News for the Combo Product/Device Industries

WuXi AppTec sends out a quarterly e-newsletter to our contacts in the combination product/medical device industry. To access previous issues, click here.

If you are not currently receiving the newsletter and would like to be on our mailing list, please email us at info@wuxiapptec.com. Please put "Combo Product-Device News" in the subject line.

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

April 2010

Contents [click on links for full story]


News from WuXi AppTec

Preclinical Testing Paradigms Appear to be Expanding to Include Efficacy for Combination Products

Pre-clinical biocompatible testing is defined by the US FDA as required to demonstrate that a device is safe prior to human use.  The normal testing paradigm is:

  • Pre-clinical testing for safety data
  • Clinical testing for efficacy

If a combination product is designed to address improved patient safety and efficacy testing is not easily support by the normal testing paradigm of the regulatory process, a new paradigm is being created.  In fact, the regulatory agencies have been open to discussions about broader approaches to pre-clinical data to support both safety and labeling claims when clinical studies may not be appropriate.   The new testing paradigm should now be considered to include:

  • biocompatibility testing
  • component testing to ensure product safety
  • selection and qualification of materials
  • final testing of the device design prior to regulatory submissions
  • efficacy claims

Preclinical studies designed to meet either singular or multiple endpoints can be an effective means to demonstrate that a product has a provable performance difference from a predicate device.  The major requirement is that valid scientific evidence be presented and the regulatory review will focus on risk-based, data driven outcomes to support efficacy.  Efficacy claims can be important to demonstrate to a variety of data consumers the utility and importance of the combination product. 

back to top


Validated MTT Assay Meets Recently Revised ISO Guidance on Cytotoxicity Tests
In 2009 the ISO technical committee on cytotoxicity issued a revised guidance document on the performance of cytotoxicity assays.  The revised document – “ANSI/AAMI/ISO 10993-5:2009, Biological Evaluation of Medical Devices—Part 5: Tests for In Vitro Cytotoxicity” – gives clarifications for the performance and evaluation of existing assay methodologies and provides guidance on new methods for evaluation of the cytotoxic potential of devices.  With the increased impetus to perform biological evaluations with quantitative endpoints, the committee spent extensive amounts of time choosing and evaluating methodologies for useful and quantitative endpoints.  Ultimately, three methods were introduced in the guidance document.  These include the MTT, Neutral Red and Colony Formation Assays. All of these assays meet the recommendation for quantitative cytotoxicity evaluations.  The user can choose any of the methods to meet the standard.  The choice can be based on timing, device characteristics, and the regulatory submission body.  As part of a continual effort to provide the most up to date test strategies, WuXi AppTec recently validated the MTT assay.

The MTT assay (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide  Assay) can be  performed on either extracts of devices or solutions of soluble products.  Logarithmically growing cultures of L929 mouse fibroblast cells are plated in 96-well culture dishes.  Next, multiple dilutions of the extract are prepared and added to triplicate wells of the culture plates.  After incubation, the MTT reagent is added to each well.  After a second incubation, the amount of formazan produced is determined through spectroscopy.  Cytotoxicity is calculated based on the formazan levels.  The intensity of the color is related to the number of viable cells.  Controls are included with each assay to demonstrate accuracy and sensitivity.

back to top

New Updated Catalog of Services Available from WuXi AppTec
WuXi AppTec has published a new, updated version of its popular catalog of services for devices and combination products. Numbering nearly 100 pages and presented in a convenient, easy-to-reference, 3-ring binder with tabbed sections, the catalog provides detailed test descriptions – including sample requirements and turnaround times – across the entire spectrum of our comprehensive services.

To request your copy of this useful resource - click here.

To access a online PDF version of the catalog – available for viewing or downloading - click here.

back to top

 

innovations / lab notes

DNA Sequencer Serves as Most Reliable Method of Microbial Identification
Because combination products can have organisms from different components – including biological, environmental, or clinical sources – performing identification of the contamination with a high degree of accuracy is crucial.  The DNA Sequencer, available from WuXi AppTec, is the current industry standard and deemed the most reliable method of microbial identification for bacteria, yeast and mold.  A particular advantage of the DNA Sequencer is that its use of PCR technology means only a minute quantity of an organism’s DNA is needed to perform an identification.  PCR has not only the advantage of accuracy but it also speeds up the identification process by saving time normally devoted to culturing the organism for one or more days.  With the DNA Sequencer, both bacteria and molds can be identified in as little as two hours.  In addition, the technology also allows for identification of nonviable organisms.

Technical Mechanism: Fluorescently labeled dideoxynucleotides, which act as DNA chain terminators, are incorporated into various length sequences of DNA during PCR amplification.  Each newly created strand of DNA differs in length by one nucleotide.  When these strands of DNA are run through a polymer, they are segregated according to their size length.  As each strand of DNA exits the polymer, the ABI 3130 Genetic Analyzer uses a laser to detect the fluorescently labeled dideoxynucleotides, revealing the sequence of bases in the original DNA sample.

back to top

 

BMP (Bone Morphogenic Protein) Assay Provides In Vitro Determination of Osteoinduction
The evaluation of activity of DBM (demineralized bone matrix) based products is an important endpoint in both the research and development of products and their lot release programs. Products that induce more bone growth will be viewed as more efficacious than those with lower potential. Osteoinduction is the ability of a product to actively induce the growth of new bone. Traditionally, this has been measured through long studies involving the use of animals. Though the use of rat or mouse models has been considered the gold standard for the evaluation of osteoinduction, in vitro methods are gaining in both popularity  and regulatory acceptance. Several methods exist for the in vitro determination of osteoinduction. These include assays such as the Alkaline Phosphatase (AP) and the measurement of BMPs ( bone morphogenic protein). The measurement of BMP has some advantages over the AP assay. First, several BMP proteins are involved in the osteogenic process. These include BMP-2, BMP-4 and BMP-7. This allows the researcher to choose from several targets. Next, BMP is a directly acting protein the development of new bone and thus represents a more direct measure of potential.

Though BMP-2 is the most common protein, both BMP-4 and BMP-7 are important markers in new bone development and osteocyte differentiation. In testing the level of BMP present in a sample, the DBM is first extracted through a guanidine extraction process. The extracts are then subjected to an ELISA process to quantify the amount of BMP present. Briefly, 96 well plates coated with an antibody to the BMP protein of interest. Next, the dilutions of the bone extract are plated, in triplicate, and allowed to incubate. After incubation, the extract is washed out and a secondary antibody is added. Once the secondary antibody has reacted, a color-producing marker is added to each well. The color intensity is measured spectrophotometrically. The intensity of the color is related to the amount of BMP present in the extract.

back to top

 

Testing of Sterile Barrier Systems Takes on Critical Importance in Light of Regulatory Changes
At the recent HealthPack 2010 meeting (the industry conference dedicated to medical device packaging) one of the hottest topics was product sterility – particularly in light of recent increased scrutiny of the regulatory requirements regarding testing and validations for medical device packaging / Sterile Barrier Systems (SBS).  This testing has taken on compelling new importance as it is critical in supplying data to demonstrate that an SBS – a product’s ultimate protection system – meets all design requirements, and verifying that it maintains product sterility and integrity during storage and shipment.

Among the required SBS evaluations are integrity, stress, seal strength, simulated distribution and stability testing programs.  As the leader in testing and evaluations of SBS for medical products, WuXi AppTec offers these testing services to meet the requirements of ASTM, ISTA and TAPPI standards, as well as providing all of the ISO 10993 testing required to demonstrate biocompatibility of the final product before regulatory submission. 

In addition, because the particular SBS chosen can have significant impact on the materials and testing of the packaging – impact ranging from the sterilization methods to the carbon footprint of the packing materials – manufacturers can look to WuXi AppTec for consulting services regarding packaging and materials selection.

A detailed presentation on Sterile Barrier System and Biocompatibility testing is available from WuXi AppTec via webcast. Click here to to request more information.

back to top

UPCOMING MEETINGS

WuXi AppTec recently participated in these industry meetings:  MD&M West in Anaheim, HealthPack 2010 in San Antonio, and Interphex in Puerto Rico.

Please stop by and see us at these upcoming shows:

BIOMEDevice  – April 21-22 at the Boston Exhibition & Convention Center – Booth # 1015

MD&M East – June 7-10 at the Jacob K. Javits Convention Center in New York – Booth # 836

back to top