Death Due to Pharmacy Compounding Error Reinforces Need for Safety Focus
Problem: Some patients may require a medication in a dose or dosage form that is not commercially available. Such medications must be specially compounded for the patient in a pharmacy. As part of an ongoing collaboration with a provincial death investigation service, our sister organization, ISMP Canada, received a report regarding the death of a child who had ingested a prescribed, compounded oral liquid suspension that contained the wrong medication.1 Below are some of the contributing factors identified in the case analysis, along with recommendations to guide pharmacies and other compounding facilities, as well as standards-setting organizations, in their efforts to reduce the likelihood of similar errors.
For about 18 months, a young child had been receiving a 3 gram dose of tryptophan 150 mg/mL suspension (20 mL) by mouth at bedtime to treat a complex sleep disorder. Tryptophan was available as a dietary supplement in capsule form, but for this child, it needed to be compounded in an appropriate dosage form, as an oral suspension. A refill of the tryptophan prescription was ordered and picked up from the compounding pharmacy that had prepared the suspension in the past. That night, the child was given the usual dose of medication; the next morning, the child was found lifeless in bed.
Post-mortem toxicology identified lethal levels of the antispasticity agent baclofen, which had not been prescribed for the child. Testing of the suspension refill revealed that tryptophan, the intended active ingredient, was not present; however, baclofen was detected at the expected concentration of tryptophan. This finding suggested that a selection error had been made at the pharmacy, whereby one ingredient had been inadvertently substituted for another. The child received a dose of baclofen more than 20 times the maximum recommended pediatric dose.
In the described case, it could not be determined how the selection error was missed during the compounding process. The incorrect ingredient may have been misidentified during the final check. Alternatively, there may have been a delay in conducting the final check of the completed product. In this latter scenario, the incorrect ingredient used to prepare the product may have been inadvertently put away before being checked, with the correct ingredient being retrieved later for the final check. However, several factors were identified that may have increased the likelihood of this compounding error.
Missing independent verification step. There was a lack of an independent verification of the ingredients before mixing, which increased the likelihood that if an incorrect ingredient was inadvertently selected and incorporated into the final compounded product, the error would not be detected.
Similar label design. The two chemicals used for compounding each product (tryptophan and baclofen) were supplied by the same manufacturer, which uses a similar design for all product labels and packages. The following specific labeling factors were identified at the time of the incident:
- Prominence of the manufacturer’s name on the label
- Small font size of the drug name (less than half the size of the manufacturer’s name)
- Presentation of the drug name in capital letters only (which reduces legibility and readability2,3)
Similar physical appearance. Both tryptophan and baclofen are white powders which, upon visual inspection, show little appreciable difference.
Confirmation bias. This phenomenon, which leads individuals to “see” information that confirms their expectations, rather than information that contradicts their expectations,4 may have played a role. Similarity of labels and packages can increase the potential for selection and verification errors related to confirmation bias.
Lack of a unique identifier. The formula and compounding record did not contain a unique identifier that could be used to verify the ingredients selected and used in the preparation. In contrast, for commercially available medications, pharmacy staff in Canada typically use the drug identification number (DIN), while in the US, the national drug code (NDC) number is used, to confirm the product selected and dispensed.
Storage of oral and topical compounding chemicals not segregated. Mixed storage of many compounding ingredients in the pharmacy intended for either oral (e.g., tryptophan powder) or topical (e.g., baclofen powder, which is sometimes used to compound a pain cream) use, combined with a similar product appearance, increases the likelihood that a product selection error could occur without detection.
Safe Practice Recommendations: Analysis of this case led to several system-based recommendations:
- ISMP Canada has called for regulatory authorities to require an independent double check for each critical step in the compounding process. These steps include calculations, selection and measurement of ingredients, and mixing technique (if applicable), as well as a final check of the finished product, regardless of the individual(s) preparing the product. In the US, the US Food and Drug Administration (FDA) requires adherence to current good manufacturing practices for 503b pharmacies (outsourcers), while licensed pharmacies that compound (503a pharmacies) are overseen by state boards of pharmacy. Independent double checks are critically important steps that must be adhered to by all compounders in Canada and the US.
- When conducting routine on-site inspections of pharmacies and drug preparation facilities, review all policies, procedures, and practices for compounding to ensure compliance with accepted standards (USP <795> in the US), and the performance of double checks (independent double checks whenever possible) during the preparation process.
Manufacturers of Chemicals used for Compounding
- Be sure chemicals used for compounding are labeled with unique item numbers and barcodes that can be used to verify identity when selecting and checking ingredients for a compounded product.
- Regulators and manufacturers of active pharmaceutical ingredients must understand how chemical product labeling can contribute to selection errors made by compounders. Much has been learned in the field of medication safety that could be applied. ISMP stands ready to assist the industry in this regard. Unique numerical identifiers for ingredients, along with barcodes, would be an excellent start.
Pharmacy Managers, Pharmacists, and Pharmacy Technicians
- Designate an area for compounding that is separate from other activities.
- Assess the availability of ready-made product formulations.
- Ensure written policies, procedures, and/or checklists are readily available for pharmacy staff to follow when they prepare a compounded product. Validate newly created procedures and checklists through user testing before full implementation.
- Verify selection of the correct compounding formula and the identity of all ingredients and their measured quantities through an independent double check prior to preparation.
- Ensure ingredients are not returned to stock until verification has occurred.
- To support verification, include a unique product number, if available, for each chemical ingredient in standard compounding formulas.
- Figure 1 outlines some of the key activities in the preparation and verification phases of compounding.
- Require documentation for each critical verification step. Document that:
- Calculations, if required, have been independently double checked before mixing
- The identity of each ingredient has been verified before mixing
- The weight and/or measurement of each ingredient has been verified before mixing
- The manufacturer, lot number, and expiration date of each ingredient have been captured
- A final independent double check of the finished product has been conducted
- Incorporate automated identification (e.g., barcode scanning) of ingredients into the compounding process.
- Specialty compounding pharmacies may consider video recording or taking sequential pictures of the compounding process to confirm preparation activities.
- Store products in a way that optimizes label readability (e.g., well-lit and organized storage spaces, ideally at eye-level). Avoiding the storage of drugs and chemicals on the counter reduces clutter and increases available workspace.
- Segregate oral and topical compounding ingredients that are intended for a single route of administration on separate, labeled shelves.
- Make use of educational resources, such as training videos. These can be especially helpful for complex compounding processes and/or preparation techniques that are used infrequently. Annually verify the competency of staff involved in the compounding process.
The selection error described above, with its tragic result, could have occurred in any community or hospital pharmacy or drug preparation facility that compounds medications. Compounding of medications is a high-risk activity that results in a final product for which ingredients cannot be verified through physical examination. Before compounding is undertaken, commercially available alternatives should be used if available, and there should be an evidence-based or otherwise appropriate clinical rationale for the use of the compounded product.
ISMP thanks ISMP Canada for allowing us to reproduce this article1 with modifications.
- ISMP Canada. Death due to pharmacy compounding error reinforces need for safety focus. ISMP Can Saf Bull. 2017;17(5):1-5.
- Health Canada. Good label and package practices guide for prescription drugs. Publ No. 160072. June 30, 2016.
- US Food and Drug Administration. Guidance for industry. Safety considerations for container labels and carton labeling design to minimize medication errors. April 2013.
- ISMP Canada. Human factors and substitution errors. ISMP Can Saf Bull. 2003;3(5):1-2.