Kristin Brooks, Associate Editor, Contract Pharma03.02.15
With large-scale generic production expected to rise considerably, and an increasing number of complex medicines approved for personalized treatments, drug packaging needs are quite varied in today’s market. The demand for sophisticated equipment offering flexible platforms, safety for operators and modular concepts to handle integration smoothly is high.
January 2015 marked the beginning of serialization criteria implementation in the U.S. While there’s significant buzz in the pharma industry, and many companies have serialization programs underway, global regulatory clarity is still lacking. In addition to serialization, compliance packaging and containment remain prominent packaging equipment trends. Also, custom packaging solutions for more complex products, such as injectables and potent compounds requiring containment, have grown substantially.
With increasing validation requirements, serialization and aggregation, companies are looking for full, integrated packaging lines rather than stand-alone equipment. Equipment manufacturers also face the challenge of reducing delivery times with highly flexible equipment.
Industry Trends & Expectations
Today’s packaging equipment must address several growing trends, such as smaller batch sizes for biologics, a greater variety of product forms and compliance packaging. Also, as Quality by Design (QbD) efforts pick up, new technologies are needed to ensure processes and final products are up to par.
With more than $60 billion spent on R&D in 2013 for 29 FDA-approved drugs—mostly for small-population biologics—packaging is increasingly specific. According to Reid Lederer, president of Pharma Packaging Solutions, “Highly segmented markets require unique branding and packaging differentiation. Patient interaction with packaging goes beyond F=1 compliance, it now includes medication reminders and instructions. Furthermore, graphic changes require more sophisticated printing and die cutting approaches.”
The trend toward small amounts of targeted drugs, particularly for the treatment of cancer, calls for flexible platforms that can handle small batches while ensuring the highest safety for both operators and products. According to Dr. Johannes Rauschnabel, chief pharma expert at Bosch Packaging Technology, “Some drug manufacturers have already built entire containment facilities, where building and equipment are optimally fine-tuned to one another. Involving the equipment supplier at an early planning stage helps ensure flexible, modular and space-saving solutions. A concept that greatly benefits this approach is continuous processing.”
As opposed to batch manufacturing, continuous processing implies manufacturing and processing materials without interruption. Implementing this concept, according to Dr. Rauschnabel, requires a thorough understanding of process interactions between different unit operations.
The FDA advocates continuous processing and using the QbD approach. An integral part of QbD is Process Analytical Technology (PAT), which aims to ensure final product quality by designing, analyzing and controlling manufacturing through timely measurement of critical quality and performance attributes of raw and in-process materials as well as processes. According to Dr. Rauschnabel, PAT has already triggered the development of new technologies, while a lot more development remains to be done.
For many years now, a variety of biopharmaceutical medications have been gaining importance. At the same time, according to Matthias Poslovski, technical sales director at OPTIMA Pharma GmbH, “The technical processing of these products, for the most part, demands requirements other than those of traditional medicines. This makes new production line types evermore necessary. The growth of self-medication is a further trend leading to growth.”
The progression of biologics has also led to increased demand for highly flexible dosing and packaging systems, namely modular machine concepts that also conform to the highest safety standards. Mr. Poslovski noted, “The turnkey aspect is of great importance in this instance. Isolators and freeze-dryers are absolutely essential for many biopharmaceuticals, and processing is thus evermore complex. Process equipment should be modular so that integration remains simple and versatile.”
Also, more and more projects go beyond the scope of “mere” processing of pre-filled syringes, vials and cartridges; special containers and unique forms of administering medicines require specific or customized processing systems. “Here we incorporate robotics, handling technology and particle-free sealing of synthetic materials to meet our customers’ expectations,” Mr. Poslovski said.
Another major trend is compliance packaging, which aims to enhance patient adherence to medications. Although many medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed. According to the World Health Organization (WHO), increasing the effectiveness of adherence interventions may have a far greater impact on public health than any improvement in specific medical treatments.
“Patient adherence is certainly a hot industry topic and the use of calendarized, compliance-prompting packaging is on the rise, according to Justin Schroeder, executive director, marketing, business development and design at Packaging Coordinators, Inc. “Oncology is a great example of where this has really taken off. There is so much focus now on not only delivering the product safely and effectively, but also gauging the health outcomes of the patients taking the medication. This is really driving a focus on the best delivery to the patient.”
Compliance packaging adds a level of complexity, and equipment designs need to be taken into consideration early on. For example, product feeding and inspection present challenges when several products of different geometries and strengths are required in a single blister pack. Other questions worth asking include: Are the secondary operations in line with primary, or is there a bulk pack out required at some point in the process? Can the project scope support automatic operations, or do some operations become manual?
Ralf Klotz, regional sales manager at Uhlmann Packaging Systems, said, “Often we have found start-ups to rely on manual work with scale-up plans if and when the market projections are realized. We strongly encourage our users to include us in the process as early as possible to ensure that the end pack is something that can be produced cost effectively and with an acceptable OEE (Overall Equipment Effectiveness). Many times, additional stations can be added to base machine models to achieve the desired results. Often these can be field integrated into existing equipment.” Mr. Klotz also noted there are projects that require completely customized solutions.
Serialization Update
The need for serialization solutions is growing every day. While the U.S. is starting to implement requirements of the Drug Supply Chain Security Act (DSCSA/DQSA) to facilitate the tracking of prescription drugs throughout the supply chain, the EU has published its delegated acts to put the Falsified Medicines Directive 2011/62/EU into practice for 2015. This year will also see two additional countries, Brazil and Saudi Arabia, transfer their serialization requirements into legislation.
“Pharmaceutical producers are under pressure to adapt their packaging processes to meet the different serialization requirements throughout the world,” said Dr. Rauschnabel at Bosch Packaging Technology. “One of the biggest challenges for drug manufacturers is establishing a process that combines the company’s IT with the serialization process of the packaging lines.” To address this, Bosch adapted its automation technology for the automotive sector to pharma requirements, enabling companies to design solutions that not only deal with the entire order management, but also control the import and export of serial numbers.
Contract Packagers are also seeing an uptick in serialization adoption. According to Mr. Schroeder of PCI, “2014 seems to be the year that many of our clients moved forward with their corporate serialization plans in earnest. Across our network of packaging sites in North America and Europe, we have been outfitting lines to meet the serialization requirements ahead of the government-mandated deadlines. In some instances this is driven from 2015 requirements in emerging markets such as South Korea and Turkey, and in other instances it’s the formal endorsement from the client base that they’ve decided to press forward in advance of the U.S./EU legislation requirement. It seems to be moving from conversation to action. I believe it’s the start of a seismic shift in the industry.”
While it’s standard to include serialization into new equipment, the challenge lies with introducing serialization into existing lines. To tackle this challenge, according to Mr. Klotz at Uhlmann, the company developed a serialization platform. “By strategically adding small, flexible, multifunctional print and inspect modules into an easily movable frame, we have been able to incorporate the latest technologies in marking and OCR/OCV (Optical Character Recognition/Optical Character Verification) with minimal downtime and validation impact.”
Michele Leonardi, regional sales manager for MG America, added, “Serialization is part of any project involving secondary packaging equipment for the pharma industry, and for this reason we have developed equipment that can be integrated on existing or new packaging lines in order to perform coding and verification of serialization codes on bottle, carton and bundle. The whole MG America range of case-packer and palletizer also has been modified in order to allow the integration of cameras on various parts of the machine, allowing verification of the serialized codes.”
Within the pharma industry, there has been a substantial increase in discussions regarding serialization, and while experts agree there’s a need for a serialization model, Charles Ravalli, CEO of Romaco North America, said it’s also clear that the efficiency of such a system would rely on a very well organized international database. “There are numerous questions of how, where and by whom this vast amount of data could be analyzed efficiently, reliably and promptly. Worldwide manufacturers of pharmaceutical products and equipment are prepared to take action, when the final decisions are made by international regulators,” said Mr. Ravalli.
Packaging Complexities
The intricate nature of many new pharma and biopharma products requires advanced equipment that meets numerous criteria, namely safety, flexibility and expert handling—for example, with highly potent compounds, and lyophilization of drug products, where containment and production time is critical.
According to Mr. Poslovski, OPTIMA develops technologies and systems designed to reduce the time between batch production, such as during the cooling phases of freeze-drying or in the case of format change. “Another important aspect is the extensive modularization of the machine systems. This, for example, also affects the design of the interfaces between filling machines and isolators, connection of freeze-dryers by means of automatic transport systems, feeding and discharging, as well as the freeze dryers themselves.”
Due to the increasing complexity, sensitivity and demand for consistency of products, it has become necessary to monitor processes online. “This means a departure from random sampling or statistical monitoring and a move to 100% control,” Mr. Poslovski said. “Further advances that address the myriad of product characteristics include machines fitted with several dosing systems that can process several different types of containers. These dosing systems can be set up quickly and adjusted to suit diverse, sensitive products. In conjunction with in-process controls, all the dosing systems attain extremely high levels of filling precision,” according to Mr. Poslovski.
Additionally, with the growth of highly potent pharmaceuticals, manufacturers need to be mindful of protecting all elements of the supply chain from their potentially harmful effects. Recent equipment solutions favor the use of automation and robotics technology to reduce human contact with the product. Also, due to stricter guidelines for aseptic filling operations from the FDA, manufacturers increasingly rely on the use of isolators.
According to Dr. Rauschnabel of Bosch Packaging Technology, “Vials remain the predominant containers handled in isolators, while the use of pre-filled syringes is rapidly growing, especially in Europe. The development of ready-to-fill, sterile, primary packaging systems in cooperation with leading equipment manufacturers has improved aseptic filling operations and paved the way for the development of new, highly flexible filling and closing machines designed to handle pre-sterilized nested syringes, vials and cartridges, such as the FXS Combi from Bosch. Also, the ability to use filling technologies with single-use components offers a cost-effective alternative to expensive cleaning operations for product contact parts,” added Dr. Rauschnabel.
Offering a contract packaging perspective on challenging products, Tee Noland, chairman and CEO of Pharma Tech Industries, said, “In our experience, reconstituted powder offers some unique advantages for certain temperamental liquid formulations. From a packaging standpoint, we tend to use foil barriers as an effective packaging solution for powders and other hydroscopic solids.” Robotics have become increasingly handy for such applications. Mr. Noland noted about 50% of his company’s packaging lines incorporate the use robotics.
Adding another layer of complexity, uniquely shaped pharmaceutical tablets are also impacting packaging equipment. “Complex product geometries and dimensions always require sophisticated product feeding systems,” said Mr. Ravalli of Romaco. “The variety of demanding product specifications is steadily increasing as our customers continue efforts to differentiate their products. This requires precisely designed feeding solutions for primary (blister and strip) and secondary (cartons) packaging challenges.”
Looking Ahead
Where will the future of packaging services and equipment lead? In addition to classic containers such as pre-filled syringes, vials and cartridges, systems for administering medication will continue to grow in importance, noted Optima’s Mr. Poslovski. “Self-medication is driving this development forward. Other methods of administering medication that are more pleasant than an injection, and alternatives to large-sized tablets and capsules, are also fields for further development that will bring new challenges to machine design and construction. Additionally, flexibility of machine systems will also be driven forward so that the greatest range of different containers can be processed. This also includes the minimizing of changing times and format parts,” Mr. Poslovski added.
According to Mr. Schroeder of PCI. “As pharma’s pipelines are challenged to bring products to market more quickly, safely and cost effectively, we are seeing more products that are not shelf stable in traditional materials or ambient environments. This places the onus on the packager to enable shelf-stable products by virtue of high-barrier materials, use of cold chain logistics, and utilization of modified environments such as nitrogen flushing, for example. The market is adapting to these new expectations and will continue to provide innovations to support speed-to-market.”
Finally, as lyophilization and other efforts to sustain the shelf life of temperamental drug products grow, managing the cold chain is paramount across the industry. “The complexity of cold-chain management continues to grow with the expansion of the biologics market,” noted Vladimir Spehar, director, strategic business development at Jones Contract Packaging Services. “We have invested in a cold chain-compliant refrigeration system to support the increased demand in this area. We are also researching temperature-management solutions on printed packaging components for drug products.” While not without its challenges, equipment suppliers and manufacturers alike must constantly assess and respond to pharma and biopharma industry trends and the demanding products they produce.
Kristin Brooks is the associate editor of Contract Pharma. She can be reached at kbrooks@rodmanmedia.com
January 2015 marked the beginning of serialization criteria implementation in the U.S. While there’s significant buzz in the pharma industry, and many companies have serialization programs underway, global regulatory clarity is still lacking. In addition to serialization, compliance packaging and containment remain prominent packaging equipment trends. Also, custom packaging solutions for more complex products, such as injectables and potent compounds requiring containment, have grown substantially.
With increasing validation requirements, serialization and aggregation, companies are looking for full, integrated packaging lines rather than stand-alone equipment. Equipment manufacturers also face the challenge of reducing delivery times with highly flexible equipment.
Industry Trends & Expectations
Today’s packaging equipment must address several growing trends, such as smaller batch sizes for biologics, a greater variety of product forms and compliance packaging. Also, as Quality by Design (QbD) efforts pick up, new technologies are needed to ensure processes and final products are up to par.
With more than $60 billion spent on R&D in 2013 for 29 FDA-approved drugs—mostly for small-population biologics—packaging is increasingly specific. According to Reid Lederer, president of Pharma Packaging Solutions, “Highly segmented markets require unique branding and packaging differentiation. Patient interaction with packaging goes beyond F=1 compliance, it now includes medication reminders and instructions. Furthermore, graphic changes require more sophisticated printing and die cutting approaches.”
The trend toward small amounts of targeted drugs, particularly for the treatment of cancer, calls for flexible platforms that can handle small batches while ensuring the highest safety for both operators and products. According to Dr. Johannes Rauschnabel, chief pharma expert at Bosch Packaging Technology, “Some drug manufacturers have already built entire containment facilities, where building and equipment are optimally fine-tuned to one another. Involving the equipment supplier at an early planning stage helps ensure flexible, modular and space-saving solutions. A concept that greatly benefits this approach is continuous processing.”
As opposed to batch manufacturing, continuous processing implies manufacturing and processing materials without interruption. Implementing this concept, according to Dr. Rauschnabel, requires a thorough understanding of process interactions between different unit operations.
The FDA advocates continuous processing and using the QbD approach. An integral part of QbD is Process Analytical Technology (PAT), which aims to ensure final product quality by designing, analyzing and controlling manufacturing through timely measurement of critical quality and performance attributes of raw and in-process materials as well as processes. According to Dr. Rauschnabel, PAT has already triggered the development of new technologies, while a lot more development remains to be done.
For many years now, a variety of biopharmaceutical medications have been gaining importance. At the same time, according to Matthias Poslovski, technical sales director at OPTIMA Pharma GmbH, “The technical processing of these products, for the most part, demands requirements other than those of traditional medicines. This makes new production line types evermore necessary. The growth of self-medication is a further trend leading to growth.”
The progression of biologics has also led to increased demand for highly flexible dosing and packaging systems, namely modular machine concepts that also conform to the highest safety standards. Mr. Poslovski noted, “The turnkey aspect is of great importance in this instance. Isolators and freeze-dryers are absolutely essential for many biopharmaceuticals, and processing is thus evermore complex. Process equipment should be modular so that integration remains simple and versatile.”
Also, more and more projects go beyond the scope of “mere” processing of pre-filled syringes, vials and cartridges; special containers and unique forms of administering medicines require specific or customized processing systems. “Here we incorporate robotics, handling technology and particle-free sealing of synthetic materials to meet our customers’ expectations,” Mr. Poslovski said.
Another major trend is compliance packaging, which aims to enhance patient adherence to medications. Although many medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed. According to the World Health Organization (WHO), increasing the effectiveness of adherence interventions may have a far greater impact on public health than any improvement in specific medical treatments.
“Patient adherence is certainly a hot industry topic and the use of calendarized, compliance-prompting packaging is on the rise, according to Justin Schroeder, executive director, marketing, business development and design at Packaging Coordinators, Inc. “Oncology is a great example of where this has really taken off. There is so much focus now on not only delivering the product safely and effectively, but also gauging the health outcomes of the patients taking the medication. This is really driving a focus on the best delivery to the patient.”
Compliance packaging adds a level of complexity, and equipment designs need to be taken into consideration early on. For example, product feeding and inspection present challenges when several products of different geometries and strengths are required in a single blister pack. Other questions worth asking include: Are the secondary operations in line with primary, or is there a bulk pack out required at some point in the process? Can the project scope support automatic operations, or do some operations become manual?
Ralf Klotz, regional sales manager at Uhlmann Packaging Systems, said, “Often we have found start-ups to rely on manual work with scale-up plans if and when the market projections are realized. We strongly encourage our users to include us in the process as early as possible to ensure that the end pack is something that can be produced cost effectively and with an acceptable OEE (Overall Equipment Effectiveness). Many times, additional stations can be added to base machine models to achieve the desired results. Often these can be field integrated into existing equipment.” Mr. Klotz also noted there are projects that require completely customized solutions.
Serialization Update
The need for serialization solutions is growing every day. While the U.S. is starting to implement requirements of the Drug Supply Chain Security Act (DSCSA/DQSA) to facilitate the tracking of prescription drugs throughout the supply chain, the EU has published its delegated acts to put the Falsified Medicines Directive 2011/62/EU into practice for 2015. This year will also see two additional countries, Brazil and Saudi Arabia, transfer their serialization requirements into legislation.
“Pharmaceutical producers are under pressure to adapt their packaging processes to meet the different serialization requirements throughout the world,” said Dr. Rauschnabel at Bosch Packaging Technology. “One of the biggest challenges for drug manufacturers is establishing a process that combines the company’s IT with the serialization process of the packaging lines.” To address this, Bosch adapted its automation technology for the automotive sector to pharma requirements, enabling companies to design solutions that not only deal with the entire order management, but also control the import and export of serial numbers.
Contract Packagers are also seeing an uptick in serialization adoption. According to Mr. Schroeder of PCI, “2014 seems to be the year that many of our clients moved forward with their corporate serialization plans in earnest. Across our network of packaging sites in North America and Europe, we have been outfitting lines to meet the serialization requirements ahead of the government-mandated deadlines. In some instances this is driven from 2015 requirements in emerging markets such as South Korea and Turkey, and in other instances it’s the formal endorsement from the client base that they’ve decided to press forward in advance of the U.S./EU legislation requirement. It seems to be moving from conversation to action. I believe it’s the start of a seismic shift in the industry.”
While it’s standard to include serialization into new equipment, the challenge lies with introducing serialization into existing lines. To tackle this challenge, according to Mr. Klotz at Uhlmann, the company developed a serialization platform. “By strategically adding small, flexible, multifunctional print and inspect modules into an easily movable frame, we have been able to incorporate the latest technologies in marking and OCR/OCV (Optical Character Recognition/Optical Character Verification) with minimal downtime and validation impact.”
Michele Leonardi, regional sales manager for MG America, added, “Serialization is part of any project involving secondary packaging equipment for the pharma industry, and for this reason we have developed equipment that can be integrated on existing or new packaging lines in order to perform coding and verification of serialization codes on bottle, carton and bundle. The whole MG America range of case-packer and palletizer also has been modified in order to allow the integration of cameras on various parts of the machine, allowing verification of the serialized codes.”
Within the pharma industry, there has been a substantial increase in discussions regarding serialization, and while experts agree there’s a need for a serialization model, Charles Ravalli, CEO of Romaco North America, said it’s also clear that the efficiency of such a system would rely on a very well organized international database. “There are numerous questions of how, where and by whom this vast amount of data could be analyzed efficiently, reliably and promptly. Worldwide manufacturers of pharmaceutical products and equipment are prepared to take action, when the final decisions are made by international regulators,” said Mr. Ravalli.
Packaging Complexities
The intricate nature of many new pharma and biopharma products requires advanced equipment that meets numerous criteria, namely safety, flexibility and expert handling—for example, with highly potent compounds, and lyophilization of drug products, where containment and production time is critical.
According to Mr. Poslovski, OPTIMA develops technologies and systems designed to reduce the time between batch production, such as during the cooling phases of freeze-drying or in the case of format change. “Another important aspect is the extensive modularization of the machine systems. This, for example, also affects the design of the interfaces between filling machines and isolators, connection of freeze-dryers by means of automatic transport systems, feeding and discharging, as well as the freeze dryers themselves.”
Due to the increasing complexity, sensitivity and demand for consistency of products, it has become necessary to monitor processes online. “This means a departure from random sampling or statistical monitoring and a move to 100% control,” Mr. Poslovski said. “Further advances that address the myriad of product characteristics include machines fitted with several dosing systems that can process several different types of containers. These dosing systems can be set up quickly and adjusted to suit diverse, sensitive products. In conjunction with in-process controls, all the dosing systems attain extremely high levels of filling precision,” according to Mr. Poslovski.
Additionally, with the growth of highly potent pharmaceuticals, manufacturers need to be mindful of protecting all elements of the supply chain from their potentially harmful effects. Recent equipment solutions favor the use of automation and robotics technology to reduce human contact with the product. Also, due to stricter guidelines for aseptic filling operations from the FDA, manufacturers increasingly rely on the use of isolators.
According to Dr. Rauschnabel of Bosch Packaging Technology, “Vials remain the predominant containers handled in isolators, while the use of pre-filled syringes is rapidly growing, especially in Europe. The development of ready-to-fill, sterile, primary packaging systems in cooperation with leading equipment manufacturers has improved aseptic filling operations and paved the way for the development of new, highly flexible filling and closing machines designed to handle pre-sterilized nested syringes, vials and cartridges, such as the FXS Combi from Bosch. Also, the ability to use filling technologies with single-use components offers a cost-effective alternative to expensive cleaning operations for product contact parts,” added Dr. Rauschnabel.
Offering a contract packaging perspective on challenging products, Tee Noland, chairman and CEO of Pharma Tech Industries, said, “In our experience, reconstituted powder offers some unique advantages for certain temperamental liquid formulations. From a packaging standpoint, we tend to use foil barriers as an effective packaging solution for powders and other hydroscopic solids.” Robotics have become increasingly handy for such applications. Mr. Noland noted about 50% of his company’s packaging lines incorporate the use robotics.
Adding another layer of complexity, uniquely shaped pharmaceutical tablets are also impacting packaging equipment. “Complex product geometries and dimensions always require sophisticated product feeding systems,” said Mr. Ravalli of Romaco. “The variety of demanding product specifications is steadily increasing as our customers continue efforts to differentiate their products. This requires precisely designed feeding solutions for primary (blister and strip) and secondary (cartons) packaging challenges.”
Looking Ahead
Where will the future of packaging services and equipment lead? In addition to classic containers such as pre-filled syringes, vials and cartridges, systems for administering medication will continue to grow in importance, noted Optima’s Mr. Poslovski. “Self-medication is driving this development forward. Other methods of administering medication that are more pleasant than an injection, and alternatives to large-sized tablets and capsules, are also fields for further development that will bring new challenges to machine design and construction. Additionally, flexibility of machine systems will also be driven forward so that the greatest range of different containers can be processed. This also includes the minimizing of changing times and format parts,” Mr. Poslovski added.
According to Mr. Schroeder of PCI. “As pharma’s pipelines are challenged to bring products to market more quickly, safely and cost effectively, we are seeing more products that are not shelf stable in traditional materials or ambient environments. This places the onus on the packager to enable shelf-stable products by virtue of high-barrier materials, use of cold chain logistics, and utilization of modified environments such as nitrogen flushing, for example. The market is adapting to these new expectations and will continue to provide innovations to support speed-to-market.”
Finally, as lyophilization and other efforts to sustain the shelf life of temperamental drug products grow, managing the cold chain is paramount across the industry. “The complexity of cold-chain management continues to grow with the expansion of the biologics market,” noted Vladimir Spehar, director, strategic business development at Jones Contract Packaging Services. “We have invested in a cold chain-compliant refrigeration system to support the increased demand in this area. We are also researching temperature-management solutions on printed packaging components for drug products.” While not without its challenges, equipment suppliers and manufacturers alike must constantly assess and respond to pharma and biopharma industry trends and the demanding products they produce.
Kristin Brooks is the associate editor of Contract Pharma. She can be reached at kbrooks@rodmanmedia.com
