David Bloch, JD
In late August, Custom RX Compounding Pharmacy announced that it had initiated a nationwide recall of its Trypan Blue 0.06% Ophthalmic Solution, which is used to stain the anterior lens capsule during removal of advanced cataracts, because of concerns that the product might be contaminated with Pseudomonas aeruginosa, one of the most virulent ophthalmic pathogens. According to a press release from the Minnesota-based company, the voluntary recall was undertaken because of two reports of vision loss associated with the product and a positive bacterial culture obtained by an outside hospital.
What is worth noting is not only the size of the recall, covering five lots of Custom RX trypan blue syringes that had been distributed to hospitals in eight states, but also the breadth of use of a compounded product, despite the availability of a commercial version of trypan blue (Vision Blue, marketed by Dutch Ophthalmic USA), approved by the U.S. Food and Drug Administration in December 2004. This exemplifies both the extent of ophthalmic compounding and its potential pitfalls, and highlights the necessity of reviewing the rationale for ophthalmic compounding, the evolution of regulations affecting the practice, and the clinical and legal ramifications for the ophthalmologist.
Compounding in Ophthalmology
Compounding pharmacies have traditionally provided a valuable service. For certain ophthalmic applications or patients, commercial products simply do not exist. For example, most periocular and intraocular medications are not commercially available. They are commonly used in surgical procedures, such as the admixture of anesthetics with other components, or for ocular inflammatory or infectious conditions, and must be compounded. Pharmacies may also be asked to extemporaneously compound ophthalmic products for patients with preservative sensitivity, such as to thimerosal or benzalkonium chloride. (See Table 1 for routinely compounded topical ophthalmic medications and periocular or intraocular injectables.)
When compounding pharmacies go beyond that traditional role, however, and compound products that are commercially available, such as cyclosporine (Restasis, Allergan) hyaluronidase and trypan blue, the rationale for using the compounded versions is questionable.
For example, when bovine hyaluronidase (Wydase, Wyeth-Ayerst) was removed from the market, compounding pharmacies met the need for a hyaluronidase spreading agent. However, the FDA recently approved several new commercial hyaluronidase products, beginning with a highly purified ovine hyaluronidase (Vitrase, Ista Pharmaceuticals) that not only provides a commercially manufactured product but, unlike its predecessor, is preservative- and thimerosol-free, further reducing the need for compounding.
While compounding pharmacies continue to make important contributions, ophthalmologists should consider two basic issues, particularly in choosing between commercial and compounded sources of product. The first involves the risks of adulterated raw material, dosing miscalculations, and compromised sterility and stability. This is an occasional consequence of small-scale production that large-scale, highly regulated commercial manufacturing may avoid. Individual compounding pharmacies generally can't devote the resources to these issues that commercial-scale manufacturers can.
The second issue arises when commercial pharmacies surpass extemporaneous compounding and manufacture products on a large scale, often with aggressive Internet marketing and national shipping. In becoming a kind of alternative manufacturing source for commercial products, these firms enter questionable regulatory waters, while simultaneously "scaling up" the potential risks inherent in compounding because of the greater volume (the current trypan blue case is an unfortunate example). While compounding services can play an important role in patient care, their routine use in place of commercially manufactured products raises potential safety and legal concerns.
Safety of Compounded Products
In general, the experience with compounding has been remarkably benign, reflecting the skill and commitment of compounding pharmacies. However, the track record for quality and safety of compounded products, regardless of the scale of production, is not without blemish. Stability, pH, potency, sterility and liability remain concerns.
A preliminary survey by the FDA several years ago underscores the fact that compounding pharmacies are not able to provide the assurance of quality and safety required of commercial manufacturers.1 Over six months in 2001, FDA tested 29 drug products, ordered from 12 compounding pharmacies selling compounded drugs over the Internet. The agency sampled a range of products, including hormonal products, antibiotics, steroids, anesthetics, and drugs for glaucoma, asthma, iron deficiency anemia and erectile dysfunction. Of the 29, 13 were sterile injectable products, nine were ophthalmic products, two were pellet implants, one was an inhalation product, and four were oral products. The samples were tested for: identity; assay; content uniformity; dissolution; pH; sterility; Limulus Ameobocyte Lysate (LAL); microbial limits; particulates tests; release rate and contaminants. Of the 29 samples, 10 (34 percent) failed one or more of the standard quality tests. Nine of the 10 failed assay or potency testing. The average percentage of declared potency for these nine products was calculated, with a range of 59 to 89 percent of expected potency. In contrast, FDA noted that between 1996 and 2001, it sampled more than 3,000 drug products from commercial manufacturers, and found an analytical testing failure rate of less than 2 percent. While the sample size for compounding pharmacies was small, and the survey limited, the results are striking.
Before the trypan blue recall, several incidents in which contamination of extemporaneously compounded ophthalmic products produced ocular infections and vision loss received some publicity.
The Regulation of Compounding
While not entirely unregulated, compounding pharmacies have not faced the scrutiny that commercial manufacturers do. Oversight of compounding is evolving but an understanding of the regulations suggests that there are still "gray areas" in which the unwary, the unscrupulous or the simply unlucky may run into trouble. Several sets of regulatory guidelines, including policies of the United States Pharmacopoeia and the FDA, apply to the selection of raw materials compounding pharmacies use, the conditions under which these ingredients are combined, and the scale of manufacturing and marketing practices.
All raw materials should meet USP guidelines for potency and purity, and should be obtained from USP-inspected, FDA-regulated providers. This process is not aggressively enforced, however, for compounding pharmacies. Pharmacies that obtain raw materials from non-regulated and non-inspected sources put the patient at risk for adverse drug events through the use of the compounded product. Non-USP grade materials are not guaranteed for potency and purity, and their use can lead to problems with sterility and stability.
Further, there are very few published formulation references available for compounding ophthalmic products. In 2004, USP Chapter 797: Pharmaceutical Compounding, was issued to establish guidelines for product classification and storage, personnel and training, environmental control for quality, beyond-use dating, and equipment storage and maintenance.2 These guidelines aim to assure that compounding pharmacies use methods of quality assurance for all compounded products they produce, that the products maintain quality after leaving the pharmacy, and that adverse drug events are prevented.
A few commercial manufacturers of products that are frequently compounded or admixed have begun to develop reference sheets for pharmacies following USP 797. For example, Ista Pharmaceuticals has produced a technical bulletin on the admixture of lidocaine and bupivacaine with Vitrase based on its own studies of sterility and stability.
Compounding pharmacies that expand the scope of their operations too far may also find themselves subject to FDA regulation. The Federal Food, Drug and Cosmetic Act (FDCA) prohibits the sale of "adulterated or misbranded" drugs. This covers a range of shortcomings, including contamination, failure to meet product specifications or any other conditions that render a product unsafe. A drug is automatically presumed adulterated if it is not evaluated and approved by the FDA prior to marketing. Moreover, any facility that manufactures a drug must register with FDA, comply with the agency's demanding good manufacturing practice standards, and be available for FDA inspection. Drugs manufactured in a facility not registered with FDA are deemed adulterated.
The FDA provides a limited exception to the new drug approval and registration requirements for drugs compounded by pharmacies, in the normal course of pharmacy practice. This exception is meant to allow for compounding in rare circumstances, to meet unique patient needs. In a compliance policy guide (CPG), FDA recognized that pharmacists may compound "reasonable quantities" of human drugs upon receipt of a valid prescription for an individually identified patient from a licensed practitioner. However, the agency expressed concern that an increasing number of pharmacies engage in compounding on a scale that goes beyond pharmacy practice, and represents commercial manufacturing and distribution of "unapproved new drugs."
For example, FDA noted that some firms receive and use bulk drug substances to manufacture large quantities of unapproved drug products in advance of receiving a valid prescription for them. Moreover, some firms sell to physicians and patients with whom they have "only a remote professional relationship." FDA's concern is that these pharmacies represent a kind of parallel stream of manufacturing that is not registered, with facilities that are not inspected for GMP compliance and products not reviewed by FDA for safety and effectiveness.
Some current ophthalmic compounding might be challenged under these guidelines, particularly in situations where an FDA-approved, commercial product also exists. In some instances, commercial products may require compounding based upon preservative sensitivity, different concentrations required, etc., but this may not be relevant in most cases.
The FDA plans to defer enforcement to the states for less significant violations related to pharmacy compounding, but may engage in coordinated investigations, referrals, and follow-up actions by the states. However, when the FDA concludes that the scope and nature of a compounding pharmacy's activities begin to resemble those of a drug manufacturer and result in significant violations of the FDCA's new drug, adulteration or misbranding provisions, the FDA may act itself.
Recent years have seen an increasing number of FDA warning letters to compounding pharmacies. Generally they have resulted from facility inspections that raised specific safety concerns. Each inspection was conducted jointly by the FDA and the state Board of Pharmacy. The state boards retain authority to conduct their own enforcement actions, including review of licensing.
Potential Liability Issues
Use of improperly compounded products may also pose liability risks for the ophthalmologist. Whenever product liability claims arise from the use of a prescription product, a plaintiff's lawyer will determine if the prescribed use has been approved by the FDA, and if warnings about known or knowable risks were given to the prescribing physicians and the patient.
In the case of compounded products, this argument could go even further, since it is the fundamental integrity of the manufacturing of the drug itself that is at question, and not just the choice of how to use a drug that has otherwise been cleared for marketing.
The vast majority of product liability claims involving prescription products arise from a claimed "failure to warn" of known or knowable risks or from the prescription of a product for an unapproved—off-label—use. In current litigation involving the prescription of two drugs in combination for an unapproved use, the patients' lawyers have claimed that the physicians failed to warn the patient that the drugs had not been approved for combination use. They further asserted that the physicians did not warn about risks associated with the combined used of the therapies and that the physicians were negligent and fell below the standard of care by prescribing an off-label combination of drugs. It is not difficult to envision that same argument being adapted to a physician ordering a compounded product without informing the patient.
A plaintiff's lawyer could assert that a defendant physician took a substantial risk by ordering a drug from a compounding pharmacy rather than from the manufacturer approved and inspected by FDA. If the pharmacy is located in another state, the plaintiff could assert that the physician did not properly investigate the pharmacy to determine if its facilities and practices provided reliable finished product. In the absence of medical need for compounded product, the plaintiff's attorney would assert that the cost differential was the primary factor in the physician's choice. If the physician did not inform the patient that the drugs used came from a compounding pharmacy, the plaintiff's attorney could assert that the physician increased the risk of treatment, but failed to disclose that risk to the patient. The uncertain legal status of the increased scope of compounding pharmacies' activities, and FDA's publicly stated concerns over the potential safety risks they pose, would undoubtedly be raised to highlight the seriousness of the "risk" that was never disclosed to the patient.
Compounded products will remain important components of the ophthalmologist's armamentarium. However, use of a compounding pharmacy may not be appropriate where a commercially manufactured product is available and no unique patient circumstances warrant compounding. To minimize the inherent clinical, regulatory and legal risks of ordering and using compounded products, physicians should:
• Avoid the use of compounded products when commercial alternatives exist, unless this use is medically necessary. Utilizing compounded product when an FDA-approved product is clinically appropriate creates unacceptable clinical, regulatory and legal risks.
• Confirm that the pharmacy utilizes USP-grade raw materials when appropriate and follows USP guidelines for compounded ophthalmic products before ordering compounded products. Confirm that the compounding pharmacy affirmatively meets standards set by USP 797.
• Determine if any technical information on sterility and stability is available from the manufacturers of products you commonly have admixed. If not, understand what reference source the compounding pharmacy is using to ensure the quality and reliability of the product.
• When use of a compounded product is deemed medically necessary, consider disclosing the fact in the informed consent.
Keratoconjunctivitis sicca (KCS)
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Mr. Fiscella is a clinical professor in the Department of Pharmacy Practice and an adjunctive assistant professor in the Department of Ophthalmology at the University of Illinois, Chicago. Contact him at firstname.lastname@example.org. Mr. Labib is assistant director of the UIC Eye and Ear Infirmary Pharmacy. Mr. Jensen is the supervising pharmacist at the John A. Moran Eye Center, University of Utah. Mr. Bloch is a partner in the Washington, D.C., office of Reed Smith.
1. FDA/Center for Drug Evaluation and Research (CDER). Report: Limited FDA survey of compounded drug products. January 28, 2003. Available at: http://www.fda.gov/cder/pharmcomp/survey.htm.
2. The United States Pharmacopoeia 27 – National Formulary 22 (USP-NF). Chapter 797: Pharmaceutical Compounding. 2004.
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