Regulatory Focus™ > News Articles > FDA Warns UK Drugmaker for Repeat GMP Violations

FDA Warns UK Drugmaker for Repeat GMP Violations

Posted 25 January 2017 | By Michael Mezher 

FDA Warns UK Drugmaker for Repeat GMP Violations

The US Food and Drug Administration (FDA) has warned UK-government owned Porton Biopharma Limited for repeat good manufacturing practice (GMP) violations at its Salisbury, UK facility.

Notably, the warning letter cites Porton for manufacturing violations related to Erwinaze (asparaginase Erwinia chrysanthemi), an orphan biologic developed by Porton and licensed to Jazz Pharmaceuticals.

Erwinaze is approved in the US to treat patients with acute lymphoblastic leukemia who have developed an allergy to E. coli derived asparaginase and pegaspargase chemotherapy drugs used to treat the disease, and is manufactured solely by Porton.

Warning Letter

The warning letter comes after two lengthy inspections, the first from 12-23 January 2015 and resulting in a Form 483, and the second from 7-18 March 2016.

According to FDA, Porton failed to adequately address the violations in its responses to the agency following both inspections.

"These repeated failures demonstrate that management oversight and control over the manufacture of drugs at your facility is inadequate, and that your previous corrective actions did not address persistent contamination hazards and drug quality issues," FDA writes.

Specifically, FDA cites Porton for failing to thoroughly investigate numerous instances where the company identified particulate matter in finished batches of Erwinaze and for issues with the company's aseptic manufacturing.

On two separate occasions, FDA says Porton found visible metal particles in batches of Erwinaze, which the company said were most likely from the stoppers used to seal the product. Additionally, the company also found fibers thought to be from paper or cardboard in one of the batches.

FDA also says it found numerous issues related to the company's aseptic manufacturing operations, including a blocked floor exhaust vent and inadequate validation for the sterilization cycle used on equipment moved to one of the aseptic filling rooms.

Lastly, FDA says Porton "failed to conduct adequate change controls prior to the use of each working cell bank" used to produce Erwinaze, and "failed to ensure sufficient change control oversight to assure the … new working cell banks were acceptable for use."

According to FDA, Porton did not get these process changes approved before manufacturing batches of Erwinaze that Jazz then distributed to customers.

"These working cell banks were not reviewed and approved by the Agency for their suitability for Erwinaze manufacture, even though the changes in the source material or cell line have a substantial potential to adversely affect the identity, strength, quality, purity or potency of Erwinaze," FDA writes.

In addition to requesting a written response from the company, FDA says it will schedule a face-to-face regulatory meeting between Porton, Jazz and agency officials to address the violations cited in the warning letter.

Potential Supply Constraints

Until the violations cited in the warning letter are corrected, FDA says it may refuse to approve new applications or supplements listing Porton as a manufacturer, and that the agency may block the company from importing products into the US.

As a result, FDA requests that Porton contact the agency immediately if a shortage of any drugs produced at the facility is expected.

While it is still unclear whether the issued cited in the warning letter may lead to a disruption in the supply of Erwinaze, Jazz has previously expressed concern over supply constraints of the drug.

"As a consequence of constrained manufacturing capacity, we have had an extremely limited or no ability to build an excess level of product inventory that can be used to absorb disruptions to supply resulting from quality, regulatory or other issues, and we have experienced, and expect to continue to experience, manufacturing and inventory challenges that have resulted in disruptions in our ability to supply certain markets," Jazz wrote in an SEC filing last year.

In an email to Focus, Jazz spokesperson Jacqueline Kirby says the company is "working in full collaboration with [Porton] and the FDA to do everything possible to avoid disruption of patient care while we accelerate resolution of the manufacturing deviations that are noted in the Warning Letter."

Focus has also reached out to Porton and will update this story accordingly.

Warning Letter

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