2016 polyethylene used in orthopedic devices; draft ......weight polyethylene used in orthopedic...

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May 11, 2016

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

RE: Docket No. FDA–2016–D–0363: Characterization of Ultrahigh Molecular Weight

Polyethylene Used in Orthopedic Devices; Draft Guidance for Industry and Food and

Drug Administration Staff; Availability

Dear Sir or Madam:

The Advanced Medical Technology Association (“AdvaMed”) is pleased to provide the

following comments on the Food and Drug Administration’s (FDA’s) draft guidance entitled

Characterization of Ultrahigh Molecular Weight Polyethylene Used in Orthopedic Devices.

The Advanced Medical Technology Association (AdvaMed) is the world’s largest trade

association representing medical device and diagnostics manufacturers. AdvaMed's member

companies produce the innovations that are transforming health care through earlier disease

detection, less invasive procedures and more effective treatments. AdvaMed has more than 400

member companies, ranging from the largest to the smallest medical technology innovators and

manufacturers. AdvaMed advocates for a legal, regulatory and economic environment that

advances global health care by assuring worldwide patient access to the benefits of medical

technology. The Association promotes policies that foster the highest ethical standards, rapid

product approvals, appropriate reimbursement, and access to international markets.

AdvaMed has both general and specific comments below.

General Comments

AdvaMed commends FDA for issuing new draft guidance to replace the existing draft guidance

Data Requirements for Ultrahigh Molecular Weight Polyethylene (UHWPE) Used in Orthopedic

Devices which was issued in March 1995. Given the many substantive requirements that are

embodied in the new draft guidance (as well as the existing draft guidance), it will be important

for FDA to finalize this draft guidance as promptly as possible.

We note that both ASTM F2759 – Standard Guide for Assessment of the Ultra High Molecular

Weight Polyethylene (UHMWPE) Used in Orthopedic and Spinal Devices and ASTM F2565 –

13 – Standard Guide for Extensively Irradiation-Crosslinked Ultra-High Molecular Weight

Polyethylene Fabricated Forms for Surgical Implant Applications exist and we recommend that

http://www.advamed.org/

Division of Dockets Management (HFA-305) Docket No. FDA–2016–D–0363

May 11, 2016

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FDA reference these standards in the final guidance. We also encourage FDA to participate in

the ASTM process to update ASTM F2759, particularly as it relates to the addition of alternative

antioxidant polyethylene (AOPE) materials.

If you have questions about any of the proposed edits to the draft guidance we recommend

below, I would be pleased to convene the AdvaMed member company UHMWPE experts that

helped develop these comments to facilitate an interactive dialogue with FDA’s UHMWPE

experts.

Specific Comments AdvaMed’s specific comments on the draft guidance are presented below in tabular form.

In closing, thank you for the opportunity to comment on the draft guidance Characterization of

Ultrahigh Molecular Weight Polyethylene Used in Orthopedic Devices.

Sincerely,

/s/

Tara Federici

Vice President

Technology & Regulatory Affairs

AdvaMed Comments on Draft Guidance for Industry and FDA Staff: Characterization of Ultrahigh Molecular Weight Polyethylene Used in Orthopedic Devices

5/11/2016 of 15 Docket No. FDA–2016–D–0363

Edit # ID # Change Reason

1 97

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99

Strike and add the following:

This guidance addresses the characterization and testing of orthopedic devices that use UHMWPE materials used in orthopedic devices. These materials include such as conventional and non-conventional UHMWPE, highly crosslinked UHMWPE, and highly crosslinked UHMWPE containing vitamin E antioxidants.

Testing of orthopedic devices is outside the scope of this guidance document per lines 128-129.

2 134

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139

Change title to the following: “III. Types of UHMWPE Materials used in Implantable Orthopedic Devices” Strike and add the following: There are currently three types of UHMWPE materials in wide-spread clinical use in orthopedics: conventional UHMWPE, highly crosslinked UHMWPE, and vitamin E containing highly crosslinked UHMWPE. A fourth type of UHMWPE, non-conventional UHMWPE, consists of any other UHMWPE material not currently in widespread use.

The UHMWPE materials used in implantable orthopedic devices may be organized into four general categories: conventional UHMWPE; highly crosslinked UHMWPE; antioxidant highly crosslinked UHMWPE and non-conventional UHWPE.

Clarification of intent for material in implantable devices, and simplification and organization.


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3 141

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145

Strike and replace the following: A. Conventional UHMWPE Conventional UHMWPE is made from UHMWPE powder and has been

exposed to a total radiation dose less than 40 kilograys (kGy). This material is

typically terminally sterilized by gamma radiation or by non-ionizing sterilization

methods.

This category covers UHMWPE materials that conform to ASTM F648 and

have been consolidated through processes involving heat and pressure

that may involve ram extrusion or compression molding into large forms,

or direct compression molding of an implantable device. These materials

may be annealed through thermal, mechanical or a combination of the

two means after consolidation to modify material properties. The

material in the final orthopedic device component form would be

packaged and then sterilized through a process that provides sterility

assurance (including but not limited to Ethylene Oxide, Gas Plasma, or

Gamma Irradiation (typically 40 kGy or less)).

The recommended change is to define the category of conventional polyethylene in more detail.

4 149

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150

Remove the following: “XLPE is made from UHMWPE powder that has been subjected to total doses of gamma and/or electron beam ionizing radiation….”

The UHMWPE powder is not exposed to radiation. Removal of the word “powder” from the definition will more accurately reflect the current process route.


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5 152 Add the following: Following crosslinking, the material is either thermally annealed, mechanically annealed, or both, to reduce free radicals or to modify mechanical properties.

Clarification.

6 157

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167

Rephrase Title to be:

C. Vitamin E Antioxidant Highly Crosslinked UHMWPE (AOPE) (VEPE)

Strike and add the following: VEPE is made from UHMWPE powder, has α-tocopherol (an isomer of Vitamin E) added to the material, and has been exposed to a radiation dose greater than 40 kGy. Antioxidants are typically added to the material in one of two ways, either by soaking UHMWPE in a solution containing the antioxidant or by blending the UHMWPE powder with the antioxidant prior to material consolidation. Similar to XLPE, following crosslinking, the material is either thermally annealed, mechanically annealed, or both, to reduce free radicals. Thermal annealing for this material is typically below the melting point, since elimination of all measurable free radicals is not needed to prevent material oxidation due to the presence of antioxidants.

Antioxidant highly crosslinked UHMWPE material may originate with

powder or consolidated form conforming to ASTM F648. A liquid or solid

phase antioxidant may be added to the UHMWPE powder or consolidated

form. The material may be thermally or mechanically annealed to modify

material properties. The material is processed (using, for example,

ionizing radiation) to create crosslinking (highly crosslinked materials

are generally achieved with radiation doses higher than 40 kGy) either in

the general consolidated form or in the final device form such as during

Clarification and accuracy of definition of antioxidant polyethylenes.


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terminal sterilization. The material in the final orthopedic device

component form would be packaged and then sterilized through a

process that provides sterility assurance (including but not limited to

Ethylene Oxide, Gas Plasma, or Gamma Irradiation).

7 169

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174

Add the following: D. Non-Conventional UHMWPE Non-conventional UHMWPE is a polyethylene material other than the three material types discussed above. Examples may include, but are not limited to, materials that are made from lower-molecular weight polyethylenes, including lower molecular weight UHWMPE’s that may or may not be extensively crosslinked, porous polyethylenes, or polyethylenes whose surfaces have been modified. These may or may not be stabilized with an antioxidant.

Revisions enable clear distinction from the other three material types and provide greater clarity on what this would entail.

8 180

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189

Add a new subtitle and move the bullets 2, 4, 5 and 6 to Section IV. Material Characterization, on line 253. Renumber following sections as appropriate. IV. Recommended Technical Information

These bullets apply to all UHMWPE and in its current location it appears only to apply to non-conventional UHMWPE.

9 181

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403

Add the following to Bullet 2 and move to Section IV (new Section V). C. at line 306 and renumber as appropriate:

Concentration and identification of antioxidant or other additives (in weight percent (wt.%) and parts per million (ppm) or as a Vitamin E index or equivalent.*

*Footnote: Oral, E, Neils, A, Muratoglu, OK. 2014. High vitamin E content, impact resistant UHMWPE blend without loss of wear resistance. J

The bullets were moved to applicable sections in order to more clearly define applicable requirements for specific materials. For bullet 2: The requirement in this line works well for blended technologies that have consistent vitamin E concentration throughout, but it does not consider diffused materials that may have a


5/11/2016 of 15 Docket No. FDA–2016–D–0363

Biomed Mater Res Part B 2014:00B:000–000.

Move bullet 4 to Section IV. B, C, and D., make the following changes and renumber as appropriate:

Radiation dose and type (e.g., gamma irradiation, electron beam, etc.) and dose or equivalent measure;

Move bullet 5 to Section IV. B, C and D, make the following changes and renumber as appropriate:

Time and temperature of all post-crosslinking consolidation thermal anneals treatments such as heating above the melting temperature of UHMWPE or annealing below the melt temperature (e.g., to reduce/eliminate free radicals, relieve internal stresses, homogenize dopant concentration, etc.);

Move bullet 6 to Section IV. B, C and D, add the following and renumber as appropriate:

Compression ratio of all mechanical anneals if applicable; and

slight gradient within the device. For bullet 4: Irradiation facilities may require different set doses in order to reach a specified crosslink density or TVI. As a result, an equivalent measure may be more meaningful than a dose setting. For bullet 5: Replace the term "anneal" with the more generic "treatment" as not all devices or raw material are annealed. Also provided more detail on the nature of the treatment. For bullet 6: not all materials undergo a mechanical anneal.

10

188 For the Terminal Sterilization method bullet, add a reference to the sterility guidance titled: “Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile: Guidance for Industry and Food and Drug Administration Staff.”

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm109897.pdf

Clarification requested.




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11 199

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209

Strike and add the following: For some of the properties, such as tensile properties, impact resistance, and density, it may be applicable to adopt minimum acceptance criteria are set forth in ASTM F648, “Standard Specification for Ultra-High-Molecular-Weight Polyethylene Powder and Fabricated Form for Surgical Implants” even for sterilized or highly crosslinked polyethylenes. If the material meets the acceptance criteria of ASTM F648, no additional information will typically be requested. However, if the material’s

properties are below the do not meet these acceptance criteria, then additional information should be provided. For example, for a 510(k), a comparison to a valid predicate device with a similar UHMWPE material (and properties) for the same intended use or a sound scientific rationale is recommended; for a de novo or PMA, a sound scientific rationale including supporting literature, clinical study results, etc. should be provided to support that the device is reasonably safe and effective; and for an HDE or IDE, adequate information to demonstrate the safety of the material for its intended use should be provided (e.g., literature, comparison to the control, animal studies, etc.).

The ASTM standard is specific to non-irradiated, non-sterilized raw material. The suggested changes make it clear that the intention for this section is to allow the use of the acceptance criteria in ASTM F648 as minimum requirements even for crosslinked polyethylene where the properties values are above the specified minimum. Where there are no standards, a comparison to a predicate or sound scientific rationale should be provided.

12 216

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217

Delete the following: For example, TVI should demonstrate that the radiation dose has been absorbed consistently throughout the sample.

Given current irradiation methods and research directions in poly, TVI is a bad example.


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13 217

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219

Strike and replace the following: OI testing should show levels of oxidation that are stable from pre- to post-accelerated aging and are not expected to adversely affect the material’s mechanical properties. Post-accelerated Aging Testing can include OI to characterize levels of oxidation pre- and post-accelerated aging, or material/device mechanical testing that demonstrates no adverse effect on product performance.

The requirement of stability from pre- to post-accelerated aging appears to be a higher bar than many of the UHMWPE products on the market today would meet (e.g., gamma-inert sterilized “conventional” poly and highly crosslinked, sub-melt annealed poly). Many clinically successful products on the market today are not capable of meeting the OI requirement as currently stated. The proposed change also affords flexibility for manufacturers to characterize and describe potential impacts on device performance.

14 222

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224

Make the following changes:

Finally, some of the properties, such as biaxial mechanical properties, fatigue crack propagation resistance and morphology (per Annex 2 of ASTM F648), and consolidation, are comparative in nature. When submitted in a 510(k), the results should be compared to a material used in a predicate device with the same intended use.

Clarification. This is also consistent with line 371 -372 of the draft guidance.

15 262 Add the following: Comparison of the total absorbed radiation dose (inclusive of terminal sterilization) to the dose of a legally marketed device with the same intended use;

To clarify that the total absorbed radiation dose includes terminal sterilization.


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16 266 Strike the following: Biaxial mechanical properties (ultimate load, ultimate displacement, work to failure);

The variability in the small punch test method makes it difficult to use and the relevant determination of properties can be detected through tensile testing.

17 267 Strike the following: Post- accelerated aging oxidation index throughout the sample testing

To be consistent with other proposed changes. In addition, the proposed change also affords flexibility for manufacturers to characterize and describe potential impacts on device performance.

18 293

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298

Strike the following: For materials annealed above the melting temperature, the free radical concentration should yield no detectable free radicals.

There are materials on the market today that are annealed below the melt temperature and have free radicals. Inclusion of this statement would preclude a substantial equivalence determination to these materials. Further this establishes a different standard for materials annealed above versus below the melt temperature.

19 306

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383

Strike and add the following (i.e., replace Vitamin E and/or VEPE each time it appears with Antioxidant UHMWPE or AOPE) on lines 306 to 313 : C. Vitamin E, Antioxidant Highly Crosslinked UHMWPE (VEPE) (AOPE) VEPE AOPE primarily differs from XLPE in that an antioxidant (Vitamin E, α-tocopherol) is added either before or after exposure to radiation and the material is not annealed above its melting temperature. In addition to the information that is requested for conventional UHMWPE in Section IV.A, and XLPE UHMWPE in Section IV.B., the following additional characterization

Replace "VEPE" with a more generic "AOPE" to include other antioxidants in clinical use or in the process of being reviewed for clinical use. This section describes a device level test which is outside the defined scope of the guidance in lines 128 – 129. To mirror the language of Annex 2 in ASTM F648.


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information should be provided to address specific concerns raised by the addition of Vitamin E antioxidants: Strike lines 330 to 367. Effect of antioxidant on the wear mechanism: α-tocopherol is a small molecule that can act as a plasticizer and may affect the mechanism by which the material wears. When submitting a 510(k), FDA recommends that you assess if the wear mechanism has been altered by characterizing the wear debris from wear testing of the new device and a legally marketed predicate device with the same intended use per ASTM F1877, “Standard Practice for Characterization of Particles.” In addition, wear testing under normal and abrasive wear conditions should be performed. An analysis of the wear surfaces in terms of type and extent of damage modes should also be provided. Alternatively, it may be possible to address this concern by supplying a scientific rationale comparing the antioxidant concentration, radiation dose, and radiation type (i.e., gamma or electron beam) to an antioxidant-containing predicate device.

When submitting a de novo, PMA, HDE, or IDE, FDA recommends that you assess if the wear mechanism has been altered by characterizing the wear debris from wear testing of the new device per ASTM F1877. In addition, wear testing of the new device under 344 normal and abrasive wear conditions, and an analysis comparing the type and extent of damage to the wear surfaces should be provided. The anticipated, or known, impact of the wear test results on device performance should be thoroughly discussed and supported with available literature and scientific rationale (e.g., comparison to the control, animal studies, etc.). The following current, FDA-recognized standards may be helpful when performing wear 351 testing: • ASTM F732 “Standard Test Method for Wear Testing of Polymeric Materials Used 353 in Total Joint Prostheses”

We have proposed revising Section C to address all antioxidants so Vitamin E should no longer be included.


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• ASTM F1714 “Standard Guide for Gravimetric Wear Assessment of Prosthetic Hip Designs in Simulator Devices” • ASTM F2423 “Standard Guide for Functional, Kinematic, and Wear Assessment of Total Disc Prostheses” • ISO 14242 “Implants for surgery -- Wear of total hip joint prostheses” • ISO 14243 “Implants for surgery -- Wear of total knee joint prostheses” • ISO 18192 “Implants for surgery -- Wear of total intervertebral spinal disc 361 prostheses” Please refer to FDA’s consensus standards database (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm) to identify the most current version of the standard recognized by FDA, as well as the extent of recognition. On line 371, strike morphology and replace with consolidation In addition renumber Section 3 as 2 and strike the following on lines 380 – 383: The concerns discussed in this section may also apply to UHMWPE materials containing antioxidants other than α-tocopherol. If additional concerns not discussed above are identified based on the material characterization, additional information, such as obtaining clinical data, may be recommended to mitigate these concerns. Renumber as appropriate and add a new sentence on line 369: 3. Biocompatibility must be evaluated per the requirements in Sec. V, Biocompatibility.


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20 402

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403

Strike and add the following: Clinical data may be requested to support the safe and effective use of non-conventional 402 UHMWPE for its intended use.

If additional concerns not discussed above are identified based on the material characterization, additional information, such as obtaining clinical data, may be recommended to mitigate these concerns

To ensure uniformity and consistency of language.

21 430

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431

Remove the following: the pertinent joint of.

The most prominent osteolysis models in the literature utilize the mouse calvaria, not a joint, to simulate osteolysis. By eliminating the joint language and leaving it as “an appropriate animal model” there is more flexibility to use and justify multiple models that may not utilize the same joint intended for the finished final device.

22 444

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452

Strike and replace the following: VI. Shelf Life

FDA recommends that you do not package UHMWPE that has not been stabilized that has not been stabilized containing unstable free radicals in air-permeable packaging because shelf-aging may degrade the mechanical properties of UHMWPE. The shelf life of UHMWPE that has not been exposed to ionizing radiation, or that has been irradiated but packaged in inert environment, is limited by the integrity of the packaging material. VI. Stability and Shelf Life

The statement is inaccurate for UMHWPE product that has never been exposed to ionizing radiation.

The proposed language clarifies FDA’s potential concerns with UHMWPE stability over the course of the product’s shelf life.


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The mechanical properties of UHMWPE that contains unstable free radicals may degrade during shelf storage if the product is packaged with air-permeable materials. In addition, the shelf life of UHMWPE that has been irradiated and packaged in an inert environment may be limited by the integrity of the packaging material. Therefore, FDA recommends that the stability of UHMWPE materials used in implantable devices should be assessed for the duration of their shelf life.

23 500 Please add to the list: 872.3940 Total temporomandibular joint prosthesis

This product is also made with UHMWPE.

24 513 Strike the following: Post-accelerated Aging Testing Maximum Oxidation Index

To be consistent with edits # 13 and 17 which allows for functional testing.

25 513 Strike and add the following: Consolidation morphology testing

Morphology is more descriptive than consolidation, and to mirror the language of Annex 2 in ASTM F648.

26 513 Strike and replace: Uniform throughout sample N/A

Some products may be designed to intentionally have a gradient in TVI and crosslinking.

27 513 In the Acceptance Criteria column for tensile properties, impact resistance, and density, add the following:

ASTM F648 only covers conventional materials – it does not cover XLPE, AOPE or non-conventional UHMWPE.


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See ASTM F648 (for conventional only) and comparison to predicate and literature for XLPE and AOPE.

28 513 Change VEPE to AOPE in Table Header

To be consistent with previous edits.

29 515

Insert after “all-inclusive” the following: The characterization listed in the table above could be applicable to non-conventional UHMWPE.

Non-conventional UHMWPE should be included in the table.

2016 polyethylene used in orthopedic devices; draft ......weight polyethylene used in orthopedic...

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