By Kelly M. Pyrek
Editor's note: This is a two-part series examining the issue of antiseptic sterility, a topic of ongoing investigation by the Food and Drug Administration (FDA). Part 1 lays the groundwork for this series and establishes what antiseptic prep products are, reviews the types of contamination that may occur, establishes what current good manufacturing practices (CGMPs) are, and provides the perspectives of clinicians and several associations. Part 2, which will appear in the July issue of ICT, dives deeper into the discussions held at a recent FDA hearing, presents the perspectives of the manufacturers and other experts and addresses if sterility of antiseptic prep products can be achieved.
In light of a number of high-profile recalls of contaminated alcohol prep products in the last several years, the Food and Drug Administration (FDA) held a hearing recently to receive expert testimony and public comment on how to address microbial contamination of these patient preoperative skin preparation drug products. It is a step in the ongoing investigational process that the agency is undertaking to determine issues related to sterility impacted by manufacturing processes.
Currently, patient preoperative skin preparations are not required to be sterile, since bacteria can contaminate these products at the time of manufacture or during product use. But because contaminated patient preoperative skin preparations have been associated with clinical infections and adverse outcomes, the FDA is exploring certain scientific and product-use issues related to patient preoperative skin preparations.
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 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. One notable recall was announced on Jan. 5, 2011, when Triad Group initiated a voluntary product recall involving all lots of alcohol prep pads, alcohol swabs and alcohol swabsticks manufactured by Triad Group but which are private labeled for many accounts to the consumer level. This recall involves those products marked as sterile as well as non-sterile products. This recall was initiated due to concerns from a customer about potential contamination of the products with Bacillus cereus. The alcohol prep pads, alcohol swabs and alcohol swabsticks affected by the recall were used to disinfect prior to an injection. They were distributed nationwide to retail pharmacies.
On Feb. 1, 2011 the FDA reminded healthcare professionals about the safe use of non-sterile alcohol prep pads to clean and disinfect the surface of the skin. In a statement, Karen Weiss, MD, director of the Safe Use Initiative in the FDA’s Center for Drug Evaluation and Research, noted, "Healthcare professionals should always check the labeling on a prep pad to determine if it is sterile or non-sterile. Non-sterile pads are not intended to prep patients prior to procedures requiring strict sterility measures and should not be used on patients with a depressed immune system, to prep patients for catheter insertion, or to prep patients prior to surgery."
Weiss added that many patients in hospitals are particularly susceptible to infections, and the FDA recommends sterile antiseptics (including chlorhexidine gluconate, alcohol or iodine applicators, pads, and swabs) in that setting. Manufacturers often package a prep pad with an injectable drug, selling them as a kit. But not all marketed pads are sterile. Some are marketed as non-sterile alcohol pads. If a pad does not state “sterile” on the label, healthcare professionals should be aware that they are using a non-sterile pad. Healthcare professionals and consumers should check the label to confirm that the product is sterile, and may also want to consider washing the area with soap and water prior to using the antiseptic for skin surface preparation.
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 non-sterile 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 non-sterile containers for product storage.
The FDA's 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) 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. The FDA asked the committee whether it should require patient preoperative skin preparations to be manufactured as sterile products. The committee did not vote on the FDA's question, but rather emphasized adherence to CGMP.
There are a number of CGMP regulations that have meaning for manufacturers of topical antiseptic drug products. Section 501(a) (2) (B) of the Federal Food, Drug, and Cosmetic Act requires all drugs to be manufactured in conformance with CGMP. The CGMP regulations provide the minimum legal requirements for conducting reliable operations.
Regarding manufacturing design and control, manufacturing facilities (21 CFR 211.42) must demonstrate processes to prevent microbial contamination. For non-sterile drug products, manufacturers must establish control procedures to monitor output and validate processes to include bioburden testing (21 CFR 211.110 (a) (6)), 211.111) and establish and follow written procedures designed to prevent the introduction of objectionable microorganisms (211.113(a)). For sterile drug products, manufacturers must establish and follow written procedures designed to prevent microbial contamination (211.113(b)).
They must conduct process validation studies to ensure acceptable output (e.g., with topical antiseptics, particularly product microbiological quality); they also must implement and validate needed changes when deficient manufacturing steps, equipment, or raw materials may be adversely affecting process control. They must ensure that operating procedures will consistently produce a quality product (211.100); they must review and evaluate any deviations or discrepancies documented during manufacturing and testing to determine if a product lacks assurance of sterility (for sterile antiseptics) or may be contaminated with objectionable microorganisms (for non-sterile antiseptics); and they must document and implement any corrective actions deriving from the evaluation. They must ensure that all equipment, including water systems, is clean, sanitary, operates consistently, and is suitable for its intended use; and they must establish and follow in-process bioburden testing procedures to help monitor in-process control, including understanding the bioburden challenge to a final sterilization process.
In-process and finished product testing is also mandatory. Manufacturers must test each lot of a drug product component and container/closure, including those that may be vulnerable to microbiological contamination, including applicator material and water used as an ingredient in the product. They also must conduct appropriate microbiological tests before a batch disposition decision is made; additionally, they must test each batch of a sterile product for sterility, and test each batch of a non-sterile product to ensure absence of objectionable microorganisms.
Since there are potentially many different root causes of product contamination by microorganisms, the FDA says it is imperative that manufacturers perform a manufacturing risk assessment to understand manufacturing failure modes and implement prevention measures. In addition, any risk assessment approach should be informed by an understanding of the microbial contamination vulnerabilities of the product. For example, some product considerations for manufacturers include:
- Determine the types of microbes that might survive or thrive in products; provide additional controls and testing based on the output of the risk assessment to ensure product quality.
- Ensure that microbial recovery methods are capable of detecting the types of microbes that may affect product quality.
- Evaluate risk of contamination from components, including during component production, storage, or due to the intrinsic risk from source materials. Consider all possible sources of microbial contamination, including the following: Components or products stored in open bins can be at risk for contamination by spore-forming microbes, such as Bacillus cereus as well as by Serratia species and other airborne microbes. Manufacturing areas exposed to windy or poor HVAC conditions may increase the potential for this environmental contamination risk. Some materials, especially from natural sources, may have high or objectionable intrinsic bioburden. Water quality can pose a significant risk, as most antiseptics include water as a key ingredient. Contaminated purified water has been the root cause of multiple recalls of antiseptics, including instances of antiseptics contaminated with Burkholderia cepacia.
One Clinician's Experience
Susan Dolan, RN, MS, CIC, hospital epidemiologist at Children's Hospital Colorado (CHCO) in Aurora, Colo., knows first-hand the impact that lack of sterility can have on patient outcomes. In 2010, Dolan and her team investigated two cases of serious Bacillus cereus infections that required intensive and extensive medical treatment. The epidemiologic investigation initially focused on three single-use, disposable items used in the treatment of both patients: sterile syringes prefilled with sterile saline solution; sterile applicators packaged with a 2 percent chlorhexidine gluconate/70 percent alcohol solution for skin preparation; and pledgets packaged with 70 percent isopropyl alcohol (alcohol prep pads [APPs]). The APPs were not labeled as either sterile or non-sterile on the outside of the individual APP packages or the box in which the APPs were contained. Bacterial cultures of samples from three saline syringes and the liquid and pads from nine packages of chlorhexidine gluconate/alcohol skin preparation applicators were negative. The internal alcohol pads from 60 APPs, obtained from various locations around CHCO, also were cultured. Hospital investigators found that 40 of 60 pads, representing eight of 10 different manufacturing lots, yielded B. cereus or Bacillus spp. All of the pads were supplied by a single manufacturer. CHCO contacted the Colorado Department of Public Health and Environment (CDPHE), which notified the CDC and the Food and Drug Administration who performed independent APP testing confirming the CHCO laboratory findings.
B. cereus isolates from eight CHCO patients with positive cultures during May through November 2010 and numerous APP isolates were characterized and compared by Repetitive sequence-based PCR (Rep-PCR) and pulsed-field gel electrophoresis (PFGE). Wide diversity was observed among the isolates, and no patient isolates matched APP isolates. Given this diversity and the time lapse between positive patient clinical specimens and subsequent APP sampling, the lack of a match between the two groups was not considered to rule out APPs as the source of the B. cereus isolated from patients.
As reported in the MMWR, Dolan, et al. (2011) note, "APPs are supplied both as sterile and non-sterile products. Sterile products are clearly labeled as such and should not be mistaken and/or interchanged for non-sterile products. B. cereus group and Bacillus species are resistant to killing by alcohol and have caused healthcare-associated outbreaks of invasive disease. Pseudoinfections caused by B. cereus-contaminated products also have been reported. Healthcare facilities, healthcare providers, and users of APPs should know whether the APPs in clinical use are sterile or non-sterile and be aware of the risk for iatrogenic infection if non-sterile APPs are used. Manufacturers should know the importance of clearly labeling their products as sterile or non-sterile to avoid misuse by healthcare facilities and healthcare providers."
Based on the findings in this investigation, Dolan, et al. (2011) TCH immediately halted any use of non-sterile APPs and began using sterile APPs exclusively from another manufacturer. In January 2011, the manufacturer voluntarily recalled all of its alcohol wipe products because of potential contamination.
Dolan's experience at her hospital parallels that of the high-profile Houston, Texas case in which 2-year-old Harrison Kothari developed lethal bacterial meningitis after surgery and died in 2010. His parents sued the manufacturers of the alcohol prep pads used on their son, claiming that they transmitted the Bacillus cereus bacterium that triggered his infection. The Kotharis settled their claim and two of the manufacturers filed for bankruptcy. It's a cautionary tale for clinicians trying to ensure the best outcomes possible for their patients, and Dolan says these cases may have opened healthcare workers eyes to previously held assumptions of sterility that were incorrect.
"While speaking throughout the country on this recall issue, I ask the question, 'How many people in this room (before the APP recall) knew that alcohol prep pads were not sterile?' and I rarely encounter one hand raised in very large room," Dolan says. "So I think maybe there was not a clear understanding of what APP products really were because of unclear product labeling. I think IPs were quite aware of contamination of similar antiseptic-type products occurring in either manufacturing or subsequently in the handling/manipulation of these product. There have been reports in the literature about contaminated skin prep and hand hygiene products, so IPs know that if we are dealing with an outbreak we should at least consider that such a product could be contaminated -- however I didn't fully appreciate that specifically that the alcohol prep pads might not be sterile. The issue was unclear because manufacturers produce them both ways -- sterile and non-sterile, but the non-sterile pads don't say that on the label."
Dolan continues, "This recall caused me to add an additional step when reviewing product labels. We should always look to see if the word 'sterile' is there and make note if it has any other descriptive words attached to it. If the word 'sterile' (alone) is not listed on a package, there's something in that package that's not sterile. As an example, one skin prep product package states that the applicator is sterile if the package is intact. So, I am trying to teach people that it's a clue when the term sterile has other words connected to it. What we learned is that while the applicator is sterile, the fluid inside that applicator is not -- you can take the applicator and put this on the sterile field, however, once you crack it and disperse the fluid, the fluid inside is not considered sterile. I think in the alcohol prep pad issue, we shouldn't have to wonder about sterility. When these APPs were first manufactured, things were much different and it was acceptable by the FDA for them to be either sterile or non-sterile. Healthcare has changed dramatically, the patient population is very different, and the frequency and ways in which we use APPs has changed requiring the need for only sterile APPs to be manufactured. Just think of the number of times we “scrub the hub” to avoid introducing organism into an intravascular catheter. As for other antiseptics, I do think manufacturers should develop mechanisms to make their products sterile, but we are hearing from some of them that it's not possible because it will denature the active ingredient in the product. There are manufacturers that have managed to make some of these products sterile. We must ask at a minimum that the product label should clearly state whether a product is sterile or non-sterile. If we are not going to get to sterility, at least we need to get better labeling on the package so that users know what they are purchasing and using on their patients."