Susan Haigney

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FDA announced on Dec. 11, 2023 that InvaGen Pharmaceuticals, a wholly-owned subsidiary of Cipla Limited, was voluntarily recalling one lot of Vigabatrin for Oral Solution, USP 500 mg. The recall comes after it was found that the product had seal integrity problems resulting in powder leakage from the pouch. Vigabatrin for Oral Solution, USP 500 mg is an adjunctive therapy for the treatment of refractory complex partial seizures in patients two years of age and olderwho have responded adequately to alternative treatments; it is not a first-line agent.

According to FDA, improper sealing of the pouch may cause powder blend to leak outside the pouch, resulting in lower product content than what is listed on the label and, possibly, underdosing. “For a small minority of patients, who might have severe or repeated breakthrough seizures, a drop in their phenytoin blood levels could result in life-threatening seizures requiring immediate emergency room treatment,” according to a press release.

The recalled product is packaged in foil pouches with 50 foil-sealed pouches in a shelf pack. The affected lot is NB301030, with an expiration date of 03/2025, and was distributed nationwide to partnered distributors and consignees.

Cipla has stated that it has not received any reports of adverse events related to the recall. Adverse events may be reported to FDA via its MedWatch Event Reporting Program.

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The product is being voluntarily recalled because of powder leakage due to seal integrity issues.

InvaGen Pharmaceuticals Recalls Vigabatrin for Oral Solution, USP 500 mg

In December 2023, FDA released two guidance documents on drug compounding using bulk drug substances. FDA provides a list of bulk drug substances that can be used in compounding, and the documents provide the agency’s interim policy for use of bulk drug substances in compounding by facilities that are considered outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and those facilities that are not considered outsourcing facilities (under Section 503A of the FD&C Act).

Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act

describes a background on compounding from bulk drug substances that includes efforts the agency made to develop the list of bulk drug substance that may be used for compounding. The document covers current nominations for the 503A bulk substance list and process for developing the list. Also included are the agencies policies on compounding from bulk drug substances on the 503A list, substances that are not nominated for the list as of the publication of the guidance, and comments about nominated bulk drug substances.

Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act - Revision 2 

features similar information but in regards to 503B facilities. According to the guidance document, “Section 503B of the FD&C Act describes the conditions that must be satisfied for human drug products compounded by an outsourcing facility to be exempt from the following three sections of the FD&C Act: section 505 (concerning the approval of drugs under new drug applications or abbreviated new drug applications); section 502(f)(1) (concerning the labeling of drugs with adequate directions for use); and section 582 (concerning drug supply chain security requirements).”

The new draft guidance documents replace guidance from January 2017.

The agency released two guidance documents on the interim policy on compounding using bulk drug substances for both outsourcing and non-outsourcing facilities.

FDA Releases Compounding Guidance

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Absci, a generative artificial intelligence (AI) drug creation company, announced on Dec. 4, 2023 that it is collaborating with AstraZeneca to deliver an antibody to treat cancer that is designed with AI. AstraZeneca will use Absci’s Integrated Drug Creation platform to accelerate the discovery of potential cancer treatments. The agreement includes an upfront commitment, R&D funding and milestone payments, and royalties on product sales.

The Integrated Drug Creation platform uses generative AI and scalable wet-lab technologies to create proprietary data by measuring millions of protein–protein interactions, according to Absci. The data are used to train the AI models to validate antibodies using the 

 AI models. Drug discovery may be accelerated by data collection, AI-driven design, and wet-lab validation, and potentially optimize multiple drug attributes concurrently.

“AstraZeneca is a leader in developing novel treatments in oncology, and we are excited to collaborate with them to design a therapeutic candidate antibody with the potential to improve the lives of cancer patients,” said Sean McClain, Absci founder and CEO, in a press release. “This agreement advances Absci’s goal of creating a new generation of life-changing and transformative therapeutics using its AI platform.”

“This collaboration is an exciting opportunity to utilize Absci’s 

 AI antibody creation platform to design a potential new antibody therapy in oncology,” said Puja Sapra, senior vice-president of Biologics Engineering & Oncology Targeted Delivery, AstraZeneca, in the release.

The Absci/AstraZeneca agreement follows the publication of Absci’s design and validation of 

 antibodies using the generative AI model, as well as previous collaborations with other organizations.

AstraZeneca will utilize Absci’s AI antibody drug creation platform to create an AI-designed antibody.  

Absci and AstraZeneca Collaborate on AI-Driven Oncology Candidate

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Operational excellence relies heavily on an organization being staffed with the adequate amount of properly trained personnel. The pharmaceutical industry has seen an increase in new modalities over the past few years, partially because of the COVID-19 pandemic. There has also been a 20% increase in demand for science, technology, engineering, and mathematics (STEM)-related talent (1).

Pharma digital talent is lower than what is needed, and recruitment of talent is challenging (1,2). Strengthening hiring and retention efforts is crucial. “A recent wave of tech-company layoffs offers the pharma industry an opportunity to scoop up critical skills and talent to drive their digital and analytics ambitions,” according to Golub et al. (2). “Pharma companies that need to upgrade their capabilities quickly can also look to M&A deals for digital, AI [artificial intelligence], and healthcare-technology talent. Given the rapid evolution of technology, acquiring tried-and-tested talent allows the company to meet the demands of innovation faster than upskilling” (2).

“Both demand for and development of novel biologic drugs continue to expand at a rapid pace. At the same time, the need for training in the biopharmaceutical industry has increased dramatically in recent years due to this and several other factors,” says Hugues Bultot, CEO Univercells. “As biopharma companies and biologics contract development and manufacturing organizations [CDMOs] have added significant capacity to meet the growing demand, this has created the need for a larger workforce at a time when there is a shortage of skilled/educated/experienced people seeking careers in the biopharma sector.”

Bultot also points to good manufacturing practice and operator training requirements that increase demand for skilled pharmaceutical personnel. “Simultaneously, deployment of single-use technologies at a commercial scale is creating the need for training on these new systems,” he states.

The increased demand for skilled workers in development and manufacturing creates a challenge for an already complicated industry. What can pharmaceutical companies and CDMOs do to address the situation and maximize operational efficiency? Empowering employees, managing burnout, and innovative training technologies may offer solutions.

Finding the right person for the right job is imperative, says John Roosenberg II, PhD, site director, Dr. Reddy’s Laboratories, Shreveport and Middleburgh. “One of the key strategies is to focus your hiring practices on finding people with the right abilities who can learn the skills they need to do the job. It will also be critical for pharma organizations to work with local educational organizations (community and local colleges) to develop classes and educational tracks that ensure there is a local talent pool for hiring,” he says.

Once the right employee is hired, onboarding new employees is where training usually begins. But training should be an ongoing process. Also, companies should be careful not to overload new employees with too much training when starting a new job can be stressful enough.

To avoid overloading employees when training, Michael Tsaconas, vice president Operations and general manager, BioCina, recommends spreading training for new staff over time to avoid too much training in a short time period. He also suggests using “on-the-job methods to facilitate the transfer of practical skills, troubleshooting techniques, and real-time problem-solving” for critical and complex tasks. Automated and flexible training is also important, according to Tsaconas, such as online training and exams. “Ensure regular check-ins with new staff members to solicit valuable feedback, monitor training effectiveness and address gaps, as needed,” he says.

Samantha Hadfield, FSP business segment lead, PPD clinical research business, Thermo Fisher Scientific, comments that streamlining and expediting onboarding for FSP engagements can be done by pairing new hires with current staff. “[We also] employ close line manager oversight and just-in-time function-specific training that combines in-person and online support. Through this ‘ready now’ risk-based approach, we’ve achieved an average of just 22 days from candidate identification to full operational capability,” she explains.

“Interactive learning makes it easier to retain information by separating book learning from hands-on experience. Going into the lab and watching something they will have to make at a commercial scale eases the learning curve. That way a new hire can understand the process and see the equipment they’ll be using. It decreases the amount of information that has to be retained at once,” says Ted Dolan, chief operating officer, Complex Chemistry, BIOVECTRA.

Empowering employees with a greater understanding of the tasks they are performing can be an effective training tool. “Operators are more likely to retain their training and make more informed decisions when they understand the science as well as the equipment,” continues Dolan.

By way of example, Dolan points to a recent approach taken at his company where a group of operators were given more interactive training for a new process—witnessing online batch reading at the bench scale and then following up with a walk-through of the equipment. “This approach emphasizes background learning, so the operators will be better prepared and empowered to make decisions during manufacturing. Traditionally, training is managed by the operators themselves but, in this case, we also included our continuous improvement (CI) and quality groups and created a video to document this novel approach for future training. The CI group will assess whether this approach trained our employees more efficiently.”

Interactive training that includes real-life scenarios can be helpful, according to Dolan. “A new employee can get dozens of training modules during the first week of their new job. They need to read the SOPs [standard operating procedures], then get tested on them,” he notes. To aid in retention of the SOPs, Dolan reveals that interactive training sessions with animations and real-life examples have proven to be useful at BIOVECTRA.

Sometimes switching tasks up can keep employees engaged. “There’s something to be said for taking a good worker who’s been in the same position for 15 years and giving them the opportunity to learn new skills and become excited about their job again. [This can be promoted] through cross-training, which leverages what someone already knows, while providing them with additional insights as to how that can be applied to different products and processes. For example, cross-training allows people [to be brought] from [a] complex chemistry division into biomanufacturing or from biomanufacturing into biologics,” says Peter Ercoli, chief operating officer, Biologics, BIOVECTRA.

However it is accomplished, training is an important and necessary task, and Bultot highlights that companies have to find solutions for providing it. “There are a few examples of universities adding centers focused on biopharmaceutical manufacturing, not only to provide graduates with a higher level of manufacturing skills, but to support training of existing industry personnel. Companies are beginning to leverage these centers to meet training needs they cannot provide internally. Others are, as mentioned earlier, leveraging computer-based and virtual training solutions that reduce the demand for training personnel and other resources. Some of these solutions are being developed through partnerships between manufacturers and equipment vendors. An industry-wide collaboration along these lines would be a great step towards overcoming the issue of training shortages,” he says.

Once the right employees are hired and trained, how do companies keep those people long term? One solution is being aware of the stress employees face. Managing burnout can be a challenge for both staff and management. Burnout, which can be caused by a variety of factors, may lead to high turnaround in staff and, therefore, loss of expertise. “Unfortunately, attracting new graduates continues to be a challenge, as many are drawn to trendier occupations such as those in the software industry. Given the high workload for operators who have remained in the industry, it is not surprising that some reach a point of ‘burnout’,” says Bultot.

According to Melissa El Khouri, head of Quality at BioCina, poor training can be one part of burnout in pharma employees. She recommends that all staff members be fully trained on systems and procedures before starting their defined roles. Managers should also ensure that workloads are reasonable. Teamwork and shared responsibility are also important, according to El Khouri, so workloads become lighter. “Implementing company policies that help staff members to have sufficient control over their work-life balance, for example generous time-off options, flexible hours,” she says.

BIOVECTRA has added additional staff to combat burnout. “The recognition of mental health—which includes stress or burnout—is much more in the daily vernacular than ever and has led to improve[d] communication among staff,” says Dolan. One such approach being employed by BIOVECTRA is regular “lunch-and-learns”, Dolan states. These sessions allow employees a forum for open discussion, and the company can listen to any concerns raised about the work environment, which ultimately has a positive impact as it takes away “unnecessary stress and fear of the unknown,” he reveals.

Denise Bell, director, Product Management, LabVantage Solutions cautions that inefficient operations and an unmanageable number of manual tasks can cause burnout for laboratory personnel. “One effective way to address this is by introducing a laboratory information management system (LIMS),” she says. “LIMS can drastically streamline lab processes by automating time-consuming tasks, such as data entry and report generation. Not only does it ensure regulatory compliance and easy documentation, but it also organizes and manages data for effortless access and analysis. Moreover, LIMS can manage consumables in an efficient manner, further relieving the load on hardworking lab staff and reducing stress.” Through integration of a well-structured LIMS, it is possible to free-up staff time as the tools being used operate smoothly, Bell explains. In turn, with more free time, employees can then focus on other tasks, such as important scientific explorations, which “can significantly mitigate the burnout and subsequent shortages in the industry,” she says.

LIMS can also offer automation of routine tasks, guided workflows, compliance control, and management of permission control, says Bell. “This not only enhances efficiency but also helps address the challenges faced by those who are still gaining training and experience within the industry,” she states.

Roosenberg points to schedule disruptions that cause last-minute changes, overtime work, and a lack of flexibility in working hours to possible stressors for pharma employees. “It is important to develop a relationship [with] team members and find ways to work with each of them as individuals to ensure the success as a whole. This may mean ensuring team members get off for family activities and having others provide coverage. This requires a very balanced approach,” he says.

Unexpected situations can put undue stress on employees, according to Ercoli. “The best way to address this is through clear communication. What [employees] have to do may not change, but their perception of it may have changed. Another cause of burnout is a feeling of loss of control,” he says.

Equipment and resources. Having the proper resources for employees can help manage burnout. “Designing equipment that is easier to use, such as single-use systems that have simple processes for installing and removing the ready-to-use reagents and disposables, as well as for running processes, is one approach and a goal at Univercells. Cross-functional training is another that enables operators to continue learning and keep their interest level high while reducing fatigue and the grind of performing the same tasks day after day,” says Bultot. “It should also be noted that retraining is required on an ongoing basis to refresh operator understanding and ensure that manufacturing personnel are familiar with any new systems.”

Aging facilities and equipment, or equipment that doesn’t work properly, are additional stressors that can contribute to staff burnout. “An equipment problem that results in schedule delays, and the potential to have a batch under investigation, creates extra work. The happiest operators are the ones who run well-functioning equipment,” says Dolan.

“Handling aging equipment is sometimes mitigated with excessive SOPs, overwhelming operators. And, as soon as it breaks down, stress levels go way up,” Ercoli agrees. Investing in technology-driven facilities with new equipment that is continuously improved is advised, he notes, and also avoids operators having to repair old equipment.

Roosenberg offers that older equipment has the benefit of fewer skills requirements and less training. “If you don’t have to train employees on new equipment and deal with many of the challenges of new software upgrades etc. Also, many of the older equipment is more manual in operation so trouble shooting it is more straightforward.”

Innovation and digital enhancements have been entering all types of industries. Automation is becoming more and more prevalent in various areas of the pharmaceutical industry, and staff will need training on these new innovations. But with innovation comes change.

Augmented reality may offer the ability to run simulations on routine issues, specifies Roosenberg. And new training enhancements can offer better engagement with personnel. “It would also be great to have manufacturers of equipment generate a digital training platform. This way changes in the training can be done in real time to the changes in the operations of equipment,” he says.

“The risk is that, with automation, operators will no longer need to understand what equipment does and could become button-pushers as opposed to manufacturers,” warns Ercoli. “This has the potential to separate workers emotionally from what they’re making—essential medicines for people. Also, from a regulatory perspective, [it will be necessary] to prove the control of systems that are intelligent enough to make a series of decisions very quickly.”

Whilst in agreement, Dolan also points out that with processes being run by humans then it is imperative that these operators are trained properly to ensure safety. “There’s so much potential value in using AI, in terms of time management and efficiency, but the concern is how to manage it,” he emphasizes. 

Digitalization of training may be the key to more efficient training. Tsaconas reveals that some of the “most forward-looking ways” of increasing operational efficiency and reliability he has experienced is through digitization and automation of key workflows. Developing interactive e-learning modules offers flexibility and convenience for operators. “These methods can also significantly reduce traditional training requirements and the accompanying investment of time and resources they demand,” he summarizes.

Dukart, H.; Lanoue, L.; Rezende, M.; and Rutten, P. Emerging from Disruption: The Future of Pharma Operations Strategy. 

Golub, A.; Lewis, J.; Tinkoff, D.; Van der Veken, L. and Zhu, D. Rewired Pharma Companies Will Win in the Digital Age. 

®
Vol. 47, No. 12
December 2023
Pages: 12-15

When referring to this article, please cite it as Haigney, S. and Murphy, J. Training for Operational Excellence. 

The bio/pharmaceutical industry is struggling with the challenge of staffing and training.

Training for Operational Excellence

FDA announced on Nov. 16, 2023 that the US District Court for the District of Utah, Central Division, entered into consent decrees of permanent injunction with two dietary supplement companies, Evig LLC and Premium Production LLC, both based in St. George, Utah, and their chief operating officers.

Evig LLC and the company’s CEO, Douglas Lex Howard, distributes Balance of Nature products, which are marketed as dietary supplements that include labeling that renders them unapproved and misbranded drugs. “[FDA] has not approved Balance of Nature products for any use, despite the company’s claims that its products could be used to diagnose, cure, mitigate, treat, or prevent diseases such as cancer, heart disease, cirrhosis, diabetes, asthma, and COVID-19,” FDA stated in a press release. The agency says the company also violated current good manufacturing practice (CGMP) requirements.

The products were manufactured by Premium Production in violation of CGMPs, according to FDA, including “failing to establish ingredient and finished products specifications for identity, purity, strength, and composition, which rendered them adulterated dietary supplements.”

FDA sent both companies warning letters in 2019 after agency inspectors found CGMP violations during facility inspections at both companies’ facilities. Evig was warned Balance of Nature products were unapproved new and misbranded drugs. According to the agency, the companies failed to address the deviations, resulting in the injunctions.

“Products intended to treat or cure diseases require FDA approval,” said Principal Deputy Assistant Attorney General Brian M. Boynton, head of the Justice Department’s Civil Division, in a press release. “Dietary supplement makers also must abide by federal health and safety requirements. The Department will continue to work closely with FDA to stop the distribution of unapproved, adulterated, and misbranded dietary supplements.”

The two companies are prohibited from distributing or manufacturing products until they comply with CGMP and labeling regulations. Both companies must hire CGMP experts and submit documents to the agency demonstrating compliance and get FDA approval before resuming operations. Evig must also hire a labeling expert.

Consent decrees were issued against Evig LLC, of St. George, Utah, and Premium Production LLC, of St. George, Utah, for unapproved dietary supplements.

Consent Decrees Entered Against Utah Supplement Manufacturer and Distributors

FDA announced on Nov. 15, 2023 that the US District Court for the District of Arizona entered into consent decree of permanent injunction that orders Smart Women’s Choice and its CEO, Jennifer A. Richard, to stop distributing unapproved contraceptive drugs in the United States until it complies with the Federal Food, Drug, and Cosmetic Act (FD&C Act).

The company has promoted its vaginal cream product as a safe and effective contraceptive despite the drug not being approved by FDA. The agency sent a 

 that it was unlawful to distribute the unapproved products; however, the company continued to distribute.

“The consent decree prohibits Smart Women’s Choice, Richard, and any persons or entities in active concert or participation with them who receive notice of the decree, from directly or indirectly manufacturing, preparing, processing, packing, repacking, receiving, labeling, holding and/or distributing any drug at or from their facilities unless and until they meet certain requirements to ensure they are operating in compliance with the FD&C Act, the FDA’s regulations and the decree, and they receive written notice from [FDA] that they appear to be in compliance with these requirements,” the agency stated in a press release.

“Americans expect and deserve drugs that have been scientifically proven to be safe, effective, and of high quality,” said Jill Furman, director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research, in the press release. “lFDA] remains fully committed to taking enforcement action against companies and executives responsible for marketing unapproved drugs in violation of federal law.”

The US District Court for the District of Arizona entered into consent decree against Smart Women’s Choice and its CEO to stop the company from distributing unapproved contraceptive drugs.