By Hal Baseman, COO and a principal, ValSource, LLC
This article is the second in a three-part series exploring the need and means to achieve improvement in aseptic processing of sterile biopharmaceutical products. Part 1 presented the current state and opportunity for improvement using innovative technology. Part 2 further discusses some of the changes in strategy that might be needed for and result from the use and improvement of technology. Part 3 presents the impact of technology changes.
In 2011, Dr. Janet Woodcock, director of the U.S. FDA CDER and former deputy commissioner, discussing supply shortages of critically needed medicines, noted that “By 2010, shortages nearly tripled to 178, three-quarters of which were injectable drugs...” Dr. Woodcock affixed much of the blame on industry’s inability to modernize aging facilities and processes, stating that “factors (they) cited were aging facilities, production lines crowded by manufacturers trying to produce various products, a lack of oversight over manufacturing subcontractors, and the economic downturn.”1
The sterile products manufacturing business does have unique characteristics that at times hamper the adoption of new technology. The industry is highly regulated, approval and validation of technology changes takes significant time and resources, focus on speed to market results in risk avoidance, and operating margins are relatively high, softening the incentive for technology improvement. However, as noted in Part 1 of this series, there will be pressure on the industry to ensure product availability, reduce healthcare costs, improve product quality assurance, and adapt to the challenges of manufacturing new personalized medicines. These demands on our industry for improved productivity and process control require better use of technology. This will impact how we plan and run our manufacturing operations.
Productivity Vs. Quality
Process control and productivity are improved through the use of new technology. Embracing new technology requires financial investment. The return on this investment is often regarded in terms of cost of quality. But, technology does not necessarily increase manufacturing cost. It is important to recognize that controlling manufacturing cost and improving process quality are not mutually exclusive, conflicting objectives. Investing in technology to achieve a higher level of process quality can have positive returns in both quality and productivity. Quality processes and designs result in fewer defects, failures, and investigations, higher yields, and lower costs. Higher yields are a good indicator of a well-controlled, managed, reliable quality process. Reliable quality processes and higher productivity can mitigate drug product shortages.
Here are just some examples of how aseptic processing productivity can be improved:
Accepting New Contamination Control Strategies
Accepting new technology means taking a critical thinking approach to contamination control. Few would argue the importance of developing effective microbiological contamination control strategies. In doing so, however, it is essential to focus on efforts that will yield real benefits to product quality.
Critical, scientific evaluation of microbiological evidence may provide conclusions that are contrary to today’s approaches. Not all microorganisms detected in the environment represent the same risk of product contamination. Evaluation of the trend of microorganisms below limits can be more useful than identification of excursions beyond limits. Reaction to trends and excursions should be based on the understanding of the capability and limitations of the contamination control measures. Proper reaction to excursions and deviations can reduce unproductive efforts that distract from more impactful issues.
Where applicable, lower temperature terminal sterilization and post aseptic lethal treatments can decrease the risk of microbiological contamination and provide opportunities for real-time, parametric release of these products. To achieve this increase in sterility assurance, companies will have to reconsider container composition and capital investment in post filling treatment systems.
The use of rapid and real-time microbiological detecting systems offers contamination detection and product release benefits. However, their widespread use will require a shift from traditional colony forming unit (CFU) detection to evaluation at smaller, even cellular, detection levels. Determining a practical correlation between detection and product quality and demonstrating such to regulators will be essential.
As monitoring technology is improved, the ability to detect microorganism increases. This will require a clear understanding of what levels of microbial observation constitute risks to patient health. Failure to do so will likely result in overly stringent control steps and the rejection of acceptable product, as more microorganisms are detected. Given the rising cost of healthcare products, the increasing focus on manufacturing costs, and the resulting business decisions affecting supply of needed drug products, these additional actions will be of questionable benefit to the public. One should recognize that it is often easier to make product acceptance decisions on a zero-sum, pass or fail test result basis than it is to carefully evaluate contamination-related evidence and judge conclusions based on that evidence. This will place additional burden on the quality unit and regulators, making it more difficult to choose the latter, more effective approach. Therefore, successful use of new contamination monitoring technology and contamination control strategies may depend on the automation of data acquisition, evaluation, and decision-making methods and tools.
Considering Changes In Aseptic Process Validation Approach
Using new technology means changing one’s thoughts on process validation. Today, validation is largely based on process testing and detection of failures. Many companies still see process validation largely as a regulatory demonstration exercise, rather than as a program to gain knowledge, confidence, and process improvement.
Validation and monitoring are essential process control tools. Yet detection effectiveness can be overstated. Reliance on media fills, monitoring, and product testing to assure quality, rather than relying on sound process design, is not effective. Preventing failure through process design is a better means of risk mitigation, and as such will be more useful for the design, acceptance, and use of new technologies.
There is an over-reliance on aseptic process simulations to validate aspects of the aseptic process. Aseptic process simulations should not be the sole judge of the capability of a process, set of process steps, or personnel. Aseptic process simulations provide value by helping to uncover process weaknesses that may otherwise be missed during process control strategy design. Relying on media fills to do more than they are designed to do is ineffective and may provide a false sense of security. Aseptic process simulations should not be used to:
Determine if the process is proper and effective. Validation of the aseptic process involves a holistic, multi-faceted approach to design and qualification.2 The passage of three replicate media fill runs without an understanding or focus on process variability does not provide a substantial challenge to ensure continued process reliability and performance. Therefore, the objective of the aseptic process simulation should change from validating the aseptic process to uncovering system and process weaknesses and variables that might have been missed in or arisen after qualification.
Qualify personnel or demonstrate their proficiency. The qualification of cleanroom personnel through replicate aseptic process simulations is burdensome and ineffective. Human performance is too variable to be effectively qualified by the presence and activities of personnel during media fills. Participation in aseptic process simulations do not necessarily test their ability to perform their job using proper aseptic technique, nor does it prove their ability to perform over long durations. Instead, aseptic processes, equipment, and technology should be designed to minimize the risk and effect of human activity variability on product quality, and personnel should be trained to perform those activities understanding and using proper aseptic practice.
Validate interventions. One should not rely on uncovering flaws in the intervention technique or related process design. The chance occurrence of a microorganism finding its way into a container during the performance of an improper intervention is insufficient. Aseptic processing interventions should be designed to use first air principles, aseptic technique, and cleanroom behavior. These are best confirmed through proper design and design review. Confidence in the acceptability of interventions should change from demonstration in media fills to carefully thought-out process and equipment design. Eliminate interventions through such means as automation or minimize the impact of interventions through such means as barrier or closed processing systems.
Establish holding, filling periods, durations, or conditions. Qualification and validation runs should not be used to set process conditions or parameters. The process, including all critical conditions and parameters, should be established during process design based on manufacturing requirements. Once set, the process can then be confirmed or demonstrated during the qualification and validation studies. Sterile or decontaminated material/product holding periods should be qualified through separate studies and tests designed to challenge specific aspects of process design, such as the integrity of seals, the microbial barrier properties of the wrap material, the consistency of the wrapping and transfer procedures, and the environmental holding conditions.
Simulate operator fatigue or show effect on performance. Where operator fatigue can affect process performance and product quality, process design steps, including automation and ergonomic designs, should be taken to minimize those effects, rather than rely on aseptic process simulations to address human endurance.
Confirm decontamination process. The aseptic process simulation does not provide a quantifiable contamination challenge to test the decontamination procedure. Decontamination and disinfection procedures should be qualified through a combination of proper equipment design, disinfectant efficacy/effectiveness studies and in situ procedure challenges.
Qualify the capability or acceptability of manufacturing equipment. Aseptic process simulations are not sensitive enough to uncover improper equipment designs, flaws, defects, wear, or poor practice use. Aseptic processing equipment, including component handling and filling systems should be designed to operate in an aseptic process, qualified in separate studies prior to inclusion in media fills, and properly maintained after qualification. Where equipment related flaws or defects are suspected, those weaknesses should be addressed through process changes, repairs, or replacement, before inclusion in media fills.
Changes In Computer System Validation
Other examples of where traditional validation approaches will need to change are automation and knowledge management. As processes become more automated and continuous, process validation will shift from a matter of process testing and replicating runs to qualification of the automated control systems that control process parameters. As manufacturing intelligence and shared data acquisition and utilization systems are used more, the notion of computer system validation based on U.S. 21 CFR Part 11 and computer software guidance may need to change.
Much of the guidance and requirements on computer system validation address closed, self-contained, stand-alone systems and were encouraged to ensure security and validity of data. Validation of computerized systems relied on confirmation of process performance and product quality results. Today, more open, cloud based, and interlinked systems are being used. Decisions will be made based on a complex set of interactive data evaluation. Automated systems will involve continuous process and quality verification and adjustment to process parameters and settings, focused on maintaining quality attributes. This will represent a shift in validation approach from confirming process parameters to confirming the ability to control product parameters to meet product quality attributes. Qualification of systems designed to address data integrity will mean more than prevention of fraudulent data recording. It will place more emphasis on prevention of the misuse and misinterpretation of data.
About The Author:
Hal Baseman, COO and a principal at ValSource, LLC, has over 40 years of experience in pharmaceutical operations, validation, and regulatory compliance. He has held positions in executive management and technical operations at several drug manufacturing and consulting firms. He is the former chair of the PDA Board of Directors, former chair of the PDA Science Advisory Board, former co-leader of the PDA Process Validation Interest Group, and co-leader of the PDA Aseptic Processing Points to Consider and Annex 1 Commenting Task Force, as well as a long-time member of the PDA Training Research Institute faculty. Baseman holds an MBA in management from LaSalle University and a B.S. in biology from Ursinus College. He can be reached at email@example.com.