Compounded 0.01% Atropine—What's in the Bottle?

Abstract

Objective: 

To describe the labeling, packaging practices, and characteristics of compounded 0.01% ophthalmic atropine.

Methods: 

A convenience sample of parents of children who had previously been prescribed low-concentration atropine for myopia management were randomized to obtain 0.01% atropine ophthalmic solution from one of nine compounding pharmacies. The products were analyzed for various important quality attributes. The main outcomes were labeling practices, concentration of atropine and degradant product tropic acid, pH, osmolarity, viscosity, and excipients in 0.01% atropine samples obtained from nine US compounding pharmacies.

Results: 

Twenty-four samples from nine pharmacies were analyzed. The median bottle size was 10 mL (range 3.5–15 mL), and eight of nine pharmacies used clear plastic bottles. Storage recommendations varied and were evenly split between refrigeration (33%), room temperature (33%), and cool, dark, dry location (33%). Beyond use dates ranged from 7 to 175 days (median, 91 days). Median pH of samples was 7.1 (range, 5.5–7.8). Median measured concentration relative to the prescribed concentration was 93.3% (70.4%–104.1%). One quarter of samples were under the 90% minimum target concentration of 0.01%.

Conclusions: 

An inconsistent and wide variety of formulation and labeling practices exist for compounding 0.01% atropine prescribed to slow pediatric myopia progression.

A report by the American Academy of Ophthalmology supports the use of low-concentration atropine to slow myopic progression.¹ In the United States, low-concentration atropine (e.g., 0.01%) can only be obtained through compounding pharmacies. In the United States, Food and Drug Administration (FDA)–approved drugs undergo rigorous testing, and manufacturers are required to follow current good manufacturing practices (GMP) to consistently produce high-quality products.² Compounding pharmacies are generally held under the authority of state boards of pharmacy, who enforce varying levels of compliance within the United States Pharmacopeia (USP) guidelines.^2,3

Compounding pharmacies may formulate low-concentration atropine by diluting 1% atropine sulfate ophthalmic solution or reconstituting atropine sulfate powder with additional inactive ingredients. Surveys of compounding pharmacies in the United States and Germany reported a wide range of practices.^4,5 Atropine is susceptible to hydrolysis, and the rate of degradation is influenced by pH and the ingredients used in formulation.^4,6 The degradation products, tropic acid, and apoatropine do not have anticholinergic activity and thus reduce efficacy.⁴ Preservatives and other excipients may also alter efficiency and safety.

Although the kinetics of atropine degradation at higher concentration are well established,⁶ lower concentrations degrade more rapidly, and stability of compounded samples are rarely reported in published clinical trials and case reports.^7–9 Recently, three groups have assessed the stability of different formulations. The first assessed the stability of atropine prepared using 1% ophthalmic solution with 0.9% sodium chloride in opaque plastic vials.¹⁰ They reported acceptable stability (within 3% of initial/target concentration) for all concentrations (0.01%–0.5%) under both refrigerated and room temperature conditions, out to six months. The second prepared 0.01% atropine using powdered atropine dissolved in saline, sodium dihydrogen phosphate dihydrate, and disodium hydrogen phosphate dodecahydrate, with and without preservatives.¹¹ The formulations had an initial pH of 6.1 and were packaged in semipermeable containers at room temperature (25°C). All atropine formulations in this study remained within 6% loss of the initial concentration up to six months. The third compounded 0.01% atropine from 1% ophthalmic solution with either balanced salt solution (BSS) or preserved artificial tears with hydroxypropyl methylcellulose (HPMC), refrigerated, or at room temperature.¹² The concentration of unopened solution was found to be within 10% of initial concentration for only 2 months at room temperature and 6 months when refrigerated. Greater degradation was observed at room temperature, when opened (simulated use), and when compounded with HPMC as compared with BSS. Thus, formulation and storage can have significant impact on potency.⁵

Compounding pharmacies are not mandated to report adverse events potentially associated with the use of their products, and efficacy is based only on the literature. Thus, neither efficacy nor adverse events associated with compounded atropine can be accurately assessed.² To our knowledge, only one study assessed the quality of ophthalmic medications obtained from compounding pharmacies in the United States. Yannuzzi et al.¹³ assessed 21 samples of bevacizumab from 11 pharmacies and found 81% to have lower than targeted concentrations within 30 days of receipt. There have also been numerous case reports of infection from compounded ophthalmic medications.¹⁴

Given the increasing use of low-concentration atropine in children, we assessed labeling practices, and quantified concentration of atropine and tropic acid, pH, osmolarity, and viscosity of compounded 0.01% atropine obtained from various US pharmacies.

METHODS

This was a single site, masked study of 0.01% atropine ophthalmic solution obtained from compounding pharmacies across the United States. The protocol was approved by an independent ethics review board (Sterling IRB, Atlanta, GA). The study complied with the Declaration of Helsinki and conformed with all applicable guidelines for the protection of human subjects.

There are challenges to evaluating compounding pharmacies because the majority are only able to fill prescriptions and cannot supply drugs directly to clinicians, institutions, or investigators. Thus, parents of myopic children were needed to participate to obtain the samples. Parents of children who currently or had previously used low-concentration atropine for myopia management were recruited from the University of Houston College of Optometry's University Eye Institute and the surrounding area through flyers, phone, and email. Parents were excluded if they or an immediate family member were an optometrist or pharmacist.

Methods of selecting compounding pharmacies have been published previously,⁵ but briefly, compounding pharmacies were identified through a survey of eye doctors, review of social media, and during conference meeting discussions. In addition, a web search for “low-dose” or “low-concentration,” and “atropine” was conducted. The 28 compounding pharmacies found were all contacted by phone to identify 13 pharmacies that compounded 0.01% ophthalmic atropine and shipped to Texas. Ten supplied the product in at least 5 mL per shipment needed for analyses.

Following consent, participants were asked to provide information about any current or previous compounding pharmacy they had used. Participants were then randomly assigned to a pharmacy. If the pharmacy was one that the participant had used previously, they were rerandomized. To assess repeatability of samples over time, participants were asked to obtain two 3-month supplies of 0.01% atropine, separated by 30 to 90 days. Two pharmacies were assigned to two participants to assess consistency between orders during the same period.

Participants delivered the atropine to investigators, unopened, with all packaging materials, within one week of receiving it. They were asked to complete a log detailing the pharmacy instructions, date, and method of receipt. The log reminded participants to follow the pharmacy's storage directions. If none were provided, participants were instructed to store at room temperature.

Investigators recorded the order and receipt dates, storage recommendations (per patient and per bottle/packaging material), approximate bottle size and type, number of bottles, date made/lot, and beyond use date (BUD). Photographs were taken of the bottles before overlabeling (masking) with tamper-resistant security labels (NovaVision, Bowling Green, OH). Bottles were marked with a letter, subject ID, and bottle number and were shipped to Nevakar Injectables, Inc, through overnight mail for masked analysis.

Samples were analyzed 30±2 days after receipt by the subject because this was the minimum time a patient would use a bottle of the size analyzed. Samples were tested for appearance (clarity and color), pH (SevenCompact pH/ion S220, Metler Toledo, Columbus, OH), osmolality (Model 3,250 Osmometer, Advanced instruments, Norwood, MA), viscosity (Rheometer DV3TLVCJ0, Brookfield Engineering Laboratories, Middleboro, MA), and percentage assay of atropine sulfate, benzalkonium chloride (BAK), and other excipients (high performance lipid chromatography.

Data were entered into an Excel spreadsheet (Microsoft, Redmond, WA) and analyzed using SPSS (v26 IBM SPSS Statistics, Armonk, NY). Summary data were presented as anonymized medians, ranges, counts, and frequencies to show general alignment or differences among compounding practices. Nonparametric Spearman correlations and Mann–Whitney U tests were used because of the small sample size.

RESULTS

Thirteen participants were enrolled. Two later withdrew because of time constraints. After the start of the study, one pharmacy received a warning letter from the FDA and was not used because of the ongoing investigation. Eleven participants completed the study, and each obtained two 3-month supplies of atropine from one of nine pharmacies located in seven states.

The median bottle size for the first order was 10 mL (range 3.5–15 mL). One pharmacy used white opaque bottles, but the other eight used clear plastic bottles. One pharmacy changed bottle size from 5 to 10 mL for the second order, but all others were consistent. Package labeling from three pharmacies instructed to refrigerate (33% of pharmacies), three to store in a dark, cool, dry place (33%), and three to store at room temperature (33%). Some pharmacies compounded atropine in advance, and others compounded to order, thus the median number of days from date made (per bottle label) to receipt ranged from 2 to 87 days (median, 8 days) for the first order and 1 to 89 (median, 9 days) for the second order. The BUD on the label for the first bottles ranged from 7 to 175 days (median, 91 days) for the first order and 10 to 171 days (median, 90 days) for the second order, although one sample did not have a BUD printed on the bottle/label, and one sample had a BUD on the bottle that was 16 days earlier than on the packaging material. All samples were analyzed before their BUD, except for two samples from one pharmacy, which had BUDs of seven and 10 days after patient receipt. These samples were in 10-mL bottles that contain enough for 100 days if used bilaterally once daily.

Because of a misunderstanding by two participants, there were 24 unique samples received for analysis. Two participants only picked up one 3.5- or 5-mL bottle, which was less than the 3-month supply prescribed and later obtained the remainder of the supply. These samples were included in the sample 1 data as independent samples because they had different dates on the label (prepared and BUD).

All samples were clear colorless solutions when visually inspected. The overall quality of the samples is summarized in Table 1. There was no difference in any characteristics between sample 1 (original order) and sample 2 (reorder) (Mann–Whitney U test, all P>0.30). Most samples had an osmolarity similar to human tears (sample median 294 mOsm, tears mean±SD=289±21),¹⁵ but two samples from one pharmacy were 18 and 19 mOsm. The median viscosity of 1.3 centipoise (cps) was near that of water (1.0 cps). The median pH of samples (6.9) was close to that of the normal ocular surface (7.1±1.1).¹⁶ The median measured concentration of atropine relative to the prescribed concentration was approximately 7% less than target (100% of 0.01%). Six samples (25%) were under 90% of target concentration. Median tropic acid concentration was 2.5% but was over the USP limit for atropine sulfate ophthalmic solution (7%) in four samples from two pharmacies. One sample was the bottle with the missing BUD, and the other three had a BUD of more than 150 days (far beyond the date of analysis). They were received by the subjects 9, 14, 14, and 41 days after the date on the label (presumably the date made). There was a significant correlation between higher pH and higher tropic acid concentration (Spearman rho=0.85, P<0.001). Median BAK concentration was 0.005%, but seven samples (29%) had less than 0.0001% BAK. Finally, the median concentration of total (known+unknown) impurities was 3.5%, but five samples (21%) had more than 10% impurities.

TABLE 1. - Characteristics of Samples Obtained (Median and Range)

Characteristic	Sample 1 (n=13)	Sample 2 (n=11)	All Samples (n=24)
Osmolarity (mOsm)	292 (18–325)	296 (19–306)	294 (19–325)
Viscosity (cps)	1.3 (0.8–6.2)	1.3 (0.9–7.3)	1.3 (0.8–7.3)
pH	7.0 (5.1–7.3)	6.9 (5.1–7.8)	7.1 (5.5–7.8)
Percentage of atropine concentration versus label claim (%) a	92.0 (80.3–103.9)	93.6 (70.4–104.1)	93.3 (70.4–104.1)
Tropic acid concentration (%)	2.5 (0.1–9.4)	2.5 (0.1–9.8)	2.5 (0.1–9.8)
BAK concentration (%)	0.005 (0.000–0.010)	0.005 (0.000–0.006)	0.005 (0.000–0.010)
Total impurities concentration (%)	4.2 (0.3–20.3)	2.6 (0.4–10.5)	3.5 (0.3–20.3)

^aAll bottles were labeled as 0.01% atropine.

BAK, benzalkonium chloride; cps, centipoise.

DISCUSSION

Compounding pharmacies play a critical role in providing alternative concentrations and formulations that are not commercially available. To date, the US FDA has not approved a low-concentration atropine product for treating myopia progression, although evidence of its efficacy^1,17,18 has led to its increased use.^19,20 Compounding pharmacies must be used to prescribe low-concentration atropine in the United States. Our analysis showed marked variation in several key variables in the samples obtained from US compounding pharmacies.

Pharmaceutical products are manufactured to meet GMP requirements, and the FDA routinely inspects facilities producing approved drugs to ensure compliance.^2,21 Traditional compounding pharmacies have not historically been held to such requirements. After numerous fatalities associated with contaminated compounded drugs, “outsourcing facilities” were established.^2,22 These compounding facilities are referred to as 503B pharmacies and are allowed to bulk manufacture drugs and distribute nationally.³ Traditional compounding pharmacies are sometimes referred to as 503A pharmacies and are primarily regulated by state pharmacy boards.³ States' commitment to federal guidelines can vary because of resource constraints and because some federal guidelines still remain in draft form.^14,21,22 Only one of the pharmacies in the study stated that they were registered as a 503B outsourcing facility. Four pharmacies stated that they were accredited by the Pharmacy Compounding Accreditation Board (PCAB).²³ The PCAB has a credentialing process, including on-site assessments of compliance with their compounding quality standards²⁴; however, their website listed three of the four pharmacies as having current certification.²⁵

Patients rely on accurate labeling of a medication to understand its proper use and storage. Compounding pharmacies are not required to follow the same labeling requirements of FDA-approved drugs.² The BUDs in this study varied from one week to six months from receipt by the participant. All samples were analyzed 30 days after participant receipt, and all bottles were at least 3.5 mL in size, approximately a 35-day supply. Thus, all samples were analyzed within the time frame that they would have been expected to have been used by a patient. The determination of the shelf life for FDA-approved products is based on stability studies conducted as per International Council for Harmonisation (ICH) Guidelines.²⁶ United States Pharmacopeia Chapter 797 states that, in the absence of data, the default BUD for sterile, compounded ophthalmic products of low-level risk is 48 hr at room temperature, 14 days under refrigeration, and 45 days frozen.^27,28 A longer BUD should be supported by sterility testing. The one pharmacy that labeled with a 14-day BUD used a 10-mL bottle, which would last approximately 3 months. This labeling is likely confusing to patients, who are unlikely to dispose of the remaining medication after 14 days.

All but one pharmacy used clear plastic bottles, with one using an opaque plastic bottle. Food and Drug Administration–approved 1% atropine sulfate ophthalmic solution is sold in opaque plastic bottles, presumably to protect against degradation from light. One third of the pharmacies stated on their package labeling to store in a dark place, but the remainder were silent as to light exposure. Only a third of pharmacies recommended refrigeration on their labeling. The package insert for FDA-approved 1% atropine ophthalmic solution states that it can be stored at room temperature (20–25°C).²⁹

The most commonly-used ophthalmic preservative is BAK.³⁰ Food and Drug Administration–approved 1% atropine ophthalmic solution contains 0.1 mg BAK (0.01%), dibasic sodium phosphate, edetate disodium, hypermellose, monobasic sodium phosphate, and hydrochloric acid and/or sodium hydroxide to adjust pH to 3.5 to 6.0.²⁹ The lowest observed concentration in an FDA-approved product³¹ is 0.003%, and maximum allowable limit is 2% for ophthalmic drugs.³² High levels of BAK could cause irritation and can be toxic to the ocular surface.³⁰ Allergic reactions are known to occur with chronic use of BAK-preserved ophthalmic medications.^30,33 Conversely, seven samples had less than 0.001% BAK, which could present a risk of microbial contamination when the bottles are opened and used for more than 30 days.

Ophthalmic drugs must be sterile and minimally toxic to the ocular surface, thus if nonsterile ingredients are used, the final product must be sterilized.³⁴ Atropine sulfate powder can be sourced from manufacturers that follow USP specifications,³⁵ but it may also be obtained elsewhere and thus may not be of the same quality.² Twenty percent of samples had impurities higher than 10%, which could have come from poor source materials, leaching from the bottle, or other contaminants during the compounding process. Other reports of the use of source products not considered suitable for use in humans has been reported previously.²¹ Any potential impurities above the approved USP limits have to be evaluated as per ICH guidelines.

The median viscosity was similar to water, which may cause lower retention time on the ocular surface and, potentially, penetration of the medication.³⁶ Most artificial tears aim for a higher viscosity to improve retention time.³⁷

Food and Drug Administration and PCAB guidelines are for actual concentrations of active ingredient to be within 10% of the prescribed/labeled concentration.¹¹ One quarter of the samples in this study were below that target. Given the modest slowing of axial elongation by 0.01%,^8,38 it is concerning that this already low concentration was not achieved in a large percent of samples.

Atropine is most stable at a pH of 2 to 4⁶; however, this range is not well tolerated on the ocular surface (pH 7). Although many ophthalmic solutions target a pH of 6.6 to 7.8, FDA-approved atropine 1% is buffered between 3.5 and 6.0. At higher pH levels, atropine degrades faster,⁶ and the primary degradation product, tropic acid, has no antimuscarinic properties.⁴ In this study, there was a significant correlation between pH and tropic acid; the samples with the lowest tropic acid levels generally had a pH of 5 to 6. Thirteen percent of samples had tropic acid concentrations more than 8% just one month from receipt. Given that most supplies were expected to last at least 3 months, further degradation would likely occur. The tropic acid USP limit for ophthalmic atropine sulfate solution is 7%.

Since passage of the Drug Quality and Security Act, inspections of compounding pharmacies have resulted in multiple warning letters and recalls.^3,21 During the course of this study, one compounding pharmacy received such a letter.³⁹ The letter advised, “patients and health care professionals not to use compounded products intended to be sterile, produced and distributed nationwide by [pharmacy name], due to lack of sterility assurance.” The published inspection letter stated the company, “released drug product in which the strength differs from, or its purity or quality falls below, that which it purports or is represented to possess.” In one lot of prepared atropine sulfate ophthalmic solution 0.2%, it was stated that it was “unclear if the sterilization conditions (were) adequate for inactivating all potential microbial contamination.” The Texas State Board of Pharmacy performed surveys of potency of selected compounded drugs between 2008 and 2010 and reported a failure rate of 23%⁴⁰; this rate decreased to 13% by 2016.⁴¹ Nevertheless, these potency failure rates are still 6 to 7 times greater than those of FDA-approved products (2%).²

The main limitation of this study is the small sample size (24 samples from nine pharmacies). Most US compounding pharmacies do not compound ophthalmic medications because of the additional sterile techniques and facilities required. Fifteen of the 28 pharmacies initially identified⁵ would not ship to Texas, thus the number of pharmacies available for sampling was limited. Although there was only one registered 503B pharmacy included, at the time of this study, there were only 76 pharmacies in the country registered as 503B²³ as compared with 605 holding the PCAB certification.²⁵ As the only targeted analysis of compounded atropine ophthalmic solution published to date, these data provide important information for the growing number of doctors prescribing low-concentration atropine in the United States. Only pharmacies that would ship atropine to Texas were included in this study, and the relatively small sample size precludes statistical analysis of factors such as bottle type and refrigeration.

In conclusion, this study sampled compounding pharmacies producing 0.01% ophthalmic atropine solution for patients in the United States and discovered a wide variety of formulation and labeling practices being used. Further research is needed to support best practices for compounding low-concentration atropine.