Forty Years of Drug Product Manufacturing Advances

Although the pharmaceutical industry is criticized for its slowness to accept change, it has made manufacturing improvements in the past decades in response to changes in drug delivery (e.g., multi-layer tablets and prefilled syringes); market demands for cost-efficiency and the flexibility to make smaller batches; and regulatory demands for higher product quality, process robustness, and worker safety. Advances in automation, process control, and connected systems have been adopted. Continuous manufacturing has not replaced traditional batch manufacturing, but its concepts are better understood and accepted, and the first commercial, continuous solid-dosage processes are up and running (see pg. 48 in this issue for more on continuous manufacturing). 

Parenteral manufacturing and fill/finish

The pharmaceutical industry’s aging manufacturing facilities, particularly for parenteral drugs, have been pointed to as a cause of drug shortages, and organizations such as the Parenteral Drug Association have taskforces dedicated to overcoming the challenges to modernization, including post-approval changes (1). In many facilities, however, modern technologies have been implemented and shown to improve efficiency, quality, and flexibility. 

One of the keys has been removing human intervention with automation and cleanroom systems, such as restricted access barrier systems (RABS) and isolators. “RABS achieves the sterility assurance level required by regulatory authorities and allows for rapid product changeover along with high safety,” explains Bernd Stauss, senior vice-president of Pharmaceutical Production/Engineering at Vetter Pharma-Fertigung. An improved RABS concept called Vetter CleanRoom Technology (V-CRT) combines the advantages of both isolator and RABS technology with fully-automated decontamination of the cleanroom using hydrogen peroxide, says Stauss. 

Blow-fill-seal (BFS) technology is another aseptic technology that reduces human intervention. In the automated process, containers are formed, filled, and sealed continuously; BFS is particularly useful for single-dose containers and terminally sterilized drug products (2). 

Other new drug-delivery systems, such as prefilled syringes and autoinjectors, and the development of ready-to-fill syringes, vials, and cartridges resulted in more flexible machine platforms for filling different formats. Automated inspection improves quality. In addition, 100% in-process checkweighing prevents product loss, adds Christian Treitel, director, Business Development Pharma, Bosch Packaging Technology.

The use of robots, particularly in fill/finish, continues to expand (3). Robotics were being used at Vetter by the 1990s, notes Stauss. Fully automated lines with robotics are the way of the future, says Treitel, who adds, “Connected industry solutions will bring more intelligence into production. These technologies will help achieve higher productivity, safety, and efficiency.”

Containment for highly potent drug manufacturing

Improvements in containment for working with highly potent drug substances have been driven by the growing use of highly potent APIs in solid-dosage drugs and antibody drug conjugates, as well as a push for better protection of workers and prevention of cross-contamination. Concepts such as occupational exposure bands (OEBs) and occupational exposure limits (OELs) allowed better definition of drug hazards and the containment strategies needed to handle them safely. “OEBs/OELs were used in the United States first, and Europe started to use them around 15 years ago, followed more recently by Asia,” notes Richard Denk, head of the Containment Group at SKAN. European guidelines published in 2014 (4) that require setting permitted daily exposures (PDEs) for each product have led to better data availability as well as an increasing need for containment equipment. 

Equipment innovations, such as new technologies for isolators and product transfer systems, have made it easier for manufacturers to operate under low OEL conditions, but there is still room for improvement. Robotics, for one, are poised for implementation in this area and would remove human intervention. In the future, equipment such as fluid-bed dryer or a high-shear mixer would benefit from being designed for integrated containment rather than being adapted for containment after the fact, suggests Denk.  

Capsule filling 

Capsule filling equipment has progressively obtained increased speeds, higher efficiency, and greater flexibility, along with quality measures such as automated weight control and inspection. “Dosing accuracy has become an essential feature of capsule filling machines,” says Treitel at Bosch Packaging Technology. 

A significant change in capsule filling has been the type of products filled. “Over the past 10 years, the production of capsules containing multiple products has increased,” says Stan Matthews, sales manager of the Processing division at MG America, the US subsidiary of MG2 of Italy, which celebrated its 30th anniversary in its New Jersey headquarters in 2017. “Combinations could include, for example, two different types of pellets, tablet and pellet, or powder and pellet. Machines that are capable of filling powder, pellets, tablets, micro-tablets, and other forms on one capsule filler give manufacturers flexibility. On-board weight-control systems are capable of measuring and controlling the net fill weight of multiple components in each capsule. These changes are driven by continued changes in market demands from consumers and new advances in pharmaceutical development.  A new trend in capsule filling technology is the continued push toward continuous manufacturing.”

In addition to these new dosage forms, Treitel points to increased yield, using the tamping pin principle as another significant introduction. “Today, powders are dosed on high-performance tamping pin stations with minimal product loss,” says Treitel. “Further requirements for capsule filling machines are combination filling, inline weighing systems that offer secure and documented processes, and containment applications in several versions for highly potent active substances. In the past 5–10 years, the focus has been more on small batches and flexible machines, as well as process analytical technology. The pharmaceutical industry is also requesting quicker product change over and shorter cleaning cycles.” 

Tableting

Tablets were a widely used dosage form 40 years ago and still are today, but the equipment used to make them has been transformed in efficiency, quality, and even safety of operation. Increasing automation and connected, “smart” machines are leading the way into the future, which is likely to see greater integration of tableting into continuous solid-dosage processes. Pharmaceutical Technology spoke with Matt Bundenthal, direct sales and communications manager at Fette; Alex Bunting, marketing manager at I Holland; Fred Murray, president of KORSCH; Michael Fazio, sales manager, Batch & Continuous Processing Systems at L.B. Bohle; and Dale Natoli, owner and president at Natoli, about how tableting has changed and what they expect for the future.

PharmTech: What have been the most significant changes in tableting in the past 40 years and in the past five or 10 years? What have been the drivers for these changes? 

Murray (KORSCH): The most significant changes in the world of pharmaceutical tableting is related to advancement in drug-delivery methodologies. The focus on simple, single-layer, immediate release therapies has been replaced by a wide range of innovative delivery platforms including bi-layer, tri-layer, and tablet-in-tablet technologies. Most recently, microchip in tablet technology has been developed to improve compliance with critical therapies. Extended-release products, combination products, and the ability to deliver drug substances exactly where and when they are needed have driven these changes.  The equipment manufacturers have responded with specialty machines that facilitate these new tablet formats, both for product development and on a commercial scale.

A second significant change is related to the clear focus on operational efficiencies and flexible equipment. Many years ago, it was not unusual to tour a manufacturing facility and see only a small percentage of the equipment in operation. Today, under significant pricing and competitive pressures, there is a major emphasis on overall operating efficiency, uptime, and product yields. The development of new and innovative drug delivery platforms requires flexible equipment that can produce a wide range of product formats, with fast changeover, for maximum utility. Today, a single tablet compression machine can produce single-layer, bi-layer, tri-layer, and tablet-in-tablet products, in combination with an exchangeable turret capability, to facilitate the production of literally any tablet size and format, with high efficiency.

In the past five years, continuous manufacturing has also been established as a viable alternative to batch processing. For some products, continuous manufacturing technology offers significant advantages for new product development and scale-up, increased product quality, and reduced operator intervention. 

Natoli (Natoli): The reintroduction of the multi-tip tool has created significant changes in tablet manufacturing. Recent developments in multi-tip tooling include assembly-type punches, which reduce costs by allowing the reuse of punch bodies and repair or replacement of individual punch tips. Vented caps allow the cleaning of punches as an assembled unit and the use of compressed air to remove residual moisture. The development of multi-tip reject verification tools provides the assurance needed by the pharmaceutical industry to validate tablet sizes and weights, making multi-tip tooling a viable option. These technological advances in multi-tip tooling, made within the past 10–15 years, have greatly increased tablet production, which reduces operational costs by saving energy, minimizing labor, and decreasing manufacturing footprints. These benefits are driven by continued pressures from both regulatory bodies and the pharmaceutical industry.

Bunting (I Holland): The requirement for higher productivity and efficiency, while maintaining top quality tablets, has become more prevalent during the past 40 years, and innovations have advanced to keep pace with the ever-growing demand driven by developing markets to produce tablets for the masses. Perhaps one of the major advancements has been multi-tip tooling, which has helped to cater to this demand. Multi-tip tooling has transformed the quantity of tablets produced and it is now considered the most productive form of tablet manufacture where it can be applied. A difference in the past decade is the request for reduced lead times; multi-tip tooling has helped to keep these lead times and allow manufacturers to meet the time-to-market demand.

The influence of developing countries is also a huge driver for change. Due to increasingly strict controls and standards, these countries are aligning with good manufacturing practices (GMP) and regulatory demands, with production volumes increasing at an astounding rate. The developing world must comply to GMP and regulatory requirements to distribute their products globally, which requires major investment in upgrading manufacturing facilities. I Holland is working in these countries to help them develop their processes and products. 

Bundenthal (Fette): Changes in tablet press technology can be correlated with the need for a higher degree of control over finished tablet quality, at higher machine speeds; the requirement for presses that can efficaciously compress more challenging formulations; a request from end users for maximum versatility in machine design; and cost-cutting targets, relating to issues such as final yield percentages. 

The introduction of pre-compression represents one of the most significant-and useful-changes. It greatly increases overall compression efficacy by helping eliminate entrapped air and reducing the incidence of phenomena such as capping and ‘picking.’ Real-time compression force monitoring and control, and the subsequent ability to automatically reject out-of-spec tablets, has led directly to increased machine speeds, better quality control, and improved yields. Computer-controlled, recipe-driven machines ultimately improved repeatability across batches, with reduced set-up time. The appearance of motorized feeders (and the elimination of ‘open’ or gravity feeders) improved die-filling characteristics. Enhancements to multi-layer functionality, especially for bi-layer tablets, include  dynamic first-layer sampling, prevention of cross-contamination, and weight control for individual layers. Inventions such as removable turret assemblies revolutionized fast changeover. The growth of potent compounds led to high-containment technologies, such as wash-in-place features, glove ports, door interlocks, and rapid transfer ports.  And the need for greater operator safety led to additions such as guards and shrouds surrounding turrets, switch-controlled interlocks on access doors, protected discharge chutes, and electro-magnetic brakes.

Fazio (L.B. Bohle): Pharma manufacturing has come a long way in terms of mechanical engineering controls.  Over the past 15–20 years, we have experienced a trending demand for highly contained capital equipment; more often, our clients’ formulations include a potent API. Contained oral solid-dosage equipment projects can be sophisticated and challenging because process air handling and mechanical interfaces must be more tightly managed. Contained process equipment serves as protection of both personnel and pharmaceuticals products alike. 

Automation, process control, and process analytical technology (PAT) has also changed, and has become crucial to ensure high-quality production of pharmaceutical products. 

PharmTech: What trends or new developments do you foresee for the near future?

Bundenthal (Fette): Tablet press manufacturers continue to design machines that offer ever-increasing versatility. Another trend is integrating tablet presses into continuous manufacturing lines, using control systems with up- and downstream control ‘handshakes.’ In addition, features allow presses to ‘talk’ to and send data to a client’s in-house network. 

Fazio (L.B. Bohle): Continuous processing is a developing manufacturing platform for the future. We have experienced an increasing number of end-user pharmaceutical companies evaluating their drug candidates on our fully continuous manufacturing line in our Pharmaceutical Technology Center, which was built in 2014. Pharmaceutical manufacturers and FDA see merit in and support the evolution of pharma manufacturing from batch to continuous because of inherent features, such as smaller footprint, faster and less costly scale up, flexible batch sizes, and improved quality. 

Natoli (Natoli): As the industry works toward continuous manufacturing, tool-to-die clearances will become even more critical in the near future. These tolerances will necessitate tooling to be engineered to meet the needs of specific powder characteristics and particle sizes. Furthermore, current estimates indicate that only 15–20% of the pharmaceutical industry use multi-tip tooling, and we predict that this usage will increase due to its advantages. 

Bunting (I Holland): The pressure for shorter lead times and cost efficiency is leading companies to investment in new technologies and processes. On top of this, stringent quality requirements drive the need to improve production from end to end, through durable tablet tooling and the associated maintenance equipment.

The adoption of continuous manufacturing, I think, will be an important trend in the future and one which will help in reducing reaction time and time to market. The challenge, then, is for the upstream and downstream processes to keep up with each other. In the case of a quality tooling manufacturer, we continue to develop even more ways to maximize uptime by producing solutions to problems that compromise the maximum output and yield. I Holland is working toward this goal with the introduction of XDF (eXtended Dwell Flat), a novel, patented, elliptical head form which has been designed to increase dwell time on existing presses without the need for expensive modifications. As the importance of increased productivity continues to grow, XDF can give users higher press speeds for challenging products and formulations, enhancing tablet compaction and cohesion.

Murray (KORSCH): These trends of more complex drug delivery platforms, and an increased emphasis on operating efficiencies will continue. The use of continuous process technology will also be more widely used and accepted. From an equipment perspective, tablet compression machines are going to become smarter and more connected. They will self-diagnose, include on-board help systems to guide the user through every aspect of the operation and maintenance, and be fully integrated to central SCADA [supervisory control and data acquisition] and manufacturing execution systems. They will monitor and report on operating efficiency, and leverage new technologies to permit remote support by service experts. 

Innovations in Coating

Harlan Hall, who founded The Coating Place 41 years ago, worked indirectly with Dale Wurster, the inventor of the Wurster fluid-bed coating process, and the protoype equipment he created. Hall shared his perspective with Pharmaceutical Technology. 

PharmTech: How has the Wurster coating process for pharmaceutical tablets changed over the past decades? 

Hall: Prior to the mid-1970s, use of the process was limited to a few companies, mostly coating fairly large particles. In the 1970s, the Wisconsin Alumni Research Foundation (WARF) did extensive work in extending the practical use of the Wurster process to smaller particles (as low as 10 micron) and helped develop a number of new products using this technology. This work continued when Coating Place was founded in 1976 and began providing contract services using this technology. In the mid to late 1970s, equipment manufacturers adopted many of the innovations pioneered by WARF, and coating of smaller particles became more common. Innovations including continuous clean filters and larger expansion chambers became industry standard, and improved Wurster plate design and linear scale-up pushed the state of the art.

The development in the 1970s of taste-masked dosage forms, and particularly chewable and liquid-dosage forms, arose from the ability to manufacture small, coated particles at commercial scale.  As equipment to prepare experimental quantities of such particles became more common, more pharmaceutical companies became familiar with Wurster technology, leading to new products. The development of water-based coatings allowed more companies to pursue this work without need to be concerned with control of solvent emissions.

PharmTech: What trends or new developments do you foresee for the near future?

Hall: A number of companies are developing more sophisticated small-particle products that combine small particle technology, multiple functional coatings, and targeted drug delivery. These new developments permit products with sophisticated release profiles and better control of higher potency APIs. 

References

1. A. Shanley, “Is Global Regulatory Gridlock Slowing Modernization?” Pharm.Tech. Quality Throughout the Supply Chain ebook (November 2016) p 27-29, 32.
2. C. Hroncich, Pharm.Tech. 40 (6) 49-51 (2016).
3. H. Forcinio, Pharm.Tech. 41 (5) 62-65 (2017).
4. EMA, Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities (EMA, Nov. 20, 2014).

Article DetailsPharmaceutical Technology
Vol. 41, No. 7
Pages: 38–47

Citation:
When referring to this article, please cite it as J. Markarian, "Forty Years of Drug Product Manufacturing Advances," Pharmaceutical Technology 41 (7) 2017.