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Compounding Pharmacies Under New Regulations

Rules improve safety yet pose challenges for retina specialists.

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Years ago, retina specialists often mixed their own drugs using equipment and skills not much different from what they learned in their college chemistry classes. Today, compounding pharmacies handle most of that work. But proposed regulations from the US Food and Drug Administration (FDA) have raised fears that the burden will once again fall on clinicians who don’t feel prepared.

HOW THE CHANGES AFFECT PRACTICE

“In general, the new guidance from the FDA requiring the extra testing and restrictions is good for safety, but our concern comes when it’s hard to get the medicine when we need it,” says Geoffrey Emerson, MD, PhD, chair of the Research and Safety in Therapeutics Committee of the American Society of Retina Specialists (ASRS).

He pointed to endophthalmitis as one of the biggest concerns because it is so often an emergency. While vancomycin is typically available in ophthalmic formulations, he said, some patients are allergic to this drug, and it isn’t effective against viral, fungal, or protozoan infections.

Also, the ASRS is concerned that new sterilization requirements could restrict the availability of biologic drugs such as bevacizumab (Avastin; Genentech). Stricter regulations are also limiting the supply of lissamine green, which is used to diagnose dry eye, says Charles Leiter, who quit his position as CEO of Leiter’s Compounding Pharmacy in San Jose, California because of the new regulations.

“Prices are going to go up and availability is going to go down,” said Dr. Leiter. “You’re seeing it now.”

On the flip side, some in the industry believe the new standards will improve the safety of compounded drugs.

The regulations are required under the Drug Quality and Security Act, signed into law in 2013 after a 2012 outbreak of fungal meningitis killed at least 64 people. Investigators traced the infections to injectable drugs contaminated at the New England Compounding Center (NECC) in Framingham, Massachusetts. Until then, states took the lead in regulating compounding pharmacies. But the pharmacies were selling more drugs in large batches across state lines. The outbreak prompted Congress to seek a role for the FDA in regulating this business.

503A AND 503B FACILITIES

Under the Drug Quality and Security Act of 2013, compounding pharmacies are divided into 2 types. Traditional compounding pharmacies, dubbed 503A facilities by the new law, are regulated primarily by individual states, but some federal regulations still apply. They can only compound drugs for individual prescriptions, though they may compound limited quantities in anticipation of receiving a prescription. They cannot distribute across state lines more than 5% of their total prescription orders, unless their state has entered into a memorandum of understanding allowing exemptions.

Outsourcing facilities, dubbed 503B facilities by the new law, must comply with federal Current Good Manufacturing Practice (CGMP) regulations. They are inspected by the FDA. They must report to the FDA twice a year about the products they have compounded in the previous 6 months, reporting adverse events and labeling their products.

Neither type of facility can compound copies of commercially available products, or drugs that are not currently approved by the FDA, except that outsourcing facilities can compound commercially available drugs that appear on FDA shortage lists. Compounders that neither register under section 503B nor qualify for exemptions under 503A are subject to the requirements of conventional drug manufacturers.

Although many pharmacies have registered as 503B facilities, they have operated in an uncertain environment because the regulations have not been finalized. “We operate as if the guidance is the law,” said Jim Rehovsky, vice president of ophthalmology for Avella Specialty Pharmacy. But, he said, this means adapting as each draft of the guidance is published.

CHOOSING A COMPOUNDING PHARMACY

Reports of contamination have raised questions about the practices of compounding pharmacies, and prescribing compounded drugs leaves the physician liable in cases of adverse events. The federal government has stepped in to enforce new standards, but the new regulations have disrupted some established relationships. Here’s what ophthalmologists need to know when looking for a compounding pharmacy.

FREQUENCY OF INSPECTIONS

The schedule of inspections for 503A facilities varies by state. The FDA inspects newly registered 503B facilities within 2 months of initial registration, if the facility has not been previously inspected. After that, the frequency of its inspections depends on the findings from the first inspection, the frequency of past inspections, the facility’s history of compliance and recalls, the inherent risk of the drugs compounded, and whether the facility has registered as an entity that intends to compound drugs in shortage.

COMPLIANCE

At the end of an inspection, the FDA issues a 483 form if inspectors have any observations. Facilities are expected to respond to these observations, which could include substances that the agency expects to be recalled. “Enforcement can include seizure, injunction and criminal procedure,” says Wiley A. Chambers, MD, director of the FDA’s division of anti-infective and ophthalmology products. “But that’s not the goal. The goal is to get the facility to produce products that are safe to use in patients.”

The agency can also request that a pharmacy recall products. “Recalls are generally voluntary,” Dr. Chambers says. “Although the agency does have the capacity to seize products and shut production down, in the vast majority of cases that I’m aware of, the pharmacies will recall the products voluntarily.”

WHAT TO LOOK FOR

Anyone looking for a facility’s record of 483 forms and other interactions with the FDA can find them online at www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ucm339771.htm . Many states maintain similar websites for the inspections they carry out.

Physicians should also ask pharmacies about their quality assurance procedures. Some pharmacies provide such information on their websites, but physicians can go beyond that and ask about any observations made by state or FDA inspectors and how the pharmacies are responding.

“If you can, go visit,” says Jim Rehovsky, vice president of ophthalmology at Avella Specialty Pharmacy in Phoenix, Arizona. “We have people who stop by when they come through the Phoenix area golfing.”

Charles Leiter, former CEO of Leiter’s Compounding Pharmacy in San Jose, California, recommends asking for a certificate of analysis for each product. “You want to know that what’s in the bottle is what it says it is.”

He recommends asking compounding pharmacies about the analysis of potency, endotoxins, and sterility of each injectable drug. “I’d want to see their records,” he says. He has seen doctors named in lawsuits against compounding pharmacies because the doctors “didn’t do their due diligence.”

Other questions to consider asking are as follows:

  • What are the procedures for environmental and air monitoring?
  • What is the training and qualifications of the staff?
  • How is the stability of the drug determined and how are expiration dates assigned?
  • Are logs kept for cleaning and disinfecting equipment?
  • How is equipment maintained and calibrated?
  • What is the water supply and how is it purified?

To help the medical community assess and select a compounding pharmacy, The International Academy of Compounding Pharmacists created the Compounding Pharmacy Assessment Questionnaire. It is available online at www.iacprx.org .

“It’s been amazing how long they’ve been in draft form,” said Dr. Emerson.

So far, the FDA has issued 21 draft guidances and 3 proposed rules, one of which has been finalized, said Wiley A. Chambers, MD, director of the FDA’s division of anti-infective and ophthalmology products. Guidances state the agency’s “best thinking” about compliance with the law, while rules give definitive directions. Dr. Chambers said it’s hard to estimate how long it will take to finalize these guidances and rules. “We’re required to go through all the comments on them,” he said. And the agency has received thousands of comments. One guidance that has raised concerns sets a 5-day beyond use date for biologics. That’s problematic for bevacizumab because it takes 14 days to test the drugs’ sterility, said Dr. Chambers.

TESTING REQUIREMENTS BURDEN BUSINESSES

Newer drafts of the guidances allow facilities to test their ability to formulate biologics and show evidence that the drugs are stable for longer. Avella, headquartered in Phoenix, Arizona, has already done tests to show its bevacizumab syringes are stable for 120 days. But the pharmacy anticipates the need for more tests as the FDA provides further guidance that will for example establish standards for subvisible particles. “Nobody has a full grasp,” said Rehovsky. “They’re looking at particle size, but they don’t say what the particle size is. So, it’s hard to test on that.”

STAYING PROTECTED

A clear concern in the retina specialist community is liability if contaminated drug were ever to affect their patients.

“Retina specialists are responsible for the quality and safety of any compounded drug that they administer to a patient,” says George A. Williams, MD, chair of the board of directors for the Ophthalmic Mutual Insurance Company (OMIC). “Obviously, this creates potential liability. Patients are entitled to full disclosure about any compounded drug, and informed consent should include a discussion about why the physician feels a compounded drug is the best choice and what other treatment options are available.” Dr. Williams adds that the OMIC strongly recommends ophthalmologists use an informed consent that addresses the risks of using compounded drugs (an example is available at www.omic.com ).

“Beyond appropriate and complete informed consent, ophthalmologists should obtain most compounded drugs from a compounding pharmacy with a 503B designation whenever possible. Some practices have chosen not to treat both eyes on the same day with any compounded drugs,” he says.

Sunir Garg, MD, from Wills Eye Hospital in Philadelphia, Pennsylvania, recommends thoroughly vetting the pharmacy before ordering drug to reduce the risk of getting contaminated medication.

“Then, once the drug arrives at your office, it’s important to maintain a log of who handled the drug, make sure that it is stored properly (and document this), and record the lot number of the drug,” says Dr. Garg.

“Your current liability carrier should cover you if you and your patient are involved in an endophthalmitis outbreak due to contaminated compounded medication,” he says.

Jay Sridhar, MD, of Bascom Palmer Eye Institute in Miami, Florida, adds that given the current cost differences between on- and off-label intravitreal anti-VEGF treatment, government officials, insurers, and providers cannot ignore the benefit of compounded off-label medication in reducing economic burden on the health care system.

“Although tort reform is an important issue, with the current legal environment and precedents, we should consider how to reduce risk now. It will be critical for all of us to continue to work together to maximize the safety of compounded drugs for all of our patients,” says Dr. Sridhar.

Each of these tests costs about $100,000, said Rehovsky. Such expenses are already driving some of the smaller compounding pharmacies out of business, he said. “The ‘mom and pops’ aren’t going to be able to handle this.”

Autologous serum tears are also “problematic” under the new regulations, says Dr. Leiter. “Now you may have to do tests on the stability of serum, and you can’t.”

As a result, many pharmacies have drastically pared down the list of products they offer. “We used to make 1,200 drugs, which was ridiculous,” says Dr. Leiter. “Now a lot of pharmacies are just making 10.”

Smaller pharmacies are still pursuing a role as 503A pharmacies compounding drugs in less demand. But if the FDA suspects these pharmacies of shipping large quantities of compounded drugs, it may inspect them and hold them to the stringent federal CGMP standards instead of the laxer standards of the US Pharmacopeial Convention, known as the USP 797, says Rehovsky. He thinks many are not prepared to meet that challenge.

In addition to driving some small pharmacies out of business, the new regulations are making it harder for ophthalmologists to get drugs in an emergency, says Rehovsky. “Instead of just reaching in the refrigerator, you have to write a prescription and send it to a pharmacy, which sends it to a physician or patient,” said Rehovsky. “So it will take longer.”

LIMITS TO AMOUNT OF DRUG COMPOUNDED

Another rule that makes emergency treatment of endophthalmitis difficult is a limit on the amount of drugs that 503A facilities can compound in anticipation of the need for them. Previously, the compounding pharmacy at Phillips Eye Institute where Dr. Emerson works used to package antibiotics into single-use vials that were stored frozen at operating rooms throughout the hospital system to which it is connected. The new regulations allow the pharmacy to stock these drugs at an adjacent operating room, but not at operating rooms more than 1 mile away.

“Prior to the changes, it was possible to immediately treat the patient at one of the suburban locations with antibiotic injections for endophthalmitis,” Dr. Emerson says. “Now, we don’t have the option to treat the patient at those other locations, and so the patient is transferred to the central location in Minneapolis. This transfer delays care.  Endophthalmitis is a true emergency where immediate care can save vision and so there is unfortunately a negative impact on the health of the patient when delay occurs.”

ARE THE REGULATIONS NECESSARY?

Meanwhile, he says, problems are continuing to crop up at compounding pharmacies. For example, the ASRS is collecting reports of silicon droplets in patients’ eyes associated with the use of syringes designed for insulin injections that use silicon oil as a lubricant.

Dr. Leiter thinks the Drug Quality and Security Act has caused more problems than it has solved. Patients would not have been sickened by the contaminated vials of preservative-free methylprednisolone acetate from the NECC if that pharmacy had followed regulations in force at the time, he says.

Rehovsky, on the other hand, thinks patients will get an overall benefit from the higher standards. “I think it’s tremendous,” he says. “I think it’s going to save lives.” RP