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ASHP Comments on Good Manufacturing Practices for 503B Facilities

Food and Drug Administration

February 11, 2019

[Submitted electronically via]
Dockets Management Staff (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

RE: Docket FDA-2014-D-0779-0024 — Current Good Manufacturing Practices — Guidance for Human Drug Compounding in Outsourcing Facilities Under Section 503B of the FD&C Act.

ASHP is pleased to submit comments to the U.S. Food and Drug Administration (FDA) on the draft guidance for good manufacturing practices for outsourcing facilities. ASHP represents pharmacists who serve as patient care providers in acute and ambulatory settings. The organization’s nearly 50,000 members include pharmacists, student pharmacists, and pharmacy technicians. For more than 75 years, ASHP has been at the forefront of efforts to improve medication use and enhance patient safety.

ASHP advocates for a strong compounding framework. We believe that a robust 503B outsourcing facility program is essential to realizing the goals of the Drug Quality and Security Act (DQSA). For many of our members, 503Bs are a vital link in their compounding supply chain. ASHP appreciates FDA’s efforts to guarantee the quality and safety of products prepared in 503B outsourcing facilities.

ASHP also shares FDA’s goal to increase the number of 503B outsourcing facilities, especially those owned by or partnered with health systems. We believe that regulations and guidance, including this current good manufacturing practices (cGMP) draft, should include the specific designs and needs of health-system 503B outsourcing facilities.

Beyond-Use Dates

ASHP supports the use of default beyond-use dates in the guidance in place of a full stability program in specific cases. This allowance will increase the likelihood of hospitals and health systems developing 503B programs, since they are far more likely to use a product within the default beyond-use date (BUD).

ASHP asks that FDA consider aligning the use of BUDs with existing standards set by USP General Chapter <797> to reduce confusion on the definition of the term. USP allows a product to be used as long as administration begins before the BUD. In lines 1161-1162, FDA states “administration to the patient should be completed before reaching the BUD.” The guidance also sets the conditions in Appendix B (line 1617) that the BUD is used as the expiration date. This should be the case only if an expiration date is the limiting factor in establishing a BUD. Having two definitions for the term BUD will make an already confusing principle even more unclear.

ASHP also asks that FDA reconsider the 1,000-unit limit on six-month aggregate batches. This threshold can be reached very quickly by repackaging products in short supply into unit-of-use package sizes. It’s highly unlikely that a traditional 503B outsourcing facility will be able to produce, package, and ship products using the default BUDs to make them practical for most customers. Therefore, default BUDs are more likely to be used by health-system-owned 503B facilities making aseptically prepared products from FDA-approved components. The concept of a default BUD was established because of the limited risk from a product aseptically prepared with proper engineering and administrative controls if used within a relatively short timeframe. The total number of products made in a six-month period should not have any impact on that level of risk.

ASHP also recommends that the term “contains a preservative” in Table D be changed to “preserved” to more accurately reflect requirements in USP General Chapter <51> — Antimicrobial Effectiveness Testing. The default BUD for nonsterile drug products references USP General Chapter <51> (line 1587), but the sterile default BUD does not. Meeting the requirements in General Chapter <51> demonstrates the effectiveness of the preservative as opposed to simply requiring the presence of a preservative.

Packaging and Labels

ASHP strongly recommends FDA include requirements in USP General Chapter <7> for packaging and product labels. Outsourcing facilities have been instrumental in health-system drug shortage management strategies. The ability to purchase products not otherwise available from commercial manufacturers has allowed us to continue providing the most effective and safe care to patients through many challenging shortages. However, there have been safety concerns about packaging and labels from some outsourcing facilities.

In May 2018, the Institute for Safe Medication Practices published a National Action Network (NAN) Alert about the availability of concentrated potassium chloride in syringe form.1 The syringe package form increases the risk of undiluted administration to patients, with likely fatal results. The NAN Alert also describes a potassium chloride vial from a 503B outsourcing facility without the black ferrule required by USP General Chapter <7>. Although the vial had a black cap, once the black cap was removed it looked nearly identical to a calcium chloride vial from the same outsourcing facility.

In March 2018, ISMP also described examples of succinylcholine and epinephrine near-misses associated with syringes lacking a prominent strength per total volume on labels per USP General Chapter <7>.2 These packaging and labeling practices pose a risk to patient safety.

ASHP appreciates this opportunity to provide FDA with feedback on cGMP for 503B outsourcing facilities. We look forward to continuing to work with FDA to develop a workable and effective compounding regulatory framework that includes guaranteeing the quality and safety of products from 503B outsourcing facilities. Please contact me if you have any questions on ASHP’s comments. I can be reached by telephone at 301-664-8617 or by email at

Michael Ganio, Pharm.D., M.S., FASHP
Director, Pharmacy Practice and Quality
Center on Medication Safety and Quality

1 Institute for Safe Medication Practices. National Action Network Alert — Safe Handling of Concentrated Electrolyte Products from Outsourcing Facilities During Critical Drug Shortages. (accessed 2019 February 8).

2 Institute for Safe Medication Practices. FDA Guidance Needed to Assure Safe Labeling Practices by 503A and 503B Compounders. (accessed 2019 February 8).