Traditionally, compounding facilities—also called 503B outsourcing facilities in the United States in reference to the section of the US regulation under which they are registered (1)—have conducted drug manufacturing operations manually; “on demand” production of a wide range of drugs needed by hospitals and pharmacies as well as drugs on FDA’s drug shortages list did not lend itself to automation in the way that longer-run, scheduled production did. Robotic automation technologies available today, however, offer benefits of greater efficiency and higher quality even for small volumes.

“Robotics offer several significant advantages for aseptic compounding. Most notable is that the greatest source of contamination, the person, is removed from the process,” says Chris Smalley, an independent compounding pharmacist advisor. “There is a robust traceability to what is performed, including volume, drug barcode scan and more, and it does not matter what hour or day of the week the robot operates,” explains Smalley. He notes that, in some cases, a robot is set up to operate on its own overnight (i.e., “lights-out” manufacturing), and the completed products are unloaded and checked the next day.

“Minimizing risks associated with aseptic processing is crucial when working with compounding systems,” agrees Randy Fraatz, vice-president of North American Operations at Steriline, which produces aseptic manufacturing equipment. “The primary benefit of robotics and automation in general is safety, coming from the reduction of human-related mistakes in the entire process.” Other benefits, says Fraatz, include the accuracy, efficiency, and reliability that result from automation. “If errors are reduced, process reliability and quality improve,” he explains. 

Despite these advantages, uptake of robotics is slow, and many 503B outsourcing facilities continue to have technicians working in laminar flow hoods or biological safety cabinets to handle beakers and flasks for solution compounding and fill vials manually using syringes, notes Smalley. He points out that some large teaching hospitals have adopted robotics for large-volume parenterals and for oncologic compounding and filling. “Smaller hospitals that focus on a specialty, such as orthopedics or oncology, appear to be the second wave,” Smalley adds.

An early example of a hospital compounding facility that adopted automation was the overall winner of the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards in 2019 (2). The Kantonsapotheke Zurich (KAZ) supplies oral, dermal, and parenteral formulations to the Canton of Zurich hospital system under current good manufacturing practice (CGMP) conditions. Exyte, the engineering firm for the project, said in the award announcement: “This facility raised the bar for quality performance to CGMP levels, which had never been done before in a hospital compounding facility” (2).

Although robotic systems have many advantages, one of the challenges is designing and programming for flexible operations. Since it takes time to set up the systems to manage different material combinations, speed can be limited. “For a compounding combination that requires a lot of flexibility, such as handling a wide range of materials to prepare one compound, the system will need more time to process materials,” says Fraatz. “In many cases, humans are typically able to handle different types of materials and combinations faster than robotics, but contamination risks are higher.” He explains that planning ahead is important for using robotics, so that the right tools, equipment, and programming instructions are ready for a specific process.

“The user requirements need to be clearly and completely defined,” agrees Smalley. “Robotics can only work with the tools that they are constructed with, for instance vacuum-assisted suction cups, pincers, barcode scanners, syringe operators, and the like. Additionally, they can only perform tasks that were included in their programming. Refitting and reprogramming can be problematic.”

Another challenge is the need to have barcodes that can be identified by the automated system. “Not all vials have barcodes, and new products or new brands of generic drugs result in barcodes not in the robot’s database. Software updates are constantly needed,” notes Smalley.

New developments are focusing on improving software and improving material handling. “Changes are being made to software to enable the robot to operate more smoothly and efficiently, as well as to make the user interface more intuitive. For material handling, some robotics manufacturers are focusing on loading cells, while others are looking at the ‘hands,’ as it were, trying to make the way the robot grasps items more securely without the danger of breaking the item,” reports Smalley.

A best practice for robotics users is periodic service by the equipment manufacturer that includes maintenance and adjustment, as well as software updates to address operational and security needs, notes Smalley.

“Routine maintenance and attention are absolutely required for robotic automation in the compounding space,” agrees Fraatz. In his experience, various hospitals tend to be familiar with using high-tech equipment such as robotics (as in some surgical settings), but the overall compounding industry is not yet as aware of how process automation can be used in compounding environments.

In particular, integrating robotics inside isolators is a relatively new technology for the compounding environment, says Fraatz. “True isolators have become very common in the pharmaceutical processing industry, and are the safest containment solution available for the compounding market as well,” he says. “From a best practice perspective, compounding organizations need to evaluate and adjust their quality risk management philosophy, including process and validation protocols for this type of automation. Evaluating [the use of isolators and robotics] is a multi-department effort, as there are also facility considerations in terms of what they may need, concerning cleanroom design or availability of utilities, for example.” Fraatz notes that it is also important to evaluate the process flow, including how materials are introduced to the compounding environment and handled after compounding. He points out that robotic equipment can be designed to be compatible with cleanroom conditions. “Cleanroom conditions require easy to clean tools, low particulate generation, and equipment designed to respect the clean airflow required,” notes Fraatz. 

A pharmaceutical manufacturing company adopting cutting-edge robotic technology for its CGMP 503B operations is Nephron Pharmaceuticals in South Carolina. The company, which specializes in producing generic respiratory medications using a fully automated process with blow-fill-seal (BFS) technology, launched its division for sterile compounded drugs in 2017 and began with manual operations, in which pharmacy technicians worked inside laminar-flow hoods to fill parenteral solutions coming from sterile filtration into intravenous (IV) bags or syringes. Now, Nephron is moving to robotic systems inside of the laminar-flow hood to perform these fill/finish operations. The company worked with the University of South Carolina (UofSC) and Clemson University in two separate projects to custom design robots for this application. In April 2021, Nephron validated the UofSC system and began commercial production, says Lou Kennedy, CEO of Nephron. A second robot is already being built, and more are planned. “We’re producing drugs on FDA’s drug shortages list, and this 503B space is growing,” she says. Robotic systems will improve productivity, reduce the burden of repetitive physical work for operators, and provide better accuracy and precision. Future projects will seek to increase speed of the robots to obtain higher throughput.

In addition to being used in commercial production at Nephron, Kennedy would like to see the robotic systems licensed to hospital compounding facilities. “What I love about both the Clemson and UofSC projects is that as we collaborate with both undergraduate and graduate students, we’re helping develop future industry employees,” says Kennedy.

Although a common fear is that robots will eliminate people’s jobs, Kennedy says this concern is unfounded. “Robotics is not eliminating people; it’s teaching people to have new skills to operate automation,” she notes. “Operators need to learn how to service the robot and work with it, to solve a jam or replenish components, for example. Operators are also needed for quality functions.”

Kennedy notes that Nephron sees a need for more pharmacy technicians, and the company works closely with local schools to help develop the future workforce. For example, Nephron built a sterile compounding lab on the nearby UofSC campus that is used to train pharmacy students at the university as well as two-year students from the local technical college in using robotics in sterile compounding.

Both developing an understanding of how robotics works and specific training with the equipment and its functions are key, adds Fraatz. “It is a new approach, which means trust needs to be gained, starting from education and understanding, so people can appreciate the purpose of robotic automation. Once they believe in the purpose, they can grow their familiarity and comfort with it.”

1. FDA, “Information for Outsourcing Facilities,” 

2. Exyte, “ISPE’s 2019 Facility of the Year Award for Operational Excellence & Facility of the Year Overall Award won by partners Exyte and Kantonsapotheke Zurich,” Press Release, Oct. 30, 2019.

Articles

Sterile manufacturing of small batches, in facilities including hospital compounding pharmacies and 503b outsourcing facilities, benefits from automation.

Robotic Automation Boosts Efficiency and Quality in Drug Compounding

On April 20, 2021, FDA released redacted details from an inspection at a manufacturing site producing the COVID-19 vaccine (1). The inspection report indicated a failure to investigate a deviation that was already recorded in the system, but not thoroughly investigated.

Inadequate investigation and lack of root-cause analysis tends to be a common observation cited by regulators, and this report underscores the crucial need to perform a critical function where traditional methods fall short. These are complex problems that require enablement beyond the traditional training, standard operating procedures (SOPs), and quality management systems. Although enterprises are actively exploring technologies and investing to improve results, increasingly there are analytics without insight, process management without process improvement, and investments that will deliver value in the future, but not today. This article discusses three ways quality organizations can move the needle on these challenging problems.

As organizations continue to promote data-driven decision-making, it is still hard to come by important data-driven insights. This challenge can be due to a variety of reasons, but three issues often rise to the top.

First, the most basic prerequisite is the availability of reliable data. Quality professionals deal with a significant amount of data from an increasingly large number of sources. Yet, quality data platforms in most organizations can be limited when compared to other areas, such as commercial or finance. Key to powerful insights is the ability to integrate multiple datasets. To effectively investigate a product complaint, you will need to review where the product was manufactured, packaged, and distributed, as well as current inventory levels and any quality issues associated with the batch. This information will come from a variety of systems, including quality management systems, enterprise resource planning, manufacturing execution systems, and laboratory information management systems.

Additionally, there must be the ability to drive advanced analysis beyond traditional reporting and analytics. In addition to technical capabilities, the skillsets necessary can be rather unique. Data scientists with quality backgrounds can be difficult to come by, and there is almost always a steep learning curve for both analytics and the business teams.

Third, and in the author’s opinion, one of the most important is the operating model. How do you work on your data? How do your analytics and business teams collaborate and test various hypothesis quickly? Increasingly, there is a trend toward data and insights as a service. While data are assets, they only start to generate value when you turn them into critical insights in a timely fashion. Working with a partner can help accelerate that process.

Another common issue that impedes a quality team’s performance is the nature of certain tasks: collecting and analyzing hundreds of data points across systems, documenting results, and preparing reports. Manual handling not only introduces room for error, but it is time-consuming—consider the manpower spent on annual product quality review (APR/PQR).

Another classic example is monitoring of chemical, manufacturing, and control (CMC) compliance. Certain types of change controls have regulatory implications and can impact product release in a market. Compliance creates a significant overhead for batch disposition teams, because these regulatory assessments are often performed manually, and the market implementation constraints must then be calculated manually as well. This process is another example where assisted automation and cross-system process orchestration can be useful. Automation of APR, field alert reports, and lot acceptance protocols, as well as various steps in the batch disposition process are examples of processes that can benefit from automation.

Enable collaboration beyond quality agreements

There is a rising trend in leveraging contract service providers to support the diverse needs in the industry. Thus, the capability to effectively enforce quality agreements will also need to evolve to monitor compliance. Often the data are exchanged manually with vendor quality managers, and latency tends to be an issue. Deeper collaboration will require the ability to exchange data and monitor protocols per the agreements, including direct system integration, collaboration portals, and tools that enable batch traceability throughout the process.

Quality lapses are not uncommon, despite rigorous training and SOPs. In the author’s experience, a digitized, quality-focused platform to help investigate and resolve quality issues will be a competitive advantage for pharma manufacturers.

Shahid Manzur is principal, Consulting, EY, shahid.manzur@ey.com

Automated systems help detect and resolve quality issues.

Best Practices for Pharma Manufacturing Quality Teams

Prefilled syringe innovations increase patient and caregiver safety and efficiency and reduce waste of product and packaging materials. “Since it is already packaged ready for the injection, the prefilled syringe saves time and avoids unneeded handling prior to the actual application, minimizing the risk of the injection errors, dilution errors, or non-sterility issues [that are a risk in] multi-dose containers,” explains Wenzel Novak, global senior director of business development at Gerresheimer Medical Systems. Novak estimates that prefilled syringes currently account for 10–15% of the parenteral market and anticipates rising demand.

“If you look at the top 40 injectable products, all are being used with prefilled syringes,” reports Dr. Nicolas Brandes, director of product management, Polymer Prefilled Syringes and Vial Containment at West Pharmaceutical Services.

Prefilled syringes can be made of glass or plastic such as cyclic olefin polymer/cyclic olefin copolymer (COP/COC) or polypropylene (PP). Glass dominates in most markets. Novak predicts, however, that the share of co-injection-molded COP/COC prefilled syringes will grow from 2% to more than 5% during the next decade.

“We have seen more approvals for products in plastics especially during the past five years,” reports Brandes. He notes plastic syringes often are chosen for specific applications such as contrast imaging agents, hyaluronic acid, and Botox as well as for products that are sensitive to silicone oil. Plastic syringes also function well in auto-injectors.

According to Novak, about 60% of prefilled syringes are staked-in needle syringes, but there are considerable regional variations. The most common prefilled syringes are 1-mL long and 1-mL short. The most prevalent applications include anti-coagulant (glass 1-mL long), vaccines (glass 1-mL short), and isotonic solutions where PP is the material of choice. “With the existing COVID-19 challenge, a significant increase in vaccines is expected worldwide,” says Novak. This growth will stem from COVID-19 vaccines as well as heightened interest in established vaccines (e.g., flu).

Prefillable syringes are delivered as bulk goods or ready-to-fill (RTF). Gerresheimer’s bulk syringes are provided as unsterilized glass bodies in flat (Rondo) trays or customized packaging designs (e.g., bags). Its Gx RTF syringes are presented as washed, sterilized RTF components to pharmaceutical and contract manufacturing operations and are available in glass or plastic. Fill volumes range from 0.5 to 5.0 mL, with the most common volumes falling between 0.5 mL and 3.0 mL.

Innovations from suppliers accentuate the ease-of-use attributes of prefilled syringes and focus on adding sizes (particularly for larger volumes), reducing waste, and patient and caregiver comfort and safety.

Gerresheimer has expanded its range of prefillable polymer syringes for sensitive biologics, biosimilars, and biobetters to include a Gx RTF ClearJect COP needle syringe, 1.0-mL luer lock.

At West Pharmaceutical Services, line extensions include insert needle syringes (the plastic version of a staked needle glass syringe) and more needle sizes and product volume options. “In the past three to five years, we have seen more approvals in the larger 2.5-mL format,” reports Brandes. The larger volume reduces the number of syringes needed per dose and improves efficiency and comfort. There’s a trend toward finer needles too. “Smaller, thinner needles mean less pain,” he explains.

User-friendliness is the goal behind a collaboration between Gerresheimer and Stevanto Group whereby Stevanato supplies its ITC twist-off closure system for Gerresheimer’s Gx RTF luer lock syringes. The integrated seal cap consists of an elastomeric component, which is available in different formulations, and a rigid, translucent polymer cap. Advantages include greater stability and shelf-life protection versus traditional luer cone systems (1).

Prefilled syringes offer sustainability benefits by eliminating multi-dose vials and related production and handling as well as product waste associated with leftover product. Still, says Brandes, “there’s a lot of room for improvement. Current systems create a lot of waste.” But efforts are being made to reduce scrap rates and to recycle tubs that hold nested containers during the fill/finish process. 

To meet the priority of product safety, suppliers seek designs to prevent needlestick injuries and to protect product quality by minimizing particulates and eliminating product interaction with tungsten or silicone residues. For tungsten-sensitive products, Gerresheimer Biological Solutions offers a metal-free manufactured syringe. With this patented technology, the pin used for conical shaping is made of a ceramic rather than tungsten or another metal.

Silicone oil is commonly used to facilitate syringe performance but can cause aggregation and particulate problems for sensitive biologics. “There’s a push by ophthalmologists and regulatory bodies to move away from siliconized formats,” reports Brandes. “Some patients have reactions to silicone, and over time with repeated injections, the material can accumulate [in the eye],” he explains.

One silicone-free option combines ImproJect plungers from W.L. Gore & Associates with syriQ BioPure silicone-free syringes from SCHOTT. The system opens the door for many sensitive products to move into the prefilled syringe format. Until the advent of a silicone-free design, “Pharmaceutical manufacturers seeking to avoid silicone-induced aggregation and sub-visible particles have had to choose vials even when they wanted to offer other delivery options,” said Christiane Gumera, product specialist at W.L. Gore & Associates. Careful attention to syringe geometry and dimensions of the syriQ BioPure syringes helps ensure a consistent gliding force and injection duration over the shelf-life of the product and maintains container/closure integrity without the use of silicone. Ultra-low tungsten residuals and minimal cannula adhesive residuals further reduce the extractible profile and the risk of container/drug interactions (2). 

To prevent potentially hazardous accidental needlesticks and comply with regulations in various parts of the globe, some syringes like Gerresheimer’s InnoSafe product incorporate a pre-applied, passive safety device. With the pre-applied device, there’s no need for post-filling assembly equipment or for healthcare professionals to install a guard before an injection is given. Advantages include improved compatibility with auto-injectors and a completely hidden needle that gives patients with needle-phobia a better experience. The design also prevents accidental reuse and runs on existing fill/finish lines without any additional equipment or process steps.

Finally, COVID-19 has spurred the development of prefilled syringes, particularly with regard to low-temperature storage. Brandes predicts, “Right now all COVID-19 vaccines are in vials, but in the next two to four years we will see a novel type of syringe that handles -80 ºC.”

1. Stevanato Group, “Stevanato Group Sings an Agreement with Gerresheimer to Provide Its Integrated Twist-off Closure System Solution, ITC, for Gx RTF Syringes,” Press Release, Oct. 6, 2020,

Glass Syringe System Reduces Injection Force without Silicone

Innovations in glass and plastic syringes reduce waste and increase safety. 

Prefilled Syringes Meet Growing Demand

Highlights:
Robotic Automation
Manufacturing Quality
Prefilled Syringes


Equipment and Processing Report 06-16-21

Robotic Automation Boosts Efficiency and Quality in Drug Compounding

Best Practices for Pharma Manufacturing Quality Teams

Prefilled Syringes Meet Growing Demand