David Bloch, JD
Richard G. Fiscella, RPh, MPH
Sami Labib, RPh
Michael K. Jensen, RPh, MBA
Salt Lake City

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.


Important Considerations

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. 

Commonly Used Compounded Ophthalmic Products
Route                                          Strength                                     Indication       
Acetylcysteine                          10 to 20% Solution                 Collenganase inhibitor for alkali burns; corneal melts;
Keratoconjunctivitis sicca (KCS)

Amikacin                                    6.7 to 25 mg/ml solution        Bacterial infections; corneal ulcers

Amphotericin B                          1 to 5 mg/ml solution              Fungal infections; yeast infections; corneal ulcers

Cefazolin                                    25 to 100 mg/ml solution       Bacterial infections; corneal ulcers

Chlorhexidine                             0.02% solution                        Acanthamoeba keratitis

Cocaine                                        4%, 10% solution                  Diagnosis of Horner's Syndrome; miotic pupils, force duction testing; Dacryocystorhinostomy (DCR)

Dexamethasone PF                     0.1% solution                          Ocular inflammatory conditions (preservative sensitivity)

Edetate Sodium                           3.7 to 20 mg/ml solution         Corneal band keratopathy/lime injury

Gentamicin Fortified                8 to 15 mg/ml solution             Bacterial infections; corneal ulcers

Medroxy-progesterone            10 mg/ml suspension                Corneal alkali burns; dry-eye disease (KCS)

Mitomycin*                                0.2 to 0.4 mg/ml solution         Ancillary treatment of glaucoma/pterygium surgery

Pilocarpine                                 0.0625 to 0.125% solution       Photophobia or diagnostic agent

Polyhexamethylene  Biguanide (PHMB)  0.02% solution       Acanthamoeba keratitis

Tobramycin Fortified                8 to 15 mg/ml solution             Bacterial infections; corneal ulcers

Vancomycin                               25 to 50 mg/ml solution            Bacterial infections; corneal ulcers; presumed endophthalmitis

Amikacin                                      100 to 400 mcg/0.1ml               Endophthalmitis

Amphotericin B                            1 mg/0.5 ml                              Subconjunctival injection for fungal infections                                      5 mcg/0.1 ml                            Intravitreal injection for fungal endophthalmitis                         

Ceftazidime                                   2 mg/0.1 ml                              Intravitreal injection for bacterial endophthalmitis

Dexamethasone                            400 mcg/0.1 ml                        Intravitreal injection for intraocular inflammation

Foscarnet                                      1200 mcg/0.1 ml                      Intravitreal injection for CMV retinitis

Ganciclovir                                   200 mcg/0.1 ml                       Intravitreal injection for CMV retinitis

Tissue plasminogen activator    12.5 to 25 mcg/0.1 ml             Treatment of intraocular fibrin deposits

Vancomycin                                   1 mg/0.1 ml                           Intravitreal injection for bacterial endophthalmitis

* Chemotherapy precautions required 

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 fisc@uic.edu. 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.

Also see:

Gonnering, R et al. The pH tolerance of rabbit and human corneal epithelium. Invest Ophthalmol Vis Sci. 1979;18:373-90.

Russell, S. Pharmacy-made drugs draw FDA scrutiny. The San Francisco Chronicle. June 5, 2002.

Associated Press. Pittsburgh woman loses eye to tainted drugs; 12 hurt. Baltimore Sun. 1990; Nov 9:3A.

Associated Press. Eye drop injuries prompt an FDA warning. NY Times. 1990; 140(Dec 9):391.