News for the Combo Product/Device Industries

WuXi AppTec sends out a periodic e-newsletter to our contacts in the combination product/medical device industry.

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For questions about any of these items or other information on WuXi AppTec’s services, contact a WuXi AppTec Account Manager.

September 2014

Contents [click on links for full story]   



WuXi AppTec's Regulatory Affairs team continuously monitors the release of new and revised worldwide regulations and guidances. Staying at the cutting edge of the changing regulatory landscape, we can assist you better by providing assistance in designing testing programs that meet current regulatory philosophies.

To contact a WuXi AppTec Account Manager for more information or to be put in touch with one of our regulatory experts, click here.

Independent Assessment of FDA Device Review Process Management:  Booz Allen Hamilton Report 

In our June 2014 Newsletter we provided highlights of the Booz Allen Hamilton (BAH) independent assessment of issues related to the 510(k) review process. This is the second and final installment of our summary reporting of issues and Findings relating to the PMA review process and staff turnover. In addition, we included the BAH assessment recommendations for improving the overall device submission review process and staff turnover.

Pursuant with the 2012 enactment of the Medical Device User Fee Amendments of 2012 (MDUFA III) and as part of its agreement with industry, the FDA committed to meet certain performance goals aimed at increasing the speed and efficiency of its premarket review programs and expediting the approval of safe and effective medical devices to market. To that end, the FDA published the MDUFA III Commitment Letter and in conjunction with industry agreed to an independent, comprehensive assessment of the medical device submission review process.  The assessment would be performed in two phases and consist of a technical analysis, a management assessment, and overall program evaluation. This first phase involves the assessment of the medical device submission review processes, FDA management systems, IT infrastructure, workload management tools, reviewer training programs, and staff turnover.

On June 11, 2014, the Booz Allen Hamilton (BAH) independent assessment of the FDA device review process was released. This final report summarizes the methodologies, findings, and recommendations supporting the BAH system-based approach in assessing whether FDA has the processes, practices, and resources in place to successfully meet MDUFA III requirements and improve the efficiency and review times for the medical device submission review process.  The final report is a comprehensive assessment and deep dive of the issues affecting the speed and efficiency of the premarket review process and comprises over 100 exhibits.   

According to the report, to analyze review times between MDUFA III and MDUFA II processes, submissions received during fiscal year 2012 (M2 Received Cohort) were analyzed.  To assess the impact of specific MDUFA III process improvements, a smaller cohort of submissions (M3 Study Cohort) were evaluated.  The M3 Cohort included 37 Premarket Notifications (510(k)s and 28 Premarket Applications (PMAs).

Following are a few key highlights from the report regarding PMA submissions, staff turnover and related recommendations for improvement.  Note that the recommendations shown below are limited to the 510(k), PMA review and staff turnover findings and we have numbered them differently than in the report.


Analysis of PMA submissions
PMA Original (PMAO), Panel-Track Supplement (PTS), 180-Day Supplement and Real Time Supplement (RTS) submissions were assessed to determine the impact of MDUFA III processes on overall review performance. Due to the limited number of PMA Original and Panel-Track Supplement submissions within the M3 Received Cohort, only a limited assessment of MDUFA III PMA process improvements could be performed. 

  • TTD for PMA Original submissions and Panel-Track Supplements was comparable between the M2 and M3 Received Cohort. In contrast, TTD for PMA 180-Day supplements decreased from the M2 Received Cohort to the M3 Received Cohort while TTD for PMA Real-Time Supplements increased from the M2 Received Cohort to the M3 Received Cohort.
  •  A thorough assessment of the impact of RTA processes on PMA Original and Panel-Track Supplements could not be performed due to the limited number of closed PMA Original and Panel-Track Supplements within the M3 Received Cohort.
  • As expected, evaluation of SI processes from our M3 Study Cohort revealed that PMA Original and Panel-Track Supplements had on average a greater number of SI issues identified per submission (7.2) than PMA 180-Day Supplements (1.0).  Furthermore, we observed a positive correlation between number of SI issues and length of TTD across the PMA submission types that require SI decisions.
  • Clinical deficiencies represented the most commonly identified deficiency type among PMA Original and Panel-Track Supplements.
  • Analysis of the MDUFA review phase within the M3 Study Cohort revealed that more than 75% of all submission types were approved by the MDUFA Goal Date.
  • Evaluation of communications among all PMA submission types within the M3 Study Cohort revealed no correlation between the number of communications and length of TTD, except for a small positive correlation observed for PMA 180-Day Supplements.
  • Similar to findings gleaned from our analysis of Traditional 510(k) submissions, the average number of communications held between FDA and Sponsors for OIR submissions was greater than for submissions from ODE for all PMA submission types.
  • Analysis of consult requests for PMA submissions revealed that PMA Original and Panel-Track Supplement reviews were associated with more consults requested per submission (17.6) than 180-Day supplements (2.5) and Real Time Supplement reviews (0.8).
  • Clinical and Statistics consults were the most frequently requested disciplines for PMA Original and Panel-Track Supplement submissions.

Assessment of Staff Turnover
To understand the impact that current attrition has on review processes, we sought reviewer opinions through our CDRH staff survey.

  • While the majority of reviewers were confident in their division’s ability to manage through attrition, OIR was significantly more confident than ODE. In addition, OIR reviewers indicated attrition had a lower degree of impact on their ability to complete timely review submissions than did ODE reviewers.
  • While standard operating procedures for management of review staff changes during the review of a premarket submission exist, formal transition and succession plans are not employed at either the Center or Office levels. ODE and OIR both incorporate informal practices at the Division level.
  • Development and implementation a succession plan will promote seamless transitions when turnover occurs and help mitigate disruption to timely and consistent reviews.



Evaluation of Review Process

1.   Develop criteria and establish mechanisms to improve consistency in decision making throughout the review process (Priority Recommendation)
A recurring issue that was identified during our analyses was inconsistent decision-making throughout various stages of the review process, in particular, a lack of transparency in thresholds or requirements used to trigger AI requests. Development of tools, criteria, and/or mechanisms for assessing and ensuring the consistency of review processes, such as an AI Request Checklist to clarify the categories of deficiencies that applications may be subject to receiving, would help ameliorate this issue.

2.   Optimize RTA process by improving awareness of and clarity around Administrative requirements for 510(k) submissions
Our analysis revealed that more than 50% of closed Traditional 510(k) submissions received within CY13 received a rejected RTA decision during the first cycle, and that submissions with a greater number of RTA cycles were associated with longer TTD and TST. The Administrative category of the RTA checklist had the most frequently identified elements during RTA Acceptance Review, with more than 80% of submissions containing at least one missing/deficient element that resulted in an RTA decision. Therefore, we recommend promoting increased awareness of and clarity for Sponsors around Administrative requirements for 510(k) submissions.

3.   Perform a retrospective root cause analysis of withdrawn submissions and develop a mechanism to minimize their occurrence
Rates of withdrawn submissions increased 50% between the M2 and M3 Study Cohorts. Further analysis of withdrawn submissions revealed that two-thirds of these were withdrawn during the MDUFA Interactive Review phase, of which nearly 30% were withdrawn with fewer than 10 days remaining on the review clock. CDRH review staff cited an inability to resolve deficiencies within MDUFA timeframes as a reason for withdrawn submissions, as well as the Sponsor’s inability to provide adequate data to support an SE decision. While MDUFA III limited FDA to one hold at Substantive Interaction to promote high quality submissions, this also inhibited reviewers and Sponsors from resolving minor deficiencies within the MDUFA III timeframe, possibly leading to an NSE decision. Analysis of our limited study sample signaled a potential issue that warrants further investigation through another study. We recommend that FDA conduct a larger-scale retrospective study using withdrawn submissions to identify submissions with characteristics that might benefit from additional review time (e.g., submissions with minor deficiencies that may be quickly resolved). FDA should communicate study findings with public stakeholders and depending on study outcomes, develop mitigation strategies, such as a limited additional hold or other mechanism.

4.   Implement a consistent practice for communicating early and frequently with Sponsors during the Substantive Review phase to address and resolve potential issues prior to Substantive Interaction
Our evaluation of communication practices for both ODE and OIR submissions revealed that OIR reviewers held more frequent communications with Sponsors throughout the course of the entire review. More specifically, OIR had more communications during the Substantive Review phase than did ODE. This increase in overall communications among OIR submissions was also associated with fewer deficiencies/issues identified within SI, and an overall shorter TTD. We recommend that FDA implement a consistent practice for early and frequent communication with Sponsors to address issues prior to SI.


Assessment of Staff Turnover

1.   Develop CDRH-wide staff transition and succession plans to mitigate the impact of turnover on submission reviews
An analysis of attrition at CDRH indicated that overall attrition has improved and that the rate is not significantly different from that of USPTO, when utilizing a common calculation methodology. ODE staff perceive staff turnover as having a more significant impact on their ability to perform timely reviews than does OIR staff. Similarly, ODE reviewers believe their Divisions are not as well prepared to successfully manage through attrition as OIR when attrition does occur. While standard operating procedures for management of review staff changes during the review of a premarket submission exist, formal transition and succession plans are not employed at either the Center or Office levels. ODE and OIR both incorporate informal practices at the Division level. Development and implementation of a CDRH management succession plan and review staff transition plan can promote more seamless transitions when turnover occurs and help mitigate disruption to timely and consistent reviews.

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WuXi AppTec Holds Grand Opening Celebration for Materials Characterization Facility

On Tuesday, August 12th WuXi AppTec hosted a grand opening celebration for our new Materials Characterization facility.  Located in St. Paul near our existing site, the new facility was designed specifically to serve our customers' growing need for quantifying the chemical safety of materials used in their products.

The 20,000-square-foot facility will offer expanded capacity for existing services, like particle identification and extractable/leachable testing, and add a new service – dynamic light scattering for nanoparticle characterization.  A unique flexible floor plan allows rapid scale-up of technologies to increase capacities for chemical analysis of medical materials.

If you were unable to join us for the celebration, or if you will be traveling to the Twin Cities area, we would be pleased to take you on a tour of the new facility.  Contact your Account Manager to coordinate your tour.

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New Service!  Dynamic Light Scattering Provides Data for Nanoparticle Analysis

As regulators worldwide have increased focus on Materials Characterization of your products, there has been a noticeable emphasis placed on nanoparticles.  Specifically, regulators are interested in the potential effects of nanoparticles and want to understand the size and distribution of those particles.  Our Dynamic Light Scattering (DLS) service analyzes an extract of the device and provides you with the data regulators are looking for.

Dynamic Light Scattering can be added to your extractables/leachables testing or can be performed as a standalone test. Our team of toxicologists can help you analyze the data and harmonize it with your other safety testing as part of a full biological evaluation of your product.

Contact your WuXi AppTec Account Manager for more information about our DSL service, materials characterization offerings, and biological evaluations.

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Validated OPA Protein Method Offers More Accurate Data for Your Cleaning Validations

As part of our effort to remain at the forefront of the FDA's expectations for cleaning validations, the experts at WuXi AppTec have validated a quantitative method for protein analysis. In reference to ISO 15883, the OPA protein method be used in cleaning validations for our clients who follow the washer/disinfector standard.

This validated and quantitative method is useful for determining the amount of residual protein on cleaning efficacy samples as well as for providing an analytical test that determines the amount of total water extractable protein associated with natural rubber and related products.  It is based on the compound, o-phthaldialdehyde (OPA), which reacts in the same fashion as other florescent agents but has the added the benefit of greater sensitivity.  This means more accurate data for your file.

For more information, contact your WuXi AppTec Account Manager.

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Clean Steam Validation Now Available

Continually expanding our test offerings to support client needs, WuXi AppTec has added Clean Steam Validations to our services.  The GMP requirements for Clean Steam are very specific, so to ensure your validation's success, let our team of experts help you validate your clean steam system for reprocessing to ensure not only that it meets the current regulatory guidelines but also follows the latest trends.

Contact your WuXi AppTec Account Manager for details about validation or re-validation of your clean steam process.

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Please Join Us for a Free "Breakfast with our Experts" Seminar

at the North Carolina Biotechnology Center in Research Triangle Park

October 24, 2014  •  8:00 a.m.-11:30 a.m.

"Biological Evaluations:  Insights for Success"
It is well known that the regulatory agencies are calling for biological evaluations, but understanding what the regulators are really looking for can be a challenge.  At this free breakfast seminar, our experts will cover the latest trends, provide insights into materials characterization, risk assessments, and biocompatibility, and explain how all of this testing works together for a successful biological evaluation.

Contact your WuXi AppTec Account Manager for details.


MD&M Minneapolis

October 29 – 30, 2014  •  Minneapolis Convention Center

Come see us at booth #820.


Life Science Alley 2014 Conference

November 19, 2014  •  Minneapolis Convention Center

Come see us at booth #405.

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