The US Food and Drug Administration (FDA) has issued a Warning Letter to Tris Pharma, a Monmouth Junction, New Jersey-based specialty pharmaceutical company, for violations of current good manufacturing practices (cGMP) for finished pharmaceuticals. The letter follows an FDA inspection of the company’s drug manufacturing facility in Monmouth Junction from February 14 to March 20, 2017. Part of the cGMP violations involved Tris Pharma’s manufacture of Pfizer’s Quillivant XR (methylphenidate HCl), a drug to treat attention deficit hyperactivity disorder (ADHD).

The FDA cited Tris Pharma for not adequately investigating product failures and defect complaints and the related root causes and for failing to implement corrective actions and preventive actions (CAPA). The agency noted that five lots of Quillivant XR failed dissolution testing between May and November 2016; three lots failed during release testing, and two lots failed when tested for stability. The agency said that the company’s investigations typically invalidated out-of-specification (OOS) results and attributed the cause to the dissolution test method rather than to manufacturing, but that the company did not adequately investigate the sources of variation in its manufacturing operation that may have caused the dissolution problems. In its Warning Letter, the FDA noted that additional assessment involving the sponsor, Pfizer, found that original test results were improperly invalidated and dissolution performance was not assured throughout the shelf-life for at least one lot. Pfizer determined that all five lots needed to be recalled in 2017.

The FDA asked Tris Pharma to provide the following: (1) an update on the retrospective review of all dissolution and assay failures for lots within expiry and a risk assessment that evaluates the quality of all distributed batches; (2) an update of CAPA plans to address dissolution method and manufacturing process variability related to Quillivant XR; and (3) an update on corrective actions implemented regarding communication with sponsors to enable changes to be promptly submitted to drug applications (e.g., dissolution test method).

Separately, the FDA cited Tris Pharma in its Warning Letter for having leaking or under-filled morphine sulfate oral solution bottles. The agency said that between July and December 2016, Tris Pharma received at least 24 complaints concerning three lots of morphine sulfate oral solution involving approximately 1,000 leaking or under-filled bottles. The agency said that the company’s initial complaint investigation concluded that the bottles were likely damaged during shipment by the distributor or storage outside of its control, but that complaints continued after the investigation. The agency said that the company did not adequately evaluate other possible root causes until after the FDA’s inspection.

The FDA is requiring Tris Pharma to provide a summary of steps it has taken to ensure timely root cause evaluations and effective CAPA for all drug products. It is also asking the company make an assessment to determine whether all containers, closures, and components are assigned appropriate expiration or retest dates, and incoming material controls are adequate to prevent use of unsuitable containers, closures, and components.

The FDA also cited Tris Pharma for not adequately addressing potentially superpotent products that resulted from a change in its filling operation and its process for identifying, segregating, documenting and destroying affected lots. The agency said that the company did not adequately address its sampling operations, investigation process, and change-management program, including evaluation of the potential effect of manufacturing changes. The issues involved certain lots of codeine polistirex, chlorpheniramine polistirex, hydrocodone polistirex, and carbinoxamine maleate extended-release oral suspension drug products.

In response, the FDA is asking Tris Pharma to provide a review of changes implemented since March 2015 to determine potential effect on product quality; an update on its improvements in risk management and a risk assessment of the lots released to the market with possible OOS units and an explanation for why potentially defective lots remained in distribution. It also requested an independent evaluation of the company’s change-management system, its overall system for investigations and deviations, atypical events, complaints, OOS results, and failures, and sampling operations, including a CAPA plan to improve upstream controls and sampling plans. It also is requesting documentation to support the destruction of all rejected shipper cases of codeine polistirex and chlorpheniramine polistirex extended-release oral suspension.

Source: FDA