Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

 annual equipment and manufacturing survey collected industry feedback on trends and the utility of equipment used in finished drug-product manufacturing. Respondents to both solid-dosage and parenteral drug manufacturing questions indicated overall satisfaction with existing equipment and equipment innovation. Data indicated that process analytical technology (PAT) is growing in use, but some users also noted a need for improvement in existing PAT equipment and in new solutions. A majority of respondents continue to view quality-by-design (QbD) principles as important, and more than 90% of respondents have a positive view of metrics and trend analysis. Responses also indicated further growth in continuous manufacturing and in manufacturing of highly potent drugs. Other areas of innovation to watch include robotics and software. 


  Existing solid-dosage equipment is generally meeting industry needs. Only one area—PAT/in-process testing—was indicated as poor or inadequate by more than one-third of respondents (see 

). Nearly one quarter of respondents also indicated that innovation is lacking in this area. This dissatisfaction is up from 2013, in which 22% indicated existing equipment was poor or inadequate and 16% said innovation was poor (1). It is interesting to note that use of PAT also increased over the past year among those surveyed. Process control/automation and powder transfer/materials handling were also flagged as needing significant improvement in existing equipment (25% and 21% respectively) and in innovation (17% and 12%); these areas were also noted in 2013. 


  The percentage of respondents involved in solid-dosage manufacturing that use continuous processes either overall or in select unit operations was nearly 40%, which was similar to 2013. Respondents expressed greater confidence in the evolution of continuous solid-dosage manufacturing, with nearly 85% predicting that the technology would evolve to allow fully continuous processing; in 2013, only 67% predicted such development of the technology. Just over one-third of respondents, however, predicted that the industry would only apply continuous processing to select operations even if fully continuous processes are available. Several individuals commented that, although continuous processing would work for high volumes, they didn’t see it being appropriate for small batch sizes. Half the respondents noted cost as a barrier to implementing continuous manufacturing, and over 40% also identified lack of expertise and insufficient PAT as barriers. 


  The majority of parenteral-equipment respondents indicated that existing equipment is good or excellent, as shown in 

 These respondents also agreed that innovation is generally keeping pace with most, if not all, of their needs. Innovation was rated as excellent or good in lyophilization (95%), barrier isolation (91%), disposables (91%), vial and cartridge fill-finish equipment (92%), and prefilled-syringe fill-finish equipment (85%). Process control and automation was a weaker area, similar to 2013, with approximately 25% saying that existing equipment is either poor or inadequate, and 18% saying that innovation is poor.


Just over one-third of respondents (in either solid-dosage or parenteral manufacturing) are involved with high-containment or high-potency manufacturing either in-house or at outsourced facilities. This percentage was up just slightly from last year’s survey; however, in 2014, 78% indicated an increase in their company’s level of activity over the past year up from 53% in 2013. When asked to identify the most challenging equipment or processing area, respondents’ answers were diverse, with 21% each indicating system setup/changeover and getting materials into or out of the system during production. Other areas chosen as the biggest challenge included containment (17%), ergonomics (14%), air flow (10%), environmental issues (9%), and personnel protection (7%).  Training and cleaning validation were also identified as challenges. 


Those surveyed overwhelmingly agreed that metrics and trend analysis enhance the ability to improve equipment operation (92% of respondents). Actual use of metrics lagged this response somewhat. Approximately 75% stated that they use trend analysis to measure process or product deviations and relate this to equipment performance; 73% report that their company culture encourages optimizing manufacturing quality using metrics and trend analysis. Approximately 66% of respondents said their company has a metric(s) specifically to measure unplanned downtime of equipment (i.e., equipment failure).   

In both solid-dosage and parenteral areas, approximately half of respondents were aware of an equipment failure that had led to significant downtime or quality problems in the past year. When asked to identify the root cause(s), contamination or cleaning problems were most frequently chosen (44%), followed by utilities (37%), process validation (26%), nonconformance (25%), and other (11%) (multiple selections were allowed).


The majority of respondents use QbD principles in their manufacturing processes to some extent (see 

). Approximately 35% apply QbD to all processes for new or all products, and nearly 43% apply QbD to select processes. Almost 22% indicated that they do not use QbD principles. Respondents noted several different challenges to implementing or barriers to using QbD (multiple answers allowed). The challenge most frequently identified was lack of knowledge or training (nearly 60% of respondents). Other challenges included  lack of clarity in regulatory guidance (40%), management buy-in (38%), and availability of necessary equipment (35%) and software tools (31%). Nearly 10% said they saw no barriers or challenges. 


In the five manufacturing areas surveyed, the use of PAT increased significantly since 2013 (see 

), with 32-46% of respondents in 2014 indicating that they currently use PAT compared to 13-21% of respondents in 2013 (1). The primary drivers for using PAT (multiple answers possible) include better process understanding (56%), increased efficiency (39%), reduced costs (34%), and shorter process times (30%). The use of PAT should continue to grow; between 20 and 30% of respondents in 2014 indicate plans to implement PAT in the coming year. Approximately one-third of respondents (33-37% depending on the application), however, do not currently use PAT and do not plan to implement it in the coming year. 


Given these plans to implement PAT and the respondents who said that existing PAT tools do not meet their needs, as discussed previously, PAT is an area ripe for suppliers to develop new and improved instruments. 

When asked about the most important area for innovation in pharmaceutical manufacturing, respondents mentioned some of the topics surveyed, such as continuous processing, QbD, and PAT, and several respondents listed automation. “Robotics are an inevitability,” said one, and another commented, “Running ‘lights out’ [i.e., fully automated] would reduce the amount of hands-on time for production personnel.” Related comments included calls for improved software to eliminate human error. A wide range of methods and technologies, including those evaluated in this survey, will play a role in the continued drive to improve product quality and process efficiency. 


Jennifer Markarian is the manufacturing editor for

Articles

PharmTech's annual equipment and manufacturing survey shows gains in process analytical technology and indicates areas for future innovation.

Trends in Manufacturing and Equipment

Blow-fill-seal (BFS) technology—in which a polymeric container is formed, filled, and sealed in one continuous process--has been used for more than 40 years to aseptically package parenteral pharmaceutical products, such as ophthalmic solutions. Use of BFS technology is expected to increase for packaging biologics, such as vaccines and protein-based materials. BFS is an automated system that minimizes human contact. Typically, the product-contact path of the BFS process is sterilized with steam, and the entire process takes place in a cleanroom environment. Noxilizer, which supplies nitrogen dioxide (NO

) sterilization systems, and BFS equipment supplier Weiler Engineering recently presented research on NO

sterilization and depyrogenation of the fill area in Weiler’s ASEP-TECH BFS systems using a Noxilizer NOX FLEX Rapid Biodecontamination System (1). 

 spoke with David Opie, PhD, senior vice-president of R&D at Noxilizer, and Chuck Reed, director of sales and marketing at Weiler Engineering, about this sterilization and depyrogenation method. 

Sterilization and depyrogenation
PharmTech: 

What are some of the concerns for sterilizing BFS equipment? 

 Aseptic processing requires rigorous and careful manufacturing practices due to the potential adverse effect on the healthcare consumer. Regulatory agencies are placing greater focus on improved patient safety and are developing standards to ensure sterile, contamination-free products. In particular, regulatory standards increasingly state that pharmaceutical manufacturers should be aware of new procedures designed to reduce risk to the product through the use of enhanced technology. One such procedure is the reduction of pyrogens during the decontamination process.

Pyrogenic contamination comes from endotoxins, which are mainly lipopolysaccharide components of Gram-negative bacterial cell walls that can cause acute febrile reactions. These endotoxins are heat stable and may be present even when viable organisms are no longer detectable. Endotoxins are impossible to eliminate from filled containers; thus, procedures are generally directed at eliminating endotoxins during the preparation process. 

The entire BFS process takes place in a cleanroom environment, and the product-contact path is sterilized in place with steam. The fill area of a BFS system is much different from the fill area of a conventional aseptic filling system, because the product is filled as soon as the container is formed, which reduces the opportunity for contamination. The critical filling zone area of a BFS machine is the area comprising the fill system shroud, which typically encompasses the fill needles and electronic modular dosing system. This enclosed area has typically been manually sanitized prior to the start of a production batch, and during production is supplied by HEPA-filtered air. We wanted to provide additional assurance for our customers of the decontamination of the fill area. The NO2 process offers a new procedure for depyrogenation and decontamination of the fill area in a BFS system to give that additional assurance. 

What are the advantages of using NO2 to sterilize the BFS fill area?

The room-temperature process combines decontamination of exposed critical zone surfaces with the potential for depyrogenation of these surfaces. The Noxilizer process is a fast (less than one hour), automated process that yields more than a six-log reduction in biological indicator organisms and more than a three-log endotoxin reduction (1). The NO2 process is a true gaseous process that has more uniform distribution than vapor processes. Another feature of the NOX FLEX system verified in this study was the remote operation of the decontamination process with up to 50 meters of conduit between the NOX FLEX unit and the ASEP-TECH system, which permits the location of the Noxilizer equipment outside of the cleanroom in which the BFS machine is installed.

 BFS technology is well suited for aseptic processing of biologics, such as vaccines and protein-based materials, which are particularly sensitive to residual sterilant in the filling environment. NO

 has been demonstrated to have a fast aeration rate that results in low residual sterilant. In addition, the automated NO

 system eliminates the human interaction required in the manual sanitization method. Finally, the integrated system is an efficient process that can be more easily validated than the manual process. 

What are the critical parameters of the sterilization cycle? 


 The cycle parameters were developed to coincide with the normal cycle time of the clean-in-place/sterilize-in-place process for sterilizing of the product path in the BFS machine. The BFS cycle parameters for the study were 30 mg of concentrated NO2, 55% relative humidity, a 40-minute decontamination time and 30-minute aeration time (1).        


1.	C. Reed, et al., “Decontamination and depyrogenation of an Asep-Tech Blow/Fill/Seal system,” poster presented at the PDA Annual Meeting (San Antonio, TX, 2014). 

Jennifer Markarian is the manufacturing editor for

Nitrogen dioxide can sterilize and depyrogenate an aseptic fill area in a blow-fill-seal process.

Sterilization of Blow-Fill-Seal Equipment for Aseptic Filling

In blow-fill-seal (BFS) technology, which is a form of advanced aseptic manufacturing, the container is formed, filled, and sealed in one continuous, automated system.  A primary advantage of this technology is reducing human intervention, which reduces the risk of microbial contamination and foreign particulates. BFS has long been used in liquid pharmaceutical applications, including small containers, such as ophthalmic and respiratory drug ampoules, as well as larger volume containers, such as saline or dextrose solutions. More recently, BFS technology has been expanding into injectables and into biologics, including vaccines and monoclonal antibodies (mAbs). 


  Catalent, which has used BFS for more than thirty years, recently launched ADVASEPT, a new technology for "glass-free delivery" of injectable drugs, using BFS technology.  The aseptically filled polymeric containers reduce or eliminate many of the concerns associated with traditional glass vials, including the potential for glass-particulate contamination and accidental breakage, the company noted in a press release.  Because the technology involves a new container closure, the stability of the drug needed to be measured in the polymer container to identify any concerns with permeation or extractables and leachables. Catalent's analytical group developed test methods for determining an extractables and leachables profile, and a two-year stability study comparing plastic and glass containers for biologics is underway, said Bill Hartzel, director of strategic execution, Sterile Technologies, at Catalent, in an interview with 

. After nine months, the data continues to be positive and shows comparability of the mAb in a glass vial to an ADVASEPT vial. 

"BFS technology embraces quality-by-design principles," adds Hartzel. "It simplifies the manufacturing process by reducing variables and removing human intervention and is heavily based on automation. We have challenged the system and identified the critical control parameters to provide enhanced sterility assurance. This proprietary filling technology is designed to drastically reduce the level of foreign particulates in the vial compared to traditional glass vial manufacturing." 


  BFS technology is beneficial for biologics, which typically cannot withstand terminal sterilization and must be processed aseptically. Although there have been concerns that the container is at an elevated temperature during the filling process, much development work has been done to control the impact of heat exposure. Tightly controlling the process is crucial in heat-sensitive applications, noted Chuck Reed, director of sales and marketing at BFS-equipment manufacturer Weiler Engineering, in an interview with 

Weiler's system controls process parameters, such as incoming product temperature and mold temperature, and has been successfully used for heat-sensitive materials for more than 20 years, says Reed. 

Catalent has been supplying a commercial biologic using BFS technology for nearly 20 years. "A challenge with large molecule products is the difficulty in extrapolating the data across molecules, and it is important to understand the process to evaluate whether the biologic is suitable in BFS," explains Hartzel. "Through its understanding of the process, Catalent has proven experience with filling commercial biologics using BFS and continues to provide additional testing on mAbs to provide confidence that this technology is suitable for biologics."  


  To enable aseptic processing, BFS equipment is operated within a cleanroom. In addition to product characteristics, container design, and equipment parameters, the production environment in the cleanroom, including controlled room temperature and humidity, is important to consider, notes Josef Trapl, technology manager for the LifeScience segment at engineering and construction firm M+W Group. For producing biologics, both GMP and biosafety requirements must be considered, and an interdisciplinary engineering approach should be used for correct integration of the equipment in the cleanroom and safe operation of the facility, says Trapl.

Inside the cleanroom, the product-contact path of a BFS system is typically sterilized in place using steam. In addition, the fill area of the system is a crucial section for maintaining sterility. The fill area has traditionally been manually sanitized. Weiler, however, recently introduced a patent-pending, automated system using nitrogen dioxide (NO

) sterilization to both sterilize and depyrogenate the fill area, which provides additional assurance of sterility. NO

 sterilization has low residual sterilant and is thus particularly suited to biologics, which can be sensitive to residual sterilant in the fill area, notes Reed. Noxilizer's NO

-based NOX FLEX Rapid Biodecontamination system is now an option on new Weiler ASEP-TECH Blow/Fill/Seal machines. Noxilizer and Weiler presented results of a study using the new system in a poster, "

Decontamination and Depyrogenation of an ASEP-TECH Blow/Fill/Seal System

," at the 2014 PDA Annual Meeting in San Antonio, Texas, and the July issue of 

 will include an interview with the companies. 

New advanced aseptic manufacturing technologies are available for filling liquid pharmaceuticals, including biologics.

Blow-fill-seal Technology Advances in Aseptic Filling Applications

Progress in continuous manufacturing for solid-dosage drugs was evident at INTERPHEX 2014, held March 18–20 in New York City. Equipment manufacturers now offer continuous lines, such as the Lodige Granucon continuous granulation and drying system and the GEA ConsiGma system that includes a high-shear granulator, dryer, in-line blender, and tablet press. Most recently, at interpack 2014, Glatt introduced the MODCOS continuous rotary chamber process insert, which can be used to convert Glatt ’s batch GPCG to a continuous fluidized-bed system. Associated equipment for continuous process lines, such as feeders, control systems, and process analytical technology (PAT), are also now available from several companies. 

“We have seen a huge increase in the amount of interest since last year’s INTERPHEX,” said Doug Hausner, associate director for industrial relations and business development with the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based at Rutgers University in New Jersey, in 

. FDA has actively promoted use of continuous processes, and a number of applications using continuous processes are currently in review by the agency. Approval and commercial production of these products is expected to give a boost to the adoption of continuous processing technology by the rest of the industry, noted Hausner. 

Hot-melt extrusion (HME) is one type of continuous processing technology that has been embraced over the past decade, noted Charlie Martin, president of Leistritz, in 

. HME is a “battle-hardened,” proven technology that has been used for 50 years in other industries. The challenge for the pharmaceutical industry is to learn this existing technology and apply its well-known processing principles to pharmaceutical processes, said Martin. One opportunity for industry members to learn more about HME is an annual Pharmaceutical Extrusion Seminar sponsored by Leistritz, to be held on June 18-19, 2014. 

One of the initial drivers for interest in continuous pharmaceutical processing was FDA’s PAT initiative. Integration of PAT into continuous lines is an ongoing focus of research and development. “Upcoming technologies will have a real effect on what can be done in terms of real-time measurement,” predicts Hausner.

Another area of development is integrating advanced control of processes, which is of interest to regulatory agencies because it can lead to greater control and thus improved quality. Advanced control moves beyond local control of individual unit operations and incorporates an overall supervisory control system. In an advanced process control solution, data from PAT is captured in a PAT or quality-management system, explained Pamela Bruen Docherty, Life Sciences industry manager USA at Siemens, in a presentation at INTERPHEX 2014.  “In a continuous process, the data comes quickly and you want to react to it quickly,” said Docherty.  “A solution must capture and interpret the data in real-time to adjust the process parameters and keep the product within control.” The goal is to manage the data and allow real-time release of the product. 

Some question how a batch can be defined when using a continuous process. “According to FDA regulations, a batch is an amount, not the manufacturing method,” explained Docherty in the presentation. A batch is defined as a specific amount produced in a unit of time (e.g., a day) or quantity (e.g., kilograms or a tablet count) that has uniform characteristics within specified limits. The batch definition should allow traceability in case of a recall. 

One of the current needs is to develop better business models and design effective tools to measure return on investment for continuous processing, because it is quite different from existing batch processes, noted Hausner in a presentation at INTERPHEX 2014. With many aspects of continuous manufacturing in active development, further progress can be expected in the upcoming year. 

Progress in equipment availability, process analytical technology, and advanced process control aids ongoing development of continuous solid-dosage manufacturing processes.

Continuous Solid-Dosage Manufacturing Moves Forward

Manufacturing execution systems (MES) are computer programs that collect and manage manufacturing data. In pharmaceutical manufacturing, MES are used to manage recipes and collect data for electronic batch records and, ideally, are part of an overall manufacturing operations management system. More companies are looking at the collection of meaningful process data in electronic form as a result of FDA’s  guidance for continuous process validation and verification, says Gloria Gadea-Lopez, PhD, associate director of Shire. 

 spoke with Gadea-Lopez and with Martin Dittmer, PharmaSuite product manager at Rockwell Automation, about how MES can improve productivity and the current challenges  faced by companies implementing MES systems. 

What benefits are driving the use of MES in pharmaceutical manufacturing?  

 MES is a key system that has tremendous potential because it provides a global view of the manufacturing operation, raw materials usage, and equipment status, to name a few.  In addition to continuous process validation and verification, more emphasis is being placed on key metrics (e.g., right first time, process discrepancies); MES is key in this area because it can enable ‘review by exception,’ which has the benefits of saving time and resources. 

Life-science companies are facing a changing healthcare landscape, generic competition, heightened regulatory scrutiny, expansion into emerging markets, and persistent economic changes (both expansion and slowdown). These challenges increase pressure across the industry to better manage risk, improve asset utilization, and drive cost cutting and speed. By having equipment capable of collecting a wide range of performance and operating data, companies can gain a competitive advantage. With optimized data collection capabilities, end users have readily accessible information that is visible across the enterprise. This information enables individuals at all levels to understand asset operation with a holistic view of the plant, helping personnel make informed decisions, reduce downtime, and improve plant productivity.

Currently, many life-science companies are faced with islands of automation, a complex application landscape, aging equipment, and/or manufacturing processes designed for validation, but not efficiency. Any modification to the manufacturing process requires change control, long lead time for quality checks, and batch-record reviews before a product is approved for shipment--a timely, often inefficient process. As equipment ages, it is inevitable that concerns about part sourcing, service, potential productivity losses from old technology, and increased risks of downtime become stronger. Best-in-class companies, however, are quickly realizing the need to leverage manufacturing technology as an asset and invest in automation systems that allow them to stay ahead of consumer demand, improve traceability, and reduce cycle times.

What limitations in existing MES technology need to be addressed?

An important benefit of a successful MES implementation is that key information generated during the manufacturing process becomes available in electronic form. Although some level of reporting is available today with MES, the task of troubleshooting and analysis in an all-encompassing manner is limited. Ideally, process information from batch records, raw-material details, and results of in-process and product-testing results should be aggregated and routinely analyzed. Successful process troubleshooting and thorough data analysis rely on the availability of data collected from GMP-compliant sources that has been transformed in meaningful ways to yield trending and visualization. Currently, organizations must customize MES to extract data and aggregate it with data from other sources to produce the desired analysis. System interfaces between MES and data-analytics tools still remain to be demonstrated.
  
  

 What challenges do companies face in improving data management in manufacturing? 


The most significant challenge is integration of data from multiple sources while maintaining an accurate representation of the complex manufacturing processes. Biologics manufacturing involves a series of linked operations with a complex lot genealogy. The correct representation of the inputs and outputs from each unit operation is needed to analyze data in a meaningful way. One area to be addressed is data acquisition from vendors/suppliers, which can be a challenge because raw-material data is typically provided as paper certificates of analysis, which require manual transcription into an electronic system. Enabling portals where raw-material suppliers can input their information is potentially one solution, but it comes with some challenges (e.g., security). Additionally, more companies are adopting single-use systems. The successful implementation of disposables in MES is still an emerging area that needs to be further explored. The algorithms used to represent ‘equipment clean status,’ for example, are no longer applicable in their traditional form. Also, raw materials and single-use equipment are intertwined, making traceability more complex.  Finally, finite scheduling (either as part of MES or in stand-alone systems) would require definition of entirely new steps, previously irrelevant in conventional stainless-steel plants. 

Pharmaceutical Technology spoke with Gloria Gadea-Lopez, associate director of Shire, and Martin Dittmer, PharmaSuite product manager at Rockwell Automation, about how manufacturing execution systems (MES) can improve productivity and the current challenges faced by companies implementing MES systems.

Data Management in Manufacturing

Continuous manufacturing promises more efficient production than batch manufacturing, with smaller-footprint equipment that can more flexibly produce small or large volumes with fewer scale-up difficulties and the potential for tighter control. Process development in continuous manufacturing is more efficient too; with a short residence time, the effects of changing process variables can be evaluated quickly. Other industries (e.g., food, chemicals, plastics) use continuous manufacturing, and it is taking hold in both solid-dosage and biopharmaceutical production. 

 has been tracking trends in continuous processes for solid dosage manufacturing, such as 

process analytical technology for implementation of closed-loop process control

continuous granulation and hot-melt extrusion

. On Tuesday morning, March 18, at INTERPHEX 2014 in New York City, 

will host several experts on Innovation Stage 2 (located on the 

 in the INTERPHEX Connects Networking Area) who will highlight developments in continuous solid-dosage processing. From 10:30-11:15 am, two presentations will focus on 

, a continuous process that is being used to improve the solubility of poorly-soluble drugs and create innovative dosage forms. Gain insight from hot-melt extrusion expert Charlie Martin, president of 

, who will explain twin-screw extrusion theories, as well as give practical tips and share recent test results, and hear Tony Listro, managing director of 

, share his experience in extrusion and shaping technologies for combination drug-device products. From 11:15 am-12 pm, gain a broad view of 

Engineering Research Center for Structured Organic Particulate Systems

 at Rutgers, the State University of New Jersey, and learn the latest is enabling integrated system control from Pamela Bruen Docherty, Life Sciences industry manager at 

focuses on the biopharmaceutical industry, which is under pressure to improve downstream processing (i.e., purification and separation) to keep up with upstream processes, and is exploring the potential of the higher efficiency of continuous processing, such as 

. On Wednesday, March 19 from 1:30–2:15 pm, experts will discuss 

continuous manufacturing for biologic drugs

. John-Bonham Carter, vice-president of business development at 

, will discuss trends and challenges in continuous biomanufacturing, and Stéphanie Dubois, Cell Culture lab manager and applications specialist at 

 will describe continuous cell-culture platforms and the  challenges addressed by alternative technologies.

 Another aspect of improved efficiency is the use of new facility designs. As reported in the 

, biopharmaceutical manufacturing is experiencing a shift to flexible, multiproduct facilities, which can be enhanced with single-use and modular technologies. From 2:15–3 pm on Wednesday, March 19, experts will share the latest trends in 

modular biopharmaceutical manufacturing systems

 and Modular Partners, will discuss standardized modular facility solutions, and Parrish Galliher, Founder and CTO of 

Xcellerex, a GE Life Sciences Healthcare 

company, will explain how to rapidly enable flexible biomanufacturing in a new or existing facility. 

Experts will examine continuous processing in solid-dosage and biopharmaceutical production.