The biopharmaceutical industry is working at unprecedented speed to develop and manufacture vaccines for the COVID-19 pandemic. Among the challenges of a pandemic is the need to scale up to billions of doses, at a larger scale than typically needed for vaccines, from raw materials all the way through to the materials for the containers for fill/finish.

Collaborative efforts to make a safe and effective vaccine against the novel coronavirus, SARS-CoV-2, are underway around the world. The timeline to develop, produce, and distribute an approved vaccine is being dramatically compressed, and companies are scaling up manufacturing “at risk,” making the vaccines before they have been approved. While pharmaceutical companies are bearing some of the risk, these efforts are being extensively funded by governments as well as non-profit organizations, such as the Coalition for Epidemic Preparedness Innovations (CEPI) foundation and Gavi, the Vaccine Alliance (GAVI). In the United States, the federal government’s Operation Warp Speed program—a partnership among the US Department of Health and Human Services (HHS), the Department of Defense (DoD), and others—is investing in vaccine development and manufacturing, fill/finish capacity, and in capacity for supply of vials, needles, and prefilled syringes. As of August 5, 2020, more than $6.5 billion had been designated to flow through HHS’s Biomedical Advanced Research and Development Authority (BARDA) for countermeasures and $3 billion for National Institute of Health (NIH) research (1).

Production of the billions of doses needed will require manufacturing at multiple sites, and innovators and contract development and manufacturing organizations (CDMOs) are partnering to come up with all the capacity that will be needed globally. Manufacturers know that it is not only the equipment, facilities, and raw materials—although these are necessary and require planning ahead—but also the knowledge and the expertise to run the process. Technology transfer is, thus, a crucial piece.

Consultants at McKinsey note that tech transfer time for vaccines normally can take 18 to more than 30 months, with transfers to external sites taking even longer. They predict, however, that by employing best practices, the time can be shortened to 8–11 months, or even six months with regulatory flexibility (2). Indeed, the tech transfer process is already well underway at CDMOs.

Everyone is working at “pandemic speed,” says Andre Goerke, head of the planning and value chain management business unit at Lonza; Goerke also is the global project lead for Lonza’s efforts to make the active ingredient for Moderna’s mRNA vaccine. The overarching challenge is to do what needs to be done in this accelerated timeline, but the team is unified in making it happen, he explains. “So far, the most significant asset has been the excellent integration of the Lonza and Moderna teams into a single group working for a common target,” says Goerke.

Having adequate raw materials, building and staffing the facilities, and tech transfer are all keys to success. Flexible, modular facility designs allow manufacturers to adapt and move quickly. Goerke says Lonza’s Ibex facilities “have been set up with exactly this challenge in mind, to allow adaptation to manufacture different kinds of products. Adaptability allows us to cut construction time considerably compared to standard builds and gives the flexibility to install a broad range of manufacturing technology. In addition, we can plug into existing infrastructure, including services (gas, water waste, etc.) as well as analytics and quality labs.”

Emergent BioSolutions says that its flexible CDMO capacity deployment model can respond quickly to demand fluctuations. The company’s Bayview multi-suite facility in Baltimore, MD is designated by the US HHS as a Center for Innovation in Advanced Development and Manufacturing (CIADM) and is designed to leverage single-use technologies to manufacture product in large quantities during public health emergencies. The CIADM can accommodate various types of vaccine platforms that can be manufactured in parallel. Four independent suites allow products or customers to move in and out quickly, explains Dino Muzzin, senior vice-president of manufacturing operations at Emergent BioSolutions. Platform-based equipment at the facility allows flexibility and facilitates tech transfer, noted Richard W. Welch, vice-president of development services at Emergent BioSolutions, in a presentation at BIO (3). Additionally, the company is adding new capacity at its Rockville, MD, and Canton, MA sites and expediting an expansion of its Camden facility in Baltimore, MD.

Several types of vaccines are being developed and tested in the hopes that at least one, but possibly multiple vaccines and of different types, will be approved. The industry is counting on the advantages of “platform” technologies, with development and manufacturing processes that can use the same or similar systems and equipment, tailored for different vaccines. Such platforms allow more rapid development and scale up and, even prior to the current pandemic, were predicted to be useful for responding to an outbreak caused by a new pathogen.

Nucleic acid-based vaccines—based on messenger ribonucleic acid (mRNA) or on deoxyribonucleic acid (DNA)—are examples of platform technologies. Moderna, Pfizer/BioNTech, CureVac, CanSinoBio, and others are making progress using mRNA platforms, with mRNA formulated in a lipid nanoparticle delivery vehicle. Inovio and others are working on DNA-based vaccines. Although nucleic acid vaccines have been tested in clinical trials, for Zika and Middle East respiratory syndrome (MERS), for example, none have yet been approved for use.

Moderna’s vaccine candidate, mRNA-1273, is encapsulated in lipid nanoparticles, and it has progressed to Phase III clinical trials. Moderna is building up manufacturing capacity, partly through its CDMO partner, Lonza, which is adding manufacturing lines in New Hampshire and in Visp, Switzerland. In an interview in late July, Goerke reported that tech transfer for the first step of the process has started as planned, and that preparation was well underway at the Portsmouth, NH facilities, with batches for the first of three process steps (the mRNA step) to be produced in July 2020. “Fit-out of our Visp facility is ongoing. We envisage the start of operations in Visp by the end of 2020,” said Goerke.

“Lonza aims to replicate the facility, equipment, and data management principles developed by Moderna,” adds David Callaert, head of global strategic growth investments and engineering at Lonza. “We plan to further strengthen and pragmatically ensure reliable supply through intense collaboration with the technical teams of Moderna. The aim is to achieve short processing times with high throughput. Going digital and maximizing the use of disposable equipment are some of the key components necessary to achieve these goals.”

Another CDMO partner of Moderna, CordenPharma, will manufacture large-scale volumes of Moderna’s proprietary lipids needed to make the lipid nanoparticle excipients. A challenge is the need to quickly scale-up by a factor of several hundred times the initial scale, says Matthieu Giraud, director, global peptides, lipids and carbohydrates platform at CordenPharma International. “We have to optimize the process for large-scale manufacturing and, at the same time, transfer to our larger assets. In addition, the scales are so incredibly large that we have to leverage our entire CordenPharma network to ensure a sustainable supply chain,” he explains.

The company’s facilities in France, Switzerland, and the US are working on the project; at CordenPharma Colorado, unique high-pressure chromatography systems usually used for manufacturing peptides have been reallocated for purifying lipids. Although making Moderna’s proprietary lipid at large scale is new, Giraud notes that CordenPharma has a long history of large-scale production of standard lipids using its platform technology. CordenPharma’s sister company, Weylchem Innotec, has been able to provide key raw materials for lipid production, Giraud adds.

Quality of the lipids is crucial because of the high proportion of lipids in relation to the mRNA. “The quality of the lipids is known to affect the encapsulation efficiency, liposome internalization by cells, and efflux rate of encapsulated therapeutic agents, all of which have implications for drug delivery and formulation shelf life. It is essential to create a very well-controlled process when manufacturing lipids,” says Giraud.

CordenPharma is on track to meet Moderna’s aggressive timeline, and manufacturing has started at three sites, says Giraud. He points to close collaboration between the company’s facilities, and he says that a rigorous risk management process identified gaps early on, so that risks could be mitigated.

Pfizer and BioNTech are also making progress on their lipid nanoparticle mRNA-based vaccine candidate, BNT162; initial results from Phase I/II studies are positive, and the companies are planning a global Phase IIb/III trial (4). Acuitas Therapeutics is providing lipid nanoparticles for the vaccine. If the trials go well, Pfizer and BioNTech plan to seek regulatory approval or authorization as soon as October 2020. Pfizer says it expects to manufacture 100 million doses by the end of 2020 and approximately 1.3 billion doses by the end of 2021. The US government placed an order for 100 million doses, and the United Kingdom (UK) government signed an agreement for 30 million doses, both pending regulatory authorization or approval (5). Pfizer says it is building inventory of existing products now to make room for vaccine production later. Additionally, according to a Reuters report, Pfizer plans to shift some of its existing drug manufacturing to CDMO partners so that it can prepare for manufacturing the vaccine candidate at three facilities in the US and one in Belgium (6).

CureVac in Germany is also working on an mRNA vaccine, CVnCoV, and Phase I clinical trials began in June 2020 in Germany and Belgium. The company has a proprietary RNAoptimizer platform, which includes an end-to-end, good manufacturing practice (GMP) manufacturing process designed for mRNA-based drugs. The company is expanding its GMP facility and completing construction of its fourth production site in Tübingen, Germany. The company said the facility has the capacity to potentially supply several hundred million doses per year, depending on the human dose defined in the clinical trials (7).

In addition to its large-scale production facilities, CureVac is developing a small-scale, portable manufacturing “facility” it calls The RNA Printer, which it envisions could be transported to outbreak regions or placed in hospitals. In early 2019, CEPI and CureVac announced a partnership to advance the automated equipment that can produce several grams of lipid nanoparticle-formulated mRNA, which could potentially be more than 100,000 doses, in a few weeks (8).

A challenge for distribution of mRNA-based vaccines is the need to keep them frozen. Inovio’s DNA-plasmid vaccine candidate, INO-4800, however, is stable at room temperature for more than a year and does not require being frozen in transport or storage, the company reports (9). Inovio announced positive interim Phase I results at the end of June and had hopes to begin Phase II/III over the summer. The company has a proprietary delivery device, the Cellectra 3PSP, that delivers the DNA-plasmid vaccine directly into the skin. The US DoD provided funding for large-scale manufacturing of the device, and Inovio says it has produced initial quantities at its San Diego, CA, facility and demonstrated that the manufacturing process could be transferred to contract manufacturers (10). An earlier version of the Cellectra has been used in clinical trials of Inovio’s DNA medicines.

Viral vector vaccines are another platform, which uses a live, attenuated virus as a vector or delivery vehicle for an antigen’s genetic code. A benefit of this type of platform is that the viral vectors are made with a standardized manufacturing process independent of the active part of the vaccine, noted CDMO Cobra Biologics (11).

Vaccines made with this type of platform from Merck, Johnson & Johnson, and CanSino Biologics have approvals for Ebola, and these companies are using their respective platforms for vaccine candidates against the novel coronavirus. China’s CanSinoBio’s viral vector vaccine for Ebola has been approved by China’s regulatory agency; the company’s vaccine candidate for the novel coronavirus uses adenovirus 5 (Ad5) and, as of August 9, 2020, was preparing to begin Phase III trials. Merck’s Ebola vaccine, approved by FDA in December 2019, uses an engineered vesicular stomatitis virus (VSV) as the viral vector; Merck currently is working on a VSV-based COVID-19 vaccine. In addition, Themis, which was acquired by Merck in June, has a platform technology that uses a measles vaccine vector.

The Janssen Pharmaceutical Companies of Johnson & Johnson (J&J) received European marketing authorization for their two-dose viral vector vaccine for Ebola on July 1, 2020 (12). The first dose of this approved vaccine uses Janssen’s AdVac viral vector platform, based on adenoviruses that are genetically modified, so they are non-replicating in humans. The AdVac platform is being used for the company’s investigational SARS-CoV-2 vaccine, Ad26.COV2-S, recombinant, which moved into Phase I/IIa first-in-human clinical trials in late July. J&J’s goal is to manufacture more than one billion doses, and it is scaling up manufacturing capacity globally. On August 5, 2020, the company announced that the US government, through BARDA, is committing more than $1 billion for large-scale US manufacturing and delivery of the vaccine following FDA approval or authorization (13). The company said its partnership with CDMO Emergent BioSolutions for drug substance, announced in April 2020, was “the first in a series of prospective global collaboration agreements designed to accelerate manufacturing” (14).

The University of Oxford and AstraZeneca’s novel coronavirus vaccine candidate (AZD1222) uses a recombinant adenovirus viral vector platform that has been used in experimental vaccines for Ebola and MERS. Phase II/III trials have started in the United Kingdom, Brazil, and South Africa, and are planned for the US, with more than $1 billion from BARDA for development, production, and delivery planned for fall 2020 (15). AstraZeneca has committed, so far, to more than two billion doses, in supply agreements with the UK, the US, Europe’s Inclusive Vaccines Alliance, the Coalition for Epidemic Preparedness, Gavi the Vaccine Alliance, and the Serum Institute of India (16).

Preparations for large-scale viral vector manufacturing capacity were picking up speed late in 2019 as the biopharmaceutical industry was beginning to address shortages due to the rapidly growing demand for viral vectors from the pipeline for cell and gene therapies and viral vaccines. Modular facilities and single-use systems are seen as one way to build capacity more quickly (17).

While vaccines based on mRNA, DNA, or viral vectors are still new, recombinant DNA vaccines made in cell-based bioprocesses are another technology that offers the potential for rapid scaleup and have been in use on the market for several years. For example, the Flublok Quadrivalent influenza vaccine, initially approved by FDA in 2013 and acquired by Sanofi Pasteur in 2018, uses a recombinant DNA technology that combines the target DNA sequence in a plasmid with a baculovirus (BV) DNA, which produces antigens in a host cell; the antigens are then collected and purified to be formulated in the vaccine. These cell-based processes are more easily controlled and scaled than the traditional egg-based influenza vaccine production method, thus the recombinant DNA technology had been recognized for its potential as a response to a pandemic.

In December 2019, Sanofi entered an agreement with BARDA to increase its domestic pandemic influenza vaccine production capabilities in Swiftwater, PA. And now Sanofi’s platform is being put to use for the COVID-19 pandemic; Sanofi and GlaxoSmithKline (GSK) are partnering to produce a vaccine candidate using Sanofi’s S-protein COVID-19 antigen and GSK’s adjuvant technology.

Novavax’ recombinant nanoparticle vaccine platform uses recombinant BV to infect Sf9 insect cells, which express the antigens that are then purified as multimeric nanoparticles. Although the company does not yet have an approved drug, the platform is used to make the company’s seasonal influenza vaccine candidate, NanoFlu, which received FDA fast track designation in January 2020. The platform is being used to make the company’s NVX-CoV2373 COVID-19 vaccine candidate, which is a stable, prefusion protein with Novavax’ proprietary Matrix M adjuvant.

Novavax received more than $1.6 billion from BARDA to manufacture NVX-CoV2373 and to stockpile raw materials needed for the Matrix M adjuvant (18). The company is working with Emergent Bio to manufacture both its NanoFlu seasonal influenza candidate and its COVID-19 candidate at Emergent’s Bayview, MD, facility.

Novavax also announced a manufacturing partnership with CDMO Fujifilm Diosynth Biotechnologies (FDB) to make the bulk drug substance for NVX-CoV2373, and FDB’s site in Morrisville, NC, began production in July (19). AGC Biologics was contracted to manufacture the Matrix M adjuvant to expand Novavax’ capacity.

China’s Sinovac is using an even more traditional technology of an inactivated vaccine for its novel coronavirus candidate, CoronaVac. The company is conducting Phase II trials in China and has been approved for Phase III clinical trials, which will be conducted in Brazil and Bangladesh. The company is building a commercial vaccine production plant that is expected to manufacture up to 100 million doses annually (20).

The importance of fill/finish for vaccines is well known, and the supply chain is ramping up capacity for materials (including injection needles and the glass for vials) and for filling. CDMO capacity will be crucial in this stage, as well. Companies expanding capacity for fill/finish include Thermo Fisher Scientific; Emergent Bio, which received fundingfrom BARDA and is working with four vaccine innovator companies; and Catalent, which is ramping up to support Janssen, Moderna, AstraZeneca, and others (21).

While the world waits for the results of the clinical trials for vaccines to prevent COVID-19 and, hopefully, regulatory approval or authorization of one or more successful candidates, pharmaceutical manufacturers are moving ahead with manufacturing at commercial scale, while also preparing to adapt to changes that arise, as development is also still being completed. The vaccine fill/finish line will, if all goes well, be the beginning of the end of the global pandemic.

HHS, “Fact Sheet: Explaining Operation Warp Speed,” 

C. O’Sullivan, P. Rutten, and C. Schatz, “Why Tech Transfer may be Critical to Beating COVID-19,” 

R. Welch, “Solutions for Rapid Development and Manufacturing Responses to COVID-19 and Other Public Health Threats,” Presentation at BIO (June 2020).

Pfizer, “Pfizer and BioNTech Announce an Agreement with US Government for up to 600 Million Doses of MRNA-based Vaccine Candidate Against SARS-CoV-2,” Press Release, July 22, 2020.

Pfizer, “Pfizer and BioNTech Announce Agreement with the United Kingdom of MRNA-based for 30 Million Doses Vaccine Candidate Against SARS-CoV-2,” Press Release, July 20, 2020.

Reuters, “Pfizer to Outsource Some Drug Production, Focus on Coronavirus Vaccine,” May 8, 2020.

CureVac, “Germany: EIB and European Commission Provide CureVac with a €75 million Financing for Vaccine Development and Expansion of Manufacturing,” Press Release, July 6, 2020.

CureVac, “CEPI Awards US$34M Contract to CureVac to Advance The RNA Printer—a Disruptive, Transportable Mrna Vaccine Manufacturing Platform That Can Rapidly Combat Multiple Diseases,” Press Release, Feb. 27, 2019.

Inovio, “INOVIO Announces Positive Interim Phase 1 Data For INO-4800 Vaccine for COVID-19,” Press Release, June 30, 2020.

Inovio, “INOVIO Receives $71 Million Contract from US Department of Defense to Scale Up Manufacture of CELLECTRA 3PSP Smart Device and Procurement of CELLECTRA 2000 for COVID-19 DNA Vaccine,” Press Release, June 23, 2020.

Cobra Biologics, “Blog: COVID-19 Vaccine Hopes and Hurdles,” 

Johnson & Johnson, “Johnson & Johnson Announces European Commission Approval for Janssen’s Preventive Ebola Vaccine,” Press Release, July 1, 2020.

Johnson & Johnson, “Johnson & Johnson Announces Agreement with U.S. Government for 100 Million Doses of Investigational COVID-19 Vaccine,” Press Release, Aug. 5, 2020.

Johnson & Johnson “Johnson & Johnson Announces Collaboration to Expand Manufacturing Capabilities For its COVID-19 Vaccine Candidate in Support of the Company’s Goal to Supply More Than One Billion Vaccine Doses Globally,” Press Release, April 23, 2020.

AstraZeneca, “AstraZeneca Advances Response to Global COVID-19 Challenge as It Receives First Commitments for Oxford’s Potential New Vaccine,” Press Release, May 21, 2020.

AstraZeneca, “COVID-19 Vaccine AZD1222 Showed Robust Immune Responses in All Participants in Phase I/II Trial,” Press Release, July 20, 2020.

Novavax, “Novavax and FUJIFILM Diosynth Biotechnologies Initiate Large Scale Manufacturing of COVID-19 Vaccine Candidate,” Press Release, July 23, 2020.

Sinovac, “Sinovac Secures $15 Million in Funding to Accelerate COVID-19 Vaccine Development,” Press Release, May 22, 2020.

PharmTech Outsourcing Resources Supplement

Jennifer Markarian is manufacturing editor of 

Vol. 33, No. 9
September 2020
Pages: 10–14

When referring to this article, please cite it as J. Markarian, "Preparing Pandemic Vaccine Capacity," BioPharm International, 33 (9) 2020.

Articles

Cover Story

Rapid scale-up to billions of doses requires collaborative, all-out efforts by innovators, their manufacturing partners, and the entire supply chain. 

Preparing Pandemic Vaccine Capacity

In recent years, there has been increasing use of single-use bags in a broad range of fields, with remarkable advances in the development and manufacture of biopharmaceuticals, vaccines, and other medical products. On the other hand, single-use bags are at risk of pinholes and other defects during manufacturing processes, and there is currently no practical equipment that enables product testing to be performed conveniently and quickly. Given this situation, the authors have developed a new method of pinhole detection for single-use bags. 

A composite film comprising two conductive layers is used as the primary material and may be checked easily for damage or pinholes in terms of insulation by applying a voltage directly on the film before and after use of the bag. Characterized by the idea that the bag constitutes part of the testing system, this method involves changing only the material, without changing the current bag design (shape, size) or attachments, such as nozzles. Various advantages are thus offered, and it is believed to be highly practical. In this paper, the authors report the principle of this method and the results of some investigations, with mention of future prospects.

Submitted: Jan. 9, 2020
Accepted: June 3, 2020

 is principal scientist of Biologics Process Development; Shinji Tsuji is associate director of Biologics Process Development; Yoshiaki Miko is associate director of Biologics Process Development; Tetsuya Moritake is associate director of Project Leadership & Operations; and Takashi Kaminagayoshi is director and head of Manufacturing Operations of Biogics Process Development; all with Pharmaceutical Sciences at Takeda Pharmaceutical. Osamu Shirokizawa is president of Life Scientia.

To whom correspondence should be addressed.


Vol. 33, No. 9
September 2020
Pages: 35–39

When referring to this article, please cite is as F. Mirasol, “Risky Business: Assessing Protein Aggregation Grows Increasingly Challenging,” 

Peer-Review Research

The increased use of single-use bags in biologic manufacturing poses the risk of pinholes and other defects that cannot currently be tested for.

Proposing a New Method of Detecting Pinholes in Single-Use 

Selecting an appropriate separation technology for biologic manufacturing is a crucial task in maximizing productivity in downstream bioprocessing. Biomanufacturers consider several key factors when selecting a best-fit process chromatography technology for their products, including the stability of the biologic, compatibility of the buffers used, and the ease with which scale-up can be achieved. Recent developments in process chromatography have addressed challenges in downstream separation and purification and led to improved bioprocessing.

The biopharmaceutical industry continues to face technical and logistical challenges in process chromatography, particularly during scale-up. Although significant work has been done in upstream bioprocessing to remove bottlenecks through the implementation of single-use technologies, better characterization of raw materials, and the use of more precisely controlled bioreactors, improvements in downstream processing have not kept pace, says Nandu Deorkar, vice-president, research & development—Biopharma Production, Avantor.

“In downstream processing, the ultimate goal for biopharma manufacturers is to improve recovery and reduce the cost per gram of protein produced. Currently, over 60% of the cost to produce a new biologic still relates back to downstream steps,” Deorkar says. “It doesn’t help that there’s approximately 30% more effort, such as resources, materials, and equipment, as harvest material goes through downstream purification due to multiple unit operations. Any percentage of improvement in downstream recovery can contribute to improving the ultimate process yield for drug product of the target biologic,” he adds.

Deorkar also notes that there is a lack of diversity in the supply chain of Protein A resin, which is used in the first downstream chromatography step in monoclonal antibody (mAb) manufacturing. “That dearth is seen especially through the limited dynamic binding capacity needed to process the high-titer cell culture harvest,” he says.

The performance reproducibility in column packing, which is essential for ensuring consistent scale-up, can accelerate technology implementation in manufacturing, says Hemanth Kaligotla, chromatography task force manager at Sartorius. “For chromatography offerings based on membranes, both the availability of devices at multiple scales and the performance across the device sizes need to be consistent. Flow distribution in the devices remain critical,” Kaligotla emphasizes.

Slow processing times are another big issue, especially because the biopharma industry is looking to shorten supply chains and make drugs “at the bedside”, says Ian Scanlon, staff researcher, and Zachary Sexton, research engineer, both at Cytiva. Reducing the costs for cleaning and cleaning validation are also challenges that many big companies and contract manufacturing organizations (CMO)/contract development and manufacturing organizations (CDMOs) discuss. “Those two steps often lead to huge amounts of ‘non-productive’ time, even with mitigation strategies. Single-use solutions can eliminate much of that downtime with a simple plug-and-play format,” says Scanlon.

“Two goals of the biopharmaceutical industry are scalability and flexibility,” notes David Beattie, head of Bioprocessing R&D, MilliporeSigma. “A downstream facility should give reliable product qualities from first clinical batches to full-scale manufacturing. It is of great importance to rely on materials, such as resins, buffers and equipment, which are designed for production purposes and available in the amount they are needed,” he states.

“The other goal, flexibility, is of particular importance for novel therapeutics. Bispecific antibodies, antibody-drug conjugates, engineered glycovariants, fusion proteins—all these molecules need to be purified with a templated approach using resins with a predictable behavior,” Beattie continues.

Fortunately, past challenges with downstream process chromatography have been overcome with innovations in technology, equipment, or methodology.

Chromatography has been a workhorse in the purification of biological products for decades, and there is a constant drive to optimize productivity and minimize the cost of goods, Kaligotla states.

“We see an increase in the use of mixed-mode resins due to the additional selectivity they offer for challenging molecules, as well as for the minimal feed stream manipulation needed to develop a robust process. Specific affinity resins are also being developed that enable an effective and straightforward capture step that results in high purity. We can see this trend in new biological targets (e.g., adeno-associated virus [AAV]) where no platform processes have been established yet. Convective flow membrane chromatography and monoliths addressed the previous purification challenges with diffusive matrices for large molecules, such as viruses (> 100 nm), plasmids, or even large protein complexes,” Kaligotla notes.

Process simplification has become a prominent solution, with processes optimized to eliminate non-value-added steps and remove disconnections between unit operations, Kaligotla adds. Process intensification is another viable approach through which equipment footprint could be reduced and manufacturing could be made more flexible.We also see work being done in the space of real-time product quality monitoring for real-time/automated event control to achieve real-time release and continuous processing,” Kaligotla says.

Meanwhile, the amount of effort needed to perform screening experiments poses another major challenge. Customers can benefit from working with vendors that support them with high throughput screening tools with pre-packed consumables, high throughput screening systems, and well-designed studies using robust design of experiment software tools, according to Kaligotla.

Sexton notes that ligand development has helped enhance the robustness of processes in development. “A ligand that has a higher affinity for its substrate or that is more resistant to harsher cleaning procedures gets preference because it saves the customers money and time,” Sexton states. Hardware innovations, such as simulated moving bed (SMB), periodic counter-current (PCC), or other systems, which allow users to make more efficient use of a resin are still emerging, he adds.

“We are also seeing that, as regulatory limits impose restrictions for ensuring customer safety, like toxicology and cleaning validation for GMP [good manufacturing practices] environments, off-the-shelf technology becomes more appealing,” Sexton states.

The development of pressure stable chromatography resins, which allows seamless scale-up with high linear velocities, was another innovation that helped the industry address past chromatography challenges, Beattie says. Another innovation addressing the need for increased flexibility is the adoption of single-use membrane-based chromatography technologies, he adds.

“Traditional, resin-based chromatography columns are often oversized due to throughput limitations and are ill-suited to flexible manufacturing. These factors impose challenges on the design of purification schemes for manufacturing of biotherapeutics,” Beattie states. MilliporeSigma, for example, developed a membrane adsorber that addresses these challenges by combining high binding capacity and high flow rates.

Membrane adsorbers deliver enhanced process flexibility and robustness and reduce cost as well as risk. Benefits include faster processing, which increases productivity; eliminating the need for column packing, which saves labor and time; eliminating the need for cleaning between batches, which allows for rapid switch over; eliminating the risk of cross-contamination between batches; and allowing for a smaller facility footprint, Beattie enumerates.

Deorkar adds that finding efficiencies and economies of scale in downstream processing involves more complex analysis and optimization. Improvements may be reached after investigating aspects of current purification steps and technologies. Such improvements include expanding the use of mixed-mode and multimode chromatography resins, particularly since using resins to target ligands for increased selectivity can help to process targeted molecules more efficiently; exploring ways to make chromatographic buffers more effective, which can be done by using new kinds of additives and prepackaged single-use buffer materials to streamline buffer exchange steps.; and making wider use of data analysis tools. Data can help quality and process optimization engineers gain deeper insight into complex material interactions in downstream process steps, particularly related to raw material characterization, Deorkar says. He adds that variability in raw materials can present serious issues that impact downstream efficiency and can lead to long investigations and potential delays in making drugs available for patients. Advanced characterization of materials, therefore, is a best practice adopted from semiconductor manufacturing that can provide biopharma manufacturers with further insights into the variability of materials within the integrated supply chain.

“New choices for Protein A, such as, for example, a new recombinant Protein A resin developed by Avantor, [can]addresses challenges of limited supply,” Deorkar continues. “The new resin is built on a proprietary ligand using an alternative supply chain. Additionally, current Protein A product formulations require flammable chemicals for storage and transportation, which require specific safety precautions and incur additional shipping and handling costs. Avantor addresses this problem by packaging its new resin in a non-flammable storage buffer that does not require restrictions or special handling in storage and transportation related to flammability,” Deorkar explains.

As continuous bioprocessing gains more attention, there is the need to evaluate whether current process chromatography technologies pose any limits or risks to implementing continuous processing. According to Scanlon, there are definite risks in moving toward continuous bioprocesses, both on the technology/implementation side and in the regulatory side of things. Among the issues discussed frequently are how one defines where a batch starts and ends and how one can minimize the impact of contamination when something inevitably goes wrong.

“It’s relatively easy with batch processes because of its definite containment. When everything blends and your monitoring is in-line, you become aware of the problem very quickly, but making that separation of what is affected or unaffected is crucial. You almost need second-order indicators—indicators of when something is moving towards that out-of-spec range to make you aware before a large continuous separation process becomes non optimal, resulting in an expensive loss of material and a potentially long and involved problem-solving investigation,” Scanlon says.

“We’ve seen vast improvements in adsorber characteristics, be it resins or membranes. These larger pore structures allow for better pressure characteristics over a longer lifetime. Perfusion titers will increase over time like batch processes have previously. This will create a need for downstream process improvements that are being developed today,” Scanlon adds.

Continuous processing also makes things more complex, from flow path complexity to connections and programming to keep processes in sync, Scanlon continues. Added to the complexity is the fact that CMOs/CDMOs use equipment from different suppliers. “Getting interoperability in a continuous process could be challenging if the equipment isn’t designed to do so and could potentially require some sort of in-between hardware that may need to be custom-made,” Scanlon observes.

“The industry is moving towards intensified, connected, and continuous bioprocessing, and we expect about 30% of new molecules moving into clinical manufacturing will be based on intensified processing in upstream or downstream operations,” observes Beattie.

One area of bottlenecking in continuous mAb polishing chromatography is the cation exchange step, which is traditionally operated in bind and elute mode to provide clearance of product-related aggregate, Beattie points out. “While bind and elute chromatography can be operated in a continuous manner using multi-column systems, buffer consumption is relatively high and product elution often occurs under high salt conditions, which drives the need for dilution or buffer exchange to maintain compatibility with unit operations further downstream. A more efficient purification strategy is to operate the cation exchange step in a product flow-through mode, rather than bind and elute mode,” explains Beattie. “From a continuous processing perspective, a flow-through cation exchange step is more easily integrated with other product flow-through purification steps, such as anion exchange polishing or virus filtration, without requiring conductivity adjustment or dilution.”

While some bioprocessing is operating on a semi-continuous basis, major limitations for complete continuous chromatography exist, such as the linking of different unit chromatography and filtration unit operations. Multiple chromatography steps use different types of buffer systems, according to Deorkar.

“As part of these process flows, buffer exchange is required and is typically difficult to link. If you think of a train, it is very easy to jump from cart to cart with a bridge. But without this connector, the train will separate and lose part of its cargo. What is needed is a seamless connector to bring chromatography and buffer exchange work together. Once this is accomplished, the supply of various buffers would need to be assured. This could be achieved by using hydrated concentrated buffers or ready-to-hydrate pre-weighed direct dispense delivery of solids to enhance flexibility and efficiency of buffer prep operations,” Deorkar explains.

Kaligotla supports the idea that the integration of multiple unit operations while maintaining robust process control and minimizing risk is an essential focus for continuous bioprocessing. “The current process technologies, such as functionally closed single-use manifolds for [chromatography] skids, pre-packed columns, and robust sensor components, enable long-term processing in a bioburden-reduced environment. The technologies are slowly maturing, and there are continued efforts on real-time in-line analytics to optimize continuous processing,” Kaligotla says.

Risks associated with these maturing technologies include the high cost of consumables, the integrity of the flow paths over extended use, limited leachable and extractable data, and bioburden concerns, Kaligotla points out.

The application of more recently developed technologies, such as single-pass ultrafiltration/diafiltration, and as well as continuous virus inactivation step post-Protein A, allows for steps to run in a truly continuous mode,” Kaligotla says

What is the downstream response to upstream scale up as the industry sees increasing titers in upstream processing resulting from increased sizes of single-use bioreactors and optimized cell culture conditions? The response in downstream processing will likely be realized in different ways for different facilities, Beattie believes.

In multi-product facilities, higher titer upstream processes can reduce the number of batches needed to produce a target product mass. This provides an opportunity to increase the number of molecules per facility, Beattie observes. “This goal cannot be achieved without highly productive single-use purification solutions which feature high throughput, quick change-over, and low cross-contamination risk,” Beattie states.

Another strategy involves increasing the total output of a single product in an existing facility, Beattie continues. “Downstream, this results in not only increased column size, but also a corresponding increase in buffer volumes that can be overcome with the use of buffer concentrates.”

Increasing the size of downstream equipment is also a response to increased upstream output, Deorkar chimes in. In addition, multi-cycling may be possible if unit operations allow faster flow. “This is like continuous processing within a unit operation. In this case, pressure is placed on the buffer train, so it is necessary to ensure that the buffer prep operation is efficient and scalable,” Deorkar states.

However, increasing the size of downstream equipment also means that costs are increased, says Sexton. He notes, though, that the industry will innovate and solve this problem creatively. “Some of that will include increasing size in the downstream sphere. However, it may include a smaller footprint to make sure existing equipment is operating as efficiently and as effectively as possible. The easy solution is to make everything larger, but the better and more effective (and more exciting) solution is to make current processes more efficient,” Sexton states.

“There is also the argument that, as we trend toward highly efficacious, personalized medicine and closing supply chain gaps, the paradigm will shift more toward smaller batches of material made in region,” Sexton adds.

The higher titers in upstream processing can impact the number of downstream operating cycles and the total process times, adds Kaligotla. The higher titers also further create challenges with process scheduling; the higher upstream productivity shifts the bottleneck from upstream to downstream. “The higher the titer, one can expect to see a corresponding increase in the level of impurities, increasing the need for depth filter area downstream. A practical way to address this productivity increase is by utilizing a multicolumn approach. This approach has recently gained traction due to the availability of functionally closed single-use manifolds that consist of robust sensor components that enable long-term processing in a bioburden-reduced environment at clinical or commercial-stage manufacturing.” Kaligotla also says that the material cost-savings and enhanced productivity benefits make this unit operation more attractive.


Vol. 33, No. 9
September 2020
Pages: 16–20

When referring to this article, please cite is as F. Mirasol, “Technology Innovations Improve Process Chromatography Performance,” 

Downstream Processing

As technology matures, inefficiencies and process limitations in downstream process chromatography are improved.

Technology Innovations Improve Process Chromatography Performance

Through its Operation Warp Speed program for COVID-19 vaccine manufacturing, the US government is paying manufacturers and contract service providers to scale up the manufacture of specific vaccine candidates. If those specific candidates are not successful in the clinic, those facilities must be able to quickly switch to production of different vaccine candidates that have been approved.

While this approach sounds like a practical approach to accelerating vaccine manufacturing, rapid changeover of biologic production process carries numerous challenges. There are a few different strategies for overcoming these challenges, with key components including facility design, equipment selection, operational considerations, and the use of appropriate plant management systems.

Challenges to rapid changeover come from many sources, including the equipment, room configuration, documentation, people, and environmental monitoring, according to Sebastien Ribault, head of end-to-end solutions at MilliporeSigma.

The traditional method of completely stripping down all equipment and installing dedicated materials and components for each product has proven to be a cumbersome and costly process for multiproduct facilities, adds Piergiuseppe Nestola, senior platform technology consultant at Sartorius. “It is not unusual for changeover to require weeks to complete when traditional methods are followed. With the changing industry tide favoring multiproduct manufacturing facilities, methods to enhance efficiency without sacrificing quality or safety are needed,” he says.

Several activities must be performed in a facility to avoid any risk of cross-contamination between Product A and Product B, in particular via a thorough cleaning-in-place of all equipment surfaces in contact with intermediates and the end product, Thibaud Stoll, global head of commercial biologics operations at Lonza, specifies.

For certain biologics, most notably viral vectors, vaccines based on live viruses, and spore-formers, precautions must be taken to prevent spread through the air and more extensive cleaning protocols are generally required, typically with airborne peroxide methodology, says Katarina Stenklo, enterprise solutions commercial activation leader with Cytiva. Any live biological agents, whether they be the host organisms or adventitious agents, must be effectively removed/inactivated from HVAC, facility, and equipment surfaces (both exterior and product paths) prior to introduction of a subsequent product, adds Syed T. Husain, senior vice president and CDMO business unit head at Emergent BioSolutions.

Stainless-steel equipment specifically presents a common challenge, as it requires cleaning and validation of product contact surfaces before the equipment can be used for a subsequent project, according to Evan Shave, director of biomanufacturing—global network operations for Thermo Fisher Scientific. Cleaning and sterilization of stainless-steel equipment is well understood, but often “overdone” in terms of cleaning and rinse times, mostly due to conservatism or a lack of time to properly optimize the process, adds John Machulski, vice president of engineering for Catalent Biologics.

Changeover of processes performed in a ballroom setting can be even more difficult than for processes run in individual suites due to the added risk of cross-contamination with other processes on top of concerns regarding product carryover, notes Steve Gravallese, enterprise solutions program director at Cytiva.

Stoll adds that some product-dedicated equipment must also be installed, in particular chromatography columns with packed resin for drug substance purification. “All these activities may potentially be quite long and on the critical path if not optimized and sequenced properly, and if the facility layout has not been designed accordingly,” Stoll states.

For drug product manufacturing, it is critical to have a lean process design due to its highly kinetic nature, according to Machulski. “Although barrier isolation technology provides the highest level of aseptic processing, long bio-decontamination cycle times remain one of the biggest challenges for achieving a rapid changeover,” he says. Stoll also notes that given the completely different types of equipment, changeover times are difficult to compare. “A change in vial format may require some significant setup activities for a filling line; the number of such changes can be optimized via the proper yearly planning and sequencing of campaigns,” he observes.

For contract manufacturers in particular, the biggest difficulty is the need for processing equipment flexible enough to accommodate different processes/scales corresponding to molecules from different clients. “This challenge is more likely to apply to drug substance rather than drug product because drug substance processes typically have significantly more variability between different products,” Shave notes.

Strategies for optimization of process changeovers differ because the equipment and room configurations for each process are different, but all are driven by the same constraints and rational, according to Ribault. “A combination of primary (process design), secondary (facility design and operation), and procedural controls and studies should be used,” states Husain.

Stoll identifies three key approaches to optimizing changeover activities: making them as short as possible, performing them during “hidden time” or in parallel, and reducing the number of changeovers by running longer campaigns. “Operational excellence/lean methodologies can be quite powerful for optimizing changeover processes, as can the use of redundant equipment or dedicating packing rooms for chromatography columns. In the latter case, there is additional capital expense, but it is usually a good investment,” he says. Running longer campaigns, though, carries a trade-off with the optimization of product inventory.

The ultimate goal, according to Gravallese, is optimizing the facility around unit operations so they can be segregated where open processing cannot be avoided and staggered changeovers are possible. “It really comes down to identifying the best methodologies and designs to stagger processes in facilities without impacting operations in the balance of the site,” he states.

Properly optimizing cleaning and sterilization cycles where stainless-steel equipment is used, validating procedures, having a well-trained staff, and having a robust yet simplified supply chain are keys to facilitating rapid changeovers, according to Machulski. “Additionally, ready-to-use primary and secondary components can be helpful, along with automation and robotic technology for drug product fill/finish manufacturing,” he says.

Ribault also asserts that it is important to look across the entire value chain and consider how to ensure the interface between process development and manufacturing works well; another consideration is to put together a team that will make the project a success in record time. “You do these things by having templates in place for process development and manufacturing that reduce the transition time. So, while rapid changeover is certainly an integral aspect of operations, it is important to keep in mind that it is one piece within the entire value chain,” he says.

In addition, a quality risk management approach may be applied to assess and continuously improve established changeover processes, according to Nestola. “All processes, including changeovers, can be improved with investment of money and resources, parallel activities, equipment design improvements, and standardization,” he asserts.

Enabling changeovers through facility design

Facility design plays an important role in facilitating rapid changeovers. Inclusion of multiple upstream suites can enable better utilization of downstream operations because upstream processing takes much more time, according to Stenklo.

For a multi-product downstream suite, Shave notes that it can be better to have the plant broken up into two or three segregated smaller rooms versus a single ballroom so changeover can start as soon as the unit operation is finished. “This approach affords the opportunity to increase facility throughput,” he says. A phased approach allows for proper and thorough cleaning as the process completes, agrees Husain. In addition, all surfaces should be smooth to allow for easier yet effective cleaning/disinfection, he notes.

Separate mechanical air handling systems should be used for independent spaces to allow some rooms to be shut down while others continue to operate, adds Gravallese. Door interlocking alarm systems are equally important because they ensure that adjacent process spaces remain separated during changeover/cleaning. The ability to monitor spaces quickly is also essential so they can be released back to operations, he adds. “Environmental monitoring of different rooms is necessary to ensure they stay within qualified requirements (temperature, pressure, humidity, bioburden, etc.) Some sampling is manual, but where possible automation of sampling can help speed up changeovers,” Gravallese says.

Other important facility design aspects for rapid changeover, according to Machulski, include: quality by design, design for manufacturability principles (i.e., lean, single-minute exchange of dies [SMED], etc.), integration of lean operating principles such as 5S for optimal equipment, material and personnel flow in the manufacturing suite, and the establishment of SMED quick changeover principles to ensure efficient reconfigurations of the equipment.

Changeovers can also be facilitated if extra rooms are included in the facility where cleaning-in-place activities on equipment can be performed in parallel, Stoll observes. “It’s not just about one aspect, but all of the aspects, including the size of the corridors, equipment placement in the suites, management of sampling, and environmental monitoring working together,” asserts Ribault.

The so-called “facility of the future,” concludes Nestola, would allow rapid changeovers due to its modular approach and because it is fit by design to accommodate single use and minimize any possible cross-contamination while still allowing detection and prevention of possible deviations.

In general, the equipment developed for the biopharmaceutical industry includes built-in functionality—both hardware and software—to make changeovers easier, according to Stenklo. If the same equipment can be used for multiple different processes to avoid having to schedule time during the changeover to move equipment in and out of storage, then changeovers can be faster, adds Shave.

Closed-system design and operation in and between unit operations also mitigates the potential for cross contamination, states Husain. Closed processing is essential because it provides a better response when using a risk-based approach, adds Nestola.

Single-use equipment is therefore one of the biggest equipment-related solutions for facilitating more rapid changeovers. “Pre-gamma irradiated single-use flow paths for all unit operations, standardized pre-sterilized tubing assemblies to connect unit operations, and aseptic quick connectors (rather than welding or heat sealing) are all designed with features that enable rapid changeover,” Shave observes.

The key advantage of single-use equipment is the elimination of cleaning and cleaning validation steps, which significantly reduces cleaning time, according to Stenklo. “With optimized consumables and consumable assemblies, the equipment can be specifically designed for the process and the facility as well,” she adds.

Single-use equipment allows a changeover in a matter of hours because it involves closed bags, according to Ribault. Both the monitoring and documentation steps are simplified because there is lower risk and the process is less complex with single-use versus stainless steel equipment. “Many people who are trained on single-use equipment find it beneficial due to its simplicity and speed of changeover,” he says. Ribault does add, though, that if a hybrid approach is used, all aspects including equipment and sampling, need to be taken into account to ensure there are no bottlenecks that can slow down the changeover process.

Shave adds that flexible hardware with single-use product-contact flow paths are ideal. For instance, he notes that a tangential-flow filtration skid can be equipped with small and large pumps and the ability to take small and larger single-use tubing sizes to accommodate a wide range of processes.

Emergent’s Baltimore Bayview facility, which is the company’s pandemic response facility designated as a Center for Innovation in Advanced Development and Manufacturing (CIADM) by the US Department of Health and Human Services, uses flexible manufacturing and single-use bioreactors to respond to the COVID-19 pandemic. “Flexible design will help enable us to complete rapid changeover and meet the stringent timelines required for producing COVID-19 candidates,” observes Husain.

Even with conventional stainless-steel equipment, there are steps that can be taken to reduce changeover times. “The ability to isolate the process equipment and transfer piping for clean-in-place (CIP) and steam-in-place (SIP) operations is critical,” asserts Gravallese. “Staggering the CIP/SIP of equipment and transfer lines can also accelerate changeovers by ensuring that the critical equipment can be isolated for priority cleaning to facilitate the start of the next campaign. Once all critical equipment and piping has been released back to operations, all secondary equipment can be cleaned for changeover, without impacting the production schedule,” he notes.

Ready-to-use components used within a filling line also allow for the cleaning step in fill/finish operations to be completely removed, while an automated high-speed filling line provides higher capacities than a traditional filling line. “Both of these design elements theoretically allow for more production runs to occur,” Machulski observes. He adds that high operational availability is achieved by reduced line clearance times and changeover times. For example, by design there are 40% fewer parts to change on an automated high-speed filling line than a traditional vial line, and 20% fewer parts to change than a traditional syringe line. Automated servo motor adjustments and robotic arms are the enablers for this step change and result in a reduction of up to 30 minutes per changeover, according to Machulski.

Implementation of rapid real-time testing for bioburden and endotoxin and total organic carbon can also be an advantageous best practice if equipment cleaning is required during change over, according to Shave.

Don’t forget operational considerations

In addition to facility and equipment design, operational aspects can contribute to more rapid process changeovers. In particular,Stoll points out thatautomation and digital tools are enabling technologies for streamlining changeovers, such as via optimized scheduling of activities and electronic checks and instructions to minimize the risk of errors. “The right manufacturing execution system (MES) can help your facility of the future be both agile and compliant,” asserts Nestola.

Automation software can provide guidance in ensuring that a single-use flow-path is properly connected, thereby saving time performing manual validation, Shave adds. The software can also generate automated batch records of installation and validation, saving the operator time doing manual paperwork. Augmented reality tools, meanwhile, can speed up the changeover process by walking the operator performing the changeover through the process as it is completed.

When one automation platform is used to integrate various pieces of equipment and provide additional functionalities, the ability to scale the whole system with the technology is facilitated, according to Stenklo. “Release handling is much easier when batch reporting, the data historian, and data analytics are maintained in a central place,” she says. “Process data can be accessed while a process is running without the need to gown up and enter the suite. Similarly, systems have been developed to support more rapid changeover approaches."

In fact, instead of weeks of review, a facility of the future can achieve real-time release without quarantining the product, notes Nestola. “In addition,” he says, “use of analysis of the data collected by the manufacturing execution system can provide information about trends during different changeovers and their possible impacts on the product, if any.”

It is important, though, notes Husain, that automation be designed to allow for plug-and-play operation. “Generally, islands of automation concepts are used. A flexible data historian design also helps in allowing for equipment flexibility yet proper operational control and data analysis,” he explains.

For final drug product manufacturing, Machulski highlights the short bio-decontamination cycle times achieved through optimized injection of hydrogen peroxide vapor and use of catalytic aeration technology within automated filling lines, which enable filling of thousands of components within minutes to hours depending on the total production run. “This allows for more production runs to happen within a set timeframe. Additionally, these automated lines mitigate the risk of human contact with the product, allowing for less variability in the time taken for a human interaction and hence quicker filling times,” he observes.

Plant management systems bring it all together

It is important to keep in mind, though, that automation and software are just tools, not an objective, per se. “They don’t speed up changeover, but can slow it down. Since a facility is the sum of equipment, automation, and people, etc., it should not be considered separately,” Ribault asserts."

In fact, anticipation, training and processes including the mapping of activities and their management through solid project management procedures can eliminate most of challenges, according to Ribault. Electronic or paper procedures that guide shop floor people through all of the steps are key to ensuring fast and error-free changeovers, particularly when combined with MES, electronic batch record systems, and automation, agrees Stoll.

To facilitate rapid changeovers, an overall plant management system should have an adaptive scheduling system that automatically adjusts in response to changes, Shave adds. Supply chain management to ensure supply of consumables is also important, according to Stenklo.

Specific components of a good plant management system include electronic batch record capability, role-based recipe management that optimizes each stage of a recipe lifecycle, data integrity features to help prevent documentation or human errors, and data analytics to monitor, control, and predict any possible variation in the process, according to Nestola.

Overall, Ribault notes that the most important features in a plant management system are people and expertise. “The expertise to run a plant is not in the systems or equipment, but in the team and its experience, including quality, regulatory, and technical experience,” he asserts.

With COVID-19 and the focus on accelerated development and production of potential vaccines, the industry is entering “brave new territory”, according to Gravallese. “It will be even more critical under these circumstances to rely on past experiences to accelerate the approach,” he says.

Any accelerated strategy that involves pushing the boundaries of the usual regulations should be identified up front and discussed with the regulators as early as possible (e.g., use of stable clone cell bank or transient transfection for good manufacturing practice production), Shave stresses. Vaccine developers also need to ensure flexibility with respect to the expected required manufacturing capacity, according to Stoll. “One approach is to work with contract development and manufacturing organizations (CDMOs) to complement internal capacity,” he observes.

When selecting CDMO partners for accelerated COVID-19 projects, vaccine developers should first conduct a risk analysis to identify their capabilities and any gaps related to the projects, according to Gravallese. “It is rare to find a perfect match, but it is important to find CDMOs with the platforms, technologies, and capacities that require the minimum level of retrofits and downtime and will allow for a reasonable best approach. Where customers lack specific knowledge, CDMOs should be able to make assumptions based on their experience combined with good engineering practice, good quality practice, and the available tools in their toolboxes,” he concludes.

It is also important today for CDMOs to specialize in a couple of vaccine platform technologies, adds Nestola. “Most of the vaccines in development are based on one manufacturing platform and many viral vectors processes are similar to each other. The same goes for the mRNA platform, where processes are similar between different candidates. By using multiple platforms, the risk for failure can be mitigated,” he explains.

In addition, given the current increased lead time of most of the critical consumables, Shave says it is imperative that processes be developed using platform raw materials that can be purchased upfront before the process is finalized. “If a CDMO is involved, there will be a need for the drug developer and the CDMO to partner closely together to balance and adjust processes as needed during these unprecedented times,” he remarks.

CDMOs also need to agree with clients on a rapid approach to document review, according to Shave. As an example, he points to the use of templated documents, which can avoid or significantly minimize the need for client review of every batch record. In addition, quality systems may require some flexibility in the usual practices around document control to account for last-minute changes, Shave adds.

One challenge when entering new territory is the rapid pace at which a larger number of activities are occurring. Standardization can, according to Gravellese, help expedite the process. “While the initial reaction of many people is they don’t have time to fit standardized approaches to their specific processes in such an environment, the truth is that standardization actually provides more flexibility. Even if standardization is only achieved on a microlevel, the focus can then be directed to items that are critical and for which true solutions don’t yet exist,” he explains

To start, facilities with segregated production suites should be selected to enable processes to be up and running quickly, but at some point, optimization should be pursued to increase throughput on the same equipment, according to Stenklo. “Similarly, while standalone equipment might provide the fastest pathway to an engineering run, integration of equipment on a single platform will likely provide more efficiency in the long term,” she elaborates.

The parallel investment in CDMOs and vaccine innovation is unprecedented and critical to being able to rapidly respond to the COVID-19 pandemic, Husain concludes. “The potential success or failure of a vaccine candidate cannot be predicted. It’s important that CDMOs continue to focus on supporting all innovators and have clinical and commercial capabilities to continuously pave the way for innovation and development of life-saving medicines for patients,” he says.

Cynthia A. Challener, PhD, is a contributing editor to 


Vol. 33, No. 9
September 2020
Pages: 22–25, 50

When referring to this article, please cite it as C. Challener, “Strategizing for Rapid Changeovers in Biologics Manufacturing," 

Manufacturing

Facility and equipment design are important, but the team and its experience matter most.

Strategizing for Rapid Changeovers in Biologics Manufacturing

Compliance with requirements published by pharmacopoeias around the world is a legal and regulatory requirement in those countries and regions in which the pharmacopoeia is applicable. This fundamental principle is presented at the beginning of a series of 12 articles (1–12) published to increase the understanding of this far-reaching and complex situation and to give practical guidance on addressing pharmacopoeia compliance. The articles appear in three 

 eBooks and can be accessed through a dedicated webpage (13) with individual links to each of the 12 articles.

The detailed information in the articles provide important compliance considerations for the bio/pharmaceutical industry, including innovator, generic-drug, virtual, and start-up companies who discover, develop, manufacture, and distribute small-molecule drug products, biotherapeutic products, and vaccines, as well as the drug substances and excipients used in these products.

This current article provides an overview and summary of key points from the series—in effect, a narrative table of contents—intended to bring greater awareness to the availability of the articles, which can help provide guidance for this important pharmacopoeia compliance work.

Why Pharmacopoeia Compliance Is Necessary

The first article in the series (1) provides the legal and regulatory basis for the fundamental principle of pharmacopoeia compliance in the United States, Europe, Japan, and many other countries, thereby establishing the foundation for subsequent articles in the series. The purpose and content of pharmacopoeias is presented, and it is noted that the pharmacopoeias impact drugs and their ingredients throughout the entire product lifecycle. Additional important points are also introduced: a company must comply with “current” pharmacopoeia requirements, meaning a company must monitor and implement updates published by the pharmacopoeias; and a company must comply with applicable pharmacopoeia requirements and also with their approved drug product registrations, so that a company must address the complexity of these compliance challenges. The information provided in the first article is useful for enabling engagement and discussion among the many stakeholders within a company who are impacted by pharmacopoeia requirements, ensuring a common understanding across the various functions, and helping to avoid the risks associated with non-compliance.

Why Pharmacopoeia Compliance Is Difficult

The second article (2) provides a comprehensive, end-to-end framework to help bio/pharmaceutical companies better understand the external and internal challenges that make pharmacopoeia compliance difficult. Among the external challenges are the lack of broad harmonization of pharmacopoeia requirements around the world and the significant number of new and revised requirements that are routinely published. Internal challenges for companies include the lack of broad understanding of the need for and the complexity of remaining compliant. Enhanced awareness provided by the second article can facilitate the establishment and maintenance of collaborative partnerships among internal stakeholders to help address the compliance challenges.

A Brief History of Pharmacopoeias: A Global Perspective

Today, there are as many as 40 pharmacopoeias published around the world. Their history, presented in the third article of the series (3), reveals a common purpose, which is to support the health of the population through consistent standards for medicines. Many, including the 

, were established to harmonize the content and remove inconsistencies between the various pharmacopoeias which then existed. Regional and international initiatives continue even today, with global pharmacopoeia standards being one potentially beneficial outcome. The global and historical perspective is helpful in understanding the complexity and challenges of pharmacopoeia monitoring and compliance.

Global Pharmacopoeia Standards: Why Harmonization Is Needed

Building on information in prior articles, the fourth article (4) provides some industry perspective on the benefit of harmonization or convergence of pharmacopoeia standards around the world. When the standards are not aligned, the differences increase the cost and complexity of compliance. The concepts of the “ideal pharmacopoeia” and “compendial globalization” are presented as potential models to help achieve consistent and appropriate quality requirements for medicines worldwide. Concluding the fourth article, readers are asked to imagine a world where there is no need for translation, because the pharmacopoeias are all saying the same thing. Global pharmacopoeia standards would help to support the availability of medicines with consistent quality for patients worldwide.

Harmonization Efforts by Pharmacopoeias and Regulatory Agencies

There are many pathways to achieve harmonization, and several approaches are currently underway. The pharmacopoeias and regulatory agencies around the world, in collaboration with their stakeholders, have been actively and successfully working toward harmonization for quite some time. The fifth article in the series (5) describes what has been achieved in this area so far and what is yet to come. Among the topics covered are the Pharmacopoeial Discussion Group and the International Council for Harmonization (ICH), with particular attention given to the ICH Q3 topic on impurities and Q4B on the interchangeability of selected pharmacopoeia text. Contributions of the World Health Organization are also described, which include their convening of the International Meetings of World Pharmacopoeias and the resulting establishment of Good Pharmacopoeial Practices to encourage harmonization of compendial standards. Also discussed is the successful collaboration between the bio/pharmaceutical industry and the pharmacopoeias to achieve prospective and informal harmonization of new monographs for drug substances and products.

Revision Process for Global/National Pharmacopoeias

As noted in the first article (1), a company must comply with “current” compendial requirements, which introduces the need to monitor and implement updates published by the pharmacopoeias. The revision processes used by the pharmacopoeias and their associated schedules for publication of proposed and official updates are detailed in the sixth article (6). Designating pharmacopoeias as either “global” or “national”, based on regulatory acceptance, can help give visibility to some of the differences between their processes. This in turn can assist individual companies in focusing their compendial work on those activities that help ensure compliance.

Surveillance Process for Industry: Monitoring Pharmacopoeia Revisions

The surveillance process used by the industry is driven by the revision process and publication schedules of the pharmacopoeias. The seventh article in the series (7) takes a detailed look at industry processes to monitor the significant volume of changes published and to achieve on-time compliance with updated requirements. Monitoring the pharmacopoeia updates provides an opportunity to respond to proposed changes and provide input that may potentially impact the decision on whether and how the updates proceed. Practical guidance is presented in the context of a compendial affairs organization within a bio/pharmaceutical company. There is also an exploration of the additional people and tools necessary to establish effective, efficient, sustainable, scalable, and successful processes for addressing the challenges of pharmacopoeia compliance.

Monograph Development: Why and When to Participate

As noted above, responding to proposed updates in the pharmacopoeias provides an opportunity for a company to potentially influence the outcome. There is an opportunity for even more proactive advocacy through a company’s participation in the process to develop new and revised monographs. The eighth article of the series (8) presents many considerations to aid a company in determining whether or not to submit a monograph proposal. Additional considerations are provided on the most appropriate timing for a submission, from the perspective of both the pharmacopoeia and the company. The potential for achieving harmonized monographs is also discussed. The article makes it clear that the answers to these questions on monograph development may not be the same for all companies, or products in the portfolio.

Monograph Development: How to Participate; How to Harmonize

Having explored in the eighth article (8) the considerations of whether and when a company should submit a monograph, once decided, there are additional practical points to consider. These include how to navigate the process of working with a pharmacopoeia and how to approach prospective or informal harmonization of the monograph through collaboration with multiple pharmacopoeias. These additional points are described in the ninth article (9), which also includes detailed considerations of which groups in a company should have the responsibility to submit the monograph and what specific information and materials are necessary to support monograph development. Taken together, the eighth and ninth articles provide a comprehensive set of tools to enable a company to understand and successfully execute the monograph development process.

A Practical Approach to Pharmacopoeia Compliance

Compliance with pharmacopoeia requirements that are applicable in a particular country, and also with product registrations as approved in countries around the world, is a significant challenge for bio/pharmaceutical companies. Effectively addressing differences between the pharmacopoeia and approved registrations can be complex. The tenth article of the series (10) tackles the specific compliance challenge that occurs when a new monograph is published in the pharmacopoeias for a drug substance or drug product in the company’s portfolio. Possible options are provided to deal with differences in limits and methods between the monograph and the previously approved registration. This practical guidance can help a company align on the best overall compliance strategy for a given situation.

A Case Study in Pharmacopoeia Compliance: Excipients and Raw Materials

The tenth article (10) dealt with externally based compliance challenges, driven by decisions made by the pharmacopoeias during the monograph development process. There are other compliance challenges that are internally based, resulting from decisions made by one functional area in the company without consideration of the broader impact to other functional areas throughout the organization. One such example can be found with raw materials and excipients, where a consistent, cross-functional approach is needed to ensure the appropriate selection, sourcing, testing, and filing of the materials used to manufacture bio/pharmaceutical products in a global environment. This case study is explored in the eleventh article (11), with principles and strategies provided to help companies ensure compliance with applicable pharmacopoeia and regulatory requirements.

Pharmacopoeia Compliance: Putting It All Together; What Is on the Horizon

Processes, people, and tools are necessary to comply with the pharmacopoeia and approved drug product registrations.

BioPharm International-09-01-2020

Preparing Pandemic Vaccine Capacity

Proposing a New Method of Detecting Pinholes in Single-Use

Technology Innovations Improve Process Chromatography Performance

Strategizing for Rapid Changeovers in Biologics Manufacturing

Pharmacopoeia Compliance: A Practical Guide

Risky Business: Assessing Protein Aggregation Grows Increasingly Challenging

Cellular and Gene Therapies Face a Manufacturing Capacity Crunch

Surge in Cellular and Gene Therapies Challenges FDA

Biopharma Gears Up Pandemic Response