[Federal Register Volume 88, Number 81 (Thursday, April 27, 2023)]
[Notices]
[Pages 25642-25657]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-08900]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Centers for Disease Control and Prevention
[Docket No. CDC-2020-0046; NIOSH-233-C]
Hazardous Drugs: Procedures for Developing the NIOSH List of
Hazardous Drugs in Healthcare Settings and Managing Hazardous Drug
Exposures: Information for Healthcare Settings
AGENCY: Centers for Disease Control and Prevention (CDC), Department of
Health and Human Services (HHS).
ACTION: General notice.
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SUMMARY: The National Institute for Occupational Safety and Health
(NIOSH) of the Centers for Disease Control and Prevention (CDC), in the
Department of Health and Human Services (HHS), announces the following
final documents are available in the docket and on the NIOSH website:
Procedures for Developing the NIOSH List of Hazardous Drugs in
Healthcare Settings and Managing Hazardous Drug Exposures: Information
for Healthcare Settings.
DATES: The documents announced in this notice are available on April
27, 2023.
ADDRESSES: The documents announced in this notice are available in the
docket at www.regulations.gov and through the NIOSH Hazardous Drug
Exposures in Healthcare website at https://www.cdc.gov/niosh/topics/hazdrug/default.html.
FOR FURTHER INFORMATION CONTACT: Jerald Ovesen, NIOSH, Robert A. Taft
Laboratories, 1090 Tusculum Avenue, MS-C15, Cincinnati, OH 45226;
Telephone: (513) 533-8472 (not a toll-free number); Email:
[email protected].
SUPPLEMENTARY INFORMATION: This notice is organized as follows:
I. Public Participation
II. Background
III. Procedures for Developing the NIOSH List of Hazardous Drugs in
Healthcare Settings
A. Section II. Purposes
1. Application to Occupational Settings
2. Coordination With U.S. Pharmacopeia (USP)
B. Section III. Background
1. Exposure to Drugs in Healthcare Settings
C. Section IV. NIOSH Definition of a Hazardous Drug
1. Investigational Drugs
2. Over-the-Counter Drugs
3. Veterinary Drugs
D. Section V. Identifying, Screening, Evaluating, and Reviewing
a Drug for Placement on the List
1. Section V.A. Step 1: Identifying Potentially Hazardous Drugs
2. Section V.B. Step 2: Screening Potentially Hazardous Drugs
3. Section V.C. Step 3: Evaluating Potentially Hazardous Drugs
a. Toxicity Criteria
b. Developmental and Reproductive Toxicity
c. Organ Toxicity at Low Dose
d. Tabular Arrangement of Hazardous Drugs on the List
4. Section V.D. Step 4: Peer Review of Potentially Hazardous
Drugs and Section V.E. Step 5: Public Review of Potentially
Hazardous Drugs
IV. Managing Hazardous Drug Exposures: Information for Healthcare
Settings
A. Peer Review
1. Charge 1.a. What additional information would improve [the
document's] usefulness and why?
2. Charge 1.b. What changes could be made to improve the utility
of the information?
3. Charge 1.c. What information is redundant, incorrect,
missing, or not needed? Please Explain
4. Charge 2. Please Provide any Additional Studies or Scientific
Information That Evaluate or Validate Engineering, Work Practice, or
Administrative Controls To Reduce Exposures to Hazardous Drugs in
Healthcare Settings
5. Charge 3. Please Provide any Additional Studies or Scientific
Information That Support or Validate the Use of the NIOSH
Recommended Control Strategies or Alternative Strategies To Control
Exposures to Hazardous Drugs
6. Charge 4. Please Provide any Additional Studies or Scientific
Information That Support or Validate Evidence-Based Strategies or
Approaches for Controlling Exposures to Hazardous Drugs That Are
Different From Those That NIOSH Has Proposed
7. Charge 5.a. What additional information would improve the
usefulness of [the Table of Control approaches in chapter 8] and
why?
8. Charge 5.b. What structural or format changes could be made
to improve the utility of [the Table of Control approaches]?
9. Charge 5.c. What information is redundant, incorrect,
missing, or not needed [in the Table of Control approaches]? Please
Explain
10. Charge 6. What improvements could be made to this risk
management information to make it more useful to employers and
healthcare workers? Please Provide Specific Examples
11. Charge 7. Please Provide Information About Your Professional
Experience, if any, of Implementing Control Strategies for Exposures
to Hazardous Drugs in Healthcare or Similar Settings. Please
Describe What You Found to be Most or Least Effective and Why.
Include Relevant Publications if Available
12. Charge 8. Please Provide any Additional Comments or
Suggestions Either as a List Below or Using Track Changes in the
Attached Draft Document
B. Public Comments
1. Glossary
2. Chapter 1.0 Purpose and Scope
3. Chapter 6.0 Risk Management Plan
a. Section 6.2 Engineering Controls
--Closed System Transfer Devices
b. Section 6.3 Administrative Controls
--Alternative Duty
--Cleaning
--Counting Tablets
c. Section 6.4 Personal Protective Equipment
--Use of Gloves
--Use of Gowns, Sleeve Covers, and Head Covers
--Use of Respirators
d. Section 6.5 Surface Contamination
e. Section 6.6 Medical Surveillance
4. Chapter 7.0 Waste and Spill Control
a. Section 7.1 Hazardous Drug Waste and Section 7.2 Spill
Control
--Waste Designation and Handling
5. Chapter 8.0 Control Approaches for Safe Handling of Hazardous
Drugs by Activity and Formulations
a. Section 8.1 Introduction to Table of Control Approaches
b. Section 8.2 Control Approaches by Activity and Formulation
--Receiving and Packaging
--Transportation
--Compounding of Drugs
--Administration
6. USP <800>
7. Other Topics
V. Summary of Changes to Documents
A. Procedures for Developing the NIOSH List of Hazardous Drugs
in Healthcare Settings
B. Managing Hazardous Drug Exposures: Information for Healthcare
Settings
I. Public Participation
In a Federal Register notice published on May 1, 2020 (85 FR
25439), NIOSH invited the public to participate in the development of a
suite of tools designed to assist with the identification of hazardous
drugs and appropriate handling practices: (1) Procedures for Developing
the NIOSH List of Hazardous Drugs in Healthcare Settings; (2) NIOSH
List of Hazardous Drugs in Healthcare Settings, and (3) Managing
Hazardous Drug Exposures: Information for Healthcare Settings.
The Procedures for Developing the NIOSH List of Hazardous Drugs in
Healthcare Settings (Procedures) establish the NIOSH definition of a
hazardous drug and a methodology for evaluating chemical properties,
pre-clinical information, and available clinical information about each
drug. The Procedures also clarify how
[[Page 25643]]
interested parties can ask NIOSH to reevaluate a determination to place
or not to place a drug on the NIOSH List of Hazardous Drugs in
Healthcare Settings, or a decision to place a drug on a particular
table of the NIOSH List of Hazardous Drugs in Healthcare Settings.
The NIOSH List of Hazardous Drugs in Healthcare Settings (List)
assists employers in providing safe and healthy workplaces by
identifying drugs approved by the Food and Drug Administration (FDA)
Center for Drug Evaluation and Research (CDER) that meet the NIOSH
definition of a hazardous drug and that may pose hazards to healthcare
workers who handle, prepare, dispense, administer, or dispose of these
drugs. In accordance with the Procedures, NIOSH's approach to
evaluating information relevant to making determinations about placing
drugs on the List, excluding drugs from the List, and removing drugs
from the List, includes the following:
(1) regularly monitoring FDA databases to identify drugs that have
the potential to meet the NIOSH definition of a hazardous drug;
(2) reviewing molecular properties and information in the
manufacturer-provided drug package insert for each identified drug;
(3) assessing, integrating, and synthesizing evidence from human,
animal, and in vitro studies of drug toxicity for each identified drug;
and
(4) evaluating the totality of the evidence regarding the molecular
properties and toxicity using the hazard characterization criteria in
Sec. IV.C. of the Procedures.
The List creates no legal obligation for employers; it is advisory
in nature and informational in content.
Managing Hazardous Drug Exposures: Information for Healthcare
Settings (Managing Exposures) offers guidance to healthcare facilities
regarding occupational exposure and risk assessments, risk management
plans, waste and spill control, and control approaches for the safe
handling of hazardous drugs by activity and formulation. Managing
Exposures builds upon previous work by NIOSH including NIOSH ALERT:
Preventing Occupational Exposures to Antineoplastic and Other Hazardous
Drugs and the table Personal Protective Equipment and Engineering
Controls for Working with Hazardous Drugs in Healthcare Settings (often
referred to as ``Table 5''), published in previous iterations of the
List. Managing Exposures creates no legal obligation for employers; it
is advisory in nature and informational in content.
The public was invited to submit written comments regarding the
three draft 2020 versions of these three documents, as well as views,
opinions, recommendations, and/or data on any topic related to the
drugs reviewed by NIOSH for possible placement on the List.
In addition, NIOSH invited comments specifically related to the
following question and statement associated with this activity:
1. Which unique ingredient identifier is the most useful for
users of the List?
2. Because there is conflicting evidence about the hazard posed
by botulinum toxins to the workers who handle these drugs, NIOSH is
not proposing the placement of botulinum toxins on the List at this
time and invites additional studies, data, and expert opinions
pertinent to this issue in order to evaluate the botulinum toxins
more fully.
The public comment period for the May 2020 notice was initially
open until June 30, 2020 (85 FR 25439), and later extended until July
30, 2020 (85 FR 37101), to ensure commenters had adequate time to
comment.
One hundred thirty-two submissions were received from commenters in
Docket CDC-2020-0046 (NIOSH-233-C). Commenters consisted of nurses;
pharmacists; safety personnel; a veterinarian; healthcare, business,
and government administrators and committees; and anonymous and
unaffiliated individuals. The commenters represented a wide range of
institutions, including academic and general medical centers and
healthcare systems; hospital, commercial drug store, and compounding
pharmacies; manufacturers of pharmaceuticals and medical devices;
professional healthcare and veterinary organizations and associations;
home infusion organizations; suppliers of cleanroom products; boards of
pharmacy; and consultant companies for healthcare improvement and the
performance of healthcare facilities, risk assessment, and waste
management. Public comments on the documents discussed in the May 2020
notice are available for review at www.regulations.gov (Docket CDC-
2020-0046). NIOSH also conducted a peer review, with four independent
reviewers, of the draft Managing Exposures Drug Exposures: Information
for Healthcare Settings.
NIOSH carefully considered all public comments and peer reviews
resulting from the 2020 notice and determined that some clarifications
and changes should be made to the draft Procedures, List, and the
Managing Exposures documents. These changes are reflected in the two
final documents described in this notice. Publication of the NIOSH List
of Hazardous Drugs in Healthcare Settings, 2023 (2023 List) will be
announced in a forthcoming Federal Register notice. The 2023 List is
not discussed further in this notice.
Public comments on the draft Procedures are summarized and answered
by NIOSH in Sec. III of this notice and significant peer review and
public comments on Managing Exposures are summarized and answered in
Sec. IV. The changes to both documents are summarized in Sec. V.
Final versions of the Procedures document \1\ and Managing
Exposures are available on the NIOSH website and in the docket for this
activity.\2\
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\1\ NIOSH [2023]. Procedures for Developing the NIOSH List of
Hazardous Drugs in Healthcare Settings. By Whittaker C, Ovesen JL,
MacKenzie BA, Hartley T, Berry KA, Piacentino J. Cincinnati, OH:
U.S. Department of Health and Human Services, Centers for Disease
Control and Prevention, National Institute for Occupational Safety
and Health, DHHS (NIOSH) Publication Number 2023-129, https://wcms-wp.cdc.gov/niosh/docs/2023-129/default.html.
\2\ NIOSH [2023]. Managing Hazardous Drug Exposures: Information
for Healthcare Settings. By Hodson L, Ovesen J, Couch J, Hirst D,
Lawson C, Lentz TJ, MacKenzie B, Mead K. Cincinnati, OH: U.S.
Department of Health and Human Services, Centers for Disease Control
and Prevention, National Institute for Occupational Safety and
Health, DHHS (NIOSH) Publication 2023-130, https://wcms-wp.cdc.gov/niosh/docs/2023-130/default.html.
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II. Background
In 2004, NIOSH published the NIOSH Alert: Preventing Occupational
Exposures to Antineoplastic and Other Hazardous Drugs in Health Care
Settings (Alert), which contained a compilation of lists of drugs
considered to be as hazardous to workers' health. NIOSH periodically
updates this list, now named the NIOSH List of Hazardous Drugs in
Healthcare Settings, to assist employers in providing safe and
healthful workplaces by identifying drugs that meet the NIOSH
definition of a hazardous drug.
In 2017, NIOSH began developing a document to make the process used
to guide the addition of hazardous drugs to the List more transparent,
entitled the Policy and Procedures for Developing the NIOSH List of
Antineoplastic and Other Hazardous Drug in Healthcare Settings (Policy
and Procedures). The Policy and Procedures document was created to
formalize NIOSH's methodology and establish a process for requesting
the addition of a drug to, the removal of a drug from, or relocation of
a drug within the List. This document was reviewed by four peer
reviewers and eight interested parties before NIOSH made the document
available for public comment in a February 14, 2018
[[Page 25644]]
notice (83 FR 6563). The peer reviewers and interested parties also
provided input on the drugs considered for placement on the List.
Consistent with the draft Policy and Procedures, NIOSH proposed the
addition of 20 drugs and one class of drugs to the List in the
framework for the draft List in the February 2018 notice. Public
comments were invited regarding any topic related to drugs identified
in the notice, the draft Policy and Procedures, and the framework for
the February 2018 update to the List, as well as the following
questions related to this activity:
1. Has NIOSH appropriately identified and categorized the drugs
considered for placement on the NIOSH List of Antineoplastic and
Other Hazardous Drugs in Healthcare Settings, 2018?
2. Is information available from FDA or other Federal agencies
or in the published, peer-reviewed scientific literature about a
specific drug or drugs identified in this notice that would justify
the reconsideration of NIOSH's categorization decision?
3. Does the draft Policy and Procedures for Developing the NIOSH
List of Antineoplastic and Other Hazardous Drugs in Healthcare
Settings include a methodology for reviewing toxicity information
that is appropriate for this activity?
Fifty-five public comments were submitted in response to the
February 2018 notice and summarized with NIOSH responses in a May 2020
notice (85 FR 25439). Those comments are available in Docket CDC-2018-
0004. The substantive input provided by peer reviewers, interested
parties, and public commenters on the February 2018 notice caused NIOSH
to reconsider certain aspects of the draft Policy and Procedures and
the draft framework for the List. As a result, NIOSH revised and
updated the draft Policy and Procedures, renamed ``Procedures,'' as
well as the draft list of drugs proposed for placement on the List.
This collective input also contributed to the development of the draft
document Managing Exposures, also announced in the May 2020 notice.
Comments resulting from the May 2020 notice are available at
www.regulations.gov in Docket CDC-2020-0046.
III. Procedures for Developing the NIOSH List of Hazardous Drugs in
Healthcare Settings
The public comments submitted in response to the May 2020 version
of the draft Procedures have been organized in accordance with the
sections of the Procedures document. Substantive public comments are
summarized below, followed by NIOSH responses. Sec. I of the Procedures
addresses the statutory authority for this activity; no public comments
were received on this section, therefore Sec. I is not discussed below.
A. Section II. Purposes
1. Application to Occupational Settings
Public comment: One commenter suggested that NIOSH make it clear
that the hazardous drug designations apply to occupational exposure
rather than patient use. The concern was for pharmacies adding warning
labels that patients may receive.
NIOSH response: NIOSH states throughout all three documents that
they are intended to address occupational exposures, not patient use.
NIOSH does not require specific labeling, nor can NIOSH control how
individual facilities implement their risk management processes to
protect workers. No change to the Procedures has been made in response
to this comment.
2. Coordination With U.S. Pharmacopeia (USP)
Public comment: Several commenters reflected on USP General Chapter
<800> Hazardous Drugs--Handling in Healthcare Settings (USP <800>) \3\
and how USP and NIOSH documents interrelate. USP has incorporated the
NIOSH List into USP <800> and some states require compliance with USP
<800>, the effect of which has been that certain healthcare settings in
some jurisdictions are required to handle NIOSH-identified hazardous
drugs in accordance with the standards in USP <800>.
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\3\ See https://www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare.
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Some commenters suggested close coordination of NIOSH and USP on
the issues of hazardous drugs handling, as well as standardizing the
language. Two commenters suggested that NIOSH specifically reference
USP in its documents. A few commenters noted that compliance with USP
<800> is burdensome if a drug is identified as hazardous. One commenter
suggested dropping the descriptor ``antineoplastic'' from both USP and
NIOSH documents as uninformative, acknowledging that cancer treatment
drugs now have a wide variety of modes of action. Another commenter
suggested limiting the scope of the hazardous drugs List to chemicals
for which NIOSH had ``definitive proof'' of hazard because USP
recommendations for application of the List may lead to overuse of
personal protective equipment (PPE).
NIOSH response: While NIOSH and USP have continuing contact and
stay informed of progress and potential areas of conflict in their
respective documents, the respective missions of NIOSH and USP differ,
and the NIOSH and USP document processes also differ. Therefore,
standardized language, while convenient for the reader, may not be
attainable. NIOSH works to ensure that the List and associated
documents are consistent with relevant sources of information and
guidance, including USP. However, the List is informational in nature
and does not confer any requirements or legal obligations on users.
Additionally, NIOSH does not specifically reference USP <800> in its
Procedures and List documents because NIOSH intends the List and
associated documents as stand-alone informational materials for
employers in healthcare settings. NIOSH has also removed some
references to USP from the Managing Exposures document, as discussed
further below.
Regarding the descriptor ``antineoplastic,'' NIOSH agrees with the
commenter that it is no longer useful for understanding the hazards
posed by individual drugs and has dropped that nomenclature from the
document title and table titles in the List.
Finally, NIOSH does not agree with the suggestion to limit the List
to drugs for which there is ``definitive proof'' of hazard. NIOSH
evaluates the evidence of toxicity to determine the potential for the
drug to be hazardous to workers. This analysis does not consider dosage
form (the physical form of the pharmaceutical drug, e.g., coated
tablet, capsule, liquid). Therefore, it is incumbent on employers in
healthcare settings to evaluate how drugs are used in their facilities
and what risks may ensue, given the dosage forms, procedures, and tasks
undertaken. This is called a ``site risk assessment'' and is described
further in Managing Exposures.
For questions or concerns about the implementation of USP <800>,
commenters should contact USP directly.
Public comment: One commenter stated, ``. . . the explicit use of
the NIOSH List by USP to enforce Chapter <800> makes the List
regulatory. Facilities that do not comply with USP Chapter <800>
standards, and thus the NIOSH List designation of hazardous drugs, can
be cited and face regulatory and legal consequences.''
NIOSH response: NIOSH did not compile the List for standardized
compliance purposes and the List creates no legal obligation for
employers. The List is an advisory statement. NIOSH does not have
statutory authority to enforce the
[[Page 25645]]
recommendations comprising the List and companion Managing Exposures.
Moreover, the List is intended to be a helpful reference tool for
use in employers' own workplace assessments. As detailed in the
Procedures, compilation of the List is a hazard identification process
in which NIOSH considers the inherent hazard of the drug. As such, the
List is intended solely as a first step for employers in conducting
their own assessments of hazardous drug risks to their particular
workers that might result from myriad drug formulations and exposure
scenarios.
Additionally, NIOSH has no ability to direct USP or the State and
local jurisdictions that have incorporated USP <800> into their own
requirements. While NIOSH has no control over USP <800>, NIOSH has
relayed commenters' concerns to the organization. No change to the
Procedures has been made in response to this comment.
B. Section III. Background
1. Exposure to Drugs in Healthcare Settings
Public comment: One commenter expressed concern that NIOSH did not
consider the impact of hazardous drugs on cleaning staff. Another
requested that NIOSH explicitly state that this applied to all
pharmacies, including compounding pharmacies and mail-order pharmacies.
NIOSH response: NIOSH considers all workers who come into contact
with hazardous drugs in healthcare settings as within the scope of the
Procedures, List, and Managing Exposures documents, no matter the type
of workplace. Accordingly, Sec. III.A of the Procedures addresses the
tasks that workers undertake (e.g., receipt, storage, preparation,
compounding, manipulation, cleanup, and disposal of drugs and patient
waste), rather than specific types of facilities. No change to the
Procedures has been made in response to this comment.
C. Section IV. NIOSH Definition of a Hazardous Drug
Public comment: NIOSH received many comments on the NIOSH
definition of hazardous drugs in Sec. IV of the draft Procedures.
Specifically, many comments were received from parties that did not
approve of the change in definition from previous versions of the
Procedures. There were several issues raised objecting to the changes.
Some public commenters and one Managing Exposures peer reviewer
objected to NIOSH changing the hazardous drugs definition from the
original 2004 definition of a hazardous drug, alleging that NIOSH made
the change in its definition without the consensus of all interested
parties. (Note: the Managing Exposures peer review comment is addressed
in this section because it relates to the hazardous drugs definition in
the Procedures document.)
Other commenters objected to specific wording changes in the
definition. Some of these commenters objected to language that
specifies how NIOSH considers drugs with high molecular weight, citing
the potential for increased risks to workers. However, there was also
some support among commenters for the NIOSH perspective, including one
commenter who noted ``. . . the procedure should be refined from a
system that focuses primarily on the intrinsic hazards of a drug to one
that considers the occupational relevance of the intrinsic hazard.''
Commenters also objected to language indicating that NIOSH was limiting
consideration of drugs to those approved by FDA CDER. These commenters
recommended that, in addition to FDA CDER approval, NIOSH also fully
consider all drugs approved by FDA Center for Biologics Evaluation and
Research (CBER) to assess all potentially hazardous drugs in the
workplace more fully. Other commenters disapproved of how NIOSH
intended to consider drugs with insufficient toxicity data as not
meeting the NIOSH definition of hazardous drugs. They recommended that
NIOSH consider to be hazardous any drugs with insufficient toxicity
data to meet the definition of hazardous drugs.
NIOSH response: The original 2004 definition of hazardous drug was
based on an American Society of Health-System Pharmacists (ASHP)
definition developed in 1990 and revised by NIOSH in collaboration with
a large group of interested parties. NIOSH has used that definition as
the basis for the List since 2004. In the Policy and Procedures
described in the February 2018 notice, NIOSH proposed revising the
definition to ``those drugs approved for use in humans by the FDA, not
otherwise regulated by the U.S. Nuclear Regulatory Commission and
either contains special handling information for workers handling the
drug in the package insert or exhibits one of the six toxicity
criteria.'' In the revised Procedures described in the May 2020 notice,
NIOSH proposed further revisions, such as specifying drugs approved by
FDA CDER. In addition, the definition included evaluating molecular
properties that may limit the potential for adverse health effects for
the exposed worker.
NIOSH notes that the definition in the final Procedures is still
based largely on the 2004 definition. The Procedures document makes
explicit the steps in evaluating the drugs that were not fully
described in earlier versions of the List, although they have been
NIOSH's long-standing practices. Except for considering molecular
properties of drugs, the definition in the Procedures reflects how
NIOSH has been implementing the 2004 definition to make decisions about
hazardous drugs. Therefore, NIOSH did not consider it necessary to
engage a large group of interested parties to make minor changes in the
definition as the underlying foundation of the definition remains the
same. In addition, NIOSH believed that the peer review and public
comment processes provided ample opportunity for such interested
parties to provide input on the changes to the definition.
Since the inception of the List in 2004, NIOSH practice is to only
consider drugs approved by CDER to be included in the List. Therefore,
to be transparent, one change from the 2004 definition includes the
clarification that only FDA CDER-approved drugs are considered for the
List. Drugs on the List that had been approved by CBER were part of the
initial compilation of lists only; however, no drugs have been added to
the List in intervening years that were subject to CBER approval. In
addition to adopting the new language to the definition of ``hazardous
drug'' in the final version of the Procedures Sec. IV, NIOSH has also
added the language to footnote 12 to clarify that only CDER-approved
drugs are included on the 2023 List. Similarly, it has not been a NIOSH
practice to consider drugs approved by the Nuclear Regulatory
Commission and this is also specified in the definition in the
Procedures.
The six toxicity endpoints--carcinogenicity; teratogenicity or
other developmental toxicity; reproductive toxicity; organ toxicity at
low dose; genotoxicity; and structure and activity profiles of drugs
that mimic existing drugs determined hazardous by the above criteria--
in the definition of a hazardous drug remain unchanged from 2004.
However, one caveat was added to the definition to clarify that a drug
may be found not to be a hazard if it also exhibits a molecular
property that may limit the potential for adverse health effects from
exposure in healthcare workers. Such molecular properties typically
include chemical, physical, and structural properties that affect the
drug's absorption, (e.g., chemical structure, molecular weight, or
mass).
[[Page 25646]]
NIOSH has always emphasized that identification of potential
hazards does not equate to occupational risks. In the 2004 Alert, NIOSH
stated that drugs may be hazardous in one exposure scenario but have
much less risk associated with another. Specifically, NIOSH noted in
2004 that ``Physical characteristics of the agents (such as liquid
versus solid, or water versus lipid solubility) also need to be
considered in determining the potential for occupational exposure.
Therefore, the caveat inserted into the current hazardous drugs
definition clarifies and extends that consideration for specific
scenarios. It recognizes that although a drug may meet the definition
of a hazardous drug in other ways, if NIOSH determines that
occupational risks are not significant because of the chemical and
physical properties of the drug, that drug may be excluded from the
List. The purpose of this exclusion is to focus the List on drugs that
have a reasonable potential for toxicity after occupational exposure,
so that workers' attention is focused on drugs that are likely to be
hazardous in occupational settings. It is important to note that this
is not an automatic exclusion. NIOSH has not established a specific
molecular weight, for example, above which drugs are automatically
excluded from the List. Instead, this is a guideline to alert NIOSH
reviewers that they should look at the totality of the evidence,
thoroughly consider the possible occupational exposure scenarios, and
evaluate whether there is significant risk under those conditions. This
would include assessing exposure by inhalation of dust, vapor or mist,
dermal absorption (including through abraded or compromised skin),
ingestion, contact with mucous membranes, and needle sticks (using
``worst case'' assumptions). This exclusion also does not apply to the
dosage form of the drug. Specifically, the Procedures notes in Sec.
V.C.4.b,
NIOSH does not consider dosage form as a molecular property of a
drug because the same active pharmaceutical product can be offered
in several different dosage forms, new dosage forms can be offered
later, and some dosage forms can be discontinued.
NIOSH has considered the public comments and remains supportive of
the idea of examining molecular properties of drugs as a consideration
of whether they should be included on the List. In addition, NIOSH has
added a column to the tables that allows for identification of those
drugs approved by CDER under a biologics license application. Unlike
the biological products approved by CBER, those approved by CDER are
often large, single-molecule protein/peptide-based drugs such as
monoclonal antibodies, intended for therapeutic use.\4\ Denoting these
drugs in the List will make it easier for users to identify drugs that
are large, single-molecule products and peptides in order to implement
the appropriate risk management strategies. In Sec. IV of the
Procedures, the final NIOSH definition of hazardous drug is a drug that
is:
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\4\ See FDA, Transfer of Therapeutic Biological Products to the
Center for Drug Evaluation and Research. https://www.fda.gov/combination-products/jurisdictional-information/transfer-therapeutic-biological-products-center-drug-evaluation-and-research.
A. Approved for use in humans \a\ by the Food and Drug
Administration's (FDA) Center for Drug Evaluation and Research
(CDER),\b\
B. Not otherwise regulated by the U.S. Nuclear Regulatory
Commission,\c\ and
C. Either
1. Is accompanied by prescribing information in the ``package
insert'' \d\ that includes a manufacturer's special handling
information (MSHI),\e\ or
2. Is determined to be a carcinogenic hazard, developmental
hazard, reproductive hazard, genotoxic hazard, or other health
hazard by exhibiting one or more of the following toxicity criteria
in humans, animal models, or in vitro systems:
Carcinogenicity;
Developmental toxicity (including teratogenicity);
Reproductive toxicity;
Genotoxicity;
Organ toxicity at low doses; \f\ or a
Structure and toxicity profile that mimics existing
drugs determined hazardous by exhibiting any one of the previous
five toxicity types.\g\
However, if a drug also exhibits a molecular property \h\ that
may limit the potential for adverse health effects from exposure to
the drug in healthcare workers, it may be determined it is not a
hazard.
\a\ Although only drugs approved by FDA for use in humans are
included in the definition of hazardous drug, some of those drugs
may be used in veterinary settings for treatment of animals and may
be a hazard for veterinary care workers.
\b\ Although biological products, such as vaccines, blood and
blood components, allergenics, somatic cells, gene therapy, tissues,
recombinant therapeutic proteins, are included in FDA definition of
a drug, they are not included in the drugs that NIOSH evaluates for
potential inclusion on the List because they are approved for use by
FDA's Center for Biologic Evaluation and Research (CBER), not by
FDA's CDER. This provision makes clear NIOSH's long-standing
practice of only considering drugs approved by FDA CDER.
\c\ 10 CFR parts 19, 20, and 35. See https://www.nrc.gov/materials/miau/med-use.html. Drugs regulated by the Nuclear
Regulatory Commission are not included on the List.
\d\ See Drug Advertising: A Glossary of Terms at https://www.fda.gov/drugs/resourcesforyou/consumers/prescriptiondrugadvertising/ucm072025.htm. ``Prescribing information
is also called product information, product labeling, or the package
insert (``the PI''). It is generally drafted by the drug company and
approved by FDA. This information travels with a drug as it moves
from the company to the pharmacist. It includes the details and
directions healthcare providers need to prescribe the drug properly.
It is also the basis for how the drug company can advertise its
drug. The prescribing information includes such details about the
drug as: its chemical description; how it works; how it interacts
with other drugs, supplements, foods, and beverages; what
condition(s) or disease(s) it treats; who should not use the drug;
serious side effects, even if they occur rarely; commonly occurring
side effects, even if they are not serious; effects on specific
groups of patients, such as children, pregnant women, or older
adults and how to use it in these populations.''
\e\ MSHI includes language that informs those handling the drug
of the need to follow heightened handling and disposal procedures.
For example, language such as ``follow special handling and disposal
procedures'' or ``procedures for proper handling and disposal of
anticancer drugs should be considered'' is frequently used in
package inserts. However, NIOSH does not consider language
pertaining to packaging and temperature controls as MSHI.
\f\ All drugs have toxic side effects, but some exhibit toxicity
at low doses. The level of toxicity reflects a continuum from
relatively nontoxic to production of toxic effects in patients at
low doses (for example, a few milligrams or less). For example, a
daily therapeutic dose of 10 milligrams per day (mg/day) or a dose
of 1 milligram per kilogram (mg/kg) per day in laboratory animals
that produces serious organ toxicity, developmental toxicity, or
reproductive toxicity has been used by the pharmaceutical industry
to develop occupational exposure limits (OELs) of less than 10
micrograms per cubic meter ([mu]g/m3) after applying appropriate
uncertainty factors. See Naumann BD, Sargent EV [1997]. Setting
occupational exposure limits for pharmaceuticals. Occup Med
12(1):67-80; Sargent EV, Kirk GD [1988]. Establishing airborne
exposure control limits in the pharmaceutical industry airborne
exposure control limits in the pharmaceutical industry, Am Ind Hyg
Assoc J 49(6):309-313; Sargent EV, Naumann BD, Dolan DG, Faria EC,
Schulman L [2002]. The importance of human data in the establishment
of occupational exposure limits. Hum Ecol Risk Assess 8(4):805-822].
OELs in this range are typically established for potent or toxic
drugs in the pharmaceutical industry.
\g\ NIOSH [2004]. NIOSH Alert: preventing occupational exposures
to antineoplastic and other hazardous drugs in healthcare settings.
By Burroughs GE, Connor TH, McDiarmid MA, Mead KR, Power LA, Reed
LD, Coyle BJ, Hammond DR, Leone MM, Polovich M, Sharpnack DD.
Cincinnati, OH: U.S. Department of Health and Human Services,
Centers for Disease Control and Prevention, National Institute for
Occupational Safety
[[Page 25647]]
and Health, DHHS (NIOSH) Publication No. 2004-165, available at
https://www.cdc.gov/niosh/docs/2004-165/.
\h\ Properties of a drug molecule that may limit adverse effects
in healthcare workers are typically chemical, physical, and
structural properties that affect its absorption (ability to enter
the cells of the body), e.g., chemical structure, molecular weight,
or mass. See Clementi F, Fumagalli G [2015]. Molecular pharmacology.
Hoboken, NJ: Wiley & Sons; Di L, Kerns EH [2016]. Drug-like
properties: concepts, structure, design, and methods. Oxford, UK:
Elsevier; Mattson P, Kihlberg J [2017]. How big is too big for cell
permeability? J Med Chem 60(5):1662-1664, https://doi.org/10.1021/acs.jmedchem.7b00237.
1. Investigational Drugs
Public comment: Two commenters remarked on the exclusion of
investigational new drugs from the definition of ``hazardous drug'' in
Sec. IV. One commenter sought guidance in how to handle those drugs,
while the second commenter supported the idea that drugs with
inadequate safety information not be automatically added to the List.
NIOSH response: Although the NIOSH Procedures are focused on drugs
that have received FDA CDER approval, and do not consider
investigational drugs, NIOSH has addressed this issue in the document
Managing Exposures. Guidance for employers developing a facility-
specific hazardous drug list is found in Ch. 3, Sec. 3.1 of that
document, Developing a Facility-Specific Hazardous Drug List, which now
states:
Toxicological data may be incomplete or unavailable for some
drugs, specifically investigational drugs. Until adequate
information becomes available, it is prudent to handle
investigational drugs as hazardous if the mechanism of action
suggests that there may be a concern.
2. Over-the-Counter Drugs
Public comment: One commenter indicated that it was unclear why
over-the-counter drugs were excluded from the definition of a hazardous
drug in Sec. IV of the Procedures.
NIOSH response: Over-the-counter (OTC) drugs are not evaluated by
NIOSH because FDA regulations at 21 CFR 330.10 require OTC drugs to
meet a safety standard that includes:
. . . a low incidence of adverse reactions or significant side
effects under adequate directions for use and warnings against
unsafe use as well as low potential for harm which may result from
abuse under conditions of widespread availability.\5\
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\5\ 21 CFR 330.10(4)(i).
NIOSH acknowledges that this does not mean these drugs are always
safe and there are circumstances under which there may be risks to
workers who handle OTC drugs. However, to focus resources on the most
hazardous drugs, NIOSH has decided to exclude drugs with an OTC form
from consideration for the List. No change to the Procedures has been
made in response to this comment.
3. Veterinary Drugs
Public comment: One commenter on the List requested that NIOSH
consider including veterinary drugs in the List because these drugs are
often approved first for veterinary uses and later approved for human
therapies.
NIOSH response: At this time the List is compiled from drugs
approved by CDER. The veterinary drugs prescribing insert often does
not include information about the toxicity criteria that NIOSH
considers. NIOSH may consider developing further resources related to
the handling of drugs approved by the FDA Center for Veterinary
Medicine in the future. No change to the Procedures has been made in
response to this comment.
D. Section V. Identifying, Screening, Evaluating, and Reviewing a Drug
for Placement on the List
1. Section V.A. Step 1: Identifying Potentially Hazardous Drugs
Public comment: One commenter was concerned that the NIOSH List
might be inconsistent with FDA labeling requirements, specifically
questioning whether NIOSH is considering individual branded product
labeling and how the criteria for carcinogenicity are applied when the
information is derived from the package insert.
NIOSH response: In developing the List, NIOSH considers the
toxicity of the drug, not a specific brand or dosage form. Regarding
the concerns about how the information on the package insert is used to
support a carcinogenicity determination, NIOSH notes that a mention of
tumors or malignancies does not automatically result in a NIOSH
determination that there is an occupational cancer hazard in handling
the drug. NIOSH takes all the available information into consideration
including therapeutic dose, carcinogenic dose in any animal studies,
and other factors in making its determination. Mention of
carcinogenicity on a package insert is insufficient to automatically
meet the NIOSH criteria for carcinogenicity. No change to the
Procedures has been made in response to this comment.
2. Section V.B. Step 2: Screening Potentially Hazardous Drugs
Public comment: Some commenters expressed concern regarding
Procedures Sec. V.B.2.b, which describes screening outcomes when there
is ``insufficient information in the drug package insert to suggest
that the drug exhibits any one of the toxicity criteria in the NIOSH
definition of hazardous drug.'' The text of the Procedures indicates
that for those drugs for which NIOSH has determined that there is
insufficient toxicity information to suggest that the drug exhibits any
one of the toxicity criteria, NIOSH will not propose to add that drug
to the List. Commenters were concerned that this decision would
increase worker hazards. Specifically, one commenter stated, ``[w]e
suggest that NIOSH consider additional parameters to ensure that any
drug that could potentially pose a hazard to employees not fall through
the cracks.''
NIOSH response: NIOSH understands the concern that it appears that
drugs that have been insufficiently studied might be removed from
consideration. However, unlike other workplace chemicals,
pharmaceuticals are subject to rigorous, required toxicity testing to
merit approval by FDA. NIOSH understands that there is a difference in
the focus of the two agencies. NIOSH notes that the FDA-required
toxicity tests, which are based on the mode of action and potential
toxicity of the drug at treatment exposure levels, provide sufficient
information for NIOSH to identify potential hazards at the levels of
occupational exposure expected in healthcare settings. In Sec. V.B.2.b
of the Procedures, NIOSH now states:
If there is insufficient information in the drug package insert
to suggest that the drug exhibits any one of the toxicity criteria
in the NIOSH definition of hazardous drug, then NIOSH will not
propose to add the drug to the List.
This does not mean that the drug has been insufficiently tested to
determine potential toxicity. Instead, it indicates that in some cases,
in its review of all available information, FDA did not find a concern
for toxicity of a particular type and such tests were not required or
that the available toxicity data are insufficient to meet the NIOSH
criteria for a hazardous drug. NIOSH has added footnote 29 with this
explanation to the Procedures in response to this comment.
3. Section V.C. Step 3: Evaluating Potentially Hazardous Drugs
a. Toxicity Criteria
Public comment: One commenter asked NIOSH to clarify whether drugs
[[Page 25648]]
are placed on the List solely based on in vitro studies.
NIOSH response: NIOSH examines the totality of the evidence from
the specified sources described in the Procedures. In Sec. V.C.3.e,
NIOSH specifies the use of in vitro studies in genotoxicity
determinations as those toxicity tests are the most common tests for
that toxicity endpoint. However, NIOSH also notes in multiple places in
the Procedures that human data are preferred over animal data and both
human and animal data are preferred over in vitro toxicity data. In
Sec. V.C.3.e.(1) of the Procedures, regarding genotoxicity data, NIOSH
states:
Human genotoxicity studies are not commonly available for
evaluation. If available, NIOSH gives preference to human
genotoxicity studies over animal and in vitro studies. However,
NIOSH considers all relevant information in its evaluation.
Public comment: One commenter questioned the NIOSH use of animal
toxicity data and in vitro data in making a hazardous drug
determination. In particular, the commenter expressed concern that the
inclusion of data from animal models or in vitro systems in defining a
hazardous drug may not be relevant to hazard risk in human exposure.
The commenter further recommended that drugs placed on the List solely
due to animal or in vitro toxicity data should be so identified.
NIOSH response: NIOSH notes in the Procedures that human data are
preferred over both animal and in vitro data for making determinations
about the hazardous nature of drugs. Data from animal and in vitro
studies designed to predict human toxicities contain valuable
information about the potential toxicity of drugs. Therefore, NIOSH
fully evaluates all available relevant scientific information regarding
the potential toxicity of hazardous drugs and does not separately
identify which determinations have been made based solely on animal
and/or in vitro data. Doing so might give an erroneous impression of
less concern for certain drugs based on the type of information
available.
Public comment: The same commenter was concerned that the language
in Secs. V.C.3.a.(5)(c), V.C.3.b.(4)(b), and V.C.3.c.(4)(b) of the
Procedures, regarding adverse effects observed in toxicity studies at
doses near, at, or below the maximum recommended human dose, indicated
that NIOSH would use such findings to support a hazardous drug
determination, even when the adverse effect may not be related to a
toxic effect.
NIOSH response: The language cited by the commenter is from the
Procedures and is parallel to language in sections on carcinogenicity,
reproductive toxicity, and developmental toxicity. The adverse effects
observed would be those associated with the specific toxicity resulting
from administration of the drug to experimental animals. The occurrence
of these effects below or near the maximal recommended human dose
clarify that they are occurring at a dose level of concern. In
considering the potential occupational hazard, it is important for
NIOSH to consider when effects occur only at doses much higher than the
human therapeutic dose, as workers are unlikely to be exposed to drugs
at those therapeutic dose concentrations or higher doses. NIOSH has
used the maximal recommended human dose as a benchmark to indicate the
high end of doses of concern. Typically, NIOSH would be most concerned
with toxic effects that occurred below this level.
Public comment: One commenter stated that the toxicity criteria in
Sec. V.C.3 should be clarified and further defined. According to the
commenter, ``unclear terms include `serious organ toxicity,' `low
doses,' and `generally support.' ''
NIOSH response: While NIOSH appreciates the desire to have more
explicit language in describing the toxicity criteria, the broad
spectrum of drugs covered makes it difficult to precisely define the
criteria in a way that will apply to both all drugs and all modes of
action considered. Language that would be precise for a particular drug
may create a situation where, when applied to another drug, is
inadequate to protect workers or results in over-protection. The
remedies for this are to either have precise language with an
exhaustive list of exceptions (assuming one could know all the
potential exceptions that are possible) or to provide as much
indication of how NIOSH views toxicity as possible, knowing that there
are exceptions that will arise. NIOSH chose the latter strategy, but
notes that for any particular drug consideration, NIOSH relies on the
professional judgement of NIOSH staff scientists, conducts rigorous
peer review of the determinations, and provides an opportunity for
public comment on how that language was applied to that drug. No
changes to the Procedures have been made in response to this comment.
b. Developmental and Reproductive Toxicity
Public comment: Two commenters suggested that NIOSH may not want to
use developmental and reproductive hazards as inclusion criteria,
citing concerns that drugs contraindicated in pregnancy may be
automatically included in the List as reproductive or developmental
hazards. The commenters also stated that the risks were easily
mitigated with normal drug handling procedures.
NIOSH response: The List is intended to identify potential hazards
in the healthcare workplace so that workplaces can further consider
what risk management strategies are appropriate for their specific
needs. This includes, but is not limited to, reproductive and
developmental hazards. Drugs that pose developmental and reproductive
hazards are identified to protect workers, both male and female, who
may be pregnant or trying to become pregnant.
Contraindication during pregnancy is not enough for NIOSH to
consider a drug to be a developmental or reproductive hazard. See
Procedures, Sec.V.C.3.b and c. No change to the Procedures has been
made in response to this comment.
c. Organ Toxicity at Low Dose
Public comment: One commenter expressed concern with the language
regarding low dose toxicity in Sec. V.C.3.d of the draft Procedures.
Specifically, the commenter did not agree with the toxicity level of 10
milligrams per day (mg/day) in human adults or 1 milligram per kilogram
per day (mg/kg/day) in laboratory animals as proposed by NIOSH. The
commenter used the drugs clonazepam and olaparib as examples of drugs
for which these criteria should not be used.
NIOSH response: NIOSH uses a dose 10 mg/day in an adult human or 1
mg/kg/day in animals as one consideration in evaluating potential
hazards related specifically to organ system toxicity at low doses.
NIOSH also may consider the human recommended dose as a threshold for
some effects. This is because occupational exposure is expected to be
lower (and therefore, less potentially hazardous) than therapeutic
exposure. NIOSH does not usually use a lethality measure
(LD50) when assessing potential hazards. In general, if the
effect of concern occurs at or below the human treatment dose, then it
would likely be considered a hazardous drug. Clonazepam is on the List
because it has developmental and reproductive effects at lower than the
[[Page 25649]]
maximum human recommended dosage. Olaparib is also on the List because
of the potential reproductive and developmental hazards at less than
the human dosage. Therefore, NIOSH does not agree with the commenter's
recommendation and has made no change in the Procedures.
d. Tabular Arrangement of Hazardous Drugs on the List
Public comment: Several commenters questioned the use of
manufacturer's MSHI as a criterion for placement in Table 1 of the
NIOSH List. Table 1 contains drugs that have MSHI in the package insert
and/or meet the NIOSH definition of a hazardous drug, and are
classified by the National Toxicology Program (NTP) as known to be a
human carcinogen and/or classified by the International Agency for
Research on Cancer (IARC) as carcinogenic to humans (Group 1) or
probably carcinogenic to humans (Group 2A). The commenters indicated
that, because MSHI is not a part of the package insert required by FDA,
linking the MSHI to placement on Table 1 would provide a disincentive
to manufacturers to provide MSHI.
NIOSH response: The MSHI is directly relevant to worker protection
from hazardous drugs and often cites the Occupational Safety and Health
Administration (OSHA) hazardous drug guidance website.\6\ Manufacturers
have provided MSHI to alert workers to how their drug can be safely
handled. By placing drugs with MSHI into Table 1, NIOSH is
acknowledging and amplifying what manufacturers, who are in the best
position to know the toxicity information for their drugs, have already
determined to be the best way to handle their product. Manufacturers do
not provide MSHI lightly and NIOSH believes it is in the manufacturers'
interest to continue to provide information to protect workers handling
their drugs. Accordingly, the Table 1 MSHI criterion has been retained.
No change to the Procedures has been made in response to this comment.
---------------------------------------------------------------------------
\6\ See http://www.osha.gov/SLTC/hazardousdrugs/index.html.
---------------------------------------------------------------------------
Public comment: Commenters also weighed in on the carcinogen
classifications by the IARC and NTP required for placement in Table 1.
One commenter suggested that when drugs are identified by IARC as known
human carcinogens ``only after prolonged exposure,'' NIOSH should
consider moving them to Table 2 of the List. Table 2 contains drugs
that meet the definition of a hazardous drug but do not have MSHI and
are not classified as human carcinogens by NTP or IARC. The commenters
also indicated that NIOSH should look carefully at the drug's mode of
action when making that determination. Another commenter noted that
NIOSH placed drugs that NTP classified as ``known to be carcinogenic in
humans'' in Table 1 but did not do so with drugs that were classified
as ``reasonably anticipated to be carcinogenic in humans.''
NIOSH response: To simplify the criteria for Table 1, NIOSH is
retaining the criteria proposed in the May 2020 notice, so that
``[d]rugs that have MSHI in the package insert and/or meet the NIOSH
definition of a hazardous drug and one or more of the following
criteria: are classified by NTP as known to be a human carcinogen, or
are classified by IARC as Group 1 carcinogenic to humans or Group 2A
probably carcinogenic to humans'' are included in Table 1. Drugs
classified by NTP as reasonably anticipated to be carcinogenic to
humans are evaluated by NIOSH and may be placed on Table 2; the
designation of reasonably anticipated alone is not sufficient to place
a drug in Table 1. However, NIOSH acknowledges that the context of the
carcinogenicity and the mode of action are important information to
consider when employers are evaluating the potential risk to workers
related to this hazard.
Table 2 of the List includes ``[d]rugs that meet the NIOSH
definition of a hazardous drug and do not have MSHI, are not classified
by NTP as known to be a human carcinogen, and are not classified by
IARC as Group 1, carcinogenic to humans, or Group 2A, probably
carcinogenic to humans. (Some may also have adverse developmental and/
or reproductive effects.)'' Of note, Table 2 includes those drugs that
meet the NIOSH definition of a hazardous drug and exhibit
carcinogenicity in humans but have not been evaluated by IARC or NTP or
have been classified by NTP as reasonably anticipated to be
carcinogenic to humans or by IARC as possibly carcinogenic to humans
(Group 2B). No change to the Procedures has been made in response to
this comment.
4. Section V.D. Step 4: Peer Review of Potentially Hazardous Drugs and
Section V.E. Step 5: Public Review of Potentially Hazardous Drugs
Public comment: One commenter stated that the process would be
improved with an opportunity for manufacturers (called ``sponsors'' in
some comments) to provide input early in the screening process
described in Sec. V of the Procedures. Specifically, the commenter
suggested that
. . . NIOSH could include an additional step in the screening
process of drugs being considered for inclusion on the List. This
step would involve notifying sponsors when their drug(s) is/are
being considered for inclusion on the List. NIOSH would then have an
opportunity to request sponsor input on inclusion of specific
products, and sponsors could choose to submit additional data
regarding the potential hazards (or lack thereof) that could be
useful to the peer review committee in their review activities.
NIOSH response: NIOSH finds the current process utilizing peer
review and public comment provides ample opportunity for interested
parties to participate in development of the List. Manufacturers
(sponsors) and others are welcome to provide relevant data and
information that may not be already available. In addition, there is a
formal reevaluation process through which manufacturers can provide
additional data for reevaluation of a drug, described in Sec. VI of the
Procedures. NIOSH notes that, to date, interested parties have provided
only limited additional toxicology information in response to
publication of the draft List in the May 2020 notice, and much of that
data was provided as part of the reevaluation process. No change to the
Procedures has been made in response to this comment.
Public comment: One commenter indicated that the peer reviewers who
reviewed the draft Procedures in 2018 were inadequately identified and
their credentials were not clear.
NIOSH response: The peer reviewers, their credentials, and the
charge to reviewers can be viewed on the NIOSH web page, Peer Review
Plan for the Procedures for Developing the NIOSH List of Hazardous
Drugs in Healthcare Settings, available at https://www.cdc.gov/niosh/topics/hazdrug/peer-review-plan.html.
IV. Managing Hazardous Drug Exposures: Information for Healthcare
Settings
In addition to the Procedures and List documents, NIOSH solicited
feedback on the guidance document, Managing Hazardous Drug Exposures:
Information for Healthcare Settings. Four peer reviewers, whose names
and credentials are available on the NIOSH Peer Review web page,\7\
reviewed the draft. Public comments follow the peer review responses
below, along with NIOSH responses. Overall, peer reviewers and public
commenters were supportive of
[[Page 25650]]
this new resource and offered many suggestions for its improvement.
---------------------------------------------------------------------------
\7\ https://www.cdc.gov/niosh/review/peer/isi/healthsafetyrisks.html.
---------------------------------------------------------------------------
A. Peer Review
The charge given to the peer reviewers for the Managing Exposures
document is available on the NIOSH Peer Review web page.\8\ Peer review
questions are listed below with the peer reviewer responses summarized
beneath each question.
---------------------------------------------------------------------------
\8\ Id.
---------------------------------------------------------------------------
Reviewers' concerns that focused on issues in other documents (for
example, the definition of hazardous drugs or the organization of the
tables in the List) are included under the NIOSH responses to comments
for those documents.
1. Charge 1.a. What additional information would improve [the
document's] usefulness and why?
Peer review: One peer reviewer suggested additional helpful
references to ``. . . resources developed by professional organizations
regarding safer handling of hazardous drugs.'' In addition, multiple
reviewers suggested more extensive referencing of USP <800>.
NIOSH response: Additional links to helpful resources were added to
the document. However, regarding USP <800>, NIOSH notes that many of
the references circle back to NIOSH recommendations, so in those
instances reference to USP <800> was not made. However, some references
to USP <800> were added into the text where the recommendations were
not originally from NIOSH guidance. A link to USP <800> has also been
added to the document's Resources section.
2. Charge 1.b. What changes could be made to improve the utility of the
information?
Peer review: One reviewer expressed concern that the definition of
hazardous drug was changed without input from a much larger and
international group of interested parties.
NIOSH response: This comment is addressed with the public comments
received in the response to comments in Sec. II of the Procedures
document.
Peer review: Another reviewer suggested that the information be
distilled into a fact sheet or job aid to encourage implementation.
NIOSH response: NIOSH has reformatted the Table of Control
Approaches for Safer Handling of Hazardous Drugs, by Activity and
Formulation (Table of Control Approaches) in Managing Exposures, Ch. 8,
to make it easy to reproduce. NIOSH is also considering the development
of additional materials to summarize the information in Managing
Exposures and help employers implement the NIOSH guidance.
3. Charge 1.c. What information is redundant, incorrect, missing, or
not needed? Please Explain
Peer review: One reviewer suggested that the narrative immediately
following the Table of Control Approaches did not add substantive
information and could be removed.
NIOSH response: Since no other peer or public comments identified
this as a problem, and in recognition that people absorb information in
different ways, NIOSH has decided not to revise or remove the narrative
following the table. No change to Managing Exposures has been made in
response to this comment.
Peer review: One reviewer noted some differences between the
Oncology Nursing Society (ONS) recommendations and the NIOSH
recommendations in the Table of Control Approaches. These included
recommendations for the use of double versus single gloves when
handling manufacturer prefilled syringes and the double flushing of
toilets.
NIOSH response: NIOSH reviewed the risks addressed in the ONS
recommendations and adjusted the text throughout the Managing Exposures
document as necessary, emphasizing that facilities are responsible for
conducting site risk assessments and developing standard operating
procedures (SOPs). The NIOSH recommendation for single gloves in
handling prefilled syringes has been retained. The recommendation for
flushing twice has been removed, specifying that a plastic-backed
absorbent pad should be placed over toilets without lids during
flushing.
Peer review: One reviewer noted that NIOSH should clarify that the
controls were in descending order of effectiveness in the Table of
Control Approaches.
NIOSH response: NIOSH has clarified the hierarchy of controls with
additional text in Ch. 6, stating, ``[t]he controls at the top of the
hierarchy are the most effective and provide the best business value.''
Peer review: The same reviewer asked whether medical surveillance
was part of administrative controls.
NIOSH response: Medical surveillance is part of a comprehensive
exposure control program complementing engineering controls, safe work
processes (administrative controls), and use of PPE. In response to the
peer reviewer's query, NIOSH has rearranged Managing Exposures and
moved the section on medical surveillance into Ch. 6 to clarify that
this consideration should be a part of the workplace's risk management
plan.
4. Charge 2. Please Provide Any Additional Studies or Scientific
Information That Evaluate or Validate Engineering, Work Practice, or
Administrative Controls To Reduce Exposures to Hazardous Drugs in
Healthcare Settings
Peer review: Reviewers commented on including references to USP
<800> and provided additional links to resources and additional
citations.
NIOSH response: As discussed above, links to suggested resources
and suggested citations have been added to the document where
appropriate.
Peer review: One reviewer requested that a citation be added
regarding the insufficient protection offered by surgical masks during
compounding.
NIOSH response: NIOSH agrees; this reference was included in the
May 2020 notice draft Managing Exposures. See Ch. 6, Sec. 6.4, Personal
Protective Equipment, in which NIOSH states:
Surgical masks that are not labeled as N95 are not NIOSH-
approved, do not provide respiratory protection, and should not be
used to compound or administer fine powders which may result from
handling hazardous drugs [citations omitted].
Peer review: Reviewers suggested specific risk mitigation
strategies, such as requiring that all employees handling hazardous
drugs wear PPE; having written policies to govern spill cleanup;
requiring the availability of spill kits; having written policies that
address medical surveillance; specifying that training should happen
prior to working with hazardous drugs and annually thereafter; and that
demonstrating and documenting annual competency were warranted.
NIOSH response: NIOSH recommends that workers performing any task
involving hazardous drugs, including all compounding, administration,
waste handling, and spill response, wear all assigned PPE to reduce the
exposure and provide a barrier of protection. The recommendations on
spill cleanup and spill kits, written policies on medical surveillance,
training prior to working with hazardous drugs, and competency being
determined and documented have been added to Managing Exposures.
[[Page 25651]]
5. Charge 3. Please Provide Any Additional Studies or Scientific
Information That Support or Validate the Use of the NIOSH Recommended
Control Strategies or Alternative Strategies To Control Exposures to
Hazardous Drugs
Peer review: One reviewer suggested including a reference on spills
and PPE use and another on the hierarchy of controls and PPE use.
NIOSH response: In response to the peer reviewer, NIOSH has added
references to Managing Exposures to support the use of the hierarchy of
controls when PPE is inconsistently used (Friese et al. 2011) \9\ and
during spill response (Friese et al. 2020) \10\ were added to document.
---------------------------------------------------------------------------
\9\ Friese CR, Himes-Ferris L, Frasier MN, McCullagh MC, Griggs
JJ [2011]. Structures and Processes of Care in Ambulatory Oncology
Settings and Nurse-Reported Exposure to Chemotherapy. BMJ Qual Saf.
21(9):753-759.
\10\ Friese CR, Wong M, Fauer A, Mendelsohn-Victor K, Polovich
M, McCullagh MC [2020]. Hazardous Drug Exposure: Case Report
Analysis from a Prospective, Multisite Study of Oncology Nurses'
Exposure in Ambulatory Settings. Clin J Oncol Nurs. 24(3):249-255.
---------------------------------------------------------------------------
6. Charge 4. Please Provide Any Additional Studies or Scientific
Information That Support or Validate Evidence-Based Strategies or
Approaches for Controlling Exposures to Hazardous Drugs That Are
Different From Those That NIOSH Has Proposed
Peer review: Reviewers suggested language clarifications and
additional references for NIOSH consideration.
NIOSH response: NIOSH agrees with many of the suggestions and
references offered by peer reviewers and has revised the final Managing
Exposures accordingly.
Peer review: Reviewers questioned the location and composition of
the recommendations for medical surveillance.
NIOSH response: As discussed above, in response to the peer
reviewer, the topic of medical surveillance was moved into Ch. 6, Risk
Management Plan. Medical surveillance should be included as a part of a
comprehensive exposure control program to protect the health of
workers. This section now includes the following recommendation:
Elements of a medical surveillance program for workers exposed
to hazardous drugs should include the following:
Consideration of a baseline clinical evaluation to
allow for an individualized point of comparison should adverse
health effects of exposure to hazardous drugs be suspected in the
future. Whether a worker should undergo baseline clinical evaluation
should be based on the availability of clinical examinations and
tests which can be targeted toward specific hazardous drugs and
health endpoints, as well as their corresponding performance
characteristics, such as sensitivity, specificity, and predictive
value. If a baseline clinical evaluation is performed, it can
include a targeted (1) medical history, (2) physical examination,
and (3) laboratory testing. Selection of baseline evaluation
components should be informed by the toxicities of the hazardous
drugs to be handled.
Health questionnaires administered by a healthcare
professional at the time of hire and periodically. The
questionnaires should include information about relevant symptoms
and medical events. Reproductive outcomes such as miscarriage should
be included whenever anticipated as an adverse outcome of hazardous
drug exposure because their occurrence may go unreported.
History of drug handling as an estimate of prior and
current exposure, including dates of duty assignment related to
hazardous drugs and similar types of information.
A follow-up plan, as needed, for workers who have had
health changes suggesting toxicity or have experienced acute
exposure (for example, from substantial skin contact or inhalation
or from cleaning a large spill [a broken IV bag, leaking IV line,
etc.]) [citation omitted].
Peer review: One reviewer suggested a reference describing controls
in urological procedures.
NIOSH response: This reference has not been included because NIOSH
determined it is a general paper and does not address specific worker
exposure from the medical procedure, bladder installation. No change to
Managing Exposures has been made in response to this comment.
7. Charge 5.a. What additional information would improve the usefulness
of [the Table of Control Approaches in Chapter 8] and why?
Peer review: One reviewer suggested adding a statement indicating
that compounding and manipulating oral hazardous drugs should be done
in a compounding area, and not a patient care area, and to alert
medical personnel of the hazards.
NIOSH response: NIOSH has provided separate recommendations for
compounding and administering in the Table of Control Approaches. It
would be impractical to try to identify all actions that would fall
under a ``do not do this'' recommendation. No change to Managing
Exposures has been made in response to this comment.
Peer review: Another reviewer mentioned that a job aid or standard
operating procedure would be of particular help associated with the
Table of Control Approaches.
NIOSH response: The Table of Control Approaches is meant to stand
alone without a standard operating procedure. NIOSH is developing a
shorter fact sheet to assist employers. No change to Managing Exposures
has been made in response to this comment.
8. Charge 5.b. What structural or format changes could be made to
improve the utility of [the Table of Control Approaches]?
Peer review: Two reviewers noted that the format of the Table of
Control Approaches should be considered for potential use as a stand-
alone document and maximized for searching online.
NIOSH response: NIOSH agrees and has developed the final Table of
Control Approaches with those considerations in mind.
9. Charge 5.c. What information is redundant, incorrect, missing, or
not needed [in the Table of Control Approaches]? Please Explain
Peer review: One reviewer suggested reference to the 2018 Oncology
Nursing Society's Safe Handling of Hazardous Drugs, 3rd edition (ONS
2018) as an additional resource for exposure control approaches and
recommended a specific control strategy when attaching needles to
closed system transfer devices (CSTDs). The same reviewer mentioned
that double flushing was no longer recommended.
NIOSH response: NIOSH agrees and has added a citation to ONS 2018
to provide an additional resource for exposure control strategies.
NIOSH has also included a link to a NIOSH topic page on CSTDs to
further describe the appropriate controls needed when using CSTDs. The
suggested revision, however, is too specific for this general
recommendation document. NIOSH concurs that double flushing was not
recommended and has revised the document to update the recommendations.
Peer review: Another reviewer stated that the content of the Table
of Control Approaches was overwhelming and suggested a bullet point
summary. The reviewer also suggested linking to the USP Reference
Standards Mobile App.
NIOSH response: NIOSH is developing a shorter fact sheet to present
a summary of the information. A reference to USP <800> has been added
to the document's Resources section. However, NIOSH has not provided a
link to a for-purchase product.
[[Page 25652]]
10. Charge 6. What improvements could be made to this risk management
information to make it more useful to employers and healthcare workers?
Please Provide Specific Examples
Peer review: Two reviewers suggested that NIOSH recommend
alternative duty for pregnant women or individuals trying to conceive
to further reduce potential worker risks and advocated expanding the
Medical Surveillance section with specific requirements.
NIOSH response: NIOSH has determined that the employer is in the
best position to ascertain the utility and feasibility of alternative
duty as a control strategy in their workplace. As discussed above, the
components and timing of medical surveillance should be determined by
the licensed healthcare professional conducting the medical evaluation.
No change to Managing Exposures has been made in response to this
comment.
Peer review: Another reviewer suggested visual abstracts and
graphics to better convey concepts and summarize key points referenced
in a 2019 study by Friese et al., entitled Randomized Controlled Trial
of an Intervention to Improve Nurses' Hazardous Drug Handling,
published in the Oncology Nursing Forum.\11\
---------------------------------------------------------------------------
\11\ Friese CR, Yang J, Mendelsohn-Victor K, McCullagh M [2019].
Randomized Controlled Trial of an Intervention to Improve Nurses'
Hazardous Drug Handling. Oncol Nurs Forum. 46(2):248-256.
---------------------------------------------------------------------------
NIOSH response: The visual aspect of Friese et al. 2019 is
inspiring. NIOSH is considering reviewing the documents to look for
opportunities to create shorter fact sheets with meaningful graphics to
improve understanding. In addition, a NIOSH visual communication team
has worked to make the Table of Control Approaches in the Managing
Exposures document easier to read and reproduce.
Peer review: One reviewer suggested adding a section on home
veterinary care, recommending information from a specific reference.
NIOSH response: The NIOSH document is geared towards employees in
healthcare settings, including veterinarians and veterinary staff, but
not pet owners doing home veterinary care. However, the veterinary
resource suggested was a ``consensus opinion'' about protecting both
veterinary workers and owners so it was added to the document's
Resources section.
11. Charge 7. Please Provide Information About Your Professional
Experience, if Any, of Implementing Control Strategies for Exposures to
Hazardous Drugs in Healthcare or Similar Settings. Please Describe What
You Found to Be Most or Least Effective and Why. Include Relevant
Publications if Available
Peer review: One reviewer indicated that there is a need for
increased signage for all staff, family, and visitors in contact with
patients receiving hazardous drugs. References were suggested outlining
the scope of the problem.
NIOSH response: The recommendation for signage has been added to
the document.
Peer review: Another reviewer asked why recommendations were made
to protect veterinary patients but not humans in veterinary practices.
NIOSH response: NIOSH has clarified that the recommendations are
designed to protect veterinary workers not the veterinary patients.
Peer review: One reviewer was concerned with potential hazardous
drugs exposures from patient or general public exposure to toilets in
outpatient settings and suggested the addition of the following
reference: Walton A, Bush MA, Douglas C, Allen DH, Polovich M,
Spasojevic I [2020], Surface Contamination with Antineoplastic Drugs on
Two Inpatient Oncology Units, Oncol Nurs Forum 47(3):263-272.
NIOSH response: NIOSH determined the reference cited contained
useful information pertaining to identification of potentially
contaminated areas and has added it to the section on surface
contamination.
Peer review: One reviewer was concerned that wipe testing be
conducted where hazardous drugs should not be found as an important
exposure control.
NIOSH response: Ch. 6, Sec. 6.5, Surface Contamination, has been
edited to include sampling where hazardous drugs are prepared,
administered to patients, or otherwise handled (i.e., receiving areas,
transit routes throughout the facility, and waste storage areas).
Peer review: One reviewer recommended NIOSH add references on the
persistence of contamination even when workplace controls are used
(i.e., Kopp B, Schierl R, Nowak D, 2013; and Walton A, Bush MA, Douglas
C, Allen DH, Polovich M, Spasojevic I, 2020).
NIOSH response: Ch. 6, Sec. 6.5 has been edited to include the
suggested references as well as others to support the premise that
workplace contamination with hazardous drugs continues to be an issue
in the United States.
Peer review: One reviewer suggested that Managing Exposures
recommend ``spill drills'' to train and refresh training for employees.
NIOSH response: NIOSH concurs and has added language to the
document recommending that workplaces practice for spills.
12. Charge 8. Please Provide Any Additional Comments or Suggestions
Either as a List Below or Using Track Changes in the Attached Draft
Document
Peer review: One reviewer suggested that Managing Exposures include
guidance from ONS 2018 regarding the use of chewing gum and tobacco and
the application of cosmetics in the areas where hazardous drugs are
handled; written policies that address spill cleanup and medical
surveillance; and the availability of spill kits.
NIOSH response: NIOSH concurs and has added language to the final
document pertaining to the suggestions. Additionally, ONS 2018 has been
both cited and listed as an additional resource.
Peer review: One reviewer recommended changing ``nurses' aides'' to
``nurses' assistants.''
NIOSH response: NIOSH concurs with the suggested change and has
revised the final Managing Exposures accordingly.
Peer review: One reviewer suggested that ``large spill'' be
defined.
NIOSH response: NIOSH concurs this should be clearer, and in the
recommendation regarding a follow-up plan for workers who have
experienced acute exposures from large spills has clarified that large
spills may result from a broken IV bag, leaking line, or similar event.
NIOSH has determined that defining ``large spill'' would be too
prescriptive because ``large'' is subjective and may depend on such
factors as the concentration of the drug and the amount of surface area
upon which it may be spilled. Accordingly, the definition of ``large
spill'' should be defined by each facility according to its own needs.
Peer review: One reviewer requested more specific language in the
recommendations for training.
NIOSH response: NIOSH agrees and has added information about
providing training frequently and when there are new hazardous drugs
brought into the facility. Workers should be trained prior to beginning
work with hazardous drugs and should demonstrate competency before they
handle a hazardous drug, clean an area where hazardous drugs are
[[Page 25653]]
used, and perform work tasks that will potentially expose them to the
body fluids of a patient who is taking hazardous drugs.
Peer review: One reviewer requested more clarity about signage.
NIOSH response: NIOSH agrees and has clarified that signage should
be placed where the hazardous drugs are used and stored.
Peer review: One reviewer requested additional information about
handling contaminated excreta.
NIOSH response: NIOSH agrees and has added language about handling
of drug contaminated excreta.
Peer review: Two reviewers commented that Managing Exposures should
specify the types of gloves that should be used for different hazards,
and that NIOSH should clarify how often PPE should be changed and the
order of doffing PPE.
NIOSH response: NIOSH disagrees that the document should provide
specifics on the type of glove to be used since different glove types
offer different protection from dermal exposure to hazardous drugs.
NIOSH does agree that providing information on when to change PPE and
the order of doffing PPE is important and has added the recommendation
``[r]emove PPE in the following order: shoe covers, sleeve covers,
outer gloves, face shield, gown, respirator/mask, inner gloves'' to
Sec. 6.4, Personal Protective Equipment. No change to Managing
Exposures has been made in response to this comment.
Peer review: One reviewer had specific suggestions regarding
controls for CSTDs, specifically regarding double gloving when using
prefilled syringes and when plastic-backed pads should be used.
NIOSH response: NIOSH agrees with the suggestion about the use of
plastic-backed pads and new language has been added to the existing
discussion on CSTDs in Ch. 6, Sec. 6.2, Engineering Controls. NIOSH
disagrees that double gloves are needed when using prefilled syringes
and has made no changes in response to this recommendation.
Peer review: One reviewer commented that eyewash stations should be
mentioned, exposure assessment through wipe sampling (at baseline and
routine intervals) could be clarified, and the heading for Sec. 8.3
could be made more explicit.
NIOSH response: NIOSH agrees and has added information to Sec. 6.5
Surface Contamination, on wipe sampling, and to Sec. 7.2, Spill
Control, on eyewash stations. The heading for Sec. 8.3 in the 2020
draft Managing Exposures has been changed to ``Additional
Considerations for Handling Hazardous Drugs'' and the section was
turned into a new Ch. 9.
B. Public Comments
1. Glossary
Public comment: NIOSH received comments from five commenters
related to definitions in the Glossary. The following definitions were
suggested:
Biological safety cabinet (BSC): ``laboratory'' may be
confusing; consider instead ``an enclosed, ventilated workspace . . .''
Cleaning: Removal of organic and inorganic material from
objects and surfaces using water, detergents, surfactants, solvents,
and/or other chemicals.
Decontamination: Inactivating, neutralizing, or physically
removing hazardous drug residue from non-disposable surfaces and
transferring it to absorbable, disposable materials appropriate to the
area being cleaned.
Deactivation: To render a compound inert or inactive.
Disinfection: A process of inhibiting or destroying
microorganisms.
NIOSH response: NIOSH has added the suggested definitions for
``deactivation'' and ``disinfection'' in the final Managing Exposures.
2. Chapter 1.0 Purpose and Scope
Public comment: A commenter asked for clarity on recommendations
for retail pharmacies.
NIOSH response: NIOSH notes that retail facilities should perform
the appropriate risk assessments. The assessments may show, due to
limited handling or manipulation of open containers, that the risks of
exposure are limited. However, the assessment of potential handling
scenarios in the facility should still be performed to determine what
those risks are. No change was made to the final Managing Exposures in
response to this comment.
Public comment: A commenter suggested NIOSH highlight potential
exposures to hazardous drugs through handling of human fluids and
wastes.
NIOSH response: NIOSH agrees and has edited Ch. 4.0, Occupational
Exposure Assessment, to highlight the potential risk from exposure to
human waste products (i.e., urine, feces, vomit).
3. Chapter 6.0 Risk Management Plan
Public comment: Several commenters on both the Managing Exposures
draft and the List draft mentioned specific issues regarding the
assessment of risk discussed in Ch. 6.0. Several asked for more
specific guidance for site risk assessments, particularly surrounding
administration and compounding.
NIOSH response: NIOSH disagrees that Managing Exposures should
provide more specific guidance for risk assessments. Each facility
should conduct its own risk assessment to determine which tasks within
the facility would be considered administration or compounding. In
response to these comments, NIOSH has revised the language in the final
document to specify that each facility should conduct its own risk
assessment and develop SOPs specific to its use of hazardous drugs.
a. Section 6.2 Engineering Controls
Public comment: Seven comments were received on engineering
controls discussed in Sec. 6.2 (in addition to comments related to
CSTDs, which are considered below). Commenters suggested adding
information about engineering controls, such as uninterrupted power
supply, negative pressure, and unidirectional flow of air. Some
commenters also suggested specific recommendations regarding use of
BSCs and compounding aseptic containment isolators (CACIs),
clarification of the recommendations regarding nonsterile preparations
in footnote 4 of the Table of Controls in Ch. 8, use of glove bags and
suggestions for various updated references. One commenter noted that
cleaning is not the only step needed to ensure the BSC or CACI is in
optimal condition to compound drugs. Proper use also includes processes
to deactivate (i.e., render a compound inert or inactive),
decontaminate (i.e., remove hazardous drug residue), and disinfect
(i.e., destroy microorganisms).
NIOSH response: BSC selection should be based on a risk assessment
of the hazardous drugs in use at each facility and be flexible enough
to allow for evolving equipment types and performance specifications.
In response to comments, NIOSH has clarified the language in the
document as follows:
Class II BSCs that exhaust filtered cabinet air to the outdoors
are recommended. BSCs that exhaust cabinet air back into the
segregated engineering control (SEC) are discouraged. When the work
activity requires handing volatiles, a risk analysis should be
conducted to identify the appropriate Class II BSC selection to
ensure that any air recirculation internal to the BSC does not
result in vapor accumulation.
NIOSH provides recommendations related to the proper use of
ventilated cabinets, and, in response to comments, NIOSH has revised
one of the recommendations to clarify that proper use requires users to
``[i]nstall, maintain, deactivate, decontaminate, clean and disinfect
the BSC.'' Another
[[Page 25654]]
recommendation has been revised to read ``[h]ave readily available or
display a current field-certification label prominently on the
ventilated cabinet.'' NIOSH has also added recommendations for negative
pressure and an uninterrupted power source.
In response to comments, NIOSH has defined the terms
``deactivate,'' ``decontaminate,'' and ``disinfect'' in the Glossary to
improve clarity.
In reference to the comment on nonsterile preparations in the Table
of Control Approaches footnote 4, the footnote is only intended for
nonsterile preparations, as stated. It should not be taken to suggest
that NIOSH recommends that sterile compounding does not need to be
performed in a sterile ventilated engineering control as long as the
person compounding is wearing appropriate respiratory protection. This
document addresses worker safety. In the interest of patient safety and
drug safety all appropriate USP guidelines should be followed. No
change to the document was made in response to this comment.
Regarding the comment on glove bag use, NIOSH is unaware of any
reason why a small sterile glove bag that does not deflect airflow to
outside of the direct compounding area could not be used inside a BSC.
NIOSH is also unaware of any confusion or conflicts created by past
glove bag recommendations. In NIOSH's experience, these are only rarely
used but they could indeed be used as described and would also be
protective. NIOSH is unaware of a unidirectional airflow requirement.
Even if used under unidirectional airflow, if the glove bag interior
and inserted supplies were all sterile, and the glove bag placed
beneath a laminar flow of ISO 5 air, NIOSH believes this still would
meet the intent of the recommendation. Of course, each facility should
conduct their own risk assessment and develop SOPs specific to their
use of hazardous drugs. No change to Managing Exposures has been made
in response to this comment.
Closed System Transfer Devices
Public comment: One commenter suggested removing or altering images
that reference proprietary names in Figures 4 and 5. Particularly in
Figure 5, which includes a photograph of a robotic drug preparation
system with the manufacturer's name in the photo credit. This device is
``not yet fully functional in the United States'' and should not be
part of the NIOSH informational document. In general, such images may
not be representative of the numerous products available on the U.S.
market for safely compounding hazardous drugs and demonstrates bias.
NIOSH response: Regarding the figures, NIOSH has decided to keep
them in the final Managing Exposures. However, in Figure 4, NIOSH has
substituted more non-specific images of two types of CSTDs that are
representative of those available in the U.S. market rather than
photographs. The following Disclaimer continues to be included on the
title page: ``[m]ention of any company or product does not constitute
endorsement by the National Institute for Occupational Safety and
Health (NIOSH).''
Public comment: A commenter suggested the removal of references to
robotic systems.
NIOSH response: NIOSH has not changed the document in response to
this comment, noting that the text already states ``robotic systems are
considered supplemental controls that should only be used in
combination with primary engineering controls (i.e., BSCs and CACIs) to
further protect against worker exposures to hazardous drugs.''
Public comment: One commenter requested clarification in the
wording related to priming IV tubing.
NIOSH response: In response to the comment, NIOSH has reworded the
sentence to state, ``[c]ompounding personnel should prime the IV tubing
and syringes inside the ventilated cabinet or prime them in-line with
nondrug solutions or by use of a CSTD to prevent the escape of
hazardous drugs.''
Public comment: Five comments were received on recommendations
regarding CSTDs, all specifically focused on issues of compatibility
with the drug product.
NIOSH response: Each facility should conduct its own risk
assessment and develop SOPs specific to its use of hazardous drugs.
NIOSH states in Sec. 8.1 that the MSHI should be consulted. However, in
response to comments, NIOSH has added the language ``when dosage form
allows'' in every case where a CSTD is recommended in the Table of
Control Approaches.
b. Section 6.3 Administrative Controls
Alternative Duty
Public comment: Two commenters made suggestions on alternative
duty. Both proposed including recommendations on the importance of
alternative duty for healthcare workers who are pregnant, trying to
conceive, or who are breastfeeding.
NIOSH response: NIOSH recognizes that alternative duty is one
method to control hazardous exposures to healthcare workers who are
pregnant, trying to conceive, or who are breastfeeding. However, NIOSH
has determined that the specific control strategies should be left up
to the employer who is in the best position to conduct an in-depth
individual facility risk assessment. No change to Managing Exposures
has been made in response to this comment.
Cleaning
Public comment: One commenter requested clarification of the terms
associated with cleaning activities.
NIOSH response: In response to the comment, NIOSH has edited Sec.
6.3 to clarify the difference between cleaning and decontamination. In
Sec. 6.3, NIOSH has replaced the term ``rags'' with ``disposable
wipes'' and has clarified that ``[w]ork surfaces should be deactivated,
decontaminated, and cleaned before and after each activity and at the
beginning and end of the work shift.'' The terms ``deactivation'' and
``decontamination'' have been added to the Glossary.
Counting Tablets
Public comment: Four commenters had questions on counting tablets,
discussed in Sec. 6.3. Specifically, the comments questioned whether
the information was considered to establish requirements or merely
recommendations, and how the recommendation to limit the use of
automated counting machines should be implemented.
NIOSH response: In this document, NIOSH is issuing recommendations
not requirements. The document is informational in nature and creates
no legal obligation. Regarding counting tablets, NIOSH has clarified
the language in Sec. 6.3 of the document recommending that automated
counting machines be prohibited for hazardous drugs unless the machine
has been evaluated and found to not release powders.
Public comment: One commenter suggested changing the NIOSH
recommendations for use of automated counting machines.
NIOSH response: In response to the comment, NIOSH has revised the
recommendations on the use of counting machines to include the
following text and references:
Tablet and capsule forms of hazardous drugs should not be placed
in an automated counting machine unless a facility risk assessment
validates that the specific machine does not introduce dust and
contamination; most counting machines can stress tablets and
capsules thereby introduce
[[Page 25655]]
powdered contaminants into the work area [citations omitted].
c. Section 6.4 Personal Protective Equipment
Use of Gloves
Public comment: Fourteen comments were received about the
recommendations on glove use discussed in Sec. 6.4. The comments
specifically addressed the use of single versus double gloves during
shipping and receiving and while handling prefilled syringes. There
were also comments on the use of spray alcohol on gloves and the use of
sleeve covers with gloves.
NIOSH response: In response to several comments, the recommendation
for receiving, unpacking, and placing in storage has been changed to
single glove. Although NIOSH already recommends employers ``ensure that
the selected gloves are not degraded by the alcohol,'' the
recommendation for use of spray alcohol was removed. NIOSH is retaining
the recommendation of a single glove for manufacturers' prefilled
syringes as it is anticipated that they have less of a chance for
exterior contamination. Facilities should conduct their own risk
assessment to determine gloving requirements for their specific
situations.
Use of Gowns, Sleeve Covers, and Head Covers
Public comment: Seven reviewers suggested that the recommendation
for sleeve covers should be removed or modified.
NIOSH response: In response to the comment, NIOSH has turned the
recommendation for the use of sleeves into a consideration:
``[c]onsider using sleeve covers if there is a gap between the gown and
the glove.''
Public comment: One commenter suggested that NIOSH state that gowns
be shown to resist permeation by hazardous drugs. Another reviewer
suggested that information about the frequency of changing gowns be
added.
NIOSH response: NIOSH has added language clarifying that gowns
should be shown ``to resist permeation by the types of hazardous drugs
used'' to Sec. 6.4, Gowns. Language has also been added to recommend
changing gowns after one use or at a frequency determined by the
employer and immediately after a spill or splash and disposing of in an
appropriate waste container.
Public comment: One commenter suggested that NIOSH should define
the term ``face shield'' to reduce the risk of confusion.
NIOSH response: Because face shields are very common in healthcare
(and the general public) the term is generally understood and no
further definition was required. No change to Managing Exposures has
been made in response to this comment.
Use of Respirators
Public comment: Five comments were received on respirator use. Some
requested detailed guidance for spill and cleaning activities. Other
comments included a request for guidance during compounding and
clarification on respirator selection when using volatile hazardous
drugs. One comment suggested that the powered air-purifying respirator
(PAPR) depicted in Figure 6 is not appropriate for use with drugs that
are volatile.
NIOSH response: Regarding the comments for specific guidance, NIOSH
reiterates that each facility should conduct its own risk assessment
and develop SOPs for specific scenarios. NIOSH has clarified its
guidance on respirator use with volatile hazardous drugs by adding the
recommendation: ``[u]se a full-facepiece combination particulate/
chemical cartridge-type respirator or a powered air-purifying
respirator (PAPR) whenever handling volatile hazardous drugs or
aerosolizing hazardous drugs for inhalation or nebulized therapy.'' The
images in Figure 6 were used as examples of the types of respirators
that could be used. to protect workers from hazardous drug exposures.
The type of PAPR in Figure 6 may not be the correct PAPR for every
situation. Facilities should choose the correct device that fits their
specific needs and as stated in the disclaimer, ``[m]ention of any
company or product does not constitute endorsement by the National
Institute for Occupational Safety and Health (NIOSH).'' Changes were
made to the text to indicate a variety of potential respirators for
different needs.
d. Section 6.5 Surface Contamination
Public comment: One comment suggested expanding the section on
monitoring surface contamination. Another noted that there was no
mention of assessing environmental contamination by surface wipe
sampling, and that this technique has become a sophisticated and useful
tool in other countries but not yet adopted by U.S. facilities handling
hazardous drugs.
NIOSH response: NIOSH has revised the document to include
additional references to support the recommendations on wipe testing
for contamination.
e. Section 6.6 Medical Surveillance
Public comment: NIOSH received several comments on medical
surveillance. Two comments mentioned the difficulty and burden of
instituting a medical surveillance program in a mobile workforce and in
small businesses. Another asked for clarity on the recommended
frequency of clinical follow-up. One commenter stated that clinical
exams and labs for medical surveillance of workers exposed to hazardous
drugs be curtailed until positive evidence was available to demonstrate
the usefulness of the practice. Conversely, a different commenter
called for the establishment of a national registry to capture the
exposures and outcomes from exposure to hazardous drugs.
NIOSH response: Regarding the difficulty, burden, and potential
lack of data showing the efficacy of a medical surveillance program,
NIOSH notes that ONS, OSHA, and USP all recommend medical surveillance
for workers in contact with hazardous drugs. Surveillance can identify
sentinel adverse health effects among workers suggesting failures in
controlling exposures and thus identify the need for improvements in
workplace controls, such as engineering or administrative controls or
personal protective equipment. Also, individual workers may benefit
from detection of disease in early stages when it may be more treatable
with better clinical outcomes. No change has been made to Managing
Exposures in response to this comment. NIOSH has no plans to recommend
a national registry at this time.
4. Chapter 7.0 Waste and Spill Control
a. Section 7.1 Hazardous Drug Waste and Section 7.2 Spill Control
Waste Designation and Handling
Public comment: One commenter requested clarification of the
difference between trace and overtly contaminated items and the
procedures for disposal of contaminated items.
NIOSH response: A new Sec. 7.1, Hazardous Drug Waste, has been
added which describes the 3 types of waste streams: hazardous waste, as
defined by the Resource Conservation and Recovery Act (RCRA); \12\
trace chemotherapy waste; and nonhazardous pharmaceutical waste. The
new section also includes a description of disposal containers. A site-
specific assessment of risk should be performed to determine facility
SOPs.
---------------------------------------------------------------------------
\12\ 42 U.S.C. 6901 et seq., 40 CFR 261.
---------------------------------------------------------------------------
Public comment: NIOSH received eight comments on waste designation
[[Page 25656]]
and handling. Several specific recommendations were offered on how to
handle waste contaminated with hazardous drugs. Several commenters
asked for clarification of terms, specifically differentiating between
waste contaminated with trace amounts of hazardous drugs and hazardous
waste.
NIOSH response: NIOSH appreciates the clarification and suggestions
regarding waste management. Several revisions to address these comments
have been made throughout the document. However, a comprehensive list
of waste handling procedures is beyond the scope of this document. The
narrative section on waste handling was expanded to clarify trace waste
from hazardous waste to address some of these concerns.
5. Section 8.0 Control Approaches for Safe Handling of Hazardous Drugs
by Activity and Formulation
a. Section 8.1 Introduction to Table of Control Approaches
Public comment: One commenter suggested deleting the Table of
Control Approaches, noting that it was unnecessary and overly
conservative. In particular, the table does not appropriately
differentiate between control measures (e.g., ventilation, respiratory
protection) based on factors such as dosage forms of hazardous drugs
(e.g., intact tablet and capsules vs. bulk active pharmaceutical
ingredients), types of hazardous drugs (antineoplastic vs. non-
antineoplastic), and other important factors that affect how
medications are handled in healthcare facilities and the degree to
which workers may be exposed. In this way, the Table of Control
Approaches is inconsistent with the risk assessment procedures outlined
in USP <800>.
NIOSH response: NIOSH disagrees, finding that the Table of Control
Approaches has broad support among peer reviewers and public commenters
who provided input on the May 2020 draft and is foundational to this
activity. Managing Exposures lays out information regarding risk
management strategies. Exposure assessments that include consideration
of many facilities' specific factors such as dosage forms and each
individual drug's potential hazards to determine the best control
measures are part of the strategies discussed in this document. The
table represents common handling situations in healthcare workplaces
and should be considered within the broader framework the document
provides. While NIOSH is independent from USP, the use of the Table of
Control Approaches within the framework of this document is consistent
with the use of risk assessment procedures laid out in USP <800>. No
change has been made to Managing Exposures in response to this comment.
Public comment: One commenter suggested considering reformatting
the Table of Control Approaches. Another commenter suggested that
gloves should be American Society for Testing and Materials (ASTM)
rated and that gowns should be impervious and single use.
NIOSH response: In response to the comment, NIOSH revised the table
to clarify that gloves should be ASTM rated and gowns should be
impervious and single use. A new line was added to the table to include
the headers Engineering Controls and PPE.
b. Section 8.2 Control Approaches by Activity and Formulation
Receiving and Packaging
Public comment: Two comments were received on recommendations
surrounding receiving and packaging, discussed in Sec. 8.2. One comment
suggested that single gloves were appropriate for unpacking, and the
other asked if repackaging was considered compounding.
NIOSH response: NIOSH agrees that single gloves for receiving and
unpacking were appropriate and has changed the recommendations in Sec.
8.2 and in the Table of Control Approaches accordingly. Repackaging
would not typically be considered compounding if it does not change the
final dosage form.
Transportation
Public comment: One commenter suggested that gloves did not provide
protection during transportation, but that they could actually increase
the hazard by spreading potential exposure.
NIOSH response: NIOSH has retained the recommendation, discussed in
Sec. 8.2, that gloves should be worn during transport of hazardous
drugs in a facility. Each facility should conduct its own risk
assessment and develop SOP specific to its use of hazardous drugs. No
change has been made to Managing Exposures in response to this comment.
Compounding of Drugs
Public comment: Four commenters commented on the recommendations
regarding drug compounding, discussed in Sec. 8.2. Commenters requested
that tablet or capsule crushing not be included in compounding,
questioned whether prefilled IV bags needed to have tubing attached and
be primed, and requested guidance on pouring liquids from one container
to another.
NIOSH response: In Managing Exposures, NIOSH has moved tablet
crushing to the administration recommendations to be consistent with
USP guidance which does not consider crushing or splitting tablets as
``compounding.''
Regarding precautions with IV bags, this would not be considered
compounding under the FDA definition, as the final formulation is
unchanged. Pouring from one container to another also would not be
considered compounding under the FDA definition. No change has been
made to Managing Exposures in response to these comments.
Administration
Public comment: Six comments were received on administering drugs
in the Table of Control Approaches. Two commenters questioned the
distinction between prefilled and in-house prepared syringes. Other
commenters asked about vented filters to remove bubbles in IV tubing,
ophthalmologic application, and procedures to minimize risks from
crushing tablets.
NIOSH response: An in-house prepared syringe may contain trace
contamination and a manufacturer's prefilled syringe can be assumed to
be clean. Accordingly, NIOSH has maintained the subsections of the
Table of Control Approaches distinguishing between prefilled and in-
house prepared syringes. The use of vented filters allows bubbles to be
eliminated from infusion lines. When inline vented filters use is
suggested for compounds prone to outgassing, an assessment of the risk
of exposure would be appropriate. It is expected that the level of drug
vapor released during infusion will be miniscule and the level of
dilution once passing through the vent into the room air would limit
the hazard posed by outgassing during infusion.
Regarding ophthalmic application, NIOSH agrees with the commenter
and has added information on ophthalmologic applications to the Table
of Control Approaches and Sec. 8.2. Regarding minimizing risks to
workers for specific scenarios, an intact coated tablet or capsule will
have a coating preventing the release of dusts/powders or liquids; and
a cut, crushed or uncoated tablet will provide a possible source of
dusts/powders or liquids that could expose the workers. Similarly, an
in-house prepared syringe may contain trace contamination and a
manufacturer's prefilled syringe can be assumed to be clean and would
have less likelihood of exposing the worker to hazardous drugs. Each
facility needs to conduct its own risk assessment and
[[Page 25657]]
develop SOPs specific to its use of hazardous drugs.
6. USP <800>
Public comment: Several commenters offered suggestions on the
document's use of USP <800>. Most were concerned that USP should be
cited more often.
NIOSH response: In response to commenters, USP <800> has been cited
in the document where it could be determined that it could provide new
information that did not originate with NIOSH (thus avoiding circular
references).
Public comment: NIOSH should be differentiating between controls
for antineoplastics and other hazardous drugs.
NIOSH response: NIOSH reaffirms that this document is intended to
apply to all drugs on the 2023 List and not just antineoplastics. No
change to Managing Exposures has been made in response to this comment.
Public comment: One commenter suggested that guidance on performing
an individual drug risk assessment that meets the USP <800> standard
would be helpful as alternative containment strategies and/or work
practices for specific dosage forms weren't included.
NIOSH response: NIOSH disagrees with providing guidance for
``specific dosage forms'' as that is beyond the scope of this general
guidance document. However, the text ``[t]he risk assessment should
include evaluating the dosage form and identifying the probability of
exposure'' has been added to Sec. 5.0 Risk Assessment, for clarity.
7. Other Topics
Public comment: One commenter noted that the term ``pills'' is
referred throughout the document, for example, on pages 38 and 66.
According to the commenter, ``pill'' is a nonspecific, outdated term
and should be replaced with the word ``tablet'' instead.
NIOSH response: NIOSH agrees and has made this change throughout
the final Managing Exposures.
Public comment: Several commenters noted spelling mistakes, errors
in tables, and other editorial improvements.
NIOSH response: NIOSH thanks the commenters for pointing out these
errors. NIOSH has accepted all appropriate editorial, spelling, and
correction comments in its revision of Managing Exposures.
V. Summary of Changes to Documents
A. Procedures for Developing the NIOSH List of Hazardous Drugs in
Healthcare Settings
As described in the responses to comments above, only limited
clarifications were made in the Procedures document. Notable changes
include a revision to footnote 12 to clarify that only CDER-approved
drugs are included on the List and the addition of a new footnote 29 to
clarify NIOSH's intent regarding drugs with insufficient information in
the package insert to determine whether the drug meets the NIOSH
definition of a hazardous drug. Other changes comprised only minor
editorial improvements.
B. Managing Hazardous Drug Exposures: Information for Healthcare
Settings
Changes were made to the document, Managing Exposures, in response
to comments received. There were some reorganizations, added references
and information, and clarification of recommendations, as follows:
In response to commenters, USP <800> was cited in document
where it could be determined that it had new information that did not
originate with NIOSH (thus avoiding circular references). ONS 2018 was
cited and listed as an additional resource.
The language in the document was clarified to specify that
each facility should conduct their own risk assessment and develop SOPs
specific to their use of hazardous drugs.
Under Administrative Control recommendations, the language
was clarified that automated counting machines should be prohibited
unless the automated counting machine has been evaluated and found to
not release powders.
In the recommendations on PPE, several changes were made
in response to comments:
[ssquf] Gloving recommendations for receiving and unpacking were
changed to a single glove.
[ssquf] Recommendation to ``spray'' sterile alcohol on gloves was
removed.
[ssquf] Recommendation for the use of sleeves was changed to
``Consider using sleeve covers if there is a gap between the gown and
the glove.''
In the Table of Control Approaches:
[ssquf] Ophthalmologic administration guidance was added.
[ssquf] Recommendation for double flushing of toilets in homes was
removed and replaced with new guidance that states ``Close toilet lid
or use a plastic-backed absorbent pad placed over the toilet without a
lid during flushing.''
[ssquf] ``Crushing or manipulating tablets or capsules'' was moved
from the compounding activity formulation column to the administering
activity formulation column.
The document was edited to highlight the potential risk
from exposure to human waste products (urine, feces, vomit). The topic
of Medical Surveillance was moved forward in the document under Risk
Management for clarity. Three new sections were added to increase the
clarity and utility of the recommendations:
[ssquf] Section 6.5 Surface Contamination
[ssquf] Section 7.1 Hazardous Waste
[ssquf] Section 7.2 Spill Control
Chapter 9 was created to reorganize information in the
previous draft for clarity:
[ssquf] Chapter 9.0 Additional Considerations for Handling
Hazardous Drugs
[ssquf] Section 9.1 Home Healthcare
[ssquf] Section 9.2 Veterinary Clinics (formerly Section 8.3 Steps
to reduce potential exposure to hazardous drugs)
Additional references were added as suggested by commenters and
peer reviewers to provide additional resources for readers.
John J. Howard,
Director, National Institute for Occupational Safety and Health,
Centers for Disease Control and Prevention, Department of Health and
Human Services.
[FR Doc. 2023-08900 Filed 4-26-23; 8:45 am]
BILLING CODE 4163-18-P