Complex and highly regulated, the pharmaceutical manufacturing process encompasses formulation, production, quality control, packaging and labeling using chemical materials to produce tablets, capsules, liquids, creams, ointments, and aerosols. The biopharmaceutical manufacturing process begins with upstream processing, which involves the cultivation of living cells to produce desired therapeutic proteins. Here, cell culture techniques are used to optimize growth conditions and maximize protein production. Biopharmaceuticals mainly include recombinant protein therapy, antibody therapy, cell therapy, and gene therapy.

Due to ever changing drug development pipelines and products, the need for flexibility to accommodate both large-scale and small batch manufacturing, containment requirements for highly potent drug products and complex biologics, and operating efficiency are among the key attributes of manufacturing equipment today. With a focus on quality and process efficiency, automation in manufacturing technology continues to play a role in improving production processes and equipment advances. Additionally, addressing today’s manufacturing challenges in tablet production, biomanufacturing scale-up, and regulatory requirements for process safety, requires flexible manufacturing processes and versatility in equipment.

Pharma & Biopharma Trends 

Growth in highly potent drugs, prefilled syringes, and soaring demand for products such as Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists, have given rise to demand for advanced containment solutions and high-performance equipment. Equipment suppliers also see continued trends in the industry’s interest to transition to continuous manufacturing for oral solid dosage and operating efficiency to improve quality and yield performance in tablet manufacturing.

Additionally, recent regulatory guidance is expected to significantly impact manufacturing operations going forward. The European Commission’s revised Annex 1 as of August 25, 2023, provides new technical guidance on the principles and guidelines of good manufacturing practice (GMP) as it relates to sterile medicinal products. Also, FDA’s March 1, 2023 publication of the International Council for Harmonization (ICH) final guidance on the use of continuous manufacturing, provides clarification on continuous manufacturing concepts, scientific approaches, and regulatory considerations.

Dr. Andreas Mattern, Vice President, Strategy & Global Product Management Pharma at Syntegon said, “August 25 was an important date in the history of the pharmaceutical industry as Annex 1 has far-reaching consequences for sterile filling operations – not only within the EU but for the global pharmaceutical industry. On the one hand, the specifications affect the manufacturing processes of drugs imported into the EU. On the other hand, the coordination of the document between EMA, WHO and PIC/S and the publication of equivalent documents by these organizations underline its global relevance.”

In oral solid dosage (OSD) production, continuous manufacturing is being explored by many companies who are looking into changing from batch processes to continuous manufacturing, Mattern contends. “This is further promoted by the FDA’s ICH final guidance on the use of continuous manufacturing in drug production – a proactive step to ease the industry’s transition. Hence, 2024 and the coming years are likely to see many innovations in this field.”

Also, the rapid growth in demand for GLP-1 drugs has boosted the need for high-performance equipment with large batch turnovers, including both state-of-the-art filling and inspection equipment, according to Mattern. Biologic drugs, including GLP-1s, have sensitive and complex structures. In addition to increasing production, special attention must be paid to the primary packaging where effective visual inspection protocols are critical for scaling up capacity and compliance.

Among the trends that have chiefly impacted manufacturing equipment are those involving containment, according to Jim McKee, Sales Manager, Processing Division for MG America – the U.S. subsidiary of MG2 of Bologna, Italy, a pharmaceutical equipment supplier. “The pharma industry has an increasing demand for equipment designed to guarantee operator safety by minimizing exposure levels. Containment is even more vital considering the emergence of high-potency, low-dose products, including those that forgo excipients. Considering this, capsule filling machines must be designed to guarantee required containment levels such as OEB5 (from 1 to 0.1 µg/m3), in addition to offering thorough washing features,” said McKee.

In tablet manufacturing, operating efficiency remains a key focus. Frederick Murray, President of KORSCH America Inc., a provider of tablet press technology solutions, said, “This includes process optimization to ensure superior tablet quality and yield performance at the highest output, while employing a streamlined changeover process to maximize production uptime. The most common technical advances being leveraged include exchangeable turret technology, where a clean and fully tooled turret can be easily installed after the machine is cleaned to minimize changeover times. In addition, product recipe capabilities minimize startup scrap by configuring the press automatically based on optimal parameters that have been establish for each product.”

Meanwhile, for the past several years, market growth for prefilled syringes and drug device combination products have been the dominant drivers for equipment dedicated to liquid filling and assembly, according to Deborah Smook, Vice President of Marketing & Business Development for TurboFil Packaging Machines LLC. “Single-dose delivery devices continue to show increased traction and unit-dose nasal delivery devices also are becoming increasingly common. There are a variety of reasons for this single-use surge, such as more exacting fill rates, meaning substantially less product wastage compared to having healthcare personnel draw from vials, and improved safety, since needlesticks are exposed only at the time of final use,” said Smook.

TurboFil recently introduced a syringe-filling machine to help pharma companies meet growing demand for this single-use format. The TipFil Syringe Filling & Assembly Machine is designed to automate all processes – from syringe loading, filling, and capping through inspection, labeling, and printing. The machine can produce up to 50 prefilled syringes per minute and incorporates monoblock modularity for as-needed manufacturing, and it can handle various syringe shapes and sizes from 1-60mls.

Today’s Manufacturing Challenges 

The industry faces numerous challenges with drug manufacturing, according to equipment suppliers, among them: balancing flexible manufacturing with compliance, quality of the finished product and process efficiency, and scale-up production from small-scale to large-scale in biomanufacturing, as well as skilled labor.

Process reliability and product and operator safety are critical to navigating regulatory requirements, according to Nils Bischoff, Product and Service Manager, Vetter Pharma International GmbH.

“Customers and global authorities are increasing their regulatory requirements for process safety including additional requirements for microbial and particulate contamination control. New and revised guidelines continue to be published. One example is the new EU GMP Annex 1,” Bischoff said.

Annex 1 addresses contamination control, quality system, quality risk management, expansion of monitoring, disinfection, cleaning, and training requirements, along with new technologies, such as isolators and restricted access systems (RABS), a type of sterile processing environment for non-sterile and sterile manufacturing.

Among the major challenges of the new Annex 1 is the separation of the aseptic process area from the operator environment, according to Dr. Mattern at Syntegon. “Pharmaceutical manufacturers therefore require at least RABS for the approval of new products. In the year following the publication of the guideline, the industry witnessed a veritable “run” on RABS upgrades of existing cleanroom lines, which continues to this day. Pharmaceutical manufacturers must decide whether to retrofit an existing cleanroom line for a new product or invest in new filling equipment that runs with isolator or RABS. We expect isolator technology to become the new “normal” as automatic bio-decontamination processes and the pressure difference from the operator environment provide additional safety, while RABS is more likely to come into play for frequent product changes and with experienced operators,” Mattern said.

Achieving quality and process efficiency, particularly for complex products, remains a challenge. In analyzing user requirements documents from pharma companies around the world, there are major challenges along two fronts, according to Jim McKee at MG America, quality of the finished product and process efficiency. “For example, with capsule fillers there is elevated demand to control all the capsules produced on a 100% basis, to best ensure proper quality along increasingly stringent tolerances. This is particularly important when handling challenging products with characteristics that may vary overtime. There are also several requirements regarding process efficiency to consider, such as yield optimization, reduced changeover times, dosages/size flexibilities and human machine interface (HMI) user-friendliness. Here, one logistical challenge has been frequent turnover of machine operators, requiring outsized time and effort dedicated to training. Simplified HMIs and operation procedures help reduce the impact of this challenge,” McKee said.

In tablet production, there is no shortage of manufacturing challenges, according to Frederick Murray of KORSCH America Inc., which can range from products with poor flow properties, to products that are difficult to compress. “The latest tablet compression technology features long filling lengths and a variety of feeder paddles to address poor flow, as well as a comparable pre- and main compression force capability for maximum flexibility. There are tablet press technologies out there that can increase the compression dwell time and thus apply compression force over a longer period of time to address issues with compressibility and low tablet hardness,” Murray said.

When it comes to biomanufacturing, customers are particularly interested in products and equipment that can solve their problems. “It is critical to have solutions that provide a simple and consistent way to scale-up production from small-scale to large-scale without the need to change anything in the process,” said John Puglia Ph.D., Senior Director, R&D, Single-Use Technologies, Thermo Fisher Scientific. “With single-use equipment, scaling is easy, and choosing equipment within the same family (i.e., moving from a 50L Thermo Scientific DynaDrive Single-Use Bioreactor (SUB) to a 5000L

DynaDrive SUB) means more consistent results without changing processes. Single-use equipment is significantly smaller than its stainless steel counterparts, requiring less manufacturing space (and lower operating costs) with replicable results at any scale,” Puglia said.

Thermo Fisher Scientific recently launched the DynaChrom Single-Use Chromatography System that allows manufacturers to scale their operations. DynaChrom features changeable line sets to allow for run customization, while also preventing cross-contamination. The line sets are built to withstand various chemicals. It’s also column agnostic, providing additional flexibility.

Additionally, skilled labor continues to be challenging to obtain and retain, noted Deborah Smook at TurboFil. “Understandably, we’re seeing an increasing need for automation in production, especially for inspection processes, record-keeping and productivity optimization. These needs are widespread, with the ongoing manufacturing labor shortage affecting each of our target industries, pushing them ever more steadily toward automation,” said Smook. “Also, companies are struggling to hire experienced mechanics and engineers to maintain equipment. This difficulty is placing added emphasis on equipment that can be easily changed over by operators and requires as little maintenance as possible. This trend also has prioritized remote assistance capabilities,” Smook added.

Manufacturing Equipment Advances

Leveraging continuous manufacturing technologies, automation, and digitalization, the latest advances in manufacturing equipment are helping to optimize production processes and improve quality and efficiency.

Jim McKee at MG America said, “We’ve already accrued some experience in the continuous manufacturing environment by leveraging the substantial advantages of 100% net weight control integrated into capsule filling equipment. That’s a highly encouraging step toward comprehensive quality control. We are also seeing more requests for adding digital components to certain processes. Data collection and information analysis is the basis for understanding a process, identifying possible improvements, and implementing them. OPC Unified Architecture technology to access machine process status in real-time is now frequently integrated into our equipment, combined with SQL Server Database connectivity for tracking the performance of mid/long-term batches.”

MG America is also working on incorporating facets of Artificial Intelligence into machine controls to further improve the production process. “Ultimately, this level of real-time analysis may lead to completely unmanned machines, an attractive prospect in a landscape where the operator workforce has shown limitations,” McKee said.

Frederick Murray of KORSCH America Inc., added, “Continuous manufacturing has been successfully deployed in a range of low-volume, high-containment applications, which ensure operator safety and eliminate the need to transfer potent or toxic products across a series of unit operations. Configured with integrated isolators and wash-in-place capability, these systems leverage the latest in continuous granulation, drying, blending, and compression technology, with a central supervisory control system. These systems can deliver OEB 4 and OEB 5 containment levels.”

The trend towards small batches is also true for OSD forms, according to Dr. Mattern at Syntegon. “Syntegon’s Xelum platform offers continuous solutions, from fluid bed granulation to direct compression and in both cases, the same feeder-blender module can be used. It doses and mixes individual packages, so-called X-keys. They ensure easy traceability and precise dosing, even for active ingredients of less than 1%. In the new configuration presented this year, the packages are continuously fed into the TPR 200 Plus tablet press, which enables efficient and user-friendly downstream processing. It features a light containment concept with dust-tight machine protection up to OEB 3. With the APD feeder, including automatically adjustable powder infeed in the filling shoe and the APD software, manufacturers can determine the optimum parameters for the formulation feed into the die,” Mattern said.

Importantly, equipment suppliers noted several key innovations in automation production processes. Nils Bischoff at Vetter, said, “Recently, we have seen an increase in built-in versatility and a high degree of automation in manufacturing technology. There is a strong shift throughout drug product production from a former human-centric approach to a fully automatic production process, utilizing robotic technology where it’s possible to reduce direct human intervention and ultimately eliminate manual intervention altogether.”

Additionally, automation is helping to address challenges associated with small batches in areas such as rare diseases. “In general, the challenge of producing high-value drugs in small batches is to maximize API yield, flexibility, and time to market. Fully automated and flexible gloveless isolators that meet Annex 1 requirements are setting a new industry standard to meet customer demands,” said Bischoff.

Meanwhile in biomanufacturing, there are a tremendous number of variables in flux, especially with increased adoption of Process Analytical Technologies (PAT), and the influences of these variables are being explored to help optimize the process, according to John Puglia at Thermo Fisher Scientific. “AI will be a critical part of understanding the data generated through PAT, considering all historical results and thus, providing predictive trends on the process. While a large mountain to climb, the goal is to isolate all the dependent and independent variables and track them to a resolution that is shown to be responsive to process changes, then manage in real time the results to make modifications to the process and realize its improved performance,” said Puglia.

In other advances, inspection sensors and cameras continue to show steady performance improvements, especially in the ability to handle faster throughput for historically difficult-to-inspect platforms such as syringes, vials and lyophilized medicines, according to Deborah Smook at TurboFil. “Increasingly, these quality control systems also incorporate certain elements of machine learning, which improves their pass/fail determinations as they become more familiar with product-specific inspection parameters. Unsurprisingly, data metrics and line optimization solutions also continue to evolve and proliferate. Today’s systems show a positive ROI by utilizing the same tools used for compliance to provide actionable intelligence regarding production optimization,” said Smook.

Innovative, high-sensitivity camera technology and monitoring systems are increasingly being used to continuously record, display, store, and analyze data, and in turn protect drug product integrity and operators. Furthermore, associated AI software in automated visual inspection machines is being leveraged for quality control.