503B Outsourcing Facility FDA Enforcement Trends

How can quality and compliance professionals take advantage of data? What insights can be gained from access to regulatory enforcement information?

Redica Systems Senior GMP Quality Expert Jerry Chapman showed how quality and compliance teams can take advantage of data during the Aug. 3 Redica Systems webinar, “A.I. for Quality and Compliance Teams.” In particular, his presentation explained how artificial intelligence (A.I.) can be used to identify potential regulatory trends.

Chapman provided two case studies, one on 503B outsourcing facility enforcement information which is covered below. Part II examines the use of A.I. and data analytics to identify data integrity trends. He gathered this data using the Redica Systems platform. 

[Related: Jerry Chapman also explained terminology pertaining to A.I. and machine learning in the first part of the webinar. To access the webinar recording, click here.]

503B Outsourcing Facility Challenges

The first case study examined enforcement data for 503B outsourcing facilities from FY2014-FY2019. Unlike 503A compounding pharmacies that produce a product formulated for a single individual by prescription, 503B outsourcing facilities manufacture larger batches of drug products for healthcare facilities. According to Chapman, the majority of products manufactured at 503B outsourcing facilities are sterile injectable products. 

503B outsourcing facilities were created in response to drug shortages. Additionally, these facilities came under scrutiny in 2012 when a facility in Massachusetts failed to follow proper technique, resulting in contaminated product that killed patients. As such, 503B outsourcing facilities are a relatively new type of entity compared to traditional pharmacy compounding. Traditional pharmacy compounders who have moved into 503B outsourcing are not as familiar with GMPs as pharmaceutical manufacturers. 

According to Chapman, the majority of products manufactured at 503B outsourcing facilities are sterile injectable products

“There are a lot of things they need to do that if you were in pharma manufacturing will sound familiar to you but are very new to these folks,” Chapman said. “For example, a quality department that is independent, developing systems and procedures for customer complaints, change management, failure investigations, CAPAs—those are all things that had to be developed by these 503B outsourcing facilities. Developing and managing those systems is a different expertise than what they had in the past.”

What Does the Data Show?

So, what are FDA investigators finding when they inspect 503B outsourcing facilities? Between 2014-2019, FDA issued 52 Warning Letters with CFR citations to 503B outsourcing facilities and 49 to traditional sterile drug manufacturing sites. Chapman used the Redica Systems platform to analyze the CFR citations in this combined dataset of 101 503B outsourcing facilities and traditional sterile drug manufacturing sites. 

“What we found for 503B was that they were a fairly homogenous lot if you will,” he said. Figure 1 shows that aseptic process validation, environmental monitoring, room and equipment sterilization, and sterility testing were common citation areas for 503B outsourcing facilities in FDA Warning Letters.

But how does this dataset compare to FDA citations for pharmaceutical manufacturers during this same time period? Figure 2 shows how 503B outsourcing facility Warning Letter citations compare to pharmaceutical sterile manufacturers.

“You can see that 503B has its own set of issues and that they are different from sterile manufacturing,” Chapman said. “Deviation investigations, as you can see, are fairly similar but the reason being they are going to be fairly similar any place in any dataset we look at because deviations in manufacturing happen.”

But what about data “hiding in plain sight?”

Chapman used Redica Systems to search through additional documents, including FDA 483 observations to identify potential areas of regulatory concern for 503B outsourcing facilities during FY2014-FY2015. Figure 3 showcases these major issues for 503B outsourcing facilities that were not cited in Warning Letters.

“You can see that approximately half of them have material sampling and testing issues,” he said. “A quarter of them have issues with cleaning validation and verification.”

Chapman ran this data past a colleague of his who has several years of experience in 503B outsourcing facilities and this colleague confirmed that these were indeed issues that 503B outsourcing facilities have faced. 

“If I were in the 503B space, I would want to know this because these are issues that are there. FDA has hinted at them or uses language that indicates they are there without them bubbling up to an actual Warning Letter citation. Issues that you need to address.”

[Related: Jerry Chapman also explained terminology pertaining to A.I. and machine learning in the first part of the webinar. To access the webinar recording, click here.]