7.

42 Regulatory Affairs
JM Hogan, M Kasser, and S Prem, Hogan Lovells LLP, Philadelphia, PA, United States
r 2017 Elsevier Ltd. All rights reserved.

7.42.1 Overview of Food and Drug Administration Regulation of Medical Devices 814
7.42.1.1 Classification System 814
7.42.1.2 Premarket Approval Pathways 815
7.42.1.2.1 510(k) Pathway and substantial equivalence 815
7.42.1.2.2 De novo reclassification 815
7.42.1.2.3 Premarket approval pathway 816
7.42.1.2.4 Humanitarian device exemption 817
7.42.1.2.5 Expedited access pathway 817
7.42.1.3 Master Files 818
7.42.2 FDA Regulatory Considerations for Biomaterials 819
7.42.2.1 Biocompatibility 819
7.42.2.2 Resorbable Materials 821
7.42.2.3 Material Changes 822
7.42.2.4 Combination Products 822
7.42.2.5 Products Incorporating Antimicrobial Materials 824
7.42.2.6 Animal-Derived Materials 824
7.42.2.7 Human Cellular and Tissue Materials 825
7.42.3 Emerging FDA Regulatory Issues in Biomaterials 826
7.42.3.1 Nanotechnology and Nanomaterials 826
7.42.3.2 Additive Manufacturing/3D Printing 827
7.42.3.3 Material-Specific Guidance 827
7.42.4 Summary and Conclusions 827
References 827

Abbreviations HDE Humanitarian device exemption

CDRH Center for Devices and Radiological Health ISO International Standards Organization
DSC Differential scanning calorimetry MAF Master file
EAP Expedited access pathway NSE Not substantially equivalent
FDA Food and Drug Administration OCP Office of combination products
FDAMA Food and Drug Administration PBS Phosphate-buffered saline
Modernization Act PHS Public health service
FD&C Food and Drug Cosmetic Act PMA Premarket approval
GLP Good laboratory practices PMOA Primary mode of action
GPC Gel permeation chromatography RFD Request for designation
HCT/P Human cellular/tissue product TRG Tissue reference group

Glossary irreversibly debilitating diseases or conditions that are subject

Center for Devices and Radiological Health
(CDRH) Branch of the U.S. Food and Drug
Administration (FDA) responsible for overseeing the
regulation and approval of medical devices.
Differential scanning calorimetry (DSC) Thermoanalytical
technique where the difference in the amount of heat
required to increase the temperature of a material sample and
reference is measured as a function of temperature.
Expedited access pathway (EAP) FDA’s voluntary program
for the expedited medical device premarket application review
for those medical devices that demonstrate the potential to
address unmet medical needs for life threatening or
to PMA approval or are eligible for de novo requests.
Food and Drug Administration (FDA) U.S. federal agency
responsible for protecting and promoting public health
through the regulation and supervision of medical device
and other health related products.
Food and Drug Administration Modernization Act
(FDAMA) U.S. law that enhanced FDA’s mission and
reformed the regulation of food, medical products, and
cosmetics.
Food and Drug Cosmetic Act (FD&C) Set of laws passed
by Congress, giving the U.S. Food and Drug Administration
authority to oversee the safety of food, drugs, and cosmetics.

Comprehensive Biomaterials II, Volume 7 doi:10.1016/B978-0-12-803581-8.09356-5 813

814 Regulatory Affairs

Gel permeation chromatography (GPC) Process that
separates analytes on the basis of size.
Good laboratory practices (GLP) Quality system of
management controls for research laboratories and
organizations to ensure uniformity, consistency, reliability,
reproducibility, quality, and integrity of data.
Human cellular/tissue product (HCT/P) Products that
contain human cellular and tissue materials.
Humanitarian device exemption (HDE) A device
designation for a product intended to benefit patients by
treating or diagnosing a disease or condition that affects or
is manifested in fewer than 4000 individuals in the United
States.
International Standards Organization (ISO) International
standard setting organization which consists of various
national standard organizations.
Master file (MAF) Set of documentation regarding a
specific material that contains proprietary data about the
material and manufacturing processes. The MAF is kept
confidential by the FDA.
Not substantially equivalent (NSE) The result of a
determination that a proposed medical device submitted
through FDA’s 510(k) process is NSE to the predicate device.
Office of combination products (OCP) FDA office that is
responsible in regulating the regulatory life cycle of
drug–device, drug–biologic, and device–biologic
combination products.
Phosphate-buffered saline (PBS) Buffer solution
commonly used in research.
Premarket approval (PMA) FDA approval process for
medical devices that present high risk, such as many
implants or life-sustaining devices that are typically
classified as Class III products.
Premarket notification (510(k)) FDA clearance pathway
for medical devices that are classified as Class II products
and present only intermediate risk.
Primary mode of action (PMOA) Is the single mode of
action of a combination product that provides the
most important therapeutic action of the combination
product.
Public health service (PHS) Government entity that
protects, promotes, and advances the health and safety of
the United States.
Request for designation (RFD) A submission process to
the FDA requesting Center assignment for a combination
product.
Tissue reference group (TRG) Cross-center unit within
FDA who is responsible for making jurisdictional
determinations for HCT/P products.

7.42.1 Overview of Food and Drug Administration Regulation of Medical Devices

While the selection of biomaterials for use in medical devices depends primarily on their functional requirements, regulatory
considerations also may impact biomaterial selection and significantly impact product testing. The U.S. Food and Drug Admin-
istration (FDA) is the federal government authority that is responsible for regulating medical products in the United States. Within
FDA, the Center for Devices and Radiological Health (CDRH) has responsibility for regulating medical devices. The FDA defines a
medical device as “[A]n instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or
related article, including any component, part, or accessory, which is intended for use in the diagnosis of disease or other
conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals.”1 Biomaterials are used in a
wide variety of products that meet this definition.
This section provides an overview of FDA regulation of medical devices. The risk-based approach used by FDA to classify
medical devices is discussed. In addition, the mechanisms for obtaining approval of a new medical device are reviewed. The
procedures by which biomaterial suppliers can support medical device submissions are also described.

7.42.1.1 Classification System

FDA regulates medical devices according to a risk-based classification system, in which low risk devices are subject to less
regulation and high risk devices are subject to more extensive regulation. According to this system, Class I medical devices are those
that present the lowest risk of harm to patients or users. Under the Food and Drug Cosmetic Act (FD&C),2 a medical device may be
marketed in the United States only with the FDA’s prior authorization, absent an exemption. Due to the low risk of harm
associated with Class I devices, the majority of these devices have been exempted from a requirement for FDA approval prior to
marketing. However, Class I devices must still comply with a number of post-market FDA requirements, known as “general
controls,” including manufacturing under appropriate quality control procedures, reporting of adverse events, and providing
accurate instructions for use.
Class II devices represent an intermediate level of risk. This class includes a wide range of products, ranging from orthopedic
implants to wound dressings. The majority of Class II devices require FDA clearance prior to marketing, while a small minority of
Class II products are also exempt from this requirement. All Class II devices are also subject to the same general controls as Class I
devices, as discussed above.
Finally, Class III devices include high risk products, life-sustaining, life-supporting, or implantable devices, as well as many
“first of a kind” devices. Class III devices require FDA approval prior to marketing, and the majority of Class III products also
require clinical testing in human subjects to support their approval, as well as compliance with the same general controls that are
applicable to Class I and Class II devices.
 Regulatory Affairs 815

FDA has established an extensive body of regulations that classify many types of medical devices into one of the above
classifications. However, completely novel products that do not fall into any established classification default into Class III. Use of
novel biomaterials may present sufficient novelty that a product may be classified in Class III, while use of more established
biomaterials may result in a lower classification and lower regulatory burden. This may, in turn, impact the mechanism, timing
and cost to obtain regulatory approval, as discussed below.

7.42.1.2 Premarket Approval Pathways

There are multiple pathways to obtain FDA clearance of medical devices, depending on their classification and, consequently, the
level of risk they present and their degree of novelty. In general, products that are the most novel or present the highest risk are
required to undergo the most rigorous testing and the most comprehensive FDA review prior to clearance. Each of the available
mechanisms for medical device clearance is described below.

7.42.1.2.1 510(k) Pathway and substantial equivalence

For devices that are classified in Class II and present only intermediate risk, FDA clearance is typically via a mechanism known as
the 510(k) pathway. Clearance of a 510(k) submission is based on establishing “substantial equivalence” to another device that
has already received 510(k) clearance, known as a “predicate device.” FDA has issued a detailed framework to assist agency
reviewers in determining whether a new device meets the standard of substantial equivalence and, thus, may be cleared via the
510(k) notification process.3 According to this framework, the first question that FDA will ask in making a substantial equivalence
decision is whether the device has the same intended use as the predicate product(s). If the intended use differs, FDA’s analysis
stops, and the device is deemed “not substantially equivalent” (NSE).
If a new device is determined to have the same intended use as a predicate product, the next question that the FDA asks in the
substantial equivalence evaluation is whether the new device has the same technological characteristics, such as design, materials,
and energy sources, as the predicate device. If the characteristics are the same or very similar, then the device may be found
substantially equivalent. However, if there are new characteristics, the FDA considers whether these characteristics could affect
safety or effectiveness and, if so, whether they raise different types of safety or effectiveness questions. If the new technological
characteristics raise different types of safety or effectiveness issues compared to the predicates, the device will be found NSE. If the
device does not raise any different questions of safety or effectiveness compared to the predicate, it may be found substantially
equivalent if accepted scientific methods exist to assess the effects of the different or new characteristics, and if data are available to
demonstrate that the new characteristics do not impact safety or effectiveness. Most 510(k) notices are cleared by FDA without the
need for human clinical testing. Thus, testing typically involves material characterization, strength testing, biocompatibility
evaluation, and in some cases animal testing.
As illustrated by the above criteria, use of novel biomaterials may impact the FDA’s determination of whether a product may be
cleared via the 510(k) pathway. For example, use of biomaterials that are bioabsorbable may raise new types of safety or effectiveness
issues if previous products used only nonabsorbable materials. FDA has broad discretion in these instances to determine whether a
510(k) may be granted with appropriate supporting data or whether another more stringent approval mechanism is required.
The type and amount of data that must be included in a 510(k) notice varies depending on the type of product, the material
used, the intended use, and the extent of new technological features. The use of specialized or novel materials may significantly
impact the nature and extent of data requirements. For example, materials used in a device that are of animal origin (eg, collagen)
may require detailed information and testing on the animal source, country of origin, animal health monitoring, viral inactivation
studies and processing information, as described in FDA guidance.4 Other novel or specialized materials may also require
additional testing, as discussed in Section 7.42.2 below.
The 510(k) pathway is the most frequently used of all FDA device approval mechanisms, with approximately 3000–4000 510(k)s
cleared annually. Because 510(k) notices vary significantly in terms of their complexity and the amount of supporting data required,
review times by FDA may also significantly vary. The average times for review of 510(k)s in past years are shown in Fig. 1.5
Once a 510(k) has been cleared, as explained in more detail in Section 7.42.2.3, if a firm makes any changes to the materials of
the device, FDA may require submission of a new 510(k) notice. In general, changes that significantly impact the indications for
use or technological features of the device trigger the need for a new 510(k) notice. FDA has issued draft guidance describing in
more detail the types of modifications that are “significant” entitled, “Deciding When to Submit a 510(k) for a Change to an
Existing Device.”6 With respect to material changes, FDA considers questions such as whether the change in material is a
formulation, chemical composition, or material processing change and whether the changed material will directly or indirectly
contact body tissues or fluids. Thus, selection of device biomaterials is important not only at the time of an initial 510(k)
submission, but also over the life of the product, in determining what FDA regulatory requirements may apply.

7.42.1.2.2 De novo reclassification

If a device is novel with respect to its intended use or technology but presents no more than moderate risk, it may be eligible for
“de novo” classification by FDA. The de novo classification pathway was created under a statutory provision enacted in the Food
and Drug Administration Modernization Act of 1997 (FDAMA).7 In this process, FDA creates a new regulation to address the
specific device type.
816 Regulatory Affairs

Fig. 1 510(k) Review times. FDA, Food and Drug Administration; FY, fiscal year; NSE, not substantially equivalent; SE, substantially equivalent.

Submissions utilizing the de novo pathway are typically supported by clinical data. In addition, where new materials are
involved, or where materials are being used for the first time in a particular application or body site, extensive material char-
acterization and safety testing are typically required. FDA also implements additional controls, known as “special controls,” as part
of the de novo classification process. Some of these controls typically relate specifically to biomaterials. For example, as part of the
de novo classification of an absorbable spacer to shield tissue during radiation treatment, FDA implemented special controls to
demonstrate that the material was biocompatible and radiation-stable.8
Because of the more extensive data requirements for de novo submissions compared to 510(k) notices, and the relatively
infrequent use of this approval mechanism, the review times are significantly longer, currently over 400 days (Fig. 2). Typically, less
than 30 de novo submissions are cleared by FDA annually, although the mechanism has been used for a number of products
incorporating novel materials. For example, the de novo classification mechanism was used for the first absorbable poly
(hydroxybutyrate) surgical suture produced by recombinant DNA technology.9 Even though FDA has cleared a variety of suture
materials, the novelty of the recombinant DNA technology was deemed by FDA sufficient to require a de novo pathway rather than
a traditional 510(k) pathway. Similarly, the first wound dressing incorporating poly(diallyl dimethyl ammonium chloride)
(pDADMAC) additive to minimize contamination of the dressing also required a de novo pathway rather than traditional 510(k)
clearance.10 Thus, the use of either novel primary biomaterials or additives may significantly impact the FDA regulatory pathway
that is followed, as well as the time required to obtain FDA clearance.

7.42.1.2.3 Premarket approval pathway

Medical devices that present high risk, such as many implants or life-sustaining devices are typically classified in Class III. These
devices generally are not eligible for the 510(k) or de novo classification pathways and typically require approval via the most
rigorous FDA approval mechanism, known as a premarket approval (PMA) application. PMA approval requires that the safety and
effectiveness of the device be established with valid scientific evidence. Virtually all PMA applications require clinical testing.
Although the size of the clinical study population required to support approval varies widely, typically studies of several hundred
subjects may be required. The amount of clinical data required to support a PMA application is often greater than the amount of
data required to support a 510(k) or de novo application.
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Fig. 2 Mean de novo review time, 2006–2016*. *2016 data through August.

In addition, PMA applications may require continued follow-up of the patient population for multiple years, even after
approval is obtained. This is particularly likely in cases where new materials are involved, as FDA may require long-term data to
assess material durability or later-arising biological responses. In some instances, FDA has required long-term follow-up of up to
10 years post-approval to assess the effects of new materials.11
PMA submissions are typically more extensive than 510(k) notices, although 510(k) notices or de novo submissions requiring
clinical data can near the complexity of a PMA. Approval of a PMA also requires detailed information on the sponsor’s manu-
facturing and quality procedures, along with a pre-approval inspection of the sponsor’s manufacturing facilities by FDA, neither of
which is required for 510(k) clearance or de novo reclassification. In addition, PMA submissions require extensive and detailed
material information. PMA applications may also require review by an Advisory Panel, a committee of independent scientific
experts outside of the FDA; Advisory Panel review has in the past often been required to assess the first use of a new material, or use
of a material in a new medical device application.12
The timeframe for FDA review of PMA applications is considerably longer than review times for a routine 510(k) notice, with
review times typically averaging approximately a year (see Fig. 3).5 Like de novo applications, PMA applications are much less
common than 510(k) notices, with approximately 30–40 PMA applications approved per year.
Once a PMA is approved by FDA, an applicant must submit a PMA supplement for review and approval prior to implementing
a new indication for use of a device, any labeling changes, a manufacturing site change, process, sterilization, or packaging change,
changes in sterilization procedures, changes in packaging, shelf-life changes, changes in performance or design specification,
including any sort of material changes. Detailed documentation is required to demonstrate that the change does not impact the
safety and effectiveness of the device prior to commercial distribution.

7.42.1.2.4 Humanitarian device exemption

An additional approval mechanism known as a humanitarian device exemption (HDE) is available for devices that are intended
for patients with rare disease, defined to include treatment and diagnosis of diseases or conditions that affect fewer than 4000
individuals annually in the United States.13 The HDE essentially is an alternative to a PMA pathway but with a lower threshold for
approval. While a PMA application requires proof of safety and effectiveness, an HDE requires proof of safety and probable
benefit. This difference in the standard for approval typically allows HDEs to be approved with smaller supporting clinical studies,
often on the order of dozens of patients compared to the hundreds of patients typically required for PMA approval.14 The review
period for HDEs is also shorter than for PMA applications. However, there are restrictions in using the HDE process, such as that
the devices cannot be sold for profit unless intended for use in the pediatric population. Manufacturers are only allowed to sell
HDE approved devices at a cost that allows them to recoup their research, development, fabrication, and distribution costs. In
addition, HDE approved devices can only be used in a facility after an Institutional Review Board (IRB) has approved their use in
that facility, except in certain emergency situations. In addition, the manufacturer must maintain records of correspondence with
IRBs and the names and addresses of the facilities to which the HDE approved product was shipped.
FDA will review the HDE application and make a determination of approval, approvable, or not approvable within 75 days of
receipt of the application.15

7.42.1.2.5 Expedited access pathway

The expedited access pathway (EAP) program is a voluntary program for certain medical devices that demonstrate the potential
to address unmet medical needs for life threatening or irreversibly debilitating diseases or conditions that are subject to PMA
approval or are eligible for de novo requests. The EAP program was created by FDA through its guidance document entitled,
818 Regulatory Affairs

Fig. 3 Premarket approval (PMA) review times. FDA, Food and Drug Administration; FY, fiscal year; MDUFA, Medical Device User Fee
Amendments.

“Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or
Irreversibly Debilitating Diseases or Conditions” (April 13, 2015) (EAP Guidance).16 The goal of EAP is to reduce the time and cost
from development to marketing decision without changing the standards associated with the PMA approval process or de novo
request process. Components of the program include priority review, more interactive review, senior management involvement,
and assignment of a case manager.

7.42.1.3 Master Files

As previously mentioned, as part of the review of a PMA, 510(k), de novo or HDE submissions, FDA must be provided with
detailed product and material information, some of which may be considered proprietary, such as material specifications, test
results, and manufacturing process flows. In addition, many medical device manufacturers use contract manufacturers to fulfill
product component and raw material needs. The subcontractor may be willing to provide the proprietary information to FDA for
their review, but may otherwise wish to maintain confidentiality of the product or material. Therefore, FDA developed the device
master file (MAF) system to help preserve trade secrets and at the same time facilitate a detailed scientific evaluation of the
proposed medical device, including its materials.
Although there are no specific content requirements, an MAF for a specific biomaterial typically contains proprietary data about
the material and manufacturing processes. FDA will not accept a MAF if it does not contain substantive information that would be
regarded as a trade secret or confidential commercial or financial information.
A MAF may also include test data such as biocompatibility, physical strength, animal testing, etc. In many cases, these tests may
be performed on materials formed into simple geometries. A manufacturer who wishes to leverage this type of testing may need to
supplement it with additional testing on the material as manufactured into a specific, finished medical device. Nonetheless,
availability of a MAF for a material can help to reduce the amount of testing that a device manufacturer is required to perform, and
thereby to accelerate product approval. Providing a detailed MAF can therefore offer a material supplier competitive advantage.
Applicants that receive permission from the MAF holder may reference the associated MAF in their FDA submissions, thereby
allowing the FDA to review detailed material information without allowing the applicant direct access to the proprietary
 Regulatory Affairs 819

information. The MAF holder must authorize the use of the MAF by providing a letter on the MAF holder’s letterhead authorizing
such use. This letter is then provided to the applicant for inclusion in their regulatory submission.
The proprietary information contained within an MAF is kept confidential by the FDA. MAF holders should clearly delineate
the information in the MAF that is regarded as trade secret and/or confidential.

7.42.2 FDA Regulatory Considerations for Biomaterials

In general, all biomaterials have two primary concerns that are evaluated by FDA, their biocompatibility and the adequacy of the
material and mechanical properties to meet the clinical needs throughout the life of the device. While the biocompatibility
requirements do not typically vary widely from device to device, their material and mechanical requirements often do. Accord-
ingly, while FDA certainly reviews medical devices that are made from biomaterials, they do not approve specific materials, as the
appropriateness of a material also depends on the intended use of the device in which it will be used. This section initially
discusses FDA’s general approach to establishing the biocompatibility of a material as it is common to all patient contacting
devices. Given the situation-specific nature of material and mechanical property requirements, they are not suited for the general
discussion of this article. However, there are consistent issues that arise for resorbable materials, which are also addressed. This
section closes with FDA’s current thinking related to post-marketing modifications to the materials and when FDA would need to
approve such changes prior to their implementation.

7.42.2.1 Biocompatibility
FDA strongly relies on international standards to define testing requirements and methods. With respect to biocompatibility, an
international standard, International Standards Organization (ISO) 10993, specifies in detail biocompatibility testing require-
ments for medical devices, as well as standardized methods for conducting those tests. FDA has recently published draft guidance
regarding the Agency’s interpretation and application of the ISO 10993 standard, titled “Use of International Standard ISO 10993-
1,” “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process,” published on
June 16, 2016.17 The guidance describes the types of testing FDA believes should be considered depending on the
nature and duration of the device’s contact with the body. As can be seen from Fig. 4, the supporting information that FDA request
is dependent upon the contact category, which tissue is being contacted, and contact duration. There are three contact categories,
surface devices that reside completely outside the body, external communicating devices that communicate from outside
to inside the body, and implants. External communicating devices include indirect contact, such as tubing to a needle that contacts
blood which is then infused into the body. Contact duration is divided into limited (less than 24 h), prolonged (one to 30 days),
and permanent (greater than 30 days). As expected, greater amounts of supporting evidence are needed for longer contact
durations.
In general, FDA requires that biocompatibility testing be performed on the final, finished part. This means that the device
should be in its final production form and subjected to sterilization. The reason for this requirement is that FDA rightly believes
that various changes can happen to a material during its manufacture (such as degradation during injection molding) and
sterilization (such as absorption of sterilant residuals). It is, on occasion, possible to convince FDA to accept testing on nonfinal
parts, but a robust scientific rationale to support that any differences between the final part and the tested part could not affect
biocompatibility is needed. For example, FDA is unlikely to accept biocompatibility testing of powder used to mold a finished
part, but is likely to accept testing of a non-gamma sterilized metallic implant, as gamma sterilization is known to not affect the
biocompatibility of the metal.
All patient contacting materials, regardless of contact category, type, or duration typically require cytotoxicity, sensitization, and
irritation or intracutaneous reactivity testing. Cytotoxicity testing is performed per ISO 10993-5 on material extracts using both
polar and nonpolar solvents. Sensitization and irritation testing is performed per ISO 10993-10 and typically uses the guinea pig
maximization test.
All blood contacting materials generally require hemocompatibility testing to ensure that they do not lead to, for example,
blood cell lysis or clotting. Indirectly contacting materials typically require only hemolysis testing, per American Society for Testing
and Material (ASTM) F756, while materials in direct contact with blood should also assess the complement activation, per ASTM
F1984. Thrombogenicity testing is needed for novel materials that do not have a history of use in contact with blood.
Material-mediated pyrogenicity is not required unless the company wishes to label the device as non-pyrogenic. If such labeling
is being sought, FDA is likely to require that both United States Pharmacopeial (USP) 34o1514rabbit pyrogen test and the
bacterial endotoxin test (per American National Standards Institute/Association for the Advancement of Medical Instrumentation
(ANSI/AAMI) ST72:2011 with a 20 European Union (EU)/device limit) be performed.
Per ISO 10993-6, implantation studies should attempt to place the finished material in a clinically relevant location, although
muscle implantation studies may serve instead or be additionally required. It is often possible to leverage an animal study being
performed for a different reason (such as demonstrating bone ingrowth, or a functional animal model) to determine the local
biological response so long as the right end points are additionally measured. Often, the device needs to be modified from its final
form to fit into the animal. Any such modifications should be accompanied with a scientific rationale why the modifications do
not affect the biological response. These studies are typically designed with sufficient animals to collect both a short-term and
820 Regulatory Affairs

Fig. 4 Summary of Food and Drug Administration (FDA) biocompatibility testing considerations. O ¼Additional tests for consideration;
X¼ Recommended tests.

long-term data. Like all animal studies, FDA expects these studies to conform to good laboratory practices (GLP), and non-
conforming studies are unlikely to be accepted unless a sufficient rationale why the areas where there is a lack of GLP conformance
does not undermine the scientific validity of the study supplied.
Although ISO 10993-1 allows for scientific rationale to justify why a single genotoxicity test is adequate for established
materials, FDA is likely to insist that all three tests be performed, even for nonnovel materials. These three tests are bacterial gene
mutation assay, such as the Organisation for Economic Co-Operation and Development (OECD) 471 bacterial reverse mutation
test, an in vitro mammalian assay, such as OECD 476 mouse lymphoma gene mutation assay, and an in vivo cytogenetics assay,
such as OECD 487 bone marrow micronucleus assay.
For the tests that FDA asks should be considered (ie, the circles in Fig. 4), it is typically acceptable to provide a toxicological
rationale why the extracts from the material do not present a risk that would require additional testing. In general, FDA recom-
mends following ISO 10993-12 to standardize extraction sample preparation. Standard extraction temperatures and times
recommended in ISO 10993-12 are adequate for most devices aside from permanent implants. Extraction for permanent implants
should be performed in polar, semi-polar, and nonpolar solvents for an adequate time and temperatures to be considered
exhaustive, but that do not artificially degrade the test article. The extracts are then examined by multiple methods, typically liquid
chromatography–mass spectrometry (LCMS) and gas chromatography–mass spectrometry (GCMS), to identify and quantify the
 Regulatory Affairs 821

leachable from the material. A toxicologist then performs a safety assessment based off of known information of the identified
leachable to justify why additional tests are not needed.
Reproductive and developmental toxicity need only be addressed for novel materials, materials with a known reproductive or
developmental toxicity, devices with relevant target populations (eg, pregnant women), and/or devices where there is the prob-
ability for local presence of device materials in the reproductive organs. It is likely worthwhile to discuss what the expectations for
such testing would be for materials presenting these risks.
The biocompatibility considerations for resorbable materials are discussed in the next section.
Importantly, if the contact category, the tissue being contacted, and contact duration does not require additional or different
tests, biocompatibility information that has been used to support one device can typically be used to support a different device,
assuming FDA agrees that the two materials are identical. Thus, testing used to support bone screw can also be applied to a total
disk replacement. FDA’s interpretation of identical materials will be elucidated in the Section Material Changes below.

7.42.2.2 Resorbable Materials

As the properties of resorbable materials are designed to change over time, FDA requires that characterization and performance
tests be performed at various time points. In general, FDA wants the material to be fully characterized (to be able to compare the
device to future and previous marketing approvals and clearances), to know how long it takes the device to resorb, to understand
how mechanical properties degrade over time, and to assure the biocompatibility of the device throughout its performance life.
FDA has published guidance regarding the use of resorbable materials in medical devices, titled “Guidance Document for
Testing Biodegradable Polymer Implant Devices,” published on April 20, 1996.18 Because the guidance is 20 years old and newer
comprehensive guidance has not been issued, this guidance may not entirely represent all of FDA’s current thinking, but still
contains useful information.
The guidance contains a list of possible characterization testing for polymeric and resorbable materials. In general, the key
pieces of information FDA typically requires include the chemical composition and concentration of all constituents of the
material, the molecular weight of the material, as determined by gel permeation chromatography (GPC) or inherent viscosity, a
description of the manufacturing methods including use of additives and thermal treatments that can affect properties, and
thermal properties, as determined by differential scanning calorimetry (DSC). Essentially, FDA requires characterization of the
initial state of the material so that they can understand how these properties change during degradation. As most of these tests are
basic material characterization, so long as the same material is used, these tests do not need to be repeated for different devices
made from the same material. Accordingly, this type of information is well suited for FDA MAFs.
Characterizing how long it takes a resorbable device to degrade can be challenging as real-time degradation tests can be very
lengthy and accelerated methods may not be accurate. There are many factors that could affect a material’s degradation, such as
temperature, stresses, and exposure to in vivo chemicals and enzymes, and accelerating the degradation caused by these factors can
be challenging. Real-time degradation testing at body temperature (371C) in a physiological solution is typically required for all
degradable devices. The selection of physiological solution should be scientifically justified, but could be as simple as phosphate-
buffered saline (PBS), if appropriate. An additional real-time study arm under constant or dynamic stress may also need to be
considered, as the application of loads may alter and accelerate material degradation. It is generally prudent to conduct real-time
testing at least for the length of time the device must retain its strength and physical properties in clinical use. For example, a
bioabsorbable fracture fixation device should be tested to demonstrate that it will retain sufficient strength to hold the fracture
together until healing occurs, applying an appropriate safety factor to account for potential delays in healing in some patients. Vital
properties, such as mechanical strength and molecular weight, should be measured at key time points to characterize the
degradation profile over time.
Due to the slow degradation rates of many resorbable materials, accelerated testing is often required to fully degrade the device.
This typically involves increased temperature, stresses, and/or reactive chemical/enzyme concentrations. Such tests should be
conducted until the device fully degrades and then the degradation rates should be compared to those observed in the real-time
study to correlate accelerated degradation rates to real-time rates. However, as FDA believes that in vitro real-time testing is not
always predictive of in vivo degradation rates, a degradation study where the device is implanted in an animal is also typically
required. Typically, this animal study can also be used to address ISO 10993-6 implantation requirements. This study typically
does not need to be run until the device fully resorbs, but should be run until a steady-state biological response is achieved.
Measures of degradation at vital time points should be taken to correlate in vivo and in vitro degradation rates.
One of FDA’s key concerns for resorbable devices is that they maintain adequate mechanical strength until healing has enabled
off-loading of the device. FDA’s guidance document requests that the strength of the device continue to be assessed until it has
fallen to 20% of the original value. However, this request is impractical for many slow degrading materials, where this would
involve real-time testing for several years. In many instances, FDA will accept testing that demonstrates adequate mechanical
strength out to the expected healing time multiplied by some safety factor. For example, FDA typically requires suture anchors to
maintain adequate pull out strength out to 3 months, while tissue to bone healing is typically complete after 4–6 weeks.
Alternatively, it may be possible to accelerate age the device to degrade its properties in a reasonable amount of time.
In regards to biocompatibility, degradation information should be provided for any devices, device components, or materials
remaining in contact with tissue that are intended to degrade. The implantation test per ISO 10993-6 is typically sufficient to
demonstrate no local toxicity effects over the course of the implantation study. However, FDA is likely to want to understand the
822 Regulatory Affairs

degradation products and their concentrations throughout the entire device’s degradation. This information can often be obtained
from chemical analysis of the physiological solution used during the real-time and accelerated degradation study. One bio-
compatibility testing consideration that is specific to bioabsorbable materials is the conditions under which the material should be
prepared for testing; these issues may require direct consultation with FDA to ensure agreement on test methodology. Similar
considerations apply to materials that polymerize in situ. FDA recommends prior consultation for “when determining how to
prepare absorbable devices for biocompatibility testing (eg, unpolymerized, pre-polymerized, partially degraded, or fully degraded
test articles).”17
An additional concern that is key to resorbable devices is shelf-life testing. While such testing is required to demonstrate the
continued integrity of packaging to maintain sterility for all sterile-packaged devices, resorbable devices have the additional
concern of degradation of the device itself on the shelf. Thus, real-time and/or accelerated aging testing of the device itself is
needed to demonstrate that the device maintains adequate properties over its labeled shelf life.

7.42.2.3 Material Changes

The freedom that a company has to modify their device after marketing clearance or approval depends on the regulatory pathway.
Devices that are approved through the PMA pathway typically require a PMA supplement to be approved by FDA prior to
implementing any changes that impact safety or effectiveness. In contrast, devices granted via de novo petitions or cleared via
510(k) notifications can in some cases be modified without prior FDA clearance based on internal analysis and documentation,
provided that the changes do not significantly affect safety or efficacy. In practice, most material changes for PMA approved
products require supplemental approval, while some changes in materials for 510(k) cleared products may not require prior FDA
clearance, particularly for non-implanted devices.
FDA has recently published draft guidance to help companies understand how FDA interprets “could significantly affect safety
or efficacy” entitled, “Deciding When to Submit a 510(k) for a Change to an Existing Device,” published on August 8, 2016.6
Although only in draft, this guidance is likely indicative of current FDA thinking. The guidance contains several flowcharts, one of
which focuses on modifications to a device’s material, see Fig. 5. Question C2 asks, “Is this a change in material type, material
formulation, chemical composition, or the material’s processing?” In the guidance, FDA clarifies that this typically includes
changes of material manufacturer (even when the same material type, formulation, and chemical composition is being supplied)
or change made by the material supplier. Thus, it is clear that FDA interprets identical material very narrowly, and requires that
material type, material formulation, chemical composition, and material’s processing all remain the same.
However, while a change in material type, material formulation, chemical composition, or the material’s processing is con-
sidered a change to the material, it does not mean that a new 510(k) would be required for this change. Rather, the guidance
specifies that a new 510(k) is required only if new biocompatibility testing was needed to address risks created by this change.
There would be no need for additional testing if the altered material is not patient contacting (C3), does not generate new or
increased biocompatibility risks (C4), or, if such risks are generated, they are not already mitigated by testing previously reviewed
by the FDA for the same material (C4.1).
In addition to the biocompatibility risk created by a change in materials, such modifications should also be assessed if they
could affect performance specifications (C5). If they could, they are assessed as any other design change, which is addressed by
flowchart B of the same guidance. In general, design changes require a new 510(k) if the change significantly affects the use of the
device (change in use environment or user population), creates new or significantly modifies existing risks, requires clinical data, or
if the verification and validation testing to support the change generates unexpected results or needs to be significantly modified
from the previous version of the device.

7.42.2.4 Combination Products

Some products may be comprised of both drug and device constituents. FDA regulates these as combination products under 21
CFR § 3.2(e), which defines a combination product as:

A product comprised of two or more regulated components, ie, drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are
physically, chemically or otherwise combined or mixed and produced as a single entity.

A combination product’s “primary mode of action” (PMOA) determines which Center within FDA has primary regulatory
jurisdiction over the product. The other Centers within the agency may provide additional reviews of the product as necessary.
Review by the non-primary Center can be either collaborative, in which the lead Center needs the agreement of the secondary
Center in order to proceed, or consultative, in which the secondary Center serves in an advisory capacity but cannot veto the lead
Center’s determinations.
The PMOA for a combination product is defined as “the single mode of action of a combination product that provides the most
important therapeutic action of the combination product.”19
In the last 20 years, there has been an increase in the number of combination products, and an increase in the complexity and
overlapping mechanisms of action by which products may achieve their intended medical purpose. To address concerns
that additional guidance and organizational oversight were needed to clarify the collaborative or consultative involvement of
more than one FDA Center in the review of such products, in 2002, FDA established the Office of Combination Products (OCP).
 Regulatory Affairs 823

Fig. 5 Materials change flowchart.

One key function of OCP is to assign which Center has primary jurisdiction for review of both combination and single entity
(ie, non-combination) products where the jurisdiction is unclear or in dispute.
FDA regulations set forth a procedure for requesting assignment to the Center that the product manufacturer believes is best suited
to review and approve the product. A submission of this kind, as noted earlier, is referred to as a request for designation (RFD).20 The
RFD mechanism allows a company with a combination product where jurisdiction is not clear to describe which Center the company
believes should have regulatory jurisdiction. Within 60 days from the filing of the RFD, the agency will issue a "designation letter"
identifying which Center will regulate the product, and the reasoning for the determination. For many products, however, past FDA
precedent has already been established to determine jurisdictional assignment without the need for an RFD.
Biomaterials may often be used in combination with drug or biological ingredients. For example, a variety of drug-eluting stent
products have been approved by FDA, generally as combination products. Where the function of the stent was deemed primary,
these products have been primarily reviewed as devices. In other cases where the biomaterial was used, for example, as a delivery
vehicle for a drug, where the drug served the primary therapeutic purpose, these products have primarily been regulated as drugs.
824 Regulatory Affairs

7.42.2.5 Products Incorporating Antimicrobial Materials

Use of antimicrobials in medical devices raises specific issues such as the potential for an allergic response and the development of
antibiotic resistance. To address these issues, in 2007, FDA issued the draft guidance “Premarket Notification [510(k)] Submissions
for Medical Devices that Include Antimicrobial Agents” (July 19, 2007) (the Antimicrobial Guidance).21 The Antimicrobial
Guidance, when issued, expressed the agency’s current thinking on medical devices that include an antimicrobial agent. As
discussed further, below, FDA’s approach to regulating medical devices to which antimicrobial substances have been added has
evolved on a case-by-case basis since the issuance of the Antimicrobial Guidance. The document, nevertheless, helps provide a
useful point of reference with respect to the identification and definition of relevant areas of FDA concern.
According to the Antimicrobial Guidance, in the vast majority of situations where an antimicrobial agent is included in or on a
device, such agent will be considered a drug and the resulting product that includes the antimicrobial drug will be considered a
combination product. CDRH regulates many combination products containing antimicrobial drugs when the PMOA is that of a
device, such as antimicrobial coated catheters, wound dressings, etc.
Adding an antimicrobial agent to a medical device that received previous 510(k) clearance represents a significant modification
of the cleared device, and will generally require a new 510(k) submission.22 In the 510(k) notice, FDA will assess whether the
antimicrobial is the same as a previously cleared predicate. FDA considers a device with an antimicrobial agent to be the “same” if:
The antimicrobial agent, when compared to the predicate, has the same:

• Identity, formulation, and concentration.

• Method of application to the device (such as attachment, incorporation, or coating).
• Mechanism by which the agent is released from the device.
• The device that includes the antimicrobial agent has the same indication for use as compared to the predicate, including the
same anatomical site at which the product is to be used.
• The device has the same design characteristics (such as material, geometry, functions) as the predicate.
The degree to which the subject device is the “same” as the predicate dictates how much information the manufacturer will
need to supply in order to support substantial equivalence. As the degree of similarity lessens, more information will need to be
supplied in order to support substantial equivalence. While most product submissions involving addition of an antimicrobial
agent to an already 510(k)-cleared device have been cleared via the 510(k) pathway, if the modification raises new questions of
safety or efficacy, the 510(k) pathway may no longer be appropriate, and a de novo petition or PMA could be required. Clinical
testing may also be requested by FDA to support any of these regulatory pathways.
Among the key issues that may be raised with antimicrobial containing products, FDA has frequently focused on questions
relating to whether the antimicrobial agent is approved for use in the same anatomical location, whether it elutes from the device in
meaningful ways and over understood and defined time frames, whether the purpose of the antimicrobial component of the product
acts locally or systemically, or whether the primary purpose of the drug component is to treat infections or protect the device in some
fashion. In addition to these questions, and independent of the product jurisdictional questions, FDA also considers whether the
risks of adding an antimicrobial substance to a device (such as increased bacterial resistance or patient toxicity) are balanced by a
clinically demonstrated benefit (such as infection reduction, shortened hospitalization, reduced follow-up, etc.).

7.42.2.6 Animal-Derived Materials

In addition to bioabsorbable materials, FDA also has established a detailed and specific set of requirements for products that use
animal-derived materials. For example, many medical devices incorporate collagen derived from a variety of animal sources
(porcine, bovine, etc.). For these products, although standard FDA requirements for biocompatibility, mechanical integrity, etc.,
remain applicable, additional requirements are also applied, such as testing to ensure that the animal source material does not
transmit viruses to human recipients. These requirements are described below.
FDA has issued draft guidance, medical devices containing materials derived from animal sources (except for in vitro diagnostic
devices) Draft Guidance for Industry and FDA staff, which describes the Agency’s requirements for animal-derived materials.4 This
begins with control over the herd from which the animal material is sourced, including detailed documentation of the following:

• animal species;
• age of animal;
• specific tissue(s) used;
• animal country of origin and residence (more specific geographic location when appropriate);
• methods for monitoring the health of herd and the health of specific animals from which tissues are collected (eg, vaccinations
with live modified viruses that can co-purify in the desired tissue, active surveillance for human pathogens);
• the United States Department of Agriculture (USDA) status of the abattoir;
• methods and conditions for transporting animal tissue (eg, tissue refrigeration and quarantine); and
• procedures for maintaining records on the above.

FDA also generally requires testing to show that manufacturing methods are sufficient to reduce the risk of viral disease
transmission. Typically, these studies require testing of four different virus types (RNA, DNA, enveloped, non-enveloped) to
 Regulatory Affairs 825

demonstrate a minimum of a 6-log reduction in viral load. The guidance further details considerations related to transmissible
spongiform encephalopathy (TSE) and bovine spongiform encephalopathy (BSE).

7.42.2.7 Human Cellular and Tissue Materials

Section 361 of the Public Health Service (PHS) Act grants FDA the authority to prevent the introduction, transmission, or spread of
communicable disease.23 FDA in turn has developed regulations regarding human cellular and tissue products (HCT/P’s), to
prevent the potential spread of disease.24 For products that are human tissues as defined by statute and regulation, FDA does
not require approval prior to marketing. However, for products that are highly manipulated or are used for applications different
from their original function in the body, FDA may consider these as medical devices or biological products, not merely tissues.
Thus, in determining whether product approval is required, a key issue is whether the product meets the definition of an HCT/P,
which does not require prior FDA approval, versus a biologic, drug, or device, which do require prior approval. This is further
discussed below.
FDA defines an HCT/P as any article that contains or consists of human cells or tissues, intended for implantation, trans-
plantation, infusion, or transfer into a human recipient. FDA has provided the following examples of HCT/Ps: “bone, ligaments,
skin, dura mater, heart valves, corneas, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated
autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue.”25 FDA has explicitly
excluded from the definition of an HCT/P “secreted or extracted human products, such as milk, collagen, and cell factors.”26
HCT/P products can be regulated in many ways, depending upon the processing of the product and their intended use. If HCT/
Ps meet specific definitional requirements as to their degree of manipulation and specific, homologous uses, as defined in section
361 of the PHS Act, they are subject only to FDA’s cGTP regulations and do not require FDA premarket review (“361 HCT/P”).
If, however, these same products are more than minimally manipulated, intended for a “nonhomologous” use, are combined
with other articles, or are living cells that act systemically within the body, the product may be subject to additional regulation by
FDA, either as a drug, device, or biological product. Under FDA’s HCT/P regulatory framework, cells and tissues meeting the broad
definition of an HCT/P do not require PMA if they meet the following criteria:
1. The HCT/P is minimally manipulated.
2. The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manu-
facturer's objective intent.
3. The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water,
crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing,
preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P.
4. Either:
a. the HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary
function; or
b. the HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
i. is for autologous use;
ii. is for allogeneic use in a first-degree or second-degree blood relative; or
iii. is for reproductive use.27

FDA has issued guidance relating to the interpretation of “minimally manipulated.” In its “Draft Guidance for Industry and
Food and Drug Administration Staff: Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products”
(December 2014), FDA has described the agency’s current thinking on this topic.28 As defined in FDA’s regulations and reiterated
in the guidance, the term “minimal manipulation” is defined for structural tissue as any processing that does not alter the original
structural characteristics of the tissue relating to reconstruction, repair or replacement. Cutting, grinding, soaking in antibiotic
solutions, lyophilization, freezing, and demineralization of bone are methods that FDA has referenced as examples of minimal
structural tissue manipulation.29 Alternatively, several of these same processing steps, if they alter an original structural char-
acteristic of the tissue relative to its intended use, have been ruled to involve more than minimal manipulation by the tissue
reference group (TRG), which is the cross-Center unit within FDA responsible for making jurisdictional determinations for HCT/P
products.
For nonstructural (ie, living or biochemically active) cells and tissues, minimal manipulation is any processing that does not
alter the relevant biological characteristics. Processing steps routinely viewed by FDA as minimal manipulation for nonstructural
tissues include density gradient separation, nonspecific cell selection from nonliving tissues, and centrifugation. For example, one
processing method that FDA has referenced as an example of minimal manipulation for cells or nonstructural tissues is performing
cell selection on a mobilized peripheral blood apheresis product to obtain a higher concentration of hematopoietic stem/
progenitor cells for transplantation.30 Two examples of processing that FDA views as involving more than minimal manipulation
are cell expansion in culture and processing of human tissues by mechanical means to alter their basic functions (eg, chemical
crosslinking of purified, denatured human collagen for use as a cosmetic dermal filler).31 Of note, FDA views cellular products that
have systemic effects on recipients or that depend upon the metabolic activity of living cells as exceeding the HCT/P definition if
these cells are intended for allogeneic use in any recipient who is not a close relative (defined at 21 C.F.R. § 1271.10(a)(4)(ii)(b) as
any recipient other than a first or second-degree blood relative).
826 Regulatory Affairs

“Homologous use” is defined as any use involving replacement or supplementation of a recipient’s cells or tissues with HCT/Ps
that perform the same basic function(s) in the recipient that the original tissues performed in the donor. FDA has stated that
homologous use does not mean the HCT/P must be used in its native location or even in a homologous location.29 According to
FDA, the homologous use requirement guards against use of an HCT/Ps for an unproven therapeutic use, such as for treating
cancer, and thus FDA will interpret homologous use narrowly.29 Examples of homologous uses include the implantation of
hematopoietic stem cells for hematopoietic reconstitution, use of acellular human dermis as a burn covering, a gingival barrier, a
urethral sling, or as a supplemental wrap for repaired tendons.29 In each of these applications, FDA did not appear to focus on the
amount of HCT/P product being placed into the body, the specific location within the body that material could be placed, or the
physical condition or method of delivery in determining whether the use was or was not homologous. Rather, FDA’s determi-
nations that specific uses are homologous appear to have focused narrowly on the basic functions of the products claimed in the
product labeling or deduced from their marketing. In contrast, previous examples of nonhomologous use include use of cartilage
in the bladder.32
In summary, human cellular materials that are not more than minimally manipulated, are intended for homologous uses, and
are not combined with other articles (as described above) are subject to FDA regulation solely pursuant to 21 C.F.R. Part 1271.
Alternatively, “HCT/Ps that do not meet all of the criteria in 21 CFR 1271.10(a) are regulated as drugs, devices, and/or biological
products. These HCT/Ps are subject to the regulations in Part 1271, in addition to the regulations specific to drugs, biological
products, or medical devices.”33

7.42.3 Emerging FDA Regulatory Issues in Biomaterials

7.42.3.1 Nanotechnology and Nanomaterials

FDA has issued guidance describing products that use nanotechnology as “products that contain or are manufactured using
materials in the nanoscale range, as well as products that contain or are manufactured using certain materials that otherwise
exhibit related dimension-dependent properties or phenomena.”34 FDA recognizes that nanoscale materials may have altered
chemical, biological, or magnetic properties, altered electrical or optical activity, increased structural integrity, or other unique
characteristics. Therefore, the Agency has established an internal task force on the use of nanotechnology across all the products it
regulates, including not only medical devices, but also drugs, device, biologics, foods and cosmetics. FDA has also initiated
internal research programs to address nanotechnology and nanotoxicology considerations.
The FDA has established two key criteria to determine whether nanotechnology considerations are presented by new products
or materials:

• Whether a material or end product is engineered to have at least one external dimension, or an internal or surface structure, in
the nanoscale range (approximately 1 to 100 nm).
• Whether a material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties
or biological effects that are attributable to its dimension, even if these dimensions fall outside the nanoscale range, up to one
micrometer (1000 nm).

If a biomaterial is selected that presents either of the above characteristics, it may require additional testing and may trigger
more stringent biocompatibility evaluation.
FDA also held a public workshop in 201035 to discuss the use of nanomaterials and nanotechnology. Among the key questions
discussed at the panel were the following:

• What types of characterization methods should be used to establish key properties (ie, size, size distribution, shape (aspect
ratio), purity, composition, surface composition (reactivity), surface charge, surface area, agglomeration/aggregation state, and
degradation), and should multiple methods be used?
• In the case of nanomaterials or structures with additional surface ligands attached, what additional characterization parameters
are important to evaluate (eg, stability of ligand, completeness and consistency of surface coating, etc.)?
• How do accelerated versus real-time aging impact the characteristics of the final nanotechnology based product? How should
shelf life, stability, and lot to lot reproducibility should be tested and evaluated?
• How do sterilization and sterilization methods impact final nanotechnology based products?
• How does entoxin control and endotoxin testing differ for nanoscaled materials compared to standard materials? Should
different methods and/or endotoxin limits apply?
• How should the potential release of nanomaterials from a device be determined, and when is it necessary to collect information
on degradation, metabolism, absorption, distribution, and excretion of released or free nanomaterials for a device which
incorporates nanotechnology?
• How should standard biocompatibility test methods be modified for nanomaterials, particularly cytotoxicity, genotoxicity?

The above issues are relevant considerations for designers and material suppliers considering the use of nanoscale materials and
nanotechnology in medical devices. Because of the rapidly evolving nature of nanomaterials, any products involving their use are
likely to require more extensive FDA review and warrant earlier consultation with FDA to ensure appropriate testing methods are
followed.
 Regulatory Affairs 827

7.42.3.2 Additive Manufacturing/3D Printing

There has been rapid proliferation in the use of additive manufacturing/3D printing in production of medical devices. To address
the dynamic increase in the use of this technology, FDA released a draft in May 2016 guidance entitled, “Technical Considerations
for Additive Manufactured Devices.”36
One of the key advantages of 3D printing is the ability to produce devices with design features that are highly complex. 3D
printing can also be used to produce devices that are customized to individual patient anatomy, for example, orthopedic implants,
dental implants, etc.
These unique features of 3D printed products also raise some specific FDA regulatory considerations. For example, if a device’s
dimensions can be modified to fit individual patient anatomy, it is not clear what device “model” should be used as a worst case
for purposes of testing. The FDA guidance states that for this reason, in addition to standard testing requirements, products made
using 3D printing techniques should include evaluation of “worst-case combinations of dimensions and features (eg, holes,
supports, porous regions).” With respect to materials used in 3D printing, the guidance further states that “[a]ll sources of the
material should be identified. Material properties known to affect interlayer bonding should be characterized and should be
representative of the final finished device.” The guidance also addresses the software that may be used both in the design and build
of 3D manufactured products, which also present special regulatory requirements.
As in the case of other novel materials or manufacturing methods, products incorporating 3D manufacturing techniques may
warrant more upfront consultation with FDA. However, given that dozens of products have already been cleared by FDA using
additive manufacturing methods and the issuance of the guidance discussed above, the requirements for 3D printed products are
becoming increasingly clear over time.

7.42.3.3 Material-Specific Guidance

FDA in some instances issues material-specific guidance documents. For example, FDA recently issued a guidance entitled,
Characterization of Ultrahigh Molecular Weight Polyethylene (UHMWPE) Used in Orthopedic Devices; Draft Guidance for
Industry and FDA Staff (2016). This guidance reviews testing requirements for UHMWPE materials due to their importance in
load-bearing applications (eg, hip replacement), the recent changes in types of UHMWPE (eg, addition of vitamin E), and the
potential for wear or degradation to impact performance.
FDA has also issued guidance for materials that are used as coatings or additives to medical devices. For example, FDA recently
issued guidance on medical devices or combination products that incorporate heparin. Thus, in considering any biomaterial for
use in a medical device, it is important to assess whether any material-specific FDA guidance has been issued. In the absence of
specific guidance, the best sources of information are prior clearances of devices using similar materials, or alternatively, direct
consultation with FDA.

7.42.4 Summary and Conclusions

As described above, the FDA regulatory system for regulation of medical devices is designed to apply a level of control proportionate
to the level of risk presented. Biomaterials may impact the risks presented, and consequently can profoundly impact the FDA
regulatory classification, pathway to approval, and time and testing required to support approval. The use of specific types of
biomaterials, such as bioabsorbables, animal-derived or human materials, or products containing antimicrobials, can require further
specific testing. New and emerging technologies such as nanomaterials and 3D printing will present further regulatory considera-
tions and challenges. Biomaterials suppliers and users should consider the applicable regulatory requirements as part of the early
design and development process, and where needed should engage with FDA directly to ensure appropriate testing is performed.

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Diseases or Conditions, April 13, 2015. Available From: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM393978.pdf,
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17. FDA Guidance. Use of International Standard ISO 10993-1, Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing Within a Risk Management Process,
June 16, 2016. Available From: http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm348890.pdf, 2016.
18. FDA Guidance. Guidance Document for Testing Biodegradable Polymer Implant Devices, April 20, 1996. Available From: http://www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocuments/ucm080265.htm, 1996.
19. 70 FR 49848 (2005). Definition of Primary Mode of Action of a Combination Product. Available From: https://www.gpo.gov/fdsys/pkg/FR-2005-08-25/pdf/05-16527.pdf
20. 21 C.F.R. § 3.7. Request for Designation Rules. Available From: https://www.gpo.gov/fdsys/pkg/CFR-2003-title21-vol1/pdf/CFR-2003-title21-vol1-sec3-7.pdf
21. FDA Guidance. Premarket Notification (510(k)) Submissions for Medical Devices That Include Antimicrobial Agents, July 19, 2007. Available From: http://www.fda.gov/
MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071380.htm, 2007.
22. 21 C.F.R. § 807.87(g). Information Required in a Premarket Notification Submission. Available From: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
FR ¼ 807.87
23. 42 U.S.C. § 264. Regulations to Control Communicable Diseases. Available From: https://www.gpo.gov/fdsys/pkg/USCODE-2010-title42/pdf/USCODE-2010-title42-chap6A-
subchapII-partG-sec264.pdf
24. FDA Previously Had Regulated Tissue Products for More Than a Decade Under 21 C.F.R. Part 1270. The Superseding Part 1271 Requirements Only Apply to Tissue
Procured on or After May 25, 2005. Part 1270, Which More Narrowly Focuses on Donor Eligibility and Screening Requirements for a More Narrowly Defined Set of
“Human Tissues” Than Part 1271, Will Be Revoked When FDA Is Confident That No More Tissue Is Available for Distribution Procured Prior to May 25, 2005.
25. 21 C.F.R. § 1271.3(d). Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products, Subpart A – General Provisions, Section 1271.3 How Does FDA Define
Important Terms in This Part. Available From: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr ¼1271.3
26. 21 C.F.R. § 1271.3(d)(3). Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products, Subpart A – General Provisions, Section 1271.3 How Does FDA
Define Important Terms in This Part? – Exemptions. Available From: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr¼ 1271.3
27. 21 C.F.R. § 1271.10(a). Part 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products, Subpart A – General Provisions, Section 1271.10 10 Are My HCT/P's
Regulated Solely Under Section 361 of the PHS Act and the Regulations in this Part, and If So What Must I Do? Available From: http://www.accessdata.fda.gov/scripts/
cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr¼ 1271.10
28. FDA Guidance. Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products: Draft Guidance, December, 2014. Available From: http://www.fda.
gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm427692.htm, 2014; p. 8.
29. 66 Fed. Reg. 5447, 5458 (January 19, 2001). Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing. Available From:
https://www.gpo.gov/fdsys/pkg/FR-2001-01-19/pdf/01-1126.pdf
30. Id. See FY 2012 Update. Available From: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm152857.htm, 2012.
31. See supra, Note 6.
32. FDA Tissue Reference Group Regulatory Summaries. Available From: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm152857.htm
33. FDA’s Compliance Program Guidance Manual. 7342.007 Addendum. Available From: http://www.fda.gov/downloads/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/CompliancePrograms/ucm095253.pdf; p. 6.
34. Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology. Available From: http://www.fda.gov/downloads/RegulatoryInformation/
Guidances/UCM401695.pdf, 2014.
35. Questions for Discussion for Public Workshop – Medical Devices and Nanotechnology: Manufacturing, Characterization, and Biocompatibility Considerations. Available
From: http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm22344, September 23, 2010.
36. FDA Guidance. Technical Considerations for Additive Manufactured Devices, May 10, 2016. Available From: http://www.fda.gov/downloads/medicaldevices/
deviceregulationandguidance/guidancedocuments/ucm499809.pdf, 2016.