Medical Device Daily Washington Editor
Keeping a handle on in-house operations is tricky enough at times, and keeping a handle on the operations of a contract sterilizer is sometimes even more nettlesome, or so the Dec. 21 warning letter to Smith & Nephew (S&N; London) seems to suggest.
The July inspection of the firm's plant in Tuttlingen, Germany, which turns out the R3 ceramic acetabular cups used in hip replacement systems, led to a warning letter with five citations addressing sterilization and validation issues. Although the firm's senior VP for global regulatory affairs, Les Sprinkle, managed to draft a response within the required 15-work day time frame, the agency found the responses lacking, and FDA indicated it would schedule a follow-up inspection to confirm the efficacy of any corrections.
The warning letter led with a citation for failure to conduct a process validation study “to support the minimum and maximum settings being used on the [redacted] for pressing different sized titanium rings onto various ceramic inserts“ for the R3 liner. FDA also alleged a failure to perform bioburden and endotoxin testing for “the tibial base plates as required by the performance qualification studies for the [redacted] and [redacted] Washers used during“ production of the acetabular lining.
FDA indicated it was unenthusiastic about the response because while the company “provided information on an engineering analysis performed for products that were produced with the modified press settings,“ S&N nonetheless failed to “provide a testing protocol or statistical rationale to support this analysis.“ The warning letter states that the firm reset the parameters on the press to those specified in the original validation and had trained employees on the procedure, but the firm also promised to revalidate the press settings via a new protocol by Dec. 1, all of which were apparently insufficient to ease FDA's concerns.
The sterilization issues cropped up in the second citation, which says that “incorrect packaging and product density“ led to below-specification irradiation dosing for two batches of an unspecified item in May 2009. The warning letter, which cited this situation as a failure to establish/maintain procedures “to verify or validate corrective action,“ notes that S&N “implemented new packaging procedures and retrained employees“ to deal with the sub-par dosing situation, although the situation arose again after the firm attempted to correct the problem. This, the warning letter states, was chalked up by the firm's management as being due to “employees not following directions.“ The firm's response to this finding from the inspection was deemed inadequate because S&N “did not describe how procedures to verify or validate corrective and preventive action would be established or revised,“ but FDA added that the response did not clearly spell out “whether other corrective or preventive actions would be reviewed to determine if similar violations exist.“
Another citation alleges that the company conducted no evaluation “to determine the need for an investigation“ of two batches of devices “that failed to meet specified minimum dose requirements.“ This citation adds that the proposed fix was insufficient because S&N did not make clear that a revised protocol had been implemented that would have mandated that “the review process [for checking the sterilization status of incoming components] is a direct responsibility of the quality department.“ The warning letter states further that S&N rewrote a contract with an outside entity requiring the contractor to let S&N know about “any deviation to the sterilization process.“ The contractor is apparently forbidden from returning an item to S&N “if it did not receive the required dose,“ and FDA adds that S&N “reviewed the sterilization release practices at all locations worldwide to ensure the issue was not widespread.“
The sterilization problem migrated to a finding for procedures for release of non-conforming product, and FDA indicated it was unhappy with the response due to lack of confirmation that the proposed fix had been rolled out. The agency also bemoaned the fact that S&N “did not demonstrate that a review of all sterilization release records between 2002 and 2010 was completed“ to check for problems with any other lots of R3 cups. The warning letter states that the company contracted a regulatory compliance consultant to determine whether any hazard existed due to the sterilization issues, which the agency states led to the conclusion that “the sterility assurance level . . . required to inactivate bioburden was attained.“
John Coles, spokesman for S&N, told Medical Device Daily, “we put in place some remedial actions in July and we've been working with FDA since then,“ but he noted, “the points they raise in their letter – which we haven't seen yet – suggest they're not happy with those.“ He said he could not comment further until the company sees the warning letter, the hardcopy of which has not arrived due to the holiday season in the UK and concomitant delays in the delivery of postage matter.
Coles said that the R3 “is also made in Warwick, UK, and Memphis, Tennessee, so there are no problems with supply.“ He also said, “no patient incidents in connection with the issue“ have been reported.
NIH releases technologies for licensing
The National Institutes of Health sits on perhaps the largest repository of basic research in the world and it occasionally offers some of its inventions for licensing or cooperative development. The agency announced several items of potential interest in this Tuesday's edition of the Federal Register, including one titled “engineered biological pacemakers,“ a development that again reminds makers of electrophysiology hardware that sooner or later, their metallic implants will face stiff competition from biological fixes.
According to the FR announcement, this biological pacemaker includes “cardiac cells or cardiac-like cells derived from embryonic stem cells or mesenchymal stem cells“ that can be engineered so as to “naturally integrate into the heart.“ These cells are said to be capable of integrating coupling factors such as cyclical adenosine monophosphate-dependent (cAMP) protein kinase A (PKA) as well as the calcium ion-dependent variant of protein kinase dubbed CaMK II, which are both capable of regulating calcium ions essential to surface membrane voltage capacitance. These cells, NIH states, can convert “irregularly or rarely spontaneous active cells into pacemakers generating rhythmic excitations.“
The FR notice claims that this source of cells carries a low risk of infection and is the subject of two articles appearing in the peer-reviewed literature, including in the American Journal of Physiology – Heart and Circulatory Physiology in May of last year (Maltsev and Lakatta).
This invention is said to be the subject of a patent application under the Patent Cooperation Treaty (PCT), the successful prosecution of which would confer protections in many EU nations. Those interested in licensing opportunities can contact Fatima Sayyid (301-435-4521, fatima.sayyid@nih.hhs.gov), while those who seek collaborative development opportunities should reach out to Vio Conley (301-496-0477, conleyv@mail.nih.gov).
Another item of interest may be a method of picking up contaminants in heparin, an especially timely development all things considered. This technology screens heparins by detecting and/or quantifying oversulfated glycosaminoglycans “based on inhibition of nucleic acid polymerases and resistance to enzymatic degradation. The development has not been fully validated but is the subject of a PCT patent application. Again, anyone interested in licensing opportunities should contact Fatima Sayyid (301-435-4521, fatima.sayyid@nih.hhs.gov) while those who seek collaborative development opportunities should get in touch with Daniela Verthelyi (daniela.verthelyi@fda.hhs.gov).
Mark McCarty, 703-268-5690