Formulating Drugs for Continuous Processing

For some time now, the bio/pharmaceutical industry has been under increasing pressure to deliver efficient therapeutic products at pace and reduced costs. Global factors, such as the COVID-19 pandemic, rising rates of inflation, geopolitics, and novel therapeutic modalities, are compounding industry pressures and leading companies to renew their focus on operational strategies (1).

Faster speed-to-market, lower operational costs, improved product quality consistency, and better process control are just some of the key benefits that can be provided to the bio/pharmaceutical industry through process intensification (2). However, despite there being considerable research in certain fields where continuous processes have been implemented, there is limited information on end-to-end continuous systems, perhaps as a result of the separation between synthetic and formulation sections (3).

Considering formulation

When approaching drug development via intensified/continuous processes, there are some important formulation considerations to take into account, such as the particle characteristics of both the API and the excipients, confirms Thomas Durig, senior R&D director, Life Sciences, Ashland. “Continuous manufacturing relies on automated, mechanical, gravimetric feeding to dispense the right proportions of the various components. Powder ‘feedability’ and flowability are therefore paramount,” he says. “Particle characteristics such as size, shape, bulk density, surface area, cohesiveness, electrostatic charging tendency, surface roughness, stickiness, and hygroscopicity can all affect successful continuous manufacturing.”

Additional care should be taken over determining whether the drug can be formulated using excipients that allow for direct compression or roller compaction (dry granulation), which are the current best-established continuous processes for oral solid dosage forms, emphasizes Durig. “If wet granulation is required, one must consider the rate limiting and potentially destabilizing step of drying the granulation, so a further consideration would be whether the product could be produced via melt granulation (i.e., twin screw hot melt extrusion), this can obviate these limitations of wet granulation. There are a lot of advances being made in this aspect by leading companies and academic institutions,” he notes.

“Process intensification and continuous unit operations are fast becoming the new normal in biologics manufacturing, as they enhance productivity through the efficient use of production suites,” adds Paresh Vadgama, fellow scientist, Biologics Product Development, Catalent. “Though the biopharmaceutical industry has successfully implemented processes for drug substance (DS), its application for drug product manufacturing is still nascent. Biologics, being complex and highly sensitive molecules, have selected excipients added to protect them against various environmental factors during production and transportation,” he says.

Other than considering the molecular stability and drug product presentation needs, Vadgama notes that understanding of other factors, such as the DS dilution ratio, product compatibility with contact parts, and risk of exposure to environmental factors, is also required. “In addition, specific dosage form needs, including particle size and its distribution for suspension, or residual moisture for lyophilized powder, as well as stability-indicative analytical methods for real-time quality monitoring, should also be considered,” he states.

Specific challenges

There are many formulation challenges that pertain to intensified processes, Vadgama continues. “One main issue to consider is the risk of a high titer or a high density/intensified fed-batch producing concentrated solutions,” he explains. “Such solutions may be too viscous to handle during filtration and filling operations. Moreover, these circumstances offer the potential for aggregation due to the absence of a stabilizer. Amino acids, such as arginine hydrochloride, or salts, including sodium chloride, can be added at the upstream stages of bioprocessing to protect protein molecules.”

Monitoring the attributes of a product in real-time during continuous process control and product quality monitoring has always been challenging, Vadgama stresses. “However, performing at-line rapid analysis using standard techniques of multiple sterile samples collected along the process flow, could potentially resolve such challenges,” he states.

Moving to downstream processes and the aggregation risk of shear-sensitive molecules can be problematic as this makes them difficult to handle in high-speed filling machines, Vadgama adds. “Optimizing stabilizer and/or surfactant ratio during formulation development can help to reduce the negative impact of mechanical interfacial stresses,” he explains. “In addition, scale-down modeling using computational fluid dynamics can be best suited to studying molecular behavior while undergoing anticipated processing conditions.”

“Generating multiple drug product batches from a single drug substance batch in a continuous mode is also very difficult,” Vadgama emphasizes. “Factors such as diverse dosage forms, product batch size, and variable market forecasts play a significant role.”

To mitigate the risks posed by the aforementioned challenges without negatively impacting the microbiological quality, Vadgama points to a few different strategies, such as splitting the DS batch or diverting material and parallel product manufacturing in dedicated good manufacturing practice suites. “The key to success is to ensure end-to-end, detailed process and raw material movement mapping and synchronization between various teams,” he says.

“Some of the specific challenges [when formulating for intensified processes] are the need for ‘feedable’ excipients and the risk of variability that would render gravimetric feeding/dispensing and process control very tricky,” asserts Durig. “Potential solutions [to these challenges] include ensuring that the process can handle the inherent variability in powder characteristics that impact feedability, and choosing only formulation components in which the powder properties are optimized, well-understood, and controllable.”

Pointing to some examples of excipients that are optimized for continuous manufacturing, Durig highlights two options available from Ashland, Benecel DC HPMC (hypromellose)—an existing, approved excipient—and Polyplasdone Plus crospovidone—which is pending approval. “[These products] are important because they are surface-optimized excipients that also include glidant and lubricant,” he states. “These factors enable powder feeding of otherwise poorly flowable and controllable finely divided solids as well as good tablet compaction.”

Continuous tablet coating can also pose a challenge to formulators as a result of the drying/mass transfer of water in the formulation, which can take an order-of-magnitude longer than the other close-coupled process times, reveals Durig. “The consequence is that drying can be rate limiting,” he says.

Some possible solutions to help with continuous tablet coating issues include advanced coaters, such as the ConsiGma coating modules (GEA, Germany), or continuous coaters, such as KOCO (L.B. Bohle, Germany), adds Durig. “However, here too, process time limitations exist. These can be overcome with purposely designed ultra-high solids, ultra-high spreadability coating products such as Ashland’s Aquarius Genesis film coatings,” he says.

Recent regulatory guidance

In June 2022, the US Center for Drug Evaluation and Research’s (CDER’s) Office of Pharmaceutical Quality (OPQ) published an article regarding the results of a self-audit that they performed about the regulatory approved products that had been manufactured using continuous processes versus those that had been batch manufactured (4). Specifically, confirms Ana Ladino, Global Regulatory Affairs director, Life Sciences, Ashland, the OPQ looked at the time to approval and market entry, manufacturing process changes reported in annual reports, manufacturing-related post-approval application supplements, and pre-approval inspections. Based on its self-audit, FDA concluded that continuous manufacturing technology has regulatory advantages and economic advantages, and that its use should be encouraged in the development and manufacture of drug substances, she notes.

Less than a year later, in March 2023, the International Council for Harmonisation (ICH) published the Step 5 version of its Q13 guidance on continuous manufacturing (5), which expands upon the guidance set out by FDA back in 2019 (6). “ICH’s Q13 guideline, soon to be effective in the EU [European Union], is the first step towards harmonizing scientific and regulatory principles covering batch definition, control strategy, process validation, and stability studies,” asserts Vadgama. “Key regulatory messages for continuous manufacturing from this guidance include: that the dossier should summarize process integration for each unit operation, along with input raw material attributes, feedforward, and feedback process controls; process dynamics should be well understood with respect to changing inputs or operational conditions or transient events, which in turn would require deeper formulation robustness studies; the mode of manufacturing can be converted from batch to continuous, with appropriate control strategies and comparability exercises, even after product approval; details of the real-time release testing model to measure protein content, residual moisture, and protein stability are to be provided as applicable.”

Overcoming obstacles

Improving speed of product development and reducing costs are the two main drivers for businesses to adopt intensified processes, Vadgama stresses. “However, the technology still needs to evolve for it to be suitable for broader implementation within the drug product space,” he says. “Several non-technical limitations may explain this phenomenon: for example, initially, high capital investment is required to automate equipment, innovate process analysis/control technologies, and standardize practices across sites. But increased productivity, higher facility utilization rates, and lower labor costs would, given time, drive production efficiencies and savings.”

When approaching continuous production as an integrated unit operation, there could be some impact on the organizational structures of the purification and formulation areas as the distinction between these facets will become blurred, Vadgama continues. “Such changes can alter working practices, due to transitioning from a batch production mindset,” he explains. “In the drive for process excellence, emphasis should be given to operational control and regulatory compliance; therefore, receiving the full support of top executives and management is vital.”

Focusing on the supply chain, it is important to note that continuous operations require an uninterrupted supply of raw materials of consistent quality, Vadgama adds. “Single-use, disposable components form the backbone of the supply chain for continuous manufacturing workflows,” he summarizes. “Diversifying supply, better long-term inventory planning, and quality assurance teams being able to thoroughly qualify vendors can help remove the risk of supply chain issues.”

“Industry and stakeholder perceptions regarding the risk of adopting newer state-of-the-art manufacturing technologies are obstacles that must be overcome,” warns Durig. “The pharma industry tends to be conservative about adopting new manufacturing and formulation technologies.” Using twin-screw melt granulation as an example, he points out that despite the advantages such a technique can offer when compared with wet granulation approaches to continuous manufacturing, perceptions still exist that the technology could have an adverse effect on API stability.

“These perceptions and the obstacles they present to new technology can be overcome through trial and investigation. Continued education and collaboration among industry stakeholders, drug product manufacturers, equipment manufacturers, excipient companies, and academia are required,” Durig concludes.

References

1. Dukart, H.; Lanoue, L.; Rezende, M.; Rutten, P. Emerging from Disruption: The Future of Pharma Operations Strategy. McKinsey and Company, Oct. 10, 2022.
2. Yazdanpanah, N. Continuous Manufacturing in the Pharmaceutical Industry. CEP Magazine, March 2021.
3. Domokos, A.; Nagy, B.; Szilágyi, B.; Marosi, G.; Kristóf Nagy, Z. Org. Process Res. Dev. 2021, 25 (4), 721–739.
4. FDA. An FDA Self-Audit of Continuous Manufacturing for Drug Products. FDA.gov, June 28, 2022.
5. EMA. EMA/CHMP/ICH/427817/2021 ICH Guideline Q13 on Continuous Manufacturing of Drug Substances and Drug Products. Step 5 version, March 3, 2023.
6. FDA. Quality Considerations for Continuous Manufacturing; Draft Guidance for Industry; Availability. Federal Register, Feb. 27, 2019.

About the author

Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.

Article details

Pharmaceutical Technology
Vol. 47, No. 4
April 2023
Pages: 24–26, 44

Citation

When referring to this article, please cite it as Thomas, F. Formulating Drugs for Continuous Processing. Pharmaceutical Technology, 2023, 47 (4) 24–26, 44.