News for the Combo Product/Device Industries

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March 2015

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.


Center for Devises and Radiological Health (CDRH) Updates and Re-Issues Plan of Action Based on BAH Final Report

BACKGROUND:  As part of an agreement with industry, the Food and Drug Administration (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. 

•   In 2012, the FDA and the medical device industry agreed to an independent, comprehensive assessment of the medical device submission review process, and the FDA engaged the firm Booz-Allen Hamilton (BAH) to conduct the assessment. 

•   In December 2013, BAH issued its initial report. 

•   In response to that initial BAH report, CDRH developed a Plan of Action and released it in June 2014.

•   On June 11, 2014, BAH issued its final report on findings and recommendations, “Deliverable 10: Final Report on Findings and Recommendations.”  This final report included four priority recommendations from the December 2013 report and seven additional recommendations in four categories. 

CURRENT:  In December 2014 CDRH updated and re-issued its Plan of Action.  The updated plan includes revisions to address the additional recommendations identified in the June 2014 BAH final report and outlines the actions CDRH intends to implement in response.  The CDRH Plan of Action designates action items as Stage 1 and Stage 2, and it is CDRH’s intent to have all Stage 1 action items completed by December 31, 2015. 

In previous WuXi AppTec Newsletters, we reported key findings of the BAH reports related to 510(k) and PMA submissions.  Based on our analysis of the December 2014 CDRH Plan of Action, along with feedback from our customers regarding FDA inquiries and interactions, we have identified the following proposed Stage 1 Action Items as having the most potential to impact the submission review program.


  • Develop criteria and establish mechanisms to improve consistency in decision-making throughout the review process.
    • Conduct a gap analysis to identify needed key processes, procedures, policies, IT, and metrics associated with 510(k) clearance decisions, PMA approval decisions, 510(k) Requests for Additional Information, PMA Major Deficiencies, and IDE approval decisions, including processes, procedures, and policies associated with cross-cutting review areas.
    • Identify Best Practices and Lessons Learned for ensuring consistent decision-making from other organizations and incorporate best practices findings into premarket processes.
  • Optimize the RTA process by improving awareness of and clarity around administrative requirements for 510(k) submissions.
    • Conduct an audit of the RTA program.
      • Identify top missed criteria.
      • Identify criteria with the greatest amount of substantive review.
    • Conduct an analysis of feedback from industry collected during the assessment of the premarket review process on their experience with the RTA policy and checklist.
    • Revise the RTA policy to increase clarity and further promote awareness of requirements.
      • Clarify boundaries around the use of discretion in the application of the RTA policy.
      • Modify criteria phrasing and/or explanatory text to improve understanding and clarity of the RTA policy.
  • Perform a retrospective root cause analysis of withdrawn submissions and develop a mechanism to minimize their occurrence.
    • Conduct an analysis of withdrawn submissions to identify trends, correlations, or patterns that may lead to withdrawn data, including reason for withdrawal.
      • Identify characteristics or patterns during the acceptance review.
      • Identify characteristics or patterns during the substantive interaction phase of the review, including the end of the review cycle.
  • 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.
    • Conduct an assessment of current practices and identify best practices for early and frequent communication during 510(k) review.
      • Interview ODE and OIR reviewers and management.
      • Collect feedback on what does and what does not work in interactive review.
    • Use the results of the assessment to develop policy, standard procedures, and metrics for communication during early 510(k) review. Use focus groups to inform development of policy, procedures, and metrics.


  • Provide increased clarity to applicants beyond existing eCopy guidance to enhance organized submission structure
    • Conduct an assessment of the eCopy program.
      • Collect feedback from staff and industry
      • Identify eCopy structural issues encountered by review staff.
      • Identify eCopy structural issues encountered by industry.
  • Evaluate tools for providing a comprehensive view of staff workload
    • Identify tools and data available to assess staff workload.
      • Determine advantages and disadvantages of each tool.
      • Identify the workload data each tool provides and determine if the data is unique or redundant.
      • Determine comprehensiveness of existing tools.
    • Identify gaps for assessing and managing current and evolving reviewer workload.
      • Determine how to address gaps, including specific data, indicators, and tools that will help managers more efficiently use staff resources.


  • Identify metrics and incorporate methods to better assess review process training satisfaction, learning, and staff behavior changes.
    • Research best practices for training evaluation in similar organizations.
    • Determine evaluation requirements for premarket review training.
      • Establish the evaluation criteria for each of the four levels of Kirkpatrick’s model.
      • Outline the requirements for obtaining data at each of the four levels of Kirkpatrick’s model.
  • Promote informal training and knowledge sharing by seasoned staff for review staff and management to share Division or science-specific review processes, lessons learned, and best practices

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Infections from Reprocessed Medical Devices

Recent news regarding deadly infections linked to reprocessed medical devices at two different hospitals (1, 2) highlights the challenges with medical device-related infections, and particularly with the cleaning and re-use of these devices.  Seven patients at one hospital, two of whom have died, were recently reported to have acquired carbapenem-resistant Enterobacteriaceae (CRE) from re-used duodenoscopes.  While this has gained attention in the current news, the clinical issue is not new, with reports of CRE infections related to duodenoscopes dating back at least to 1987 (3).  Since January 2013 the FDA has received reports on 135 patients with possible microbial contamination from reprocessed duodenoscopes (4).

Duodenoscopes are flexible tubes that are inserted through the throat and stomach into the area of the small intestine called the duodenum.  These scopes provide access to pancreatic and biliary ducts, allowing physicians to visualize and obtain biopsies from these tissues or help drain fluids from blocked ducts.  One of the challenges with these particular devices is the complex design at the tip, which makes cleaning and disinfecting extremely difficult.  Also, its exposure to the gut microbial flora – which contains Gram negative strains with increasing antibiotic resistance such as the CRE – produces a significant clinical challenge.  While there have been no reports of incorrect cleaning procedures or failure to follow manufacturers’ cleaning instructions for the scopes in question, concerns arise as to whether cleaning procedures are sufficient and/or the device design is too complex to assure thorough and consistent cleaning to prevent future infections.

In response, the FDA is now asking manufactures to provide evidence of the efficacy of their disinfection methods, which it previously had not required (5).  With high profile cases such as these, the industry is likely to see heightened regulatory attention on cleaning procedures and validations, as well as the advancement of new antimicrobial options associated with medical devices to reduce the occurrence and spread of device-related infections from reusable devices.  WuXi AppTec has extensive experience in both areas of testing, and we welcome the opportunity to discuss your testing needs for the development of medical devices.

 1.  S. Tavernise, Feb.19, 2015. “Deadly CRE Germs Linked to Hard-to-Clean Medical Scopes,” New York Times.  (

 2.  “Superbug outbreak extends to Cedars-Sinai hospital, linked to scope”


4. (Feb. 19, 2015)


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Designing Successful Cleaning & Sterilization Studies for Reprocessed Devices

Reprocessed medical devices have been in the news and regulators now have heightened focus on cleaning and sterilization processes. In today’s regulatory environment, how do you design successful cleaning and sterilization validations for your reprocessed devices? 

Our experts have developed a list of tips to consider when designing validation testing programs to successfully demonstrate the efficacy of your procedures.

Review and/or Update Your Reprocessing Instructions

You should anticipate that new Instructions for Use (IFUs) will need to be written and new cleaning studies conducted if you have a device that utilized reprocessing instructions from a predicate.  This pertains to both devices currently cleared as well as new device submissions.  

If you have multiple products, we recommend setting up product families based on device features.  Then specify a “master product” for each product family to develop IFUs and a cleaning validation. 

Manufacturers must specify predetermined cleaning endpoints.  Based on updates to guidances over the past several years, spore log reduction is no longer the recommended endpoint to demonstrate  cleaning efficacy. The FDA now expects at least two markers be used for validating cleaning efficacy:

Protein                                <6.4 ug/cm2 (based on TIR 30)

Hemoglobin                        <2.2 ug/cm2

Carbohydrate                     <1.8 ug/cm2

TOC                                    No universal endpoint has been established

Use the “Most Challenging Conditions”

For cleaning validations, the “most challenging conditions” – either the worst-case parameters or “least rigorous” conditions – must be used.  This means selecting samples for your validation that have been used in the field – for a device already cleared – and subjecting the product to multiple cycles of soiling. 

If a device hasn’t been cleared, consider soiling with extended hold times and multiple cycles of soiling and cleaning. Then, select cleaning parameters based on worst-case practices, such as shortest soak times.

Your validations should be performed using accumulation cycles and practices that fall outside your IFU recommendations, e.g., longer soil-to-clean times than indicated.

The artificial soil used in cleaning studies must also represent a worst-case exposure for the devices.  Based on the device’s intended exposure, specific additives should be selected and combined with standard test soil.

Include Replicates in Your Studies

You need to use a statistically significant number of replicates to ensure your results are statistically valid and reproducible.  Use at least 3 replicate devices of each study product per study and run the cleaning for each study in triplicate. Always use a positive and a negative control to demonstrate process control.

Exhaustive extraction is requested for validating recovery of residual soil, including both positive and negative controls.  Exhaustive extraction on the positive control sample will allow for a recovery factor to be determined. 

Test for Residual Detergent or Cleaner

Consider testing for residuals on critical devices to show that any detergent or cleaner has been removed to an acceptable level. This can be critical to avoid biocompatibility complications for the patient later.  Many detergents can cause local irritation or even cell death.

Take Further Steps for ISO 17664 Compliance

To claim ISO 17664 compliance, you will need to dry your products following disinfections/thermal disinfection, inspect the device to assess presence of moisture, and document your findings.


With our many years of experience in the field, WuXi AppTec’s sterility assurance team can help ensure the success of your validation testing programs.  To learn more about our Cleaning and Sterilization Studies, contact your Account Manager today.

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Coming Soon:  A New WuXi AppTec White Paper on Extractables/Leachables Program Design

The following is an excerpt from our soon-to-be-released whitepaper, “Avoiding Common Mistakes in your Extractables/Leachables Program Design,” authored by Kimberly Ehman, Ph.D.; Sherry Parker, Ph.D.; and Sandi Schaible, M.S.  To ensure you receive your copy when it is published, contact your Account Manager.

Mistakes in program design for extractables/leachables testing can lead to significant delays, rounds of questions, and the need for additional testing.  And, in some cases, all of the extractables/leachables testing may need to be repeated.  To avoid these costly mistakes, it is important to understand the current standards as well as the current interpretations and opinions from regulators interpreting these standards.

The ISO 10993 guidances are often used as a reference to determine chemical testing approaches for medical devices.  Multiple sections need to be considered in tandem to meet the expectations of regulators.  Although 10993-17, “Methods for the establishment of allowable limits for leachable substances,” isn’t about chemistry, it provides the mechanisms to interpret the analytical data generated as a result of 10993-18, “Chemical characterization of materials.”

Part 18 of the standard is a useful guide for developing a chemical characterization protocol as part of an overall assessment of the biological safety of a medical device.  Chemical characterization can include measurement of extractable and/or leachable substances, screening of potential new materials, and determining chemical equivalence between devices following minor changes (e.g., comparing a proposed material to clinically established materials or comparison of a final device to a prototype).  Part 18 does not address the identification or quantification of degradation products as those determinations are covered in other parts of the standard.

The standard acknowledges that different materials require different analytical approaches. Four main medical device material classes are covered in Part 18: polymers; metals and alloys; ceramics; and natural macromolecules.  The standard provides example parameters to be analyzed under each material class including both physical properties of the materials and identification of a material’s chemical make-up.

Along with a list of example test parameters, Part 18 identifies analytical instruments or example methods for the determination of the analysis parameters. 

ISO 10993 - Part 17 provides an outline for the safety evaluation of the extracted or leached chemicals identified in your Part 18 study. These sections of the standard are tied together and both are needed for a complete extractable/leachables assessment. Part 17 offers the user a mechanism for consistently evaluating the chemical data and its potential risk to patients.

The above is only a excerpt from the soon-to-be-published WuXi AppTec White Paper.  Contact your WuXi AppTec Account Manager for more information.

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Defining Exhaustive vs. Exaggerated Extractions

Two terms often used in conjunction with extractables studies are “exaggerated extractions” and “exhaustive extractions.”  Both are defined in multiple sections of the ISO 10993 standard. It is important to understand the difference between these terms as they are often used interchangeably or erroneously even in regulatory requests. And further complicating the situation, expectations are slightly different for chemical analyses versus biological testing.

Exaggerated extractions are extractions intended to result in a greater amount of a chemical constituent being released compared to the amount generated under simulated conditions of use.  This definition closely follows the process of a typical extractable study and those most commonly used for biocompatibility.

Exhaustive extractions are defined as repeating extraction until the amount of material in a subsequent extraction is less than 10% of that detected in the initial extraction or the point at which there is no analytically significant increase in the cumulative material levels detected.

In most cases, exaggerated extractions meet requirements for a regulatory submission.  If you are asked to exhaustively extract or perform an exhaustive extraction, we recommend you get clarification of the term as often the intent of the request is to perform an exaggerated extraction, not an exhaustive extraction.

Contact your WuXi AppTec Account Manager for more information on our extractables and leachables testing services .

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Dr. Sherry Parker Elected as Councilor for SOT Medical Device and Combination Product Specialty Session (MDCPSS)

Dr. Sherry Parker, a Technical and Regulatory and Director at WuXi AppTec, was recently elected for a two-year term as a Councilor to the Society of Toxicology's (SOT) Medical Device and Combination Product Specialty Section (MDCPSS). According to SOT, the MDCPSS was formed in Fall 2009 with the purpose of providing an international forum where government, industry, and academic toxicologists can share state-of-the-art knowledge and develop new approaches for the evaluation of medical devices.

Dr. Parker has over 19 years of toxicology and medical device research experience, and is an expert in analytical, pharmacological, and toxicological evaluations of devices and novel combination products. After receiving her Ph.D. in Molecular and Cellular Pharmacology from the University of Miami, Dr. Parker spent 10 years in toxicology research for the University of Miami, the U.S. EPA (Neurotoxicology Division) and RTI International before moving into the medical device industry, where for more than six years she was involved with device development, safety and efficacy testing and regulatory submissions for OrbusNeich Medical. In her current position at WuXi AppTec as Director of Technical and Regulatory for Medical Devices / Combination Products, Dr. Parker provides manufacturers with guidance on global regulatory and technical requirements and testing program design, and is a U.S. Delegate for TC 194, the technical committee for ISO 10993.

To learn more about WuXi AppTec's biological evaluation program, click here

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