Breaking Through Barriers to Continuous Manufacturing

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Pharmaceutical manufacturing is inching towards implementing more efficient and sustainable processes, including continuous manufacturing (CM) of solid-dosage drugs. Advantages of CM include the potential for faster development, easier technical transfer, and more efficient and flexible commercial production with tighter process control. Although early adopters have realized benefits, and suppliers continue to improve the equipment and systems used in CM (1), some barriers to broader industry adoption remain. A collaborative effort between industry, regulators, academia, and other stakeholders is driving slow progress toward overcoming these hurdles.

The success of the cooperation between government and the private sector to rapidly develop and build capacity for vaccines and treatments to combat the COVID-19 pandemic is an example of what is possible, in the normally slow-acting and risk-averse pharmaceutical sector, say industry experts. They hope to see a similar boost to the uptake of advanced manufacturing technologies, such as CM.

Reducing barriers to CM

One positive sign is greater acceptance of public-private partnerships by FDA and the US Congress, due to the successes demonstrated during the pandemic response, said Jennifer Luray vice-president of strategy and communications at Research!America, during a panel discussion hosted by the US Pharmacopeia Convention (USP) (2). This openness may help partnerships seeking government funding.

Another factor demonstrated during the pandemic was that the alignment of regulators and industry on the need for speed-to-market acted to lower the barrier to using new technologies. The challenge during “normal” times is to continue this agreement.

“Regulators and industry are aligned in their desire to create safe and effective medicines, but there is often a misalignment because industry is also concerned about the risks to development costs and speed-to-market,” said Kelley Rogers, technical program director for Biosciences within the Material Measurements Laboratory at the National Institute for Standards and Technology (NIST), during the USP discussion (2). If government can do more to take into account these business concerns, it will help “de-risk” adoption of new technologies.

“Adoption of CM can be accelerated considerably if policy makers introduce financial incentives and regulatory incentives,” suggests Moheb Nasr, principal at Nasr Pharma Regulatory Consulting and Pharmaceutical TechnologyEditorial Advisory Board member. These could include tax breaks, expedited approval, or exclusivity periods, for example, Nasr and his colleagues suggested in a 2019 article (3).

Generic-drug manufacturers recognize the need to innovate, but justifying the cost of investing in CM is even more challenging for them, said Lisa Parks, vice-president of Sciences and Regulatory Affairs at the Association for Accessible Medicines (2). “For any company to make a business case regardless of whether they are an innovator or generic, they need to assess the technology to gauge the appropriateness and value add of the investment,” she explains. “They need to consider whether the technology has the capability to lower manufacturing cost or meaningfully increase quality. We’ve heard that CM can increase quality by tightening specifications, but we need to better understand how this actually affects quality. We need to be asking: Does adopting CM for a particular product improve the clinical outcome for the patient in terms of safety or efficacy? Does the adoption of CM create unintended barriers for generic entry?”
Other barriers mentioned frequently in relation to CM are regulatory uncertainty and potential differences between regional authorities. The draft version of the International Council for Harmonisation (ICH) Q13 guidance on continuous manufacturing published in July 2021 (4) helps alleviate some of this concern by providing a harmonized guideline supported by the regulatory members of ICH, which include FDA, the European Medicines Agency (EMA), and many others.

“Many health authorities are very supportive of CM, but many do not have much experience and their requirements are not always clear,” says Lawrence De Belder, executive consultant at Pharmatech Associates, a USP company. “This uncertainty is a hurdle because companies are concerned that, while a product made with CM might be approved by most countries globally, there might be a few countries that would require additional data or process changes. ICH Q13 is a good step in the right direction with an agreement or suggestion on a number of aspects, but it is not yet a full harmonization.”

Dennis Hall, vice-president of manufacturing services at USP, said that one of USP’s goals is to help develop more regulatory clarity by exploring the possibility of developing standards for CM (2). First, however, USP is working with manufacturers to develop methods specific to products made in the CM environment. In addition, Pharmatech Associates, acquired by USP in 2021 (5), is helping industry to evaluate how they might use CM. USP can help fill the gap that exists in access to knowledge, experience, and laboratory capabilities for PAT model development and process development, adds De Belder.

“Implementing advanced manufacturing [including CM] is knowledge intensive. To make this happen, we need to make knowledge and technology available at a low entry cost,” said Fernando Muzzio, distinguished professor of chemical and biochemical engineering at Rutgers University and Pharmaceutical Technology Editorial Advisory Board member, in a PharmTech podcast (6).

Investment cost for CM equipment is currently a barrier to wider use of CM in the industry, partly because, in some business cases, CM equipment is competing with batch equipment that is already in place, adds De Belder. In addition, equipment needs to be more flexible. “If you could buy a CM line for one product knowing that you could adapt it easily for other products in the future, it would lower the investment cost,” he explains.

Although some advances in modularity and integration have been made (1), more of these features in equipment designs are crucial for allowing greater flexibility in production “Having interchangeable unit operations would be helpful, so that if something changes in the future, a manufacturer can more easily make a change. To make this easier, equipment designs need to be modular and interfaces need to be standardized,” says De Belder.

“Production systems that are more modular and flexible to implement than currently available offerings from vendors would be attractive,” agrees Gregory Connelly, senior director at Vertex. “Such systems should be able to leverage the processing benefits that CM affords (i.e., blending at small scale to ensure robust blend uniformity), while being easily adaptable to various pharmaceutical profiles, such as dose, tablet weight, product demand, and also material tracking requirements.”

Improving operations

Early adopters of CM are reaping benefits and, at the same time, continuing to improve CM processes and operating procedures. Vertex, for example, has three approved products made using CM technology, with the first approved by FDA in 2015. “The biggest benefit we have realized for our portfolio is the ability to advance more quickly through late-stage development,” says Connelly. To provide more space for development, the company is considering expanding its CM capabilities with additional platforms that can offer more modularity and flexibility for both development work and commercial production. For now, the company is using one qualified line for production that will soon be joined by a second line at a contract manufacturer. One of the challenges has been the effort required to convert a CM line from one product to another. Vertex has reduced this change-of-line burden through use of a digital tool that guides operators through the complex process of disassembly and cleaning. “Programs such as Tulip], which, among other capabilities, provides a platform for organizing video clips showing proper assembly/disassembly procedures, are a huge advance over paper-based standard operating procedures [SOPs] or even digital versions of static documents,” says Connelly.

Innovation in process analytical technology (PAT) tools and growing experience in how they are best used are also key to improving CM processes. “In the early years of CM development, we thought to use PAT to measure as much as possible, sometimes even with redundant measurements,” says De Belder. “In process development, using a lot of PAT is beneficial for helping you understand the process. In commercial manufacturing today, however, PAT is being used more judiciously, because it is resource-intensive to create and maintain PAT models. Manufacturers are performing risk analyses to see where PAT is really needed on commercial lines for the process control strategy.”

“Some PAT systems are more suited to a development environment, where the goal is to gain process understanding and knowledge about the product, but those systems may not be robust enough for routine deployment on a commercial process,” adds Connelly. “In general, we aim to implement PAT at points where the material is undergoing some change, in order to best monitor the quality of the product and the state of the process. Soft sensors, equipment controls, and process models certainly offer additional ways to maintain a desired state of control for a CM process.”

Quality systems

The same data used for process understanding and for process control can also be harnessed for real-time release, which relies on process data, rather than end-product testing, to assure critical quality attributes (CQAs).

Harnessing real-time data will allow manufacturers to get closer to fully realizing the benefits promised by CM, says Doug Hausner, senior manager of Continuous Manufacturing, Pharma Services, Thermo Fisher Scientific. “If you’re still using traditional analytical testing, it can be a limiting factor in turn-around times and per-batch/campaign savings that are important benefits of using CM. Traditional analytical is still critical in development, but manufacturers need to consider PAT, at-line testing, and data analytics for real-time process control and real-time release during Phase 3 as they approach commercial launch,” says Hausner. Thermo Fisher is expanding its oral solid dose CM capabilities at its Greenville, NC manufacturing site, and the contract development and manufacturing organization is currently supporting a number of products through clinical trial manufacturing using CM processes and preparing for commercial manufacturing upon market approval.

“Real-time release could leverage the data already being collected and save time,” agrees Nasr. “Using real-time release testing, however, doesn’t necessarily mean no end-product testing at all. It is up to the manufacturer to decide which quality attributes, if any, will be tested at the end of the process [when they submit a regulatory filing].”

De Belder agrees that there may be a business case for real-time release of some CQAs, but not always for all. “Dissolution, for example, is difficult because it cannot be measured directly in-line. Some companies have achieved real-time release using a surrogate method that has been proven to be directly related to dissolution, but this is not available for every product and requires significant effort to develop and maintain models,” he explains. “Other CQAs, such as product identification, can be directly measured inline, so the business case for these is easier to make.”

New measurement tools

Equipment and instrument suppliers are developing new ways to measure CQAs. Pharma Technology Inc., for example, introduced equipment designed for CM, for in-line tablet inspection that measures mass and content uniformity of every tablet at rates up to 120,000 tablets per hour and rejects out-of-specification tablets. A multi-point near infrared spatially resolved spectroscopy (NIR-SRS) probe predicts the API fraction (i.e., content uniformity) in each tablet. NIR-SRS allows high-speed measurement in production environments. A patented three-dimensional microwave resonant sensor measures individual tablet mass. An embedded, automated 4-P tablet tester uses conventional sampling to measure weight, thickness, hardness, and diameter of a sample of tablets at-line, and it serves to automatically calibrate the on-line weight measurement. The real-time data can be used to control a continuous mixer or tablet press, for example. Pharma Technology conducted experiments with Novartis that demonstrated the capability of the inspection strategy as a step toward real-time release (7).

Another PAT tool in development uses ultrasonic technology to measure physical properties of tablets in-line, as an alternative to off-line, destructive testing. Pharmacoustics Technologies, a start-up company founded by Clarkson University researcher and professor Çetin Çetinkaya, received a National Science Foundation Small Business Technology Transfer grant in 2021 to commercialize the patented technology in pharmaceutical manufacturing and development for continuous manufacturing and real-time release applications.

“In oral solid dosage drug production, ultrasonic PAT can rapidly measure microstructural viscoelasticity and porosity, which can be related to CQAs of tensile strength and dissolution,” explains Cetinkaya. “It can be measured continuously, in real-time, and can be used to provide feedback for process control and data for quality assurance for real-time release.”

End-to-end

End-to-end CM for small-molecule drugs, which starts with raw materials to make APIs and continues directly to the final dosage form (e.g., solid-dose, liquid, parenteral), offers benefits but also some extra challenges compared to CM processes that begin with the API as a starting material. Two companies working on end-to-end manufacturing are Novartis, which has a facility in Switzerland, and US-company Continuus Pharmaceuticals, which is building a facility with its integrated continuous manufacturing (ICM) platform.

Advantages of an end-to-end integrated process include bringing manufacturing closer to “on demand,” which is useful for personalized medicines and supply-chain challenges. The ability to manufacture APIs in the same location as drug products could alleviate some of the problems with the current API supply chain. There is also the potential to streamline regulatory requirements for filing and process validation, says Nasr, who serves as senior regulatory advisor to the Continuus ICM Factory Advisory Team that was formed in 2021. “A fully integrated process means you don’t need to isolate the API,” he explains. “You do need to assure the quality of the API, but you don’t need separate stability testing and documentation or batch release of the API, which offers considerable savings of time and resources without diminishing quality.”

Real-time release is likely to be used, to some extent, with an integrated process, because the data needed for drug product release is being generated for process monitoring and control, suggests Nasr. Other advantages of an end-to-end process include streamlined warehousing and reduced equipment footprints via modular and intensified technologies, says Nasr. He adds that challenges include a lack of experience (in industry and regulatory bodies) and, as of yet, lack of regulatory precedence. On the technical side, process developers need to account for potential differences in output from drug substance unit operations and feed-rates into drug product unit operations. Innovative approaches to operational procedures, including equipment maintenance and cleaning and cleaning validation protocols, need to be developed, says Nasr.

“For example, it is costly and time-consuming to take the whole line apart to clean. Another approach could be to have cleaned equipment ready to ‘plug in’,” suggests Nasr. “Good manufacturing practice (GMP) requirements don’t change, but there could be different ways to achieve GMP. There is an opportunity for equipment suppliers to develop more ‘plug and play’ equipment or to find creative solutions for cleaning parts and filters, for example.”

Equipment reliability is key to long process runs. Bayan Takizawa, chief business officer at Continuus Pharmaceuticals, says that the company is designing more robust versions of its prototype unit operations, which will soon be tested at its facilities.

Sensors for PAT tools, including liquid-level sensors and Raman spectroscopy probes, need to have lengthy reliability as well, adds Bethany Silva, industry manager, Life Science, Endress+Hauser USA. “In batch manufacturing, you can perform maintenance and calibration of sensors during equipment downtime. In CM, there is no routine shutdown,” says Silva. Endress+Hauser uses in-line verifications to make sure sensors are working as installed while the process is running. “These in-line ‘health checks’ are called ‘verifications’ rather than ‘calibrations’ because a calibration requires a NIST [US National Institute of Standards and Technology] reference. In developing our tools, we have followed ICH Q13 and FDA’s guidance for CM, which provide specific guidance for controls and measurement,” Silva explains. She adds that new SOPs, replacing the SOPs used in batch processes, need to be written for these extended calibration intervals in CM.

Outlook

Adoption of advanced manufacturing technologies could gain momentum by riding the current wave of business and government support for innovation that delivers medicines where and when they are needed. Reducing investment cost and other barriers, along with improving equipment technology, could make CM more attractive to a wider range of manufacturers.

References

1. J. Markarian, Pharm.Tech. 45 (10) 34-37 (2021).
2. USP, “Advanced Manufacturing Technology Panel Discussion,” at the virtual USP Convention Exchange Series: A Resilient Global Supply Chain (Feb. 25, 2022).
3. C. Badman et al., J. Pharm. Sci. 108 (11) 3521-3253 (2019).
4. ICH, Continuous Manufacturing of Drug Substances and Drug Products Draft Guidance (July 27, 2021).
5. USP, “USP Acquires Pharmatech Associates, Inc. to Expand Services that Help Ensure the Quality of Medicines,” Press Release, July 7, 2021.
6. M. Rivers and C. Spivey, “Securing Manufacturing Independence Through Reshoring Facilities to USA,” PharmTech.com Drug Solutions podcast (March 1, 2022).
7. D. Brouckaert et al., J. Pharma and Biomedical Analysis, 209, 114491 (2022).

About the author

Jennifer Markarian is manufacturing editor for Pharmaceutical Technology.