Validation of Procedures for Processing of Human Tissues Intended for Transplantation

I.          INTRODUCTION

This guidance document applies to you, all tissue establishments.  We, the Food and Drug

Administration (FDA), want to remind you that under current FDA regulations, you must

prepare, validate, and follow written procedures to prevent infectious disease contamination or
cross-contamination (both subsequently referred to as "contamination") during tissue processing
(21 CFR 1270.31(d)).  Contamination may be caused by a variety of infectious disease agents
including viruses, bacteria, fungi, and transmissible spongiform encephalopathy (TSE)-
associated prions.  The regulations concerning human tissue intended for transplantation are
found in 21 CFR parts 1270 and 1271.  Relevant portions of the regulation state that:

·     "Processing means any activity performed on tissue, other than tissue recovery, including

preparation, preservation for storage, and/or removal from storage to assure the quality and/or sterility of human tissue.  Processing includes steps to inactivate and remove adventitious agents."  21 CFR 1270.3(p).

·     "There shall be written procedures prepared, validated, and followed for prevention of

infectious disease contamination or cross-contamination by tissue during processing."

21 CFR 1270.31(d).

·     "[A]ny facility may use current standard written procedures such as those in a technical

manual prepared by another organization, provided the procedures are consistent with and at least as stringent as the requirements of this part." 21 CFR 1270.31(e).

II.        GUIDANCE ON VALIDATION

As we explained in the preamble to Part 1270, the requirement to validate written procedures for
preventing contamination by tissues during processing is intended to "facilitate the timely
processing of tissue when necessary (e.g., skin and cornea) while maintaining quarantine and
continuing current good practices performed by industry in daily tissue processing." (62 FR
40429, 40437, July 29, 1997).  Current good practices performed by the tissue industry include 

procedures to prevent or reduce the risk of contamination by adventitious agents, such as viruses,
bacteria, fungi, and TSE-associated prions, during processing.  The procedures used to prevent
contamination during processing may vary, depending on the type of tissue and how it is
processed.  No matter which procedures are chosen, however, you must prepare, validate, and
follow those procedures before you release human tissue for transplantation from quarantine
(§§1270.31(c) and (d)).  If you adopt and use current standard procedures, such as those in a
technical manual of another organization, those procedures must be consistent with and at least
as stringent as the requirements of Part 1270 (§1270.31(e)).  This means that the current standard
written procedures you may use have been previously validated as required under §1270.31(d).
You are not required to revalidate current standard written procedures; however, you should
verify that the procedures have been fully and properly implemented (see below).

Validation shows that the procedure or process is effective, i.e., that you have established by

objective evidence that a process consistently produces a result or product meeting its

predetermined specifications.  The FDA regulations under Part 1270 do not specify how to

perform validation.  Validation studies conducted by your establishment or by experts in the field
may be acceptable.  Additionally, we realize that currently, with existing technology, there is no
adequate validation method for procedures intended to address contamination with TSE-
associated prions.  As technology progresses and validation methods become available, you will
be required to prepare, validate, and follow procedures to prevent contamination with TSE-
associated prions during tissue processing in accordance with §1270.31(d).  Moreover, whenever
processing may increase risk of TSE, (e.g., commingling of tissues from different donors during
processing)¹, we strongly encourage you to prepare and follow procedures now that are
scientifically reliable and effective to reduce the risk of TSE-associated prions transmission.  For
example, heightened screening and stringent recovery procedures may significantly decrease the
risk of receiving tissue contaminated with TSE-associated prions before processing.  In addition,
TSE clearance studies should be considered.

In general, you may obtain validation data to document the effectiveness of a procedure to prevent contamination in several ways, for example, by:

·   Verifying full and proper implementation of a previously validated procedure such as
      may be found in a technical manual of another organization, or

·   Conducting literature searches to demonstrate that the procedures implemented are

known to be effective in preventing the infectious disease contamination (e.g.,

Environmental Protection Agency-approved chemical sterilants for laboratory surfaces),
or

·   Conducting off-line or on-line challenges with indicator organisms, as appropriate, or
      evaluating the capacity of the manufacturing process to prevent contamination during

processing.

¹ In the proposed rule for Current Good Tissue Practice (GTP), FDA has proposed to prohibit the commingling of human cell and tissue-based products from two or more donors during manufacturing (proposed §1271.220(c), 66 FR 1508, 1555, January 8, 2001).  We are reviewing comments on this proposal in consideration of a final GTP rule. Commingling of tissue is not expressly prohibited under current regulation.

You must prepare and follow written procedures to prevent infectious disease contamination during processing (§1270.31(d)).  Following a written procedure to prevent infectious disease contamination during processing is a significant step in the performance of the requirements under Part 1270.  You are required to maintain records concurrently with the performance of each significant step (§1270.33(a)).  Therefore, you must document that you and your
establishment follow the written procedures you have prepared to prevent infectious disease contamination (§§ 1270.31(d), 1270.33(a)).

During FDA inspections, we may review your validation data to ensure you are using effective procedures to prevent infectious disease contamination (§1270.41(d)).  If you do not have
validation data or do not follow your validated procedures to prevent contamination, we will
include those findings on a List of Inspectional Observations (Form FDA-483) and discuss them with you.  We may also collect copies of records for further FDA evaluation, for example, when the validation data are complex or the procedures do not appear adequate to prevent infectious disease contamination (§1270.41(d)).

We encourage you to evaluate your current validation information to ensure that the data

demonstrate that the procedures will reliably prevent infectious disease contamination during

processing.  In your evaluation, you should consider both whether your procedures are effective and whether your validation is adequate.  For example, you should ask questions such as:

·   Are decontamination procedures for surfaces and instruments that may contact tissue
      contaminated with viruses (e.g., hepatitis, human immunodeficiency virus) or other

pathogenic organisms (e.g., bacteria, fungi) effective in removing or inactivating

adventitious agents, so that tissue is not cross-contaminated?

·   Are there repeated instances where test results or adverse reaction reports

demonstrate that the final product is contaminated?  If there is contamination and the
positive test results cannot be demonstrated to be due to equipment malfunction or
operator error, your validation effort may not have adequately accounted for process
variability.

Our current regulations and guidances concerning human tissue intended for transplantation are
available at http://www.fda.gov/cber/tiss.htm.

Reusable Medical Device Reprocessing

Adequately reprocessing medical devices is a critical step in quality patient care.

Inadequate reprocessing between patient uses can result in the retention of blood, tissue and other biological debris (soil) in certain types of reusable medical devices. This debris can allow microbes to survive the disinfection or sterilization process, which could then lead to Health care-Associated Infections (HAIs). Inadequate reprocessing can also result in other adverse patient outcomes, such as tissue irritation from residual reprocessing materials, such as chemical disinfectants.

Reducing the risk of exposure to improperly reprocessed medical devices is a shared responsibility among various stakeholders. This includes the FDA; health care facilities responsible for cleaning, sterilizing or disinfecting the devices; and manufacturers, responsible for providing adequate reprocessing instructions that are user-friendly and proven to work.

Retention of debris in reusable medical devices should not happen. We can solve this problem by engaging all stakeholders that have a role in reprocessing.

Three areas of focus are:

• Device Design
• Advancing Regulatory Science
• Improving Collaboration

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Device Design

Based on the agency's many years of experience reviewing reprocessed devices and research conducted by the agency and others, the FDA has identified designs that foster innovation in next-generation reusable medical devices. These design features facilitate cleaning, disinfection and sterilization and reduce the likelihood of retaining debris.

These design features include:

• Smooth surfaces, including smooth inner surfaces of the long, narrow interior channels (lumens)
• The ability to disassemble devices with multiple components
• Non-interchangeable connectors for critical connections (For example, tubes used with endoscopes for direct patient connection that cannot be interchanged with tubing used for waste drainage)
• Clear identification of connecting accessories, such as drainage tubing
• Clear indication and identification of components that must be discarded after patient use and cannot be reprocessed or reused
• Disposable components for the hardest to clean areas
• Designs that address how fluid flows through the device, and areas of debris build-up within devices

The FDA is also working with standard-setting groups, such as the Association for the Advancement of Medical Instrumentation and ASTM International, to develop consensus on a series of best practices. New standards and technical information reports (TIRs) will provide manufacturers with guidelines for designing devices that can be adequately reprocessed as well as effective test methods and criteria for validating reprocessing methods for reusable medical devices.

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Advancing Regulatory Science

The FDA is also taking actions to advance the science of reprocessing.

To help manufacturers improve their premarket submissions for new reusable medical devices, the FDA has issued the “Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling” Final Guidance. The guidance document reflects the scientific advances in knowledge and technology involved in reprocessing reusable medical devices, many of which have become highly complex in design and are more difficult to reprocess. The recommendations in this guidance are intended to improve the safety and effectiveness of devices with reprocessing labeling. Appendix E of the guidance document identifies a subset of medical devices that pose a greater likelihood of microbial transmission and high risk of infection if not adequately reprocessed. 510(k) submissions for these devices should include data to validate reprocessing methods and instructions. Data to validate reprocessing methods and instructions includes protocols and test reports that demonstrate reprocessing instructions work reliably and consistently and are able to be followed as intended.

This guidance provides manufacturers with clarity on how to present reprocessing information for their devices, and outlines principles for adequate labeling and scientific validation (demonstrating the adequacy) of cleaning, disinfection, and sterilization processes to assure that reusable devices can be effectively reprocessed and the instructions for reprocessing are clear for health care facilities. It is critical that the cleaning, disinfection and sterilization processes must be effective and practical, taking into consideration what health care facilities can reasonably perform.

FDA researchers are working to advance our scientific knowledge of reprocessing.

To strengthen regulatory science in this area and use it to further improve the design of reprocessed devices, FDA is investigating the use of computer modeling to study the flow of fluid and debris within devices. This type of modeling may help manufacturers determine the extent to which specific design features make a device prone to debris retention, and allow them to improve their designs prior to device manufacture.

FDA researchers have been investigating the relationship between device design and debris accumulation and retention over multiple cycles of soiling and cleaning. They are also developing a method to quantify particulate biological debris retained in reusable medical devices which can be used to determine if various cleaning methods are effective. Conventional test methods may underestimate the presence of debris such as tissue, cartilage, and bone. These underestimations could lead to the design and manufacture of reusable devices that are prone to retaining debris.

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Improving Collaboration

We can make advances in solving problems related to reprocessing medical devices by engaging all stakeholders who have a role, including manufacturers, health care facilities and staff, accrediting organizations and government agencies.

The FDA receives a lot of information that cuts across entire medical device types, such as product submissions from manufacturers and adverse event reports from health care providers. By communicating with all external stakeholders, the FDA is in a unique position to facilitate collaboration among the many stakeholders that are vital to a successful reprocessing program.

To this end, the FDA hosted a workshop on June 8-9, 2011 to bring together manufacturers, health care facilities, standards organizations, health care accreditation organizations, government agencies, and professional societies to share their experiences and work towards finding solutions for the current problems and innovative designs for new devices.

While the FDA can provide guidance documents on device design and clear instructions, a critical component of reducing infection is the implementation of a thorough Quality Assurance program by health care facilities that is specific to reprocessing devices.

One important quality assurance step is for health care facilities to make sure their staff follow the manufacturer instructions and reprocessing guidelines. Some data have shown that many facilities do not consistently follow guidelines on reprocessing.¹ In 2009, the FDA issued a joint Safety Communication with the Centers for Disease Control and Prevention and the Veterans Administration that cautioned health care facilities about the risks to patients if endoscopes and their accessories are not properly cleaned and recommended steps to reduce these risks. To help health care facilities achieve their goal of improving reprocessing Quality Assurance programs, the FDA developed the Information for Health Care Facilities page to share existing resources that provide reprocessing guidance and best practices.

In fall of 2013, the CDC first alerted the FDA to a potential association of multi-drug resistant bacteria and duodenoscopes. Upon further investigation and collaborations with federal partners, it became clear that these cases of infection were occurring despite confirmation that users were following manufacturer cleaning and disinfection or sterilization instructions. Since that time, the FDA has been working with federal partners, manufacturers, and other stakeholders to better understand the critical factors contributing to these infections and how to best mitigate them. For more information, visit Infections Associated with Reprocessed Duodenoscopes.

The FDA is committed to learning more about the challenges health care facilities face in device reprocessing, including ones related to device design, manufacturer’s instructions, and facility oversight of the process. FDA is collaborating with professional societies, health care facilities, including MedSun partner facilities, to better understand the effectiveness of reprocessing methodologies used in health care settings.

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¹ Rutala, WA, Weber, DJ, and the Healthcare Infection Control Practices Advisory Committee (HICPAC). Guidelines for Disinfection and Sterilization in Healthcare Facilities, 2008. Centers for Disease Control and Preventtion. Web. 1 March 2011.

Standards and Guidances for Neurological Devices

Established standards, guidance documents, and other requirements are an important part of the device development process.

Standards

To make the review process comprehensive and predictable, the FDA recognizes certain standards developed by organizations such as the International Organization for Standardization (ISO) and American Society for Testing and Materials (ASTM) International.

Sponsors can find FDA recognized national and international standards related to neurological devices by selecting the "Neurology" category under Specialty Task Group Area of the FDA Recognized Consensus Standards database.

Guidance Documents

Guidance documents represent the FDA's current thinking on a particular subject. They provide recommendations on fulfilling FDA's regulations and describe expectations for developing and monitoring medical devices. FDA guidance documents do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used if it satisfies the requirements of the applicable statute, regulations, or both.

Sponsors can find FDA guidance documents related to neurological devices by selecting "Neurological Devices" in the subject field of FDA's Search for Guidance Documents database.

Additional Recommendations

Neurological devices have unique characteristics that require special study. Sponsors can familiarize themselves with the following standards and guidance to help them demonstrate the safety and effectiveness of their medical device:

Biocompatibility Evaluation

Biocompatibility of a medical device refers to the ability of the device to bring about the desired biological response without causing any negative or harmful effects in the body. Biocompatibility depends on the body's responses to the device as well as the device's responses to the physiological environment inside the human body.

Relevant Standards:

• ISO 10993-1:2009 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process

Animal Studies

Animal studies, while not always necessary, are intended to demonstrate that the device under study is sufficiently safe for early human experience (e.g., to support an investigational device exemption [IDE] application, or to demonstrate device safety in support of a marketing application, while incorporating modern animal care and use strategies).

The FDA recommends that animal studies be conducted in accordance with Good Laboratory Practice (GLP) as outlined in CFR 21§58.0 (GLP Regulations).

Sterility

Sterility of medical devices should be validated to assure appropriate assurance levels. For detailed information about sterilization processes for 510(k)s for devices labeled as sterile, refer to the following consensus standards and FDA Guidance:

FDA Guidance Related to Sterility:

• Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile

Relevant Standards:

• AAMI ANSI ISO 11135:2014: Sterilization of health care products - Ethylene oxide - Requirements for development, validation and routine control of sterilization process for medical devices.
• AAMI ANSI ISO 11137-1:2006/(R)2010: Sterilization of health care products - Radiation - Part 1: Requirements for development, validation, and routine control of a sterilization process for medical devices
• ISO 17665-1 First edition 2006-08-15: Sterilization of health care products - Moist heat - Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices
• AAMI ANSI ST79:2010 & A1:2010 & A2:2011 & A3:2012 & A4:2013: Comprehensive guide to steam sterilization and sterility assurance in health care facilities
• ISO 10993-7 Second edition 2008-10-15: Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals

Pyrogenicity

The Agency recommends that devices meeting pyrogen limit specifications be labeled "non-pyrogenic." We recommend that sponsors refer to the following consensus standards and guidance document for additional guidance on LAL testing:

FDA Guidance Related to Pyrogenicty:

• Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers (June 2012)
• Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"

Relevant Standards:

• AAMI ANSI ST72:2011: Bacterial endotoxins - Test methods, routine monitoring, and alternatives to batch testing
• USP<161> Medical Devices - Bacterial Endotoxic and Pyrogen Tests