PLASTICS

Medical device manufacturers usually do not make the component materials that go into their devices, and yet they are responsible for demonstrating that the materials in the devices are safe. Product clinical performance design criteria aside, device manufacturers must carefully consider the component material's surface activity, potential extractable components, and their potential effect on the host. To address this issue, in May 1995, FDA issued a blue book memorandum announcing that the old Tripartite Guidance would be replaced with ISO 10993 as the criterion for evaluating the safety of materials used in medical devices.¹ This article focuses on silicone, but the methodology is applicable to many other biomaterials including thermoplastics, thermosets, synthetic and natural rubbers, composites, and metallics.

Although ISO 10993 has specific test guidelines based on use classifications, the most important part is stated as follows:

The biological evaluation should be planned and carried out by knowledgeable and experienced individuals capable of making informed decisions based on the advantages and disadvantages of the various materials and test procedures available.

Without knowing the details of the composition and testing of the materials, making informed decisions is difficult. In most cases, the raw material supplier must make some concessions regarding the proprietary technology behind its products or materials to assist device manufacturers.
FDA recognized the dilemma that raw material suppliers face in qualifying their products into medical devices versus protecting its intellectual property. The agency created a provision for submission of device master files (MAFs). The Guidance on Scientific and Technical Information states the following about MAFs:²

A premarket approval (PMA) application or an investigational device exemption (IDE) application usually contains data and other information that the applicant has developed and regards as trade secret or confidential commercial financial information. Often the applicant needs to use another party's product (e.g., ingredient, subassembly, or accessory) or facility in the manufacture of the device. In order that a sound scientific evaluation may be made of the PMA, IDE, or other device submission, the review of data and other information related to the other party's product, facility, or manufacturing procedures is required. The other party, while willing to allow FDA's confidential review of this information, may not want the IDE, premarket notification [510(k)], or PMA applicant to have direct access to the information. To help preserve the trade secrets of the ancillary medical device industry and at the same time facilitate the sound scientific evaluation of medical devices, FDA established the device master file system. In addition, a master file may be considered when several applications may be submitted for different products which may use a common material or process, etc., such as the same sterilization method.
Device Manufacturer versus Materials Supplier

The difference between a medical device manufacturer and a component materials supplier must be well understood. Under the Medical Device Amendments of 1976, as now defined in 21 CFR Part 820, medical devices are articles intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body but which do not create their effect by chemical or metabolic action. This definition often excludes raw material and some component suppliers. Such exclusion changes the way suppliers, medical device manufacturers, and the regulatory agencies interact.
MAFs are only accepted from those organizations or persons who have not submitted or will not directly submit the information in a PMA, IDE, 510(k), or other device-related submission to FDA.
When a device manufacturer must supply supporting data on the raw material components, it has different options. It can run extensive chemical tests to identify and toxicologically assess each potentially extractable component and its pharmacokinetic fate. It can also rely on its raw material supplier, which is usually much more adept at knowing the actual chemical risk. The raw material supplier provides such information to the device manufacturer for confidential submission to FDA or other regulatory bodies. Ideally, all suppliers of raw materials for critical medical devices should be able to provide MAFs for such purposes. This is true for most Class I, II, and III medical devices that incorporate a wide range of fluid, thermoplastic, elastomeric, and metallic materials.
Many suppliers of raw materials for medical devices have already assembled the toxicology assessment information for device manufacturers to use. Some make this information public whereas others only submit it in the form of an MAF to FDA or other regulatory body. There are now more than 1500 MAFs registered with FDA.

Although the Biomaterials Access Assurance Act of 1998 gives some legal protection to raw material suppliers, there are still risks.³ Before a device manufacturer chooses a raw material and supplier, it should know about the supplier's quality system and supporting data. If a raw material supplier is unwilling or unable to provide such data, a combination of the device design, cost of independent testing, and business risk must be carefully assessed.
Since the controversy in the 1990s regarding the chemical toxicity of silicone in breast implants, FDA and other regulatory agencies have steadily raised the bar for evaluating the biological safety of silicones incorporated into medical devices. In the past, FDA recognized medical-grade silicones as generally safe, and it received little scrutiny as late as 1994.^4,5 In the case of medical devices incorporating silicone, FDA has now developed more-specific guidelines and criteria for assessing safety and efficacy, particularly (but not excluding) guidelines for long-term breast implants.⁶ However, not all Class I and Class II devices require such extensive testing. Although there is a tremendous library of scientific information on many silicone materials and applications, FDA demands that a device manufacturer complete a specific risk-analysis assessment of the silicone incorporated into its device. The technology and skill to do this is highly specialized, and most device manufacturers cannot justify developing it for their applications. Therefore, cooperation from raw material suppliers to supply MAFs becomes critical.

If a device manufacturer were to submit its product's extensive chemical formulation and the supporting toxicological data as a part of its PMA, IDE, or 510(k) submission, FDA might make such information public under the Freedom of Information Act. Implantable-grade silicone manufacturers typically regard this information as highly proprietary and do not want it to fall into the public domain for use by competitors. Although there are exceptions, information provided through an MAF to FDA on the safety of medical device materials is regarded as confidential and proprietary and is not made publicly available. As an example, a long-term implantable silicone device manufacturer should be prepared to offer information, directly or indirectly, through an MAF on several factors (see the sidebar, “Information Manufacturers Should Submit through an MAF”).
Suppliers of silicone for medical devices typically have performed the tests referred to in the sidebar. They have refined the methodology and reporting in the MAFs to be useful in connecting the data in the MAF to the risk assessment of the finished medical device. For data to be useful, the device manufacturer must demonstrate that the silicone in its medical device is essentially the same as the materials tested and reported in the MAF. Factors that might make the finished device different from the sample tested can include the following:
•Cure cycle.•Contamination during processing.•Damage from gamma or dry-heat sterilization.•Leaching of components adjacent to the silicone in the device and packaging.•In vivo exposure factors such as high acidity or Candida albicans flora.•Fragmentation failure.•Cyclic fatigue.•Iatrogenic damage.•Sudden trauma failure.
Connecting Raw Material Supplier Data to a Medical Device
The art of successfully using an MAF involves connecting the data reported to the risk assessment of the finished medical device. The underlying premise is that silicone, when used properly, is not intended to create its effect by chemical or metabolic action.

Suppliers of silicone raw materials for critical devices typically do not provide the device manufacturer unfettered access to such information. As a result, it is often advisable to hire a knowledgeable third-party consultant who has developed a rapport with the material supplier and has the combined expertise of understanding the contents of the MAF and the nature of the medical device application. This consultant may serve to dovetail the raw material supplier's preclinical information on safety with the device manufacturer's regulatory submission. Because the device manufacturer often cannot include a copy of the MAF with its submission, accurate reference page and paragraph lists must be prepared by the consultant in an acceptable manner for FDA or other regulatory body reviewers.

In the case of a PMA submission, it's important that the finished medical device manufacturer is notified of any changes to the MAF that may affect the material reference in the submission either during review or after approval.
If one can demonstrate that the molecular exposure potentials of the test protocols reported in the MAF are the same in the subject finished medical device, FDA typically accepts data in the MAF, possibly requesting a few verifying tests. Verifying tests can include the following:
•Pyrogenicity.•Cytotoxicity.•Hemocompatibility.•Gas chromatography–mass spectrometry of exhaustive hexane extraction.•Fourier transform infrared spectroscopy of extraction.•Heavy metals by induction plasma coupling.•Trace volatile per EPA 8260.
How to Use an MAF in Regulatory Submissions

The holder of the MAF, typically the raw material supplier, puts specific information on its letterhead and sends it to the device manufacturer, not to FDA. The device manufacturer will then include this authorization letter with its 510(k), IDE, PMA, or other submission to FDA. Then the agency can retrieve the registered copy from its archives and match the reference lists provided by the device manufacturer. For a sample document that includes the required elements, see the sidebar, “Using an MAF for a Regulatory Submission.”
Conclusion
FDA and many other regulatory bodies are adopting more-comprehensive criteria for approval of silicone medical devices. In many cases, the raw material supplier has confidential archive data on preclinical chemical and biological testing that are useful to support safety and efficacy of medical devices. However, raw material suppliers may only have proprietary information on its material referenced in a drug master file. In that instance, the finished medical device manufacturer may need to request that the raw material supplier submit an MAF to FDA on the material that the finished device manufacturer is using. If a drug master file is the only reference, it can sometimes be difficult for the medical device reviewer to obtain access to the file, making the review of the regulatory submission difficult and potentially extending the submission review time.
The MAF is a good tool for raw material suppliers to provide confidential information to device manufacturers on the chemical and biological testing of its products. Once deposited with FDA or another regulatory body by the raw material supplier, the data in the MAF can be referenced by the device manufacturer while still maintaining the propriety and confidentiality of the raw material supplier's data.
Alastair Winn is president of Applied Silicone Corp. (Santa Paula, CA).
References

1.“Use of International Standard ISO 10993, ‘Biological Evaluation of Medical Devices, Part 1: Evaluation and Testing,” Blue Book Memorandum G95-1, Rockville, MD, FDA, CDRH, Office of Device Evaluation, May 1, 1995; available from Internet: www.fda.gov/cdrh/g951.html.

2.Guidance on Scientific and Technical Information, (Rockville, MD: FDA, CDRH); available from Internet: www.fda.gov/cdrh/dsma/pmaman/appdxc.html#P7_2.

3.R Campillo and K Costello, “Suppliers and the Biomaterials Act: A New Avenue for Protection?,” Medical Device & Diagnostic Industry 21, no. 11 (2000): 42.

4.A Winn, “Factors in Selecting Medical Silicones,” Medical Plastics and Biomaterials 3, no. 2 (1996): 16-19.

5.“Silicone Devices Affected by Withdrawal of Dow Corning Silastic Materials,” Federal Register, 58 FR:36207 (September 8, 1993).

6.Guidance for Industry and FDA Staff, Saline, Silicone Gel, and Alternative Breast Implants, (Rockville, MD: CDRH, FDA, November 2006); available from Internet: www.fda.gov/cdrh/ode/guidance/1239.pdf.

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