Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

  With the growing acceptance of single-use systems in parenteral manufacturing, there is a need to be able to connect plastic subsystems to each other and to permanent stainless equipment. Manufacturing flexibility achieved through the adoption of single-use components is an important consideration in improving production economics. Aseptic connectors are one piece of equipment that can impact production costs and adaptability.  

 “Connectors are a small component within the manufacturing system, but they are critical to achieving overall system integrity and performance, and if implemented appropriately, they can have a real impact on the efficiency and cost-effectiveness of drug production,” notes John Boehm, business unit manager for bioprocessing at Colder Products Company. Recently, they have become even more important as closed single-use systems have become more prevalent. With a move to create complete unit operations with single-use technology, these systems often increase in size and complexity, which creates new challenges for packaging, sterilizing, and handlings such large systems.  The response has been to build and irradiate smaller subsystems. Of course, these subsystems then must be integrated within a manufacturing facility, which is enabled by sterile connectors.

The need to produce a large number of smaller-volume parenteral drugs is also driving demand for connector technology. “Drug manufacturers are no longer building large stainless facilities, but [are using] smaller, single-use or hybrid sites located around the world that can meet the needs of the local population. Being able to make a number of different products at such a site is very important and requires that the production equipment be both reliable and flexible,” Boehm explains.


  As a company focused solely on connection technology, Colder observed these trends and realized that the industry needed a more robust aseptic connector that was easy to use and didn’t require any external clamps or other parts to ensure sterility. The company’s first solution offering under the AseptiQuick brand was a gendered connector (male and female halves that mated together to form the seal) that is assembled by clicking together the two halves, followed by removal of a sterile membrane (by pulling a tab on the connector) and then twisting of a lock ring to increase the pressure rating from 30 to 60 psi.

 Although these gendered connectors are robust and easy to use, Colder recognized that having gendered parts meant the system did not offer maximum flexibility, according to Boehm, because system designers and process engineers still had to be concerned about the gender of the parts when determining how to connect different systems together. 


  The next-generation AseptiQuik G connectors being introduced by Colder address this problem and incorporate additional features (see 

). Genderless connectors simplify system integration and process design, says Boehm. “If a genderless connector is specified, then there is no concern for whether the connector on other subsystems is male or female. Customers see these types of connectors as building blocks for their single-use systems, and in some cases have already been doing beta-testing of the new designs. They have determined that costs will be driven down as a result of the increased flexibility they provide.”
  Boehm also believes that with common connectors it will be possible to change the industry norm of creating new customized system configurations with each new project to a new paradigm of implementing standardized subsystems as building blocks. A parenteral manufacturer can develop and use a catalog of subassemblies from which it will be possible to construct customized and complex manufacturing systems. “Standardizing subsystems, which is made much easier and efficient with the use of genderless connectors, will mean that drug manufacturers won’t need to have to wait 12 or more weeks for custom production equipment to be built. That means faster time to market and reduced costs.” 


Perhaps the most important feature of the company’s new genderless format is a patent-pending seal design, which provides the consistent reliability and robust performance required of an aseptic connector, according to Boehm. “The performance of our wide-format silicon seal allowed us to simplify the connection process, which limits the risk of operator error.”  A connection can be made simply by 1) unsnapping and flipping down the protective pull tab covers on each connector half, 2) aligning the connector halves, sliding them together, and independently squeezing each side of the connector until an audible click is heard, and3) snapping the pull tabs together and pulling the membranes from the connector to complete the connection (see 

 “A significant difference with our new design compared to others on the market is that a sterile seal rated to 60 psi is achieved when the connectors are first clicked together; no additional fixtures or clamps are needed prior to or following membrane removal in order to ensure that the sterile barrier is maintained,” Boehm adds.

 One advantage of such sterile connectors is that connections do not need to be made in a laminar flow hood like conventional connectors do. Because the connection can be made anywhere in the cleanroom, there is no need for permanent hoods with extra long tubing runs or space for mobile hoods to be brought in to the production area.

  This space savings further maximizes the advantages of single-use systems for biopharmaceutical manufacturers, according to Boehm. He gives as an example using cell-culture processes. With the increased titers now possible, several smaller 1000-L single-use bioreactors that fit into a room can replace large 10,000-L stainless-steel reactors that must be installed in a multistory space. The use of genderless, aseptic connectors thus further reduces the space requirements as well as reducing the facility construction time.


  Boehm notes that some customers are testing the performance of Colder’s aseptic connectors outside of the cleanroom. The belief is that if the connectors meet specifications outside of the cleanroom, then they clearly will provide the needed performance inside the cleanroom. “More interesting, though, is the longer-term goal of convincing regulators that it is possible to achieve an aseptic environment outside of the cleanroom with closed systems. If this goal can be achieved, then some processes that currently must be run in a cleanroom could be carried out in a declassified production environment, which could lead to tremendous cost savings,” Boehm observes. “Cleanrooms are very expensive to build. Reducing the amount of required cleanroom space would lead to significant savings in capital investment and much shorter lead times.”

 Boehm also notes that during the last pandemic threat, governments realized the criticality of gaining timely access to vaccines and are interested in developing smaller vaccine production facilities that can serve local populations, which could be possible if the production of such vaccines could be carried out without a cleanroom. Highly robust, sterile connectors may assist in making such a scenario plausible.


  Colder’s sterile connector offering has increased to include solutions ranging from 1/8- to 1-inch flow, with both gendered or genderless options depending on the manufacturers’ preference.  “We will continue to focus on the development of new connection technologies that address the evolving needs of parenteral manufacturers, whether for smaller-scale clinical runs or full-scale commercial production, and whether the manufacturer’s strategy is for completely disposable technology or hybrid facilities,” states Boehm.    

Articles

Aseptic connectors provide the flexibility and robustness needed for modern parenteral manufacturing operations.

Will Aseptic Connectors Make Production Outside of the Cleanroom Possible?

Softgel capsules are a drug-delivery form that offers pharmaceutical manufacturers a tool to overcome the growing formulating challenges presented by poorly soluble drugs and highly potent APIs. Advances in softgel technology are making it possible to use this drug-delivery approach for a wider selection of APIs, including those that must be processed at higher temperatures or wider pH ranges. New printing methods also reduce process time and make counterfeiting more difficult. Ted Andrew, Rx softgel product manager with Catalent Pharma Solutions, spoke with Cynthia Challener, editor of the 

Pharmaceutical Sciences, Manufacturing & Marketplace Report

, about these developments and future applications of softgel technology.

Pharmaceutical Sciences, Manufacturing and Marketplace Report

: What are the key trends driving interest in softgel technology? 

: Bioavailability challenges associated with poorly soluble APIs (Biopharmaceutics Classification System (BCS) Class II and IV) are driving a lot of interest in lipid-based drug-delivery systems that are ideal for softgel formulations. As drug-discovery teams travel deeper into libraries and derivatives, the resulting, more complex leading candidates are typically less soluble and/or permeable than previously developed drugs. It is estimated that as many as 70% of new chemical entities are either poorly soluble, poorly permeable, or both. 

Softgel technology offers a drug-delivery solution with the formulation flexibility to overcome these challenges. For example, lipid-based formulations can be used to overcome issues created by APIs that are practically insoluble in water and that spontaneously emulsify in gastric juices by keeping these APIs in solution for absorption and preventing precipitation. The technology offers good 

 performance with fast release of fill, has good development profiles, and is compatible with a wide range of excipients and formulations. 

In addition, as clinical trials become more complicated and expensive, companies are increasingly looking for the optimal therapeutic profile; softgels can in many cases provide the fastest path and best chance for clinical success. 

: When are softgels an appropriate delivery vehicle? 

: Softgels are the ideal delivery vehicle for an increasing number of applications. We have demonstrated that our softgels are particularly suited for very low dose APIs where content uniformity can be problematic (< 3 mg); potent compounds, hormones, and cytotoxic compounds where safe handling is required; poorly soluble or poorly permeable APIs; oxygen-labile APIs; APIs that are unstable in light or liquids; and in abuse- deterrent applications. In addition, we have developed a new technology that allows semisolid fills with a wider range of excipients, enhancers, and APIs, thus enabling more drug candidates to benefit from the therapeutic advantages of softgel technology. 

: What are some recent advances in softgel capsule technology? 

: The two technologies that I think are worth noting are inline printing and the use of new materials in the shell that impart added performance properties. 

For example, Catalent’s proprietary inline printing technology facilitates the printing of any required logo or graphic onto the softgel ribbon prior to encapsulation. The advantages of labelling prior to encapsulation include product differentiation through branding, process-time reduction, and reduced risk for counterfeiting because the label is in the same location on each and every capsule. The process also ensures a higher level of quality; mislabelled products may be outside of specification in some other way and can be quickly identified. 

Meanwhile, softgel capsules manufactured using our [Catalent] new OptiShell technology containing starch and carrageenan in the shell, makes it possible to use a wider range of excipients, which in turn, expands the range of pH values and processing temperatures (up to 70 °C) that can be tolerated. As previously mentioned, these softgels can also be filled with semisolids.

: What are the limitations of the technology? 

: A key limitation that we find is the perception that the softgel form is a “low” technology solution. Although there are tremendous advantages to formulating as a softgel, including a faster formulation time, improved stability, and a better therapeutic profile, the balance between the shell, excipients, and fill formulation is crucial for the long-term success of therapies. We are working to overcome this challenge by developing in-depth expertise in softgel formulation. In addition, with our in-house component library, it is possible to rapidly develop an optimal formulation and provide a smoother and quicker path to commercialization. 

Another perceived limitation of the technology is that softgels are primarily an immediate-release technology. With recent advances in shell and fill formulations, such as shell technology with starch and carrageenan, it is now possible to provide a much wider range of therapeutic profiles, including extended- and modified-release. 

: Where do you see softgel capsule technology going in the future? 

: As the number of lead candidates that are difficult to formulate continues to grow and the costs of commercialization increase, softgel technology will continue to provide the industry with a faster, more effective path to market. 

We expect that further advances will provide even more options to drug manufacturers that will help them overcome formulating challenges and bring their innovative products to market. One such example is the opportunity presented by the conversion of intravenous formulations to oral dose forms. Incorporating macromolecules into softgels may provide tremendous therapeutic and cost benefits to the marketplace. 

The lipid-based method provides a tool for delivery of highly potent, poorly soluble, and unstable APIs. And new in-process capsule printing and shell technologies expand softgelsâ€™ applications further.

Advancing Softgel Technology for Poorly Soluble or Highly Potent APIs

Successful vaccination programs have been recognized as key contributors to enhanced public health. In an effort to improve existing vaccine therapies, drug manufacturers are seeking technologies that will enable the production of more robust and longer-lasting immune responses. One solution has been the development of more sophisticated conjugated vaccines. The manufacturing process for these vaccines is very complex, however, and involves the synthesis of several different polysachharides and proteins and the numerous possible valences of the conjugated vaccines. 

Annelies Onraedt, global market manager for vaccines with Pall Life Sciences, spoke with Cynthia Challener, editor of the 

, about the manufacturing process, recent developments that have helped improve the efficiency of the process, such as the use of chromatography rather than solvent precipitation and single-use systems for the final filling steps, and what issues remain to be addressed.

You can listen to the conversation below.

Conjugated vaccines are meeting the need for longer-lasting immune responses, but the production process is complex, and manufacturers are looking for simpler solutions.

Single-Use Systems and Chromatography Purification Techniques Improve Conjugate Vaccine Manufacturing

The major purpose of aseptic manufacturing  equipment is to ensure the production of products that are free from  contamination. As drug products become more potent, workers must be protected  as well. The use of new barrier technologies, the introduction of greater  automation and single-use technologies, and the development of more efficient  systems are helping pharmaceutical manufacturers maintain safety and quality  while increasing productivity and reducing costs. Christian Treitel, head of  business development for pharma with Bosch Packaging Technology, Matthias  Poslovski, technical sales director at Optima Pharma,  and Tim Kram, general manager of  Rommelag USA spoke  with Cynthia Challener, editor of the 

Pharmaceutical  Sciences, Manufacturing & Marketplace Report

, about the key attributes  of effective aseptic-filling equipment and  drivers for recent and future advances in the technology.

Pharmaceutical  Sciences, Manufacturing and Marketplace Report

: What are  the top qualities that pharmaceutical companies are looking for in aseptic-filling  equipment for parenterals and why are these characteristics important?

: The requirements placed on aseptic-filling machines  depend heavily on the product being processed. Generally speaking, however, the  safety of operators and patients always ranks at the top. For instance, when  dealing with toxic products, suitable barrier systems, such as isolator technology or closed restricted access barriers (cRABS), are a must. Very high-priced products demand techniques such  as 100% in-process control to continuously optimize filling accuracy so that the  product batch is nearly fully utilized. On the other hand, very small batch  sizes require extremely flexible facilities. In cases where further technology,  such as freeze-drying systems, need to be integrated, the turnkey expertise of  the machine builder is in great demand. 

: Pharmaceutical  companies are looking for safe and flexible equipment for their varying aseptic-filling  processes. Advances in oncology and immunology have led to an increased use of  highly potent and cytotoxic substances. 

When  high-potency pharmaceuticals are used, manufacturers must pay more heed to  protecting both the product and all persons involved in the production process,  which adds significantly to the complexity in manufacturing, as processes have  to be defined early and concepts must be fit for implementation.

Flexibility  is also necessary for the pharmaceutical industry as batch sizes decrease and  more fill-finish operations are performed by contract manufacturing  organizations (CMOs). The equipment must be applicable not only for current but  also for future products and containers. 

:  Customers want to have consistent  and reliable production capabilities and minimize risk by controlling all of the  components that go into the production of parenteral products. Aseptic-filling  systems need to have high overall efficiencies with only scheduled maintenance. Blow/fill/seal technology is a highly automated process that does not require  regular operator input and has very high overall equipment effectiveness (OEE).

With blow/fill/seal technology, the raw plastic resin from which the containers  are formed is the only material that must be supplied that is not found in a  normal aseptic facility, which minimizes the supply chain and on-site storage  requirements that are associated with systems that use pre-formed glass or  plastic containers.

: What recent advances have been made with respect to aseptic-filling  equipment used for parenteral drug formulations, and what have been the drivers for these advances?


: Barrier  technology is becoming increasingly important because it allows fully enclosed,  sealed, and pressurized units completely separated from the operators. It also offers far greater sterility assurance than conventional cleanrooms and can  significantly lower costs associated with more traditional fill–finish methods.  The processes for production with isolators have also been refined. More and  more customers are building up experience for daily work with isolators and  generating additional output at lower cost.  

The other big advance is the introduction of single-use components. When processing  biotech products, the cleaning and validation of parts is an expensive and  time-consuming procedure. Single-use components decrease the cleaning time,  validation efforts, and save considerable costs. 

:  Advances in blow/fill/seal technology have  focused on three primary areas: compatibility, efficiency, and automation. It is important to adapt blow/fill/seal systems to better allow sensitive products  to utilize the technology. Two examples include the development of a cool-filing process for heat-sensitive biotech products, such as live  attenuated vaccines, and coextrusion technology to place barriers into the  container walls for products that are gas-(i.e., oxygen, CO2) sensitive. 

With  respect to efficiency, customers like to have larger systems that allow for  better cost of goods and lower overall operating costs. With recent  developments, it is possible to achieve a return on investment in six to eight years  when only considering the raw-materials savings over traditional systems. 

Automation,  meanwhile, helps achieve the major goal of aseptic manufacturing, which is the  production of products free from contamination. The primary source for  that contamination is people in and around the aseptic systems. Therefore, raising the automation level helps minimize the interventions that are  necessary into and around the blow/fill/seal process. 

: There have been many innovations and  developments to increase the flexibility of machines, especially for new  biopharmaceutical drugs and small batch sizes, such as using up to three  different dosing systems (e.g., rotary piston pumps, peristaltic pumps, and  time pressure). Modular concepts are also relatively new in the pharmaceutical  industry and make it possible to alter functionality or increase performance.  For safety devices that protect against needle-stick injuries, for example, flexible  assembly systems that can also process backstops are available. In addition,  robotic technologies are increasingly used for flexible processes. 

Separately,  disposable tanks, pumps, hoses, and filling needles are frequently used today when  processing highly potent ingredients, which helps minimize the risk of cross-contamination.

: Does process analytical technology (PAT) have a place in aseptic-filling  processes, and if so, what are equipment manufacturers doing in this area?

: There are different aspects to process  analytical technology, such as 100% in-process control, optical control for  stoppers, and crimp quality control, and glass surfaces are often monitored for  scratches and damage. There is also a trend to use early controls because  rejecting a container due to an imperfection after filling would mean  discarding a potentially high-priced product.  

Other  aspects include the software analysis methods that are specially developed for  filling and packaging machines. The OEE of machinery can be determined, and  areas that might cause downtime can be identified in many cases.

: The main goal of PAT is to ‘build quality into products’ instead of inspecting  quality after the product has already been manufactured. Equipment  manufacturers are developing in-process technologies that closely monitor all  process steps. In larger lines, dozens of parameters are monitored, and  corrections are triggered, for instance through temperature control of the  sterilizing tunnel, or sophisticated in-process control of net weight at high  speeds. The residual oxygen level after gassing is also monitored, and feedback  loops are established.

In  parallel, we still see the need for inspection of parenterals for particles and  cosmetic container defects at the end of the production process. Manual,  semi-automated, or fully automatic inspection machines are used to ensure 100%  quality of the pharmaceutical products 

: Rommelag has recognized this need  for real-time automated inspection capability, and in response has developed a system  that enables measurement of the critical quality attributes (CQA) of final  containers. The results are then used as feedback parameters to control the  critical process parameters (CPP) in the blow/fill/seal system.

: What issues remain that have not yet been addressed? What  are parenteral drug manufacturers looking for in the next generation of aseptic  filling equipment and why?

: Aseptic product quality standards and regulatory requirements are ever increasing. Processes  for the filling of products into glass containers struggle to increase their  speed and efficiency while at the same time overall glass quality seems to be  decreasing (size specifications, cracks, chips, beads, and delamination). Fortunately,  inspection systems developed to prevent the release of unacceptable products continue  to improve in ability and speed. In fact, better and new inspection  methods are being developed by many companies.

: Every drug manufacturer will always be searching for faster, more efficient and  cost-effective machinery. Equipment manufacturers will continuously be  challenged to fulfill these requirements. Rising cost pressures in production  will also press manufacturers to further improve productivity with respect to OEE  while still offering the highest quality possible.

The  optimization of machines in terms of flexibility, automation, easy changeover,  and scale-up also enables manufacturers to develop new drugs and bring them to market more rapidly, while still complying with strict regulations. One big  challenge we see is to support our customers in handling flexible equipment  while gaining high OEE as well as achieving even higher outputs with our  barrier systems. 

:  We believe that there are two areas that  promise increasing potential for plant operators. On the one hand, line  flexibility can be further developed. If the line flexibility can be  successively increased, the productive time and profitability of an investment can  be further enhanced. In addition, plant availability can be improved. Time-consuming  processes, such as cleaning-in-place and sterilization-in-place with high  temperatures that require a subsequent cooling phase and isolator decontamination  cycles, are examples of nonproductive down times that need to be minimized.

: What are equipment manufacturers doing to try and overcome  these issues? What new technologies are on the horizon?

:  Blow/fill/seal technology produces a new container that inherently does not  have the quality problems that are found in glass, but BFS containers are still required to meet the same inspection requirements driven by glass  containers. This situation is specifically the case with injectable  products. The optical qualities found in the plastic resins used in BFS  containers limit the ability to accomplish vision-based inspections  systems. There are several near-term inspection solutions being developed  with better camera systems linked to more computing power and new higher-energy  inspection methods. From the container-manufacturing side, Rommelag is  working to introduce plastic resins with better optical qualities.

:  Robotic technologies are increasingly finding  their way into pharmaceutical engineering. Processes can be flexibly designed  to transport containers through equipment or for handling, assembly, and other  functions. As an example, the liquid level in aseptic containers must remain  constant, and this need creates an important opportunity for robot transport  functions for unsealed containers, such as the new robot control for the handling  pharmaceutical liquids that Optima Pharma developed. 

Catalytic  aeration, a technology also introduced by Optima Pharma, has been successfully  tested and implemented as a retrofit solution for existing isolators. It  significantly reduces non-productive downtime (by up to 50%) because the aeration  phase is the most time-consuming cycle during H2O2 decontamination.

: Bosch  Packaging Technology is working on innovative solutions for higher productivity  combined with the highest quality and flexibility. Improved processes, easy  handling, and reduced product loss are the main focuses of our development  teams. We combine proven technologies with new promising approaches to provide  drug manufacturers with short time to market and flexible machinery.

Adoption of single-use systems and more flexible systems drive innovation.

The Next Generation in Aseptic-Filling Equipment

Tablet  coatings in the pharmaceutical industry can serve many purposes. Although originally  largely used to help maintain the integrity of the tablet, today, coatings  often impart other functionality, such as sustained-release capability, and may  even contain an API. Tablet-coating equipment manufacturers are thus being  challenged to develop systems that can operate at desired speeds while still  providing the necessary level of accuracy and uniformity that is required for  each tablet. They are responding with the development and implementation of  both new coating technologies and new methods for evaluating coating  performance.

Efficient  mixing, spray distribution, heating, and air flow

A  good coating process first requires efficient mixing without stressing the  tablet core, good distribution of the spray solution over the tablet bed, and controlled air flow for effective drying without  excessive spray drying, according to Martin Hack, vice-president and general manager  for LB Bohle. “Heat exchange during the drying process is critical for good  mixing and dictates the consistency of the tablet load,” adds Francesco Nigris,  president of Nicos Group, the US Branch of Nicomac. He also notes that  cleanability of a pharmaceutical tablet-coating system is also very important.

 Changes in the formulation of tableted  therapies are also affecting the coating process. “The use by drug  manufacturers of active coatings for  either dual ethical formulations, which have one active in the core and one  active in the coat, or for the application of an active that is more easily  dispersed in solution then mixed as a solid and compressed is increasing. The  use of functional coats for time-release and other applications is also  becoming more prevalent. These types of applications require very high  performance coaters that can deliver a very uniform coat to the tablets,”  explains Hack, He also notes that a very uniform coat has a relative standard  deviation (RSD) of < 4%.

The  growing number of highly potent APIs is also an issue for tablet-coating  operations. “When highly potent tablet products are being coated, it is very  important that not only the product quality be maintained, but the operators  must be protected as well. That need is leading to greater automation of all  aspects of drug production, including tableting-coating processes,” notes Nigris.

The  greater need for uniformity and worker protection comes at a time when  pharmaceutical companies are also looking for greater flexibility in their  tablet coating processes in order to meet variable demand for their products.  Traditionally, perforated coating pans have been used for tablet coating. Using  a solid pan, however, according to Nigris, increases the drying efficiency and  provides more flexibility. “Not only can a solid pan handle a greater range of  product types, from pellets to microgranules to even powders, it can be operated  at as low as 20% of the maximum capacity, which provides more flexibility with  respect to production scale.”

 Tablet beds with increased surface area  have helped improve coating performance, according to Hack. “The increased surface area of tablet beds with elongated pans and  reduced diameters enables the use of a larger number of spray nozzles for  higher spray rates and, consequently, shorter process times combined with  better distribution of the solution over the bed surface,” he observes. He adds  that minimization of spray drying has also been achieved by changing the path  of the airflow so that the air is directed straight into the bed, rather than  across the spray zone.

  The use of process analytical  technology (PAT) also has the potential to improve the performance of tablet-coating  equipment. “While true online process control is still in its infancy, it is  enabling technology that will lead to advances in tablet-coating processes. At LB Bohle, therefore, we have conducted trials with the University of Dusseldorf with  respect to the use of Raman spectroscopy for the online measurement of film  coat thickness with good success.  We are now striving to implement this capability  as an option in our coating line,” Hack says.

While progress is being made, real  implementation of online PAT is still a challenge, though. The implementation  of effective continuous processes is also a need in the pharmaceutical  industry. “Current continuous coaters provide  processes with very high RSDs  as  measured by weight gain, and thus are ineffective in ethical formulations because  they have a high rate of over-coating,” notes Hack. He adds that LB Bohle is  striving to deliver a continuous coating process that can be used for both  cosmetic and functional applications.

  Despite recent improvements in flexibility  and cleanability, Nigris believes these two issues still require further  advancements. “Pharmaceutical customers want tablet-coating systems that are  easy to clean and easy to validate. Movement towards less-perforated pans is  helping to address this need. A solid surface is much easier to clean.” 

  Nigris  also points to the increased automation of tableting coating equipment as being  important for further advancement of coating technology. “Automated humidity  controls are having a positive impact today. In the future, fully automated  systems, including in terms of product handling, will go a long way to increase  the ability for tablet-coating equipment to effectively interface with both  upstream and downstream processing for automated loading and unloading.” 

  To  that end, LB Bohle is partnering with both customers in the pharmaceutical industry and with  universities to develop a new technology center on its main campus in  Ennigerloh, Germany that will focus on a complete continuous process line that  incorporates the latest technologies for dispensing, granulation, drying,  compression, and coating, with an emphasis on PAT for each stage, according to  Hack.

  Meanwhile,  Nicomac has focused its efforts on the development of a solid, nonperforated  pan that can be used for process development and optimization as well as  commercial production. “Having such flexibility in the production scale is a  real advantage for smaller companies that can’t afford to purchase separate  tablet-coating equipment for their R&D and production groups,” Nicos  states. The company also believes that mega pans for the production of up to 2  tons can be an alternative to continuous coating operations using a series of  standard pans.

Greater automation and the adoption of solid versus perforated pans are some recent advances.

Raising the Bar in Tablet Coating Equipment and Processing

Aging populations, rising obesity levels, and the  global effort to reduce the incidence of vaccine-preventable diseases is  driving demand for biopharmaceutical drugs, many of which are smaller-volume,  niche products for targeted patient populations. The ability to construct  smaller-scale, modular biopharmaceutical production facilities with minimal  set-up time while still maintaining high quality is enabling the cost-effective  production of products that can meet the increased demand on a local level. Olivier Loeillot, general manager of enterprise solutions,  GE Healthcare Life Sciences, spoke with Cynthia Challener, editor of  the 

Pharmaceutical Sciences,  Manufacturing & Marketplace Report

: What are the drivers behind the introduction of modular-type  biopharmaceutical manufacturing facilities? 
    

: When commissioning a new facility, biopharmaceutical manufacturers want  high quality construction to help ensure a consistently high quality product,  anywhere in the world, as rapidly as possible. 

Most demand  for such an offering comes from either large multinational companies wanting to  build or expand “in-country for-country” manufacturing capacity in local  markets, or governments looking to build in-country for-country local  manufacturing capacity themselves. In either case, the need for additional cost-effective  capacity stems from an increasing worldwide demand for biopharmaceuticals that  is caused by aging populations, rising obesity levels, and the global effort to  reduce the incidence of vaccine-preventable diseases.

 At the same  time, the age of blockbuster therapeutics has diminished, to be replaced with  so-called ‘nichebusters’ that aim to address unmet clinical needs for targeted  subsets of the patient population. This change in turn will lead to  biopharmaceutical companies taking a new approach to manufacturing, for example,  by producing smaller batches and adopting greater flexibility.

Biologics and  monoclonal antibodies can be very costly to the healthcare system and to  patients, making it more attractive to deploy such a modular facility for  biopharmaceuticals.  As part of this  approach, the speed and flexibility benefits of single-use components are now  well-recognized across the industry, and the next step is harnessing this  potential and packaging it for rapid deployment wherever a customer requires.

: What are the critical components of such a modular manufacturing  approach? What are the important factors that will lead to successful construction  of a modular facility?

: Biopharmaceutical manufacturers are  looking to minimize financial and operational risks by opting for an approach  that delivers shorter set-up times, scalability, quality, and the ability to  maximize the use of single-use manufacturing technologies, such as bioreactors,  storage and mixing tanks, and chromatography columns.

From  a facility perspective, a shorter set-up time can be achieved through  simplifying and standardizing the modular components as much as possible.  Coupling this facility approach to a single-use manufacturing line reduces  design-to-production timelines while enabling quicker validation and increasing  the product manufacturing turnaround. Scalability is achieved by having a  facility footprint that readily accommodates growth in production capacity as  required.

Incorporating  single-use technologies is also about flexibility by allowing easy switching of  product if required, but also by enabling greater use of continuous processing  and other opportunities to improve efficiencies.

: What specifically does KUBio entail? How does it work?

: GE Healthcare’s KUBio is an  off-the-shelf cGMP-compliant facility designed for the production of monoclonal  antibodies (mAbs) for the treatment of a wide variety of diseases, such as  cancer and rheumatoid arthritis, that can be assembled anywhere.    

The complete production facility consists  of modules that come fully fabricated for assembly at the required site. KUBio  has an approximate footprint of 1200 m² and a total area of 2200 m² split over  two levels: the upper level comprises gowning areas and heating, ventilation, and  air conditioning (HVAC)  installations and the lower area contains process and utilities rooms.

The facility includes a single-use  process technology production train that is adaptable to a customer’s specific mAb  process with a standard bioreactor setup of 2 x 1000-L bioreactors feeding one  harvest and downstream processing line. The bioreactor size, however, can be  increased or decreased if required. KUBio also has the option to be supplied  with fill and finish capabilities.

We coordinate the entire project and  partner with both local and global experts in process development, engineering,  and construction. By cutting months off the typical construction time and  streamlining the whole execution process, a mAb manufacturing facility at a  fixed investment cost can be delivered in a timeframe of 14–18 months.

: What types of facilities can be constructed with KUBio? Is it suited for specific biopharmaceutical manufacturing  processes/scales?

: Our initial modular facility is  configured for the manufacture of mAbs and is designed to reach production  volumes of over 100 kg/ mAb/year. This level has been chosen to meet most local  capacity demands.

: Is GE doing further work on KUBio? What can be expected in the future as  far as expanded offerings go? 

: We are in the process of designing  off-the-shelf facilities for the manufacture of other biopharmaceuticals. We are also constantly evaluating customer feedback in order to design new  solutions for their evolving manufacturing needs.

The growing demand for targeted biopharmaceutical therapies is driving interest in modular production facilities that can be rapidly constructed while still minimizing risk and cost.