American Pharmaceutical Review, July/August 2015
Environmental monitoring during pharmaceutical and biopharmaceutical production is crucial for ensuring the safety of formulated drug products.
While requirements for the control of both viable (living microorganisms) and non-viable particles (e.g. dust, hair, etc.) and other contaminants (i.e. trace metals, volatiles, etc.) for aseptic manufacturing operations are more extensive than those for non-sterile processes, the quantity of samples that must be analyzed and the amount of data generated can be daunting regardless of the final drug form, particularly for global companies with multiple production facilities.
The consequences of an ineffective environmental monitoring program can be quite serious, with the worst-case scenario being plant shutdowns and product shortages for patients in dire need of medication. It is concerning, therefore, how the potential for error with traditional paper - and spreadsheet-based systems has increased significantly as the volume of reporting requirements has grown. Fortunately, electronic environmental monitoring systems coupled with more automated sampling and data analysis techniques have been introduced to the market that reduce errors, increase efficiency, and lower the cost of this important but nonrevenue generating activity.
Real Interest in Electronic Data Capture and Automation
The growing interest in electronic data capture (EDC), and particularly cloud-based data management, as a tool for increasing efficiency and productivity is reflected in the results of the most recent Nice Insight Pharmaceutical and Biotechnology Outsourcing survey. When asked which technological advancements adopted by contract research organizations (CROs) and contract manufacturing organizations (CMOs) have the greatest potential to provide cost and time savings, 62% of the more than 2,300 outsourcing-facing pharmaceutical and biotechnology executives that responded to the 2015 Nice Insight survey indicated that cloud-based data management services are important.1
Because these respondents represent big pharma (16%), specialty pharma (20%), emerging, niche, or start-up pharma (9%), large biotech (20%), emerging biotech (14%) medical device (17%), and generics/ biosimilars (5%) companies with positions in C-suite (17%), Operations (17%), Manufacturing (16%), Quality Assurance (16%), R&D/formulation (13%), and Data/Clinical Trials Management, Purchasing, and Regulatory Affairs (5-8% each), this result suggests a widespread interest in EDC and real-time data management systems.
Participants in the survey believe that the use of advanced technologies has the greatest impact on enhancing safety. They also indicated that technological innovation has the potential to benefit quality control, research and development, manufacturing, distribution and labeling and packaging in that order. In fact, 96% of respondents indicated that they have at least some interest in forming outsourcing partnerships with service providers that adopt state-of-the-art technologies to increase efficiency, safety, quality and traceability.
Automated laboratory systems are also clearly of interest to participants of the 2015 Nice Insight Pharmaceutical and Biotechnology Outsourcing survey. Half of respondents indicated that the use of robotics labs to perform routine tests is an important mechanism for achieving cost and/or time savings when outsourcing these activities.
Leaving No Surface Untested
All companies manufacturing drugs – whether sponsor companies or CMOs – must have standard operating procedures in place for performing environmental monitoring as part of their drug release processes. Good Manufacturing Practice (GMP) requirements for tracking trends and identifying contaminant sources are increasing. In sterile production facilities, all surfaces, equipment, personnel clothing, masks, and gloves, and the air must be tested on a regular, scheduled basis, at unexpected times and in response to various events. Ingredients/raw materials and finished product are also tested, as in water used in production processes or as water-for-injection (WFI) in final formulations. The requirements are not as extensive for non-sterile manufacturing operations, but testing is still required to confirm no contamination of products.
The result: the continual generation of up to tens of thousands of samples on a monthly basis that all must be carefully tracked and analyzed. Tests can include particle counting (both viable and nonviable), numerous surface analyses as well as air, other gas and water monitoring. Often temperature, relative humidity, and pressure differentials are also continuously evaluated, particularly in cleanroom. Any out of specification (OOS) or out of trend (OOT) results and missed samples must be investigated and potential problems addressed (and possibly reported) following established procedures.
Thus, environmental monitoring programs involve much more than sampling and data collection. A sampling plan must be developed for each process based on a thorough risk analysis, necessary equipment identified and maintained, workflows and staffing resources managed, and verification and reporting activities completed to meet regulatory requirements. In the past, most of these activities have been managed manually, making environmental monitoring a very resource– and time–inefficient aspect of pharmaceutical manufacturing.
Manual Systems are Error Prone and Inefficient
Even for smaller manufacturers that only process hundreds or thousands of samples each month rather than tens of thousands, the manual processing of large quantities of data provides numerous opportunities for error – incorrect sampling procedures, missed or mislabeled samples, misplaced data, misread results, etc.2 Dealing with paper-based records for each of these tests compounds the problem.3 A significant amount of time is required to enter the data into spreadsheets, with each data entry event serving as another opportunity for error. Matching each paper record to the actual test can also become difficult, compounding the inefficiency of the system and creating additional changes for mistakes to occur. Sharing the information between sites within a company or between a CMO and sponsor adds further complexity.
The Promise of Automation and Cloud-Based Data Capture
The best way to reduce error in pharmaceutical environmental monitoring systems is to reduce the human manipulation of samples and data. The industry has recognized this need and responded with the development of methods for linking sampling instruments to automated systems for data capture and analysis, which in turn are coupled to advanced EDC platforms specifically designed for the management of electronic monitoring programs for the pharmaceutical industry.
The key to success for automated systems is that they still perform the compendia method and require the same sample preparation. The benefit is reduced operator time and potential for error while achieving the same quality. Frequently less time is also required to obtain results, which means that potential problems can be identified more quickly. In addition, in some cases the sensitivity may also be improved.4
For example, with the MET ONE “Simply Paperless” option from Beckman Coulter Life Sciences, air particle count data goes direct to PDF and Excel-compatible files, is automatically exported to a USB memory stick, or uploaded directly to a network server. The company claims that, in addition to avoiding data transcription errors, up to two operator-hours per counter, per day can be saved with the device by eliminating the need to manually tear, tape, scan, and copy portable particle counting print-out data.2 Many other firms, such as Lighthouse Worldwide Solutions, offer dedicated remote particle counters that offer real-time monitoring and alarming with very high sensitivities.
More recently, electronic management systems for environmental monitoring of pharmaceutical processes have migrated to the cloud for real-time access to data from various web-enabled devices. For instance, BIOVIA (then Accelrys) collaborated with pharmaceutical industry partners to develop a cloud-based enterprise web software application for the centralized and paperless management of sampling plans for microbiological environmental monitoring — from qualification of inventory materials to plant campaigns to microbiology lab ID testing and reporting. The fully compliant BIOVIA Environmental Monitoring platform, according to the company has been demonstrated to significantly reduce compliance deviations and operational cycle times, plus contribute to cost reductions in drug manufacturing.5
CMO Lonza also presents a noteworthy case with respect to the benefits of advanced EDC systems for environmental monitoring. The company invested in the MODA™ mobile data acquisition platform for automated, paperless, QC processes and found the system to be so beneficial that it acquired developed MODA Technology Partners and has since improved the platform technology.6 The MODA-EM™ module includes a comprehensive suite of functions to manage the entire environmental monitoring lifecycle and integrates with standard monitoring equipment, such as particle counters, total organic content (TOC) meters, and endotoxin devices, for direct data acquisition. According to the company, the system also includes administrative tools for defining operational and security parameters, tools for planning and scheduling to meet QC guidelines and other requirements, an automated workflow engine, and extensive reporting and trending functions. The system also leverages mobile computing technology and advanced visualization tools for increased operational efficiency, improved quality, and reduced costs.6
More Rapid Testing
Conventional microbial testing requires significant manual manipulation, visual determination of microbial growth, and long assay times. However, the pharmaceutical industry was initially reluctant to adopt rapid microbiological methods (RMMs) that have been used in other industries due to concerns over validation and regulatory approval. Several companies have since clearly demonstrated the benefits offered by several new methods designed specifically for pharmaceutical applications. In addition, regulatory agencies now encourage the adoption of rapid methods and are working to address concerns about validation.4
Automated systems that allow rapid, non-destructive analyses and use established, or compendia, methods are of significant interest. These technologies eliminate the need for manual plate counting and data entry and provide information more quickly. Rapid Micro Biosystems, for instance, has developed a rapid visual analysis system based on the detection of the natural auto-fluorescence of microbes that can detect colony formation much sooner than is possible with the human eye.7
Newer polymerase chain reaction and DNA sequencing assays are receiving a lot of interest and seeing growing use due to their improved performance and reduced analysis times.
One new product introduced for the rapid testing of pharmaceutical water sources was introduced by Bio Vigilant in October 2014, the IMD-W™ rapid microbial detection system for real-time water monitoring. On-line (or at-line) water bioburden analysis (OWBA) is achieved using laser-induced fluorescence, and involves the simultaneous determination of particle size and viability/nonviability via light scattering.
More Sensitive Particle Detection
Real-time sampling of air and water using spectrophotometric devices that can both count particles and distinguish between inert and viable particles is in fact a key development in the field of pharmaceutical environmental monitoring.8 The ability of matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) to rapidly discriminate between and identify different types of microbes is also leading to significant gains in efficiency.
Validation Is The Big Hurdle
The biggest hindrance to the adoption of new technologies for environmental monitoring – whether it is more rapid microbial tests or automated versions of conventional air sampling systems – is validation.4 Not only does validation require time and resources that are in short supply, there is often uncertainty about both what protocol(s) to use and whether regulatory agencies will accept new methods/techniques. U.S. Pharmacopeial Convention (USP) “Validation of Alternative Microbiological Methods” was revised in 2014 to clarify some of these concerns.
- 2015 Pharmaceutical and Biotechnology Outsourcing Survey, Nice Insight, January 2015
- B. Latimer, “Application Note: Paperless Environmental Monitoring for Aseptic Pharmaceutical Manufacturing,” March 26, 2014, pharmaceuticalonline, http://www.pharmaceuticalonline.com/doc/paperless-environmental-monit-pharmaceutical-manufacturing-0001
- D. Jansen, “Microbiological Environmental Monitoring,” Contract Pharma, March 7, 2014,http://www.contractpharma.com/issues/2014-03-01/view_features/microbiologicalenvironmental- monitoring
- “Microbiological Monitoring Roundtable,” American Pharmaceutical Review, August 27, 2014, http://www.americanpharmaceuticalreview.com/Featured-Articles/167343-Microbiological-Monitoring-Roundtable/
- BIOVIA, “Accelrys, Technology Brief: Accelrys Environmental Monitoring,” Document No. TB-4704-0113
- Press Release, May 12, 2010: “Lonza agrees to acquire MODA, a global leader in paperless quality control.” (MODA-EM™ Paperless Environmental Monitoring),http://www.lonza.com/products-services/pharma-biotech/informatics/moda-paperless-qc-micro-solution/moda-em-paperless-environmental-monitoring.aspx
- C.A. Challener, “Advances in Rapid Microbiological Testing,” Pharmaceutical Technology, March 27, 2013, http://www.pharmtech.com/advances-rapid-microbiological-testing
- T. Sandle, “Applying spectrophotometric monitoring to risk assessments in biopharmaceutical cleanrooms, “Clean Air and Containment Rev, 20, 22-25 (2014).
If you want to learn more about Nice Insight, the report or about how to participate, please contact Guy Tiene by sending an email to firstname.lastname@example.org
The Nice Insight Pharmaceutical and Biotechnology Survey is deployed to outsourcing-facing pharmaceutical and biotechnology executives on an annual basis. The 2014-2015 report includes responses from 2,303 participants. The survey is comprised of 240+ questions and randomly presents ~35 questions to each respondent in order to collect baseline information with respect to customer awareness and customer perceptions of the top ~125 CMOs and ~75 CROs servicing the drug development cycle. Five levels of awareness, from “I’ve never heard of them” to “I’ve worked with them,” factor into the overall customer awareness score. The customer perception score is based on six drivers in outsourcing: Quality, Innovation, Regulatory Track Record, Affordability, Productivity, and Reliability. In addition to measuring customer awareness and perception information on specifi c companies, the survey collects data on general outsourcing practices and preferences as well as barriers to strategic partnerships among buyers of outsourced services.