In the aseptic environment, an automated EM program ensures optimum control over potential contamination
By Bob Toal, MODA Technology Partners
With increased demand for production of modern therapies using vaccines, injected drugs, and human tissue, there is an increase in the number of manufacturing facilities requiring aseptic processing conditions. In aseptic processing, where the end product cannot be terminally sterilized, it is especially critical that product is manufactured in an environment free of contaminants. And once the aseptic environment is established, it must be closely watched via comprehensive environment monitoring (EM) programs to ensure processing areas are under control for potential viable and non-viable contamination.
Current state of EM: Bigger, but not better
Although the requirements for EM have been growing in terms of number of samples and sampling sites, the paper-based, labor-intensive programs that are so prevalent in the industry are not capable of delivering the maximum value desired.
According to J. Agalloco et al., “Comprehensive EM programs have been a general practice in the industry since the late 1980s. Since then, these programs have become more expansive. Unfortunately, there is no evidence that the EM programs of today are functionally superior to those of 15 years ago. They are certainly more costly and far more time-consuming, but it is not generally believed that they do a better job of assessing product safety.”1
The paper-based QC process
From the smallest biotech operation to the largest pharmaceutical manufacturer, the traditional EM process is manual, paper based, time consuming, and error prone. First, the process relies on paper schedules to drive the work. Next, in cleanroom areas, technicians refer to the paper schedules and in many cases, use permanent markers to mark information about samples taken onto the sample media (petri dishes, vials, etc.). In the laboratory, manual reconciliation steps precede numerous manual entries in paper logbooks to track lab testing and processing activities. Finally, when test results are ready for recording, they are manually entered into spreadsheets, small database applications, or perhaps a laboratory information management system (LIMS). Notifications on any deviation found are sent via manual e-mail.
The massive amount of EM test data generated is fair game for agency audits. Today this typically involves sifting through volumes of binders with paper-based results and reports. For corrective and preventive action (CAPA) purposes, building a set of trend reports may require more than eight weeks. Unfortunately, by the time a trend of activity is developed and recognized, the condition causing the trend is likely to have changed, making it difficult to support corrective action activities and nearly impossible to perform meaningful preventive actions.
Concepts for automation
Organizations like the Parenteral Drug Association (PDA) are actively promoting automation in the cleanroom and in the laboratory to remove the manual processes and paper. In the cleanroom, the clear recommendation is for automated collection of data as quickly as possible at the point of sample. From the EM Handbook published by PDA:
- “ consider cleanroom touch pads or computer terminals that allow for automated data entry in the room.”2
- “For those procedures which involve manual data collection, palm pilot-type of data collection devices may be necessary that can directly download to the computer system, and allow for direct data transfer without the risk of contamination.”2
And in the laboratory, the call is for automation in reporting as well. From the same EM Handbook publication:
- “ analysis and trending of environmental data is essential to aid in the interpretation of process stability and assess overall control performance.”
- EM reports must be “ accurate, traceable, timely, and well-documented.”3
EM automation challenges
Leveraging automation to increase the efficiency of collecting and tracking environmental samples in an aseptic environment poses significant challenges. In traditional manufacturing and packaging environments, computers are commonplace and dramatically increase the overall efficiency and quality of operations. However, computers, like all other equipment in a cleanroom environment, must be sanitized in order to destroy potential contaminants that might be growing on their surfaces. Heat, radiation, and chemical disinfectants cannot be used on standard business computers without damaging them. Industrial or “rugged” computers that can be sanitized exist but are typically deployed as a fixed workstation used to control or monitor a specific operation.
Figure 1. Sampling cart with mobile data acquisition devices mounted.
The EM sampling technicians must travel throughout the aseptic facility, on a pre-defined route, collecting and labeling samples. A fixed workstation would not improve operational efficiency and in fact would result in increased foot traffic and potential congestion within the facility. Installing multiple EM kiosks throughout the facility is not economically feasible, as industrial computers that can withstand chemical disinfection are significantly more expensive than traditional business computers.
Mobile technology overcomes challenges
The ideal device is small, lightweight, transportable, and capable of being sanitized with commonly used cleaning agents. It is able to leverage wireless or radio frequency (RF) technology to provide connectivity to and communication with other computer systems that support the manufacturing process. It also provides the ability to read and print barcodes and RFID tags to eliminate the need for paper schedules and hand-written sample labels and sampling records.
The individual components of an ideal solution include a rugged wireless tablet PC with touch screen, a wireless barcode scanner, and a rugged, thermal barcode printer with sterile label stock. And these components can be pulled together and mounted on hardware that is already commonly used for sample collection: a stainless-steel cart. The shelves of the cart can continue to be used to carry sampling media and portable testing equipment such as air particle counters.
Best practices requirements
With an automated, paperless solution, a QC department can enter and maintain all EM program standard operating procedures (SOPs) electronically. Sampling and lab processing tasks are assigned based on the rules as defined in the SOPs. By using a sampling cart with mobile data acquisition devices as described, technicians can simply move to a sampling site and run a scan on a fixed barcode that identifies the site. The scanned barcode can then trigger all sampling tasks required for that site.
Rather than using a permanent marker on media plates to record information, the system can generate a barcode label that is placed on the sample media. The barcode labels are produced from a thermal printer on sterile stock, all suitable for a cleanroom environment. Information about each sample is uploaded to a data repository immediately at the point of sample.
In the laboratory, there will no longer be a need for manual reconciliation of actual vs. planned samples taken. All of the remaining lab processes, including automatic notification on deviations, will be driven by electronic workflows and tracked through completion. Analytical tools should include a comprehensive set of reports that not only meet audit requirements but enable execution of meaningful investigations for both corrective and preventive action resolution.
Based on industry best practice, here are the top 10 requirements for an automated EM program.
1. Workflow driven. The solution must provide the user with a means to define and maintain their EM program SOPs in electronic form. The SOPs identify the test protocols, sampling sites, and frequency of monitoring needed to comply with cleanroom standards, operational procedures, and validation criteria. These workflow definitions are then used to drive the required EM tasks and to help ensure compliance.
2. No paper records and manual error-prone processes. Scheduling of work is driven automatically as defined by the electronic SOPs. Work assignments are made electronically without paper schedules. Working in a cleanroom, technicians move from site to site to collect samples and perform tests. A sanitized, mobile, touch-screen computer supports a paperless operation to automatically collect and upload information about each sample. The system will read barcodes on sites and equipment (e.g., air particulate counter or viable air sampling device) to quickly identify scheduled tasks and assure valid use and calibration of equipment. For personnel samples, labels for the correct number of samples needed are generated based upon the people in the room at the time of sampling and the sites (e.g., glove and gown location) to be sampled. The system also must enable the technician to record the identity of the individual from whom the sample was taken.
3. 21 CFR Part 11 compliant. In a paperless solution, all of the electronic records created must contain proper audit information and all electronic signatures must be performed in compliance with regulating agency requirements.
4. Support full spectrum of test methods. The solution must be able to support all viable and non-viable testing activities including tests of air, surfaces, utilities (water, gas), and personnel.
5. Disconnected operation. The solution must be able to support operations in a disconnected mode in the event of a wireless network connection drop. While performing sampling operations in a cleanroom area filled with many stainless-steel items, it is a common occurrence for the wireless network to be temporarily unavailable.
6. Device integration in cleanroom. Where possible, the solution should support device control from the mobile platform and a direct download of data. A common example of this integration is with non-viable air particulate counters. Another is with in-line water testing for total organic carbon and conductivity.
7. Device integration in lab. Many utility and water tests are typically performed in the laboratory. Devices that produce electronic output should be integrated to provide either a direct download or a file-based transfer of results. This includes devices that test for endotoxin, conductivity, and total organic carbon.
8. Comprehensive reporting. Reports are required to monitor daily operations and assist in audits, product release decisions, and performing investigations. Reports must include:
- Results by a specific batch/lot, to support batch closeout.
- Results and trends for a specific room and time period.
- Results and trends for specific personnel over specified time periods.
- Results and trends for a specific organism found over specified time periods.
- Results and trends for a specific media lot, to review sterility assurance
9. Automatic notifications for out-of-spec events. The solution generates alerts and actions with immediate notification via e-mail for out-of-range results and for trends, such as three consecutive non-zero counts.
10. Ability to handle exception cases. The solution needs to be able to gracefully handle common cases where the process did not go exactly as planned (e.g., dropped media plates, nobody in room for personnel testing, etc.).
Process for viable sample collection
The typical paper-based process for a sample collection regimen is as shown about 8 hours per person, per shift.
By employing a best practices-based, mobile data acquisition platform for sample collection, the process time is cut in half–to 4 hours per person, per shift. This savings has significant implications when it is applied to multi-technician, multi-shift operation for a one-year period.
Process for non-viable air testing
A typical paper-based process for collection of results from non-viable air particulate devices is shown in Fig. 4. In this process, a paper printout of results generated by the device is pasted into a logbook. The results are then hand-typed into a spreadsheet and reconciled vs. the printout. Once data are entered into a spreadsheet, trend lines over periods of time can be manually produced via a reporting tool.
The paperless process for collection of results from non-viable air particulate devices starts with the mobile collection tablet that will drive the devices with a user interface that includes commands for initialize, start, stop, and collect results. The connection to the device could be wired via USB, etc., or it could be wireless. Results collected are automatically uploaded to the data repository where reports and trends can be viewed in real time. Any results exceeding alert or action levels will generate automatic notification via e-mail.
By removing the error-prone, manual data entry steps, the effort and time savings over the paper process is significant, with an average savings of 6 hours per person per shift. As with the viables sampling, when this savings is applied to multi-technician, multi-shift operation over a one-year period, it is very compelling.
Case study results
The opportunity for time and cost savings is most evident in high-volume operations where hundreds of thousands of samples are taken on a yearly basis. The transformation of a paper-based EM operation for handling 360,000 samples per year to a paperless solution turned a positive return on investment within six months. Key drivers for savings were elimination of batch data entry, reduction of missed samples, and elimination of template-to-media reconciliation. Another area for savings was in the production of reports where the paper-based monthly trending reports required 30 person-days. This task was effectively eliminated.
It is important to note that there are organizations with rather low-volume sampling programs that have automated their EM processes primarily for enhanced compliance and decision support. In one case, where an organization produces patient-specific therapeutics, the cost of losing even one product batch to an untraceable EM excursion is just too high.
Best practices-based automation concepts for EM are actively promoted by leading, well respected industry organizations like PDA. These automation concepts are also consistent with the FDA initiative for process analytical technologies (PAT) , which aims to automate more of the drug manufacturing process, remove variability, anticipate problems, and make corrections earlier in the process before an entire product batch has to be rejected.
Implementation of an automated, paperless, best practices-based solution for the entire QC microbiology process associated with EM, utility, and product testing, provides an opportunity for significant, tangible return on investment due to the reduction in time needed to execute the required protocols. An additional benefit is the immediate availability of higher-quality information that can quickly and accurately provide EM evidence to support batch release and ensure regulatory compliance.
Bob Toal is a director at MODA Technology Partners in Wayne, PA (www.modatp.com) with more than 25 years’ experience in IT systems integration.
- J. Agalloco, J. Akers, and R. Madsen, “Aseptic Processing: A Review of Current Industry Practice,” Pharmaceutical Technology, 2004.
- J. Moldenhauer, Environmental Monitoring–A Comprehensive Handbook, Vol. 1, p. 24, PDA.
- J. Moldenhauer, Environmental Monitoring–A Comprehensive Handbook, Vol. 2, pp. 33, 50, PDA.