Answering the Call for Personnel Training in Single-Use Technologies

Deployment of single-use technologies (SUT) has accelerated over the past few years as manufacturers adopt SUT at the commercial scale. The spike in demand has exacerbated an existing shortage of employees trained in the handling, installation, and use of disposable production systems. Knowledge transfer regarding how to use SUT must be achieved in a rapid and scalable manner to enable the workforce to operate good manufacturing practice (GMP)-compliant, aseptic, single-use bioprocesses successfully and reliably.

A collaborative investigation of the specific training requirements around SUT and key aspects of adult learning led to the joint development of an integrated SUT training approach by Lonza Pharma and Biotech and Pall Corporation. The program relies on digital technologies, such as virtual classes, enhanced digital videos, and virtual reality, but also includes face-to-face courses and hands-on learning. The result is an effective, accelerated training program with reduced time spent in cleanrooms.

In this two-part article series, the authors begin by exploring the reasons for the SUT training gap. Part one addresses why SUT training is crucial to biopharmaceutical manufacturing. Part two outlines the fundamental aspects of training related to adult learning principles, the value of digital and virtual learning elucidated, and an approach to training.

A growing industry

The biopharmaceuticals sector has seen a flurry of activity further driven by the COVID-19 pandemic. Growth rates continue to expand, as do capacity constraints. A critical factor of capacity is experienced labor force. Even though the sector currently employs more than 200,000 operations personnel, lack of access to technical and production staff is one of the top constraints noted to be challenging the industry (1).

The need for rapid deployment of novel therapies and vaccines against the SARS-CoV-2 virus has accelerated the deployment of SUT from clinical manufacturing to full commercial upstream/downstream with fill/finish production. This move to SUT is occurring at a time when several drugs whose clinical batches were manufactured using SUT are receiving fast-track approvals and scaling almost immediately to commercial production.

Given the highly regulated nature of the pharmaceutical industry, including requirements for training of manufacturing staff according to current GMPs (CGMPs), effective and efficient training is essential. It imparts safety and quality as well. It has, in fact, become crucial to the continued, successful expansion of the industry considering that more than 40% of new hires over the next five years are expected to support bioprocessing operations (1).

Achieving the appropriate level of training during a period defined by rapid expansion combined with accelerated implementation of SUT solutions is creating challenges for many biologic drug and vaccine manufactures.

GMP-compliant training methods

According to CGMP regulations, training is compulsory and must be properly documented to achieve compliance. New employees must receive adequate training to become competent to fulfill all tasks associated with their jobs. Despite the importance of ensuring employees have the knowledge required to perform their jobs safely and effectively, gaps in employee and contractor training remains one of the frequent observations that drug manufacturers receive in GMP compliance inspections by regulatory authorities (2).

There are several causes for the existence of training gaps. A general challenge is the need to get to the clinic and the market as quickly as possible. Training is planned, but with time of the essence and employee turnover combined with workforce shortages, companies easily find themselves putting training off until there is “spare” time on the production line—a situation that is unlikely to occur any time soon.

In some cases, training gaps can be linked to the recent arrival of new equipment or the implementation of new manufacturing processes and/or introduction of products. Comprehensive employee training is essential under these circumstances to ensure reliability of supply and to stay fully compliant.

SUT-specific training challenges

Single-use systems are now widely used for all bioprocessing unit operations in the manufacture of biologic drug substances and drug products, including critical steps, from lab to commercial scale. Despite the extensive effort made by SUT vendors to ensure the integrity of their single-use systems and components, as illustrated in Figure 1, improper handling once the SUTs are in the hands of the end user can easily cause damage, leading to leakage/breakage of sterile barriers of SUT equipment and causing contamination and loss of product (3).

Figure 1. Integrity assurance throughout the single-use (SU) technology product lifecycle. Figures are courtesy of Pall.

Most established commercial bioprocessing facilities were initially designed around the use of stainless-steel equipment for all aspects of manufacturing and waste disposal. Operators are familiar with these conventional processes, which largely involve making non-sterile connections and sterilizing assemblies afterwards.

In single-use processes, operators must unpack, visually inspect, and install large biocontainers as well as make sterile connections right first time, then disassemble and dispose the used biocontainers. This sequence of operations (see Figure 2) is clearly more complex with numerous manual operations than what is required for processes performed in permanent stainless-steel equipment. In addition, single-use materials become vulnerable once removed from the packaging; therefore, special precautions must be taken.

Figure 2. A single-use system's lifecycle.

Operator training regarding the installation and use of SUTs is essential to ensure aseptic or sterile operation as well as avoiding damage that can lead to leaks, contamination, and ultimately to batch failures.

In a 2021 survey of biologics manufacturers conducted by BioPlan Associates, single-use biocontainer (bag) breakage was found to remain a key concern and one of the top three reasons preventing more widespread use of SUT (1). This concern is reasonable, given that integrity failure of single-use systems can have major consequences on safety, quality, delivery, and cost, negatively affecting employees and patients.

The same BioPlan Associates survey further found that operator error was considered one of the top causes of batch failures. Survey respondents said that approximately 4.3% of commercial batches and 3.5% of clinical batches at their facility were lost annually to operator error (1). Overall, it has been reported that approximately 50% of all deviations can be attributed to human error (4).

Any failures at commercial scale, in particular, are serious and costly. Leakage of a single-use bag was reported by BioPhorum (a global collaboration of biopharmaceutical industry leaders and subject matter experts) to cost from $50,000 to more than $20 million depending on the type of bag and the material it contains (4).

The expenses associated with single-use bag leakage can be numerous. Reprocessing is often not possible, and product marketing and sales can potentially be disrupted, which can be disastrous, both for patients and drug companies. Costly and time-consuming forensic studies may also be required to identify the cause(s) of the failure to ensure safety of patients and proof for regulators.

Notably, the BioPhorum also acknowledged that improved training methods would considerably decrease the occurrence of leakage (4). In a 2004 presentation, for example, Bayer reported details of damage that caused bag chamber failures at its Berkeley, Calif. manufacturing site, which used bag assemblies of 4 to 2000 L in combination with single-use tubing, manifolds, and aseptic connections (5). Nearly three quarters of the 4% leak rate were found to be attributed to improper handling during insertion, hoisting, and filling of the bags and operator error during fluid transfer. Most leaks were due to chevrons that occurred during bag adjustment and installation. In addition to bin and bag design changes and supplier corrective actions, Bayer identified increased training to educate operators and increase their awareness of proper single-use bag handling and use as effective means for significantly decreasing the percentage of leaks. The training program was designed by a single-use subject matter expert and included information on the site’s leak history and trends, the root cause analysis identifying key factors leading to bag leakage, how chevron damage occurs, and proper bag filling techniques. Once training was complete, the percentage failure rate was consistently reduced, as tracked over several months. Bayer concluded that effective training is crucial, along with in-house technology and knowledge, detailed equipment design and a good material management program, for operation of reliable single-use systems (5). 

The design of efficient training in the handling and use of SUTs must be accomplished by applying the best learning and training methodologies while understanding the constraints of single-use technologies. 

SUT best practices

Training alone will not solve all the challenges posed by the rapid adoption of single-use technologies in bioprocessing. History has shown that improving the design of SUTs and components and driving for more standardization both contribute substantially to reducing failure rates (6).

One of the first issues to address is the complexity of current SUT workflows and the need to design new workflows that better integrate with other bioprocess operations. Some areas that can be improved include organization of systems storage areas; materials interlocks; inspection area designs; and mobile equipment. These workflows can then be incorporated into training programs.

Joint efforts by suppliers and end users under the auspices of BioPhorum have led to the development of good concepts geared toward performing root cause analyses of SUT failures and new training tools (4). The development and deployment of effective training methodologies, however, has not yet been achieved throughout the industry.

When thinking about effective and fast SUT training deployment in the biopharmaceutical industry today, several important aspects must be taken into consideration:

• Most of new employees have limited or no experience in practical biopharmaceutical manufacturing.
• Training must be more self-directed when there are travel restrictions.
• Training must be available in several languages.
• Accessibility of actual installed single-use systems and cleanroom suites is limited.
  • It is important only to place operators in real situations once the discovery phase and initial training on basics and fundamentals are completed.
  • Specially designed training rooms and practices will be required for this initial introduction to SUT handling.
• In addition to training on SUT handling, it is essential to ensure that operators also fully understand the rules and procedures for maintaining aseptic conditions throughout a given bioprocess.

In the second part of this article, the authors will take a deeper look at key considerations for SUT training and the blended approach developed that shifts the “one-size-fits-all” training paradigm by combining digital and virtual learning with face-to-face and hands on training.

References

1. BioPlan Associates, 18th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production A Study of Biotherapeutic Developers and Contract Manufacturing Organizations (BioPlan Associates, April 2021).
2. Online GMP Training, “Top 10 GMP Audit Failure Reasons: FDA and TGA Inspection Findings,” onlinegmptraining.com (Oct. 21, 2019).
3. BPSA Alliance, “Design, Control and Monitoring of Single-Use Systems for Integrity Assurance” (July 7, 2017). 
4. Biophorum, “Disposables: Single-Use Systems Bag Assembly Leakage and Defect Toolkit,” biophorum.com (Oct. 23, 2020).
5. W. Beh, “Operational Considerations for Robust Single-Use Systems,” Presentation at IBC’s 5th Single-Use Applications for Biopharmaceutical Manufacturing (San Diego, June 2, 2008).
6. A. Pralong, A. Schmutz, and H. Pora, Innovations in Pharm. Technol. 70, 41-45 (October 2019).

About the authors

Michael Moedler, PhD, is head of Training at Lonza Biologics Operations Visp, and Helene Pora, PhD, is vice-president of Technical Communication and Regulatory Strategy at Pall Corporation.