The Food and Drug Administration (FDA) is holding a public hearing Dec. 12-13, 2012 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, the FDA is interested in obtaining public comment about certain scientific and product use issues related to patient preoperative skin preparations.
The public hearing will be held from 9 a.m. to 4 p.m. at the DoubleTree by Hilton Hotel Washington, D.C./Silver Spring, 8727 Colesville Rd., Silver Spring, Md.Â The meeting may be extended or may end early, depending on the level of public participation. The public hearing is free, and seating will be on a first-come, first-served basis.
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(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.
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 (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 (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.
The 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 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?
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.
Source: U.S. Federal RegisterÂ