful per se, FDA’s policy guidance fails to adequately distinguish between traditional pharmacy compounding of animal drugs and manufacturing of animal drugs. The key difference between traditional pharmacy compounding of animal drugs on the one hand, and manufacturing of animal drugs on the other, is that the former is conducted in response to a prescription order based on a valid Veterinarian-Client-Patient relationship in the course of professional practice, whereas the latter is not so circumscribed. 

    As FDA acknowledges, its policy guidance on animal drug compounding lacks the force of law. Moreover, in issuing that policy guidance, FDA failed to comply with its own regulations, which require that, prior to issuing such guidance, the Agency must provide notice and an opportunity for interested parties to submit comments. 

    As we understand the factual record in this case, the animal drug compounding that Defendants-Appellees conduct is within the scope of traditional pharmacy practice. The district court’s decision therefore should be affirmed. 

The Former FDA Officials are careful to point out that the "factual record" on appeal did not support manufacturing of drugs.  The FDA failed to present this argument in the district court.  Frank's in his brief argues that this argument is waived on appeal.  Normally, if an issue is not raised in the district court it can be considered waived by the appellate court.  If the 11th Circuit wants to avoid the hard issue of what is traditional compounding and what crosses over into manufacturing then it can do so by applying the waiver doctrine.