Novel Equipment Solutions: Leading to Manufacturing Efficiency and Productivity

Pressure to be first-to-market with new therapies that provide demonstrated value is steadily intensifying. The implications for drug manufacturing are significant. Pharmaceutical companies are increasingly turning to equipment suppliers for forward-thinking solutions, novel equipment and process technologies to help them achieve greater efficiency and productivity, accelerate drug development and facilitate the commercialization of next-generation therapies.

The outlook for the pharmaceutical equipment markets (production and packaging) is quite positive. According to PharmSource, the market size for bio / pharmaceutical industry spending on investment for new plant and equipment was $18.6 billion in 2013 and rose to $21.4 billion in 2014 — an increase of 13%.¹ Meanwhile, the pharmaceutical packaging equipment market was valued by Markets and Markets at $5.18 billion and predicted to grow at a compound annual growth rate of 6.9% to reach $7.24 billion in 2020.² In addition to general expansion of the overall pharmaceutical market, the key driver for growth of these equipment sectors is the need for novel and flexible equipment to maintain competition.

Survey Says: Spending Is On The Rise

Strong growth rates are mirrored by the results from the 2016 Nice Insight Pharmaceutical Equipment Survey of nearly 500 professionals involved in the evaluation and purchasing of processing and packaging equipment.3 Over two-thirds (69%) of participants from around the world (41% North America, 40% Asia and 19% Europe) representing biopharma/biotech (45%), branded pharma (27%), generic pharma (16%), over-the-counter (6%) and contract manufacturing organizations (CMOs, 4%) of all sizes (large: 46%, medium: 38%, small / emerging: 16%) saw their equipment budgets increase from 2013 to 2015. Equipment expenditures remained steady over that period for 25% of respondents, while just 4% indicated their company decreased its annual equipment budget.

In addition, over half (57%) of survey respondents have an annual equipment budget of greater than $50 million, with an additional 28% working for companies that spend $10 to $50 million. Importantly, 56% of the participants in the survey are part of a decision-making unit that selects pharmaceutical equipment at their firms, while the other 44% belong to teams that establish criteria for and make recommendations on equipment. Furthermore, 76% of survey respondents are authorized to approve expenditures on capital equipment; of those, one quarter have a spending limit of $250,000 and higher, 37% claim $100,000–$250,000 and 28% hold a budget of $50,000–$100,000.

While a strong majority of respondents are interested in purchasing pharmaceutical processing equipment (93%), there is also significant need for laboratory (87%) and biopharma processing (81%) as well as fill / finish and packaging (77%) equipment. Top drivers for the purchase of new equipment include the need to meet quality / sterility standards, address changing market needs, meet increased demand for existing products, improve equipment effectiveness, upgrade to new equipment, install capacity for new drug substances / products and expand their technical capabilities.

Increasing reliability is the key driver for the selection of a specific piece of new equipment according to survey participants, but they are also looking for equipment and suppliers that can help them improve process integrity, provide better customer service, reduce their total cost of ownership and increase overall equipment efficiency. Not surprisingly, therefore, equipment suppliers that offer products with manufacturing / process integrity, good product life cycle management, customer service, equipment troubleshooting and the ability to inspect or test their equipment are preferred. Similarly, poor performance with respect to product / system quality, durability, reliability and poor customer service are top sources of dissatisfaction.

Novel Technologies For Novel Therapies

In addition to the need for greater efficiency and cost-effectiveness, the increasing complexity of drug substances (including small-molecule, biologics and next-generation therapies) moving through clinical trials are driving the development of new manufacturing technologies.

Regulators, especially the FDA, have worked hard to create an environment where the development of medicines to treat rare conditions for smaller patient groups is financially feasible. This is reflected in the updated drug review process; the time needed for FDA review has decreased over the last 20 years from years to months. With this pressure on speed to market, FDA has become known as the leading global regulatory agency, in terms of new drug approvals and speed of review.⁴ Gert Moelgaard, Head of Strategic Development at NNE Pharmaplan, an engineering and consulting company focused on life sciences, noted in a recent trade journal that “Specialty medicines and facilities of the future are the new challenges — the biggest pharmaceutical products are now specialty medicines. Not ‘biggest’ from a volume perspective, but from a value perspective. This has significant implications for manufacturing, especially on flexibility needs.”⁵

As the industry shifts towards smaller and more specialized medicines, the result is a much closer link between the pharma company and target patient group. “This link is even more visible when we talk about small diseases or … orphan diseases,” continued Moelgaard. “Pharma companies tend to work closer with their patients and adapt their products to serve their patients in the best possible way, which often means that the need for manufacturing flexibility increases.” Ultimately, he has asserted that Pharma must expect target diseases and patient groups to become more specific, implying “that the demand for manufacturing flexibility is not going away any time soon.”⁵

Flexibility, scale, time and cost savings are being achieved in biopharmaceutical manufacturing with the adoption of single-use technologies, not only at lab and pilot-plant scales, but also for commercial production. Disposable technologies allow for decreased capital expenditures and operating costs, due to the reduction of cleaning and sterilization steps and the need for validation. Single-use equipment systems offer increased flexibility, decreased set-up time and a lower risk of cross-contamination.

Single-use systems are also ideally suited for continuous manufacturing. The introduction of numerous disposable solutions, specifically designed for this purpose, is facilitating the move toward fully integrated continuous biopharmaceutical production, which is strongly encouraged by FDA.⁶ Continuous manufacturing leads to more consistent products and processes, reduced consumption of resources (raw materials, energy, water), less waste generation and often lower operating costs. Modular facilities are expected to provide the speed to production, flexibility and reproducibility required in the future for small-volume, multi-product production plants.

Smaller Can Be Better

The advent of personalized medicine, and the pursuit of specialized pharmaceuticals for smaller target groups, has prompted the introduction of equipment that has flexibility in scale and output, as well as performance and efficiency. Dramatic gains, for example in small-molecule production, can be made in flexibility and scale by implementing a continuous manufacturing line instead of a batch process.

CONTINUUS Pharmaceuticals, developed at the Novartis-MIT Center for Continuous Manufacturing and launched to apply Integrated Continuous Manufacturing (ICM) technology, signed an exclusive license with MIT (co-exclusive with Novartis) for a number of novel unit operations.⁷ CONTINUUS has adopted an interesting strategy of designing, building and running manufacturing processes directly at client sites. According to the company, its success is based on the establishment of long-term client partnerships. Typically, a phased investment approach is used to reduce the risk of switching to continuous processing. 

Process technologies / equipment that CONTINUUS implements for clients include: continuous reactors for the handling of solids in flow; a membrane separator bypass that allows automated cleaning in place of liquid membrane separators; heterogeneous crystallization on crystalline or polymeric excipients to eliminate the need for granulation and other downstream processes; integrated nucleation / tubular crystallizer to produce particles with mono-disperse size distributions, continuous small-scale rotary filtration and washing system for the purification of concentrated suspensions; small-scale continuous dryers that form dry powders from concentrated or diluted API suspensions; integration of extrusion / moulding processes for continuous tablet production; and thin-film / electrospinning process for the conversion of solutions / suspensions into tablets.⁷

Continuous manufacturing provides flexibility unparalleled by like technology. Equipment manufacturers are examining their current scales and introducing “downsized” systems to better serve the needs of biopharma processors playing in “Pharma 3.0” markets, or seeking positions in niche or other specialty products where scale is a relative construct.

Shown at Interphex 2016, Comecer introduced its “Baby Phil” parenteral, aseptic small-batch, vial-filling system for that specific reason. According to Comecer, Baby Phil has an extremely reduced-footprint, all-in-one system that integrates well with isolation technologies. The plug-and-play solution features short changeover time, and includes controls such as weight check, stopper check and crimp inspection. 

Advances Bring Continuous Bioprocessing Closer

Continuous manufacturing has been adopted by numerous industries from the automotive sector to commodity chemicals. In pharma, the value of flow-through chemistry for the production of active pharmaceutical ingredients (APIs) and continuous tableting for final product manufacturing has been recognized for many years. While widespread adoption has not occurred yet, FDA has approved two continuous processes: Vertex received approval in July 2015 for the continuous production of its cystic fibrosis drug Orkambi (lumacaftor / ivacaftor), and more recently (April 2016) Janssen Products received the first agency approval for a change from batch to continuous processing for Prezista (darunavir), a drug for the treatment of HIV-1 infection.⁶

In order to achieve continuous manufacturing, flow chemistry is often employed. This process allows manufacturers greater accuracy and efficiency, which lends to an increased flexibility in scale-up. Flow chemistry also enables technicians to perform hazardous reactions in demanding conditions, such that batch models do not.

Many CMOs have the capability to perform continuous-flow chemistry at commercial scale using microreactor technology. One recent example is Hovione, which announced in March 2016 that it plans to host and operate a commercial-scale continuous manufacturing facility as part of an agreement with Vertex Pharmaceuticals.⁸ In addition, branded drug manufacturers, including Johnson & Johnson (Janssen) and Eli Lilly, have already or are currently investing in continuous technology.⁹

Adoption of continuous manufacturing for biopharmaceutical processing has been slower, but as mentioned above, the growing acceptance of disposable technologies and an increasing commitment by equipment suppliers to provide novel solutions that enable continuous processes is leading to greater interest for the production of both biologic drug substances and final products. 

Pall Life Sciences, for instance, announced near the end of 2015 that the company has made a significant commitment to provide a comprehensive range of single-use components and devices for integrated continuous processing from cell culture to fill /finish.¹⁰ To that end, Pall has been busy developing and acquiring technologies to support continuous downstream unit operations.

At Interphex 2016, the company launched its single-use Cadence Acoustic Separator (CAS) for the clarification of cell culture bioprocess fluids, including those from continuous perfusion processes, using acoustic wave separation technology licensed in 2015 from FloDesign Sonics (FDS).¹¹ “The CAS technology is truly revolutionary, eliminating reliance on centrifugation for cell culture clarification, reducing buffer requirements by around 75% and creating a continuous feed stream for direct integration with our full portfolio,” says Michael Egholm, Vice President and General Manager of Biopharmaceuticals.

The Cadence InLine Concentrator, which is based on single-pass tangential flow filtration (SPTFF) technology, enables the concentration of bioprocess fluids in a single pass (unlike conventional TFF); the short residence time and lower shear exposure reduce the risk of product damage and aggregation. It is readily integrated with other downstream bioprocesses to facilitate continuous operations.¹¹ Pall is also developing Cadence technologies for continuous viral inactivation and in-line diafiltration.¹²

The Allegro line of single-use products (bioreactors, mixers, tubing, connectors, etc.) also supports continuous biopharmaceutical manufacturing. In particular, the Allegro MVP system is designed to automate bioprocesses such as media and buffer preparation, pH adjustment, membrane chromatography, sterile, depth and virus filtration, bioburden reduction and virus inactivation, as well as final formulation and filling. The system comes with a large selection of pre-designed manifolds and sensors, connectors, tubing types, filters and pre-filters, offering greater flexibility, productivity, consistent product quality, reduced labor costs and operator errors.¹³

Going Modular

In late October 2015, GSK joined an existing partnership between Pfizer, GEA and G-CON manufacturing to develop self-contained, POD-based mini-factories for the continuous manufacture of oral solid dosage (OSD) forms.¹⁴ A portable, continuous, miniature and modular (PCMM) prototype unit is already being implemented at Pfizer’s labs in Connecticut. The miniature continuous manufacturing system can be enclosed in a portable, modular facility that can be shipped by truck to any location in the world and quickly assembled for immediate operation. This system can be used for manufacturing on a commercial scale, in the production of clinical trial material and for development. The system also boasts a significantly decreased footprint, at 60-70% less, in comparison to a traditional facility. In addition, a PCMM facility takes about one year, or less, to set up and start running (from the time the decision is made to construct a new facility) compared to 2–3 years for standard processes, according to a GEA spokesperson.

Individual PODs in the PCCM development and manufacturing system contain the elements needed for a pharmaceutical continuous manufacturing line. This includes processing equipment, control systems and cleanrooms; these components are manufactured separately and then assembled at a central location. Importantly, the PCCM system being developed by this partnership is designed to be disassembled and redeployed.The PODs are self-contained, autonomous and include HVAC and other utilities, so they can be quickly integrated, yet malleable.

In this vein, Bayer Technology Services, in conjunction with the F³ Factory consortium (the 25 research-focused partners from 9 EU states), are developing a downstream processing unit for continuous manufacturing, within a modular unit.¹⁵ Transfer of the chemical synthesis to an intensified fully continuous process (operated for several days at bench scale) was found to provide a significant reduction in processing steps, reaction time and solvent use, as well as a reduced footprint and lower equipment, design and installation costs.

Biopharmaceutical manufacturers are also leveraging modular technology. In November 2015, JHL Biotech’s pre-fabricated KUBio plant manufactured by GE Healthcare Life Sciences was assembled from 62 containers in Wuhan, China in 11 days.¹⁶ KUBio facilities meet FDA and EMA GMP standards, are based on single-use technology for rapid switching between processes and include all necessary components, such as cleanrooms, piping and HVAC systems. GE also consulted with China’s Food and Drug Administration. According to the company, the cost of a KUBio plant can be as much as 45% lower than a comparable, traditional facility.

Increasing Productivity

Processing capacity in pharma has less to do with square footage and more to do with throughput; for solid-dose manufacturers especially, any system that can produce more in less space is sure to become popular. One recent example is Fette’s new filling machine, the FEC40, which can fill 400,000 capsules per hour and sets new standards in the efficiency of this type of machine, according to its manufacturer. Fette notes that the compact design of the FEC40 allows more production capacity from the same or less floor space — which means the same number of personnel users can reduce the production costs per 1,000 capsules by up to 30%. 

This performance boost, said Fette at its Interphex 2016 unveiling, “is delivered by a patent-registered drive and control concept.” According to Jan-Eric Kruse, Managing Director at Fette Engineering, “For the very first time, we are using established servo and torque motors in a capsule filling machine to set each process step separately. Among other things, this has enabled us to set each process step separately. This enables the user to significantly reduce the overall cycle time, for example, without increasing product loads.”¹⁷ 

Whether doing more with more, or more with less, pharmaceutical manufacturers are embracing new technologies and production systems at increasing rates. Similarly, as drug owners continue to outsource the many phases of drug development to contract suppliers, thoe companies are also seeking competitive advantage by adopting game-changing technologies needed to position themselves as leading preferred manufacturing partners. Ultimately, pharma’s future is inexorably linked to how well companies can accept, adapt and integrate contemporary manufacturing technologies.

References

1. Bio/Pharmaceutical Outsourcing Report. Rep. PharmSource. May 2015. Web.
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3. The 2016 Nice Insight Pharmaceutical Equipment Survey.
4. “White Paper: FDA and Accelerating the Development of the New Pharmaceutical Therapies.” U.S. Food and Drug Administration. Mar. 2015. Web.
5. Moelgaard, Gert. “Why Small Scale Pharmaceuticals Require Special Solutions.” Process Worldwide. 19 Nov. 2014. Web.
6. Yu, Lawrence. “Continuous Manufacturing Has a Strong Impact on Drug Quality.” FDA Voice. U.S. Food and Drug Administration. 12 Apr. 2016. Web.
7. CONTINUUS Pharmaceuticals. CONTINUUS Pharmaceuticals. Web.
8. Hovione and Vertex Partner in Continuous Manufacturing. Hovione. 10 Mar. 2016. Web.
9. Challener, Cynthia A. “The History of Continuous Processing: Why Has the Biopharmaceutical Industry Been So Late to Adopt?” BioProcess International. 27 June 2016. Web.
10. “INTERPHEX: Pall Launches Commercial Cadence Acoustic Separator for Intensified Bioprocess Clarification.” Manufacturing Chemist. 28 Apr. 2016. Web.
11. Ayturk, Engin, and Jeannette Marshall. “Advanced Concentration and Analytical Technologies Accelerate Development and Manufacture of MAbs, Vaccines, and Biosimilars.” BioProcess International. 27 June 2016. Web.
12. Levinson, Peter. “Moving One Unit Operation At a Time Toward Continuous Biomanufacturing: An Overview of Pall Solutions for Integrated Continuous Biopharmaceutical Production.” BioProcess International. 27 June 2016. Web.
13. Grace, Julie, Chris Irving, and Alain Vanhecke. “Flexible Automation for Continuous Unit Operations.” BioProcess International. 27 June 2016. Web.
14. Pfizer Announces Collaboration with GSK on Next-Generation Design of Portable, Continuous, Miniature and Modular (PCMM) Oral Solid Dose Development and Manufacturing Units. Pfizer. 29 Oct. 2015. Web.
15. “Modular, Flexible Continuous Production of Active Pharmaceutical Intermediates.” F3 Factory. Web.
16. Khan, Natasha. GE Ships Ready-Made Drug Factories From Berlin to Beijing. Bloomberg. 1 Nov. 2015. Web.
17. “THE FEC40: A New Class of Hard Capsule Filling.” Fette Compacting. Web.