Manufacturers, Compounders Clash As FDA Prepares Final Offer On Office Compounding

Pharmaceutical manufacturers and compounders are in opposition over the US FDA’s plans to carve out a place for pharmacies that want to keep physicians’ offices stocked with small amounts of product. Who will the agency disappoint this time?

US FDA’s effort to step up compounding enforcement but with a carve-out for organizations providing small amounts of office compounding illustrates how difficult it is to include some flexibility as new regulatory requirements are imposed.

Commissioner Scott Gottlieb recently indicated that new compounding guidance is imminent. But comments on draft guidance the agency revised in December indicate some stakeholders are certain to be disappointed, and possibly all of them will be.

The revised draft says FDA would limit its enforcement of good manufacturing practices for traditional 503A compounding pharmacies that upgrade to 503B outsourcing facilities – which are legally required to meet drug GMP requirements – at least until the agency promulgates reduced requirements for outsourcing facilities. (Also see "FDA’s Revised Draft For Compounding Pharmacies Opens Door To Compounding For Office Use " - Pink Sheet, 17 Dec, 2018.) The draft defines situations where it might use enforcement discretion based on factors such as batch amounts.

The document drew comments from an array of groups, including the Pharmaceutical Research and Manufacturers of America and the Association for Accessible Medicines. Perhaps predictably, those organizations argue that the proposed enforcement discretion was too generous to compounders, while organizations representing compounders said it was so limited as to be practically worthless.

Gottlieb Firm On Limits Of Traditional Compounding

In testimony at a recent congressional appropriations hearing, Gottlieb provided insight into the agency’s thinking as it explores how to let traditional compounding pharmacies stock physicians’ offices with their products despite restrictions in the November 2013 Drug Quality and Security Act.

Gottlieb acknowledged in Feb. 27 testimony before a House appropriations subcommittee that some traditional compounders regulated under Section 503A of the Food, Drug and Cosmetic Act “do want to engage in larger-scale manufacturing and stock local doctors' practices and will argue they've done that for years and they've done it safely.”

But in a reference to the New England Compounding Center fungal meningitis tragedy, he said, “those are the kinds of conditions that created the public health risks that led to the passage of the DQSA and the implementation of a new regimen.” (Also see "NECC Crisis Festered in Ambiguity That Reigns Over Compounding" - Pink Sheet, 29 Nov, 2012.) Given the intent of Congress in passing DQSA, “we do not believe that a 503A pharmacy can engage in large-scale manufacturing and advance shipping,” Gottlieb said. Rather, he said, such pharmacies must compound only in response to individual patient prescriptions. 503A pharmacies might be able to get away with a little office compounding, Gottlieb said. “But once they try to do it on any scale, they're going to get on the radar of not just the state officials but the federal officials, so they're effectively capped.”

However, the FDA commissioner said he wants to “try and make it as efficient as possible for the 503A pharmacies that want to engage in that activity to become 503B pharmacies where they're subject to at least good manufacturing practices oversight to ensure the safety of those products.”

Toward that end, he said the agency is about to issue guidance that will enable small pharmacies to convert to 503B outsourcers without spending millions of dollars. Applying for 503B status should become a more viable alternative for office compounding under the pending guidance.

Proposed Arrangement For Small Outsourcers Questioned

FDA is reviewing comments on revised draft guidance that would carve out a set of reduced compliance requirements the agency would enforce for 503B facilities that do very small amounts of office compounding.

The Dec. 10 revised draft takes the approach of setting thresholds for reduced enforcement: reduced release testing for batches of less than 60 units, reduced stability testing for batches of less than 1,000 sterile drug units or 5,000 non-sterile drug units. Plus, drugs could be released before sterility testing results are in.

FDA has precedents for enforcement discretion for both very small amounts of manufacturing activity and for periods of transition toward more stringent requirements. For example, the agency exempts clinical materials used in Phase I clinical trials from drug GMP requirements, and exercises discretion in enforcing GMPs in Phase II and III. (Also see "Risk and Reward: Pharmacy Compounding of Clinical Materials" - Pink Sheet, 27 Feb, 2014.) More recently, the agency has used discretion in enforcing drug serialization deadlines. (Also see "Survey Shows Drug Makers Don't Expect To Begin Serializing All Packages By November Deadline" - Pink Sheet, 19 Oct, 2018.) The agency also is providing a grace period for stem cell clinics to determine whether products need to be submitted for biological license applications, taking a risk-based approach to enforcement in the meantime. (Also see "FDA Ups Pressure On Stem Cell Therapy Makers To Follow Product Approval Rules " - Pink Sheet, 3 Jan, 2019.)

In its comments on the compounding guidance, PhRMA cautioned that the risk-based enforcement discretion should be properly informed.

FDA has a better idea of the risks posed by PhRMA member facilities because of all the information on manufacturing processes and facilities that must go into new drug applications, something compounders don’t file. Therefore, PhRMA suggested the agency inspect enough compounders to “appropriately gauge the risks of activities conducted at outsourcing facilities.”

AAM urged FDA to consider specifying in the guidance that outsourcers should rely on someone who is qualified to oversee manufacturing quality instead of leaving that duty to the supervisory pharmacist.

While AAM generally agreed with reduced testing for small batches, the association questioned the proposal to let outsourcers release batches before obtaining final sterility testing results.

The association, which represents generic and biosimilar drug makers, suggested that the lack of application review for outsourcers increases their risk of giving patients infections that could be difficult or impossible to treat.

AAM also suggested reducing the size cutoff for batches that would qualify for reduced stability testing requirements, aligning the default beyond use dates in FDA’s enforcement policy for sterile drugs with those of USP’s revised draft chapter <797>, and imposing a 10 times stricter batch-size cutoff for enforcing reserve sample retention.

Like AAM, the Pharma & Biopharma Outsourcing Association, which represents contract manufacturing organizations, said many of the revised draft’s batch-size cutoffs for enforcement discretion were too high, and that batches shouldn’t be released until sterility testing results are in.

The American Society of Health-System Pharmacists, whose members are customers and in some cases operators of outsourcing facilities, urged alignment of various provisions with those of USP, including for sterile-product beyond use dating, as well as for antimicrobial effectiveness testing and for packaging and labeling.

A Different Understanding

Professional Compounding Centers of America complained that the proposed 60-unit-batch relief threshold is too low, saying the cost of release testing FDA would expect 503B facilities to conduct after every 60 units would be prohibitive.

But PCCA, which sells supplies and training services to a network of compounders, gave a thumbs up for the reductions in antimicrobial effectiveness testing and stability studies that FDA would enforce.

The group, which also lobbies on behalf of its network, urged FDA to track drug shortages in a more all-encompassing way, like the American Society of Health System Pharmacists does. FDA lets facilities compound drugs from bulk ingredients if it says the drugs are in shortage.

The International Academy of Compounding Pharmacists asserted that FDA’s effort to get 503A pharmacies to apply for 503B status appears doomed by separate guidance the agency has drafted that would “impose severe restrictions” on the ability of 503B facilities to compound from bulk drug substances.

Further, IACP complained that inconsistent interpretation and enforcement of drug GMP standards at outsourcing facilities augers against seeking 503B status.

The association of compounding pharmacists complained about the cost in time and money of various sterility assurance, cleaning validation, ingredient testing, release testing and stability testing activities FDA requires.

The 60-unit threshold for enforcement discretion is far too low to be of any value, the group said.