Insight from company leadership, employees and FDA records provides new context of Nephron recalls

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Published: Aug. 11, 2022 at 5:59 PM EDT|Updated: Aug. 11, 2022 at 6:26 PM EDT
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LEXINGTON COUNTY, Sc. (WIS) - Nephron Pharmaceuticals Owner and CEO Lou Kennedy said sterility is the “crux” of her company’s operations, producing sterile drugs for the customers and patients who rely on them under “stringent” FDA regulation.

Dating back a decade to Nephron’s time in Florida, Food and Drug Administration records show the FDA has cited “lack of assurance of sterility” as the reason for multiple Nephron product recalls.

That includes two voluntary and ongoing recalls for millions of Nephron products.

The first involved 2.1 million doses of medicine and equipment which the company initiated in May. It included 20 products.

The second is recall of 1.6 million syringes and bags of product, which began in late June. This included 37 products.

WIS has identified no instances of contaminated medicine nor harmed patients.

Kennedy said the “lack of assurance of sterility” labels are misleading, and her company does not have sterility problems. “I don’t understand it, because unless they’re trying to lump something into a category and not go for specific issues, they have not cited us for sterility issues,” she said.

Kennedy said the FDA “has the ability to have drop-down menus, which means they have to use what the heading says, but then they go on to say specifically and explain it.”

Kennedy’s assessment of the “lack of assurance of sterility” label was echoed by Amicus GMP Consultants CEO Kristopher Le, a consultant for pharmaceutical compounding companies.

Le formerly worked for Nephron from 2015 to 2017 and said he has worked for its local competitors in the past.

Le said he left Nephron through an amicable separation.

He declined to answer any questions directly related to Nephron, but answered WIS’ questions about the industry, the FDA and its inspections.

WIS interviewed current employees, a former employee, Nephron leadership and studied FDA records to breakdown the most recent inspection, the recalls and the company’s prior interactions with the FDA.

A spokesperson for the FDA said the administration does not comment on ongoing compliance matters.

The lead-up to the FDA inspection this spring

FDA records show six inspectors were onsite at Nephron for 16 days between March 28 and April 20, 2022.

Kennedy and current/former employees told WIS the company was aware inspectors would be coming before they arrived.

Kennedy said the FDA notified the company on the Friday before the inspectors’ arrival on Monday, March 28.

“They called on Friday. This is a new procedure for them because they wanted to make sure that we were a COVID-free safe work environment for them to have the investigators arrive,” she said.

A former employee said the “buzz” was the FDA had inspected Richland County-based pharmaceutical company Ritedose prior, so an inspection was expected.

The current employees estimated the company was expecting an inspection a week in advance due to cleaning work being done around the facility.

FDA records show one inspector reviewed Ritedose for eight days between March 7 and March 18, 2022.

The inspector observed the company did not “thoroughly investigate” mold found in 2021.

Ritedose is in an on-going recall over incorrect barcode labeling for Sodium Chloride injections.

Jody Chastain, President and CEO of The Ritedose Corporation submitted a statement reading:

In March 2022, the USFDA performed an inspection of our 503B Outsourcing facility. The inspection resulted in a singular observation. The observation was easily addressed and no commercial product was impacted.

The former employee echoed claims Nephron began holding meetings to “try to clean things up.”

Additionally, the former employee said part-time employees were kept home for the FDA inspection.

“My mindset is if we have to do things differently, when we’re audited, then we’re not doing things the right way,” the former employee said.

Kennedy confirmed temporary employees were not asked to come in on the first day of the inspection.

“I felt like it was too many moving parts. When you have 200 or 300 people and I wanted all our management available to answer any questions, so I said let’s see how the first day is going to go and they were brought back the second day,” she said.

A current employee said only certain personnel were allowed to go to where the FDA would be and alluded to procedural changes for the FDA’s arrival.

Kennedy denied that any operational changes or clean-up took place prior to the FDA’s arrival, however there was a “routine” review of facility.

“I would say three or four weeks, we started a new program where all of upper management, [Vice President of Manufacturing Operations Lance Rogers] included, walked the buildings together, being heavily prepared, because I said to the staff, surely, it’s been almost two years. We normally get an inspection once or twice a year, it’s got to be coming soon,” she said.

The Spring 2022 observations and ongoing recall

On April 20, 2022 the six inspectors issued their observations of the Nephron facility.

Their report included seven observations.

Observations 1 through 6 revolve around the inspector’s observations of Nephron’s production and how it investigates potential issues with that process.

Specifically, it critiqued Nephron’s investigative procedure and lack of investigations when it identified organisms in their production environment and personnel.

Here are the topline descriptions verbatim:

  1. There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.
  2. Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.
  3. Test procedures relative to appropriate laboratory testing for sterility are not written and followed.
  4. Procedures designed to prevent microbiological contamination of drug products purporting to be sterile did not include adequate validation of the aseptic process.
  5. All records of production and control associated with a batch of drug product were not maintained at (redacted) after the expiration date.
  6. Laboratory records are deficient in that they do not include the initials and signature of the (redacted) person reviewing the record for accuracy.

Le declined to address Nephron’s recall, but said the toplines of observations are often very broad.

“The subpoint of that could be a relatively minor incident or oversight at the facility that could be very, very easily corrected or that does not have a significant impact,” he said.

He later explained:

“Observations by the FDA are just that, they’re purely observations or interpretations of regulation by the auditor that’s actually onsite,” he said.

WIS requested specific responses from Nephron to each of the first six observations. They are as follows:

  1. Nephron was in the process of updating its specifications to align with FDA guidance. All actionable events were investigated per the specifications implemented at the time of the inspection per USP<797>. It is critical to note that all distributed batches passed sterility testing and met the Nephron established specifications.
  2. Nephron monitors aseptic processing areas for every batch and trends the data quarterly – as is the industry standard – and 99.4% of all samples taken are within acceptable limits. Again, as Nephron continued the process of aligning with FDA guidance, specifications were reduced for all viable environmental monitoring (EM) and personnel monitoring (PM) samples collected within ISO 5 classified environments.
  3. Nephron maintains appropriate test procedures for sterility testing and these procedures are followed. The FDA has accepted Nephron’s sterility test procedures through the approval of Abbreviated New Drug Applications.
  4. Nephron performs validations for sterile production processes. The investigators had a different assessment of the worst-case scenario for operating manual filling within laminar flow hoods.
  5. Nephron maintains all production and control records associated with drug production for at least one year after the expiration date. When anomalies are reviewed by subject matter experts, video footage may be utilized, and due to data storage limitations, the footage may not be maintained, as they are described within the investigation record.
  6. Nephron, which was performing rapid sterility testing per the approved equipment manufacturer, always follows appropriate test procedures, including reviewing records for accuracy.

Kennedy attributed the observations in part to the company’s shift from compounding pharmaceutical standards to manufacturing processes.

Le said if a facility is registered as a compounding facility with the FDA, they are expected to operate under the “more complicated” manufacturing rules.

“There’s a higher bar to reach because of the amount of documentation and supporting evidence and science you need to simply back up your process,” he said.

Le said despite the hurdles, the manufacturing process helps expand a company’s customer base.

FDA records show Nephron’s initial registration as an outsourcing facility was July 15, 2014 and re-registered on Jan. 20, 2022.

Kennedy said the manufacturing rules are stricter on how many colony forming units (organisms) can be found in the production environment.

“We neglected to move our company from three [colony forming units] (the compounding pharma standards) to zero (the manufacturing rules). Noticed it in November, started routing it through our change control process and made it final on April the 8th,which was the second day I think they were even here” she said.

In the aftermath of the interview, WIS asked for clarification on why the transition took place. Kennedy sent a statement reading in part:

Nephron appreciates the opportunity to work with the agency, as well as experts Lou Kennedy brought into the company following the inspection, to update processes and procedures and make Nephron and its team even stronger, as it plays a leading role in providing patients around the country with life-saving medications.

Nephron analyzes its environmental monitoring data in our production areas according to the industry standard – and 99.4% of all samples taken in our most sterile environment – ISO 5 – are free of microbial growth. At the end of the day, the company followed a guidance document specific to drug compounding – USP <797>, which required a < 3 CFU - and was in the process of updating to the FDA sterile guidance standards (requiring 0 CFU) at the time of the latest inspection. This update process began in November 2021.

Kennedy argued some of the observations revolve around the same issue explained different ways.

“They’re write up the same observation but one inspector writes in his words, the other inspector writes in their words and they’re allowed to write up what they want even if it’s the same thing three, four, five, six times,” she said.

Le said growing compounding pharmaceutical companies do often have FDA observations related to investigations.

“That lack of investigation or procedures around performing the investigation could leave the agency to make an assessment about whether or not that facility has the sterility assurance level they are expecting,” he said.

Kennedy also elaborated on the lack of investigations. Both she and Rogers said objectionable organisms were investigated, following proper procedure.

They said the FDA observations focused on non-objectionable organisms and scenarios where less than three were identified.

“[Non-objectionable organisms] could be a flake of skin sloughed off of your face, and that was found. That’s not an objectionable organism and it’s too small to see with the naked eye,” she said.

A National Institutes of Health study defines objectionable organisms as organisms which harm the patient or the product.

Le said the presence of an organism or the likelihood it could make it into a product, whether objectionable or not, would compromise sterility.

Kennedy said the rate organisms being identified was within FDA limit.

Le said the rate of organisms being identified per sample has taken on greater emphasis in the industry.

The former employee expressed frustration and concern with the lack of investigations. “We’ll say we had an issue, but we never did an investigation, and that’s pretty critical. But yet we released this lot? Well how did you release this lot if you didn’t do an investigation to see what the root cause was?” they said.

A current employee raised concerns about the training being done at the company when it comes to the sterile drug production environment, referred to as the “clean room.” Specifically, that proper training can be expedited for speed.

When asked about leadership and training, Kennedy stressed the training requirements, including a two-week bootcamp and on the job training.

“Every single thing we do except for maybe sneeze here has a procedure,” she said.

She said resources for procedures are readily available and quality teams follow up on how procedures are followed.

“All of those procedures are kept on tablets in every area of the company, so that if a person even has even the minute of hesitation about while the procedure works, they go to the tablet 10 feet away from them, swipe right through it” Kennedy said.

“There are about, I don’t know, 50 checks and balances, that if one person makes even one mistake, it doesn’t transpire all the way through there until all of those boxes are checked.”

Rogers echoed Kennedy, saying every six months the equipment and personnel are subjected to a “media fill,” essentially a test of the system’s sterility.

“If these individuals don’t have proper aseptic technique, they would never pass a media fill,” he said.

Observation 7 involved the production of an ulcer medication drug without the FDA’s approval. Its’ topline reads verbatim:

7. Your outsourcing facility compounds drug products using bulk drug substances that cannot be used in compounding under section 503B because they (a) are not used to compound drug products that appear on the drug shortage list in effect under section 506E of the Act and (b) do not appear on a list developed by FDA of bulk drug substances for which there is a clinical need. Specifically, your firm compounds glycopyrrolate.

Kennedy said the observation was the result of the company making a batch of the drug, glycopyrrolate, after it had come off the FDA bulk drug substances list.

“We did it two weeks after it came off the list in February. I mean just want to slap yourself on the hand. We were two weeks missing it,” she said.

She said the issue was the result of not having updates on the FDA bulk list on Google alerts, but that has since been corrected.

Kennedy said the observations led to the company’s May recall.

On May 18, 2022, Nephron initiated a voluntary recall of 2,158,351 pieces of medicine and equipment, that include syringes and bags for “lack of assurance of sterility.”

Without directly addressing Nephron’s recall, Le said he often sees this label and described it as a catch-all.

“In general when I see a facility that has issues that are associated with lack of sterility assurance, it may mean the facility lacks certain process controls or certain quality systems elements, that the FDA expects to be there in order to provide that assurance,” he said.

However, Le also said the FDA can be inconsistent with enforcement in part due to relatively new presence of the industry.

The FDA labeled the recall as Class II, defined as:

“a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.”

Kennedy said the FDA requested the recall.

“[The FDA’s Center for Drug Evaluation and Research] asked for us to be on a phone call. Which we did and they said they believed the product should be recalled and what did I want to about it and I said well if you believe it should be recalled we’ll agree to do it, and we did,” she said.

She maintained the products on the May recall list “had perfect testing results,” adding only 7 percent of the products have been returned at the time of the interview because hospitals were in the process of using them.

Kennedy released a statement at the time of the recall reading:

“Out of an abundance of caution, Nephron is proactively cooperating with the Food and Drug Administration on a voluntary recall of a limited number of product lots. We do not take this lightly. While there has been no impact to patient safety, and there is no evidence of contamination, Nephron has decided in the interest of patients to proceed with this recall process. The company is prepared to provide the resources and information necessary to health care providers and patients to make certain they have anything they need and any questions answered. They remain our top priority,”

The company released the same statement for the June recall.

How does Nephron’s recalls compare to the recalls of its counterparts?

Nephron is facing two sets of recalls representing 57 products and 3.7 million doses.

FDA records list 81 companies nationwide which utilize drug compounding outsourcing facilities, including Nephron.

WIS studied the 20 facilities which the FDA has addresses for in nearby states, including the Carolinas, Alabama, Florida, Tennessee, and Virginia.

Of those 20 facilities, there is no FDA compliance data for three of them.

  • Of the remaining 17 facilities, only five have ongoing recalls.
    • Of those five companies, two have ongoing recalls for “lack of assurance of sterility.”
      • One company has an ongoing recall for 53 products, representing 190,346 doses
      • A second has an ongoing recall for ONE product representing 18,960 vials
    • A third company has an ongoing recall for “non-sterility,” carrying a more serious designation.
      • The company has two products recalled, representing 1,890 syringes and 49 vials respectively
  • Of the 17 facilities, only two have prior recalls for lack of assurance of sterility
    • One company recalled 1 product, translating to 253 syringes in July 2021
    • The other recalled 80 products representing 223,330, doses in Sept. 2019

Le said it’s hard to create a threshold for recall size, saying it depends on the organization size, the duration of the recall, and how many batches are impacted.

“I would never use the size of a recall as a rationale for saying that one facility has a better state of control than another,” he said.

Leading up to May recall, the FDA had labeled at least five recalls as “lack of assurance of sterility”

The FDA maintains online dashboards of the companies it monitors.

The dashboards include inspection data, recall data and other assorted compliance information.

Dating back to June 2011, Nephron’s dashboard shows the FDA has labeled five Nephron product recalls (for seven products) as “lack of assurance of sterility” prior to the 2022 recalls for the same reason.

Without addressing Nephron, Le addressed the issue of repeat lack of assurance of sterility recalls.

“Being cited for the same issue multiple times is usually in the facility is indicative of a general lack of a state of control, or an inability to correct an issue the FDA has previously observed,” Le said.

Kennedy sent a statement reading:

“Nephron has occasionally recalled products out of an abundance of caution, working directly with the U.S. Food and Drug Administration. It is worth noting in each of the instances cited below, the recall was voluntary and initiated by Nephron. The company worked collaboratively with the FDA throughout the processes, and they have been closed out. We hold the company and our team to the highest standards of quality and sterility because patient safety is our top responsibility and priority.”

6/22/2011 recall – Reason: Lack of assurance of sterility

  • The product: Albuterol Sulfate Inhalation Solution (helps patients breathe)
  • 56,028 cartons
  • Class II
  • Voluntary recall

Kennedy sent WIS a statement that this recall was attributed to a labeling issue. She told WIS in the interview Albuterol was packaged in the container of a different product.

An FDA inspection document from June 2011 references Albuterol Sulfate Inhalation Solution and that Nephron identified an organism in the sterility environment.

Nephron sent a statement reading:

“This happened over a decade ago, on a lot in question from 2009. The sterility failure was investigated and a root cause was assigned. Nephron retested the lot, and obtained passing results, per Nephron procedure. FDA was not satisfied with the root cause. In another example of Nephron working with the agency proactively and collaboratively, the company voluntarily, out of an abundance of caution, recalled the lot.”

10/2/2013 recall – Reason: Lack of Assurance of Sterility: Nephron Pharmaceuticals Corporation conducted a routine periodic aseptic process simulation and discovered bacterial growth in a number of media fill vials, exceeding the allowable limit.

  • The product: Albuterol Sulfate Inhalation Solution (helps patients breath)
  • 689,568 cartons
  • Class II
  • Voluntary recall

Kennedy sent WIS a statement that this recall “was a preventative maintenance issue, and thanks to Nephron quality control, an issue was identified and mitigated.”

It’s unclear if there is a direct correlation, but Albuterol is referenced in an August 2012 FDA inspection document. Inspectors raise concerns that “annual product reviews are not always completed on a timely basis or according to procedural timeframes.”

8/21/2015 recall – Reason: Lack of Assurance of Sterility; potential exposure to non-sterile lubricant during the filling process

  • The product: Ipratropium Bromide and Albuterol Sulfate Inhalation Solution (helps patients breath)
  • 85,248 cartons and 35,292 cartons, respectively
  • Class II
  • Voluntary recall

Kennedy sent WIS a statement reading: “While there was no direct contact with product, lubricant was found on an external vial.”

An FDA inspection document from July and August 2015 referenced “black stains” caused by excessive industrial lubricant.

11/16/2015 recall – Reason: Lack of Assurance of Sterility: Internal dye ingress test failure to assure the integrity of the vial.

  • The product: Sodium Chloride Inhalation Solution (helps patients clear out their lungs)
  • 13,692 cartons
  • Class II
  • Voluntary recall

11/16/2015 recall – Reason: Lack of Assurance of Sterility: Internal dye ingress test failure to assure the integrity of the vial.

  • The product: Sodium Chloride Inhalation Solution (different product) (helps patients clear out their lungs)
  • 11,208 cartons
  • Class II
  • Voluntary recall

Kennedy sent a statement reading: “Dye Ingress evaluates container closure integrity of a drug product. A voluntary recall was initiated as a result of a potential container closure integrity failure at the expiry month for sodium chloride inhalation solution.”

No 2015 FDA records in WIS’ possession directly address dye ingress.

Kennedy stressed the products were devices, not sterile drugs.

“This had a little plate missing and we recalled some nebulizers,” she said.

10/9/2019 recall – Reason: Lack of Assurance of Sterility; bags have potential to leak

  • The product: del Nido Cardioplegia Solution (used in pediatric cardiac surgery)
  • 1,047 bags
  • Class II
  • Voluntary recall

10/9/2019 recall – Reason: Lack of Assurance of Sterility; bags have potential to leak

  • The product: Amino Acid Injection
  • 162 bags
  • Class II
  • Voluntary recall

Kennedy reiterated there were leaking bags for the products and elaborated with a subsequent statement reading:

This was a vendor level recall. We received vendor product, and used it, and then received notification from the vendor that they were initiating a recall. Therefore, since Nephron had utilized part of the product prior to the vendor recall, we initiated our own voluntary recall out of an abundance of caution.

No 2019 FDA records in WIS’ possession address leaking bags.

Kennedy described the FDA’s use of the label “lack of assurance of sterility” as incorrect, describing the phrase as a “broad category.” She stressed Nephron does not have problems with sterility.

“If it doesn’t pass sterility, it doesn’t leave our doors. It’s put to waste,” she said.

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