[Federal Register Volume 77, Number 225 (Wednesday, November 21, 2012)]
[Notices]
[Pages 69863-69865]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-28357]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-1040]


Antiseptic Patient Preoperative Skin Preparation Products; Public 
Hearing; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public hearing; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
announcing a public hearing to obtain input on how to address microbial 
contamination of patient preoperative skin preparation drug products. 
Currently, patient preoperative skin preparations are not required to 
be sterile. Bacteria can contaminate these products at the time of 
manufacture or during product use. Contaminated patient preoperative 
skin preparations have been associated with clinical infections and 
adverse outcomes. At this public hearing, FDA is interested in 
obtaining public comment about certain scientific and product use 
issues related to patient preoperative skin preparations.
    Date and Time:The public hearing will be held on December 12 and 
13, 2012, from 9 a.m. to 4 p.m. The meeting may be extended or may end 
early, depending on the level of public participation.
    Location: The public hearing will be held at the DoubleTree by 
Hilton Hotel Washington, DC/Silver Spring, The Ballrooms, 8727 
Colesville Rd., Silver Spring, MD 20910.
    Contact Person: Lee Lemley, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Silver Spring, MD 20903, 301-796-3441, FAX: 301- 847-8753, email: 
[email protected].
    Registration: The public hearing is free, and seating will be on a 
first-come, first-served basis. Attendees who do not wish to make an 
oral presentation do not need to register. If you need special 
accommodations due to disability, please contact Lee Lemley (see 
Contact Person) at least 7 days in advance.
    Requests for Oral Presentations: If you wish to make an oral 
presentation during the hearing, you must register by submitting a 
written or electronic request by close of business on November 27, 
2012, to Lee Lemley (see Contact Person). Provide your name, title, 
business affiliation (if applicable), address, telephone and fax 
numbers, email address, and type of organization you represent (e.g., 
pharmaceutical company or consumer organization). You also should 
submit a brief summary of the presentation, including the discussion 
topic(s) that will be addressed and the approximate time requested for 
your presentation. We encourage individuals and organizations with 
common interests to consolidate or coordinate their presentations to 
allow adequate time for each request for presentation. Persons 
registered to make an oral presentation should check in before the 
hearing.
    Participants should submit a copy of each presentation to Lee 
Lemley (see Contact Person) no later than December 7, 2012. We will 
file the hearing schedule, indicating the order of presentation and the 
time allotted to each person, with the Division of Dockets Management 
(see Comments). We will mail, email, or telephone the schedule to each 
participant before the hearing. In anticipation of the hearing 
presentations moving ahead of schedule, participants are encouraged to 
arrive early to ensure their designated order of presentation. 
Participants who are not present when called risk forfeiting their 
scheduled time.
    Comments: Interested persons may submit either written comments 
regarding this document to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852 or electronic comments to http://www.regulations.gov. Comments will be accepted after the hearing until 
February 12, 2013. Persons who wish to provide additional materials for 
consideration should file these materials with the Division of Dockets 
Management. You should annotate and

[[Page 69864]]

organize your comments to identify the specific questions identified by 
the topic to which they refer. It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at http://www.regulations.gov.
    Transcripts: Please be advised that as soon as a transcript is 
available, it will be accessible at http://www.regulations.gov. It may 
be viewed at the Division of Dockets Management (see Comments). A 
transcript will also be available in either hard copy or on CD-ROM, 
after submission of a Freedom of Information request. Written requests 
are to be sent to the Division of Freedom of Information (ELEM-1029), 
Food and Drug Administration, 12420 Parklawn Dr., Element Bldg., 
Rockville, MD 20857.

SUPPLEMENTARY INFORMATION: FDA is announcing a public hearing to obtain 
input on how to address microbial contamination of patient preoperative 
skin preparation drug products. To provide the public with additional 
background, FDA is making information available that is pertinent to 
this safety issue. This information is available electronically in the 
docket for this Federal Register notice on the Internet at http://www.regulations.gov and on FDA's Web site at http://www.fda.gov/Drugs/NewsEvents/ucm319621.htm. This information is also available at the 
Division of Dockets Management and by mail (see Comments).

I. Background

    Patient preoperative skin preparations are over-the-counter (OTC) 
topical antiseptic drug products used to reduce the number of bacteria 
on the skin prior to medical procedures or injections. Although they 
are marketed predominantly to healthcare facilities, the use of these 
products extends beyond the healthcare facility setting. For example, 
consumers with medical conditions requiring regular injections (e.g., 
of insulin or heparin) may use these products at home.
    Patient preoperative skin preparations are marketed through one of 
three regulatory pathways: an OTC drug monograph, an approved new drug 
application (NDA), or an approved abbreviated new drug application 
(ANDA). Many patient preoperative skin preparations contain antiseptic 
active ingredients subject to an OTC drug monograph, such as povidone-
iodine or alcohol. Products that are marketed under approved NDAs or 
ANDAs include those that contain chlorhexidine gluconate (either alone 
or in combination with an alcohol).
    Patient preoperative skin preparations are marketed as solutions, 
swabs, pads saturated with a solution, and applicators containing a 
solution. Some patient preoperative skin preparation products are 
intended for one-time use only (single-use); others are intended for 
repeated use from the same container (multiple-use). Multiple-use 
containers of patient preoperative skin preparations may also be 
labeled for other indications, such as surgical hand scrub, healthcare 
personnel handwash, or skin wound and general skin cleanser.
    Despite their inherent antimicrobial activity, patient preoperative 
skin preparations may become contaminated with bacteria. A number of 
product recalls have been prompted by the identification of bacterial 
contamination (see FDA's Archive for Recalls, Market Withdrawals, and 
Safety Alerts at http://www.fda.gov/Safety/Recalls/ArchiveRecalls/default.htm). Furthermore, infections related to bacterial 
contamination of patient preoperative skin preparations have been 
described in the literature (Ref. 1). Some of these infections have 
remained localized at the site of an injection, but others have 
resulted in sepsis and death.
    Contamination of patient preoperative skin preparations occurs by 
two known mechanisms. Intrinsic contamination occurs when 
microorganisms gain entry to the product during the manufacturing 
process and remain viable. Bacterial contaminants have been isolated 
from pharmaceutical water supplies and nonsterile antiseptic 
manufacturing environments. By contrast, extrinsic contamination occurs 
when microorganisms are introduced into a finished product by the end 
user. Extrinsic contamination can arise from a variety of causes, 
including dilution of the product with contaminated water, failure to 
use appropriate aseptic techniques during handling, and repeated use of 
nonsterile containers for product storage.
    Our current good manufacturing practice (CGMP) regulations require 
manufacturers to have appropriate procedures in place to prevent the 
presence of objectionable organisms in drug products that are not 
sterile (21 CFR 211.113). However, the microbial limits test (United 
States Pharmacopeia Chapter 1111 (Ref. 2)) currently in use by many 
manufacturers may not detect very low levels of microbial contamination 
and does not screen for the types of intrinsically antiseptic-resistant 
organisms frequently identified as contaminants in patient preoperative 
skin preparations, such as Burkholderia cepacia and Bacillus cereus. 
Therefore, a product that passes the premarket microbial limits test 
may still support the growth of contaminating microorganisms and become 
the source of clinical infection.
    The subject of contaminated patient preoperative skin preparations 
was discussed at an Advisory Committee meeting held on August 5, 2009 
(Ref. 3). FDA asked the Committee whether we should require patient 
preoperative skin preparations to be manufactured as sterile products. 
The Committee did not vote on FDA's question, but rather emphasized 
adherence to CGMP.
    Reports of contaminated patient preoperative skin preparations, 
which have led to product recalls and clinical infections, raise a 
public health concern. Consequently, FDA has decided to hold a public 
hearing to hear from interested parties, including healthcare 
facilities, healthcare professionals, manufacturers, consumers, and 
others, about ways that these issues might be addressed.

II. Scope of the Public Hearing

    FDA is holding this public hearing to seek input from interested 
members of the public on how to address microbial contamination of 
patient preoperative skin preparation antiseptic drug products. This 
hearing may be of interest to a wide range of audiences, including 
product manufacturers, those representing healthcare facilities, 
healthcare professionals, and consumers who use these products. FDA is 
interested in obtaining information and public comment on the following 
issues:

A. Intrinsic Contamination

    1. Are healthcare providers and consumers aware that patient 
preoperative skin preparations generally are not sterile? What measures 
can be taken to increase awareness of this fact?
    2. In light of the adverse events associated with contamination of 
patient preoperative skin preparations, should all such products be 
manufactured sterile?
    3. Are manufacturers currently producing, or planning to produce, 
sterile patient preoperative skin preparations? If so, what method(s) 
are or will be used (e.g., terminal sterilization or validated aseptic 
manufacturing)?
    4. What technical challenges, if any, are there in producing 
sterile patient preoperative skin preparation products? For a given 
manufacturer, approximately how long would a manufacturing switch take 
to allow for

[[Page 69865]]

production of a sterile preoperative skin prep product?
    5. How would the market change if all patient preoperative skin 
preparations were required to be manufactured sterile?
    6. What can FDA do to help manufacturers overcome challenges in 
this area?

B. Extrinsic Contamination

    1. Products manufactured sterile can be contaminated as soon as 
they are opened for the first time. What steps can be taken to reduce 
the risk of extrinsic contamination of patient preoperative skin 
preparations?
    2. Excluding the use of these products before surgical procedures 
or injections, are these products used for other purposes in healthcare 
or home settings (e.g., wound care or maintenance care for indwelling 
catheters)? If so, what is the extent of these uses in healthcare or 
home settings? What settings or uses comprise the majority of 
utilization for single-use products? What settings or uses comprise the 
majority of utilization for multiple-use products?
    3. To what extent are multiple-use containers of patient 
preoperative skin preparations further processed (e.g., diluted, mixed, 
or repackaged for subsequent redistribution) in healthcare or home 
settings? If these products are diluted, mixed, or repackaged, are they 
handled aseptically? Why are these products diluted?
    4. Should patient preoperative skin preparations be marketed only 
in single-use containers? If single and multiple-use containers are 
permitted, in which ways could single-use containers be clearly 
distinguished from multiple-use containers (e.g., by labeling, size, 
volume, presence/absence of applicator)? What technical and practical 
challenges would manufacturers and users face should there be 
regulatory requirements that limit package sizes for multiple-use 
patient preoperative skin preparations?
    5. Can product labeling, for example, instructions to ``discard X 
days after opening,'' be used to reduce the risk of adverse events 
associated with extrinsic contamination of patient preoperative skin 
preparations? How could a ``discard by'' date be established for 
individual products and how meaningful would such a date be in the 
context of current practices?
    6. Are healthcare facilities or other entities providing 
information or training on safe use of multiple-use patient 
preoperative skin preparations, or taking other steps to reduce the 
risk of extrinsic contamination of these multiple-use products? If so, 
please describe these efforts and any available information on their 
effectiveness.

III. Notice of Hearing Under 21 CFR Part 15

    The Commissioner of Food and Drugs is announcing that the public 
hearing will be held in accordance with part 15 (21 CFR part 15). The 
hearing will be conducted by a presiding officer, who will be 
accompanied by management and technical personnel from the Center for 
Drug Evaluation and Research.
    Under Sec.  15.30(f), the hearing is informal, and the rules of 
evidence do not apply. No participant may interrupt the presentation of 
another participant. Only the presiding officer and panel members may 
question any person during or at the conclusion of each presentation 
(Sec.  15.30(e)). Public hearings under part 15 are subject to FDA's 
policy and procedures for electronic media coverage of FDA's public 
administrative proceedings (part 10 (21 CFR part 10), subpart C and 
Sec.  10.203(a)). Under Sec.  10.205, representatives of the electronic 
media may be permitted, subject to certain limitations, to videotape, 
film, or otherwise record FDA's public administrative proceedings, 
including presentations by participants. The hearing will be 
transcribed as stipulated in Sec.  15.30(b) (see Transcripts for more 
details). To the extent that the conditions for the hearing as 
described in this notice conflict with any provisions set out in part 
15, this notice acts as a waiver of those provisions as specified in 
Sec.  15.30(h).

IV. References

    The following references have been placed on display in the 
Division of Dockets Management (see Comments) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.

    1. Weber, D.J., W.A. Rutala, and E.E. Sickbert-Bennett, 
``Outbreaks Associated with Contaminated Antiseptics and 
Disinfectants,'' Antimicrobial Agents and Chemotherapy, 51:4217-
4224, 2007.
    2. The United States Pharmacopeia 35-National Formulary 30. The 
United States Pharmacopeial Convention, Inc., MD, ``Microbiological 
Examination of Nonsterile Products: Acceptance Criteria for 
Pharmaceutical Preparations and Substances for Pharmaceutical Use,'' 
Chapter 1111:691, 2012.
    3. Pharmaceutical Science and Clinical Pharmacology Advisory 
Committee meeting transcript, available at: http://www.fda.gov/downloads/AdvisoryCommittee/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM179891.pdf, 2009.

    Dated: November 16, 2012.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2012-28357 Filed 11-20-12; 8:45 am]
BILLING CODE 4160-01-P