By Alain Pralong, VP, New Product Introduction & Technical Life, Cycle Management, GSK Vaccines
Today, GMP-compliant manufacturing of biopharmaceutical drugs and vaccines is still only partially automated and not at the level of other manufacturing industries. Critical process steps such as sampling, sterile connection, or column packing are carried out manually by operators, which can negatively impact process reproducibility, product quality, and — in the worst case — even patient safety.
To mitigate risk and achieve compliance, extensive quality management systems (QMSs), including personnel education and training, have been built based on SOPs. Review of recent FDA enforcement actions (e.g., warning letters issued on 7/18/13 to Wockhardt Limited and on 8/9/11 to Beckman Coulter, Inc.) raises serious doubts about the efficacy of the current approach toward quality management and associated knowledge transfer methodologies. The FDA’s findings indicate that personnel education/training, a lack of written procedures, and not following written procedures were among the top reasons priming enforcement actions.
Settlement of warning letters normally comes at very high cost. For example, Wockhardt executives mentioned that the cost of a warning letter could reach $100 million. Correction and control of this major quality risk exposure requires biopharmaceutical companies to adopt alternative approaches for integration of operator education and onthe- job training (OJT) with comprehensive quality management systems.
THE BIOPHARM INDUSTRY IS BEHIND
Greek philosopher Socrates spent significant time developing an education and training method for his students based on stimulation of the individual’s power of reasoning. Since then, various other researchers (e.g., Ivan Pavlov, Hermann Ebbinghaus, Edward Thorndike) have strived to improve upon the process of efficient knowledge transfer. Interestingly, though, the biopharmaceutical industry has rarely adopted the concepts developed by these researchers and philosophers. Instead, highly educated process engineers and scientists have written comprehensive SOPs and batch records in an attempt to capture in wording all instructions and handling necessary for the execution of practical activities. Then, on the shop floor, operators with less scientific, GMP, and engineering understanding face the challenge of back-translating these instructions from words into practical execution of activities. This situation is prone to errors. Person-to-person understanding or interpretation of wording can vary and lead to issues with compliance since reproducibility is not ascertained. This situation is further aggravated by the widespread practice of operators not routinely consulting SOPs when executing tasks.
In the most modern stainless-steel-based biopharmaceutical manufacturing facilities, some of these problems have been addressed using process automation where applicable. Facilities are operated with sophisticated electronic building management and batch record systems (BMS and e-Batch Record) that improve process control and reproducibility by preventing operator errors. These complex systems come, however, at significant cost ($400 million+) and are most efficient in large-scale routine manufacturing. Interestingly, knowledge transfer to personnel is still based on SOPs, and a further negative consequence of this automation approach is that operators may lose track of process rationales and detailed understanding of executed activities. This exposes biopharmaceutical companies to significant risk of GMP noncompliance and process inconsistencies as a consequence of a “push-the-button” approach.
During the last 20 years, increasing cost pressures on biopharmaceutical manufacturing have primed development of single-use systems (SUS). Today, single-use technologies exist for almost all biopharmaceutical process applications. But capturing the inherent benefits of single-use technologies requires significant changes to current shop-floor procedures, process flow architectures, and facility layouts. While multiple studies confirmed the positive impact of SUS on capital and operational expenditures (CAPEX & OPEX), these studies also indicated that various activities normally automated in traditional facilities were again executed by operators manually when implementing SUS. This change of the shop-floor work environment driven by introducing SUS now requires adaptation of current competencies to mitigate risk of GMP noncompliance and process inconsistencies. This means replacing the current GMP compliance-driven, SOP-based push–the-button approach, with an efficient education and training approach focusing on honing operator competencies and skillsets.
"The objective must be active involvement of students in the knowledge transfer rather than just relying on them to read an SOP."
VP, New Product Introduction & Technical Life Cycle Management, GSK Vaccines
Many activities executed in biopharmaceutical facilities are very similar to — and/ or as regulated as — the ones carried out in industries such as food processing or aircraft maintenance. These other industries commonly employ apprentice programs to help quickly educate their operators. For example, Kraft foods has developed two- and four-year apprentice programs where students learn (from mentors and in classrooms) how to maintain either complex manufacturing equipment or to run high-volume manufacturing processes. Student skills are honed to enable them to contribute immediately and meaningfully to the business.
This kind of success further supports the implementation of apprenticeships in the biopharmaceutical industry. As outlined earlier, current approaches are fulfilling GMP compliance despite being unsuccessful with risk mitigation and process consistency. Therefore, novel, simple personnel education and training methods that bridge the gap between proven apprenticeship methodology and GMP requirements/constraints are required to move away from the current situation.
PARADIGM SHIFT IN PERSONNEL TRAINING AND EDUCATION
Over the last few years, training and education programs have been developed that don’t put a manufacturer’s GMP compliance at risk but still significantly increase operator capabilities and maturity. The approach consists of three tiers that are interconnected through enriched interactive ebooks and dedicated videos showing the activity to be executed in its process conditions and context of the manufacturing environment. Each activity is broken down into key steps along with process logic and timing.
TIER ONE: EDUCATE THYSELF
In the first tier, students are educated at their own pace by watching training videos and using ebooks related to their job function(s) as often as needed to help gain ownership of the tasks. Following this self-education, students review the content under supervision of a trainer. The trainer can stress specific and important information to take into consideration while assessing a student’s learning curve. This step can be done face to face in workshops or through a Web-based platform. Quizzes made up of OJT images and videos help trainers further assess and validate each student’s learning success.
TIER TWO: EMBED INTO QUALITY MANAGEMENT SYSTEM
In the second tier, the content of the video is transformed into a series of pictograms identifying the relevant steps. The pictograms create the link between the SOP and the lessons learned in tier one.
TIER THREE: SIMPLIFY ACCESS AND GMP COMPLIANCE
In the third tier, a sticker showing the most important pictograms of the illustrated SOP is placed directly at the point of use. This approach ensures operators have access to the most relevant information of the activity each time they execute it. Furthermore, these stickers allow trainers to educate and train students on the shop floor, leveraging the knowledge transferred in tiers one and two.
THE PATH FORWARD
The biopharmaceutical industry has embarked on a dead-end street when it comes to personnel education and training. The current training approaches have exposed the industry to significant risks of GMP noncompliance and process inconsistencies priming enforcement actions from regulatory authorities.
A paradigm shift is required that is inspired by methodologies proven in other highly regulated industries that ensure first-time-right success and process robustness by reducing operator error and process inconsistencies.
The objective must be active involvement of students in the knowledge transfer rather than just relying on them to read an SOP. Furthermore, trainers must act as craftsmen, tailoring knowledge transfer to each individual’s capabilities and needs. This approach makes trainers responsible for successful knowledge transfer, which is significantly different from the typical well-documented, “GMP-compliant” excathedra teaching.