Automated compounding devices have become ubiquitous in hospital pharmacies as they provide an efficient means of compounding complex, multicomponent admixtures. These devices can deliver 20 or more individual additives in predetermined formulations with precision and accuracy while maintaining sterility, and thus, can consistently produce TPN doses matching a hospital’s daily need. While automated compounding devices (ACDs) have historically been associated with TPN compounding automation, now the term also encompasses the new IV and chemotherapy robotic fill systems presently available. Used correctly, ACDs can increase medication safety, streamline pharmacy efficiency, and positively impact overall patient care. Nonetheless, it is essential to support ACDs with sufficient laboratory data to document the validity of the devices’ ability to produce accurate and sterile medium-risk CSPs.
Process Simulation Testing
By validating ACDs, performance characteristics can be established for the devices, and process simulation testing is an effective means to this end. Process simulation or media fill is an overall assessment of asepsis in the dispensing function of an ACD. This quality assurance strategy is designed to mirror the compounding process by utilizing sensitive microbiological media as a substitute for source components. Testing should be performed under worst case compounding scenarios to purposely provide additional stress factors to the overall compounding process. The ability to produce sterile compounding preparations under duress exhibits process robustness and ruggedness—major factors in both equipment and process validation. For example, ACD process simulation validations should be routinely conducted at the end of a shift or at the end of a TPN batch process. At these times, ACD operators are tired, the work environment tends to be sullied, and equipment and components have had multiple interactions; these are the desired conditions under which to perform a test. Keep in mind, tubing sets should not be changed prior to testing.
These postshift or postbatch situations represent common conditions that can impact the overall sterility of the CSP. If CSP sterility is proven under worst-case conditions, then the ACD compounding process—which includes the ACD unit, the operator’s aseptic technique, the ISO 5 environment, and a standard disinfection program—verifies a reliable and reproducible sterile compounding process. The frequency of ACD validation tests should be tied to the frequency of the device’s use; semiannual validation is appropriate for third-party, independent contract, sterile-compounding facilities that have multiple ACDs and compound products for many institutions, while annual validation is recommended for hospitals that compound relatively infrequently.
From a usage standpoint, an ISO 5 environment is required for ACDs and written standard operating procedures (SOPs) should be in place to define the operation, start-up and shut down procedures, preventive maintenance, calibration, software checks, and quality specifications. ACD operators should be trained and their training must be documented to demonstrate evidence of operational proficiency on this specific device as it is used in the pharmacy.
USP <797> mandates calibration, verification, and documentation for ACDs and calls for daily record keeping to exhibit dose accuracy. Furthermore, USP <797> emphasizes data review to avoid clinically significant errors over time. However, the chapter does not stipulate process simulation studies, per se, for ACDs. Despite this lack of specificity, the media fill for ACD validation is paramount for challenging the aseptic process of the overall operation of automated compounding devices. The media fill test exposes microbiological growth media to contact surfaces of containers, tubing, pump mechanisms, technician manipulations, and critical ISO 5 environments. This systemic approach is why process simulation testing is used for ACD validation. Possible sources of contamination include tubing connections, improper aseptic technique and/or sanitization processes, inadequate facility design, and HEPA failures and/or faulty container closures.
ACD validation using media fills should also incorporate environmental monitoring procedures to demonstrate compliance to USP <797>. Viable and nonviable monitoring provides data on the environment surrounding the device. Because airborne microorganisms in the ACD environment can increase contamination risks, monitoring with an active air sampler during media fill ACD validation provides additional data on the ISO 5 controlled environment. Surface level monitoring with contact plates also affords feedback on overall cleanliness and disinfection.
Media Fill Tests
The microbiological media used in an ACD process simulation should be a general nutritional formulation that provides growth to a wide variety of microorganisms. Trypticase soy broth (TSB), also known as soybean casein digest, is generally the media of choice in this scenario, as it has good clarity to better enhance visible sterility checks during and after incubation. These forms of media are readily available from multiple vendors and should be documented as sterile before use, so ask for a certificate of sterility at the time of purchase. Potential dilution of the microbiological media throughout the ACD validation testing should be factored into your testing process. If media dilution is greater than 10%, then growth promotion testing should be reevaluated on the diluted media.
Growth promotion testing (GPT) demonstrates the ability of the media to support microbial growth, even at low levels. GPT is essential to exhibit the functionality of the medium in providing true results, and is typically done using inoculum levels of 10 to 100 colony-forming units. The types of microorganisms used in GPT include both aerobic and anaerobic bacteria, yeast, and mold as specified in the USP <71> compendial methodology.
To meet GPT specifications, the media must demonstrate growth of these organisms within a specific number of days at specific incubation temperatures and then demonstrate appropriate recovery versus the positive controls. Once this occurs, successful growth-promoted media has been qualified to give true results for subsequent validation activities. TSB can be obtained in various containers (syringes, mini-bags, vials, ampoules, etc) and appropriate volumes (1 mL to 3000 mL) depending on need. Using specific source containers that mimic the actual TPN compounding process offers a stronger validation scenario. The more rigorous the challenge, the greater your confidence will be that the ACD process is proven and consistent. TSB also can be filled aseptically in specific customized containers if proper availability is an issue. If this approach is taken, keep in mind that the container must be incubated for 14 days to ensure sterility before initiating ACD validation activities.
Performing the actual validation involves filling all tubing lines between components with sterile, growth-promoting TSB. It is recommended that the hospital follow a TPN formula that is routine for their institution. The goal is to sequence the appropriate source components combined with the device’s micro and macro mixing capabilities. The sensitive TSB media will contact all ACD surfaces including tubing, connectors, fluid pathways, pump heads, and final IV bags. This comprehensive contact will provide robust feedback for verifying sterility integrity. The number of TSB samples taken should reflect normally produced batch sizes, but remember that TPN volumes can call for a large amount of TSB to be used.
Following the ACD validation sequence—via process simulation activities— will produce TSB-filled IV bags, which should be labeled and incubated for 14 days. The TSB filled bags should then be checked by a microbiologist, as specified by USP <71>, on days three, seven, and 14. Incubation temperature should be held at 20-25°ºC for the first seven days followed by 30-35º°C for the last seven days. This rotational incubation optimizes growth conditions for yeasts, molds, and bacteria, respectively.
During the incubation time, visual checks should be performed to assess turbidity, and the microbiologist will look for color change, gas production, and particle generation. If the TSB-filled bags generated from the ACD validation process demonstrate sterility, then the ACD validation meets acceptance criteria and is deemed aseptic. However, if the TSB-filled bags are turbid and/or show contamination, management should be immediately informed and an investigation should be performed to determine the root cause. This investigation should also include microorganism subculture and identification, as this will provide clues to the source(s) of contamination. For example, Staphylococcus species are skin bacteria and contamination would indicate a human source, whereas Pseudomonal contamination would indicate a water source. Environmental monitoring during validation testing is invaluable at this point because it provides information on the ISO environment and the effectiveness of overall cleaning practices. Personnel observation practices should also be investigated and maintenance records for all components should be reviewed. Pay attention to valve assembly replacements, load cell calibrations, occlusion detection, and pump motor and software version verification records.
ACD validation protocols should be inclusive and outline the validation study from the standpoint of purpose, scope, responsibilities, references, SOP documentation, equipment used, procedural steps, acceptance criteria, and summary and approval. The hospital pharmacy’s quality control representative(s) should review these protocols. If weights are being used with your ACD, calibration is especially recommended, and the weights should be calibrated to NIST to ensure accuracy. Be sure to include all calibration and accuracy logs with the ACD validation testing results.
Ultimately, ACD process simulation studies are the most robust way to demonstrate sterility in a reliant and reproducible manner. As the popularity of robotic fill systems for both IV medication and chemotherapies increases in hospital pharmacies, ACDs will account for a greater percentage of CSP production and therefore will require more frequent media fill validation.
Fran McAteer, MS, MBA, is vice president at Microbiology Research Associates, Inc, an FDA-registered microbiology testing laboratory specializing in USP <797> compliance, consulting, environmental monitoring, cleanroom certification, ACD validation, and CSP sterility and endotoxin testing. Fran has expertise and experience in implementing USP <797> compliance programs and acts as a consultant for numerous hospitals. Fran can be reached at (978) 263-2624.