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Zimmer Biomet (ZBH) published a response to the Form 483 issued by FDA in April 2018, related to inspectional observations at the Warsaw North Campus manufacturing facility (WNC). The company reiterated that none of the observations identified specific performance issues with particular products, and that all products continue to be manufactured in the facility.
The Form 483 issued in April included three new and eight repeating observations from the inspection conducted from September to November 2016 (which yielded 14 observations). The April Form 483 included observations addressing corrective actions to prevent recurrence of bacterial failures in polyethylene devices, sterilization cycle validation, risk analysis for sterile packaging, lack of documentation on test methods, procedures to control environmental conditions, inadequate training procedures, etc.
In its published 98-page response, ZBH stated disagreement with certain aspects of some of the technical CAPA topics, based on perceived misunderstanding on behalf of the investigators, a lack of context, incomplete information reported by ZBH representatives, etc. Specifically, the company gave responses to four observations; excerpts are shared below. For the complete responses to these four observations, please examine the company’s detailed response.
Observation 1(A): ZBH did not implement corrective actions sufficient to prevent recurrence of bacterial endotoxin text excursions.
Zimmer Biomet response excerpt: We believe that the investigators misunderstood or lacked important context about the information reviewed by ZBH’s Global Recall Committee (GRC) when it decided that no field action was required. Specifically, the observation claims that a ZBH study report did not provide objective evidence sufficient to support the no-field-action decision. This study, however, was not the sole or even primary source of data that the GRC relied upon when making its decision. Further, the observation cites deficiencies in the study, as if the study was a validation. The study, to the contrary, was not a validation; it was a characterization study for a new cleaning process.
Observation 1(B): ZBH has not taken action commensurate with risk with respect to cleaning validations; certain cleaning processes currently in use at WNC are not in a state of control, due in part to low process capability (Ppk) values. Further, a [redacted] cleaning process has not been validated.
Zimmer Biomet response excerpt: These aspects of Observation 1(B) are a byproduct of a misunderstanding between the investigators and ZBH personnel. … ZBH is confident that cleaning processes currently in use at WNC are operating in a state of control, either as validated processes, or as non-validated processes subject to adequate interim controls and monitoring via control charting.
Observation 2: Relates to validation of a sterilization process (previously used, now replaced), stating that [redacted] was not properly validated and that studies performed “in lieu of” revalidation are not sufficient to ensure the sterility of previously distributed product.
Zimmer Biomet response excerpt: As reported in response to Observation 1(B) from the 2016 FDA 483, and as set forth in the attached response, [redacted] was, in fact, fully validated in 2003 and thus no revalidation was or is needed. Further, [redacted] remained in a validated state, passing all of its annual re-qualifications.
Observation 10: ZBH did not adequately establish process controls for a specific packaging sealer (since removed in accordance with an obsolescence plan) because ZBH did not include pressure as a process control. The observation quotes the sealer’s instructions manual as evidence that there are pressure control features in the sealer that ZBH should have, but did not, use.
Zimmer Biomet response excerpt: We respectfully disagree with this observation. The necessary process controls were established to ensure that the sealer conformed to ZBH’s established specifications. ZBH is not required to use all available features on a piece of equipment, but it must identify, qualify, control and monitor the critical features and the resulting process. … ZBH notes that the manufacturer of the packaging material sealed by the sealer at issue indicates that, for most heat seal materials, pressure is the least significant of the three factors required to make an adequate heat seal. … Supported by robust data, ZBH is confident that its use of in-process temperature monitoring and product attribute monitoring (for seal strength and integrity) ensured the validated state of the now-obsoleted sealer and continuous product conformance to specifications.
ZBH requested a meeting with the Agency to discuss its response, FDA’s feedback and review of remaining actions and projected timeline. The company will provide regular updates to this initial DA 483 response.
In the company’s 1Q18 call, CEO Bryan Hanson noted that recovery in knee, hip and S.E.T. is on track with a goal to restore supply in substantially all key brands by the beginning of 3Q18.
