See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/282252219 Cleaning Validation of medical products Chapter · May 2015 CITATIONS READS 0 14,574 All content following this page was uploaded by Steven Richter on 28 September 2015. The user has requested enhancement of the downloaded file. 7 Cleaning Validations of Medical Products By Steven G. Richter, PhD Introduction Medical devices come in all shapes and sizes—from speculums to colonoscopes and everything in between. Generally, these devices are expensive and require cleaning, disinfection and sterilization. This chapter describes the salient points for validating the process necessary to allow a reprocessed medical device to be used safely. It covers only the cleaning process. Inadequately cleaned devices cannot be disinfected or sterilized, and hospital technicians and employees working in central service must understand and be thoroughly trained on the cleaning process. Unfortunately, the diversity of critical instructions in medical device instructions for use (IFUs) can be a challenge for most hospital reprocessing departments. The labeling is important, as each manufacturer must now validate recommended sterilization methods and drying times to obtain clearance from the US Food and Drug Administration (FDA). Moreover, reusable medical devices have been implicated in hospital-acquired infections (HAIs) resulting from inadequate cleaning and sterilization practices and procedures that do not specify how to remove blood, tissue and feces (FDA: Reprocessing of Reusable Medical Devices1). FDA’s requirement for validation studies for both cleaning and disinfection helps reduce the risks to physicians and patients. This chapter assists manufacturers in determining the best practices for performing these pivotal studies. Qualification studies are important for obtaining pertinent cleaning data that lead to the next phase of the project: validation. Exposing medical devices to “simulated real world” challenges is critical. A minimum of two markers should be used. Blood and protein markers are available for these studies. Artificial test soil also is used with the blood/carbohydrate and protein to simulate patient use. The purpose of cleaning is to ensure the device is scrupulously clean for the next patient. This means when the device is dissembled and microscopically inspected (including internal lumens and contact surfaces), there is no evidence of tissue/body fluids/feces (TBF) materials. The IFUs should be provided to the laboratory prior to validation activities. At the laboratory, technicians will develop qualification challenges to detect challenge materials in or on the device after hand or automated cleaning activities. FDA Considerations In 2011, FDA’s Draft Guidance for Industry and FDA Staff-Processing/Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling2 was distributed for comment. This document superseded the April 1996 document Labeling Reusable Medical Devices for Reprocessing in Health Care Facilities: FDA Reviewer Guidance and other secondary reference documents. The majority of the requirements in this chapter are drawn from the 2011 FDA guidance. Currently, the Association for the Advancement of Medical Instrumentation (AAMI) has a working group developing an industry Technical Information Report (TIR) that will provide a more reasonable approach to reusable medical device cleaning validation. This chapter helps the reader develop a validation program to meet the requirements. FDA has identified industry consensus standards to support the cleaning The Medical Device Validation Handbook 65 Figure 7-1. Examples of typical Reusable Medical Devices protocols and FDA data requirements. The following is a list of consensus standards: • ST-79 Comprehensive guide to steam sterilization and sterility assurance in health care facilities3 • ST-81 Sterilization of medical devices— information to be provided by the manufacturer for the process of resterilizable medical devices4 • ST-58 Chemical sterilization and high-level disinfection in health care facilities FDA places the primary responsibility for developing and validating effective reprocessing methods for a reusable medical device on the device manufacturer. The manufacturer is expected to validate how a device can be cleaned and disinfected or sterilized adequately to allow it to be reused. As outlined by FDA, the manufacturer must test and validate any labeling claims of fitness for reuse that are provided in the instructions for device handling, cleaning, disinfection, packaging and sterilization in a healthcare facility. To demonstrate compliance with label claims, cleaning agent manufacturers must validate that the agent provides the expected level of soil removal and determine materials compatibility. AAMI TIR30 (A compendium of processes, materials, test methods, and acceptance criteria for cleaning reusable medical devices)5 addresses the issues related to manufacturers’ validation testing for cleaning medical devices. Regulatory Expectations Although the ISO/AAMI cleaning standards are not consensus standards, FDA has accepted them with limitations. FDA issued a draft guidance 66 The Medical Device Validation Handbook in May 2011 to address some of the limitations of AAMI TIR30. This draft guidance document has precipitated industry discussion and resulted in formation of an AAMI task force to develop a new cleaning standard. Industry has embraced the guidance, with the understanding that changes from the older TIR30 concepts were required. The TIR recommended challenging the device with a microbiological suspension of Bacillus spores (spore tag method). Bacillus spores are used because they are easy to place on the device and easy to count after the cleaning process. FDA indicated the spore tag method and Hucker’s Soil challenges are inadequate to validate a cleaning program. Although this guidance is not legally enforceable, it describes the agency’s “current thinking and should be viewed as recommendations.” Therefore, it is incumbent upon industry to modify the current best practices and test, challenge and validate (TCV) reusable medical device cleaning methods using protein, carbohydrates, red blood cells and lipids. Another issue of note is that cleaning, disinfecting and sterilization validation activities should be performed separately, which drives up test costs. The ASTM Simulated Use Test, which was the gold standard for many years, now is deemed inappropriate by FDA. Manufacturers may wish to review the archived validation protocols to determine whether re-validation studies may be needed. An array of analytical chemistry cleaning validation methods to inspect for the presence of residual proteins, carbohydrates, lipids and red blood cells has been proposed. These studies can be the next gold standard for industry. However, what are the pass/fail criteria? Each method requires validation along with adequate controls for system suitability requirements. Using total organic carbon (TOC) analyzers can provide a broad-stroke cleaning indication. However, other instruments such as high pressure liquid chromatography (HPLC), infrared (IR) or enzyme-linked immunosorbent assay (ELISA) will be required under this new guidance. Is a three-log reduction adequate for cleaning validations? This is expected to change with time. A three-log reduction means one device in 1,000 processed has a high probability of not being cleaned adequately (borrowing from the sterility assurance level (SAL) math). This number is expected to change to a cleaning assurance level (CAL) of one contaminated device in 10,000 or 100,000 processed. As the document relates to new medical devices, industry also is required by statute to reduce manufacturing materials such as metal particles, lubricants and other contaminants to safe levels. • • • Regulatory Violations FDA regulatory actions related to reusable medical devices have been limited. This is due primarily to the inappropriate reporting system for HAIs. Determining whether irritation is caused by inadequately rinsed disinfectants is another issue. Therefore, the number of HAIs attributed to inadequately processed devices is unknown because it often is not investigated as a cause. The following FDA reports resulted from endoscopic retrograde cholangiopancreatography (ERCP) procedures: 1.FDA report, dated 3/07/2014 (US)— at least eight patients were infected or colonized with carbenepenum-resistant Enterobacteriaceae (CRE) at one hospital after undergoing ERCP 2.FDA report, dated 1/28/2014 (US)—five patients tested positive for CRE after undergoing ERCP using the same endoscope cleaned and disinfected between patients (Report No. 2951238-2014) FDA/AAMI/ANSI and ISO Definitions • • • • • bioburden—population of viable microorganisms on or in product and/or sterile barrier system biofilm—accumulated biomass of bacteria and extracellular material that is tightly adhered to a surface and cannot be removed easily cfu—colony forming units cleaning—removal of biological contamination from a medical device to the completeness required based on validated activities decontamination—use of physical or chemical means to remove, inactivate or destroy blood borne pathogens on a surface or item to the point where they are no longer capable of transmitting infectious particles, and the surface or item is rendered safe for handling, use or disposal (29 CFR 1910.1310) • • • • • • disinfection—a validated process that ensures targeted microorganisms are destroyed using chemical processes lumen—internal cavity or channel inside a device materials stability—ability of a material to resist physical and chemical degradation that could destroy the ability for the device to perform its intended use medical device—any instrument, apparatus, appliance, material or other article used for diagnosis, prevention, monitoring, treatment or alleviation of disease; examples include endoscopes, surgical instruments, syringes, needles, catheters, software, organ stability fluid, surgical trays, etc. microorganism—bacteria, fungi, viruses and protozoa prions—transmissible pathogenic cellular protein agents that can cause neurodegenerative disease in humans and animals; these can be similar to protein refolding issues in Alzheimer’s disease reprocess—validated instructions to clean, decontaminate, disinfect, repackage and/or sterilize a medical device used for a prior treatment for a different patient reusable medical device—device intended to be cleaned and disinfected or sterilized between patient use SDS—sodium dodecyl sulfate, a detergent used in cleaning medical devices Chapter 7. Cleaning Validations of Medical Products A determination of the levels of safety is the major issue. This is somewhat similar to an earlier determination for ethylene oxide residuals that resulted in a proposed Federal Register document in the early 1980s for release criteria. Figure 7-2. Notebook studies can provide data to build appropiate validation activities The Medical Device Validation Handbook 67 Figure 7-3. Automated cleaning equipment typically should be validated prior to use. • • • • sterilization—validated process that renders a device sterile and free from microorganisms (except prions) according to FDA requirements test soil—material designed to mimic contamination typically found on medical devices after procedures; used to validate the IFU actually are cleaning the device prior to disinfection and sterilization user verification—documented activity establishing the cleanliness requirements have been met validation—documented procedure that challenges cleaning methods with test soils to determine whether the IFUs are appropriate for the healthcare facility and personnel; validation documents the cleaning process (performance qualification) with data Industry Guidance Documents: AAMI TIR 12 and 30 AAMI Technical Information Report TIR12, Designing, testing and labeling reusable medical devices for reprocessing in health care facilities: A guide for medical device manufacturers,6 covers the salient points for manufacturers to validate the cleaning requirements it sets forth. There obviously is some confusion regarding these standards in terms of continuity and compliance. The TIR reports are 68 The Medical Device Validation Handbook published to guide the practitioner in developing a validation protocol. Each medical device is different in its principal, engineering and body contact area. The cleaning studies should be performed as separate studies. Endpoint information is gathered from TIR30 for the validation process. Validation studies require endpoints. The importance of notebook studies cannot be overstated. These studies can be invaluable for setting the procedures for successful validation outcomes. Qualification studies are worked out with the project manager. The following are important aspects of this process: • challenge material—soil choices and simulated body fluid choices • cleaner type—enzymatic category (lipase, proteinase) • presoak/soak contact time and water temperatures • water quality (pH and hardness) • brushes for manual cleaning • pre-cleaning rinse • post-cleaning rinse • drying time and temperature • pass/fail criteria—endpoint analysis TIR30 is the penultimate cleaning document used in the medical device industry. This report contains a compendium of test methods and acceptable criteria for the cleaning of reusable medical devices. Proteinase/lipase dual enzyme lichen-based enzyme cleaners are the general choice of most manufacturers for both manual and automated cleaning. Enzyme cleaners work best within narrow pH and temperature ranges. Various enzyme cleaners are used for medical devices. Manual cleaning elements are broken down into the following categories: • hydration—adding water to the device causes the extraneous material to absorb water molecules • friction—a mechanical process whereby the extraneous material is mechanically removed • digestion—a chemical process that removes material by breaking down the large molecules to smaller ones more soluble in water • solubilization—a chemical process whereby extraneous materials’ surface characteristics change the affinity for water molecules • fluidics—the use of water to remove extraneous materials from medical devices Bacterial Challenges—Points to Consider Adding microorganisms to the soil may be required for certain medical devices. These studies may be in combination with a disinfectant study. The choice of bacterial species depends on the device used and the treatment. For example, endoscopes are used in the gastric area and normally encounter gram-positive and gram-negative bacteria, along with yeasts and molds. Endoscopes also would encounter blood, mucous, saliva and tissue. Typical bacterial cleaning challenges are 1 x 10(e4) CFU per device. FDA may require a three-log reduction. A robust study would utilize gram-positive and gram-negative bacteria as tags. The selected soil marker would be inoculated with these bacteria. The device would be dried for one hour and then cleaned. After cleaning, rinsing and drying, the device would be extracted to determined residual levels of soil (protein, carbohydrate, endotoxin or hemoglobin). The author would like to point out that no single test soil is appropriate for all medical devices. For instance, bacteria would not be appropriate for devices that enter sterile body cavities. Devices used in the GI tract may require an endotoxin challenge specific for the clinical application. Endotoxin challenges are difficult to quantitate due to the stickiness of the lipopolysaccaharide molecule. So, the validation must show the recovery of the endotoxin positive controls to within one two-fold dilution of the standard. This is difficult to attain experimentally. Other types of soil can be hemoglobin or protein based. These are the markers of choice for most (90%) of studies. AAMI TIR30 (Table 6) lists 12 soil types for the practitioner’s choice in cleaning studies. Historically, Hucker’s soil was the number one choice. However, Hucker’s soil was concocted for washer-disinfection units used for anesthesia equipment and bed pans. Data indicate Hucker’s soil is beyond the worst-case scenarios seen in soiled devices used on patients. AAMI TIR12 also references Hucker’s soil. Yet, other soils are becoming more appropriate due to medical device design characteristics and use. ATS-B soil contains bacteria, protein, CHO, endotoxin and hemoglobin. This test soil type is recommended for flexible endoscopes, which are one of the most frequently used devices in the US. Other devices may require a spore tag or bacteria coupled with soil emulsions to meet EU requirements (ISO 17664 ref ). TIR acceptance criteria are based on published data primarily from endoscopes. Endoscopes were the first devices suspected (in the 1980s) of causing nosocomial infections due to inadequate cleaning and disinfection. Acceptance criteria listed in TIR30 recommend a three-log reduction of bacterial challenges as a reasonable expectation. The FDA guidance does not require the bacterial challenges. EU regulators are requiring the spore challenges for acceptance. AAMI has a working group that will evaluate best practices and current soil challenges for future revisions. Chapter 7. Cleaning Validations of Medical Products Each element has a beneficial effect on the removal of body fluids, tissues or excrement such as saliva, blood, stool, urine, mucus, protein and fat. Pre-soaking prior to cleaning is one of the most important processes for the removal of bodily fluids and tissue. The challenge soil should approximate the exposure level of bacteria and body fluids and tissues. A device will require a thorough analysis of potential cleaning based on worst-case scenarios to achieve a robust and comprehensive study outcome. Verification and/or Validation Steps Notebook studies will be important for determining the propensity for IFU failures prior to extensive validation activities. These studies are not performed under Good Manufacturing Practice (GMP)/Good Laboratory Practice (GLP) documentation and are for informational purposes only (IPO). They help with the development of the study protocols and potentially obviate erroneous data by focusing on the study’s engineering aspects. The definition of the cleaning study from the notebook work can be used to develop rigor in the protocols. Rigor will be essential for reducing assay variability. Chemical analysis for protein and hemoglobin require equipment specificity and suitability assays before the assays can be utilized for regulatory work. This chapter does not discuss these processes. Study designs are required under the medical device Quality System Regulations (QSRs) 21 CFR 820 and 21 CFR 58 (GLP). Most cleaning studies require two quantitative soil markers, such as a protein/hemoglobin or a protein/ATS (artificial test soil) soil marker. Product Families If a manufacturer supplies a number of different medical devices that share common features and attributes, these devices may be grouped for The Medical Device Validation Handbook 69 Table 7-1. TIR30 Acceptance Criteria Protein <6.4 ug/cm3 Hemoglobin <2.2 ug/cm3 Carbohydrates <1.8 ug/cm3 TOC Less than 500 ppb or defined by project Bacterial Endotoxin <2.2 EU/cm3 Detergent residuals Reduce to safe levels Bioburden Three-log reduction validation exercises into a product family. This should make it possible to select a product family member or master product that represents worstcase scenarios. The selection criteria should be documented in the validation documents. Master products are selected based on product-related variables that can affect the “cleanability” of the product family. It must be demonstrated that the product group can be bracketed with a challenge defined as being equally harsh to all devices. For example, all endoscopes have essentially the same features except length. Therefore, the master product should be selected based on the worst-case cleanability assumption of length. However, materials and matted surfaces may allow a choice of something smaller if design warrants the selection. In any case, it would be a simple exercise to qualify a master product based on data collected during a notebook study. Once this master product is determined, adding additional members to the validation (by equivalency) can become a quick notebook study. Computer Based Cleaning Studies iPads and smart phones are becoming more integrated with medical products. FDA considers these devices to be medical devices and requires a cleaning protocol (IFU) for the clinic. The author’s recommendation for the practitioner is to test the device with a protective case that keeps it hermetically sealed during use and cleaning. Hermetically sealed cases are commercially available. The device manufacturer must test these cases during the validation prior to marketing. The salient points of TIR12 are important to a facility’s technical staff. They cover items such as water quality for cleaning, cleaning implements, rinsing and pre-cleaning and labeling requirements for manufacturers that recommend manual cleaning. Manufacturers should develop test procedures (wipe tests) that can detect cleaning levels. AAMI TIR12 references ASTM’s E2314 Standard Test 70 The Medical Device Validation Handbook Method for Determination of Effectiveness of Cleaning Processes for Reusable Medical Instruments Using a Microbiologic Method (Simulated Use Test). Although FDA is not accepting spore bacterial challenge testing as mentioned above, this test may have value for some devices. Validation Set-Up and Review It is important to bracket the device families with the hardest to clean areas targeted during validation activities. The worst-case specification always should be specified during the validation phase. For instance, if the soil drying time is five to 10 minutes, use the 10-minute drying time. The longer drying time allows the soil to adhere or absorb to the device. Rinse times should be based on the minimal scale of the specification. Use the brush stipulated in the IFU. Manual scrubbing times should be based on the minimum required in the IFU. Cleaning times should be worst case, e.g., if the IFU indicates scrubbing for three to five minutes, use three minutes during the validation protocol. A minimum of 10 devices should be tested during a cleaning validation. If 10 are not required, the smaller number must be justified by performing repeated studies on the same device(s) for a total of 10. Level of detection (LOD) is determined prior to validation activities. The laboratory’s analytical department will have LODs determined for protein, CHO and hemoglobin. Adequate recovery must be developed as part of the validation work up. Generally LOD is set at three times the standard deviation of the blank or noise (instruments). Case Studies Failure to comply with cleaning and disinfectant instructions can cause disease. Therefore, if the validation data indicate a failure, changes to the IFU may be warranted. The contract laboratory will play an important part in this process. It may have expertise available regarding the validation process. It is equally important the laboratory managers be provided the correct information regarding patient care level and criticality. Testing has revealed most device designs do not consider the ability of the device to undergo cleaning and disinfection. Endoscopes typify one of the main issues because of the channels and mechanics required to actuate the devices. Engineering changes may be required to ensure that the device The validation process and protocols are the same for manual cleaning. Final Outcome References 1. US Food and Drug Administration. Reprocessing of Reusable Medical Devices. 30 June 2014. FDA website. http://www. fda.gov/medicaldevices/deviceregulationandguidance/reprocessingofreusablemedicaldevices/default.htm. Accessed 21 January 2015. 2. International Organization for Standardization. ISO 17664:2004 Sterilization of Medical Devices-Information to be provided by the manufacturer for the processing of resterilizable medical devices. ISO website. https://www.iso.org/ obp/ui/#iso:std:iso:17664:ed-1:v1:en. Accessed 21 January 2015. 3. Association for the Advancement of Medical Instrumentation. AAMI/ANSI ST-81: Sterilization of Medical Devices: Information to be provided for the reprocessing of resterilizable medical devices. 2010. AAMI website. https://my.aami.org/store/detail.aspx?id=ST81. Accessed 21 January 2015. 4. Association for the Advancement of Medical Instrumentation. AAMI/ANSI ST-79:Comprehensive Guide to steam sterilization and sterility assurance in health care facilities. 2010. AAMI website. https://my.aami.org/store/ SearchResults.aspx?searchterm=ST79&searchoption=ALL 5. Association for the Advancement of Medical Instrumentation. AAMI TIR30: A compendium of processes, materials, test methods , and acceptance criteria for cleaning reusable medical devices. 2011. AAMI website. http://marketplace.aami.org/eseries/scriptcontent/docs/Preview%20 Files/TIR301108_preview.pdf.Accessed 21 January 2015. 6. Association for the Advancement of Medical Instrumentation. AAMI TIR12: Design, testing, and labeling reusable medical devices for reprocessing in health care facilities: A guide to medical device manufacturers. 2010. AAMI website. http://marketplace.aami.org/eseries/scriptcontent/ docs/Preview%20Files/tir121009_preview.pdf. Accessed 21 January 2015. The final validation report should encompass the cleaning process with endpoints using at least two soil materials. One must have drawings indicating inoculation areas that equate to determining the amount of soil per cm3 of device. Cleaning itself can leave residues from the enzyme detergents, and these must be taken into account in the validation package. The cleaning agent is considered a process material and should be reduced to safe levels prior to patient use. The validation protocol should be signed off by the study director (GLP) and client prior to starting the study. After the study is completed, the study director will submit the results and conclusions using language such as “the study data indicates that it meets the requirements of the validation protocol and TIR30 document.” Laboratory vs Hospital Cleaning Programs The correlation of these two programs is a growing area of concern for FDA. The author believes much work needs to be done in this area. Hospitals require automated systems that can take the guesswork out of the technician’s hands. They need access to all IFUs and appropriate training to clean the devices according to the instructions. This area is of great concern and requires a new paradigm to alleviate the propensity for contamination and disease. Automated Washers The equipment requires typical validation prior to being used for any GLP or GMP studies. The typical instrumentation protocols for validation can be found in ST-81 (ref ). The laboratory requires the instrument to perform according to its stated operating procedures. Therefore, it must go through installation qualification, operational qualification and performance qualification similar to that of a sterilizer. Each washer is different and requires engineering involvement for appropriate water and electrical connections. Water quality is a main concern with washers. Detergent foaming must be minimized during validation. Devices cleaned using automated systems should be validated under worst-case conditions. Trays generally are used during this process. Use of custom trays must be spelled out in the instructions. Chapter 7. Cleaning Validations of Medical Products can withstand proper cleaning, including covering certain areas on the device or a change in materials. Biography Steven G. Richter, PhD, is the founder of MicroTest Laboratories, Inc. (now Accuratus Lab Services, Inc.), providing contract microbiological and analytical support to medical device, pharmaceutical and biotechnology clients since 1984. Richter founded MicroTest after a distinguished career at the US Food and Drug Administration as a regulatory microbiologist. He has more than 35 years of experience in the medical device and pharmaceutical testing area. He has authored numerous papers and has presented at industrial trade shows regarding regulatory microbiology and sterilization. The Medical Device Validation Handbook 71 72 The Medical Device Validation Handbook View publication stats
