A New View on Quality Control?

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The COVID-19 pandemic has impacted the way the biopharmaceutical industry deals with the already challenging task of manufacturing biologics, which are complex in nature. “Biologics necessitate more focus on contamination control (environmental and utility monitoring, aseptic technique, personnel/equipment/material and waste flows) and data integrity,” says Lisa Alexander, vice president, Quality and Regulatory, at LakePharma, now part of Curia.

The quality of biologics can be impacted by minor variations in manufacturing processes, according to Natasha Rivas, vice president of Quality and Regulatory, at Genezen; therefore, she stresses that “identifying and monitoring critical quality attributes (CQAs) to ensure control of the process is crucial. Ensuring that the overarching quality systems are providing sufficient control in the production and laboratory processes is very important in an internal facility inspection.”

Some biopharmaceutical companies have had to make changes and adjustments in their procedures to adapt to the new normal. But will these changes, spurred by the specific nature of the COVID-19 pandemic, take hold and transform the future of quality control for biopharmaceuticals?

Speed to market

The biopharmaceutical industry has seen an increase in demand for vaccines, monoclonal antibodies, and other treatments for COVID-19 and a variety of other diseases. This rising demand has also seen an increase in speed to market, which has placed an emphasis on new approaches to processes, according to Kelly Smeltzer, principal consultant at CAI. These new approaches include rapid microbiology methods such as rapid sterility testing, in-house organism identification, environmental monitoring, and early detection of colonies on plates. Smeltzer says that these and other technologies improve manufacturing processes and quality assurance, which in turn, improves speed to market.

“An example of accelerating technology adoption includes the concept of single-use [technologies], which reduces costs associated with cleaning and cleaning validation, provides more flexibility in the use of manufacturing space, minimizes the potential for cross contamination, and overall increases productivity by reducing time to market for product development,” says Smeltzer. “The Industry 4.0 concept embraces new tools and technologies that enable manufacturing processes to become ‘smart’. With more ‘intelligent’ factories, integrated IT systems, and the Internet of Things (IoT), quality and reliability are increased while waste is reduced.”

Using tech to ensure quality

Technology is used in a variety of ways to develop and manufacture biologics. And it is an important part of assessing and maintaining quality of these products.

“Industry 4.0 is the new roadmap for the digital age and the interconnected manufacturing process, design of new products, and control of distribution. The route to get there is through digital transformation; and this process has many journeys, ways of thinking, and different technologies,” says Jackie Karceski, chief technology officer at CAI. This new roadmap is being used across different departments within pharmaceutical companies, according to Karceski, including R&D, manufacturing, and distribution. “At the end of the process, both the digital pharmacy (embracing new ways of ordering stock) and the patient (where data can be collected by connecting the patient back to the firm, as with connected technology), have seen advances in terms of digital transformation,” Karceski says.

“Industry 4.0 means that people, processes, equipment, and the supply chain are better connected, thanks to the introduction of cutting-edge devices, allowing manufacturers to have full visibility of operations—increasing quality. This technology, in essence, brings automation to a whole new level. For example, if during production, the temperature of a batch becomes too high or too low, the equipment itself can detect this change and adjust rather than requiring the operator to manually intervene,” says Smeltzer. “Advances within Industry 4.0 could also mean that, in the future, machine learning algorithms (artificial intelligence—AI) will be able to automatically adjust manufacturing lines depending on demand as well as being able to identify when maintenance may need to take place prior to an issue arising—this real-time responsive decision-making is driving quality assurance improvements and is crucial to ensuring future operational efficiency for manufacturers.”

Technologies have evolved to improve cross functionality, according to Karceski. “These developments include a combination of technologies to either expand the range of applications that are used to perform a [quality management system] QMS audit or to minimize risk by coordinating and standardizing applications used to collect, verify, and store data generated during an audit,” says Karceski. Available technologies used for audits, according to Karceski, include audit applications for managing internal or external audits, messaging platforms (e.g., Jabber and Teams), and video platforms (e.g., Teams, Zoom, Barcode, Vimeo).

“The use of electronic quality systems greatly enhanced our ability to quickly locate and access records, regardless of whether the team was on-site or working remotely,” says Alexander. “We also were able to take advantage of screen sharing through our remote meeting platforms to facilitate record review. We also installed live cameras in our [good manufacturing practice] GMP manufacturing suites.”

Validation and qualification

Paperless validation offers one the ability to process documents in less time due to parallel reviews and electronic signatures, explains Connie Leech, global director, Quality, Compliance & Regulatory, at CAI. Tools for preparing and executing validation and qualification protocols (e.g., Kneat and ValGenesis), however, have had a slow start in the pharmaceutical industry, according to Leech, but their use has increased in the past few years. “Within the ISPE C&Q Community of Practice, a working group recently formed that is likely to soon be formally established as a subcommittee on paperless validation, and many large companies are now beginning to adopt this technology,” she says.

Some parts of validation and qualification have been automated for a long period of time, according to Siegfried Schmitt, vice president, Technical at Parexel. “Automated screen capture instead of wasting paper by making screen prints during validation has been available for well over 20 years. Nothing new, but at least it may now become more widespread. Also video capture of say room qualification has been used for many years, but again it is hoped that the new-found expertise with video capture will lead to more professional and usable footage,” says Schmitt.

Training personnel remotely

Technology may also be used to train quality personnel. Training is shifting to online and in-time learning, according to Leech, with training performed via smartphones and other portable technologies. “Many large companies [that] have instituted new learning methods use technology in a savvy, social way such as gamification,” Leech says. “Virtual training consists of e-learning (self-paced, web-based), blended learning (a mixture of various options per course), rapid e-learning (quick online microlearning sessions), mobile learning (the course is accessible anywhere the learner is) and ubiquitous learning (available anytime/anywhere, and activities are led by daily tasks). Many of these methods are useful to remote workers, learners with very little down time, and employees who enjoy learning at their own pace.”

Remote training is not new or unique, points out Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, with online training already being used for remote employees. There are benefits to remote training, however, according to Schniepp.

“These programs have the capability of allowing the instructor to tape the information and embed questions into the presentation that must be answered before that trainee can continue. This is a great way to train people and measure the effectiveness of that training. Another approach would be to deliver the training as a webinar using a multiple person meeting app. You can prepare and distribute the information you will cover in the training, schedule a meeting time, deliver the training, and take questions from the employees during the webinar. If you have multiple manufacturing shifts, you can schedule a training session during each shift to make it easier for second- and third-shift employees to receive the training. The bottom line is even though people are working remotely, and in-person training may not be feasible, there are still opportunities to ensure employees receive the required training to meet your company’s training expectations,” says Schniepp.

Technology and internal audits

Performing internal audits of a biopharmaceutical company’s facilities and processes is an important task in ensuring product quality. However, due to the pandemic, travel restrictions and limitations on staff being onsite impacted in-person audits, according to Alexander. Some companies, therefore, have implemented new remote strategies for performing internal audits and inspections.

“The biggest change we made to our internal audit program was to limit the number of auditors that performed each audit. In line with the overall reduction of staff on site during the pandemic, one lead auditor was assigned to each audit, as opposed to up to three auditors dividing the workload and reviewing different types of procedures and records,” says Alexander.

However, Lake Pharma, now part of Curia, did not change its process for addressing quality issues found in audits. “The biggest challenge was ensuring that the operational groups followed up with [corrective and preventive actions] CAPAs in a timely manner. COVID-19 impacted on-site availability of staff; therefore, the focus was on ensuring day-to-day, critical operations stayed on-track. Essential activities took precedence over continuous improvement initiatives,” says Alexander.

Genezen was able to build and implement a quality process into its new manufacturing site instead of making changes to its internal audit program. “We are building and implementing a thorough process that allows us to ensure the various operations are appropriately implemented, executed, and monitored. Ensuring that all processes continue to meet the demands of an ever-changing regulatory environment is a crucial part of this program,” says Rivas.

Using technology, such as remote witnessing and remote inspections, to reduce field work is gaining acceptance, according to Leech. “Vendors are beginning to wear headset cameras to allow their clients to witness testing from their living rooms. Another method gaining traction is the use of a ‘digital twin’ facility, a simulated facility that can be used to trial new automation sequences without ever impacting field operations until the bugs have been shaken out,” says Leech. “It should also be noted that modern approaches to quality risk management are best supported by information managed as data, as opposed to documents, and we are beginning to see hints of this turning as well. However, there are other uses of technology that are somewhat less visible but potentially even more impactful.”

The demand for technology to perform remote inspections has increased, according to Schniepp, and companies are evaluating the choices in what technologies are currently available. But she cautions that companies must be aware of the risks. “One major concern with technology platforms and conducting remote audits is the platform security. This is a potential risk and needs to be addressed as the industry continues to explore the benefits of remote audits,” says Schniepp.

Technology may be used in a variety of ways to perform internal inspections of facilities, according to Leech. “Technology that is cloud based, integrable, and easily configured allows an auditor to quickly share information with team members and auditees, provide feedback on potential audit issues, and store data for use in subsequent reporting and/or remediation activities,” says Leech.

“The use of remote visual inspection tools such real-time online video, streaming tours of GMP facilities and the capability of camera pixels to read and record documents, labels, and logbooks during the audit tour improves efficiency, lowers cost, and speeds delivery of an internal audit,” says Leech. Companies can also virtually map facilities for inspectors using virtual reality technology before a virtual live stream tour, according to Leech.

“Internal audit activities, as a function of quality, are partners on the same road with the digital transformation of pharmaceutical manufacturing. Internal audits are a measurement of quality performance and must utilize all available technological advances to keep pace with speed-to-market demands,” says Karceski.

Benefits of remote audits

The COVID-19 pandemic created a unique situation where remote audits became a necessity for a variety of industries, including the biopharmaceutical industry. This necessity, according to Siobhan Ashmore, associate director, Quality at CAI, created challenges and opportunities. “Nothing beats boots on the ground. However, when a pandemic limits or otherwise prohibits travel, other options must be considered,” says Ashmore. “The COVID-19 pandemic exposed the vulnerability of the supply chain and the lack of emphasis placed on contingency planning. Remote internal audits were and still are a viable alternative to ensure continued compliance with GMP requirements and help to ensure continuous supply of much-needed drugs, worldwide,” she says.

Some of these opportunities created by internal audits, according to Ashmore, include a reduction in costs and time lost (to travel from site to site), flexibility in scheduling, minimization of product contamination, less disruption of manufacturing processes, and enhanced collaboration between auditors and auditees via technology.

Schniepp agrees that remote inspections save time and costs. “Conducting remote inspections saves time for both the auditor and the facility being audited provided the audit is conducted efficiently,” she says. “From a facility point of view, this would be providing necessary documentation to the auditor in a timely manner and being available to answer their questions. From the auditor point of view, this would be making sure the first request for various information is complete and accurate and questions are compiled and provided to the facility for discussion.”

On-site, in-person inspections are still important and cannot be fully replaced, according to Schmitt. “To come as close as possible to on-site audits, the respective [standard operating procedures] SOPs need to be updated, the technical tools implemented or upgraded (e.g., WiFi signal in all parts of the factory to permit virtual tours), and where possible, paper processes should be replaced by electronic ones. Electronic systems allow much easier access to the information for remote auditors,” says Schmitt.

But Schmitt does note the benefits that remote audits provide, especially during the current global pandemic situation. “As travel is still seriously curtailed, remote inspections are the obvious choice where auditors could not otherwise perform their duties. Costs are another factor. The pandemic really has forced industry to adopt this model as an alternative to on-site audits. But the warning remains: they are never better than an on-site visit, if even equivalent,” he says.

The future of remote audits

“Given the world’s adjustment to remote work due to the COVID pandemic, it is very likely that companies will find a way to implement remote strategies, including remote inspections, for the long-term. Being able to perform thorough inspections remotely has allowed these to be executed in a more cost effective and efficient manner, and manufacturers will want to continue this wherever possible,” says Rivas.

The trend toward quality culture, where everyone in the company is responsible for quality, will cause internal facility inspections to develop into self inspections by each department, according to Schniepp. “In other words, engineering would inspect engineering, operations would inspect operations, and so forth. The results of these self audits and potential solutions could then be communicated with the quality unit for discussion. I think some of this could be accomplished remotely provided the individuals in the departments responsible for these self-inspections are appropriately trained and educated in quality matters,” she says.

“Before the pandemic, virtual audits and inspections had been discussed as a potential way to perform preliminary assessments. Once companies were required to institute policies consistent with the pandemic guidelines the concept of virtual inspections became a reality. In my opinion, virtual audits and inspections are going to become an accepted industry practice based on the time and cost savings incurred by conducting audits in this manner,” says Schniepp.

One of the lessons learned from the pandemic, according to Alexander, is how important flexibility is when performing internal audits. She emphasizes the need to build flexibility into procedures. She also sees a future for remote audits. “The option for remote audits and inspections will remain a tool to help mitigate the unpredictable challenges we face in this ever-changing world. Technology that facilitates remote activities will become the norm,” says Alexander.

Schmitt cautions that in-person audits will always be preferable.“As costs (no travel) are lower, management may prefer remote audits. That is dangerous as some operations in particular, such as aseptic techniques, cannot truly be assessed remotely (several inspectorates have made this very clear). But even seemingly straightforward operations, such as warehouses, often require an in-person visit to truly discover the actual state of operations,” he summarizes.

About the author

Susan Haigney is managing editor of BioPharm International.

Article Details

BioPharm International
Volume 34, Number 11
November 2021
Pages: 10-14

Citation

When referring to this article, please cite it as S. Haigney, "A New View on Quality Control?," BioPharm International 34 (11) 2021.