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Data analytics, modular equipment, digital tools, and risk-based validation improve speed, flexibility, and quality.
Many areas of pharmaceutical and biopharmaceutical manufacturing—solid-dosage drugs, vaccines, cell and gene therapies, viral vectors, and others—are facing demands for faster time-to-market and the ability to have more flexibility, with faster changeovers from one product to the next, to match the shift to smaller batch sizes for more personalized medicine. Advances in equipment and data analytics technologies, along with digital tools and risk-based methods for qualification and validation of equipment and processes, are helping meet this need for speed.
“Industry 4.0” technologies, which collect large volumes of data from sensors installed on equipment and use these data in data analytics software to optimize equipment and processes, continue to penetrate pharma manufacturing. Equipment and facility control systems can be designed for connection using standard protocols, providing better communication between control systems.
“The module type package (MTP) communication standard provides a framework of standardized connectivity between OEM [original equipment manufacturer] equipment and centralized control systems to streamline connectivity and interoperability,” says Michalle Adkins, director of life sciences consulting at Emerson. “For example, it can be used to enable much easier integration between a programmable logic controller used to control OEM equipment, such as a deionized water skid, and a distributed control system.” Easier integration enables flexible manufacturing. “Operations teams can use MTP to unlock modularity, using different equipment on demand, with MTP automating and simplifying the integration process,” says Adkins. “And users of these OEM packages can tie multiple systems together without the need to re-engineer solutions, making new equipment less costly to instal, validate, and maintain.”
“Plug-and-produce initiatives are driving towards increased data availability and accessibility, where data is interfaced and contextualized in a smarter way to embrace data integrity and analytics,” says Petter Mörée, managing director for EMEA and industry principal for Life Sciences and Pharmaceuticals at Seeq. Data analytics enable predictive or condition-based maintenance, which improves equipment reliability by reducing unplanned downtime. Data analytics also drive improved time-to-market, quality, and product and equipment availability, continues Mörée. Digital asset models (sometimes called digital twins) can be used to monitor and predict equipment functions, so that overall equipment efficiency in the facility can be improved. For example, a model of process chromatography can be used to predict when a chromatography column needs to be repacked.
More data and their analysis lead to increased knowledge and improved risk assessment. Use of data analytics, along with first principles, prior experience, and risk assessment, enhances the ability of process experts to improve operations and to perform qualification and continued process verification, adds Mörée.
When travel was restricted during the pandemic, many equipment vendors and users pivoted to using video and web conferencing tools for activities such as factory acceptance testing (FAT). Companies are continuing their use of remote FAT even when travel is possible because it speeds qualification and eliminates duplication, for various types of equipment, including the automation systems.
“Instead of testing systems at the supplier’s site and then testing again when equipment is installed at the plant, teams are eliminating duplicate work by using cloud-based FAT tools to remotely connect to equipment at the supplier, run tests using the actual system configuration, and generate documentation,” says Adkins. “Once testing is complete and equipment is on site, the team can use those same cloud tools to move the configuration from the development system to the production system.”
In addition, simulation technologies, such as digital twins and augmented reality, are being successfully used to speed timelines for equipment installation and counteract the effect of long lead times and supply-chain delays, contends Adkins. “Fit-for-purpose simulations allow engineers to test before the equipment is installed, and operators to train as though they were working with real equipment. Using these tools, teams can ensure their processes work properly and their people are ready even as they wait for equipment to arrive, taking training and testing off the critical path,” she explains. “Emerson customers are often surprised by the amount of time they save by using cloud technologies and simulation to support some of their qualification steps remotely. The ability to perform stages in parallel not only saves time, but it also contributes to lower costs by addressing problems earlier in the project, bringing new manufacturing lines online more quickly, while eliminating waste.”
Digital tools also save time by eliminating the time-consuming aspects of paperwork associated with input/output (I/O) designs and verification of connection testing. Modern control systems provide flexibility with automated “I/O on demand,” emphasizes Adkins. “These systems typically have interchangeable terminal blocks installed in the field and are connected to the control system via a single Ethernet cable. I/O is automatically mapped to the control system and field wiring of any signal type can be terminated on any I/O module. This simplifies wiring documentation and eliminates hundreds of hours labelling wire terminations and verifying cabinet drawings. Teams can move right to loop testing without spending significant amounts of time on documentation and testing because complex wiring and mapping are eliminated.”
Class-based systems can streamline validation of equipment. In automation systems, class-based control creates unit classes containing all the operations associated with a single unit, says Adkins. “Teams test the class-based unit once, and then only need to test any minor differences among units, instead of testing each unit individually,” she explains.
OEM equipment with integrated control systems can also reduce validation requirements. “Commercial off-the-shelf (COTS) control systems that are integrated using libraries of firmware-based objects are generally considered to be a configured product, rather than a solution based on custom code,” says John Hatzis, life sciences industry consultant at Rockwell Automation. “More OEM equipment is being built with COTS control systems as a standard offering. This reduces the validation scope of the producer since the process control comes validation ready from the OEM. Producers can get a bioreactor installed, commissioned, and validated for use in production in as little as six months. This OEM equipment is designed to fit into several processes with minimal reconfiguration.”
The industry has been increasingly moving toward risk assessment and risk management in validation, directed by International Council for Harmonisation (ICH) guidelines and, specifically for equipment, ASTM E2500 (1). Recent International Society for Pharmaceutical Engineering (ISPE) good practice guides, such as the second edition of the Good Engineering Practice Guide (2) and the second edition of the Commissioning and Qualification baseline guide (3), for example, include risk management concepts.
“Recent regulatory changes focus on an increasing practice of risk assessment and risk management while reducing reliance on strictly worded guidance for any given topic,” suggests Moria Feighery-Ross, senior validation engineer at Pharmatech Associates. The new revision to the European Union’s Annex 1 (4), for example, “…demonstrates a reduction in prescriptive practices and an increased emphasis on risk assessment and sound scientific justification for how subjects are addressed throughout an organization’s quality management system,” she says.
Protocol templates that use a one-size-fits-all approach and don’t consider risk should be avoided, says Feighery-Ross. “For example, not every HVAC [heating, ventilation, and air conditioning] system is the same. Single-use aseptic processes are frequently performed in isolators and closed cartridge systems that reduce the reliance on the environmental quality. Therefore, HVAC in a facility with closed systems, [such as a personalized cell and gene therapy facility], should not be qualified using a template designed for an oral solid dose facility that uses open processing,” she explains.
One example of an area that has benefited from risk-based validation is viral vector manufacturing. Manufacturers have been expanding viral vector production capacity to meet the industry’s needs that have been driven by rapid growth in cell and gene therapies and in use of viral vectors for large-scale vaccine production (5). Subsequently, the need for commissioning and validation of new or renovated manufacturing facilities has also increased, says Wai Wong, vice-president of validation at Pharmatech Associates.
Viral vector facilities typically use lab-scale equipment because batches are smaller in size, scaling out to multiple lines, he explains. Utility requirements are often less complex compared to traditional pharma or biopharma facilities. “Requirements for process gasses and purified water or water-for-injection are minimal, so many companies can rely upon bottled water rather than implementing skid-based utility systems,” says Wong. With these differences, validation should also be different. “Validating this new type of facility requires a nimble and flexible approach,” says Wong. At the same time, there have been diminishing resources of personnel, equipment, and raw materials. “Moving to a risk-based approach to validation based on critical quality attributes for the facility, utilities, and equipment is essential to meet demand,” he concludes.
“The trend toward risk-based validation reduces the CQV [commissioning, qualification, and validation] burden as requirements are based on specific attributes for the product rather than a broad brushstroke of requirements that apply to all types of facilities, systems, and utilities,” says Wong. “Risk-based validation allows us to focus our qualification activities on areas that provide the most impact to product quality rather than on unnecessary tests that are unlikely to affect critical attributes.”
Flexibility is crucial for contract development and manufacturing organizations (CDMOs) because they must accommodate a wide variety of products and processes. “A significant aspect of flexibility within an operation such as Catalent is segregation and multi-unit configuration, which allows multiple products to be processed simultaneously, in the same facilities, and often in the same production unit,” says John Machulski, vice-president of engineering, biologics, and gene therapy at Catalent. “An example would be segregating formulation from filling, or the ability to handle multiple product configurations [e.g., vials, syringes, or cartridges in various sizes] in one filling area.”
Catalent was one of the winners of ISPE’s 2022 Facility of the Year Social Impact Category for its Project Mercury, which rapidly transformed a shell space at its Bloomington, Ind. manufacturing site into flexible vaccine manufacturing capacity during the pandemic. Speed of validation was crucial, because every day made a difference in the ramp-up process to meet demand for COVID-19 vaccines and therapies, explains Machulski. Risk-based approaches, supported by documented risk analyses, were a key aspect of making the validation process efficient. A second key was leveraging prior work. The project referenced activities performed earlier in the project lifecycle (e.g., FAT and site acceptance testing) in later qualification phases, to avoid the need for repetition. A third key was using a family approach to equipment validation, which leveraged the work done on one piece of equipment in the validation of similar or identical equipment, again supported by risk analyses, explains Machulski.
Risk-based approaches can also be used in changeover between products in an existing facility. “Family validation approaches allow quickly qualified changeovers, reducing down-time, which, in turn, increases efficiency and the contribution made by that equipment,” concludes Machulski.
1. ASTM, ASTM E2500-20: Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment (2020).
2. ISPE, Good Practice Guide: Good Engineering Practice, Second
3. ISPE, Baseline Guide Vol. 5: Commissioning and Qualification, Second Edition (2019).
4. EU, Annex 1: Manufacture of Sterile Medicinal Products (August 2022).
5. F. Mirasol, BioPharm Intl. 35 (8)
Jennifer Markarian is manufacturing editor for Pharmaceutical Technology.
Volume 46, Number 11
When referring to this article, please cite it as J. Markarian, “Streamlining Equipment Quality and Flexibility,” Pharmaceutical Technology 46 (11) 2022.