Hyaluron slapped with 14-item 483 for inadequate records, testing.

Hyaluron, Burlington, MA NE District

FDA investigators Brenda King, Amber Wardwell and Anthony Warchut issued a 14-item 483 following their inspection of Hyaluron's drug manufacturing facility in Burlington, MA.

Procedures to prevent microbiological contamination of drug products were not established, the inspectors found. Smoke studies done in aseptic filling rooms were not done under dynamic conditions, nor was there a protocol for these studies.

There was no written protocol to be followed for conducting media fills and no specific instructions that required the sampler to be charged prior to being moved. Media-filled vials rejected after capping were not incubated, and the investigators wrote that they found no final reports for media fills.

An organism was identified in a media fill but Hyaluron did not conduct an investigation to identify the source, according to the 483, which was dated May 15-24, 2006.

Batch production records included a discrepancy report concerning a problem with splattering due to misalignment of filling needles and vials. However, the company did not have a written standard operating procedure (SOP) on how to handle this type of potential contamination, the inspection revealed.

The FDAers cited four instances in which production and control records for drug products were not reviewed and approved by the quality control (QC) unit before release.

Hyaluron's supplier qualification SOP did not specify how many samples of a raw material or component were to be tested before a supplier was considered qualified, the report noted. The procedure also did not address validation of supplier test results at appropriate intervals.

Records failed to include an individual inventory record of each component, drug product container and closure with sufficient information to determine associated batches or lots of drug products. One issue FDA noted dealt with bin cards; the SOP that directs the use of such cards was not being followed.

Hyaluron's drug product testing was deficient because at least one specific test to verify the identity of each component was not performed, the FDA inspectors observed. Specifically, one API had pass/fail criteria for visual inspection for tampering and appearance and required that the COA matched the lot number of material provided. However, Hyaluron did not have an identity test for this API.

Written procedures were not followed for receipt and handling of components, containers and closures, according to the 483. The company's SOP required use of a QC Material Release Form, which was not being used or completed by Quality Control.

Sampling procedures regarding sterile equipment and aseptic sampling techniques for components were deficient. These procedures did not contain descriptions of aseptic sampling techniques, sterile equipment or environmental conditions used for sampling drug products' sterile APIs.

The method qualification report for Determination of Total Solids did not define acceptance criteria, the FDA team wrote. The "Method Qualification of Hyaluron Analytical Test Methods" did not include any acceptance criteria that defined the number of tests to be run before the method could be considered successfully transferred.

Laboratory controls did not include scientifically sound and appropriate sampling plans and test procedures to ensure in-process materials and drug products conformed to appropriate standards, the inspection found. The procedure to be followed in the event of out-of-specification (OOS) test results referred to two sections of the procedure that did not exist. It also called for re-sampling OOS material without adequate justification, the 483 noted.

The investigators determined that Hyaluron products that did not conform to specifications were not adequately controlled. One report of an unplanned deviation involved a fire during sterilization, which resulted in a nonconforming batch. That batch was used in production before acceptance criteria had been defined in the deviation and before QA reviewed the deviation and test results, the FDAers observed.

Document approval records did not include the document approval dates or signatures for the approving official.

A review of complaints revealed that a number of complaints were not initiated on the appropriate forms and within the time limits required by procedure, the investigators added. Tracking and coding of deviations had begun but no analysis had been performed to identify existing and potential causes of nonconforming procedure or other quality problems.

There was no documentation of revalidation of processes in response to changes or process deviations.