Can Vaccine Development Be Safely Accelerated?

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CAN VACCINE DEVELOPMENT BE SAFELY ACCELERATED?

UPSTREAM PROCESSING

Pandemic Response I Biosimilars I Audit Preparation Preparation I Audit I Biosimilars Response Pandemic OPTIMIZING BIOREACTORS

DOWNSTREAM PROCESSING NEW TECHNOLOGIES

MANUFACTURING SINGLE-USE SOLUTIONS

ANALYTICS CONTAMINATION CONTROL

QUALITY/REGULATIONS INTERCHANGEABILITY STANDARDS

OPERATIONS SUPPLIER OVERSIGHT COLD-CHAIN PACKAGING PREFILLED SYRINGES

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BioPharm International integrates the science and business of biopharmaceutical research, development, and manufacturing. We provide practical, peer-reviewed technical solutions to enable biopharmaceutical professionals to perform their jobs more effectively.

COVER STORY 10 Can Vaccine Development Be Safely Accelerated? Biopharma companies responding to the COVID-19 outbreak think accelerating the development of vaccines is safe.

Cover Design by Maria Reyes Images: BillionPhotos.com

FEATURES

UPSTREAM PROCESSING QUALITY/REGULATION BIOBUSINESS Bioreactors Redefine Biosimilars Tackle Lower Taxes, More Flexibility Crucial Upstream Productivity Interchangeability Standards to Retaining Pharma Employment Agnes Shanley Feliza Mirasol Agnes Shanley and Lauren Lavelle New bioreactor designs, better media, Demonstrating interchangeability can Biopharmaceutical companies are process intensification, and analytics ensure biosimilar substitutability at the moving to states with lower taxes. ��52 drive improvements. �� 14 pharmacy level. ��28 COLUMNS AND DEPARTMENTS DOWNSTREAM PROCESSING OPERATIONS What’s New in Being Vigilant in Supplier Oversight FROM THE EDITOR Downstream Technologies? Susan Haigney As the coronavirus pandemic unfolds, Lauren Lavelle Risk assessments, audits, and good pharma must practice science over hype. New chromatography resins and systems, communication are key elements of Rita Peters ��6 valves, and membrane purification supplier oversight. ��34 columns are profiled. �� 18 REGULATORY BEAT Packaging Preserves the Cold Chain FDA is encouraging alternative MANUFACTURING Hallie Forcinio insulins and challenging Seeing Success with More sustainable and functional cold- anticompetitive practices. Single-Use Solutions chain packaging protects temperature- Jill Wechsler ��8 Felicity Thomas sensitive drugs. ��38 Single-use solutions grow thanks to the SHOW GUIDE ��54 cost and time efficiencies they can afford On Point: Biologics Drive biopharma companies. ��22 Growth in Pre-Filled Syringes UPCOMING EVENTS ��55 Felicity Thomas ANALYTICS The rising use of biological drugs PRODUCT SPOTLIGHT ��56 Contamination Control is driving increased use of for Cell Therapy prefilled syringes. ��44 AD INDEX ��57 Feliza Mirasol Assays detect bacterial, fungal, and viral OUTSOURCING ASK THE EXPERT contaminants in the human source cells Ensuring Smooth Tech Transfer Data integrity, quality culture, aging used for cell therapies. ��26 of Bioprocess Operations facilities, CAPA, and risk management Cynthia A. Challener are key when conducting audits. Experience, communication, Susan Schneipp ��58 collaboration, planning, and more contribute to success. ��47

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4 BioPharm International April 2020 www.biopharminternational.com

From the Editor

Biopharma’s Leadership Role in a Pandemic he coronavirus pandemic is sweeping around the globe at a rapid pace, forcing governments, regulatory authorities, healthcare systems, and the bio/ T pharma industry to take novel measures to address the crisis. Some public health officials and doctors sounded early alarms about the spread of a novel coronavirus—severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—in January 2020; however, many people and governments did not heed the alarms or were slow to respond to the spread of coronavirus disease (COVID-19). As politicians weigh protecting public health versus the impact on the economy, medical professionals beg for adequate supplies of face masks and ventilators. Meanwhile, many drug companies and research organizations have announced R&D Rita Peters is the efforts to test approved therapies as treatments to minimize the effects of COVID-19. editorial director of The research focus of drugs in development have been redirected to target corona- BioPharm International. virus symptoms. And, groups around the world have accelerated efforts to develop much-needed vaccines. Following initial criticism for delays in approving diagnostic testing to detect who had the virus, FDA stepped up its activity, issuing more than a dozen guidance As the coronavirus documents in March 2020. Actions included issuing emergency authorizations for diagnostic test and ventilators, easing regulations for remote monitoring of patients pandemic unfolds, and clinical trials, allowing the compounding of hydroxychloroquine sulfate under certain conditions, releasing guidance for the preparation of hand sanitizers, the bio/pharma and facilitating access to COVID-19 convalescent plasma for use in patients with life-threatening infections (1). industry must The immediate goal is to “flatten the curve” of new cases of COVID-19 to reduce strain on the healthcare system. Staying home, avoiding crowds, and washing your practice science hands are simple measures we all owe the medical professionals, first responders, grocery store clerks, delivery services, transportation workers, and others on the over hype. front lines of maintaining our basic needs to get through this crisis. Obviously, these non-pharmaceutical measures are only part of a temporary solution; therapies are desperately needed to treat COVID-19 patients, and vaccines ultimately required for long-term control of the virus. Bio/pharma researchers, development and manufacturing professionals, and companies supporting drug development and manufacturing are essential to these efforts. At the same time, patients still need effective, affordable therapies to treat chronic diseases, cancers, and other conditions. A reliable drug supply is vital to maintain health and alleviate public concerns. During the past few weeks, we have learned about many drugs and vaccines as potential cures. The world could use a “magic pill” right now. But drug developers know the challenges of working the science and producing the data to ensure that the therapy is safe and efficacious. One challenge for those in the bio/pharma industry is to avoid using excessive hype about a potential therapy, which can create false hope. Now is the time to lead with the message that science—not hopes or gut feel- ings—should drive all healthcare decisions. The BioPharm International team thanks those working to develop new treatments and vaccines and those maintaining the drug supply; we are here to support those efforts. In addition to our normal coverage, we offer added coverage of COVID-19 drug development programs, links to research, industry suppliers, and regulatory updates. You can find the latest news, updates, and access to an archive of previ- ous issues on www.biopharminternational.com. Stay safe, and we wish you success in your drug development efforts. Reference 1. FDA, Coronavirus Disease 2019 (COVID-19), www.fda.gov, accessed March 26, 2020. ◆

6 BioPharm International April 2020 www.biopharminternational.com Peptide Quantification Methods

A Case Study Using Oxytocin

A large, global, multi-laboratory collaborative study to evaluate and compare different analytical methods for the quantitation of peptide materials

• In addition to USP, 14 laboratories in 10 countries representing industry, government, metrology and standard-setting organizations collaborated in this effort

Study focused on three analytical approaches:

• HPLC assay • Quantitative nuclear magnetic resonance (qNMR) * Amino acid analysis (AAA) These methods were compared for their suitability with the nonapeptide oxytocin.

See the latest about use and suitability of three distinct analytical methods for peptide quantification: HPLC, qNMR and AAA. Published article can be downloaded from https:// www.usp.org/biologics/peptides

Get involved with USP Biologics Learn more and collaborate with us. Get the details on peptides and explore our full biologics catalog at usp.org/biologics. Regulatory Beat

Biosimilars Poised for Gains in US Market FDA is encouraging alternative insulins and challenging anticompetitive practices.

he 10th anniversary of the enactment and most proteins—specifically any alpha amino of the Biologics Price Competition & acid polymer with the specific, defined sequence T Innovation Act (BPCI) in March 2020 greater than 40 amino acids in size (1). The new has focused attention on the advances made rule aims to “bring down prices and help patients over the past decade and main challenges have access to more choices for these life-saving ahead. Despite general disappointment over the drugs,” said FDA Commissioner Stephen Hahn. slow pace of consumers gaining access to less FDA also issued explanatory documents for con- costly biotech therapies, new FDA guidance and sumers (2) and physicians (3) to clarify that treat- clarified policies provide added support for bio- ments approved under the new program will be similar development and approval, particularly just as safe and effective and accessible as brand for diabetes treatments. FDA also has teamed insulin reference therapies. up with the Federal Trade Commission (FTC) to Efforts to bring insulin competitors to market counter anticompetitive practices that thwart builds on FDA guidance issued in November 2019 development and raise concerns about biosimi- outlining a streamlined development pathway for lar safety and effectiveness. these long-established therapies (4). That advisory A positive sign is that the pace of FDA proposes reduced clinical immunogenicity studies approvals of biosimilars has picked up in recent for products that present strong comparative ana- months, with more than 26 approved prod- lytical assessments demonstrating high similarity ucts as of early February 2020—10 approved to the reference drug, and no residual uncertainty in 2019—and more than a dozen competitors regarding immunogenicity. In May 2019, FDA pro- on the market. In addition, the World Health vided detailed advice on designing and evaluating Organization has begun to prequalify biosim- such analytical studies and on providing scien- ilar versions of “essential medicines” to make tific and technical information for the chemistry, these treatments more available and affordable manufacturing, and controls (CMC) portions of in less developed countries. an application for a biosimilar in draft guidance (5). At that same time, FDA published long-awaited INSULIN COMPETITORS guidance on developing interchangeable biosim- An important FDA initiative aims to ilars, again noting the importance of analyzing encourage manufacturers to prepare critical quality attributes and identifying analyti- the data needed to support applications cal differences between the reference product and for follow-on versions of insulins now the proposed interchangeable (6). deemed to be licensed as biologics and thus eligible for competition from bio- MISINFORMATION CRACKDOWN similar or interchangeable therapies. In The FDA–FTC initiative further aims to encourage February 2020, FDA issued a final rule prescribing and reimbursement for biosimilars by Jill Wechsler is defining the new process, as established taking aim at “misinformation” campaigns backed BioPharm International’s by the BPCI and revised in legislation to by brands to discourage biosimilar uptake. The Washington editor, clarify that the deeming process applies regulators outline how they will work together to

[email protected]. to insulin, human growth hormone, promote competitive markets for biological prod- W.Scott McGill - Stock.adobe.com

8 BioPharm International April 2020 www.biopharminternational.com Regulatory Beat

ucts that “contribute significantly a supplemental application with ufacturers that make misleading to drug costs,” noted Commissioner data supporting the expanded uses, claims to counter competitions. Hahn (7). as seen in an advisory outlining The two agencies also offered to how data and labeling should be REFERENCES 1. FDA, 21 CFR Part 600, Federal Register, help biosimilar makers gain ready presented to add previously omit- 85 (35), Feb. 21, 2020. access to samples of reference prod- ted conditions of use (8). FDA says 2. FDA, Information for Patients About ucts needed to develop and test it will review such supplements Regulatory Changes for Certain Biological Product Medications, FDA.gov, follow-ons—a difficulty that also within six months, much faster undated, accessed March 5, 2020. has plagued the broader gener- than the usual 10-month time- 3. FDA, Information for Health Care Providers About Regulatory Changes for Certain ic-drug industry. And FTC is taking frame set for supplements to biolog- Biological Product Medications, FDA.gov, a close look at patent settlement ics license applications (BLAs). undated, accessed March 5, 2020. agreements involving biologics and And to ensure that promotional 4. FDA, Clinical Immunogenicity Considerations for Biosimilar and biosimilars to detect any antitrust messages related to biosimilars by Interchangeable Insulin Products, Draft violations. A joint public workshop both brands and competitors are Guidance (CDER, November 2019). 5. FDA, Development of Therapeutic Protein held on March 9, 2020 addressed truthful, non-misleading, and bal- Biosimilars: Comparative Analytical these efforts and other strategies to anced, FDA draft guidance issued Assessment and Other Quality-Related build a more competitive market Feb. 3, 2020 instructs brands to Considerations, Draft Guidance (CDER, CBER, May 2019). for biological products. avoid implying in its messages that 6. FDA, Considerations in Demonstrating In a related move, FDA also a reference product is safer or more Interchangeability with a Reference Product, Guidance for Industry (CDER, published guidance in February effective than an approved biosim- CBER, May 2019). 2020 outlining the process for ilar, or that the follow-on is “not 7. FDA, “FDA and FTC Announce New Efforts to Further Deter Anti-Competitive seeking FDA approval of a subset highly similar” to the reference Business Practices, Support of approved indications of a ref- product, even if the competitor is Competitive Market for Biological erence product. This approach not licensed for all indications (9). Products to Help Americans,” Press Release, Feb. 3, 2020. applies when patent and exclusiv- The guidance emphasizes that a 8. FDA, Biosimilars and Interchangeable ity provisions may prevent a newly biosimilar product is not required Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference licensed biosimilar from including to be identical to the brand to be Product Has Been Licensed, Draft all indications of a reference prod- licensed, but just that it be “highly Guidance (CDER, CBER, February 2020) uct on the label, a situation that similar” and without “clinically 9. FDA, Promotional Labeling and Advertising Considerations for often involves pediatric or orphan meaningful differences” in terms Prescription Biological Reference and disease treatments. But once those of safety, purity, and potency. An Biosimilar Products, Questions and Answers, Draft Guidance (CDER, CBER, added proposal is that the FTC take limitations expire, FDA encourages February 2020). ◆ the follow-on manufacturer to file antitrust action against brand man-

FDA Scales Back Domestic Inspections

Due to the COVID-19 pandemic, FDA announced that it agency will take steps such as evaluating records in lieu of will temporarily postpone all domestic routine surveillance conducting onsite inspections. facility inspections, those conducted every few years based “From our experience across the agency, we also believe on a risk analysis. In a March 18, 2020 statement (1), FDA-regulated firms understand and appreciate their shared FDA Commissioner Stephen M. Hahn said the agency will responsibility to ensure the integrity of the supply chain, and evaluate all domestic for-cause inspection assignments and we will continue to communicate with them during this time “will proceed if mission-critical.” On March 10, 2020, FDA to underscore this partnership,” Hahn said in the statement. announced a postponement of foreign inspections (2). References “I want to assure the American public that we have full 1. FDA, “Coronavirus (COVID-19) Update: FDA Focuses on Safety of Regulated Products While Scaling Back Domestic Inspections,” confidence in the safety and quality of the products we all Press Release, March 18, 2020. use every day and that the FDA will continue to leverage all 2. FDA, “Coronavirus Disease 2019 (COVID-19) Update: Foreign available authorities to continue to ensure the integrity of Inspections,” Press Release, March 10, 2020. the products we regulate,” Hahn said in the statement. The —The Editors of BioPharm International

www.biopharminternational.com April 2020 BioPharm International 9 Cover Story: Vaccine Development

Can Vaccine Development Be Safely Accelerated? Biopharma companies responding to the COVID-19 outbreak think accelerating the development of vaccines is safe.

CYNTHIA A. CHALLENER

uman coronaviruses (HCoVs) in the past were con- mensional (3-D) structure of the spike protein suggests that sidered to cause nothing more than the common cold it binds more tightly to human cell surface receptors than H in healthy people. That changed with the advent of SARS-CoV, a possible reason that this coronavirus exhibits severe acute respiratory syndrome coronavirus (SARS-CoV) greater infectivity (2). and Middle East respiratory syndrome coronavirus (MERS- Platform diagnostic methods have been rapidly adapted to CoV) in the past decade. The latest coronavirus—2019-nCoV, include COVID-19 for early identification of cases. Several since renamed by the World Health Organization as academic and industrial researchers have also focused on COVID-19—emerged in December 2019 in Wuhan, China. applying novel vaccine development and manufacturing plat- As of late February 2020, it had sickened tens of thousands forms to the accelerated development of a COVID-19 vaccine. and killed nearly 3000 people. In terms of vaccine development and protection against Four of these large, enveloped, positive-strand RNA viruses dangerous viral pathogens, there is nothing particularly are endemic globally and thought to cause 10–30% of upper unique about coronaviruses, according to Eric von Hofe, chief respiratory tract infections in adults (1). They possess a surface scientific officer of NuGenerex Immuno-Oncology. “All of spike (S) glycoprotein that binds to host cell receptors, and the recent potentially pandemic viruses, including SARS and the nature of this protein is believed to determine the main MERS and two flu viruses (avian and swine flu), have the properties of each coronavirus. SARS-CoV was the first coro- common feature that they simply had never been seen before navirus to jump from animals to humans; MERS-CoV and by the human immune system. That said, we now know a lot COVID-19 have as well. The genetic sequence for COVID-19 was released to pub- CYNTHIA A. CHALLENER, PhD, is a contributing editor to lic databases on Jan. 10, 2020 by the Shanghai Public Health BioPharm International. Clinical Center & School of Public Health (1). The three-di- BillionPhotos.com/Stock.Adobe.com

10 BioPharm International April 2020 www.biopharminternational.com Help ensure clinical success.

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magentablackcyanyellow ES121820_BP1019_041_FP.pgs 09.27.2019 01:14 UBM Cover Story: Vaccine Development

about how the human immune system duced, the protection may be short- senger RNA (mRNA). Cambridge, protects against viral infections and can lived, as there is no guarantee that MA-based Moderna—which has rapidly identify the critical parts of a immunological memory will be gener- developed numerous prophylactic new virus to target for vaccine develop- ated as is possible with a whole virus mRNA vaccines with positive Phase ment,” he says. vaccine,” he comments. I clinical readouts and also has a fully integrated clinical-material manufac- PLATFORM TECHNOLOGIES THE DNA APPROACH turing site—is progressing its COVID- ARE IDEAL FOR DEVELOPMENT AGAINST COVID-19 19 vaccine candidate (mRNA-1273) Traditional vaccines, like the seasonal Inovio Pharmaceuticals is one com- into the clinic (4,5). The Vaccine flu vaccine, are made by growing up pany developing a DNA-based vaccine Research Center (VRC) of the National large quantities of the virus and in some against COVID-19. The biotech was Institute of Allergy and Infectious way killing or inactivating it so that it the first to advance a vaccine (INO- Diseases (NIAID), part of the National can be used safely as a vaccine. This 4700) against MERS-CoV into human Institutes of Health (NIH), collabo- approach is an old technology from the testing and is currently preparing to rated with Moderna to design the middle of the past century, according to initiate a Phase II trial for INO-4700 vaccine. NIAID will conduct investiga- von Hofe. “The main problem here is in the Middle East. This vaccine, how- tional new drug-enabling studies and a the time it takes to produce the vaccine, ever, cannot be used against COVID- Phase I clinical study in the US. which is at least a year and can be sev- 19 because the two coronaviruses are Moderna’s mRNA vaccines can con- eral. Ideally, we’d have a platform tech- too different. tain multiple mRNAs coding for differ- nology that could be used to produce a To develop a new vaccine, Inovio ent proteins and mimic natural infection, vaccine in a few months,” he observes. first converts the virus’ RNA into DNA thus stimulating a more potent response, Such technology platforms should and identifies short sections that will, according to the company. Only the be flexible enough to respond to any according to computer simulations, coding region of the mRNA must be new viral threat. “We would like to have generate the greatest immune response. changed for each new vaccine. The rapid a simple ‘plug-and-play’ setup where The plasmids are then produced in large discovery approach and the manufac- the critical components of a new virus quantities using bacteria. The overall turing agility of mRNA vaccine design required to make the vaccine can be development and approval timeline is and production also make it an effective determined by rapid computer analysis thereby significantly reduced. platform technology. and plugged into the platform to gener- Inovio began animal testing of INO- Just 42 days after sequence selec- ate a vaccine,” von Hofe notes. “Getting 4800, its COVID-19 vaccine candidate, tion, Moderna shipped the first batch all of the critical components produced in February 2020 and is aiming to begin of mRNA-1273 to NIAID for use in a and structured in a way that perfectly human safety testing in early summer planned Phase I clinical study in the US. models the vaccine is the big challenge,” 2020. The company will conduct tests The mRNA vaccine encodes for a pre- he adds. in both the United States and China, fusion stabilized form of the COVID- the latter in collaboration with Beijing 19 S protein. A REDUCTIONIST Advaccine Biotechnology Co. (3). Work German biotech CureVac also has an APPROACH IS BEST in the US is supported by a $9-million mRNA platform technology for vaccine The best way, von Hofe says, is to follow grant from the Coalition for Epidemic development and manufacturing suited a reductionist strategy to identify key Preparedness Innovations (CEPI). The for rapid response to viral outbreaks, it viral components that alone produce collaboration with Beijing Advaccine says (6). Using an extensive in-house complete protection in a safe vaccine is anticipated to accelerate developed nucleotide sequence library, CureVac that can be manufactured rapidly and on INO-4800 in China by providing is able to identify optimum sequences in a cost-effective manner. “Clearly this access to not only its vaccine expertise, for any given vaccine target and elimi- is a tall order, but we’re making good but also its relationship and experience nate the need for chemical modification, progress in that direction,” he asserts. with Chinese regulatory authorities and shrinking the development timeline. As an example, von Hofe points to clinical trial management in the country. The company has also developed the development of subunit vaccines specific carrier molecules for its mRNA that rely on recombinant DNA to PROPHYLACTIC products, including lipid nanoparticles encode a critical subunit of the vaccine MESSENGER RNA VACCINES (LNPs), developed in partnership with that generates a response. There are Two companies, both also supported Acuitas Therapeutics and Arcturus additional challenges to this approach, by grants from CEPI, have developed Therapeutics). It is developing The however. “While responses can be pro- platform technologies based on mes- RNA Printer, a mobile, automated pro-

12 BioPharm International April 2020 www.biopharminternational.com Cover Story: Vaccine Development

duction unit for rapid supply of LNP- way as of late February 2020, and the Sanofi Pasteur, the vaccines global formulated mRNA vaccine candidates. researchers hope to begin clinical test- business unit of Sanofi, is also collab- ing by mid-2020. orating with BARDA, using its estab- STABILIZING THE lished recombinant DNA technology PRE-FUSION VIRUS FORM LEVERAGING platform to accelerate the development of A fourth group receiving funding COMPUTER TECHNOLOGY a potential COVID-19 vaccine (11). This from CEPI for application of a vac- NuGenerex Immuno-Oncology is technology produces an exact genetic cine platform technology to acceler- focusing on what von Hofe refers to as match to proteins found on the surface ated development and manufacture the smallest and simplest fragments of of the virus, which are then expressed of a COVID-19 vaccine is located at the virus needed to produce an immune using Sanofi’s insect (baculovirus) expres- Australia’s University of Queensland response. These short fragments of sion platform. The technology is used for (UQ) School of Chemistry and proteins are identified by a computer Sanofi’s licensed recombinant influenza Molecular Biosciences (7). Its rapid algorithm and can be made rapidly vaccine and a SARS vaccine that has response technology relies on molecular by entirely synthetic means. They are been shown in non-clinical studies to be clamp technology, an approach devel- modified to ensure that they activate immunogenic and afford partial protec- oped by UQ researchers and patented immune cells that are key in production in animal challenge models. by UniQuest. ing immunological memory. “While The molecular clamp technol- these virus fragments may not produce REFERENCES 1. C. I. Paules, H. D. Marston, and A. ogy is used to create subunit vaccines as complete a response as whole inac- S. Fauci, JAMA, online, doi:10.1001/ against class I and III enveloped viruses tivated viruses, they basically produce jama.2020.0757 (Jan. 23, 2020). by stabilizing the pre-fusion form of a ‘memory’, so when a person treated 2. T. Hesman Saev, “To Tackle the New Coronavirus, Scientists Are viral fusion proteins, thus mimicking with our vaccine does encounter the Accelerating the Vaccine Process,” the protein conformation found on live virus, he or she is more prepared to www.sciencenews.org, Feb. 21, 2020. virus and generating a strong immune mount an effective response,” von Hofe 3. Inovio, “Inovio Collaborating with Beijing Advaccine To Advance INO-4800 response. A polypeptide is used to explains. The technology is also a plat- Vaccine Against New Coronavirus in maintain the pre-fusion structure and form approach because it can be applied China,” Press Release, Jan. 30, 2020. prevent the protein from folding after to virtually any virus that may emerge 4. Moderna, “Moderna Announces Funding Award from CEPI to Accelerate entry into the cell. as a threat. Development of Messenger RNA (mRNA) The platform technology, which does Vaccine Against Novel Coronavirus,” not require prior knowledge of a pro- BIG PHARMA Press Release, January 23, 2020. HAS PROGRAMS, TOO 5. Moderna, “Moderna Ships mRNA tein’s quaternary structure, therefore Vaccine Against Novel Coronavirus facilitates the expression of recombi- While these smaller biotechs have gen- (mRNA-1273) for Phase 1 Study,” nant viral glycoproteins without loss erated attention for their accelerated Press Release, Feb. 24, 2020. 6. CureVac, “CureVac and CEPI extend of native antigenicity (8). It has previ- development platforms, Big Pharma their Cooperation to Develop a ously been used to produce chimeric companies have also been actively work- Vaccine against Coronavirus nCoV- polypeptides that mimic the pre-fusion ing on COVID-19 vaccine candidates. 2019,” Press Release, Jan. 31, 2020. 7. University of Queensland, “Race conformations of several enveloped Both Johnson & Johnson and Sanofi are to Develop Coronavirus Vaccine,” viruses. The goal is to complete preclin- collaborating with the US Department of Press Release, Jan. 24, 2020. ical development within 16 weeks and Health & Human Services (HHS). 8. K. Chappell, D. Watterson, and P. Young, “Rapid Response Pipeline then progress directly to Phase I clinical Johnson & Johnson’s Janssen for Stabilized Subunit Vaccines,” trials, with completion of that step in Pharmaceutical Companies unit is col- Presentation at the Vaccine Technology 10 weeks, followed by large-scale pro- laborating with the HHS’ Biomedical VIII Conference (June 2018). 9. University of Queensland, “Significant duction of more than 200,000 doses in Advanced Research and Development Step in COVID-19 Vaccine Quest,” eight weeks. Authority (BARDA) to rapidly Press Release, February 21, 2020. For its COVID-19 vaccine, the UQ advance the initial stages of Janssen’s 10. Johnson & Johnson, “Johnson & Johnson Announces Collaboration with researchers created a first candidate in COVID-19 vaccine development pro- US Department of Health & Human the laboratory in just three weeks (9). gram, which is based on its AdVac and Services to Accelerate Development This work confirmed that the engi- PER.C6 platform technologies (10). of a Potential Novel Coronavirus Vaccine,” Press Release, Feb. 11, 2020. neered vaccine candidate is readily rec- BARDA is funding accelerated devel- 11. Sanofi, “Sanofi Joins Forces with US ognized by the immune system and opment of a candidate into Phase I Department of Health and Human triggers a protective immune response. clinical trials, while Janssen is upscal- Services to Advance a Novel Coronavirus Vaccine,” Press Release, Feb. 18, 2020. ◆ Plans for preclinical testing were under- ing its manufacturing capacities.

www.biopharminternational.com April 2020 BioPharm International 13 Upstream Processing

Bioreactors Redefine Upstream Productivity New bioreactor designs, coupled with better media, process intensification and analytics, continue to improve upstream bioprocessing.

AGNES SHANLEY

ecades ago, bioreactors were little more than the ves- development scene, as data showed their potential to boost sels in which fermentation or cell culture took place. production capacity (2). As designs improved, the contract D Each bioreactor was a bit like a black box, as devel- development and manufacturing organization (CDMO) opers focused on process measurements that would keep Lonza Pharma and Biotech became an early adopter of cells viable and boost output. As their efforts have shone single-use systems for Phase II and III programs, says Atul more light on the biopharma design space, the bioreactor Mohindra, Lonza’s R&D director for biomanufacturing. is no longer viewed as a black box, but an integral part of Another major trend is the widespread use of process a much larger interactive ecosystem. On the very front end, intensification (e.g., the application of perfusion to boost cell-line and antibody expression platforms have reduced cell density). Bioreactor design efforts continue to focus on the time required for cell-line development and antibody integrating spectroscopy and better sensors and to improve expression, with some platforms reported to reduce the time process control. Over the next few years, experts predict a required from months to days (1). Knowledge of processes, focus on single-use bioreactors better designed to handle the cells, and media and their interaction has led to process higher cell densities that result from perfusion, by offering improvements, but also improvements in bioreactor design, improved mixing and oxygen transfer (3). and virtually redefined upstream productivity. “We’re seeing At Millipore-Sigma, says Darren Verlenden, the compa- a significant shift in what we consider normal productivity ny’s head of bioprocessing, one area of focus in bioreactor for a protein biological process,” says Patrick Gammell, exec- development is in new sparger and impeller designs. Their utive director for process development at Amgen. goal is to improve the volumetric mass transfer coefficient, Results are being seen upstream, in improved single-use KLa (a measure of the rate of oxygen used for fermentation) bioreactor systems. Once used exclusively in research set- and mixing so that the bioreactors will be better able to han- tings, single-use systems have become entrenched in the late dle increased cell densities. Traimak/Stock.Adobe.com Ivan

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REDUCING SHEAR Verlenden. Currently, he says, the com- tor for process development, shared Another focus will be optimizing shear pany’s customers expect that 40-50% insights with BioPharm International. and improving cell retention, through of their processes will use continuous BioPharm: What are the most sig- use of fixed-bed bioreactors and other capture and flow through polishing nificant improvements you have seen in technologies (3). To meet these goals, technologies over the next five years. bioreactors within the past few years? Pall offers the iCELLis fixed-bed bio- Gammell: Single-use bioreactors reactor as well as the Cadence product ANALYTICS AND CONTROL have evolved significantly in terms of line, which incorporates acoustic wave Improved analytics and control is also design enhancements to drive leak- separation technology, designed to guiding new product development. Pall free robustness, mixing, and gassing improve cell retention without increas- Life Sciences has incorporated super- improvements to allow these bioreac- ing shear. visory control and data acquisition tors to sustain long-term high-density Also using the fixed-bed approach capabilities into its bioreactors, while cultures. A number of these enhance- is a hybrid single-use bioreactor design Sartorius’ latest Biostat STR bioreac- ments have come as a result of the developed by Univercells, which links tors incorporate automation and pro- continued push within the industry to a structured fixed-bed bioreactor to cess analytical technologies, in an effort drive process intensification through an automated tangential flow filtra- to simplify configuration changes improvements in cell lines, media for- tion concentrator. This design reduces for users, not only during develop- mulations, and through the use of per- process footprint, processing time, and ment but also for manufacturing. GE fused formats. building and operating costs, according In addition, the application of com- to product manager Alex Chatel. It As understanding putational fluid dynamic modeling as also reduces the solid impurities sent well as other advanced modeling tech- for downstream processing, reducing of the design niques has been instrumental in helping the time and number of operations to optimize bioreactor design. These required to generate materials for space improves, improvements in bioreactor and perfu- downstream processing, he says. sion technologies (e.g., filter formats) Univercells has been focusing the bioreactor is have come from close collaboration mainly on applications in vaccine between the manufacturers of biologic development and manufacturing. no longer a black medicines and the single-use suppliers. In March 2020, it launched a new A number of suppliers and academic CDMO, Exothera, that will use its box, but part of institutions are also working on the own as well as other technologies to potential to directly integrate sensor develop viral vector processes for gene an interactive technologies into single-use systems to and cell therapies, with the goal of further dematerialize the process and reducing costs and time to market. The ecosystem. ancillary equipment required for robust company will perform this work at a manufacturing. The outcome of all of 15,000-m2 site in Jumet, Belgium. Healthcare is using improved sensors, the recent work on bioreactor opti- In general, the industry is mov- to help users better assess critical qual- mization and, in particular, the use of ing towards intensified, connected, ity attributes (CQA) and aggregate modeling technologies is also driving and continuous bioprocessing, says the data sets that will be the basis for improvements in the tech transfer and Verlenden. GE Healthcare Biotech is process modeling, the development of scale up of processes. Where, in the past, updating its bioreactors to enhance digital process twins, and use of arti- developers used to take a somewhat process intensification (e.g., by intro- ficial intelligence, according to Avril empirical approach to these efforts, the ducing an automatic perfusion system Vermunt, strategic technologies part- use of models allows us to digitally opti- that can be integrated directly into the nerships leader at GE Healthcare’s mize prior to use with actual cells, and Xcellerex bioreactor platform). life-sciences division. this practice continues to transform the Upstream and downstream opera- way that we work today. tions are being integrated more closely, DESIGN ENHANCEMENTS BioPharm: What overall improve- and downstream bottlenecks addressed Amgen Corp. is putting many of ments have been made in commer- by technologies such as continuous these concepts into practice at a new cial-scale upstream bioprocessing? capture chromatography and flow- facility in Rhode Island, which is Gammell: Over the past two to through polishing tools and improved expected to start up in 2020. Patrick three years there have been signifi- buffer and media preparation, says Gammell, Amgen’s executive direc- cant improvements in terms of process

16 BioPharm International April 2020 www.biopharminternational.com Upstream Processing

intensification resulting from tech- came as a result of the application Next-generation biomanufacturing nological advances across the lifecy- of the QTPP (quality target prod- plants also offer greater environmental cle of the upstream process. Cell-line uct profile) concept, which drives us benefits. Within the plant, the equip- development and innovations in auto- to design products by starting at the ment is portable and smaller, with a mated clone selection have had a great patient and working backwards. The significant deployment of single-use impact, along with the development of QTPP approach necessitates very care- components, which results in much enriched nutrient media formulations. ful integration from device designers, greater flexibility and speed when These formulations promote and then formulators, purification scientists, and manufacturing different medicines sustain highly viable cultures and pro- upstream developers. This [collabora- simultaneously. cess formats that allow unprecedented tive] approach is key to an integrated cell densities and productivities. process design strategy that has already DATA MANAGEMENT In addition to developments in allowed us to better integrate from BioPharm: Amgen recently started a upstream technologies, the continued upstream, through harvest and into project that aimed to improve digital advancement of high-throughput ana- purification. data management for raw materials. lytical product characterization has The continued intensification of How is that work progressing? allowed us to better understand the upstream processes in terms of cell Gammell: Amgen has invested regulation of how products are formed densities and titer creates new oppor- heavily in our data infrastructure to within living cells. This knowledge tunities for harvest/cell separation allow us to integrate all of our data allows manufacturers to design process technology development, and the sources, including process monitoring, control strategies to ensure consistent higher product concentrations also lead sensors, equipment, and product testing and reliable product quality. to challenges in terms of sizing the via an enterprise data lake. This capa- purification operations and how they bility allows an unprecedented ability FUTURE INNOVATIONS are cycled. Continued research into to detect and understand the sources of BioPharm: What will be key areas for higher capacity and cleanable purifica- process and product variation. innovation in the near future? tion resins will remain important. A significant potential source of Gammell: Continuous manu- variation comes from raw materials, facturing for biologics is an area of NEXT-GEN BIOPROCESSING so Amgen has been working with sup- intense focus for many academic BioPharm: What are Amgen’s plans pliers such as GE to integrate sup- and industrial researchers, and cre- for the new Rhode Island facility? plier data with process and product ates new and interesting challenges Gammell: The new biomanu- data. This [integration] not only allows for innovative thinking, in particular facturing plant in Rhode Island will us to better understand and predict the challenge of integrating appropri- be structurally complete in 2020 and issues as a result of material variation, ate in-line analytical technologies in will use Amgen’s prove next-genera- it also allows us to collaborate with combination with complex multivar- tion biomanufacturing capabilities to key suppliers to continuously optimize iate model-based control systems to manufacture products for the United and improve the consistency of our ensure that, over an extended process States and global markets. In contrast materials. Our goal is to continue to format, the process remains in a state to conventional plants that leverage gain access to data sources, including of control and that product output fixed bioreactors and tanks at scales data from the suppliers to our suppliers, remains consistent. A number of these of up to 20,000 L, next-generation which increases our understanding and, individual components already exist manufacturing plants have adopted a again, our ability to predict and pre- today. The innovation will come from flexible, modular design that leverage vent issues that may impair our ability integrating them to ensure robust per- much smaller 2000-L vessels that are to serve every patient every time. formance in a continuous format. portable and accommodate single-use BioPharm: Is biopharm improving bioreactor bags. REFERENCES 1. Pharmaceutical Technology upstream-downstream integration? These smaller, modular biore- editors, “New Berkeley Lights Gammell: In the old paradigm, actors can produce as much protein Workflow Speeds Drug Discovery,” upstream process designers were as the large stainless-steel tanks cur- PharmTech.com, January 7, 2019. 2. GE Healthcare Life Sciences, “Process focused on titer and did not necessar- rently used at conventional plants. The Economy and Production Capacity ily consider the impact of upstream impact of these innovations results in Using Single-Use vsl Stainless Steel process design decisions on harvest a 50% reduction in construction time Fermentation Equipment,” White Paper, gelifesciences.com, 2015. operations or purification complexity and approximately one half of the 3. A. Shanley, BioPharm or yields. A significant improvement operating cost of a traditional plant. International 33 (3) (2020). ◆

www.biopharminternational.com April 2020 BioPharm International 17 Downstream Processing

What’s New in Downstream Technologies The latest advances in downstream technologies include a fluid chromatography system, sensing and control units for hygienic valves, a compact valve platform, a membrane purification column, and a protein A affinity chromatography resin.

LAUREN LAVELLE

s the biomanufacturing landscape continues to The system comes equipped with a combination injector/ advance, downstream technologies are evolving fraction collector, a carbon dioxide pump with a compact A to meet users’ needs. The following products have integrated chiller, a novel gas-liquid separator design for been developed to support the bioprocessing industry. high recovery and low carryover, and preparative software for streamlining operations. Additionally, the SFC shortens FLUID CHROMATOGRAPHY SYSTEM purification run time and dry down time while eliminating Nexera UC Prep from Shimadzu and the Enabling the need for the solvents used in typical phase prep LC. Technologies Consortium (ETC) is a preparative “The Nexera UC Prep system is an improved purification supercritical fluid chromatography system (SFC) that instrumentation that meets the specifications and provides semi-prep purification for the pharmaceutical requirements from SFC users across the pharmaceutical industry (1). Built on the Nexera ultra high-performance industry,” said Mirlinda Biba, PhD, principal scientist, liquid chromatograph platform, the system can be adjusted Merck & Co. Inc., and ETC lead for this project, in a for user specifications to perform various purification press release. “This new generation system provides functions including chiral or achiral purifications, single improved hardware and software features that answer the injections, stacked injections, and fraction collections from pharmaceutical industry’s demand for an efficient and robust microliters to liters. prep SFC system.” Ioana Davies (Drutu)/Stock.Adobe.com Davies Ioana

18 BioPharm International April 2020 www.biopharminternational.com A HEALTHY WORLD

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UPDATED SENSING AND preventative maintenance cycles, Protein A affinity chromatography CONTROL UNIT FOR and a larger production capacity for resin for the purification of antibodies HYGIENIC VALVES manufacturers. during monoclonal antibody (mAb) Alfa Laval introduced an updated “The unique EnviZion design production. The resin is used during version of its second-generation valve has set a new standard for valves in the Protein A affinity chromatography sensing and control units for hygienic the BioPharm industry,” said Dave step of mAbs manufacturing. It also valves, the Alfa Laval ThinkTop V50 Loula, global product director for works in conjunction with current and V70 (2). The new addition, the ITT Engineered Valves, in a press manufacturing standards to guarantee Alfa Laval ThinkTop IO-Link, is a release. “We have incorporated the stability in workflow processes and communication protocol for point-to- same patented technology into a compliance protocols (6). point communication between hygienic fractional size valve and added new “Biopharmaceutical developers and valves and automation systems via real- features to overcome challenges related manufacturers are urgently seeking time data exchange, improved diagnostics, to dimensional limitations. This new tools to drive more efficiency and simplified configurability and control. provides manufacturers with improved in their production processes. But Like the V50 and V70, the IO-Link performance and reliability for critical they cannot compromise on quality is equipped with butterfly, single-seat, sampling and low flow installations.” standards as they work to provide double-seat, and special valves to meet powerful medicines to patients in all valve requirements. Additionally, the CHROMATOGRAPHY a timely, safe, and efficient manner,” new device includes M12 connectors and COLUMN FOR said Dr. Ger Brophy, executive vice- automatic recording of the hygienic valve MEMBRANE PURIFICATION president for Biopharma Production stroke duration for faster installation time, The CIMmultus EV monolithic at Avantor, in a company press release. the ability to assign priority to critical column from BIA Separations is a “Our resin provides customers with data, parameters that can be changed pre-packed chromatography column a best-in-class, high-performing from a remote automation system, and that works to eliminate non-exosomal alternative to existing purification data storage, availability, and analytics vesicles and concentrate exosomes in a technology, with the benefit of greater help for improved operations. low shear atmosphere (4). supply chain flexibility and security.” “Suddenly it’s easier to capture, store, The column comes with sizable analyze, and act upon meaningful data,” flow-through channels that are REFERENCES 1. Shimadzu, “Shimadzu’s New said René Stietz, product management formulated to work with large proteins, Nexera Preparative Supercritical Valves & Automation, Hygienic viruses, virus-like particles, and pDNA Fluid Chromatography System Fluid Handling, Alfa Laval, in the as single-use disposable or multi-use Meets SFC Purification Needs for the Pharmaceutical Industry,” press release. “You get all the finesse columns (5). Additionally, the column Press Release, Sept. 30, 2019. of the newly reengineered Alfa Laval is made of epoxy thermoset materials 2. Alfa Laval, “Alfa Laval ThinkTop ThinkTop—and valuable benefits like and carbon fibers, which gives it the IO-Link Boosts Real-Time Data Exchange And Valve Performance,” more data, higher productivity, and similar strength and structure of Press Release, Jan. 27, 2020. higher yields.” stainless steel. 3. ITT, “ITT Engineered Valves Introduces “Exosomes represent the next- Ultra-Compact EnviZion Valve COMPACT VALVE PLATFORM Product Line for BioPharm Industry,” generation delivery strategy for nucleic Press Release, Nov. 18, 2019. ITT unveiled a new addition to its acids and other therapeutics, as well 4. BIA Separations, “BIA Separations EnviZion valve product line, the as being evaluated as a platform for Introduces CORNERSTONE Exosome Process Development Solution to BioviZion, a fractional size valve for regenerative medicine with high hopes Enable Industrial Scale Manufacture 0.25–0.5 in. applications that includes of bringing more therapeutic options of Therapeutic Exosomes,” Press a mechanical thermal compensation to chronically ill patients,” said Aleš Release, Oct. 10, 2019. 5. BIA Separations, “Products for system, a quick-change bonnet, and Štrancar, CEO at BIA Separations, Preparative Applications,” www. stainless-steel and patented diaphragm in a press release. “We are all looking biaseparations.com, Feb. 21, 2020. studs (3). forward to seeing the impact of our 6. Avantor, “Avantor Launches New Protein A Chromatography Resin – PROchievA The platform features a 360° tools on this novel therapy space.” – that Provides Supply Chain Flexibility active seal protection for a leak- and Improves Downstream Purification free operation that removes the risk PROTEIN A AFFINITY Performance for Monoclonal CHROMATOGRAPHY RESIN Antibodies (mAbs) Production,” of contamination and the need to Press Release, March 18, 2020. ◆ re-torque after thermal cycling. It Avantor introduced the J.T.Baker also provides less downtime, lengthier Bakerbond PROchievA, a new

20 BioPharm International April 2020 www.biopharminternational.com BIOSTAT STR® Generation 3 and BIOBRAIN

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Seeing Success with Single-Use Solutions Single-use solutions continue to grow in popularity, largely as a result of the cost and time efficiencies they can afford biopharma companies.

FELICITY THOMAS

he market for single-use equipment within biopharma tions afford biopharmaceutical manufacturers several benefits: worldwide is expected to grow by a compound annual The speed of changeover through the elimination of non-value- T rate of 13.4% over the next five years (1). Growth in added steps, such as clean-in-place (CIP) operations or requiring this market is expected to be driven by companies seeking sterilization-in-place, and the risk reduction of cross contami- more cost-effective solutions, the integration of single-use nation between batches. These benefits translate into more effi- technologies in continuous processes, and the rapid advance- ciency and increased production capacity. ment of biologics. Kirchmair (Single Use Support): Single-use technologies BioPharm International sat down with Johannes Kirchmair, address exactly the challenges the industry is facing with their managing director, Single Use Support; and Jon Van Pelt, development portfolio of products and in commercial manu- general manager Bioprocess Single Use and Enterprise, GE facturing. During development, biopharma companies must be Healthcare Life Sciences, to discuss the benefits, important flexible with production floors potentially ready for a range of considerations, and trends of single-use solutions in bio- products and product classes. As a result of these requirements, pharma in more detail. single-use solutions prove beneficial because it is possible to mix several products in one set of hardware and it is possible to pro- DESIRABLE PLATFORM duce individual products cost-effectively. BioPharm: Single-use solutions have continuously increased Even if a company reaches the commercial scale, there is no in popularity over the years, could you elaborate on why these guarantee that the product will perform once it is commercially solutions are proving desirable and the benefits they afford users? available on the market. However, single-use solutions afford Van Pelt (GE Healthcare): The reality is that single-use is companies the flexibility to scale-up and scale-down produc- an established accepted platform within biopharma. The solution easily or use the same floor/set of hardware for another oatawa/Stock.Adobe.com

22 BioPharm International April 2020 www.biopharminternational.com CREATING TOMORROW’S SOLUTIONS

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product if required. Furthermore, with a management system—corrective actions age waste would be an ideal solution—so, single-use contact surface, the number of and preventive actions management where waste is collected and treated in a qualification and validation exercises that and complaint management), technical professional way, similar to the disposal are needed is reduced. expertise (issues such as robust product of confidential documents. This service development, materials understand- platform could be an attractive business PROMOTING SUCCESS ing; and manufacturing (issues such as model and environmentally friendly at BioPharm: How can single-use solu- manufacturing workmanship, rigor, and the same time. tions promote increased success for com- capacity). You should also understand Van Pelt (GE Healthcare): panies within biopharma? single-use workflows within your facil- Sustainability is an area that has been Kirchmair (Single Use Support): ity; you should account for the need for on our radar for over 10 years. The first Through single-use solutions, biopharma large enough storage facilities to house comparison of single use to stainless steel companies can enter the market rela- sufficient inventory and for the waste Life Cycle Assessment (“cradle to grave”) tively easily. For example, some suppliers management needed to process the performed to the ISO 14040 standard of single-use solutions offer end-to-end used materials. Training is very import- concluded that single use was favorable solutions where it is possible to receive a ant, as without this, people commonly from an environmental impact (2). The prequalified set of products from seed to experience higher failure rates related to energy to fabricate reuseable components fill/finish. Moreover, the use of single-use improper installation and use. and the utilization of thermal energy for solutions in the contract manufacturing Kirchmair (Single Use Support): sterilization and water for injection for organization (CMO) space can give rise Personally, I would advise never getting CIP operations had a higher environ- to rapid turnaround times and, hence, locked in with one consumable pro- mental impact versus single use. reduced costs. In general, I believe that by vider, because if something goes wrong However, the transport of single-use using single-use solutions, barriers, such with the supply chain, you are trapped. components is an area that should be as cost to bringing a molecule to clinic However, there are regulatory challenges studied more closely because transport and market, are lowered. that need to be considered. Filing for is the largest contributor to the car- Van Pelt (GE Healthcare): Speed- commercial products needs to be well bon footprint. Conversion of waste is to-market is often cited by companies thought out, for example, so it is possi- another point for consideration. Plastic using single-use technologies. Single-use ble to switch your primary contact layer components, especially film, cannot be promotes efficient utilization of produc- even during the commercial phase. In my recycled other than as fillers for con- tion resources particularly with process opinion, the future will be with single-use struction materials. Films are challenging set-up time at all scales of operation. The [bag] provider agnostic platforms, such because they are engineered composites ability to design a process flow from cell as a bioreactor hardware that can handle of multiple layers consisting of differ- expansion to purification in reduced time, bioreactor bags from several providers, ent functional materials. Low extractable rapidly scale up to clinical, then convert or a freeze/thaw platform that is able to polyethylenes, oxygen barriers, tie layers to commercial production are governing handle bags from several suppliers. all contribute to the final film that can- success factors. These factors also contrib- not be separated. Conversion to fuels is ute to a more timely use of capital funds WASTE MANAGEMENT another possibility that is being pursued as companies go through clinical trials, BioPharm: What about waste manage- as a solution. reducing financial risk. ment? Should companies be seeking extra measures in this regard? WORK IN STANDARDIZATION POTENTIAL PITFALLS Kirchmair (Single Use Support): BioPharm: Is there any work being BioPharm: Are there pitfalls that com- Reusable systems are not really an option, done to standardize single-use solutions? panies should be aware of when looking in my opinion, but times are changing Van Pelt (GE Healthcare): to implement single-use consumables and environmental aspects should be Participation between suppliers and within biomanufacturing processes? considered by everyone, including the biopharma working groups such as Van Pelt (GE Healthcare): Unlike biopharma industry. In general, the envi- BioPhorum Operations Group, ASTM stainless steel, where you buy and use, ronmental impact of single-use solutions International, and British Pharmaceutical again and again, you are in an ongoing is not too bad (several independent stud- Students’ Association provide a forum relationship with your single-use sup- ies are showing that) but it’s still plastic! and are actively moving toward standard- plier. You should assure security of supply So, the suppliers have to help their cli- ization frameworks. (issues such as financial stability, robust ents to treat the waste properly to make Kirchmair (Single Use Support): supplier quality, mapping of supply risk); sure that the impact is minimal. A global There are a lot of good ideas in place, quality (issues related to a robust quality service platform to help companies man- but ultimately the variety of products is

24 BioPharm International April 2020 www.biopharminternational.com Manufacturing

part of the single-use business model in passive inventory management will be solutions in the near future include the industry. Therefore, it is possible that linked to cloud-based information trans- automation, increased robustness, elim- there is not sufficient passion for stan- mission that facilitates predictive, staged ination of manual interaction, scale-up dardization in industry. However, if there shipments while minimizing wasteful of more commercial processes, cell and is an absolute need for standardization transport. Mid-term, single-use on-line/ gene therapy products, and essentially of single-use components, the pressure in-line sensor technology will lead to the industrialization of the single-use probably has to come from the end users connected processing enabled by smart operation. Fully automated, online to force it to materialize. Currently, it process control. Finally, long-term, the monitored, consumable provider inde- does not look like this pressure is coming. data obtained will then evolve to pre- pendent platforms will be the future. Standardization would lead to a smooth dictive process control through artificial That’s a natural evolution. interaction between biotechs, the end-us- intelligence algorithms. ers, CMOs, and the suppliers. Obviously, The single-use industry will be instru- REFERENCES 1. Market Research Engine, “Single-Use standardization would be a desirable mental in helping biopharma customers Equipment for Biopharmaceutical Market outcome as it would mean the industry accelerate their path towards delivering by Product (Single-Use Bioreactors would be able to collaborate more easily advanced therapies to market as quickly (SUBs), Membrane Adsorbers, Mixing, Tangential Flow Filtration, Tubing, on a global scale. and cost effectively as possible. This trait Connectors, Preassembled Tubing is especially true in the emerging areas and Rigging, Depth Filtration, and ON THE HORIZON? of cell and gene therapy. In addition to Buffer Containers), End User (Hospital, BioPharm: Clinic, and Other), and By Region, What trends do you foresee delivering flexibility in scale and speed Market Analysis Report, Forecast as being important in single-use solu- in operations, single-use providers and 2020–2025,” marketresearchengine. tions in the near future? biopharma customers will need to work com, Market Research, January 2020. Van Pelt (GE Healthcare): 2. V. Pizzi, et al., “An Environmental Life A on streamlining the consumable design Cycle Assessment Comparing Single-Use series of cascading trends are on the space for improved efficiency. and Conventional Process Technology,” horizon in the near and longer term. Kirchmair (Single Use Support): BioPharm Int., Nov. 2, 2011. ◆ Short-term, sustainability through Big trends that will impact single-use

INQUIRE TODAY! TOSOH BIOSCIENCE LLC • Customer service: 866-527-3587 • Technical service: 800-366-4875, option #3 TOYOPEARL, TSKgel and Tosoh Bioscience are registered trademarks of Tosoh Corporation. Ca++Pure-HA is a registered trademark of Tosoh Bioscience LLC in the USA, EU, India, and Japan. SkillPak is a registered trademark of Tosoh Bioscience LLC in the USA.

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www.biopharminternational.com April 2020 BioPharm International 25 Analytics

Contamination Control for Cell Therapy A variety of assays should be used to detect bacterial, fungal, and viral contaminants in the human source cells used for cell therapies.

FELIZA MIRASOL

hough cell therapy is a recent innovation, with the first taminants found in critical zones of the cleanroom environment therapies approved by FDA in 2017, the use of human can endanger patients’ lives, and have a devastating impact on T cells has been a standard of care for decades in hematol- finances and reputation (3). ogy and oncology (1). A cell therapy can be derived from a vari- Maintaining an aseptic environment is critical to minimizing ety of sources, including hematopoietic, skeletal muscle, neural, the risk of contamination from extrinsic sources. Intrinsic con- and mesenchymal stem cells (i.e., adult stem cells that differen- tamination risks also exist in the cell manufacturing processes, tiate into structures such as connective tissues, blood, lymphatics, however, primarily due to the fact that the source cells cannot be bone, and cartilage). Lymphocytes, dendritic cells, and pancreatic sterilized. This can raise concerns over the risks of contamination islet cells can also function as source cells. Many cell-based as well as cross-contamination. therapies currently in development are based on induced plu- Contamination control over the manufacturing of a cell- ripotent stem cells (iPSCs), adult cells that have been genetically based product requires mapping out the entire process (4). This reprogrammed back into a pluripotent state (i.e., so that they can approach helps developers and manufacturers understand the differentiate into one of many types of cells in vivo) (2). risks involved at each step of the manufacturing process. Having There are two types of cell therapy: autologous and allogeneic. a proactive contamination-control mindset is key to mitigating In autologous cell therapy, the source cells come from the patient risks in general. to whom the therapy is administered. In allogeneic cell therapy, “There are unique challenges in both allogeneic and autologous the source materials are cells from an independent donor, and cell therapy production, given the human origin of the cells,” says the therapy can be administered to a number of patients. Andrew Bulpin, head of process solutions, MilliporeSigma. In Given the urgency of ensuring good patient outcomes, it is allogeneic therapies, these cells typically come from healthy essential to have a strategy in place for preventing contamination donors, Bulpin points out, but there is a limit to how many doses of source cells, as well as the resulting cell therapies. Any biocon- can be grown from a single donation, given the limited number Delwood/Stock.Adobe.com

26 BioPharm International April 2020 www.biopharminternational.com Analytics

of times a cell can double. This intro- recipient. Tests include the use of trans- should be fully validated and qualified duces the need to address donor-to-do- mission electron microscopy, NGS, and in the presence of a test matrix using a nor variability in incoming material for in-vitro cell-based assays,” he says. minimum of three batches under a formal therapeutic uses. product-specific qualification, Bulpin says. “Autologous therapies have the other COMMERCIAL SCALE A battery of tests is generally used extreme—each dose starts with the cells For commercial-scale manufacturing in to assess and validate the purity of the of the sick patient. This introduces supply the case of allogeneic cell therapies, it is cell therapy end-product. Tests include chain challenges (i.e., harvesting, shipping important to perform cell banking and PCR assays for viral pathogens and from the patient, manipulating, shipping cell characterization to support scale up. mycoplasma and a sterility assay for to the patient, and administering cells),” This includes establishing and testing bacteria and fungi. For cell therapies Bulpin adds. Care must be taken to ensure the working cell bank (WCB) and cells that have been transduced using a viral the chain of custody so that each patient at the limit of in-vitro cell age (LIVCA) vector, the risk of replication-competent receives his or her own cells. Adding to separate from the original master cell virus being present must be addressed, the complications is the variability in cell bank (MCB). Bulpin asserts. This is typically done health from the patient, which demands Bulpin points out that the specific using a detector cell-based in-vitro that processing be extra robust. requirements for the detection of con- cultivation assay with a vector-specific taminants at the WCB and LIVCA level endpoint test. “Furthermore, purity of CELL HEALTH ASSAYS are laid out in relevant regulations and the cell therapy must be authenticated To assess cell health and the presence guidelines for advanced therapy medic- to the level of the individual. Finally, of any contamination in autologous or inal products (ATMPs). These require- assays used for lot release of clinical or allogeneic therapies, a range of assays is ments are similar to the requirements for commercial material should be suitably required to test the source materials. the MCB, with less testing required at validated and qualified in the presence According to Bulpin, this includes assays the WCB level. “In particular, the risk of test matrix,” he concludes. that are highly sensitive and specific to a of introducing contaminants during particular target contaminant (e.g., poly- scale-up must be addressed through test- ADVANCED ASSAYS merase chain reaction (PCR) assays), ing, including the detection of human The complex nature of cells and cell-to- as well as assays that offer broad detec- viruses, bacteria, fungi, mycoplasma, and cell interactions calls for advanced assays tion capabilities, such as next generation pyrogens,” he says. to help detect even minute levels of con- sequencing (NGS), in-vitro cell-based The requirements are similar for contamination and to validate their purity. assays, and in-vivo assays. trolling the vector material and associated The most advanced analytical assays “The choice of assay is influenced by a production cells. Rigorous testing should that are used for detecting contamina- number of factors, including the ability of be performed on all starting and in-pro- tion in human cell sources include novel the contaminant to be cultivated in vitro cess materials, such as plasmids, vector molecular sensitive techniques with broad or tested in vivo, but also the expectations production cell banks, vector bulk harvests, molecular detection capabilities. Examples of the regulatory agencies that will be and purified bulk, says Bulpin. It is at this include deep sequencing/next-generation reviewing the assay data,” Bulpin states. stage that specific risks, such as the pres- sequencing/high-throughput sequencing, PCR assays are used to detect myco- ence of replication-competent viral vec- degenerate polymerase chain reaction for plasma and disease-causing viruses in both tors in bulk harvest and transduced cells whole virus families or random priming autologous and allogeneic source cells, must be addressed, he explains. methods, hybridization to oligonucleotide Bulpin says, and they typically generate arrays, and mass spectrometry, according results in one to three days. A broader cul- CELL PURITY VALIDATION to Bulpin. tivation assay—based on a rapid, semi-au- When moving from clinical to commer- tomated method—is often employed for cial-scale manufacturing for a cell therapy, REFERENCES 1. D. Clarke, et al., Cytotherapy the detection of bacteria and fungi, and other considerations must be taken into 18 (9) 1063–1076 (2016). usually generates results in five to 10 days, account, and phase-appropriate valida- 2. ARM, “Cell Therapy,” alliancerm. he says. “Turnaround of these assays is tions used to assess the materials. During org/technologies/cell-therapy, accessed March 20, 2020. time critical in delivering successful treat- early clinical phases, for example, assays 3. R. Hansen, “Reducing the Risk of Bio- ment to the patient from whom the cells used for the release of clinical material contamination in Gene, Cell and CAR-T have been isolated. For allogeneic cells, should be suitably validated and qualified Therapy,” Bioquell.com/news, August 2018. 4. Microrite, “Mitigating Contamination broad detection assays are also used to in the presence of a test matrix that uses Challenges in Cell Based address the risk of ‘unknown’ and known a single batch of material. For late-stage Regenerative Therapies,” microrite. contaminants being passed from donor to or commercial-scale development, assays com, accessed March 13, 2020. ◆

www.biopharminternational.com April 2020 BioPharm International 27 Quality/Regulations

Biosimilars Tackle Interchangeability Standards Demonstrating interchangeability can ensure biosimilar substitutability at the pharmacy level.

FELIZA MIRASOL n May 2019, FDA published a final guidance (1) on Because biosimilars, unlike small‑molecule drugs, are demonstrating biosimilar interchangeability and recom- manufactured in living cell lines using processes that cannot Imended what analytical assessments and data should be be exactly replicated from one manufacturer to the next, bio- included for a biosimilar to qualify as a substitution for a similar manufacturers must demonstrate that the biosimilar prescribed originator biologic. Unlike the generic versions of is highly similar to and has no clinically meaningful differ- small-molecule innovator drugs, biosimilars cannot simply ences from an existing FDA-approved reference product in be substituted for branded biologics. terms of safety and effectiveness, adds Leah Christl, executive director, Global Regulatory and R&D Policy, Amgen. VARIABILITY PLAYS A ROLE “An additional showing is needed to support an inter- A generic version of a small-molecule drug has to be shown changeability determination,” Christl continues, “If FDA as being chemically identical to its predecessor, but the term determines that a biosimilar meets the interchangeability “identical” cannot be used in discussion about biologics for standard, that biosimilar may be substituted at the pharmacy the simple reason that there is variability among lots in all under state pharmacy laws.” biologics, including reference products, notes SangJoon Lee, “What makes the US biosimilar market different from senior executive vice-president at Celltrion. “These inherent other highly regulated markets, such as Europe, Canada, variabilities are based on factors such as heterogeneous pro- Japan, or Australia, is that the regulatory pathway in the tein production from a living organism cell line and changes United States includes a determination of ‘interchangeability’ in manufacturing processes. The extent of variations in between the reference product and biosimilar—a designation different lots of the original biologic should be measured by that permits pharmacists to substitute a biosimilar for its ref- biosimilar companies to regard these variations as acceptable erence medicine without needing to first obtain permission boundaries for a biosimilar,” says Lee. from the prescribing physician. Without this designation, Julia/Stock.Adobe.com

28 BioPharm International April 2020 www.biopharminternational.com Multi-Level Workflows for Quantitative N-Glycan and Sialic Acid Analysis of Biotherapeutics

Event Overview Biotherapeutics such as monoclonal antibodies (mAbs) are frequently glycosylated, and Presenters the structure of attached N-glycans can affect immunogenicity, pharmacokinetics and pharmacodynamics. This can make glycosylation a critical quality attribute (CQA), making characterization of N-glycans an essential part of the development process. We present Dr. Aled Jones complete N-glycan quantitation workflow solutions using liquid chromatography (LC) with Bioconsumables fluorescence detection (FLD) or mass spectrometry (MS) for four levels of biotherapeutic Marketing Manager analysis: intact mass, mAb subunits, glycopeptides, and released glycans. Released Agilent Technologies N-glycans are labeled with InstantPC (a glycan dye that provides high FLD and MS signal) or 2-AB (a traditionally-used label) prior to separation by hydrophilic interaction liquid Dr David Wong chromatography (UHPLC-HILIC). Sialylation of biotherapeutics can also be important, and Sr. Applications Scientist we present a plate-based streamlined workflow for quantitation of total sialic acid. LC/MS Solution • Relative quantitation of mAb glycoforms at intact protein and mAb subunit level using MSD Division the highly sensitive LC/Q-TOF system Agilent Technologies • Use of HILIC column for glycopeptide separation and quantitative analysis by LC/MS • Rapid and reproducible sample preparation for released N-glycans (1 hour for Moderator InstantPC, 2 hours for 2-AB) • Analysis of InstantPC labeled mAb and Fc fusion protein N-glycans, including relative Laura Bush quantitation by LC/FLD and glycan structure assignment by LC/MS Editorial Director • Quantitation of total sialic acid using a plate-based colorimetric assay with a broad LCGC range of detection Key Learning Objectives Sponsored by • Importance of N-glycan analysis for biotherapeutic proteins • Multi-level LC/FLD/MS approaches to quantitate N-glycans and sialic acid content of biotherapeutics • Choosing a fluorescent dye and analytical separation method for released N-glycans

Presented by Who Should Attend • Biopharmaceutical analytical development scientists

For questions or concerns, email [email protected]. Quality/Regulations

pharmacists first need to contact and that itself exhibits batch-to-batch vari- between the approved biologic and the obtain permission from the prescrib- ability,” Sunstrom clarifies. biosimilar are not greater than the risk ing physician before they substitute a Variations in PTMs of a protein, of using just the approved biologic,” biosimilar for an originator biologic,” including the molecule’s glycosyla- Mallory says. says Hillel P. Cohen, PhD, executive tion profile and formation of di-sul- The additional hurdles are designed director, Scientific Affairs, Sandoz, a phides, are cell line dependent, says to ensure that a biosimilar may be sub- Novartis company. Matt McGann, field applications and stituted for the reference biologic with- An FDA-approved biosimilar does marketing manager at RedShiftBio, a out the need for intervention by the not necessarily need an interchange- Burlington, MA-based provider of ana- health care provider who prescribed the ability designation to be approved for lytical instrumentation. original reference biologic, Mallory adds. all indications of the originator bio- “Many innovator pharmaceutical As part of FDA’s standard, a manu- logic, however, notes Noelle Sunstrom, companies have gone to great lengths facturer of a proposed interchangeable founder and CEO of NeuClone, an to develop unique cell lines for pro- biosimilar product must show the prod- Australian-based clinical-stage bio- duction of a biotherapeutic product, uct is highly similar to, and has no clin- pharmaceutical company. “For exam- thereby limiting the ability to simply ically meaningful differences from, its ple, while none of the five Herceptin copy a drug substance,” McGann says. reference product, states Christl. Christl (trastuzumab) biosimilars approved “The processes involved in develop- also points out that biosimilarity is not by FDA are designated as ‘inter- ing a biosimilar result in variations in equivalent to interchangeability. The changeable’, they all are approved for the protein from primary to quaternary latter is intended to support automatic the same indications as the originator. structure,” McGann continues. “The pharmacy-level substitution and needs Interchangeability only relates to the new FDA guidelines for interchange- to be positively established on a case- practice of a pharmacist substituting a ability of a biosimilar highlight these by-case basis, Christl also says. biosimilar for an originator biologic,” differences by recommending that bio- “It is important to note that a biosim- Sunstrom emphasizes. similarity not only be established based ilar without an interchangeability des- “A major reason a biosimilar is not in pharmacological attributes of the drug ignation is not inferior to a biosimilar ‘simply’ designated to be substituted, substance but also clinical data, such as with the designation,” Christl points out. in the same way as a small-molecule clinical end-points and interchangeabil- “Instead, an interchangeability designa- generic, relates to the variable struc- ity. Demonstration of an equal or better tion reflects a determination by FDA ture of biologic medicines, which can patient outcome is considered required that the biosimilar can be substituted affect their potency and blood half-life evidence to justify the licensing of a bio- for the reference product at the phar- in patients,” Sunstrom says. “For small similar drug, which is described at the macy without the consent of the pre- molecules drugs, the precise atomic totality of evidence by FDA.” scriber. This determination is based, in structure of the originator product part, on additional data showing that is well defined and expected not to CLARIFYING patients can be switched back and forth change. Thus, following patent expiry INTERCHANGEABILITY between the reference product and the of the originator small-molecule drug, For practical purposes, clarifying biosimilar with no additional risk.” another manufacturer can manufac- what “interchangeability” means Based on its own internal analyses, ture a generic alternative that is an is helpful in biosimilar development. Amgen believes that only about 10% exact replica of the originator, and “Interchangeable” means “biosimi- of biological products (excluding insu- can be highly controlled down to the lar plus,” where the product must first lin and human growth hormone) are atomic level.” meet the requisite hurdles to qualify expected to lose regulatory exclusivity “However, with biologics, such precise as a biosimilar, notes Jennifer Mallory, by 2023 in the US. These products are replication cannot be achieved because partner at Nelson Mullins Riley & dispensed at retail pharmacies where all biologics—whether an originator or Scarborough, a Columbia, SC-based automatic substitution could occur, a biosimilar—vary from one batch to law firm. Following this, the biosimilar Christl notes. “We are seeing many bio- the next. This inherent variation is the manufacturer must meet heightened similars contribute to competition and result of using living cells used to man- evaluation and testing requirements. attain strong uptake in the US, even ufacture biologics that are heteroge- “These are designed to ensure that though FDA has not yet designated any neous mixtures of different molecules the biosimilar produces the same clin- biosimilar as interchangeable.” with different post-translational modi- ical result as the approved biologic in Christl also states that FDA’s inter- fications (PTMs). So, biosimilars can be any patient and that the safety and changeability guidance does not sub- ‘highly similar’ to an originator biologic efficacy risks arising from switching stantively address analytical testing or

30 BioPharm International April 2020 www.biopharminternational.com Quality/Regulations

analytical standards beyond what the IS INTERCHANGEABILITY the US [as of press time]. In compari- agency already has addressed in ear- STATUS IMPORTANT? son, the European Medicines Agency lier guidance on the demonstration of The importance of interchangeability is (EMA) has approved 64 biosimilars, biosimilarity. “In terms of clinical test- particularly relevant for biologics dis- 59 of which are available for use in ing, FDA’s interchangeability guidance pensed by pharmacists for patients with Europe. While we are encouraged that states that sponsors seeking an inter- chronic illnesses because these patients healthcare systems in the US are imple- changeability designation for a product require treatment over a long period of menting biosimilars into their clinical intended to be used more than once time, notes Sunstrom. practices at a growing rate, there are by an individual are generally expected However, Sunstrom explains, if a still hurdles that need to be addressed to conduct switching studies, in which treatment is only for a short duration, to support a biosimilar market that can patients start with the originator prod- such as with many oncology biolog- generate success like what we’ve seen in uct and are randomly assigned to switch ics, the patient can receive fewer doses, Europe,” states Cohen. to the biosimilar or continue using the thereby reducing the opportunity for One hurdle includes the challenges originator product. According to the switching between an originator and posed by FDA’s approval process for guidance, the ‘switching’ group would biosimilar. If the prescriber is also interchangeability, specifically, the be expected to incorporate at least two administering the biologic (i.e., no fact that to obtain interchangeability, switches between the originator and decision by the pharmacist), the pre- sponsors are required to conduct an biosimilar products and at least two scriber has total control over whether extensive, comparative pharmacokinetic exposures to each product,” says Christl. an originator or biosimilar is admin- (PK) study using multiple switches fol- “Amgen believes that FDA’s current istered with no opportunity for phar- lowed by an extended follow-up period. standards for demonstrating inter- macy-level substitution, making an “This criterion is not mandated for PK changeability are scientifically appropri- interchangeability status in cases such studies of originator biological drugs ate,” she adds. as these less significant. when manufacturing process changes “It is quite important for a biosimi- “Note that, as of March 12, 2020, are implemented that lead to struc- lar to demonstrate ‘interchangeability’ none of the 26 FDA-approved bio- tural changes of the biological drug because, unlike generics, a biosimilar similars have been designated as inter- itself. The additional research burden can be prescribed by physicians under changeable,” Sunstrom observes. and costs for a biosimilar drug to be the current law. Despite biosimilar use Further, there has been debate considered interchangeable are substan- over the years, there has been a hes- over the need for an FDA inter- tial and may deter biosimilar manufac- itation to prescribe them because changeability designation at all. turers from seeking interchangeability,” of potential risks, such as diminished “Interchangeability is an additional Cohen emphasizes. efficacy or expectation of immuno- attribute to a biosimilar that comes at The value of the interchangeable genicity after switching to a biosimi- a substantial investment in clinical trial attribute, therefore, is in the automatic lar,” says Lee. Lee notes, however, that design, which incorporates switching substitution at the pharmacy level. “In the designation of interchangeability originator with biosimilar and back Europe, there is no equivalent desig- based on efficacy results from multi- again in large-patient-number trials. nation from the European Medicines ple switching will encourage physicians It does not designate the interchange- Agency (EMA) and switching between and patients to use biosimilars more able biosimilar as being superior in any originators and biosimilars is a med- often. Furthermore, interchangeability way to those without this designation,” ical matter typically at the discretion status ultimately allows for any product Sunstrom states. of the prescribing physician, not the among available interchangeable prod- Cohen holds a similar opinion, say- pharmacist. As argued by Ebbers & ucts to be dispensed at pharmacy level, ing that, as a scientific matter, a biosim- Schellekens (2019), biosimilars should which is expected to accelerate access to ilar is developed to match its reference be interchangeable by default rather biosimilars. medicine with regard to these attributes. than needing to meet additional The interchangeable designation in “Therefore, it is our position that an requirements to be designated as such: the US requires additional clinical data approved biosimilar should be consid- ‘there is no reason to doubt that bio- beyond that provided to establish bio- ered interchangeable with its reference similars are interchangeable and that similarity, Cohen points out. “It is not medicine, meaning that a patient can the risk of increased immunogenicity of a higher quality standard because an expect an equivalent treatment out- switching to a biosimilar is no greater interchangeable biologic and biosimilar, come,” Cohen adds. than switching between two batches of by definition, match the reference prod- “To date, there are 26 FDA-approved any biologic. We argue that the default uct in safety, purity, potency, and efficacy. biosimilars, but only 16 are marketed in should be that biosimilars are inter-

www.biopharminternational.com April 2020 BioPharm International 31 Quality/Regulations

changeable, unless there is compelling Celltrion backs up that perspective. Given FDA’s perspective, it is evidence otherwise’.” Sunstrom cites (2). Lee says that, instead of providing any therefore helpful that the guidance specific analytical recommendations repeatedly emphasizes that sponsors ANALYTICAL GUIDANCE that biosimilar developers can imple- are encouraged to reach out to the When it comes to analytical recom- ment, the new guidance explains the agency to conduct early discussions mendations in the FDA interchange- agency’s position, which discusses the and schedule meetings. “Additionally, ability guidance, a key phrase to take planned development approach. This as stated in the Federal Register notice note of is in Section V.A.1.: “Advances approach includes any proposed justifica- regarding the guidance, FDA is not in analytics may allow for extended tion for reducing the extent of informa- suggesting that this will be its final analytical characterization that affect tion needed to support a demonstration word on interchangeability. Indeed, in the extent of other data and informa- of interchangeability by the extended February 2020, FDA issued additional tion needed to support a demonstration analytical characterization. “Our com- draft guidance, entitled Biosimilars and of interchangeability…” (1). pany is planning to discuss reasonable Interchangeable Biosimilars: Licensure McGann points out that this state- approaches for each product with the for Fewer than All Conditions of Use for ment highlights the fact that improve- regulatory authority to reduce the burden Which the Reference Product Has been ments in analytical methods for of clinical trials,” Lee states. Licensed (3). We can expect upcoming characterizing biotherapeutics can dras- What the guidance does provide are agency guidance and other actions that tically impact the totality of evidence examples that sponsors may employ as hopefully will provide more insight for required to support the claims of bio- benchmarks to assess the approaches developers of biosimilars and inter- similarity. “Improvements in instrumen- they are thinking of using to demon- changeable biosimilars,” Mallory con- tation capabilities, such as sensitivity, strate interchangeability and to develop cludes. resolution, or precision that can more their product development plan, says “The analytical processes and tools clearly demonstrate biological similar- Mallory. Mallory also notes that it is used in biosimilar development are ity could reduce the burden of proof advisable to identify the approaches very similar to those used in the devel- required to demonstrate both biosimilar- highlighted in the guidance document opment of originator biological prod- ity and interchangeability,” McGann says. that a sponsor already used in its devel- ucts. The primary difference is how Advanced analytical tools (e.g., opment work and previously submitted those tools are used in the iterative AQS3pro, RedShiftBio) can offer a 30x to FDA in connection with the biosim- process of biosimilar development. improvement in sensitivity and the abil- ilar approval process. “Likewise, spon- While the methods and tools are tech- ity to measure secondary structure in sors would be well-served to determine nically complex (thus, not simple), they formulation conditions. The latter mea- which approaches in the guidance doc- can be utilized in a fairly straightfor- surement was not previously possible, ument do not appear applicable (and ward manner to develop biosimilars and it could provide evidence of biosimi- why), and any short cuts that potentially that meet the criteria of ‘highly similar larity that reduces the burden of proof in may be available. Some of this analysis with no clinically meaningful differ- other areas, McGann says. ideally would take place even before early ences’,” Christl adds. “For this reason, biosimilar developers discussions with FDA so that the spon- need to ensure that their analytical tools sor can be comfortable with the specific REFERENCES are at the cutting edge of technology. As goals and objectives that it would like 1. FDA, Guidance for Industry, a company, they need to be constantly FDA to green-light or begin to consider,” Considerations in Demonstrating reviewing their capabilities to ensure that she highlights. Interchangeability With a Reference they stay at the forefront of technology An important theme in the guidance, Product Guidance for Industry relative to the market,” McGann adds. Mallory emphasizes, is that FDA is not (CDER, CBER, May 2019). “FDA, in recent years, has taken less suggesting that there is a one-size-fits-all 2. H.C. Ebbers and H. Schellekens, of a prescriptive stance when it comes approach for demonstrating interchange- Drug Discovery Today, 24 to what types of analytical characteriza- ability. Rather, the agency used the (10) 1963–1967 (2019). tion should be used, preferring to move guidance to confirm that demonstrating 3. FDA, Draft Guidance for Industry, the responsibility to the pharmaceutical interchangeability is complex, much like Biosimilars and Interchangeable company to justify why a measurement the complex molecules involved. “Thus, Biosimilars: Licensure for Fewer Than is not required rather than requesting FDA noted in the guidance that the ‘data All Conditions of Use for Which specific tests to be performed. This and information necessary to support the Reference Product Has Been change can be attributed to the rapid a demonstration of interchangeability Licensed Guidance for Industry change in technology in recent years,” need to be considered on a case-by-case (CDER, CBER, February 2020). ◆ explains McGann. basis.’,” Mallory says.

32 BioPharm International April 2020 www.biopharminternational.com Maximize Your Molecule’s Full Potential

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Being Vigilant in Supplier Oversight Risk assessments, audits, and good communication between sponsor and supplier are key elements of supplier oversight.

SUSAN HAIGNEY

he bio/pharmaceutical industry is a global network that and/or a third-party GMP certification. Incoming materials ties together an array of developers, manufacturers, and should have their identification verified and the quality depart- T suppliers. Bio/pharmaceutical companies, therefore, may ment should give its approval to release the materials for use. source APIs and excipients from companies thousands of This includes performing—at a minimum—an identification miles away. This global aspect of the industry, naturally, cre- test, and may include other tests necessary to ensure the qual- ates a complex supply chain that could leave patients vulner- ity for the intended use as per 21 Code of Federal Regulations able if not properly overseen. The discovery of nitrosamine 211.84(d)), advises IPEC-Americas. impurities, including N-nitrosodimethylamine (NDMA) and Risk assessments of both suppliers and materials should also N-nitrosodiethylamine (NDEA), found in angiotensin II recep- be performed, according to IPEC-Americas, with a specific tor blocker (ARB) medicines (1) in 2018 is an example of how focus on the intended use of the material. The risk assessment ingredient issues can affect patients and the supply chain and the should also evaluate possible concerns with efficacy, variability, importance of testing ingredients. Now, the global COVID-19 safety, and quality. And this evaluation should not end with the coronavirus pandemic has the potential to disrupt supply chains, risk assessment. The sponsor should “[establish] a process for site inspections, and other activities associated with supplier continued monitoring of the supplier and the quality of incom- qualification and oversight. ing materials,” according to IPEC-Americas. Sponsor companies and manufacturers are responsible for ensuring the components they use are safe and effective. FDA QUALIFYING SUPPLIERS has cited companies for failing to test their incoming API and How do sponsor companies choose and monitor material sup- raw materials “to determine their identity, purity, strength, and pliers to ensure the ingredients they are purchasing are fit for other appropriate quality attributes” (2). According to a spokes- purpose? Linda Evans O’Connor, vice president and chief of staff person for IPEC-Americas, sponsor companies must verify the at Lachman Consultant Services, Inc., suggests that sponsors quality of materials, which includes qualification of the supplier start by obtaining information from the supplier about its capa- through on-site good manufacturing practice (GMP) audits bilities and compliance history through a questionnaire. Material bradcalkins/Stock.Adobe.com

34 BioPharm International April 2020 www.biopharminternational.com Operations

Manufacturing APIs and the Supply Chain

BioPharm International spoke with Jens Andersson, Andersson (Cambrex Karlskoga): The main challenge purchasing director at Cambrex Karlskoga, about the is that for suppliers of critical raw materials we need to best way to ensure the security of the bio/pharmaceutical make a much more thorough initial qualification and risk materials supply chain. assessment. This can be time consuming and, at times, it BioPharm: What is the contract manufacturing can be difficult to get the data and information needed. At organization’s (CMOs) responsibility in ensuring the quality Cambrex, we do have a robust supplier network where of materials they use in the production of APIs? we have been able to establish strong relationships over a Andersson (Cambrex Karlskoga): Cambrex prefers to number of years that mitigates this risk. take full responsibility for ensuring the quality of the raw BioPharm: When there have been reports of suppliers materials that are used in our manufacturing processes. falsifying certificates of analysis (CoAs), how can a pharma Ultimately, we are responsible for the quality of the final API company or contractor be sure the information they are produced at our sites and ensuring that it meets customers’ receiving from a supplier is correct? Is this why testing of specifications. Therefore in our opinion, it makes sense materials is important? that we take the responsibility to source raw materials of Andersson (Cambrex Karlskoga): For critical raw the correct quality to undertake the campaign or product. materials, we will always carry out our own analyses to We also find this process to be quicker and more cost- confirm the vendor’s CoA and ensure the quality of the effective than if the end customer undertakes the sourcing material. For less critical raw materials such as common and sends material to us, as we can use our own supplier solvents or regularly used bulk acids and alkalis from network and can use suppliers with which we have a reliable and trustworthy vendors, goods can be received well-established relationship without having to necessarily only on CoA, but we will undertake random tests to ensure qualify new suppliers. the CoAs. BioPharm: What are the steps and/or best practices for BioPharm: What should a pharma company or qualifying suppliers? contractor do when FDA puts a supplier on import ban? Andersson (Cambrex Karlskoga): There are several Should companies have a backup plan to prevent product steps that are undertaken when we qualify suppliers, with shortages? the first being to evaluate the quality of raw materials Andersson (Cambrex Karlskoga): A company needs against the specifications to ensure that they meet both the to be proactive and should always aim for dual sourcing stated purity and the demands of the project we intend to capabilities for critical raw materials, so that any risk of use the materials for. Then we send questionnaires to the supply is minimized. A risk assessment should always be suppliers that cover a wide range of topics, from quality carried out to evaluate the danger of interrupted deliveries. to health and safety practices, as well as environmental BioPharm: What has the recent N-Nitrosodimethylamine policies and responsibilities, and ethical guidance of the (NDMA) impurity issue taught the industry about materials company. If needed, audits are carried out on-site by our QA quality and the importance of testing materials? [quality assurance] specialists for suppliers of raw materials Andersson (Cambrex Karlskoga): Given that the with critical impact on the final product quality, such as the situation with the NDMA is still ongoing, it is too early to say main building blocks of the final API. what lessons need to be learned from it. However, in 6–12 BioPharm: How often should suppliers be audited? months the situation will hopefully be clearer, allowing for Andersson (Cambrex Karlskoga): For critical raw a detailed review to take place and evaluation of any future materials and services we re-evaluate suppliers every two risks to be made. It is paramount that patient safety is the years. We carry out on-site audits every two to three years highest priority so the industry as a whole has a duty to depending on how critical the raw material or service is; ensure that decisions are made that do not compromise this however, audits can also be initiated outside of the regular in any way, and that any oversights that have been made schedule for other reasons, such as quality or supply issues. previously do not happen again. BioPharm: What additional challenges do high-risk —Susan Haigney materials pose? Does the oversight of these suppliers intensify?

www.biopharminternational.com April 2020 BioPharm International 35 Operations

samples should also be obtained to deter- (e.g., API, excipient, sterile, non-sterile, the use of questionnaires and video con- mine if they are fit for their intended complex dosage form, etc.), location, past ferencing. If visuals are required for the purpose. Site audits should be performed, regulatory or audit history, recalls, qual- supplier assessment, the use of an elec- and quality agreements should be put in ity of incoming goods, complaint history, tronic device or video streaming options place, she says. Finished product trials importance to the business of the mate- could be employed. Bottom line, to keep should be performed if the materials meet rials (i.e., Is this an API for your block- the supply chain viable during crisis mode, the requirements. Batches should then be buster drug and lack of supply would have we need to think outside of our normal tested for stability. Periodic monitoring a material impact on the business?). A operating procedures and experiences,” of the supplier should be performed with minimum frequency per material type says Schniepp. data reviewed on a predefined basis in should be defined (i.e., for an API, every If travel is limited due to global situ- addition to performing surveillance audits, two years),” O’Connor says. ations such as the COVID-19 epidemic, according to O’Connor. IPEC-Americas IPEC-Americas agrees. “Whether the O’Connor suggests getting creative. “For stresses, however, that an appropriate risk supplier is an excipient manufacturer, con- example, performing a virtual audit, assessment cannot be performed without tract manufacturer, distributor, or service while not ideal, is a possibility, and would onsite audit information. provider (e.g., a contract testing lab), the require cooperation of the sponsor and Susan J. Schniepp, executive vice-presi- initial audit frequency should be based on the manufacturer. Document review and dent of post-approval pharma and distin- results from the initial supplier/excipient interviews can be performed remotely. guished fellow, Regulatory Compliance risk assessment along with any additional Companies could even look at virtual Associates, says that companies should mitigation measures identified. Based on facility tours using appropriate technology. begin the qualification with an onsite on-going monitoring, a sponsor company However, these types of audits are not audit. “Once the audit is performed and should determine whether to adjust the ideal, and shouldn’t replace on-site audits. any identified concerns resolved, the two audit frequency.” Another solution is to partner with a local parties, purchaser and supplier, can enter A quality risk management plan is company that has the local resources to into a quality agreement. After the quality key, agrees Schniepp. Frequency of audits perform the on-site portion of the audit. agreement is approved, the purchasing should be based on the criticality of the This will allow on-site audits to occur company can start the process of ‘qualify- material and the past performance of the even when international travel bans are in ing’ the supplier. This qualification usually supplier. “This plan should identify sup- effect,” says O’Connor. involves testing of the material to confirm plier vulnerability (i.e., single source, sec- the supplier’s certificate of analysis (CoA) ondary supplier, etc.), which should help THE ROLE OF COAs is accurate and develop a history that determine audit frequency. The quality CoAs provide manufacturers with demonstrates the ability of the supplier agreement should reflect the risk plan, detailed information about materials to continually provide a suitable product,” but there should always be a contin- including material manufacturer, quality says Schniepp. gency to allow for-cause audits as needed. testing information, specifications, batch The supplier should then be placed Laboratories used by either the supplier numbers, and other information (3). FDA on an approved supplier list, according to or the purchaser should be audited and has been known to cite companies for Schniepp. “The initial qualification for included as an element of the risk plan,” incomplete or incorrect information on a supplier to be considered an approved says Schniepp. CoAs (4). So, how reliable are these doc- supplier usually involves complete con- uments and how much emphasis should firmatory testing on the first 10 lots of Auditing under sponors put on them when it comes to material received and then a periodic difficult circumstances ensuring material quality? check and confirmation by the purchaser Having a consistent and properly exe- O’Connor suggests that sponsor com- of the entire testing regimen listed on the cuted audit program is paramount to panies create a library of CoAs or labels CoA received from the supplier.” maintaining the timeliness and integ- so they can verify that the information is rity of the supply chain, says Schniepp. correct. “Also, maintaining a relationship PERFORMING AUDITS Audits, and the information obtained with suppliers is key. Anything unusual Peforming audits of material suppliers during them, allow one to assess a sup- needs to be flagged,” says O’Connor. is key for ensuring the quality of mate- plier’s risk, especially during crises such Building trust between the sponsor rials, but how often should these audits as the COVID-19 pandemic. “Having and supplier is important, agrees IPEC- be performed? O’Connor suggests that the baseline knowledge of your suppliers’ Americas. “A robust supplier qualifi- a risk-based approach should be used to operations will help assess where critical cation program, including an onsite determine when and how often a sup- resources need to be allocated during a GMP assessment of a supplier, by either plier is audited. “Many factors can go into crisis period. While not ideal, audits can the sponsor or a qualified third party, the risk model, such as type of material still be performed on suppliers through and development of a partnership with

36 BioPharm International April 2020 www.biopharminternational.com Operations

the excipient supplier are necessary to system. Even if the material meets the O’Connor says that while both spon- establish and build trust in the validity testing qualifications listed on the CoA, it sors and CMOs share responsibilities, of their CoA,” says IPEC-Americas. may not be suitable for use due to other the sponsor has the “ultimate” responsi- Annual confirmation testing of CoA potential GMP violations that might be bility of its supply chain. “Sponsors and results is also necessary, says IPEC- present at the supplier facility,” she says. CMOs share responsibilities, but the Americas (5). “Full testing of an excip- “In the case of falsification, the pur- selection, qualification, and oversight of ient is required until a robust supplier chaser should be concerned with data suppliers is the sponsor’s responsibility, study has been completed and a reduced integrity issues that lead to the falsifi- whereas day-to-day testing is generally testing program has been approved. cation in the first place. If a purchaser the CMOs/CDMOs, although some- Only once trust has been established suspects a supplier is falsifying the times that goes to the sponsor as well. can the sponsor move to a reduced test- results on a CoA they need to initiate The sponsor has ultimate responsibility ing program. However, identification a for-cause audit and quarantine the for the entire supply chain, so even if testing is always required to ensure the suspect material until they can confirm it delegates part of that responsibility identity of incoming materials.” it was satisfactorily manufactured fol- to the CMO/CDMO, it is ultimately To establish that the quality testing lowing cGMP expectations. Passing test responsible.” information included in the CoA is results does not confirm compliance to Sponsors must ensure that they have accurate, incoming materials must be cGMPs,” Schniepp explains. signed agreements in place with any tested against the requirements in the CMOs and/or CDMOs they are using CoA, Schniepp insists. “The best way to THE ROLE OF CMOs that identifies the responsibilities of ensure the CoA is accurate is through Many drug sponsors engage contract each party when it comes to ensure complete testing. In cases of falsification manufacturing organizations (CMOs) the quality of materials, according to a of the CoA, results testing is mandatory to conduct drug production steps. So spokesperson for IPEC-Americas. to make sure the material is suitable for what is the CMO’s responsibility in use; however, it must be coupled with ensuring that materials are safe and a review of the supplier’s overall quality effective? Contin. on page 56

FROM CHROMATOGRAPHY TO DOWNSTREAM PROCESS SKID FOR BIOLOGICS

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www.biopharminternational.com April 2020 BioPharm International 37 Operations

Packaging Preserves the Cold Chain More sustainable and functional cold-chain packaging protects temperature-sensitive drugs.

HALLIE FORCINIO

roper storage and transport temperatures for drugs, handle and process product at these ultra-low temperatures especially biologics, are essential to protect prod- as quickly and efficiently as possible,” notes Davidson. P uct efficacy and patient safety. “As strong growth continues across the global pharmaceutical industry, the PACKAGING TRENDS sub-category of temperature-controlled products is surging In addition to the growing number of temperature-sensitive ahead—growing at twice the rate of the industry overall,” products, three trends are driving the need for tempera- said David Williams, president of Pelican BioThermal in a ture-controlled packaging, according to a survey by Pelican press release (1). BioThermal. First, quality demands increase as more sensi- Joe Cintavey, product specialist at W.L. Gore, agrees, tive products bring logistics complexity and greatly expanded noting, “The pipeline of biologic drugs in development risk. Yet, while awareness of temperature-controlled require- are becoming more temperature-sensitive, resulting in an ments is high, the survey shows temperature excursions hap- increase in storage of bulk drug substance at frozen tempera- pen frequently (1). tures (-40 to -70 °C).” Second, the distribution range is expanding as products Rory Davidson, Business Development Manager at move further and through more climatic zones. More than Almac Pharma Services, adds that labeling, packing, and half of survey respondents (51.8%) regularly ship products distributing cell and gene therapy products often requires internationally, creating an increasingly complex web of local, products to be stored and processed at ultra-low tempera- regional, and international connections that require a broad tures (-20 to -80 °C), with the products only being defrosted range of transport modes (1). immediately prior to use. “If these products are not kept in exact conditions, they become unusable. We have seen some HALLIE FORCINIO is packaging editor at BioPharm International, cases of product becoming unusable within a minute of [email protected]. being out of frozen conditions and so we need to be able to felipecaparros/Stock.Adobe.com

38 BioPharm International April 2020 www.biopharminternational.com Understanding Oligonucleotides from Every Angle: Utilizing Mass Spectrometry for Characterization and Quantification

ON-DEMAND WEBCAST: Aired Tuesday, March 17, 2020

Event Overview Therapeutic oligonucleotides continue to grow in their contribution Presenters to the pipelines of pharma and biopharma companies. Oligonucle- Sean McCarthy otides are a chemically distinct class from small-molecule or protein therapeutics and present their own unique challenges for charac- Global Technical Marketing terization and quantification. As a consequence of their highly serial Manager, Biologics synthesis and use of modified nucleotides, oligonucleotides are SCIEX uniquely susceptible to fairly high levels of synthetic impurities. Quantification of oligonucleotides is complicated by the typical use Moderator of ion-pairing reagents. A simple way to overcome this is to use a Laura Bush lower flow that maintains system uptime and increases sensitivity. Editorial Director In addition, this webcast will provide details on the advances of current techniques for microflow LC-MS quantification of LCGC oligonucleotides.

Key Learning Objectives Who Should Attend • Gain a broad understanding of the different classes of • Scientists or lab directors already supporting oligonucleotide therapeutic therapeutic oligonucleotides currently in development development or those considering • Discover how microflow LC-MS allows us to get the doing so highest sensitivity of oligonucleotides in complex biomatrices

• Learn how high-resolution mass spectrometry (HRMS) allows you to get definitive confirmation of oligonucleotides’ synthetic impurities Sponsored by

Presented by

For questions or concerns, email [email protected] Operations

The third trend identified in the “Regulations governing these types In addition, “Seasonal temperature survey is the need to optimize the of highly sensitive products are grow- changes can substantially affect the total cost of ownership (TCO) due ing stricter,” adds Adam Tetz, direc- internal facility environment and to relentless competition and margin tor of worldwide marketing at Pelican shipping environment,” warns Joe pressures. A full 70% of survey respon- BioThermal. “For example,” he says, Luke, vice president of sales and dents agree that TCO is “import- “China has become particularly strict marketing for Reed-Lane, a New ant” or “very important,” while 10% and requires real-time tracking on all Jersey-based provider of contract consider only basic packaging costs pharmaceutical shipments.” packaging services. and transport rates. This exploration Many local governments want of TCO is spurring interest in reus- to reduce or eliminate the use of TESTING able containers, with 79% of survey expanded polystyrene foam (EPS), a To ensure packaging will perform respondents saying reusable contain- common insulating material, because it as specified, Cryopak tests it against ers—though more expensive than is rarely recycled. “California and New extreme ambient temperature profiles in single-use containers—are worth the York are limiting the amount of EPS its ISTA-certified lab following protocols investment. More than one-third of foam that can be delivered into their and internal standard operating proce- respondents (37.6%) are already using states,” says M. Ryan Corbin, director dures. “Our shipping systems are then reusable rental programs in their cold- of marketing at Kodiakooler. These qualified with repetitive testing to assure chain logistics operations, and 25% are requirements are forcing makers of consistency and performance repeatabil- actively exploring this option (1). temperature-sensitive drugs and bio- ity,” explains Barakat. “The real shipment As a result, validated, off-the-shelf, logics to look for alternatives. is then monitored with temperature data or customized protective packaging loggers to prove operational performance options continue to evolve for all There is strong and quality assurance,” he concludes. temperature ranges, including con- To test the durability of reusable, pas- trolled room temperature, refriger- demand for more sive thermal packaging systems, Pelican ated, frozen, and cryogenic. “The BioThermal is developing a mechanical challenge is optimizing the design, sustainable designs, test method. In addition to mimicking materials, and components to min- the real-world use environment, the test imize overall size and weight including re-use method also allows assessment of the of the shipping solutions,” says impact of dynamic use on thermal per- Mark Barakat, general manager of programs to formance. Tetz reports that results are Cryopak, a subsidiary of Integreon promising. He says, “The test standard (formerly TCP Reliable). He con- reduce the carbon would give pharmaceutical manufacturers tinues, “Achieving peak performance even more confidence in choosing reus- while minimizing size, weight, and footprint. able thermal packaging over single-use cost is typically contradictive.” Cold- options to reduce costs and advance envi- chain engineering experience and ronmental initiatives.” tools like thermal modeling software In addition to insulation, tempera- “Current standards assess par- and testing equipment play import- ture-controlled packaging includes cel thermal packaging systems during ant roles in optimizing tempera- single-use and reusable parcel one intense shipment from point A to ture-controlled packaging. and pallet shippers, thermal pallet point B,” explained Bill Mayer, director covers, and phase-change materi- of research and development at Pelican MEETING REQUIREMENTS als. Sometimes, customized designs BioThermal. “Throughout the devel- There is also strong demand for are needed, especially for products opment of this new test method, we more sustainable designs, includ- that will experience particularly addressed the challenges of exposing sys- ing re-use programs to reduce the hostile conditions or need to be tems to the multi-leg and multi-mode carbon footprint. Interest in tem- maintained at cryogenic tempera- shipping route and more of an average perature-controlled packaging also tures. Regardless of the application, trip with parcel thermal packaging used is being impacted by changing reg- optimized temperature-controlled multiple times” (2). ulations and standards. For exam- packaging depends on the answers ple, “Temperature profiles issued by to three questions: Where is it being COLD-CHAIN OPTIONS ISTA [International Safe Transit shipped? What temperature must Innovations in temperature-con- Association] have changed within be maintained? How long does that trolled packaging center on sustain- the past five years,” reports Barakat. temperature need to be maintained? ability, performance, and cost. To

40 BioPharm International April 2020 www.biopharminternational.com Simple and Effective Methods for Purification and Determination of Molecular Weight of DMT-on and DMT-off Oligonucleotides

LIVE WEBCAST: Wednesday, April 22, 2020 at 11am EDT | 8am PDT | 4pm BST | 5pm CEST

Event Overview Presenters The pipeline of oligonucleotide drugs has never been stronger. This has created the need for innovative purification and analytical Bill Evans characterization techniques. In this presentation, new simple, fast, Process Chromatography and effective methods for the purification—as well as the molecular Technical Specialist weight analysis—of DMT-on oligonucleotides and DMT-off Tosoh Bioscience LLC oligonucleotide therapeutics are discussed, including: • Purification of a protected or DMT-on oligonucleotide using Moderator hydrophobic interaction chromatography (HIC)

• Purification of a charged-oligonucleotide using anion exchange Rita Peters chromatography (AEX) Editorial Director • Use of a fast and effective analytical method to determine the BioPharm International molecular weight of oligonucleotides by HPLC size-exclusion chromatography (SEC) coupled with light scattering detection For questions or concerns, email Key Learning Objectives [email protected]. • Understand purification methods recommended for purifying a protected or DMT-on oligonucleotide Sponsored by • Learn purification methods recommended for purifying a charged-oligonucleotide • Understand why size-exclusion chromatography coupled with light scattering detection is considered an effective and innovative method to determine the molecular weight of an oligonucleotide Presented by Who Should Attend • Chromatographers, method developers, and process engineers who are involved with the development of purification processes, as well as the analysis, of oligonucleotide therapeutics Operations

improve sustainability, OptumRx, station. The company, which is head- materials that typically become brit- a pharmacy care services provider, quartered in Germany, specializes in tle when exposed to temperatures has transitioned from rarely recy- vacuum insulation panels and phase- below -40 °C, which can lead to cled foam packaging to recyclable change materials that offer five-day cracks or leaks in the bags,” explains packaging made from renewable temperature protection without the Cintavy. The proprietary high- cotton-based Kodiakotton from need for external energy sources. A strength fluoropolymer material Kodiakooler, which was recently rental service business offers a fleet of used for the Sta-Pure flexible freeze acquired by Airlite Plastics. The cold-chain containers and boxes (7). containers is durable after freez- Kodiakotton insulating material is Reuse is possible with the ing at -86 °C (-123 °F) and offers biodegradable, compostable, reusable, AcuTemp Plus Series of shippers the convenience and scalability of and recyclable. OptumRx projects from CSafe Global through its Repaq a single-use system that efficiently the new packaging will save mil- program. Proprietary, high-perfor- uses freezer space. In addition to lions of gallons of water, pounds of mance ThermoCor vacuum-insulated durability, the container’s chemically carbon dioxide, and kilowatt-hours panels control payload temperatures. inert, biocompatible, high-purity flu- of energy (3). “OptumRX has had Simple to deploy, the shippers are oropolymer composite film has a low great success with our sustainable available in multiple sizes and tem- extractables profile (10). products,” reports Corbin. “Part of perature profiles with integrated Gore Sta-Pure flexible freeze con- the initiative is ongoing education track-and-trace options (8). tainers come in sizes from 50 mL for their consumers on the benefits to 12 L with tubing and connector of recyclable materials,” he adds. Although reusable options to meet different pharmaceu- In addition to Kodiakotton lin- tical and bioprocess applications. A ers, Kodiakooler offers the patented packaging has hard-shell carrier is available for easier Kwikpack system. This is a bundled handling. If carbon dioxide or oxygen kit of two Kodiakotton liners with an gained ground, permeation is a concern, an optional, easy-to-remove, recyclable band. The vacuum-sealable, secondary barrier liner bundle cuts insertion time and one-way shippers wrap minimizes ingress (11). results in a packout-ready shipper in Reed-Lane recently added cold less than six seconds (4). remain a viable storage (2–8 °C) capabilities and a Fiber-based options, which can dedicated climate-controlled room be recycled in the corrugated or choice and for vial and ampule kitting, shown waste-paper streams, also are popu- in Figure 1, at its packaging facil- lar. To address this market, Thermo continue to evolve. ity in Wayne, NJ. Temperature and Fisher Scientific has developed the humidity sensors constantly mon- Invitrogen Paper Cooler. The 100% itor the cold storage area to docu- paper alternative to EPS foam cool- Although reusable packaging has ment conditions and ensure there are ers meets thermal requirements for gained ground, one-way shippers no product-damaging temperature overnight shipments (5). Another remain a viable choice and continue excursions. “Most crucially, our envi- paper-based product, ClimaCell insu- to evolve. AeroSafe Global, a supplier ronmental monitoring solutions are lation from TemperPack, is designed of reusable shippers, has added a dis- able to provide email alerts should to replace EPS insulation and reduce posable option to its portfolio. The any specified environmental condi- packaging waste. In addition to being A20 insulated shipper is designed to tions be exceeded,” says Luke. He recyclable in the corrugated stream, serve shipments needing protection explains, “Additional sensors are the ClimaCell material protects tem- for 24 to 48 hours. It is fully prequal- deployed to provide alerts pertaining perature-sensitive shipments for up to iﬁed to ISTA 7D summer and winter to ... power outages, which would 80 hours. The material also is mois- proﬁles. Minimal components sim- result in an immediate onsite power ture-resistant and can be customized plify packouts (9). generator startup to maintain speci- with printed graphics/messages (6). Gore Sta-Pure flexible freeze fied temperature continuity.” Another player in the insulation containers from Gore PharmBIO The dedicated room for kitting tem- market, va-Q-tec, has opened a US Products are designed to protect perature-sensitive products includes headquarters and production facility high-value bulk drug substances space for labeling vials and ampules in Langhorne, PA, to manufacture its from container breakage or leakage and assembling them with other com- small boxes and containers. The loca- during frozen handling. “Traditional ponents such as printed literature. Its tion also serves as a rental and repair single-use bags are constructed from location adjacent to the cold storage

42 BioPharm International April 2020 www.biopharminternational.com Operations

Figure 1. Reed-Lane recently added cold storage 2. Pelican BioThermal, “Pelican BioThermal to Present capabilities and a dedicated climate-controlled room for vial Development of Laboratory Mechanical Testing Protocol for Reusable Thermal Packaging at and ampule kitting at its packaging facility in Wayne, NJ. ISTA Forum,” Press Release, May 14, 2019. 3. OptumRx, “OptumRx Introduces 100% Sustainable Packaging for Medication Home Delivery,” Press Release, Aug. 16, 2018. 4. KodiaKooler, “Kwikpack, Assembly Instructions,” Video, https://kodiakooler.com/kwikpack/. 5. Thermo Fisher Scientific, “Invitrogen Paper Cooler,” Thermofisher.com/order/catalog. 6. TemperPack, “TemperPack Launches ClimaCell, a Certified Recyclable Packaging Solution for Perishable Shipments,” Press Release, May 10, 2018. 7. va-Q-tec, “va-Q-tec Expands in US,” Press Release, Jan. 19, 2018. 8. CSafe Global, “CSafe Expands Cold Chain Offerings for the Cell and Gene Therapy Market with Launch of High-Performing Acutemp Plus Series of Temperature- Controlled Packaging,” Press Release, Dec. 13, 2019. 9. AeroSafe Global, “AeroSafe Global Introduces Lower-Cost, Single-Use A20 Insulated Shipper Line,” Press Release, Oct. 23, 2018. 10. W.L. Gore & Associates, Inc., “Gore to Launch GORE STA-PURE Flexible Freeze Containers at BioProcess International,” Press Release, August 24, 2018. 11. W.L. Gore & Associates, Inc., “GORE STA-PURE area minimizes intra-facility travels and exposure to tempera- Flexible Freeze Containers,” Gore.com. ture excursions. 12. SAVSU Technologies, “SAVSU Technologies Launches Two New evo Smart Shipper Models to Improve Apheresis Introductions from Pelican BioThermal include a new ver- Collection Shipments and Cryopreserved Cell and sion of its ProEnvision web-based asset management track-and- Gene Therapies,” Press Release, Jan. 22, 2019. trace software, which allows integration of its CoolPall Flex bulk 13. Cryoport, Inc., “Cryoport Introduces Cell & Gene Industry’s First Dedicated Shipper for Advanced shipper into the Internet of Things. The CoolPall Flex shipper Therapies,” Press Release, Sept. 18, 2019. ◆ serves refrigerated, frozen, and room temperature ranges. A high BioPharm Intl AdvFlex qtr Apr20.qxp_Layout 1 3/10/20 3:27 PM Page 1 level of flexibility allows the system to address different time, weight, and payload requirements. For cryogenic products, SAVSU Technologies has expanded its portfolio of dry vapor shippers, which maintain biologic payloads at -196 °C during storage and transport. Positioned between the DV4 and the DV10 shippers, the DV7 unit offers seven days of thermal autonomy and a more compact form fac- In stock – ships tor with a payload capacity similar to the DV10 shipper. With within a its smaller size, the DV7 shipper is easier to handle and store week! and less expensive to ship (12). Cryoport Express Advanced Therapy Shippers from Cryoport have been developed to meet demand from biopharma customers and in anticipation of more stringent government regulations. The shippers are dedicated to human use and certified as such. Validated to ISTA 3A and 7E Transportation Standards, a new vapor plug design further doubles the holding time if shippers are mis-orientated during transit. The shippers also provide complete traceability of use history and assurance • Weldable and sealableTPE that each dewar is requalified for each trip for physical suitability, • Moldable for container closures & fluid transfer systems cleanliness, liquid nitrogen capacity, and shipment hold times. • Ideal for Single-Use Validated cleaning processes reduce the risk of cross-contamina- applications tion during use, delivery, and distribution (13). 888-579-0751 REFERENCES 1. Pelican BioThermal, “Pelican BioThermal Reveals 2019 Made in USA www.advantapure.com/bp3 Biopharma Cold Chain Logistics Survey Insights Amid Surge of with Solar Power Temperature-Controlled Products,” Press Release, July 26, 2019. MANUFACTURED BY AdvantaFlex®, NewAge Industries AdvantaPure® EMPLOYEE OWNED SOUTHAMPTON PA USA & NewAge® reg. TMs NewAge® Industries, Inc. - , , FIGURE COURTESY OF REED-LANE. OF COURTESY FIGURE

www.biopharminternational.com April 2020 BioPharm International 43 Operations

On Point: Biologics Drive Growth in Pre-Filled Syringes As a result of the rising use and development of biological drugs, the biopharma industry is witnessing an increase in the adoption of prefilled syringes.

FELICITY THOMAS

ith an aging population, the resultant increase syringes; therefore, prefilled syringes make it easier to deliver in prevalence of chronic diseases, and more the intended dose.” W demand from patients for dosing convenience, By removing the requirement of larger overfill volumes, the biopharma industry has seen an exponential increase such as those required when using vials for example, there in adoption of biological therapies delivered in prefilled is less waste of the drug solution with money and materials syringes. The overall prefilled syringes market is forecasted being saved when using prefilled syringes, asserts Sacha. to be worth nearly $10 billion by the year 2025, according These cost savings and reduction in waste are key advantages to market research (1), driven in part by the rise in use of of prefilled syringes, in addition to patient convenience, as biological drugs. the dose is already prepared and ready for administration, “There are definitely more prefilled syringes compared to he adds. 10 years ago,” confirms Gregory Sacha, senior research scientist, Baxter BioPharma Solutions. “This is certainly due to A VARIETY OF CHALLENGES the increase in therapeutic biologics.” “Biologics as proteins by their very nature create a variety Another reason, in Sacha’s opinion, for the growth seen of challenges with respect to subcutaneous delivery via in the prefilled syringes market is the expanding ophthalmic a prefilled syringe,” says George I’ons, head of product market, where drugs are intended for injection into the eye strategy and insights, Owen Mumford Pharmaceutical for the treatment of macular degeneration and other com- Services. “These challenges include the potential for inter- plications related to aging and diabetes. “The volumes for actions with many substances, which is why glass has his- injection into the eye are very low, around 20 µL to 30 µL,” torically been the material of choice for primary containers, elcovalana/Stock.Adobe.com he explains. “The low volumes are challenging to draw into including prefilled syringes. However, due to technological

44 BioPharm International April 2020 www.biopharminternational.com Operations

advances in polymer chemistry, plastic “Additionally, challenges with bio- on the efficacy and safety of biologic prefilled syringes are now beginning logics filled into syringes typically drugs, potentially giving rise to harm- to emerge on the market.” include possible interactions with the ful side effects for patients. Looking beyond glass and plas- molecule and silicone used to lubri- Discussing the intricacies of combi- tic, I’ons notes that prefilled syringes cate the barrel of the syringe and the nation products, I’ons adds that human comprise other materials that can also needle,” Sacha continues. “Interactions factors (HF) are essential consider- interact with biologic therapeutics. For with silicone can lead to the forma- ations in the development and regu- example, tungsten—frequently used tion of aggregates.” Aggregates are latory approval processes. “A rigorous for needle mounting—and silicone— well known to have a negative impact HF process is key to understanding routinely applied in formulations to the syringe barrel for lubrication of the plunger—can interact with biological substances. “Newer innovations in syringe technology are exploring ways to limit or remove these substances,” I’ons states. Common materials used for prefilled syringes include cyclic olefin polymer, cyclic olefin copolymer, polypropylene, and polycarbonate, adds Sacha. “However, there are less advances in the materials of construction than there are in the types of syringes that are available,” he says. “For example, there are syringes in development that require substantially lower overfill volumes. There is also a syringe in development that consists of multiple layers that include an oxygen barrier. And, there are needles available with narrow diameters to reduce pain upon injection.”

SAFETY CONSIDERATIONS When formulating biologics, the solution can often be highly viscous, which leads to specific challenges in terms of administration via prefilled syringes. “Viscosity can impact variables such as force to inject, dose delivery time, and needle gauge which all need to be determined and tested,” states I’ons. Agreeing, Sacha emphasizes that although there is less concern for breakages with syringes than glass vials, viscosity can cause difficulties and, as a result, early studies often include flow of the solution through the needle intended for use and conducting break force and glide force studies to monitor the pressure needed to initiate movement of the plunger and continuation of the movement.

www.biopharminternational.com April 2020 BioPharm International 45 Operations

user interaction and shaping user-cen- extractables and leachables, notes cone, adds Sacha. “Both solutions can tered risk management relating to the Sacha. “The materials are often com- be helpful for reducing interactions drug delivery device,” he says. “HF will plex mixtures that have the potential with the molecule and silicone,” he examine the device in a series of use to interact with certain components in says. “In addition, using less silicone scenarios with a sample of all intended the injectable formulation,” he says. on needles can prevent, or at least users, including those with impair- Additionally, once the compo- reduce, the amount of silicone that is ments, to ensure safe and effective use.” nents of the device have been filled, deposited in the injection site, which In I’ons opinion, a key safety con- then break force or glide force stud- is particularly useful in intraocular sideration for combination products ies can be conducted, which allow injection.” using prefilled syringes is effective companies to ensure that the prefilled Discussing drug delivery devices needle shielding, which also requires syringe functions correctly. These further, I’ons reveals that there are companies to be compliant with studies are also performed at certain several trends taking place and emerg- needlestick prevention regula- time points during stability testing, ing within the industry. “Many com- tions that are in place in the United Sacha remarks. panies are working on designs for States (2) and Europe (3). “These Testing, such as for biocompati- connected devices, which allow the regulations are key with respect to bility, aging studies, and transit test- transmission of key usage data from preventing transmission of blood- ing, along with normal validation and the device to the pharma company borne viruses such as HIV and hep- verification sequences, forms part of and third parties, such as payors,” he atitis C,” he notes. “The regulations the routine development process for says. “In addition, the use of devices state that employers are responsible combination products, I’ons continues. connected to apps creates an opportu- for the safety of their staff whether in “The goal is always to demonstrate nity for pharma to provide the patient an acute hospital setting, an alternate that the final combination product is with education, training and support site, or domestic home environment. safe for the end user,” he says. around their medication and disease Therefore, designs that incorporate management. It is hoped that provi- automatic or passive deployment of EMERGING SOLUTIONS sion of this type of information will the needle shielding during use are AND TRENDS aid compliance and ultimately may seen as advantageous as no additional As a result of challenges during for- positively impact patient outcomes.” steps are required by the user as part mulation development of biologics Furthermore, I’ons points out that of the routine injection procedure.” or biosimilars, many companies are there is an increasing focus on sus- considering and developing higher tainability. “This focus is also result- TESTING FOR SAFETY volume prefilled syringes, asserts I’ons. ing in pharma companies examining “Injection devices that contain drugs “Therefore, the industry is seeing a the number of disposable devices they and biologics are known as combi- projected increase in demand for pre- market and therefore looking at alter- nation products and have a specific filled syringes with a volume greater natives such as reusable devices to regulatory pathway via the FDA for than 1 mL (which is the common help reduce waste,” he summarizes. the US market,” explains I’ons. “In the volume used), typically to a volume European Union (EU) no such cate- of 2.25 mL,” he notes. “Consequently, REFERENCES 1. Global Market Insights, “Prefilled gory exists at present, although there prefilled delivery devices for 2.25 mL Syringes Market Size by Type (Glass, is ongoing work to create one, so drug– primary containers are now starting to Plastic), by Design (Single-Chamber, device combination products are still emerge on the market, most of which Dual-Chamber), by Applications (Diabetes, Rheumatoid Arthritis, approved as medicinal products.” are also incorporating needle stick Anaphylaxis, Antithrombotic/ For combination products, it is injury safety features.” Thrombolytic Therapy), Industry necessary for companies to ensure all Moreover, with the upswing in Analysis Report, Regional Outlook, Application Potential, Competitive necessary development and testing are trend for increased volumes, indus- Market Share & Forecast, 2019– performed on drug delivery devices, try is also witnessing growing inter- 2025,” gminsights.com, July 2019. as would be the case for any medi- est in wearable drug delivery devices. 2. M.F. Tatelbaum, Pain Physician, 4 (2) 193–195 (2001). cal device, to ensure safety. “Testing “These wearable devices can poten- 3. European Commission, “Council is required even though drug delivery tially accommodate volumes in excess Directive 2010/32/EU of 10 May devices are not subject to the usual reg- of 10 mL,” says I’ons. 2010 Implementing the Framework Agreement on Prevention from Sharp ulatory approvals, such as 510(k) in the Other solutions in development, Injuries in the Hospital and Healthcare US market,” confirms I’ons. and also some that are already on the Sector Concluded by HOSPEEM and Components of both the syringe market, are silicone-free syringes and EPSU” (Brussels, July 17, 2009). ◆ and plunger should be tested for any needles with reduced amounts of sili-

46 BioPharm International April 2020 www.biopharminternational.com Outsourcing

Ensuring Smooth Tech Transfer of Bioprocess Operations Experience, communication, collaboration, transparency, planning, and prioritization contribute to success.

CYNTHIA A. CHALLENER

echnology transfer of bioprocesses, while common in Ritacco, director of scientific and technical affairs for pharma the biopharmaceutical industry, can be complex and services at Patheon, part of Thermo Fisher Scientific. T present numerous challenges. Projects with accel- Abel Hastings, director of process sciences at Fujifilm erated development timelines that also involve multiple Diosynth Biotechnologies, adds there are some themes that contract service providers have the potential to magnify often slow the progression of sponsor projects, including the difficulties. Both contract manufacturing organizations materials challenges, specification ambiguity, and challenges (CMOs)/contract development and manufacturing organi- with historical change management. “The implications of an zations (CDMOs) and sponsor companies can facilitate the ill-selected material can linger and hinder manufacturability. process using pragmatic approaches that mitigate risks and Once selected, materials dogma can be difficult to unpick ensure cooperation between all parties involved. because of the fear of the unknown,” he notes. With respect to specifications, Fujifilm splits them into MATERIAL, SPECIFICATION, AND two general categories: safety/efficacy and manufacturability. CHANGE-MANAGEMENT ISSUES It is important, according to Hastings, to convey the known When transferring a bioprocess to a CDMO, manufacturers safety/efficacy limits as early as possible and communi- often face multiple challenges that can include meeting the cate what events might cause specifications to change. “As material demands of their clinical or commercial strategy and a CDMO, our primary goal is often to adjust the process achieving aggressive timelines. These constraints must be met while accommodating the facility fit and scale-up needs CYNTHIA A. CHALLENER, PhD, is a contributing editor to determined by both the established process and the CDMO’s BioPharm International. turgaygundogdu/Stock.Adobe.com platform, equipment, and capabilities, according to Frank V.

www.biopharminternational.com April 2020 BioPharm International 47 Outsourcing

design to reliably meet these specifica- the defined timeframe are indicators “can be minimized by having a good tions, and knowing the status of spec- of a successful transfer of the manufac- depth of knowledge of the facility’s ifications up-front helps us guide our turing process to the CMO/CDMO, specific equipment and well-estab- clients,” he explains. according to Andrew Bulpin, head of lished scaling models.” Issues can arise, however, if spon- process solutions at MilliporeSigma. Variations in equipment and mate- sors establish specifications that are “This overall challenge,” he says, “is rial handling at facilities can compli- rooted in manufacturability too early mainly linked to the process itself, but cate the tech transfer process, agrees and then the process performance it also relates to the capacity to transfer Bulpin. “If the target facility uses differ- changes in the development stage or the process knowledge built for several ent equipment, the raw materials must when moving a program from one years to the CMO/CDMO that will be compatible with that equipment,” he site to another. Establishing expec- be integrated to ensure a successful explains. In addition, to ensure a suc- tations for process performance with tech transfer.” cessful scale up, it is critical that raw limited data can, Hastings says, often It often also varies depending on the materials are available at large scale and over-constrain the development team, development phase of the bioprocess equipment capacity is evaluated. “The leading them to necessarily forego being transferred. Sponsor companies’ scale-up strategy of the CMO/CDMO, improvements in order to achieve a early-phase programs are typically as well as its expertise in various process manufacturability specification. challenged by transferring processes types, molecules, and innovative process Change management during process that do not fit into their external part- methods—including perfusion, precip- development, meanwhile, can challenge ners’ platform operations, according to itation, and single-pass tangential flow both sponsors and CDMOs as they Emily Schirmer, senior director of pro- filtration—is also key,” asserts Bulpin. work to expedite processes. “In this day cess development at Catalent Biologics. For cell-culture processes in particu- and age of accelerated processes and “Those partners that can offer a high lar, scale up can be challenging because ever-changing team members, cap- level of flexibility and unit operation scaling to larger volume is not linear, turing rationale for change becomes expertise are more successful in accom- and multiple engineering parameters increasingly important to guard against modating unique or non-traditional must be optimized to match process knowledge loss as team members leave processes,” she remarks. performance developed at the bench a company and to help guide devel- In addition, as programs progress scale and confirmed at pilot to manu- opment in an unemotional manner,” through clinical stages, process transfer facturing scales of 2000 L and beyond, Hastings asserts. becomes more difficult because there according to Ritacco. Harvest and While commercial processes typi- is less inherent flexibility allowed and downstream purification processes also cally have robust quality and change- process changes or adaptations become need to be scaled up to match product control systems, earlier-phase projects more challenging to justify, Schirmer quality and impurity profiles, and some- can often change quickly and with lim- adds. Bulpin agrees that the process times adapted to address differences ited traceability. “We recommend taking parameters in Phase I or II can be in product titer and impurity profiles a balanced approach in order to capture slightly adapted or adjusted to ensure a observed at larger scale. pertinent information while not hinder- successful tech transfer, while in Phase Even if projects don’t involve scale-up, ing development,” comments Hastings. III the process is more locked with generally they still require a thorough Some sponsors use iterative risk assess- defined critical process parameters, crit- investigation of which parameters need ments or failure mode and effects anal- ical raw materials, and designated criti- adjustment to fit best within the CMO/ ysis tools to quickly capture changes cal quality attributes (CQAs). Thus, any CDMO facility and equipment con- and build catalogs of development and changes in Phase III should be assessed, straints without impacting specifica- lifecycle changes. “This approach allows justified and, if necessary, validated. tions, Hastings observes. “In our view, the user to both convey historical details scale changes and facility-fit adjust- and to project forward-looking risks in SCALE-UP, EQUIPMENT, AND ments are not complications but rather order to steer development in a planned PARAMETER ADJUSTMENTS just part of what we do,” he says. way,” Hastings observes. Adding in a scale-up element when transferring a process increases the ACCELERATING PHASE-RELATED CHALLENGES overall risk for project success and COMPLICATIONS The overall challenge in tech transfer comparability. “It is difficult to discern Many new biologic drug candidates is to ensure that the sponsor’s process the differences observed from facility are awarded some form of accelerated will be reproduced in a similar, robust, to facility and any disparities that can approval designation. While acceler- and compliant way. Manufacturing be observed on scale up independently,” ated approval designations may allow a product in the quality and quantity in Schirmer says. “These risks,” she notes, faster path to the clinic or to commer-

48 BioPharm International April 2020 www.biopharminternational.com Outsourcing

cial approval for breakthrough ther- a partner who has extensive experi- what success looks like. Ensuring all apies, the time it takes to develop a ence with tech transfer and scale up members of the team work together bioprocess that will be robust, scalable, into commercial launch, according to to settle on the right balance of yield and reproducibly deliver target product Schirmer. “A typical program with an and CQA reliability will ensure teams quality remains significant, according external partner is designed to have aren’t derailed by conflicting priorities,” to Ritacco. “Fast-tracking the timeline a process-acquisition phase, which observes Hastings. and schedule without compromising includes a paper transfer followed by One problem Hastings has observed, product quality and patient safety is an establishing the process at a small scale. however, is that as teams turn attention additional challenge,” Bulpin says. Then the scale up occurs within the to accelerating development timelines, While some product development facility infrastructure. These scale-up they have a tendency to uninten- steps can be reduced, Bulpin insists activities can, however, be minimized tionally reduce the circle of commu- that risk analysis and decision justifi- by performing the process acquisition nication. “The most successful teams, cations should not be underestimated. at the manufacturing scale to meet however, enlarge their circle to engage “Sufficient understanding of the pro- accelerated timelines,” she says. all functional areas, allowing everyone cess is necessary to ensure control of Fujifilm often observes three partic- to be part of the process of building operating parameters to consistently ular challenges with accelerated pro- the best balance of speed, reliability, deliver safe and efficacious product grams: prioritization, collaboration and and risk,” he asserts. to patients, and achieving this on an communication, and planning. Most Planning for an accelerated desig- accelerated timeline requires a skilled sponsors with accelerated designations nation project, meanwhile, requires a team leveraging well-established pro- greatly reduce timelines, Hastings says, balance of creativity, dedication, and cesses and methods, as well as past by focusing on refining their processes pragmatism, according to Hastings. experience to streamline development to reliably achieve CQAs, often at a “Teams need to be able to challenge and avoid pitfalls,” adds Ritacco. cost to the yield. “The most successful their platform expectations to strike It is also extremely important for projects have a cross-functional team a balance to improve timelines. This sponsor companies to work with that is clear on their priorities and planning cannot be done once, but

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rather needs to evolve as the scientific of the same staff throughout transfers clear responsibilities, and planning. understanding of the process grows to minimize the chances that so-called Dedicating one individual to the man- and teams need to be aware that any tribal knowledge is lost,” he observes. agement of one CMO/CDMO group new data might require an adjustment Transparency between all team helps with this approach, except for to the project plan,” he adds. members, adds Schirmer, can actually quality assurance and regulatory topics, be the catalyst to a successful develop- which Bulpin says should be managed ENGAGING WITH MULTIPLE ment, scale up, and tech transfer of a globally to ensure process compliance. OUTSOURCING PARTNERS drug with an accelerated approval des- The preparation and review of thor- For many projects, it is necessary to ignation. “Whether the process technol- ough process descriptions, facility fit, transfer a bioprocess from one CMO/ ogy transfer occurs between the sponsor and tech transfer documentation, with CDMO to another. Regardless of the company and the external partner, appropriate quality review and oversight, reason, it is essential that everyone or between two external partners, the go a long way toward achieving a suc- involved does not overlook the com- importance of transparency is the same. cessful tech transfer, adds Ritacco. The plexities associated with leveraging pre- Communication is also critical. If all par- experience and expertise of the teams vious data and maintaining technical ties are aligned and understand the path involved is also critical. “A highly skilled continuity, according to Hastings. forward, it is much more likely that the and experienced team will anticipate To proactively address this issue, transfer will be a success,” she comments. potential challenges and leverage their Fujifilm identifies new, unique, or dif- The general constraints are the same deep understanding of bioprocess devel- ficult (NUD) elements, such as pro- for any tech transfer process, including opment, tech transfer, and manufac- cess-specific factors that depend on those between outsourcing providers, turing to achieve the desired process equipment idiosyncrasies that may not although the confidentiality becomes performance and product quality in a be fully evident to a sponsor while the more marked and the training pro- new facility, even when the timeline process is running at a CDMO. “When cess can be slightly different. “The aim may be challenging,” he asserts. a process is moved from one CDMO remains the same,” Bulpin says. “In It is also important, according to to another, the receiving site rarely has addition, any process, analytical, equip- Hastings, for everyone involved in a access to complete equipment-specific ment, raw material, and/or regulatory tech transfer project to recognize details, which can make interpretation gaps should be listed and mitigated to up-front that priorities may change of previously generated data challenging meet specifications and ensure a suc- during the development cycle for bio- and incur risk,” Hastings says. cessful tech transfer.” logics with accelerated approval desig- “At Fujifilm, we work hard to identify nations. Risk-based tools can be used to NUDs as early as possible and then cat- MINIMIZE RISK FOR segment process characterization into egorize them as equipment-specific ver- OPTIMUM SUCCESS two or more phases and to design the sus equipment-agnostic. This approach Technology transfer introduces additional process to prioritize CQAs over yield. allows us to suggest studies that may risk to the development and commercial- “Using this approach, it is possible for improve facility fit,” he adds. ization of biopharmaceuticals, so mini- sponsors to start their process perfor- Differences in equipment throughout mizing risk is fundamental to successful mance qualification (PPQ) in paral- the process, as well as differences in technology transfer of bioprocesses. lel with some process characterization scale, require optimization of multiple A clear project plan with milestones work, thereby shortening the timeline engineering parameters to match pro- that are mutually agreed upon sets the from clinical manufacturing to PPQ,” cess performance in cell-culture, harvest, stage for a successful program, Schirmer Hastings observes. and downstream purification processes observes. “Risks should be identified On the other hand, it can result in between facilities, Ritacco agrees. He at the onset of the project and con- post-approval yield fluctuation, which also points out that analytical methods tinuously re-evaluated to determine makes business-planning difficult. have to be transferred, established, qual- effectiveness of mitigations and any Fujifilm sees this issue as an opportu- ified, and ultimately validated to assure additional risks,” she says. In addition, nity to move through a natural transi- consistency in analytical results between risk assessments should be backed by tion point. “Purposefully pivoting from manufacturers. scientific reasoning and process data. biologic license application-enabling Hastings also notes that some pro- The main strategy, according to activities to business-enabling process cesses include historical elements that Bulpin, is to consider tech trans- improvements at the optimum time will are difficult to translate into and out of fer—with or without scale up—as an allow programs to benefit from both batch records. “In some cases, sponsors entire project with dedicated subject accelerated PPQ and long-term com- deal with this issue by maintaining some matter experts, communication flow, mercial pay-back,” he concludes. ◆

50 BioPharm International April 2020 www.biopharminternational.com Covering the science and business of biopharmaceuticals • Quality/Analytics • Upstream Processing • Downstream Processing • Peer-Reviewed Technical Notes • Product Spotlight • Perspectives on Outsourcing

BP-HouseAd-2019-FP.indd 1 1/28/2019 12:39:28 PM BioBusiness

Lower Taxes, More Flexibility Crucial to Retaining Pharma Employment As politicians focus on drug cost reduction, biopharmaceutical companies in the US are moving to states with lower taxes and relocating some facilities that had been offshore.

AGNES SHANLEY AND LAUREN LAVELLE

ublic pressure to reduce drug costs has led to a Operating costs vary highly among major life-sciences number of proposals to reduce drug prices. Among sites, and labor costs make up roughly 60% of those costs, P the alternatives discussed so far have been de facto says Boyd. In the US, Austin, TX, and Raleigh, NC, are price controls and syncing prices with those in other global currently among the fastest growing metropolitan areas, markets. In December 2019, the United States Department and both are attracting biopharma investment. So far, the of Health and Human Services introduced a Safe Importation Raleigh-Durham area in North Carolina offers the lowest Action Plan outlining two pathways for allowing the safe operating costs of any US location, Boyd says, and boasts reimportation of lower cost drugs from Canada (1). the presence of some leading universities such as Duke, Although these proposals have not yet become law, University of North Carolina, and North Carolina State. biopharmaceutical company executives are reacting to Eli Lilly recently selected Raleigh as the location for a regulatory uncertainty by focusing more intensely on reducing new $474-million, 462-employee facility to manufacture operating costs, according to John Boyd, CEO of the Boyd injectable and other diabetes therapies (2). The Austin area, Company, a site selection advisory company. “Operating costs meanwhile, is seeing increased investment in biopharma, due

have always been important for life-sciences site selection, to life-sciences developments such as the University of Texas’ /Stock.Adobe.com but they’ve never been as important as they are now, as the Dell Medical Campus and facilities affiliated with nearby industry focuses on price reduction. Many of our pharma Texas A&M. clients see site selection as a preferred market-based way to Bill Bullock, the senior vice president for economic reduce operating costs,” he told BioPharm International. development and statewide operations at the North Carolina

52 BioPharm International April 2020 www.biopharminternational.com BioBusiness

Biotechnology Center in Durham, NC, “In the US, there has already been personal income moving to lower cost, referred to the life-sciences hub as a a mass exodus of human capital to more corporate friendly locations. New “good investment” for the state. states that have right-to-work laws,” Jersey officials have also proposed a “Agriculture was, and remains, the says Boyd. These laws establish “at will” millionaire’s tax that would impose state’s largest revenue producer. So that employment and make membership 10.75% in income tax on individuals became a natural sector to absorb gene- in labor unions voluntary, reducing earning $1 million per year or more. based and other new technologies,” he union power as well as labor costs The proposed regulations could affect says. “Concurrently, the state tweaked for employers (4). There has also 20,000 state residents, many of them its educational infrastructure to prepare been a trend to “reshore” some business owners, and could decrease a workforce to handle tableting and operations and bring them back to investment in the state. New York, fill-finish where textiles and furniture the US in lower-cost labor states, he California, and Massachusetts already once reigned. Thus, the foundation for says. “For areas such as Bangalore have similar laws in place. a biomanufacturing bonanza that has in India, the initial numbers may As for North Carolina, the state’s even evolved into global leadership in be compelling, but investors have 2.5% corporate income tax is the lowest gene and cell therapy manufacturing.” found additional hidden costs,” he rate of states that levy this tax, according North Carolina also offers says, including training, and, in the to Bullock. It also boasted the seventh incentives for companies looking to US, boosting corporate participation lowest commercial and ninth lowest house their sites in the life-sciences in federal procurement programs has industrial effective property tax rates in hub, according to Bullock. They become a political issue that has both the country in 2017. include a job development investment Republican and Democratic party “The state offers a number of sales grant, the One North Carolina Fund, support, he says. Boyd notes that new and use tax exemptions,” Bullock both discretionary performance-based life-science regional hubs may be on says. “For example, in 2018 North programs to respond to job creation the horizon, depending on how new Carolina significantly increased long- projects, and public infrastructure and regulations take shape in the US. term business cost savings through transportation programs. Amgen, for example, is building a new single sales factor apportionment for “Incentives provided by local units of 1600-employee facility in Greenwich, multistate corporations. There are government are key components of a RI. Other potential areas for future also exemptions for manufacturing broad incentives package that can help development could include Southern machinery and related equipment, companies expand or relocate. Most Florida, Phoenix, AZ, Las Vegas, NV, as well as raw materials, fuel, piped are based on investment, anticipated and the Winston-Salem area of North natural gas, and electricity used for taxes, and/or the number of jobs to be Carolina near Wake Forest University. manufacturing. Other exemptions created,” Bullock says. “North Carolina and credits are available for R&D offers life-science companies an HOLDING THE LINE ON and software publishing, pollution educated workforce, access to hundreds MORE STATE TAXES abatement equipment, recycling, and of life-science companies and service In the meantime, many municipalities historic preservation.” providers, a well-established supply are getting the message loud and clear, chain, and a creative and competitive to hold the line on new corporate REFERENCES 1. HHS, “HHS Announces New Action landscape to support location costs and taxes, says Boyd. New Jersey, which is Plan to Lay Foundation for Safe facility expansion. It’s the best value in the nation’s largest biopharmaceutical Importation of Certain Prescription biomanufacturing.” and pharmaceutical development and Drugs,” Press Release, July 31, 2019. 2. North Carolina Biotechnology Boyd’s latest analysis compared manufacturing center, may offer a Center, “Lilly Building $474M Pharma major operating costs in 2019 cautionary tale. Factory in RTP, Hiring 462 Workers,” for a representative 300,000-ft2 The state recently increased Press Release, Feb. 11, 2020. 3. J. Boyd, “Results of 2020 biomanufacturing facility employing corporate and personal income taxes, Biomanufacturing Cost Study,” 300 hourly staffers (3). Examining on top of high property taxes, making presented at a Boyd Co, Inc. costs for 25 US, European, and it more difficult for companies located meeting, Delta Hotel, Woodbridge, NJ, January 14 and 15, 2020. Asian locations, research found that in the state to remain competitive 4. Vittana, “20 Pros and Cons of Right they ranged from $58.7 million in and reducing disposable income for to Work,” vitanna.org, Feb. 11, 2020. Copenhagen to $13.7 million in working professionals, says Boyd. Over 5. New Jersey News Network, “Murphy Renews Hope For Millionaires Bangalore. In the US, costs ranged the past 15 years, he noted in a December Tax,” newjerseynewsnetwork. from $55.4 million in New York to 2019 interview (5), higher taxes in the com, Feb. 11, 2020. ◆ $37.2 million in Raleigh/Durham, NC. state have resulted in $30 billion in

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54 BioPharm International April 2020 www.biopharminternational.com BIO/PHARMA INDUSTRY EVENT UPDATES

The global coronavirus pandemic has forced CPhI Southeast Asia you can “Experience Science through the postponement of many industry events. July 1–3, 2020, Bangkok, Thailand Commercialization.” The dates listed below reflect the scheduled www.cphi.com/sea/en/home.html and rescheduled dates for major bio/pharma 69th PDA Annual Meeting industry events as of March 25, 2020. For the CPhI North America July 20–22, 2020, Raleigh, NC latest information, contact the event orga- Sept. 9–11, 2020, Philadelphia, PA www.pda.org/conference/2020-pda-annual- nizer, or visit www.BioPharmInternational. www.cphi.com/northamerica/en/home. meeting/home com/events. html This year’s event theme will be “Enhancing the Future with Innovative Medicines and BIO International Convention CPhI Japan Manufacturing” and the meeting will feature June 8–11, 2020, San Diego, CA Sept. 30–Oct. 2, 2020, Osaka, Japan plenary and group sessions focused on devel- www.bio.org/events/bio-international-con- www.cphi.com/japan/en/attend/register- oping new modalities, targeting real-time and vention to-attend.html parametric release, engineering data solutions, Hosted by the Biotechnology Innovation and modernizing products and manufacturing. Organization, the event features more than CPhI Worldwide 1100 biotechnology companies, academic Oct. 13–15, Milan, Italy AAPS 2020 PHARMSCI 360 institutions, state biotechnology centers, and www.cphi.com/europe/en/home.html October 25–28, 2020, New Orleans, LA related organizations across the US and in www.aaps.org/pharmsci/annual-meeting more than 30 other nations. INTERPHEX 2020 This four-day conference will cover chemical July 15–17, 2020, New York and biomolecule areas, as well as the research CPhI China www.interphex.com/Register/ and recent challenges in pharmaceutical sci- June 22–24, 2020, Shanghai, China INTERPHEX is the premier pharma- ences today. www.cphi.com/china/en/home.html ceutical, biotechnology, and device development and manufacturing event where

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Operations— Contin. from page 37 pliers have greater risk than others, either ‘communication schedule’ of the quality based on the product type, location, etc. agreement to avoid unnecessary supply- Both sponsors and CMOs/CDMOs These suppliers should receive more scru- chain interruptions.” must have an active role, accord- tiny,” she says. Sponsors also must not ing to Schniepp. “The specific level cut corners or do what is convenient, says REFERENCES 1. FDA, “FDA Statement on the FDA’s of involvement of the sponsor may O’Connor. For example, she notes, it is Ongoing Investigation into Valsartan depend on the confidence they have in inconvenient, but necessary to audit sup- and ARB Class Impurities and the the CMO/CDMO organization. The pliers in China and India. In addition, Agency’s Steps to Address the CMO/CDMO should make sure they sponsors should also not make supplier Root Causes of the Safety Issues,” Press Release, Jan. 25, 2019. involve the sponsor in decisions involv- decisions based on price or availability 2. FDA, Warning Letter to Henan Kangdi ing material quality so the sponsor is instead of quality and safety, says IPEC- Medical Devices Co. Ltd, MARCS-CMS aware of the impact on their product,” Americas. 587699, Dec. 3, 2019, www.fda.gov/ inspections-compliance-enforcement- says Schniepp. Communication is key to supplier and-criminal-investigations/warning- oversight, says Schniepp. “Both parties letters/henan-kangdi-medical- need to be willing to talk as frequently devices-co-ltd-587699-12032019 ENSURING QUALITY as needed to address issues before they 3. A. Shanley, Pharmaceutical Technology IS ABOUT VIGILANCE 42 (4) 60-69 (April 2018). manifest into a disruption in the supply 4. FDA, Warning Letter to Spectrum Maintaining a safe supply chain is cru- chain. The frequency of these conver- Laboratory Products, Inc., MARCS- cial in the bio/pharmaceutical industry. sations are not necessarily defined in a CMS 579958, July 31, 2019, https:// www.fda.gov/inspections- The efficacy and safety of the materials quality agreement. They are important in compliance-enforcement-and- used in drug products is of utmost impor- establishing an open relationship between criminal-investigations/warning- tance. And it is the sponsor’s responsibil- the supplier and the purchaser so issues letters/spectrum-laboratory- ity to ensure the quality of all materials can be solved before supply chain dis- products-inc-579958-07312019 5. FDA, 21 CFR 211.84(d), Title 21–Food used in their products. Sponsors must ruption occurs. Not all problems can be And Drugs, Chapter I–Food And Drug not rely on others to ensure quality, says solved through the terms included in the Administration, Department Of Health O’Connor. Also, not all suppliers should quality agreement and both parties must And Human Services, Subchapter be treated the same. “Clearly, some sup- be willing to work outside the defined C–Drugs: General, April 1, 2019. ◆

56 BioPharm International April 2020 www.biopharminternational.com Ask the Expert

Ask the Expert — Contin. from page 58 a knowledge of the plan, how it is incorporated into the culture, and making sure it is revised as needed to and identifies gaps so the company can implement reflect current practices is critical to having a success- changes to ensure continuous improvement. ful outcome should you be audited on this topic. The bottom line is that the regulatory landscape is AGING FACILITIES changing, and it is conceivable that companies will Aging facilities are of concern because they can lead begin to be audited on programs and process that are to drug shortages. It is hard to achieve compliance to more subjective than tangible. To be prepared for an current regulatory expectation when manufacturing audit that touches on the intangibles of a functioning new and novel products on manufacturing lines that quality management system, companies should being are more than 30 years old and the analytical results to formulate programs and systems that address the rely on outdated methodology (5). The age of the line aforementioned topics. usually indicates that the processes being run on those lines are non-automated and require human driven REFERENCES steps. In these situations, it is critical a company 1. Office of Pharmaceutical Quality, FDA Pharmaceutical Quality Over- sight, One Quality Voice, FDA whitepaper. demonstrates it has a quality mindset because of the 2. S. Schniepp, Pharmaceutical Technology 43 (10) 2019. human/product interface. The best way to address this 3. World Health Organization, Annex 5, Guidance on Good Data and issue in an inspection is to demonstrate that the com- Record Management Practices (WHO, June 2016). 4. S. Schniepp, Pharmaceutical Technology 42 (10) 2018. pany has a plan to update its facility over time. The 5. S. Schniepp, Pharmaceutical Technology 40 (8) 2016. plan should indicate what needs to be updated and a 6. S. J. Schniepp, Pharmaceutical Technology 43 (12) 2019. timeline for implementation. 7. S. Schniepp and A. Harrison, Pharmaceutical Technology 40 (2) 2016. 8. S. Schniepp and A. Harrison, Pharmaceutical Technology 39 (10) INVESTIGATIONS/CAPA 2015. 9. S. Schniepp and A. Harrison, Pharmaceutical Technology 39 (8) The need for a robust investigation/CAPA process is 2015. clearly defined in global regulations, but it seems the 10. S. Schniepp, Pharmaceutical Technology 44 (2) 2020. industry still struggles with conducting and docu- 11. S. Schniepp, Pharmaceutical Technology 43 (8) 2019. ◆ menting root cause when it comes to investigations based on FDA 483 observations (6). The purpose of an investigation is to identify the root cause of a devia- tion and take appropriate action to correct the issue Ad Index across the manufacturing/product line. The best way Company Page to demonstrate proper control of this process during an investigation is to ensure you have a robust inves- AJI BIO PHARMA 19 tigation process, which routinely identifies root cause AGILENT TECHNOLOGIES 29 and that once the correction is made, it does not recur ADVANTAPURE 43 (7). The ability to demonstrate this depends on the BAXTER HEALTHCARE 33 understanding and training of the people involved CATALENT 60 in the investigation process and data that shows the problem was addressed and solved (8, 9). CYGNUS TECHNOLOGIES LLC 11 FG CLEAN WIPES 45 RISK MANAGEMENT NOVASEP PROCESS SAS 37 Every company should have a quality risk manage- PDA 2 ment plan (10). A well-written and well-implemented PENDOTECH 55 quality risk management plan is an integral and valuable element of an effective quality system. Quality PHARMAFLUIDICS 49 risk management plans are important because they PUROLITE CORPORATION 59 help improve a company’s ability to provide quality SARTORIUS STEDIM BIOTECH 21 product to patients. They are contingency plans with SCIEX 39 identified actions that help to ensure a continuous STERIS 55 supply of product to the market that meets the expectations of being safe, effective, and available. They THERMO FISHER ADVANCED BIOPROCESSING 15 are dynamic documents that require integration into TOSOH BIOSCIENCE 25,41 and data inputs from all departments in order to be USP 7 successfully implemented at a company (11). Having WACKER CHEMIE AG 23 the plan available for discussion and demonstrating WUXI BIOLOGICS 5

www.biopharminternational.com April 2020 BioPharm International 57 Ask the Expert

Susan J. Schniepp is executive vice-president Critical Knowledge for Preparing Audits of post-approval pharma and distinguished Data integrity, quality culture, aging facilities, CAPA, fellow, Regulatory and risk management are key when conducting audits. Compliance Associates.

I am preparing my site for an audit and manufacturers and products and enhance the Q: have prepared and trained our employ- production, utility, and consistency of the ees on the usual topics (training program, establishment inspection reports standard operating procedures [SOPs], change control, etc.). I am concerned that this tradi- DATA INTEGRITY tional approach may not be enough in the cur- Every company should have a program to rent regulatory environment. Can you offer address data integrity issues that include guid- some guidance into other issues I should focus ance on what data integrity is, how to recognize on in preparing for the audit? it, how to prevent violations, consequences for This is a great question and shows an violating the company’s data integrity policy, A: insight into the changing regulatory etc. The program should also address the fre- landscape. I think it will be critical in the com- quency and effectiveness of employee training ing years to focus on addressing certain intan- on this topic. The program should demonstrate gible topics during routing regulatory audits. an understanding of regulatory expectations as These topics should be addressed as part of your well as an explanation of how those expecta- company’s overall improvement plans and pro- tions are incorporated into the data integrity grams. program. The program needs to go beyond the I would focus on the following topics as a concepts of ALCOA (attributable, legible, con- part of preparing for any routine audit: data temporaneous, original, accurate) and include integrity, quality culture, aging facilities, inves- the four new attributes in ALCOA+ (complete, tigations/corrective actions and preventive consistent, enduring, available) (2, 3). actions (CAPA), and risk management. I am of the opinion that these topics will become rou- QUALITY CULTURE tine areas of focus for regulatory inspections The concept of quality culture came about with regardless of the affiliation of the regulatory the introduction of quality metrics. FDA intro- authority performing the audit. These topics are duced the concept of collecting quality metrics not new to the industry. There has been much in 2013 (4). Since that time, the industry and discussion on their impact on drug shortages. It regulatory authorities worldwide have embraced is my opinion that developing robust programs the idea that in order to rely on the metrics col- addressing these issues and incorporating them lected, the company needs to have a culture into everyday routine operations will improve that supports an open, transparent reporting the drug shortage situation, improve a com- of “deviations, errors, omissions and aberrant pany’s operating performance, and improve results at all levels of the organization, irre- the outcome of regulatory inspections for the spective of hierarchy” (3). There has been work company. done by the Parenteral Drug Association and FDA has been publishing guidance on these University of St. Gallen suggesting the there issues over the years, and now as the agency is a correlation between mature quality attri- gets ready to finalize the New Inspection butes and quality culture behaviors. To address Protocols Project (NIPP), it is time to revisit the issue of a quality culture during a regula- some of these recommendations and imple- tory inspection, the company should be able to ment some of the advice offered. The intent of demonstrate their quality system is functional the NIPP program (1) is to provide inspectional assessments to support tracking and improve- Contin. on page 57 ment of performance across pharmaceutical freshidea - Stock.adobe.com - freshidea

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