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Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors

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Abstract

Introduction

Medications are compounded when a formulation of a medication is needed but not commercially available. Regulatory oversight of compounding is piecemeal and compounding errors have resulted in patient harm. We review compounding in the United States (US), including a history of compounding, a critique of current regulatory oversight, and a systematic review of compounding errors recorded in the literature.

Methods

We gathered reports of compounding errors occurring in the US from 1990 to 2020 from PubMed, Embase, several relevant conference abstracts, and the US Food and Drug Administration “Drug Alerts and Statements” repository. We categorized reports into errors of “contamination,” suprapotency,” and “subpotency.” Errors were also subdivided by whether they resulted in morbidity and mortality. We reported demographic, medication, and outcome data where available.

Results

We screened 2155 reports and identified 63 errors. Twenty-one of 63 were errors of concentration, harming 36 patients. Twenty-seven of 63 were contamination errors, harming 1119 patients. Fifteen errors did not result in any identified harm.

Discussion

Compounding errors are attributed to contamination or concentration. Concentration errors predominantly result from compounding a prescription for a single patient, and disproportionately affect children. Contamination errors largely occur during bulk distribution of compounded medications for parenteral use, and affect more patients. The burden falls on the government, pharmacy industry, and medical providers to reduce the risk of patient harm caused by compounding errors.

Conclusion

In the US, drug compounding is important in ensuring access to vital medications, but has the potential to cause patient harm without adequate safeguards.

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Acknowledgments

We gratefully acknowledge the contributions of Shannon Manzi, PharmD, Assistant Professor of Pediatrics at Harvard Medical School and Manager of the Boston Children’s Hospital Emergency Department and Intensive Care Unit Pharmacy Services, to this manuscript.

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Authors and Affiliations

  1. Harvard Medical Toxicology Program, Boston Children’s Hospital, 333 Longwood Avenue, Mailstop 3025, Boston, MA, 02215, USA

    C. James Watson & Michele M. Burns

  2. Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    C. James Watson & James D. Whitledge

  3. School of Law, Boston University, MA, Boston, USA

    Alicia M. Siani

  4. Division of Emergency Medicine, Boston Children’s Hospital, Boston, MA, USA

    Michele M. Burns

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Contributions

Study concept and design: CJW, JDW, AMS, MMB

Acquisition of the data: CJW, JDW

Analysis and interpretation of the data: CJW, JDW, AMS, MMB

Drafting of the manuscript: CJW, JDW, AMS, MMB

Critical revision of the manuscript: CJW, JDW, AMS, MMB

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Correspondence to C. James Watson.

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CJW, JDW, and AMS report no conflicts of interest. MMB reports that she is the Pediatric Toxicology Section Editor at UpToDate.

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Appendix

Appendix

Supplemental Table 1 Contamination compounding errors
Full size table
Supplemental Table 2 Supratherapeutic and subtherapeutic compounding errors
Full size table
Supplemental Table 3 Compounding pharmacy errors without documented patient harm.
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Watson, C.J., Whitledge, J.D., Siani, A.M. et al. Pharmaceutical Compounding: a History, Regulatory Overview, and Systematic Review of Compounding Errors. J. Med. Toxicol. 17, 197–217 (2021). https://doi.org/10.1007/s13181-020-00814-3

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