Enhancing Quality Through Training

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People around the world rely on medicines to improve—and often save—their lives. These therapies must not only be effective, but also safe for people to use. Regulatory bodies offer guidelines and regulations to ensure medicines are properly developed and manufactured. These guidelines are commonly referred to as good manufacturing practices (GMPs), among other ‘good practices’, in the United States and are outlined in the Code of Federal Regulations (CFR) and ensured by FDA (1). In Europe, GMPs are coordinated by the European Medicines Agency (EMA) and compiled in the EudraLex (2,3). Knowledge and proper implementation of these guidelines is key to the production of safe and effective medicines.

For patients, a lack of quality in a therapeutic product can have a dire impact. From a business perspective, a lack of training can result in delays getting product to market, product recalls, and regulatory scrutiny. Regulators want the assurance that a company’s training is adequate. “Regulators consistently review training programs during quality inspections,” says Peter Phillips, vice president, Quality Operations, BioVectra (a part of Agilent). “This is typically examined in two contexts: either as part of an investigation into specific incidents or as a standalone area of focus. Inspectors also assess how well the training aligns with employees’ job descriptions and actual responsibilities, ensuring that staff are properly trained to perform their tasks in compliance with regulatory requirements.”

The development and manufacture of medicines, however, is a complex process that involves early development scientists, pre-marketing analysts, manufacturing engineers, quality control personnel, contract organizations, and a variety of other personnel. If these many and varied individuals are not properly trained in their individual tasks, there may be a negative impact on the final drug product.

In an example of poor training impacting drug quality, Lara Ionescu Silverman, principal consultant at LIS BioConsulting, shares the story of a company’s quality department tracking results from a new analytical method that showed a decreasing trend in one value across all evaluated materials. “After an investigation, it was determined that the operator was slowly morphing the method and did not recognize the change, which resulted in the shift in values. Due to the criticality of the test, many contract projects had to be notified and retested at great expense. This could have been avoided through more frequent retraining, operator observation, and the use of multiple operators (to more quickly reveal any issues from a single operator),” says Silverman.

Training should be a constant, living element in a bio/pharmaceutical organization to prevent these kinds of problems. “Consistent, repeatable processes are critical to ensuring a robust product and process, and these processes rely on thorough and appropriate training. This includes not only technical and equipment operation training, but also safety protocol training and regulatory requirements,” says Phillips. “If personnel are not adequately trained … and a well-structured training program put in place, it can lead to process variability, safety risks, and non-compliance,” he warns.

Training in drug development

Development of a drug is the first step in getting a therapy into the hands of patients. This step involves choosing the building blocks of the drug, from ingredients to delivery method to process development.

“It is critical to ensure that the research and development staff understand the future activities required to get a novel biologic or small-molecule drug approved,” says Silverman. “These scientists are doing incredible work to uncover novel mechanisms, drugs, and treatments. But, if they don’t keep the end in mind, issues can arise down the road. Providing basic training on the regulatory, manufacturing, and commercialization requirements can help scientists understand future activities and drive their present-day work.”

A lack of training in those individuals involved in the development of a drug can impact the quality of that drug in a variety of ways, according to Tony Cucinella, vice president, head of Quality and Regulatory Affairs at Selkirk Pharma. He points to poor aseptic techniques as a risk factor for contamination. “This [factor] is particularly critical for biologics, which are highly sensitive to microbial contamination,” says Cucinella. Improper training of processes can lead to variability, which can lead to inconsistencies in batches of product, he reports. Proper handling and storage of materials and the final product is also essential. “Improper training can result in mishandling, degrading the drug’s efficacy and safety,” Cucinella says. Lastly, he stresses that accurate documentation is key to drug quality. “Poor training can lead to errors in data recording, which can compromise the integrity of the development process and regulatory submissions.”

Utilizing reagents and equipment properly in a GMP setting with good controls and consistency is essential, specifies Silverman. “These materials and equipment should come from reputable manufacturers and allow for large-scale production, enabling the company to meet their market size goals to achieve ultimate commercial success. Also, it is important to gather (and organize!) analytical data from the ancillary materials, the process, and the final drug substances/products to allow for future comparability as well as the development of suitable control strategies to enable efficient GMP manufacturing,” she stresses.

Errors such as choice of delivery technology can happen when a development scientist is not properly trained, according to Chris Moreton of FinnBrit Consulting. “From my own experience, such a failure can cause a delay of about two years in the time to get to a reliable Phase I clinical trial result. This would be a fatal delay for many biotech start-up companies,” Moreton says.

Cucinella stresses that a comprehensive and ongoing training program for all those involved in drug development is essential for quality. “Trained personnel are better equipped to identify and troubleshoot issues during development. Without proper training, problems may go unnoticed or unresolved, affecting the drug’s quality,” he states.

Training in manufacturing areas

A variety of unexpected events can happen during drug manufacturing, warns Michael Pinaud, senior vice president of Operations at Ascend Advanced Therapies, that can result in a final product that is unsuitable for use. “Without proper training on how to deal with the unexpected, the result can have detrimental impact on the quality and the ability to release drug product, says Pinaud. “Training operators to follow the appropriate procedures and keep good batch records should be considered the bare minimum expectation. Capturing all the relevant information and keeping a thorough timeline of events (through investigations and real time interviews) also helps to ensure that if/when something happens, it is clear if/how the quality of final drug product might be impacted because you have a detailed record of what actually occurred to refer to.”

Drug products are manufactured under strict quality requirements, especially biologics, according to Phillip Hernandez, head of Quality, Andelyn Biosciences; therefore, personnel working in these areas must be thoroughly trained in processes, gowning, the flow of the facility, aseptic techniques, contamination control, and documentation. “Improper training can lead to breaches in contamination control, introducing harmful microorganisms or particles into the drug product, which can have serious implications for patient safety. Proper training in documentation practices is crucial for maintaining compliance and traceability,” Hernandez stresses. “Manufacturing processes require precise execution of protocols and batch records. Variability in execution can result in batches that do not meet established quality standards, affecting efficacy and safety.”

Hernandez points to the example of a vaccine manufacturing facility that received an FDA Form 483 for multiple quality control deficiencies that resulted from poor training. “As a result of these findings, the company faced regulatory action and had to implement multiple corrective actions, including enhancing their training programs and reinforcing SOP [standard operating procedure] compliance among all personnel,” Hernandez warns. “This incident highlights the critical importance of effective training in ensuring product quality and regulatory compliance, particularly in high-stakes environments like vaccine manufacturing.”

Gaps in training

While training is obviously not new in the pharma industry, Pinaud stresses that teaching the ‘how’ of an operation isn’t the only thing that matters. Personnel should also be taught the ‘why’ of what they are doing. “Training has been a focus for years now, so the actual execution of manufacturing is covered for the manufacturing operators. What we can tend to see is a focus on how to perform each operation and less of a focus on why each unit operation matters and what each step is accomplishing. Understanding the why is just as important as the how when taking a holistic approach to quality training,” he says.

Often, it’s the method of training that is lacking and/or how the training is conducted, according to Siegfried Schmitt, vice president, Technical at Parexel, often relying on great amounts of SOPs to be read and remembered. “If the training of the SOP were conducted in conjunction with performing the tasks, then this is much more efficient as visual experience is much better remembered than pure text, especially when unrelated to practical experience,” says Schmitt. “Training on the job beats mere theoretical training hands down.”

When training lapses or fails, it’s often up to training programs that have not been updated to include new technologies and changing regulatory expectations, according to Phillips. Management skills, especially, can be undervalued. “This area of training is critical, as poor management can lead to issues such as employee retention problems, insufficient follow-up on corrective actions, and decreased overall team performance,” says Phillips.

“I think the biggest area lacking training is around regulatory requirements,” says Silverman. “This area is particularly important because so much of the activities that occur at GMP facilities are a direct result of FDA requirements. Implementing such training is challenging because FDA regularly releases updated guidance documents and information; however, ensuring that staff are aware of regulatory topics can lead to smoother operations overall.”

Cucinella agrees that rapid advancements in technology are a challenge, with automation, artificial intelligence, and machine learning requiring continuous learning. In addition, Cucinella says, “With the increasing reliance on digital systems, ensuring data integrity and cybersecurity is paramount. Training on how to handle, store, and protect data is often lacking.”

“Pharmaceutical companies and contract manufacturers often lack robust and continuous training programs in GMP compliance and in the nuances of understanding analytical testing methods and interpreting data,” says Shailesh Vengurlekar, senior vice president Quality and Regulatory Affairs, LGM Pharma. “Personnel may lack training in data integrity and the importance of accurate and traceable data in manufacturing, especially with electronic record-keeping systems. Many contract manufacturers ignore the importance of instrument maintenance programs, which could lead to several product quality issues including contamination.”

Lee McKinley, director, Organizational Development, BioVectra (a part of Agilent) points to personnel not being able to fully observe processes and often not having full access to equipment for training. “Providing a safe environment for hands-on training, where employees can practice without disrupting ongoing operations, is crucial. Without this, ramp-up times can be significantly delayed, affecting overall efficiency and performance.”

Keeping training robust

How can training be conducted to ensure the quality of bio/pharmaceuticals? Moreton suggests the appointment of a ‘training officer’ who’s job and authority is to ensure proper training is taking place for both new and existing staff. “The training officer must also monitor the quality of training and keep records of attendees and also monitor individual training records. In the event of an error or incident that compromises quality, the training officer should be part of the investigation team,” says Moreton.

A comprehensive onboarding program that focuses on GMP training is essential, remarks Cucinella, as are detailed SOPs. Training for the role is also important, he says, to be sure the employee is trained on their specific roles and responsibilities. Creating a quality culture that fosters continuous improvement is also key, notes Cucinella.

Cyrill Kellerhals, COO at Andelyn Biosciences takes onboarding of personnel seriously by going “well above-and-beyond” when it comes to minimum requirements. The company also has a partnership with a university for new staff training and incorporates on-site training before a new operator begins. “[We also have] on the job training to ensure more experienced operators are working with new staff members while they build up their comfort level and ability to execute,” says Kellerhals.

After onboarding, Diem Hoang, director of Quality, LGM Pharma recommends that a training timeline be established to set training expectations going forward, then follow up with documentation to track the employee’s progress. Recertification should be scheduled if needed.

McKinley stresses that training should incorporate diverse learning styles and backgrounds, with clear lay-person language, in-person sessions, e-learning, hands-on practice, interactive elements, and feedback.

An electronic data management system (eDMS) should be implemented, according to Hernandez. “An effective eDMS provides up-to-date, dynamic reporting on the training records of every staff member and serves as a repository for the version history and current revisions of all SOPs and quality documentation,” he says.

The effectiveness of training should be measured with pre- and post-assessments, according to McKinley. Assessments enable one to identify where improvements in the training program are needed. “Additionally, incorporating refresher training later in the onboarding process helps reinforce key concepts. Repetition is vital to ensure that staff internalize GMP standards and consistently follow quality procedures. All of this contributes to a successful training program,” says McKinley.

Industry groups offer expert training. Utilizing industry groups is a tool bio/pharmaceutical companies can use to ensure a robust training program, specifically for GMPs, according to Phillips. These groups are usually knowledgeable of current regulations and often offer their own training programs that can be tailored to group members. “In addition, participating in these networks creates opportunities for knowledge sharing, adding insights to courses, and accessing further training resources,” says Phillips. “However, it’s equally important to have an effective mechanism for integrating this training into the organization. Often, employees attend external training sessions but fail to share their learnings with the broader team, which represents a missed opportunity for company-wide improvement. Establishing a system for disseminating and reinforcing acquired knowledge can enhance the overall impact of training,” he stresses.

“Such [professional] training can be used to augment any in-house training. They can also be used to audit company in-house training and overall training. In-house trainers must also be properly trained in training techniques and methods of instruction,” agrees Moreton. “Not everyone can train, but even good trainers can improve their effectiveness with proper training.”

Biologics and new modalities

With the global biologics market expected to reach US$1,374.51 billion by 2033 (4), it would suggest that this growth would create a demand for experience in the development and manufacture of these products. But how can bio/pharma companies and contract organizations keep up with the training their employees will need to meet this demand?

Moreton suggests that training in new modalities not be left to non-technical staff and that information available in the scientific literature be reviewed. “This can be achieved in several ways; one of the most effective is to engage the scientific and technical staff and ask them to review literature sources and add any noteworthy information to a central repository that is reviewed and discussed at regular meetings of the technical and scientific staff for relevance and importance,” he says.

“Maintaining effective training in the evolving field of biologics requires active engagement with industry groups and networking with other companies, as mentioned above,” says Phillips. “By staying connected to what is currently happening in the industry and understanding emerging standards, companies can continuously adapt their training programs to meet new challenges and requirements.”

The trainer also needs training to keep up with these new modalities, explains McKinley. “It is crucial to ensure that trainers possess the necessary expertise to effectively deliver training. This includes staying up to date on best practices by regularly participating in ‘train the trainer’ programs and professional development sessions,” he says. “These sessions should focus on emerging training technologies, innovative learning modalities, and adult learning principles, which are essential for adapting to the rapidly changing environment of biologics manufacturing.”

Conclusion

Quality in the bio/pharmaceutical is the responsibility of everyone involved in the development and manufacture of drugs. But if those individuals are not properly trained, mistakes can happen, resulting in either unsafe and/or ineffective drugs. Therefore, training should be an important part of a pharmaceutical company’s and/or contract organization’s procedures.

“While the quality department is ultimately responsible, it is critical for individuals in manufacturing, supply chain, and other functions to also understand what might impact quality, so that investigations can be initiated if concerns arise,” stresses Silverman. “Such inquiries can be especially important in highly complex drug products such cell and gene therapies, where the product characteristics can be hard to understand.”

References

1. FDA. Current Good Manufacturing Practice (CGMP) Regulations. FDA.gov. https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations (accessed, Nov. 1, 2024).
2. EMA. Good Manufacturing Practice. EMA.Europa.Eu. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/compliance-research-development/good-manufacturing-practice (accessed, Nov. 1, 2024).
3. EC. EudraLex–EU Legislation. Health.ec.europa.eu. https://health.ec.europa.eu/medicinal-products/eudralex_en (accessed, Nov. 1, 2024).
4. Nova1Advisor. Biologics Market Size, Share & Trends Analysis Report by Source (Microbial, Mammalian), By Product (MABs, Recombinant Proteins, Antisense & RNAi), By Disease Category, By Manufacturing, By Region, And Segment)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2024–2033. Report, April 2024.

About the author

Susan Haigney is lead editor of BioPharm International®.

Article details

BioPharm International®
Vol. 37, No. 10
November/December 2024
Pages: 8–11

Citation

When referring to this article, please cite it has Haigney, S. Enhancing Quality Through Training. BioPharm International.2024 37 (10).