Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

	The Global Health division of the Bill and Melinda Gates Foundation is seeking solutions for health problems, such as infectious diseases, that impact the developing world. One of the challenges is identifying drug delivery forms to compensate for the lack of infrastructure in these regions. “The lack of healthcare providers means there is a need for simple delivery to avoid mistakes,” explained Niya Bowers, senior program officer for Chemistry, Manufacturing, and Controls in Global Health & Integrated Development, Gates Foundation (1). “Another problem is poor access and a limited supply chain; the last mile is often carried by person, animal, or motorcycle on poor roads. Rugged, lightweight, and compact products are needed. Combination products also help so patients don’t have to travel to the clinic frequently. Drug stability is also a challenge due to the lack of a cold chain in many areas.” 

	Solutions must be both inexpensive and protect drug quality, added Bowers. The Foundation funds research programs with various partners. Of the 60 programs in their pipeline, 40% are complex solid oral delivery forms, not just simple tablets. For example, a long-acting oral drug for malaria prevention was developed in Dr. Robert Langer’s laboratory at the Massachusetts Institute of Technology using funding from the Gates Foundation and is being further developed for other potential uses at a spin-off company called Lyndra (2). Another example is a long-duration implant for HIV prevention. At the end of 2016, Intarcia received funding from the Gates Foundation to develop an anti-HIV prophylactic therapy using its Medici Drug Delivery System, which is a matchstick-sized, osmotic mini-pump implanted under the skin (3).  

	According to the Gates Foundation, these and other innovations could reduce and eventually eradicate infectious diseases such as malaria. The Foundation has committed nearly $2 billion in grants to combat malaria and more than $1.6 billion to the Global Fund to Fight AIDS, Tuberculosis, and Malaria (4).

	1. N. Bowers, “Leveraging Modern Manufacturing for Global Health-Is this Possible?” presentation at IFPAC (North Bethesda, MD, 2018).
	2. MIT, “New Capsule Achieves Long-Term Drug Delivery,” Press Release, Nov. 16, 2016.
	3. Intarcia, “Intarcia Secures Second Close of the Series EE Equity Financing for an Additional $206M; As Part of the Financing and a New Strategic Initiative, Intarcia Now Aims Its Medici Technology Towards Preventing HIV,” Press Release, Dec. 29, 2016.
	4. Gates Foundation, “Malaria: Strategy Overview,” 

www.gatesfoundation.org/What-We-Do/Global-Health/Malaria


	Vol. 42, No. 10
	October 2018
	Page: 18

	When referring to this article, please cite it as J. Markarian, "Drug Delivery Innovation Funded by the Gates Foundation," 

	Jennifer Markarian is manufacturing editor for 

Articles

The Global Health division of the Bill and Melinda Gates Foundation is seeking solutions for health problems, such as infectious diseases, that impact the developing world, including identifying drug delivery forms to compensate for a lack of infrastructure in these regions.

Drug Delivery Innovation Funded by the Gates Foundation

The pharma industry is increasingly focusing on patients as it considers drug development. Both innovative dosage forms, such as implantable drug–device combination products, and novel manufacturing methods, such as three-dimensional printing, are creating opportunities for solving drug-delivery challenges.

	Interest from both pharmaceutical companies and medical device companies in developing drug-device combination products, such as drug-loaded implants for local delivery, is growing. Device makers in this arena typically seek to add a drug functionality to a device, such as a steroid-eluting pacemaker lead or an antimicrobial-eluting catheter, notes Jim Arps, director of Pharma Services at ProMed Pharma, a contract manufacturer of polymer-based, drug-releasing dosage forms and combination device components. Pharma manufacturers, on the other hand, are typically looking for a drug-delivery format, particularly for controlled release. “The beauty of these systems is their capability for long-term, consistent release,” says Arps. 

	Drug-loaded implants can improve patient compliance by reducing dosing and side effects.  “Side effects are minimized because the drug is delivered at the site of action and does not have to travel through the many natural barriers in place in the human body (e.g., stomach and other organs), and dosing can be reduced because the implants deliver the dose over a long period of time (e.g., weeks or months) as opposed to hours for oral dosage forms,” says Tony Listro, vice-president of Technical Business Development at Foster Delivery Science. 

	One of the commercial uses for drug-loaded implants is ocular drug delivery; ocular indications are difficult to treat with oral dosage forms, and the eye itself has many barriers to protect it from topical treatment, notes Listro. 

	Approved uses are expanding into other areas. Titan Pharmaceuticals, for example, produces the Probuphine (buprenorphine) Implant, a six-month subdermal implant for long-term maintenance treatment of opioid addiction that was approved by FDA in 2016. The product is being commercialized by Titan in the United States and, upon approval by the European Medicines Agency, will be commercialized in Europe and certain other territories by Molteni Farmaceutici of Italy. The company says that the proprietary ProNeura implant technology has the potential to be used in developing treatments for many chronic conditions such as Parkinson's disease, Type 2 diabetes, hypothyroidism, and others for which consistent, around-the-clock dosing is important. 

	Some of the earliest commercial drug-loaded implants were contraception products that are matchstick-sized rod-shaped implants injected subcutaneously into the arm, where they release the drug for multiple years and then are surgically removed. For years, researchers have hoped to develop biodegradable implants that would eliminate the need for surgical removal. 

	Most recently, Hera Health Solutions, a start-up out of the Georgia Institute of Technology, is developing proprietary, biodegradable implants for extended-release drug delivery using existing generic drugs in combination with FDA-approved structural materials, notes company cofounder and CEO, Idicula Mathew. All of the company’s potential products use bioresorbable excipients and are intended to eliminate the need for an implant removal procedure, and the company’s biodegradable contraceptive arm implant, Eucontra, is currently concluding 

testing. The company’s proprietary manufacturing process creates a layered drug-excipient matrix that erodes over a long period of time and retains its shape, strength, and flexibility, notes Mathew.

	Drug-loaded devices deliver controlled release of a drug either by diffusion or by an erodible matrix. “In diffusion-controlled drug delivery, the polymer matrix remains intact while the drug is gradually deployed to the therapeutic site, either by encapsulating the drug in a polymer shell or coating, or by distributing the drug throughout a non-degradable (i.e., biodurable) polymer matrix,” explains Listro. “Erodible matrix implants are produced through the encapsulation or distribution of the drug in an erodible polymer, such as a water-soluble or bioresorbable polymer. As the polymer erodes in the body, the drug is released.”

	Biodurable polymers that can be used as matrices for drug-loaded devices include low density polyethylene (LDPE); ethylene co-vinyl acetate (EVA), at various levels of vinyl acetate; polyurethanes; and silicone. Polymer excipients used for hot-melt extrusion of oral dosage forms (e.g., polyvinylpyrrolidones, cellulosics, and acrylics) can also be used. Bioresorbable polymers include polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polydiaxanone (PDO), and others. PLA and PGA are commonly used, but they degrade by hydrolysis into acidic byproducts; other polymers that have enzymatic degradation pathways may work better with certain APIs, notes Arps. 

	Drug-loaded implants are typically manufactured by mixing the API into the excipients before forming the final shape, using extrusion to make simple shapes (e.g., fibers, monofilaments, rods, tubes, sheets, or other profiles) or injection molding to make either simple or complex, three-dimensional shapes. An alternative method sometimes used with silicones is to form the implant and then infuse it with the drug.

	High-precision injection molding creates tight dimensional tolerances (controlled within a few microns) and good surface finishes, says Arps. “In addition to complex shapes, such as stents, injection molding can be beneficial for simple shapes, such as rods, especially if the material is brittle and difficult to cut. A drawback for rods is that molding may be a little slower in overall throughput and produce more waste material than extrusion,” Arps adds.  

	Coextrusion can be used to make multi-layer shapes, such as a drug core with a rate-controlling membrane. “The drug-loaded layer can also be the outer layer with a [unloaded] polymer used on the inside as a strength member for explantation,” adds Listro. The type of extrusion equipment used can be selected depending on the formulation (i.e., the processing conditions it can handle) and the tolerance needed in the final part, with a variation of less than 10 microns possible. 

	Understanding the physicochemical characteristics of the API (e.g., melting point, degradation temperature, flow characteristics) and any API-excipient interactions is important in developing the formulation and optimizing the manufacturing process. Twin-screw extruders used for mixing the API and excipient can be optimized for a formula, so getting a formulation to work can be more of an engineering exercise, notes Listro. Choosing an appropriate feeder, feeding point, screw design, and temperature profile, for example, are important variables. 

	Sensitivity of the ingredients to processing temperatures, shear energy, and moisture are other considerations. “Some silicones can be mixed and cured at room temperature. Thermoplastic polymers are processed in the range of 100–150 °C, and the API will need to be able to handle those temperatures for a short time period,” says Arps. He adds that some degradable materials may have moisture sensitivity and require processing under low humidity conditions to avoid degrading the polymer, which would affect the drug release. 

	While extrusion and injection molding are traditional methods of forming polymer devices, three-dimensional printing (3DP) is an emerging manufacturing technology being used to produce medical devices and, since the 2015 approval of Aprecia Pharmaceuticals’s Spritam (levetiracetam), solid-dosage drug forms as well. 3DP, also called additive manufacturing, is a category of manufacturing methods that are used to form a product by building it layer-by-layer using digital control. 3DP lends itself to customization of complex products, and it has been described as a way to allow personalized and even on-demand medicine, once requirements such as quality control and safety testing can be achieved. 

	3DP is also being investigated as a manufacturing method for microneedles used in transdermal patches, in which the ability to quickly change geometries could be useful for prototyping, and for making complex, delayed-release capsule shells that could be used in clinical trials (1). 

	Aprecia, which manufactures what is currently the only FDA-approved 3D-printed drug, is employing 3DP for cGMP manufacturing of solid-dosage drugs marketed through the conventional, FDA-approved regulatory path. Tim Tracy, CEO of Aprecia, comments that the greatest advantage of the process is “the ability to produce novel dosage forms that are not possible by traditional tablet and capsule processes. 3DP allows us to produce unique shapes, varying degrees of dispersion and disintegration, customization of dosage, and the potential for flexibility and combining multiple drugs.” The company uses its ZipDose technology to produce a tablet that combines the benefit of rapid disintegration in the mouth with taste-masking ability and high drug load; Spritam tablets, for oral suspension for treatment of seizures in adults and children with certain types of epilepsy, provide an easy-to-swallow alternative to existing, large pills. The technology could also be used to make extended-release forms. In December 2017, Aprecia announced a partnership with Cycle Pharmaceuticals to develop and commercialize orphan drugs using ZipDose technology, and an initial product is in the development and formulation stage. 

					To read an interview with researchers from the University College London and FabRx on their work in 3DP, go to 

www.PharmTech.com/considering-3d-printing-solid-dosage-forms

	FabRx, established in 2014 by researchers from the University College London, is focused on optimizing 3DP technology for manufacturing solid-dosage drugs and identifying drugs that would be most suitable for using 3DP for personalized medicine. “3DP offers many opportunities to researchers by creating customized formulations that will be useful in clinical trials for testing new drugs, in the treatment of rare diseases (where the number of patients is low and costs are high), or in treatments where doses change frequently depending on therapeutic needs (e.g., narrow therapeutic index medicines),” says Alvaro Goyanes, director of Development at FabRx. Ensuring that this novel manufacturing process can accurately produce quality drugs is crucial, notes Goyanes, who adds: “We are working to integrate a quality control system in the printer to enable both the production and real-time release of medicines at the dispensing point. In the near future, we envision that hospitals and pharmacies will have 3D printers on-site, enabling healthcare professionals to print out tailor-made medicines on-demand.” 

					One method of three-dimensional printing (3DP), called fused filament fabrication or fused deposition modeling (FDM), uses a continuous filament of thermoplastic polymer, which is heated to its melting point and then layered to form the final shape. Foster Delivery Science produces monofilaments of custom formulations for use in 3DP for pharma applications. The API and excipient are mixed in a twin-screw extruder, and then drawn into a monofilament, which is wound on a spool. Implementing methods to control tension are key to producing a tight tolerance product, and feedback control systems can be used to control dimensions by automatically adjust process parameters, explains Tony Listro, vice-president of Technical Business Development at Foster Delivery Science. 

					Leistritz, which manufactures twin-screw extrusion systems for pharmaceutical and polymer applications, installed a filament production system in its process laboratory that can be used to develop new filaments and formulations. According to the company, formulations can be modified "on the fly" for rapid sampling of filaments with different formulation percentages, and a sample can be produced every 10 minutes (1).

					1. Leistritz, “Leistritz Extrusion Expands NJ laboratory: Installs ZSE-3D Filament System Installed for Pharmaceutical, Nutraceutical, and Medical Device Development,” Press Release, Aug. 27, 2018. 

	3DP could be a disruptive technology in pharmaceutical manufacturing. Once technical and regulatory issues are addressed, it could enable the development of more personalized therapies. How soon this technology advances and to what extent it might replace traditional manufacturing remain to be seen. Considering how 3DP has found a niche in other manufacturing industries, however, pharmaceutical manufacturers should monitor 3DP developments closely. 

	1. A. Procopio, “3D Printing for Dosage Form Design and Delivery,” presentation at IFPAC (North Bethesda, MD, 2018). 


	Vol. 42, No. 10
	October 2018
	Pages: 16–21

	When referring to this article, please cite it as J. Markarian, "New Dose Forms Focus on the Patient," 

Innovative technologies, such as drug-loaded devices and 3D printing, enable advances in implantable devices and other novel dosage forms.

New Dose Forms Focus on the Patient

Twin-screw extruders, which have found commercial use in making amorphous solid-dispersions for improving drug solubility and in loading drugs into polymers that can be shaped into drug-delivery devices, are also emerging as equipment for continuous wet granulation. The same machine can be used for wet granulation as for hot-melt extrusion, but the hot-melt extrusion process requires external barrel heating to raise the temperature above the melting point (T

) of the polymeric excipient, while granulation takes place at lower temperatures, below the excipients’ T

	The ongoing development and commercialization of continuous manufacturing for oral solid-dosage (OSD) pharmaceuticals is creating a growing opportunity for continuous granulation processes, and twin-screw granulation (TSG) is already being used in commercial continuous manufacturing. Some continuous systems, such as GEA’s ConsiGma and Glatt’s MODCON, for example, use TSG. Twin-screw extruders are available in models designed for pharma processing from manufacturers including Coperion, CW Brabender, Leistritz, Steer, Thermo Fisher Scientific, and others. 

	The primary benefit of TSG is that the extruders are intended for continuous manufacturing, notes Dirk Leister, technical marketing manager, process and pharma extruders for Thermo Fisher Scientific. “Extruders are time-based production-the same equipment can be used for different amounts of material. One can potentially use the same extruder for R&D as for production, by simply running longer. Or, the process can be scaled up to a larger extruder for higher throughput.” Thermo Fisher’s Pharma 11 (11-mm diameter) and Pharma 16 (16-mm diameter) twin-screw extruders are designed for both R&D and production. These extruders can be set up for both granulation and hot-melt extrusion, using conversion kits for the necessary hardware modification. Thermo Fisher recently introduced the Thermo Scientific Pharma 24 TSG, a 24-mm diameter twin-screw extruder dedicated for twin-screw granulation with a throughput rate of up to 70 kg/h. The extruder can be either integrated into a continuous production line or used as a standalone instrument for project development or small-scale production using either wet or dry granulation (1). The extruder has a 40:1 ratio of length to diameter that offers flexible adaptation for processing length, screw setup, and introduction of ingredients into the process. Minimal downtime is needed for cleaning, and online monitoring facilitates detection and segregation of out-of-specification product.

	In addition to flexibility of scale, continuous processes offer the potential for improved process control compared to batch processes and for on-line, real-time monitoring. The twin-screw extruder is considered a small-volume continuous mixer, and it creates a more uniform mixing history for more homogeneous distribution of drug, excipient, and binder (2).

	“Consistency is a big advantage,” notes Michael Thompson, professor in the department of Chemical Engineering at McMaster University in Ontario, Canada. “TSG can reduce lot-to-lot variation of the granulated product and reduces reliance on a specific seasoned operator in order to get the correct product quality by knowing when to stop the batch mixer.” TSG may need less binder or less water to produce equivalent granules to batch systems, which could reduce production cost. 

	How the primary variables in the TSG process affect product properties is relatively well understood at this point, although each formulation would need to be optimized. “Just about any formulation based on known pharmaceutical ingredients can be made into granules so long as the formulator has a working knowledge of the different techniques to ‘wet out’ the powders,” says Thompson. “I would always recommend to a company to study the binder-to-powder needs in each new formulation as if starting from scratch, but the initial machine setup and operating conditions can be treated as relatively generic.” Scaling up from a small laboratory machine to larger production equipment poses more challenges, however. “One can’t truly know a process until it has run for several hours, with the machine heated up by mechanical rotation and the feeders having gone through several fill cycles to fully learn the bulk density of the process’s ingredients,” cautions Thompson. “A product made from a 20-minute lab trial doesn’t necessarily translate to a continuously operated production process.”  

	Process analytical technology (PAT) is a crucial part of understanding and controlling a continuous process, and in-line measurements are used in advanced process control strategies and in quality-by-design studies. Innopharma Technology’s Eyecon2, for example, is a direct optical imaging system that captures images of the granule particles and analyzes them in real-time. “In continuous processing, the particle analyzer can be used to monitor particle size after a twin-screw, a continuous drier, or a mill,” says Chris O’Callaghan, senior product manager at Innopharma.

	In a continuous system, data are needed for both feed-forward and feed-back control to maintain key parameters and attributes as close to an ideal setpoint as possible, despite some variation in the inputs and outputs of each process stage. “While feed-back control is critical in ensuring that deviations do not continue to grow unchecked, feed-forward control can enable compensation of upstream variations in subsequent processing steps to ensure that variations introduced in early stages can be partially or fully corrected in the final output material,” explains O’Callaghan.

	“By measuring particles after granulation, deviations in the measured size can be used to alter parameters of the twin-screw (e.g., liquid addition and screw speed) to correct for the variation in particle size, while the speed of a downstream milling step may be temporarily increased or decreased to more finely or coarsely mill the granulate currently entering, thereby maintaining a more consistent output particle size.”

	More work is needed to further develop different types of PAT for TSG, says Thompson. In the McMaster University laboratory, researchers are looking at ultrasonic acoustic sensors to see what information about properties exiting the twin-screw granulator, such as granule size and moisture content, can be measured. Eventually, the researchers hope to also identify technology that can monitor incoming powders, which can also have a significant effect on end properties. For example, the size of a binder particle is known to affect granule size in hot-melt granulation, but a supplier of binder material might not measure or report binder particle size or changes in grinding because they wouldn’t affect chemical properties, notes Thompson. It would be difficult to track a problem with off-spec granules back to the feed materials, and a formulator might mistakenly assume something inside the extruder had gone wrong. 

	Sensors that are already built into extruders can also be used as PAT signals. The torque of the extruder drive motor, for example, should stay constant during steady-state processing, and can be used in process control, notes Leister. 

	TSG has been found to be a useful unit operation for high drug load formulations that inherently have poor flow properties. These formulations would not be suitable for traditional dry granulation, explained Steve Pafiakis, senior research scientist at Bristol-Myers Squibb, in a presentation at the Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar (3). Pafiakis is researching TSG for his doctoral thesis at the New Jersey Institute of Technology in close collaboration with the Polymer Processing Institute (PPI). For the formulations Pafiakis is studying, challenges include high drug loading, low bulk density, and cohesive blends that result in extremely poor flowing input material. These material properties have beenshown to affect the manufacturability of the TSG process by causing build-up inside the extruder. To mitigate these effects, several screw configurations were evaluated to investigate whether the formulation could be successfully processed over an extended period of time, which is a requirement for any continuous manufacturing process. An initial screw design imposed high shear and lead to barrel fouling, but a less shear-intensive screw configuration, along with barrel cooling near the kneading zones was found to be acceptable. Pafiakis explained that understanding the fundamental mechanism for TSG-that frictional energy dissipation (FED) is the driver for granule growth in the extruder and the heat generated is from the relentless rubbing of particles in the compacted state in the kneading section-was important. This set-up controlled the heat generated by FED and led to the desired granule attributes.

	The food and polymer industries successfully transitioned from batch to continuous processing using twin-screw extruders fifty years ago, and use of TSG is expected to continue to evolve in the pharma industry, say experts (2). 

	1. Thermo Scientific, “New Twin-screw Granulator Helps Maximize Throughput in Continuous Drug Manufacturing,” Press Release, June 25, 2018.

	2. N. Kittikunakorn, et al., “Processes, Challenges, and the Future of Twin-Screw Granulation for Manufacturing Oral Tablets and Capsules,” AAPS News Magazine, March 2018. 

	3.  S. Pafiakis, “Twin Screw Granulation: A Case Study for Enabling an Adaptive Study Plan,” presentation at the Leistritz Pharmaceutical-Nutraceutical Extrusion Seminar (Clinton, NJ, 2018). 

	When referring to this article, please cite it as J. Markarian, "Considering Twin-Screw Granulation," 

A twin-screw extruder can be used as a continuous wet granulator.

Considering Twin-Screw Granulation

	When handling highly potent materials in oral-solid dosage (OSD) manufacturing, appropriately designed equipment and safe practices are crucial for protecting the operator from exposure and for protecting the drug product from potential cross-contamination. Containment of airborne particles (i.e., dust) is important when producing capsules and especially when making tablets. 

spoke with Jörg Stadelmann, head of Technical Sales at Bosch Packaging Technology, about some best practices in this area.

What are the primary considerations for designing containment in OSD manufacturing facilities? Are there different considerations for capsule filling vs. tableting? 

Containment in OSD facilities is all about maintaining the required occupational exposure limit (OEL) during production, cleaning, and maintenance. First of all, a safe product transfer into the machine is essential, as well as the transfer of the finished product from the machine to the following peripheral equipment.

	During production, safe sampling and troubleshootingare important. Sampling can be done, for instance, by integrating split valves with a washing cap or with a suction point on the active valve to minimize the so-called ‘ring of concern,’ whichis the ring on the split valve between active and passive containment parts of the machine. 

	The use of endless hose ejection systems, glove ports, rapid transfer ports (RTP), and H13/H14 high-efficiency particulate air filter systems are further options that are important not only for sampling but for the complete containment process. 

	To uphold the required OEL during cleaning between and at the end of batches, the machine can be accessed via gloves, while the remaining product can be pre-cleaned with an integrated suction hose. Fine mist from the spray nozzles binds airborne particles. Manual or fully automated washing-in-place (WIP) processes can be used.

	As far as maintenance activities are concerned, it is important to seal the drive section room, for example through bellows, double, or air-flushed seals, as well as negative pressure in the production room.

	The more a machine is automated, the less operator intervention is required, which naturally reduces the risk of exposure to highly potent products. With some of our fully automated capsule filling machines, intervention is not required at all, apart from very rare interventions. Bosch has also developed a ‘closing force detection’ to ensure that only completely closed capsules are transferred into the good capsule ejection area, so that the contents of open capsules will not contaminate this area.

	In general, the main considerations for containment capsule filling and tablet pressing are identical. However, tablets will create additional dust before coating due to additional transportation and handling processes. Hence, the processes following tablet compression must be designed carefully to avoid contamination of the environment.

: What types of engineering controls are available? 

Engineering controls include monitoring of the negative pressure in the cabin and the overpressure of the inflatable seals. Redundant systems can be designed in many different ways; two examples are a combination of inflatable and static seals and establishing negative pressure in the production cabin by an exhaust system and vacuum pump. In the event of a system failure, warnings should be issued. Before production starts, the production cabin must be checked for leaks, and a glove testing unit performs pressure decay tests of the gloves before the batch starts. In any case, a room contamination control process must be established, which includes cleaning procedures, swabbing, personnel protective equipment (PPE), and personal monitoring. 

What are some best practices for handling dust created during manufacturing with highly potent materials?

My main credo would be to avoid or at least minimize dust as much as possible. A ‘no cap, no fill’ function on the dosing stations definitely helps. Otherwise, additional suction points in the machine chamber and integrated suction hoses for pre-cleaning after batch completion are a good option. One of the most important factors of containment machine design is negative pressure in the production chamber. At Bosch, we have created a sophisticated zone concept with pressure barriers during production. 

	Hygiene and cleaning ability are also important factors, which can be influenced by the choice of surface material and cleaning media. Wetting (i.e., creating fine mist in the machine chamber to bind airborne particles before opening the equipment) is another possibility to reduce dust development, as well as surface pre-cleaning by WIP. And, most importantly, the use of suitable peripheral equipment (e.g., dedusters) can help a lot. It is extremely important to always check the entire system for adequate product handling.

What are some best practices for containment during sampling? 

Sampling is a crucial step that requires systematic monitoring by the technical staff. For sampling there are both manual and automated samplers.

	With our Bosch GKF capsule filling machines, we use an integrated in-process control (IPC). Samples are taken automatically, weighed, and transported to a sample container-of course, all contained. The weight results are recorded in the batch report.

	There are several possible systems that can be used for containment during sampling. For instance, an endless hose system offers the possibility of crimping or cutting off during production. Other options are a contamination-free removal of the complete sampling system, rinsing the complete system at the end of production, or attaching a split-butterfly system.

What are some best practices for cleaning and maintenance of equipment in containment? Can you describe best practices for manual cleaning and explain when automated, wash-in-place systems should be used? 

After the end of a batch, the first step is preparing the machine for cleaning. Glove ports allow the operator to access the machine through the closed machine doors. The safe transfer of size parts out of the production chamber can be done via RTP, while the remaining product is pre-cleaned with an integrated suction hose. Fine mist from the spray nozzles binds airborne particles. 

	If products with an OEL < 1 µg/m³ are manufactured, a WIP process is mandatory. It should therefore also be considered to wash the interfaces, pipe work, and peripheral equipment. Apart from occupational safety, it is paramount that product safety is considered and cross-contamination from one product to another is avoided. For this reason, validated cleaning procedures must be performed, monitored, and documented. 


	Vol. 30, No. 10
	October 2018
	Pages: 26–27

	When referring to this article, please cite it as J. Markarian, "Optimizing Containment in OSD Manufacturing," 

Engineering controls and safe practices for containment protect both operator and product in tablet and capsule production.  

Optimizing Containment in OSD Manufacturing

	Three-dimensional printing (3DP) is also known as additive manufacturing because these technologies create a part by adding material layer by layer, guided by a 3D computer model. Various types of 3DP are being used in manufacturing in industries ranging from aerospace to medical devices, and some of the 3DP technologies are being explored for use in manufacturing of oral-solid dosage (OSD) drugs and drug-device combination products. 

spoke with Abdul Basit, professor of Pharmaceutics at the University College London (UCL) School of Pharmacy, and Alvaro Goyanes, director of Development at FabRx, which was started up in 2014 by researchers from UCL, about their 3D-printed tablets they call printlets and the different methods of 3DP that can be employed to manufacture OSD drugs. Basit is also one of the editors for a recently published book, 

What are the advantages of 3DP for drug manufacturing?

The possibility of easily creating 3D printed tablets (printlets) or medical devices just by modifying a digital file offers many opportunities. For example, by changing the object size or the infill (i.e., percentage of material inside the object), the mass of the printlet, and hence the dose of the medicine, can be flexibly altered. Conventional pharmaceutical manufacturing processes are inherently laborious, resource intensive, and dose inflexible. Indeed, there are limited commercially available dosages for certain medications, often requiring patients to split or crush their tablets to get the right dose. Instead, 3DP can enable the efficient design and preparation of small batches of medicines, comprising an individualized dose, shape, and size for each patient. In turn, this technology could reduce the risk of medication errors and side effects, while improving treatment efficacy and adherence. Due to the compact and user-friendly nature of the 3D printers, it could be possible to integrate this technology into a hospital or community pharmacy setting, enabling on-demand medicine production on the front-line. This technology is likely to be transformative in pediatric medicine, in which the dose of medicines can change rapidly, depending on the age or weight of the child. Furthermore, it is possible to combine two or more drugs into the same printlet, reducing the number of tablets that one person has to swallow, which is especially important in geriatric populations. Therefore, our aim at FabRx is to optimize the 3DP technology to enable the production of personalized medicines for each individual patient.

	We are confident that 3DP will cause a paradigm shift in the way that medicines are designed and manufactured, moving away from a ‘one-size-fits-all’ approach toward small-scale personalization. 3DP offers many opportunities to researchers by creating customized formulations that will be useful in clinical trials for testing new drugs, in the treatment of rare diseases (where the number of patients is low and costs are high), or in treatments where doses change frequently depending on therapeutic needs (e.g., narrow therapeutic index medicines). In the near future, we envision that hospitals and pharmacies will have 3D printers on-site, enabling healthcare professionals to print out tailor-made medicines on-demand. 

	The use of 3DP for customized medical devices has been widely explored for many types, including hip replacements, prosthetics, and even in dentistry. We are confident that in the future these devices will also incorporate drugs, such as antibiotics or anti-inflammatory drugs, which will help with the healing process and increase the success rate of these implanted devices. These devices can be tailored for each individual in terms of size and shape using a 3D model obtained from imaging techniques, and they can also be personalized in terms of the drug and the dose that they incorporate.

What are some of your current projects? 

We are identifying and formulating the most promising drugs for personalized medicine that could benefit from 3DP technology to be first on the market. At the same time, we are working to develop and adapt this technology for printing medicines, as well as integrate a quality control system in the printer, to enable both the production and real-time release of medicines at the dispensing point. We are also working in formulation development to ensure that the right formulations containing the right materials are produced, which can then be printed at the touch of a button. Furthermore, we are planning to conduct clinical trials and human studies to demonstrate that our technology is safe and fit-for-purpose.

	Not all 3DP technologies are suitable for medicines. We are screening which ones are suitable, testing them by printing medicines, and trying to bring them to the market as soon as possible. We need to employ technologies that can be adapted to use pharmaceutical-grade excipients and medicines and that will be safe. We also need to be able to completely control the quality of the 3D-printed medicine.

	We are focused on developing the world’s first pharmaceutical printer, because there are currently no printers adapted for these formulations. We are aiming to place the first printers within hospitals in two years, although we have started the first studies with patients in a hospital in June 2018. A critical factor centers around regulatory requirements; right now, it is not clear how the approval process will be constructed, if the printing process is going to be considered a manufacturing step (which has much higher control and regulation) or a compounding step (which is performed every day in hospitals with less strict regulation). As a company, we are scoping out which medicines could benefit the most from 3D printing and will demonstrate these formulations are safe within clinical trials, animal and human studies.  

What 3DP technologies are you considering for OSD drug manufacturing? 

We are evaluating a wide variety of 3DP technologies, in particular those that offer the best potential in developing better medicines, including selective laser sintering (SLS) and fused deposition modeling (FDM). Our novel FDM-type 3DP process involves a semisolid material being heated and extruded through a nozzle, which quickly solidifies on the build plate to create the designed printlet. 

	We are very excited by the use of SLS 3DP; the process is very simple and enables the production of printlets just by using a laser to bind a drug-powder mixture. It is not necessary to get a filament by hot-melt extrusion as in FDM technology, and depending on the materials that we select, we can get very fast or targeted release of the drug in specific regions of the gastrointestinal tract. Although SLS is more expensive than FDM technology, the costs are going down due to the development of new desktop printers.

Can you describe your stereolithography (SLA) process for drug-loaded devices? What are the pros/cons of this compared to extrusion? 

In SLA, the starting material is a resin that gets solidified by the action of a laser or light. This technology is fast; incorporation of the drug within the solution is easy; and the resolution is really high. We think that SLA could be the best approach for the manufacture of medical devices, where the resolution of the object is important (such as with stents). The main drawback of this technology is the use of excipients that are not GRAS (generally recognized as safe) approved by FDA. A lot of research is currently underway to overcome this drawback, and it is only a matter of time before the market will see new resins and polymers approved for pharmaceuticals, in the same way that they are approved for dental applications. 

	1.    American Association of Pharmaceutical Scientists, A. Basit and S. Gaisford, Eds., 

AAPS Advances in the Pharmaceutical Sciences Series 31 (Springer, 2018). 

3D printing is being explored as a manufacturing method for on-demand, personalized medicine.

Considering 3D Printing for Solid Dosage Forms

In aseptic and sterile drug fill/finish and inspection, automation can reduce or eliminate operator intervention, which reduces contamination potential and improves efficiency. Traditional, one-axis automation works well for high-speed processes, but multi-axis robotic arms offer repeatability with the flexibility to easily change the process or the type of container being filled. Technology advances have made robotic systems suited for aseptic processing and easy to operate. 

	While the pharma industry may be more familiar with robotics used in packaging operations, advances in technology, such as “near zero particle generating designs and complete tolerance to 

biodecontamination cycles with gaseous hydrogen peroxide” have made robotics compatible with aseptic manufacturing, explains Josh Russell, director of business development and technical sales at AST. 

	Today’s robotic systems are also easily reprogrammed for changes after the system is set up, without requiring a programming specialist on staff, say suppliers. Some platforms, such as those from AST and Vanrx Pharmasystems, are recipe-driven, and an operator inputs the recipe information-such as the type of container and volume to be dispensed-through a touchscreen interface. 

	Flexible and repeatable filling are becoming more crucial due to changes in the biopharma industry, notes Chris Procyshyn, CEO at Vanrx Pharmasystems. “The focus on targeted therapies for smaller patient populations creates a challenge for companies to produce a higher number of smaller batches into different container formats. Biologics, plus new modalities such as cell and gene therapies, are more complex and process intensive. The use of robotics is growing in response to these changes,” explains Procyshyn. 

	A potential drawback to robotic systems is running speed. “These systems aren’t yet designed to run 500,000 unit batches or produce 100 million units a year. But that’s not where the demand is anyway, and conventional systems weren’t meeting the need for small batch flexibility,” says Procyshyn. “If a company is making high-value drugs into multiple formats or sizes, they want a robust, repeatable process that reduces risk. That happens best with a closed robotic filling system.”

	“Traditional aseptic systems are proving to not be well suited to address these personalized therapeutic products because they lack the ability to efficiently produce low-volume, high-mix batches,” agrees Russell. “However, robotic systems that have recipe-driven operation and the ability to process syringes, vials, and cartridges on a single platform are an ideal solution.” In addition, more companies are finding that robotic systems give them the flexibility, ease of use, and sterility assurance they need to replace manual filling of clinical batches. 

	“From a staffing standpoint, automating these tedious and repetitive processes reduces the risk associated with precise dosing and employee fatigue, and automation can reduce scrap and re-work [compared to manual methods],” adds Walter Langosch, Global Business Development director at ESS Technologies. For example, the company’s TaskMate robotic syringe filler/capper, which was introduced in December 2016, replaces manual methods and can fill and cap up to 15 syringes per minute. 

	“We clearly see a high demand for robotics in aseptic filling,” says Sebastien Schmitt, Robotics division manager, North America, at Stäubli. One growing use is in automated compounding pharmacies in hospitals, in which robots can be programmed flexibly to produce drugs on demand, adds Schmitt. Robotics provide consistent performance, with less equipment inside an isolator, hence, reducing risk and facilitating maintenance. 

	Steriline Robotics, a spin-off company created by Steriline with Milan Polytechnic, produces aseptic filling machines primarily used in hospitals and in pharmacy compounding. “The machine we developed uses two robots cooperating to help pharmacies in targeted drug reconstitution for each patient, according to their specific prescription,” notes Federico Fumagalli, chief commercial officer at Steriline. 

	Steriline is focused on “zero-loss” aseptic filling systems that aim to increase production efficiency and reduce the waste associated with rejects using traditional automation. Their robotic system can, for example, identify a filled vial that is missing a stopper and send it to be stoppered during a second cycle, preventing the loss of that vial, says Fumagalli. Steriline’s systems run faster than some other robotic systems due to their artificial-vision system, reaching a filling speed of almost 100 vials/min, he says. 

	Nested vials have been available for more than five years, and the technology to optimally handle vials in this format is now catching up, says Russell.  In AST’s ASEPTiCell and GENiSYS aseptic filling and closing machines, six-axis articulated robots perform all the critical aseptic operations, including removing the tub from its sterile overbag, opening the tub, and denesting the containers (i.e., vials, syringes, or cartridges). After filling, the robot closes the containers almost immediately, resulting in less time that the sterile drug product is exposed to the aseptic environment. “The system is completely closed. It eliminates operator intervention and allows a completely aseptic fill,” says Russell. Depending upon the application requirements, the system can be used inside a restricted access barrier system (RABS), isolator, or laminar airflow hood. 

	The robotic system allows a streamlined deck that is easier to clean than traditional automation, explains Russell. Another advantage over fixed automation is that the robot has various pre-programmed “maintenance positions” where it is ergonomically positioned for operators to access the disposable fluid path and to perform other necessary aseptic tasks without violating basic “first air” principles. In addition, the robotic system enables a real-time fill-weight check. AST’s machine uses an in-process feedback loop to the filling pump for closed-loop control. In addition to the commercial-scale ASEPTiCell i100 line, a laboratory-scale line GENiSYS was introduced in October 2017 for small-scale filling for R&D (e.g., stability studies), for clinical production, and also for small-scale commercial production, such as cell and gene therapy. 

	A common use of robots in aseptic processing is to use a robot to replace certain operations, such as removing the cover from a nested container tub. Entirely rethinking the aseptic filling process, however, allows manufacturers to take full advantage of robotics. Procyshyn explains, “First, robots provide a highly repeatable production process. Using recipe-driven processes, they are able to produce multiple drug products at equally high quality levels into different containers. Second, robotic systems are agile and change quickly between vial, syringe, and cartridge formats. Robots can handle every type of container the same way if the containers and closures are nested, so there are limited change parts. Without traditional electro-mechanical components complicating the machine’s interior, decontamination cycles are much shorter too. Third, robots allow the design of gloveless isolators. A gloveless isolator can run much cleaner than a conventional isolator and be completely closed. [There are] no mouse holes, conveyors, glass-to-glass contact, or sortation bowls, which all create risks to the batch.” 

	Procyshyn notes that Vanrx Pharmasystems SA25 Aseptic Filling Workcell gloveless isolator technology is based on a standard design, which allows filling operations to be built faster than before (with lead times of less than a year) and in less space. The workcell design provides agility, with the ability for one machine to fill multiple container formats with minimal changeover times. “Gloveless isolator technology provides better aseptic assurance than conventional isolators or RABs,” adds Procyshyn. The workcells are entirely closed to the outside environment, and they also use single-use product-contact materials. 

	Contract development and manufacturing organization (CDMO) FUJIFILM Diosynth Biotechnologies announced in a May 23, 2018 press release that it was investing in the SA25 Aseptic Filling Workcell gloveless isolator technology as it expanded its gene therapy and viral vaccine fill/finish capabilities to provide services in support of late-phase candidates and commercial supply (1). Fujifilm highlighted the advantages of automated environmental monitoring and no glass-to-glass contact.  

	Vanrx Pharmasystems recently introduced a smaller-scale gloveless isolator system, theMicrocell vial filler, designed for rapid scale-out of personalized medicines, such as cell and gene therapies and immuno-oncology products, from clinical through commercial manufacturing. (2). The system replaces manual filling and small-volume filling machines in biosafety cabinets, RABS, or isolators, says the company. The Microcell can fill 2R-50R nested vials with toolless changeover and decontamination in 15 minutes. 

	PTI–Packaging Technologies & Inspection’s new robotic inspection system uses the company’s MicroCurrent High Voltage Leak Detection (HVLD

) to test the container closure integrity (CCI) of prefilled syringes. The E-Scan 665 tester is a fully automated system in which a six-axis robot picks and places rows of syringes from the nested trays into the HVLD

and returns good product to the tray and faulty product to a reject tray. The inspection equipment company chose to use robotic actuations for the automated system because of the complex and delicate component handling required, says Oliver Stauffer, CEO of PTI. Robotic handling can have throughput limitations and may not work for higher speed processes, he notes, but it is suitable for this application, in which a tray of syringes is checked in less than three minutes. “Robotic systems provide flexibility in handling and adjusting for different format types and sizes. Technical requirements can often be achieved by simply adjusting positioning with the same end-of-arm tool,” says Stauffer.

	Stäubli’s TX Stericlean series was the first robot introduced in 2008 for aseptic production areas, says the company, which reports that its new TX2 line of collaborative robots (i.e., cobots) are also a first for aseptic processing. The use of cobots allows glove boxes to be located next to the robot, so that the operator can intervene in the isolator without stopping the production process. The TX2 robots are Industry 4.0-compatible, in that they can collect production data and are capable of communicating with each other, reports the company.

	1.    Fujifilm USA, “Fujifilm Announces the Expansion of Its Fill Finish Services to Include Late Phase and Commercial Production of Gene Therapies and Viral Vaccines to Become an End-to-End Solutions Provider,” Press Release, May 23, 2018.  

http://www.fujifilmusa.com/press/news/display_news?newsID=881420


	2.    Vanrx, “Vanrx Microcell Wins INTERPHEX ‘Best in Show’ Award,” Press Release, April 18, 2018. 

https://vanrx.com/vanrx-microcell-wins-interphex-best-show-award/

	When referring to this article, please cite it as J. Markarian, " Robotics Solve Aseptic Filling Challenges," 

Pharmaceutical Technology APIs, Excipients, & Manufacturing 

Automated robotic arms manipulate nested trays and containers inside closed aseptic filling systems.