Comments Due Oct 15 for Animal Bulk Drug Compounding Guidance

Highlights of FDA’s Center for Veterinary Medicine (CVM) activities in FY 2020 include:

  • Releasing a draft guidance for industry on Compounding Animal Drugs from Bulk Drug Substances
  • Managing animal drug shortages, implementing a new system that enables U.S. exporters of animal food, drugs, and devices to apply for and obtain various types of export certificates online
  • Completing 48 domestic and 14 foreign animal drug GMP inspections

Director of CVM’s Office of Surveillance and Compliance Tim Schell provided details on his office’s 2020 accomplishments and insights into the guidance, Compounding Animal Drugs from Bulk Drug Substances (BDS) at the 2020 PDA/FDA Joint Regulatory Conference held virtually in mid-September.

[Related: For information on compounding for human drug products, download the July 30 webinar featuring the author and Jason McGuire, “Delivering Personalized Medicine and Helping Mitigate Drug Shortages: The 503B Outsourcing Story.”]

Download Compounding Webinar

GMP Facility Inspections Resuming

One of the highest priorities of FDA’s CVM, Schell said, is its post-market activities. The goal is to assure that animal drugs are safe, effective, and properly manufactured. CVM’s Office of Surveillance and Compliance, in cooperation with FDA field offices, monitors marketed animal drugs to assure their safety and effectiveness.

One way CVM monitors animal drugs is through GMP inspections. Due to COVID-19, CVM paused onsite foreign inspections in March 2020, and soon afterward, paused domestic surveillance inspections. The Center, however, continued mission-critical inspections.

In July, CVM announced the resumption of domestic surveillance inspections beginning the week of July 20. For now, inspections remain risk-based. Onsite visits occur only if there is a risk to animal/human health and remain preannounced. This allows investigators to coordinate with the inspection site on safety precautions (e.g., social distancing, personal protective equipment, etc.).

There is no change in the status of foreign inspections. CVM continues to work with its foreign counterparts to ensure the safety of imported products. Additionally, the safety of inspectors and facility personnel remains a priority. To date in FY2020, CVM has completed 48 domestic and 14 foreign animal drug GMP inspections.

COVID-19 Challenges

One of many challenges CVM experienced due to COVID-19 was fraudulent products. Throughout the pandemic, CVM has been aggressively monitoring the marketplace for fraudulent products. The Center categorizes fraudulent into two types:

  • Animal products used in humans to treat or prevent COVID-19 (examples include chloroquine and ivermectin)
  • Products used in animals to prevent or treat COVID-19 (many different types of products are in this category, including ozone treatments, lasers, and drugs)

CVM has successfully removed many products from the marketplace, but it also continues to issue warning letters for these products. In this fiscal year, CVM has issued 20 Warning Letters for marketing unapproved drugs. Five are related to COVID-19 activities, including the marketing of unapproved drugs with chloroquine. Most of the 20 warning letters were part of the collaborative agency effort to address unapproved drugs containing Cannabidiol (CBD). Two involved compounded animal drugs. The agency also continues to issue untitled letters and have regulatory meetings with firms.

It is important to note that there are no approved CBD products for animals. The agency has determined that CBD is not Generally Recognized as Safe (GRAS) for use in human or animal food.

There is no change in the status of foreign inspections

The agency continues to have safety concerns with CBD and is taking enforcement actions with priorities on products with therapeutic drug claims and products for use in food animals.

Focus on Drug Shortages

COVID-19 brought on another challenge for CVM this year—maintaining the animal drug supply. At the beginning of the outbreak, CVM primarily focused on addressing critical shortages in the availability of personal protective equipment such as masks, gloves, and surgical gowns. Shortly thereafter, attention shifted to potential shortages of drugs, particularly those produced in China where the outbreak began.

As the virus spread, the agency looked at the potential for global drug shortages. CVM reached out to manufacturers individually and worked with them to identify potential shortages. When a potential shortage was identified, CVM evaluated whether the drug in question fit the criteria for status as a medically necessary veterinary product. If it met the criteria, CVM prioritized efforts to avert shortage of the drug. If it did not meet the criteria, the agency still assisted in keeping the product available, just at a lower priority.

There are no approved CBD products for animals

CVM also developed guidance to help the industry with the process of managing potential shortages. So far this year, 32 shortages were identified, 13 were successfully averted, 18 are pending and for one it was not able to avert the shortage. The agency continues to work closely with companies to avoid shortages and its communication with them is critical in keeping animal drugs on the market.

ECATs is Now Online

Schell shared that CVM had established a new system allowing companies to obtain various types of export certificates. In June, it initiated the Electronic Export Certification and Tracking System, referred to as ECATs. The system enables U.S. exporters of animal food, drugs, and devices to apply for and obtain export certificates online.

The certificates include: 

  • Certificate of Exportability (COE)
  • Certificate to Foreign Government (CFG)
  • Certificate of Free Sale (COFS)
  • Current Good Manufacturing Practice (CGMP) Certificate
  • Certificate of Pharmaceutical Product (CPP)

A trace of the status of any requests can also be obtained through email notifications. And the certificates can be printed from the online version except for the Certificate of Pharmaceutical Product, which by regulation cannot be printed from the online version. CVM’s hope is that this new process will enhance the ability of industry to get the certificates companies need in a timely way.

Draft Guidance for Industry

In addition to regulatory actions, CVM continues to provide guidance to industry. Last November it published a draft guidance, GFI 256, Compounding Animal Drugs from Bulk Drug Substances (BDS). If finalized, the guidance will describe the agency’s current thinking about animal drug compounding from bulk drug substances. It is out for comment, with comments due by October 15, 2020. The guidance can be accessed here.

It identifies circumstances under which the agency does not intend to take regulatory action against the compounding of drugs from bulk drug substances. The Food, Drug, and Cosmetic Act (FD&C Act) permits compounding an animal drug using finished approved drugs, either human or animal as the source of the active ingredient. This can be for a legal extralabel use (ELU) if extralabel use regulations are followed (21 CFR Part 530). The Act, however, does not authorize compounding animal drugs from bulk drug substances.

How is compounding from a bulk drug substance different from compounding via an approved drug?

For animal drugs, the FD&C Act does not distinguish between compounding animal drugs from bulk drug substances and other methods of animal drug manufacturing. Therefore, all requirements for approval, labeling, and manufacturing apply to animal drugs compounded for bulk drug substances as they do with other new animal drugs.

Simply put, animal drugs compounded from bulk drug substances are new animal drugs and do not have legal marketing status without approval.

Another important point is that if a compounded drug is produced from the same bulk drug substance as an approved pioneer or generic animal drug, it is still not an approved drug. The agency approves finished drug products, not bulk drug substances.

Why is FDA concerned about animal drugs compounded from bulk drug substances?

Drugs compounded from bulk drug substances have not been evaluated by FDA and therefore do not have the same assurances of safety, efficacy, manufacturing quality, and labeling adequacy as approved drugs.

Deaths Due to Improper Compounding

CVM has received reports of illness and in some cases, death, in animals administered compounded drugs from bulk drug substances. 

“In some cases, these drugs were super potent, contained the wrong active ingredient, or lacked sterility, stability, or potency,” Schell explained. “A few compounded drugs that were super potent due to compounding errors led to multiple animal illnesses and deaths.”

Animal drugs compounded from bulk drug substances are new animal drugs

It is important to point out that there is no regulatory requirement for reporting adverse events and product defects associated with drugs compounded from bulk drug substances. Therefore, adverse events with these drugs can go unreported.

FDA recognizes that there may not be an FDA approved product to treat every illness and condition that can occur in the many different species of animals veterinarians treat, and that a drug compounded from bulk drug substances may be the only treatment option for an animal. “Animal drug compounding is important to CVM and we recognize its importance to veterinarians,” Schell pointed out.

Striking a Balance

“We want compounding to continue to be a tool for veterinarians when necessary,” Schell emphasized. “But we also want to make sure that these products are made safely and that approved drugs are used when one is available, because the safety and effectiveness of approved drugs have been established.”

“We issued draft guidance GFI 256 with the intent of striking a balance between FDA’s current understanding about the risk of animal drugs compounded from bulk drug substances and the need for those drugs when no FDA approved or index drug is available.”

Based on the agency’s current understanding of the risk, it is prioritizing its efforts on drugs compounded from bulk drug substances that:

  • Present human or animal safety concerns
  • Are used in food-producing animals
  • Are copies of legally marketed animal drugs—whether approved, conditionally approved, or indexed, or
  • Are compounded without a patient-specific prescription and sold to veterinarians as “office stock.”

Drugs that present human or animal safety concerns include situations where drugs contain more or less than the labeled amount of active ingredient or have bacterial or fungal contamination.

In some cases, these drugs were super potent

For example, in 2019, three horses died after treatment with a compounded product containing 18 to 21 times the labeled drug amount. Similarly, in 2014, four horses died and six others became sick when given a compounded drug containing 20 times the labeled drug amount. Drugs compounded with bulk drug substances are a special concern in food-producing animals because of the human health concern of potential drug residues in edible tissues.

We want compounding to continue to be a tool for veterinarians when necessary

As part of the drug approval process, FDA reviews data on human food safety and the approved labeling contains science-based conditions of use, such as withdrawal and discard times, to prevent harmful residues. Compounded drugs from bulk drug substances have not been evaluated by the agency for human food safety.

“We do recognize that there are times that call for exceptions,” Schell said. “Compounding copies of FDA approved or index drugs concerns us because it discourages firms from investing in animal drug development, which undermines animal health because fewer approved, proven animal drugs are available.”

In 2019, three horses died after treatment with compounded product

What is the Concern with Office Stock?

The use of office stock—bulk drug substances used for compounding certain animal drugs without a patient-specific prescription—also concerns CVM because it potentially exposes large numbers of animals to drugs of unproven quality. It also can undermine the integrity of the approval process.

“However, we are aware that there are situations where there is not enough time to wait for a pharmacy to compound and dispense a drug under a patient-specific prescription,” Schell pointed out. “Therefore, we are proposing a list of bulk drug substances approved to be compounded in drugs needed on hand for immediate treatment.”

“CVM understands that there are occasions when it is necessary to have office stock on hand to address specific or urgent situations. Accordingly, it has developed a list of bulk drug substances which it would not have concerns with if used in making office stock. Additionally, we recognize there are times when food animals may need antidotes and we are asking for proposals for those bulk drug substances to be included on the list as well,” Schell said.

Links

Bulk Drug Substances Nominated for Use in Compounding

How to submit nominations to the bulk drug substances list (According to Schell there is no deadline for nominating to this list; nominations are reviewed on a rolling basis.)

GFI 256, Compounding Animal Drugs from Bulk Drug Substances (Comments due Oct. 15)

[Related: For information on compounding for human drug products, download the July 30 webinar featuring the author and Jason McGuire, “Delivering Personalized Medicine and Helping Mitigate Drug Shortages: The 503B Outsourcing Story.”]

Download Compounding Webinar

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