This article is Part 2 of 3 in our series on Understanding Certification Report Requirements. Part 1 discussed Certification Reports for SECs and is available at pppmag.com/article/2694. Part 3, which will be published in a subsequent issue of PP&P, will focus on certification testing for CAIs and CACIs.
While engineering control certification is a requirement of USP <797>, the chapter does not specify how it must be performed and what information must be documented on a certification report. As a designated person responsible for ensuring that your cleanroom is compliant with current USP standards, it can be challenging not only to deduce from a certification report whether the appropriate testing has been performed, but also to interpret the results and determine if all aspects of testing have been properly documented. It is critical that the certification report contain the necessary information so pharmacy personnel and regulatory inspectors can verify and interpret the results to ensure the applicable requirements meet engineering control certification compliance.
The chapter references CAG-003, the Controlled Environment Testing Association (CETA) Certification Guide for Sterile Compounding Facilities, which provides guidance on certification requirements for sterile compounding facilities.1 The chapter also indicates that an equivalent may be used; however, as there is no other guide specific to the certification of sterile compounding facilities, it is strongly recommended that certification be performed in accordance with CETA’s guidelines in order to ensure adequate testing procedures are followed.
Primary Engineering Control (PEC) Requirements
Certification is required every 6 months to ensure that the PEC is operating in accordance with the manufacturer’s specifications and ISO 14644-1 for ISO classification. Because there are various types of PECs that are designed to provide different types of protection, the certification tests will vary depending upon the type of unit and manufacturer. All PECs used for sterile compounding will require, at a minimum:
Additional tests may be required that are specific to each type of laminar airflow system (LAFS). These tests are intended to verify the performance of the LAFS. It is strongly recommended that you read your user manual carefully and be familiar with any certification testing requirements that are specific to your device.
Dynamic Airflow Smoke Pattern Tests
Dynamic airflow smoke pattern tests also must be performed every 6 months in all PECs; however, they may be performed internally, if desired. A dynamic airflow smoke pattern test serves to identify the location of the direct compounding area (DCA) within the PEC where the critical sites are exposed. During the test, smoke is introduced at the supply air diffuser as simulated dynamic compounding is being performed. The goal is to show compounding personnel how to utilize the airflow to maintain first air at the critical site. Additionally, this test helps establish whether the PEC has been placed appropriately and whether there are outside influences on the PEC affecting the airflow in the DCA. The test must be video recorded and documented on either the certification report or the internal report (if performed in-house). The DCA must be identified on the report, and a statement of acceptability must be included stating that the device provides unidirectional airflow with no dead spots or refluxing at the DCA during dynamic operating conditions.
Laminar Airflow Workstations
A laminar airflow workstation (LAFW) is used to provide product protection through unidirectional HEPA filtered air in the work zone. The following tests are required for certification, and the associated data must be documented:
Airflow velocities must be measured in each LAFW. The velocity measurement locations and acceptance criteria will vary depending upon the type of unit and manufacturer. The nominal set point of the unit is determined by the manufacturer; typically, +/- 10 feet per minute (fpm) from the nominal set point would be the acceptable range. The criteria provided by the manufacturer must be documented on the certification report so that the actual average velocity can be verified as acceptable. Additionally, the grid pattern method in which the measurements were taken must be identified on the report, along with the calculated total CFM, which is determined by averaging the velocity readings and multiplying by the filter area. All intermediate values must be reported so that the results can be verified.
HEPA Filter Integrity Testing
HEPA filter integrity testing must be performed on the filter located within the LAFW. The site of aerosol introduction in this case would be before the motor blower that delivers the supply air to the PEC device. A photometer is then used to scan the downstream filter face. The upstream concentration (typically 10-90 micrograms per liter) in this case could be measured either through a manufacturer supplied measurement port or calculated. Documentation should include the downstream penetration percentage, the average velocity used to calculate the CFM or the actual measured challenge, along with the final result as well as any repairs that occur.
Induction Leak/Backstreaming Tests
Induction leak/backstreaming tests are performed on the LAFWs to ensure that they are free from construction joint leaks and any backstreaming of airflow into the workspace openings where contamination could enter the critical area. The induction leak test is performed by elevating the background particle concentration outside of the unit to exceed the ISO particle count classification and then scanning with a particle counter around the welded joints and seams on the interior of the unit.
The backstreaming test utilizes a visual medium that is introduced along the exterior of the unit, including all openings into the LAFW. This test identifies areas where backstreaming of airflow may occur around the perimeter openings. The certification report must identify the location and level of any induction leaks that are detected, as well as the location and source of any detected backstreaming observed in the workspace opening. Any corresponding corrective actions should also be documented in the report.
Total Particle Count Testing
Total particle count testing must be undertaken in the LAFW during dynamic compounding conditions or with simulated compounding activities that are representative of the actual compounding activities. By requiring dynamic conditions, the testing ensures that the PEC is maintaining the desired classification and state of control during operations. As such, the dynamic conditions must be conducted by pharmacy personnel, not the certification technician.
The sample volume must be at least two liters, with a minimum sampling time of 1 minute at each location. The LAFW must be certified to meet ISO Class 5 particle count concentration levels no greater than 3,520 particles per cubic meter (particles/m3). The report must indicate that the conditions of sampling were dynamic, include a diagram of the sampling locations, and document each individual count reported as particles per cubic meter (PPCM). The sample volume and sample time also must be reported.
Biological Safety Cabinets
The purpose of a biological safety cabinet (BSC) is to provide product, personnel, and environmental protection. In the pharmacy, BSCs are typically used for sterile compounding of hazardous drugs. Most BSCs are NSF-listed, which means that the specific cabinet model has been tested against the rigorous performance tests listed in the NSF/ANSI 49 standard, and thus meets the criteria to be NSF-listed as a Class II BSC. Within the NSF/ANSI 49 standard, Normative Annex 5 (formerly Annex F) is used for the field testing of the cabinets. This annex contains the required tests that must be performed for the BSC to be certified in accordance with the NSF standard. Cabinets used for sterile compounding must be certified every 6 months to meet the criteria as noted in NSF/ANSI 49. For BSC certification, the following tests are required and the associated data must be documented:
Downflow velocities are performed in the work zone of the cabinet to ensure the air from the supply HEPA filter is operating within the manufacturer’s specifications. The manufacturer of the cabinet has determined the exact locations in which the velocity readings must be taken. These specifications can be found on the BSC data plate, typically located on the front of the cabinet. Velocity readings are taken using a calibrated thermal anemometer (see FIGURE). Each individual velocity reading and the corresponding grid location, the high and low values, and average velocity must be reported. Additionally, the individual readings must not vary more than +/- 25% or 16 fpm (whichever is greater) from the average downflow velocity and must be documented on the report.
Inflow velocities are measured at the work opening of the cabinet. The inflow velocity is critical to the air balance of the cabinet and the ability to maintain containment within the BSC. Measurements must be taken using a direct inflow measurement (DIM) or by using an alternative method that has been validated and provided by the manufacturer. This information is also included on the data plate located on the front of the cabinet. If the DIM method is used, the large, tent-like capture hood is placed over the work area opening and sealed, then a minimum of five readings are taken. The individual volume readings must be documented and averaged for the final inflow volume. The volume must then be calculated by the work opening area to determine the calculated inflow velocity. All values must be reported along with all intermediate calculations.
If using an alternative method, such as the constricted access opening, the sash height has to be reduced to the manufacturer’s determined height and velocity readings are then taken along the opening in the grid pattern as defined by the manufacturer. The individual readings must be documented, averaged, and then multiplied by the measurement area to convert to CFM and then divided by the actual work area opening. A correction factor may need to be applied to the calculations and will be noted on the cabinet data plate, if applicable. Additional details can be found in NSF/ANSI 49.
Airflow Smoke Patterns Test
An airflow smoke patterns test is required and must be performed at each certification. Do not mistake this test for a dynamic airflow smoke pattern test, as this test is not meant to demonstrate that first air is supplied to the DCA. Rather, the airflow smoke patterns test consists of four separate tests wherein smoke is utilized to visualize the airflow to ensure proper performance:
The name of each test must be reported along with a statement of pass or fail.
HEPA Filter Integrity Testing
HEPA filter integrity testing is performed on both the supply and exhaust HEPA filters. The method for aerosol introduction will vary depending on the type of cabinet that is being tested. For example, in an A2 cabinet the challenge aerosol will be introduced on the work surface of the cabinet and the supply and exhaust filters can then be scanned. For a B2 cabinet, the aerosol will be introduced into the supply motor to challenge the supply filter and then introduced on the work surface to challenge the exhaust filter. For any BSC that has been used for hazardous drugs (HDs) or any hazardous item, the challenge aerosol must be calculated to prevent exposure from contaminated air within the plenum.
In order to calculate the challenge aerosol concentration, the area and CFM of the filters must be determined and then calculated by the specific challenge constant and number of nozzles. Supply and exhaust HEPA filters that can be scanned must have a downstream penetration of ≤0.010% leakage of the upstream concentration, and exhaust filters that cannot be scanned (eg, B2 BSCs) must be probed and have a downstream penetration of ≤0.005%. The report must include all calculations along with the results and a statement of pass or fail. Likewise, any leaks or repairs must be documented.
Site Installation Assessment Tests
Site installation assessment tests are performed during each BSC certification to ensure that the cabinet is integrated properly into the facility and that the alarm functions are operating as intended. The specific tests will depend upon the type of cabinet and whether the cabinet is ducted. Note that for HD applications, USP <800> requires that the cabinets be externally vented; however, if the cabinet is used for non-HD applications and is not externally vented, then not all tests apply. The sash alarm test does apply to all cabinets: When the sash is raised 1” above the manufacturer’s recommended height, an audible and visual alarm must sound. If the cabinet is newer than 2014 and NSF listed, there will also be a requirement to test the sash at 1” below the manufacturer’s recommended height. The sash alarm test and statement of pass or fail must be reported.
The exhaust alarm system must be tested, if present. For a type A2 cabinet, the containment loss of the canopy connection must also be verified at each certification. During this test, the exhaust airflow is reduced as a visual smoke medium is introduced into the canopy intakes of the exhaust transition. When the loss of containment is demonstrated visually, the cabinet alarm must respond within 15 seconds. Testing a type B2 cabinet is more complex and requires that the exhaust be lowered by 20% of the total exhaust. The alarm must then sound within 15 seconds and the blower interlock must also shut down within 15 seconds. The report must include the names of the tests and statement of pass or fail.
Total Particle Count Testing
Total particle count testing must occur in the BSC during dynamic compounding conditions or with simulated compounding activities that are representative of the actual compounding activities. By requiring dynamic conditions, the testing ensures that the BSC is maintaining the desired classification and state of control during operations. As such, the dynamic conditions must be conducted by pharmacy personnel, not the certification technician.
The sample volume must be at least two liters, with a minimum sampling time of 1 minute per location. The BSC must be certified to meet ISO Class 5 particle count concentration levels no greater than 3,520 PPCM. The report must indicate that the sampling conditions were dynamic and include a diagram of the locations as well as document each individual count reported as PPCM. The sample volume and sample time also must be reported.
Additional Documentation Requirements
Equipment calibration requirements will vary depending on the instruments used and the manufacturers’ recommended procedures. Nonetheless, it is critical that calibration certificates be included with the final report for each piece of certification equipment that requires calibration. This ensures that the equipment used to perform testing is operating within its tolerated calibration interval. Ultimately, calibration documentation provides the evidence needed to establish the credibility of the report’s findings.
PEC certification is a key requirement of USP <797> and <800>, yet the chapters do not detail what information should be documented on a certification report. For LAFWs and BSCs, airflow velocities, HEPA filter integrity testing, and dynamic total particle count testing are required. Furthermore, thorough and accurate documentation of the testing processes is necessary to demonstrate that proper testing occurred and to provide regulatory inspectors with sufficient data to verify the results.
Kimberly Coughlin, BS, director of microbiology at Kastango Consulting Group, a TRC Healthcare Company, provides consulting on environmental monitoring, remediation, and facility design performance. She is the 2019-2021 President Elect for the Controlled Environment Testing Association (CETA) and serves as a subject matter expert for the CETA National Board of Testing (CNBT). Kimberly received NSF accreditation for the field certification of Class II Biosafety Cabinets and is accredited through the CNBT as a registered certification professional in the sterile compounding facility (RCP-SCF) discipline. Kimberly also played a lead role in the writing of ISPE’s Good Practice Guide: HVAC and Process Equipment Air Filters.
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