Shoring up Drug Delivery for Pandemic Response

Volume 33 Number 7

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BioJuly 2020 PharmThe Science & Business of Biopharmaceuticals JULY 2020 www.biopharminternational.com

SHORING UP DRUG DELIVERY FOR

Remote Audits I Onshoring Drug Manufacturing I Drug Delivery I Drug Manufacturing Drug I Onshoring Audits Remote PANDEMIC RESPONSE

DEVELOPMENT RNA FOR GENE THERAPIES

UPSTREAM PROCESSING BUFFER AND MEDIA PREP

DOWNSTREAM PROCESSING RESIDUAL IMPURITY TESTING

MANUFACTURING

SCALE-OUT FOR CELL THERAPIES

ANALYTICS BIOSIMILAR PRODUCT QUALITY MICROBIAL CONTAMINATION

QUALITY/REGULATIONS INVESTIGATING ROOT CAUSES

OPERATIONS BIOLOGICAL SAFETY CABINETS Volume 33 Number 7 33 Number Volume

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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 8 COVID-19: Shoring Up the Drug Delivery Infrastructure Manufacturers and the US government are investing heavily in traditional and non-traditional forms and materials to ensure supplies of containers and delivery devices for COVID-19 treatments and vaccines. Cover Design by Maria Reyes Images: Mr.Ilkin - Stock.adobe.com

FEATURES

DEVELOPMENT ANALYTICS OUTSOURCING Can Using RNA Simplify Analytical Assays Determine Contractors Balance Increased Gene Therapy Development? Biosimilar Product Quality Demand During COVID-19 Cynthia A. Challener Feliza Mirasol Susan Haigney RNA is easier to manipulate than DNA but Appropriate analytical assays are needed The COVID-19 pandemic has created challenging to deliver to the right cells. � 13 to determine and ensure that biosimilar a rise in demand for R&D and a shift in critical quality parameters are on track. �32 focus for some contract organizations. �43 UPSTREAM PROCESSING Improving mAb Manufacturing Detecting Microbial COLUMNS AND DEPARTMENTS Productivity by Optimizing Buffer Contamination in Bioprocessing and Media Prep Process Flow Feliza Mirasol FROM THE EDITOR Nandu Deorkar and Pranav Vengsarkar Safeguarding against microbial Data and science must guide FDA Innovative approaches, including ready- contamination requires rapid detection in making pressure-filled COVID-19 to-use materials and in-line dilution, and innovative technology. ��34 vaccine and therapy approval decisions. can significantly streamline overall Rita Peters ��5 bioprocessing operations. �� 17 QUALITY/REGULATIONS Succeeding With OOS and REGULATORY BEAT DOWNSTREAM PROCESSING Root-Cause Investigations FDA can better monitor quality production Eliminating Residual Impurities James P. Stumpff of domestic versus foreign firms. Starts with a Strategic Plan Investigating the root causes of OOS Jill Wechsler ��6 Cynthia A. Challener conditions, product defects, Identifying the source, assessing the risk, and batch failures requires a systematic, PRODUCT SPOTLIGHT ��48 and removing residual impurities requires thorough approach. ��36 a strategic approach. ��22 AD INDEX ��48 OPERATIONS MANUFACTURING Minimizing Contamination ASK THE EXPERT Overcoming Operational and During Biopharma R&D It is important to consider the Regulatory Challenges in David Phillips feasibility, benefits, and limitations Autologous Cell-Therapy Facilities The right approach to biological safety of each type of audit in advance. Francesca McBride cabinets, and collaboration between Siegfried Schmitt ��50 Manufacturers must address engineers and those who will operate the scale-out challenges for equipment, is crucial to preventing cell- commercial manufacturing. ��28 culture contamination. ��40

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4 BioPharm International July 2020 www.biopharminternational.com From the Editor

Navigating Uncharted Waters

or researchers involved in the development of new treatments and vaccines to combat COVID-19, the past five months have been a scramble to research potential F therapies, collect and analyze data, accelerate clinical trials, and plan manufacturing processes. While the biopharma industry knows these development efforts are moving at record pace, for some patient groups, policymakers, and the public, the efforts are not moving fast enough. When someone is seriously ill, family members and healthcare providers are desperate for an effective treatment. History has shown that many “promising” therapies initially raised the hopes of patients, only to disappoint when the therapy did not work as pre- dicted. During this global pandemic, public and policymaker pressure can make the R&D Rita Peters is the task more difficult. editorial director of For example, earlier this year, hydroxychloroquine was touted as a possible treat- BioPharm International. ment for COVID-19; FDA faced criticism when it issued emergency use authorization (EUA)—based on limited data—on March 28, 2020. When subsequent clinical trials showed the drug was unlikely to be effective as a treatment for COVID-19, and the car- diac side effects outweighed the benefits, FDA withdrew the EUA on June 14, 2020. Data and science Keeping pace with the rapidly emerging research about the SARS-CoV2 virus, its medical impact on humans, and the successes and failures of therapies and vaccines to combat must guide FDA COVID-19 is a monumental task. Thousands of scientific papers have been released, and drug companies and research organizations have been collaborating and sharing informa- in making tion on levels often described as unprecedented. These findings need to be assessed and verified to ensure decisions about therapies are based on solid data rather than political pressure-filled motives, or undue influence. Missteps and misinformation related to diagnostic testing, distribution of personal COVID-19 vaccine protective equipment from the strategic national stockpile, and the wearing of face masks have eroded public trust in the abilities of FDA and other government authorities to and therapy manage this pandemic. While anecdotal evidence points to the potential availability of a vaccine before the end of 2020, public confidence in FDA, the government, and drug approval decisions. companies needs to be established. FOLLOWING THE “NORTH STAR” During the BIO 2020 digital event on June 10, 2020 (1), FDA Commissioner Stephen M. Hahn emphasized the importance of science-based decision making, as well as regulatory authority independence to make approval decisions, key factors to assuring the public that the vaccines and therapies are approved with public safety and health at the forefront. As applications for emergency use and investigational new drug applications poured into FDA in the initial days of the pandemic, Hahn says the agency reviewed all applications, and prioritized those with the highest level of science behind them and the greatest chance of making it to clinical trials. Some bio/pharma companies are participating in and receiving funding from the federal government’s Operation Warp Speed and Accelerating COVID-19 Therapeutic Interventions and Vaccines programs. Hahn noted, however, that FDA has established a “barrier” between itself and these public-private partnerships to reinforce the agency’s regulatory independence. “We will prioritize based on science, we will not prioritize based on who comes through the door,” he said. “We are agnostic with respect to the sponsor, but we are very much aligned with where the science appears to us to be the highest level.” Hahn said he understands the “enormous amount of pressure” related to the pandemic; however, the Agency’s “North Star” will be data and science. The agency may have to update decisions as new data are available, he noted, but will continue to make decisions based on science. REFERENCE 1. BIO, Fireside Chat with FDA Commissioner Dr. Stephen M. Hahn, BIO 2020 Digital Event, June 10, 2020. ◆

www.biopharminternational.com July 2020 BioPharm International 5 Regulatory Beat

Pandemic Spurs Efforts to Boost Pharma Manufacturing in US FDA can better monitor quality production of domestic versus foreign firms.

ngoing shortages of critical medicines, mented how production of APIs and generic many linked to supply chain disrup- drugs moved to India and China and other O tions due to the COVID-19 pandemic, regions in the 1980s to reduce costs. One result continue to generate calls to shift production of has been ongoing product shortages, many drugs and pharmaceutical ingredients from for- related to quality manufacturing issues, as firms eign nations to the United States. The globaliza- at home and abroad delayed improvements and tion of the biopharmaceutical industry during modernization of facilities and accepted ingre- the past 30 years has encouraged production dients with limited quality assurance. of drugs, particularly generic medicines and Members of Congress have proposed multi- APIs, in regions offering cheap labor and less ple measures to address US reliance on foreign restrictive environmental and other regulations. drug production, some specifically targeting Now the White House and some members of products made in China to protect access to Congress look to “on shore” drug production to vital medicines in case of a trade war. Other better ensure reliable access to vital medicines bills seek to encourage more US manufacturing now produced overseas. through tax credits and other economic incen- An example of how the Trump Administration’s tives, and to require firms producing finished “Buy American” campaign could apply to pharma- drugs to disclose more information to FDA on ceuticals is the announcement on May 19, 2020 of sources for APIs and starting materials. There an initial $354 million, four-year award to Phlow is little talk, though, about accepting higher Corp. by the Biomedical Advanced Research and prices for generic sterile injectables to ensure Development Authority (BARDA) to boost US pro- product quality. duction for both the ingredients and finished dosage forms of certain drugs experiencing supply INSPECTING QUALITY shortages (1). Peter Navarro, director of the White One rationale for boosting pharma production House Office of Trade and Manufacturing Policy, in the US is to facilitate FDA oversight of prod- made clear that a prime objective is to uct quality and compliance with good manu- reduce US reliance on foreign manufacturing practices (GMPs). The rise in foreign facturing and supply chains for “our drug production has strained FDA efforts to most important medicines and active monitor and inspect manufacturers that export pharmaceutical ingredients,” to avoid to the US, a situation aggravated by the halt to placing “Americans’ health, safety, and all drug facility inspections since March 2020 national security at grave risk” (2). due to the pandemic (3). A main question about the BARDA FDA oversight of foreign drug manufactur- award, which can rise to $801 mil- ing was revisited at a hearing before the Senate lion over 10 years, is whether the Finance Committee in early June, following up Jill Wechsler is investment can ensure access to on earlier Congressional reviews of the need BioPharm International’s high-quality, made-in-the-USA drugs for FDA to increase its oversight of overseas Washington editor, at affordable prices without the large firms, particularly those in China and India

[email protected]. government subsidy. It’s well docu- (3). FDA reported to the Senate panel that it W.Scott McGill - Stock.adobe.com

6 BioPharm International July 2020 www.biopharminternational.com Regulatory Beat

was conducting more inspections produce needed drugs in short sup- approaches to better handle future of foreign plants in recent years, ply. Additional tax incentives would emergencies, which may include a development supported by the encourage relocation of foreign oper- strategies to support more drug Government Accountability Office ations to the US, and FDA would manufacturing in the US. (GAO), which has conducted reg- streamline regulatory processes to ular assessments of FDA’s foreign expeditiously approve new facilities REFERENCES pharmaceutical inspection pro- and tech transfer processes (6). 1. HHS, “HHS, Industry Partners Expand U.S.-Based Pharmaceutical gram since 2008 due to concerns Advocates for boosting phar- Manufacturing for COVID-19 about inadequate oversight of for- maceutical production in the US Response,” Press Release, May 19, eign producers (4). Yet, GAO con- emphasize that FDA can better 2020, tinues to criticize FDA for routinely ensure the quality of these prod- 2. Phlow Corporation, “Phlow Corporation Awarded $354 Million HHS/ASPR/ providing advance notice to for- ucts through more regular and BARDA Contract to Manufacture eign manufacturers of planned site comprehensive inspections and Essential Medicines in Shortage,” visits, as opposed to unannounced oversight, while also address- prnewswire.com, Press Release, May 19, 2020. inspections in the US. FDA for- ing concerns about security and 3. US Senate Committee on Finance, eign inspectors also have to rely product availability. At the same COVID-19 and Beyond: Oversight of on local company translators and time, FDA officials would like to the FDA’s Foreign Drug Manufacturing limited time frames for examining see manufacturers, particularly Inspection Process, June 2, 2020, 4. M. Denigan-Macauley, “Drug Safety, extensive foreign facilities. those gaining public support for COVID-19 Complicates Already Pharma companies, not sur- constructing new facilities, adopt Challenged FDA Foreign Inspection prisingly, oppose requirements advanced manufacturing sys- Program,” GAO Testimony Before the Committee on Finance, US Congress, to shift manufacturing to the US tems better able to ensure more June 2, 2020. or to disclose proprietary infor- efficient and reliable production 5. N. Longo, “America’s Global mation on ingredient sources. of quality medicines, and to bol- Leadership in Biopharmaceutical The Pharmaceutical Research ster supply chain redundancy and Manufacturing,” The Catalyst, PhRMA, June 4, 2020, and Manufacturers of America reliance. One hope is that policy 6. AAM, “A Blueprint for Enhancing the (PhRMA) emphasizes that US makers assess issues raised by the Security of the U.S. Pharmaceutical firms support more than four current pandemic in considering Supply Chain,” accessiblemeds.org. ◆ million jobs in the US, including 120,000 high-wage manufactur- FDA Publishes Guidance on CGMPs During COVID-19 ing positions at more than 1300 facilities. PhRMA maintains that FDA published guidance on June frequently; updating cleaning and “geographic diversity” in drug pro- 19, 2020 detailing the agency’s rec- sanitizing procedures for production duction can best ensure supply ommendations for current good areas; expanding existing manufacturing practices (CGMPs) stability and warns that efforts to procedures to include gloves, face requirements for addressing COVID- masks, and/or gowning if not already shift all global manufacturing to 19 infection in employees engaging in place; and restricting employee the US would upset the entire sup- in drug manufacturing (1). access to manufacturing areas. ply chain (5). “As with any potential new risk, According to the guidance Generic-drug makers also are not FDA expects pharmaceutical document, manufacturers should enthusiastic about made-in-America manufacturers to evaluate whether follow Centers for Disease Control requirements, but are more receptive SARS-CoV-2 poses contamination guidance regarding when COVID- to economic incentives for boosting risks under existing manufacturing 19 exposed, or potentially exposed, US operations. The Association of controls that prevent drug workers can return to work. Affordable Medicines (AAM) issued contamination and whether the virus a supply chain security “blueprint” adversely impacts drug safety or Reference in April that calls for the federal gov- 1. FDA, Good Manufacturing Practice quality should contamination occur,” Considerations for Responding to COVID- ernment to identify certain “prior- FDA stated in a press release. 19 Infection in Employees in Drug and ity medicines” to set the stage for Some of the recommendations Biological Products Manufacturing (FDA, negotiating long-term price and include cleaning and sanitizing June 2020). —The editors of volume guaranteed contracts with nonproduction areas more manufacturers and for funding con- BioPharm International struction of US-based facilities to

www.biopharminternational.com July 2020 BioPharm International 7 Cover Story: Drug Delivery

COVID-19: Shoring Up the Drug Delivery Infrastructure Manufacturers and the US government are investing heavily in traditional and non-traditional forms and materials to ensure supplies of containers and delivery devices for COVID-19 treatments and vaccines.

AGNES SHANLEY he COVID-19 pandemic brought uncertainty into meet both existing market and pandemic requirements. On almost every aspect of life in 2020. As the pipeline of June 16, 2020, CEOs from three of the leading glass manu- T potential vaccines and treatments for COVID-19 grows, facturers and suppliers, SCHOTT Pharmaceutical Systems, questions linger about which ones will succeed, how soon they Gerresheimer AG, and Stevanato Group, pledged to ensure can be brought to market, and whether the existing bio/pharma- sufficient supply of type-1 borosilicate glass vials and other con- ceutical supply chain will be robust enough to support them. tainers for any COVID-19 vaccine and treatment, in any part Since May 2020, experts have raised concerns about the of the world (5). availability of primary parenteral packaging, particularly the vials, stoppers, and syringes that would be required to fill and MATERIAL CHALLENGES package new prophylactics and therapies (1,2). Borosilicate Despite the economic benefits of type-1 borosilicate glass, the glass, the workhorse container material, is generally consid- material can present problems including breakage, lamination, ered the easiest and least expensive choice, but fundamental and particulate formation, an issue that has led to expensive drug supply problems, including shortages of the types of sand recalls in the past. With some drugs, the glass can interact with required for medical-grade glass production, have raised the formulation within the vial, triggering the need to refor- concerns about future supply. Since 2015, industrial sand mulate, a process that can be extremely expensive, especially for supplies have been dwindling, while illegal sand mining has oncology drugs and immunotherapies. led to an increase in crime in some nations (3,4). The past decade has brought improvements in glass mak- Borosilicate glass vial manufacturers began to increase capac- ing and vial design to address these issues. SCHOTT, for ity in 2019 and are confident that supplies will be adequate to instance, offers hotforming technology designed to prevent Mr.Ilkin/Stock.Adobe.com

8 BioPharm International July 2020 www.biopharminternational.com Cover Story: Drug Delivery

vial delamination; coatings to improve during a pandemic, the device could per- Even before the COVID-19 pan- processing and prevent glass and mit 330 million vaccine doses to be man- demic, borosilicate glass vial manufactur- drug interaction; and an alternative ufactured each week (6). ers had made substantive investments in vial geometry to minimize breakage, The US government and Big Pharma new supply and operational excellence according to spokesman Björn Weller. have been investing heavily in all these programs to keep pace with a healthy On the services side, Stevanato Group alternatives for fast-track COVID vac- biopharmaceutical market and ongoing and SCHOTT offer the option of cine and therapeutic development and 3-5% annual growth in demand. In 2019, shipping pre-sterilized vials to pharma commercialization. In June 2020, the demand stood at roughly 50 billion con- customers, saving them the expense of US Department of Defense’s (DoD’s) tainers worldwide, according to Stefan sterilizing vials onsite. Biomedical Advanced Research and Schmid, vice-president of global sales and Development Agency (BARDA) marketing at SCHOTT, which has its PLASTIC CONTAINERS awarded Corning a $204-million con- own captive supply of raw material glass However, new container forms and tract to supply Valor for COVID-19 tubing. The company has poured approx- materials other than glass are also being therapies and vaccines and signed a imately $1 billion into new glass tubing developed to improve processing and $143–million supply deal with SiO2 and conversion capacity at its facilities. transportation, and prevent potential Materials Science; the previous month, By the end of 2021, SCHOTT expects immunogenic responses in patients. Valor, Pfizer entered into long-term Valor to have brought on 40,000 tons of new an aluminosilicate glass developed by purchase and supply agreements with glass tubing capacity, enough for 7 billion Corning in partnership with Pfizer and Corning, while the DoD and US vials, says Fabian Stöcker, SCHOTT’s Merck, is one such alternative. Its for- Department of Health and Human vice-president of strategy and innovation. mula eliminates boron, which becomes Services signed a $138–million contract During the pandemic, SCHOTT has unstable at the temperatures used to form with ApiJect (7–10). optimized shifts and staffing to minimize glass. In traditional processing, boron The choice of which container com- impact on operations, working closely can vaporize and be redeposited on glass ponents and materials to use on inject- with customers and local authorities to surfaces, leading to variability in the able medicines, including vaccines, is prevent problems with plant access and chemical composition of the container. anything but trivial, says Cindy Reiss- other issues when border closings and According to Corning, Valor reduces par- Clark, senior vice-president of commer- travel restrictions were in force, he says . ticulate contamination, improves durabil- cial markets and commercial solutions Andrea Zambon, marketing and prod- ity, and can enable 50% improvements in at West Pharmaceutical Services, which uct management director for Stevanato filling and capping speed, compared with specializes in elastomeric closures as Group, expects to see global glass pri- traditional borosilicate materials. well as seals, syringes and injection mary packaging market consumption of Glass-coated plastic vials are devices, and contract manufacturing between 45 and 50 billion units in 2020, another alternative, and clinical tri- services. The selection process requires reflecting approximately 5% injectables als are now underway for COVID- meticulous testing and verification of growth, with different levels of demand 19 treatments using SiO2 Materials compatibility, followed by formal sta- for vials, cartridges, and syringes. Peak Science’s vials, which are made of bility testing and scenario planning for demand for glass primary packaging cyclic olefin polymer with an ultrathin potential scale-up, should a therapeutic linked to COVID-19 is likely to reach inner coating of silicon dioxide. make it past clinical trials, she notes. 1–2 billion, he says, but can only be con- Another non-glass device has been “Failure to choose compatible contain- firmed once vaccines, treatments, and developed by ApiJect Systems America, ment and delivery components can dosages are defined. “Another variable whose founder and CEO pioneered result in impurities and/or reduced effi- is the fact that some drug development single-dose autodisposable injectors cacy, with potentially devastating health projects will likely experience delays, due in the 1980s. ApiJect is collaborat- impacts on patients,” Reiss-Clark says. to the need to prioritize development of ing with the RAPID (short for Rapid The time pressures posed by the COVID-19 drugs,” he says. Aseptic Packaging of Injectable Drugs) COVID-19 pandemic have made the Like other glass manufactur- Consortium, as part of its Jump Start selection process even more challenging, ers, Stevanato Group, which also has program on the blow-fill-seal (BFS) but Big Pharma and small innovators an agreement to offer Corning’s Valor formed, prefilled syringes. Composed are working with both traditional and glass, has increased supply. “Since the of a container and a separate needle alternative materials and exploring ways outbreak of COVID-19, we’ve been hub, the device’s parts would be shipped to improve the fill/finish process. Many securing supplies. We’ve hired more together and activated when combined are also considering new alternatives to at the treatment site. RAPID claims that, parenteral delivery forms for the future. Contin. on page 12

www.biopharminternational.com July 2020 BioPharm International 9 Keep Pace with the Latest Industry Trends with PDA The Parenteral Drug Association (PDA) is the leading global provider of science, technology, regulatory information, and education for the bio/pharmaceutical community. For nearly 75 years, since its founding as a non-proﬁ t in 1946, PDA has been committed to developing scientiﬁ cally sound, practical technical information and resources to advance science and regulation through the expertise of our more than 10,500 members worldwide.

PDA is a truly global organization, with membership PDA draws its strength from its members, which nearly equally divided between those working in includes a corps of 2,500 active volunteers. Our the U.S. and in other regions around the world. conferences, meetings, and training courses bring Represented in this diverse membership is a growing together pharmaceutical manufacturers, suppliers, end number of young professionals and students. users, academics, and regulatory offi cials in person Recognized for our expertise and authority in the fi eld and online for an unprecedented level of exchange on of parenteral science and technology, PDA is leading timely issues of mutual interest and concern. the way in promoting the exchange of information on Through the development of Technical Reports on rapidly evolving technology and regulations to ensure pressing industry topics and responses to regulatory high-quality pharmaceutical production. initiatives, PDA and its members infl uence the future course of pharmaceutical products technology. A natural progression was for PDA to expand this expertise into PDA supports its mission to advance the world of creating standards that provide guidance pharmaceutical and biopharmaceutical science to industry on best practices for drug manufacturing for and regulation so members can better serve patient use. In 2017, PDA was accepted as an ANSI- patients by: accredited standards developer. PDA recently released • Providing global forums, both in person its fi rst standard on purchasing controls. Work is and virtually, for the scientifi c community, underway on multiple additional standards, with several regulators, and industry professionals on scheduled to be published this year. emerging trends within the industry Our internationally recognized publications, PDA • Delivering unique, hands-on, interactive Journal of Pharmaceutical Science and Technology education and training courses through PDA’s and PDA Letter, keep pharmaceutical manufacturing manufacturing training facility and online professionals up to date on the latest science and • Fostering career-long learning and professional current industry and regulatory news. development Together, these activities promote the advancement Encouraging scientifi c information sharing • of pharmaceutical science in the interest of the among industry peers ultimate end-user—the patient. • Serving as a leading contributor of information and expertise to infl uence global industry and regulatory solutions.

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OCTOBER 5-6 EXHIBITION: OCT. 5-6 2020 PDA COMBINATION PRODUCTS WORKSHOP: OCT. 7 TRAINING COURSES: OCT. 7-8 #PDAups

PDA is committed to maintaining opportunities for volunteers and individuals from the pharmaceutical industry to meet, wherever we can do so. PDA considers safety and health of event attendees as a subject of utmost importance. PDA has implemented a set of measures to protect participants and staff from potential risks related to COVID-19 as best as possible. This includes a close and regular monitoring of the situation, adherence to recommendations of health authorities and oﬃ cial travel warnings, precautions being implemented at our venues, and the possibility of remote presentations or virtual events. Cover Story: Drug Delivery

Cover Story: Drug Delivery — rier of glass which most vaccines and by SmartSkin Technology (11) is cur- Contin. from page 9 biologics require, in containers that won’t rently being used by 14 Big Pharma break, don’t need washing or depyroge- companies to improve fill/finish staff and redesigned shifts so that we nation, do not form leachables or extract- lines. Developed 10 years ago by a can produce without any stop and ables, and can be produced quickly. “We biomedical engineering student at deliver products while preserving our can build capacity that would take glass the University of New Brunswick, staff ’s health and safety,” says Zambon. plants up to 24 months, in three months,” SmartSkin uses pressure sensi- Ganti says.The vials also prevent immu- tive, skin-like nanomaterials to make FUTURE DEMAND nogenic responses in patients. “Especially force-sensitive replicas of packag- Since the COVID-19 pandemic began, during pandemics, time is not on your ing containers. These replicas move the biggest challenge for container manu- side. You want to avoid reformulation at via drone along with containers on facturers has been assessing true demand, all costs,” he says. SiO2’s vials can be kept the filling line, so that they experi- given the huge number of therapies being at temperatures as low as – 40 to – 70 °C, ence and measure the forces acting on explored. As Schmid puts it, 600 poten- which are required for some drugs that the containers, allowing conditions tial COVID-19 therapy and vaccine use mRNA or DNA technologies. to be optimized and controlled. So candidates are currently being developed Novartis began to work with SiO2 far, SmartSkin has allowed users to around the world, but no one knows three years ago and uses its contain- reduce yield loss and defect-related which—or how many—will be successful, ers for Lucentis, its biologic ophthal- downtime by more than 80%, reduc- or when. “Everyone is asking for vials, mic treatment for infants, which was ing the workload on employees (e.g., but we all know or must assume that commercialized in December 2019. for visual inspection and defect-related only a few candidates will ultimately be Currently, 13 other pharma companies product investigations), and saving commercialized. The multiplying effect are also working with SiO2, which is millions of dollars per year per fill- of inquiries makes it difficult to assess involved in 16 different clinical trials, ing line, says CEO Evan Justasson. true demand and timing,” he says. There a number of which are in Phase II and REFERENCES are also questions about how demand will III. Three of the clinical trials are test- 1. J. Bort, “Bill Gates Is Working to Fix a break down between single- and multi- ing potential COVID-19 treatments, Surprising Problem Hindering a COVID- 19 Vaccine: Finding Enough Glass Vials,” shot (i.e., 2–mL vs. 10–mL) vials. says Ganti. Businessinsider.com, May 11, 2020. Established 10 years ago in Alabama, The future may see increased use 2. R. Bright, Office of Special Council, Complaint of Prohibited Personnel SiO2 Materials Science has begun to of alternatives to parenterals (i.e., Practices and Other Prohibited Activity commercialize pharmaceutical applica- transdermal forms such as micronee- by the US Department of Health and Human Services, May 5, 2020. tions, says Lawrence Ganti, president dles [both solid and hollow-tipped 3. M. Marschke, et al., “Roving Bandits of customer pperations. Working with types] and inhalable forms. A num- and Looted Coastlines: How the Global Appetite for Sand is Fueling a Crisis,” scientific advisors from Auburn and ber of COVID-19 therapy develop- theguardian.com, July 2, 2018. Harvard Universities, the Massachusetts ment programs are examining these 4. M. Bendixen, et al., “Time is Running Out for Sand,” nature.com, July 2, 2019. Institute of Technology, the University forms, which are also a specialty for 5. Gerresheimer AG, “Leading Pharma of California at Santa Barbara, and the Kindeva, a new drug delivery specialist Packaging Companies Commit to Supply for COVID-19 Fight,” Press University of Chicago, the company hired that was formed when 3M spun off Release, June 16, 2020. Bob Pangborn, former head of research its drug delivery division earlier this 6. RAPID USA website, rapidusa.com. 7. Corning Incorporated, “U.S. at Dow Chemical, as a chairman of the year. Kindeva is building upon 3M’s Departments of Defense, Health & scientific board. SiO2 has refined a plas- legacy in inhalation and transdermal Human Services Select Corning Valor Glass Packaging to Accelerate Delivery ma-enhanced chemical vapor deposition drug delivery, and CEO Aaron Mann of COVID-19 Vaccines,” Press Release, (PEVCD) process that it uses to coat sees tremendous potential for inhalable June 9, 2020. 8. Corning Incorporated, “Corning and plastic (typically a cyclo-olefin poly- dosage forms, a major focus for the Pfizer Announce Supply Agreement mer [COP] or cyclic olefin copolymer company’s R&D, formulation, devel- for Corning Valor Glass,” Press Release, May 28, 2020. [COC]) with a 0.3–nanometer coating opment, and commercial business, in 9. SiO2 Materials Science, “SiO2 Materials of pure silicon dioxide that is covalently treating COVID-19. At the same time, Science Receives $143 Million Contract from U.S. Government,” Press Release, bonded and cannot be removed. The pro- he says, microneedle dosage forms are June 8, 2020. 10. US Dept. of Defense, “DOD Awards cess results in a material that releases no being explored in more COVID-19 $138 Million Contract, Enabling leachables or extractables, no metal ions, vaccine research programs. Prefilled Syringes for Future COVID-19 Vaccine,” Press Release, May 12, 2020. and no particles, says Ganti, thus prevent- Fill-and-finish operations, so cru- 11. A. Siew, “In-Line Force Analysis During ing immunogenic side effects. Marrying cial to parenteral supply, are also being Vial Filling,” PharmTechEurope 30 (1) 15 (2018). ◆ SiO2 with plastics offers the oxygen bar- optimized. One approach developed

12 BioPharm International July 2020 www.biopharminternational.com Development

Can Using RNA Simplify Gene Therapy Development? RNA is easier to manipulate than DNA but challenging to deliver to the right cells.

CYNTHIA A. CHALLENER

riginally it was thought that the only role of ribonu- specific genes that are drivers of disease mechanisms. One cleic acid (RNA) was to translate genetic information example is small interfering RNAs (siRNAs), which accord- O encoded in DNA into protein sequences that perform ing to David Evans, chief scientific officer at Sirnaomics, are critical biological functions. While messenger RNA (mRNA) is useful as therapeutics where the gene(s) to be targeted is (are) crucially important, it is just one of many types of RNA involved overexpressed in the diseased state and where silencing these in a range of activities that affect the transmission of genetic genes may produce a therapeutic benefit. information and the functioning—or dysfunctioning—of cells. Indeed, Doug Fambrough, president and CEO of Dicerna Appropriately designed RNA-based therapies can thus mod- Pharmaceuticals, believes that while supporting protein pro- ulate genetic information in a controlled and targeted manner, duction is useful in a few contexts, such as treating rare effectively acting as gene therapies. They also offer several genetic diseases or making vaccines, there are far more uses for advantages over DNA plasmid-based therapies. silencing genes. “For example, silencing can be used to treat Strands of RNA by themselves, however, are unstable and viral diseases, cardiovascular conditions, cancer, inflammatory degrade rapidly in the bloodstream. Delivery to specific targeted diseases, fibrotic diseases, select rare diseases, and generally cells is one of the main challenges that developers of RNA- any condition where biological processes are inappropriately based gene therapies are tackling today. activated,” he asserts. RNA technologies fall into two main categories: those that Sirnaomics and Dicerna are both focusing on RNA inter- directly interfere with expressed mRNA or mRNA expression, ference therapies. Belgium-based biotech company eTheRNA blocking protein production, and those that cause the expression of target proteins whose deficiencies can lead to disease. CYNTHIA A. CHALLENER, PhD, is a contributing editor to The first type includes RNA interference (RNAi) and BioPharm International. petarg/Stock.Adobe.com antisense therapies, which in effect silence the expression of

www.biopharminternational.com July 2020 BioPharm International 13 Development

immunotherapies, on the other hand, has MORE DRUGGABLE TARGETS ble, and this approach can also help elected to focus on mRNA-based tech- With the rapid progress made in to make the RNA less immunogenic, nologies that lead to the expression of sequencing the human genome, there Tiest notes. proteins the body is unable to produce on is now a wealth of information on Similarly, the inhibitory or expression its own, according to Wim Tiest, a special sequences of genes, some of which effect wanes as the RNA degrades inside advisor at the company. have been identified as playing the cell. Self-amplifying RNA can to a direct role in the etiology of dis- some extent prolong this active period, ADVANTAGES OVER DNA eases, according to Evans. “Many of according to Tiest. The need for regular, Unlike DNA-based gene therapies that these therapeutic targets, however, are repeated dosing and maintenance of a must be delivered into the nucleus and undruggable by traditional small mol- sufficient active dose is therefore also a create permanent changes, RNA ther- ecules or antibodies but are upregu- major bottleneck. He does note that local apies only need to reach the cytoplasm lated in disease states like cancer and administration helps to overcome some to perform their post-transcriptional fibrosis,” he notes. “siRNAs are readily of this limitation. activity and are not permanent, thus designed against these gene sequences Overall, careful selection of targets treatment can be modified or halted if and can silence expression of the pro- that require short interventions and necessary. They are also smaller, more teins that are driving disease, produc- can benefit from the increased safety easily manipulated and do not present ing therapeutic benefit to patients profile of RNA is required to fully the risk of unintentional genetic effects. with disease,” Evans says. profit from RNA-based therapy devel- “Messenger RNA and other RNA- In addition, RNAi therapies offer a opment, Tiest concludes. based therapies have the advantage of highly versatile approach that can ben- being versatile (they can code for a efit patients with an array of diseases, ASSESSING MULTIPLE broad range of targets), easy to pro- Fambrough points out. “Today, we can DELIVERY SOLUTIONS duce (basically the production pro- create siRNAs to match almost any Like most DNA plasmid-based gene cess is transposable between mRNA messenger RNA. In effect, the RNAi therapies, RNA therapies can also designs), and safe (due to the transient approach to drug development can be delivered into cells using viral vec- expression of the target and absence of silence virtually any gene,” he notes. tors, but the majority of these therapies risk for integration into the patients Another benefit of RNA thera- under development today rely on non- genome),” asserts Tiest. “Additionally,” pies compared to many conventional viral methods, such as organic (lipid) or he says, “mRNA is compatible with small-molecule and biologic drugs is inorganic nanoparticle-encapsulated a range of systemic and local delivery the possibility of reducing the treat- complexes, extracellular vesicles, and modalities and can be designed to be ment burden for patients, according to patient-derived dendritic or mesenchy- nearly invisible to the host’s immune Fambrough. “With a longer duration of mal stem cells, allowing delivery even system, thus avoiding any vector-di- effect, RNAi therapies can be admin- across the blood-brain barrier (1). rected immune responses.” istered with infrequent subcutaneous Delivery technologies for intravenous, RNAi technologies such as siRNAs injections, and depending on the disease subcutaneous, and intramuscular admin- also provide high target specificity modality, can be self-administered at istration are largely focused on preventing by using gene sequences that match home,” he observes. RNA-based therapies from degrading in with targeted genes and rely on nat- the blood stream. For mRNAs adminis- urally occurring cellular enzymes to STABILIZATION AND tered in this manner, lipid nanoparticle mediate gene silencing, according to DELIVERY CHALLENGES solutions appear to be most common. Fambrough. Due to this high specific- RNA by its nature is rapidly degraded Other delivery technologies are designed ity—and reversibility—they offer the once injected. As such, delivery to the to enable local administration of mRNAs potential of fewer side effects. “Unlike targeted cells is the main hurdle at this to the target site or organ, according to gene therapy or gene editing, which time. “We need to ensure that the siR- Tiest. “For cancers,” he explains, “intratu- can be permanent and could have NAs are able to reach their target tis- moral injection of mRNA offers advan- unknown, unwanted, and irreversible sue and cell types,” Evans states. In tages in safety (very local effect), dosage consequences, RNAi therapies can offer cancer, for example, that means accu- (no need to saturate circulation and reach targeted, effective treatment that does mulation of nanoparticles, for instance, the target), and easier combination with not permanently edit or change DNA. at the tumor site with delivery of the other existing therapies.” An RNAi therapy’s effect is targeted, RNA into the tumor cells specifically. Lipid-based nanoparticles have precise, and can be stopped at any time Stabilization of RNA by modification also been used for siRNA-based by discontinuing treatment,” he explains. of the chemical backbone is possi- drugs, including some that have been

14 BioPharm International July 2020 www.biopharminternational.com Development

approved by regulatory authorities. siRNA payload into the cytoplasm where they represent only a small portion of N-Acetylgalactosamine (GalNAc)- the siRNAs function to silence targeted candidates moving through clinical mediated delivery of chemically modi- genes,” he observes. development. fied siRNAs has been demonstrated to eTheRNA is mainly active in oncol- result in significant delivery and silenc- CONTROLLING ogy, with both vaccines against tumor ing of genes within the hepatocytes mRNA ACTIVITY targets and intratumoral injection of of the liver and has also resulted in an A third challenge has been regulation of mRNA expressing targets involved in approved product. mRNA activity once it is delivered to cell death and immune stimulation Dicerna’s GalXC platform is a the right cells, which is needed to ensure in its portfolio that leverage propriety leading example. “This approach uses the right dose of the targeted thera- LNP and immune stimulation (Trimix) a unique, proprietary, and rationally peutic protein is expressed. A research technologies. Currently, the company designed tetraloop configuration of team at the Massachusetts Institute has an ongoing Phase I/II program in double-stranded RNA molecules that of Technology developed one possible melanoma and breast cancer. It also interfaces effectively with the RNAi solution: incorporation of additional recently entered the field of infectious process and allows us to easily mod- genes for RNA-binding proteins (2). diseases and is working on a cross-pro- ify a compound’s chemical structure The interaction between the mRNA and tective coronavirus vaccine based on to maximize stability and potency,” RNA-binding proteins is controlled using T-cell response that is administered Fambrough explains. He adds that it a small-molecule drug, and thus dosing intranasally, according to Tiest. offers the potential for more convenient of the small-molecule drug regulates the Sirnaomics has developed a com- administration, infrequent dosing, high mRNA activity. bination of two siRNAs targeting specificity, a high therapeutic index, and TGFbeta 1 and Cox2 within an HKP scalable, straightforward manufactur- BREAKTHROUGH APPROVALS nanoparticle that it has formulated for ing. So far, the company has focused on Inhibitory RNA approaches are most intratumoral delivery (STP705 in Phase treating diseases of the liver, but is now advanced, while mRNA therapies are IIs in non-melanoma skin cancer) and exploring the use of its GalXC platform at earlier stages, with some vaccines intravenous administration (STP707 across different organs, systems, and in Phase II trials and candidates using for delivery to key liver cells for fibro- rare and common diseases. mRNA for in-vivo expression of anti- sis treatment; it also has demonstrated Sirnaomics uses a polypeptide bodies that target a specific therapeutic in animal models to mitigate hepato- nanoparticle consisting of a histidine-ly- effect, according to Tiest. cellular carcinoma [HCC]). STP707 sine branched-chain polypeptide (HKP). The two RNAi therapies that have has further been shown to increase the HKP mixed with siRNAs spontaneously received approval to date were both activity and improve the efficacy of forms nanoparticles due to the charge- developed by Alnylam Pharmaceuticals. anti-PDL1 antibodies against HCC, charge interaction between the negative Onpattro (patisiran) was granted according to Evans. phosphates on the siRNAs and the pos- approval by FDA in August 2018 for The company is also working on chi- itively charged lysines, Evans notes. An the treatment of the polyneuropathy meric siRNAs that combine a small-mol- advantage of this technology over some of hereditary transthyretin-mediated ecule therapeutic into the structure of the other delivery mechanisms, he says, is its amyloidosis (3). It has received market- siRNA. “Once inside the tumor cell, the ability to deliver multiple siRNAs to a ing authorization from the European small molecule is released from the sense cell at the same time, allowing synergis- Medicines Agency. This drug halts the strand where it is designed to augment tic effects of two siRNAs to be utilized production of faulty transrethrytin. the activity of the siRNA inhibitor and as a therapeutic. In November 2019, Alnylam received produce a synergistic effect,” Evans says. HKP-based nanoparticles can also FDA approval for Givlaari (givosiran) The activity of these constructs has been accumulate near tumors, possibly medi- for the treatment of adults with the rare demonstrated against a number of tumor ated by the enhanced permeability and genetic disease acute hepatic porphyria types including pancreatic tumors, colon retention (EPR) effect, according to (4). This RNAi therapy targets amino- cancers, bladder cancer, and head and Evans. They further benefit from the levulinic acid synthase 1. neck cancers. presence of histidines, because these moi- Dicerna is leveraging its GalXC tech- eties have a pKa of approximately 6.3 and NUMEROUS PRODUCTS nology on its own and through several become protonated during acidification IN DEVELOPMENT collaborations. The company’s lead candi- of the endosomes that are intermediary The three companies interviewed for date, nedosiran, is in development to treat in the uptake of siRNAs by the nanopar- this article alone have several RNA- primary hyperoxaluria (PH), an ultra-rare ticles. “This protonation helps release the based therapies in development, but and devastating condition that causes

www.biopharminternational.com July 2020 BioPharm International 15 Development

calcium oxalate crystals to form in the that can then open up the field into an ciated with DNA-based gene therapy. kidneys and often results in kidney fail- increased development of RNA-based Technology has now reached a level ure. Nedosiran silences the lactate dehy- therapeutics,” Tiest states. of maturity, particularly around stabi- drogenase enzyme, which is implicated Over the next year, Evans expects lization and delivery of RNA, and the in all three types of PH. It is currently an influx of additional siRNAs target- upcoming flow of clinical data could being evaluated in the PHYOX clinical ing liver diseases and being targeted to enable the break-through of this tech- development program, which includes an the hepatocytes using GalNAc conju- nology onto the main stage of drug ongoing registrational trial. gates because this approach has already development,” comments Tiest. Two other top candidates include an demonstrated success. “Efforts will also Looking specifically at RNAi therapies, siRNA therapy to treat alpha-1 anti- be focused on additional chemically Fambrough notes that while the tech- trypsin-associated liver disease (Phase modified siRNAs with different targeting nology is a newer approach to treating I/II) and RG6346 for the treatment ligands that enable delivery to tissues and disease, it has experienced a “coming of of hepatitis B virus infection (Phase I), cells outside the liver, with the biggest age” in the past couple of years. “We have which is being pursued in collaboration obstacle being avoidance of uptake by the seen not only the first approvals in the with Roche. “Between Dicerna and our liver for any and all systemically delivered space, but also a surge of interest among collaborative partners, we currently have siRNAs,” observes Evans. Big Pharma and big biotech companies more than 20 active discovery, preclini- Fambrough agrees that the next fron- seeking an entry into RNAi,” he says. cal, or clinical programs focused on rare, tier for RNAi therapies will be non-he- cardiovascular, cardiometabolic, viral, patic tissues. “There is significant interest REFERENCES 1. X. Tang, et. al. Front.Oncol., 9:1208 (2019). chronic liver, and complement-medi- and persistent unmet need across a range 2. MIT, “This RNA-Based Technique ated diseases, as well as neurodegenera- of disorders,” he says. Could Make Gene Therapy More tion and pain,” Fambrough notes. Effective,” Press Release, Oct. 16, 2018. MOVING TO THE MAIN STAGE 3. Alnylam Pharmaceuticals, “Alnylam BROADENING APPLICATIONS Announces First-Ever FDA Going forward, the key advantages Approval of an RNAi Therapeutic, Both mRNA and siRNA therapeutics of RNA-based therapies compared to ONPATTRO (patisiran) for the and vaccines are advancing through DNA-based gene therapies will con- Treatment of the Polyneuropathy the clinic, with a steady stream of read- tinue to drive greater interest in all of Hereditary Transthyretin- Mediated Amyloidosis in Adults,” outs expected in the next few years. types of RNA treatments. “RNA com- Press Release, Aug. 10, 2018. “Apart from clinical data, these results bines the advantages and versatility 4. FDA, “FDA Approves Givosiran for should validate a number of delivery of genetic-based therapy modalities Acute Hepatic Porphyria,” Press ◆ and chemical modification platforms with the lack of (perceived) risks asso- Release, Nov. 20, 2019.

Drug innovation engine performs during pandemic

While the global health community anxiously awaits eye disease, idiopathic constipation, cardiovascular the bio/pharmaceutical industry to produce approved disease, migraines, Cushing’s disease, multiple sclerosis, therapies and vaccines to treat the COVID-19 pandemic, Parkinson’s disease, and malaria. innovator drug companies have been very productive. Game therapy As of June 15, 2020, FDA’s Center for Drug Evaluation On June 15, 2020, FDA announced approval of the first and Research approved 24 new molecular entities and prescription-only game-based device, EndeavorRx. This new therapeutic biological products, compared with 12 digital therapeutic device is designed to improve atten- approvals as of the same date in 2019 and 16 in 2018. tion function in pediatric patients ages 8 to 12 years old FDA’s Center for Biologic Drug Evaluation and with attention deficit hyperactivity disorder. Research approved five therapies through June 26, 2020, including vaccines for meningococcal disease References and influenza A (H1N1) and a treatment for peanut 1. FDA, Novel Drug Approvals for 2020, www.FDA.gov, accessed June 26, 2020. allergies (2). The number of biologic license application 2. FDA, 2020 Biological License Application Approvals, www.FDA.gov, approvals in 2020 lags the number of approvals in 2019 accessed June 26, 2020. and 2018. 3. FDA, “FDA Permits Marketing of First Game-Based Digital Thera- peutic to Improve Attention Function in Children with ADHD,” Press Many newly approved drugs target specific cancers Release, June 15, 2020. including lung, breast, gastrointestinal, thyroid, and —The editors of BioPharm International bile duct. Other approved therapies treat thyroid

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

Improving mAb Manufacturing Productivity by Optimizing Buffer and Media Prep Process Flow Innovative approaches, including ready-to-use materials and in-line dilution, can significantly streamline overall bioprocessing operations.

NANDU DEORKAR AND PRANAV VENGSARKAR

t is common for biologics manufacturing processes to buffer preparation using single-use systems, reactors, and require hundreds of raw materials, ranging from media in-line dilution can both help eliminate or reduce weigh and I and media supplements, buffers, and salts to other process dispense operations. chemicals. Buffers and salts are typically the largest constitu- The modularity of single-use systems allows site-specific ents by volume used in the downstream processing steps for and process-specific solutions to be implemented quickly manufacturing most biopharmaceutical products. A typical without requiring significant capital expenditure. Single- monoclonal antibody (mAb) process may require 2000 L of a use raw material delivery systems, in powder or liquid form, buffer and more than 100,000 L per batch based on titer and can help reduce the risk of contamination and minimize bioreactor volume (1, 2). As a result, the variety of buffer solu- the need for frequent cleaning steps. Raw material quality tions used across a biopharma manufacturing facility requires control (QC) testing can also be reduced or eliminated by flexible, cost-efficient infrastructure and on-time delivery to implementing single-use technologies, saving time from meet process demand. reduced process steps as well as labor costs. At the same time, the growing use of single-use systems The increase in titers and the trend toward continuous offers many advantages in managing raw materials used in biomanufacturing will lead to increased demand in buffer bioprocessing. Single-use technologies add flexibility, reduce NANDU DEORKAR is vice-president, Research & Development— capital requirements, and improve ease-of-use in biopharma Biopharma Production, and PRANAV VENGSARKAR is manager, manufacturing operations. Solid or hydrated buffers and Process Development; both at Avantor. Grispb/Stock.Adobe.com salts that come ready-to-dispense in single-use bags and

www.biopharminternational.com July 2020 BioPharm International 17 Upstream Processing

Figure 1. The use of pre-packaged materials can help address some of the • Solid agglomerates (or material challenges faced with typical powder-handling processes, such as subdividing, clumps) can cause damage to weighing, and dispensing. single-use or stainless-steel tanks. The use of pre-weighed and kit- ted materials can help address some of these issues (Figure 1). There are several ways to implement a new process depending on the buffer/salt component, buffer volume requirements, production schedule, and desired flexibility (Table I). One approach uses materials in single-use, ready-to-dispense packaging supplied at custom weights; the other uses modular packaging provided at standard weights. Single-use powder and liquid formulations can help reduce overall cost of goods.

Manufacturing sites dedicated to volumes and prep times. To address pensed into a single-use or stainless-steel producing a limited number of products this gap, strategies for improving mAb mixing vessel according to the specific following a stable schedule are likely to manufacturing productivity by opti- amount needed for a given process. have greater success using the custom mizing powder and liquid buffer and Most of these material handling weight approach. A biopharma man- media prep process flow are worth processes take place in a classified ufacturer could request the supplier to considering. When combined with environment as a segregated opera- provide material at a precise weight (e.g., innovative new technologies such as tion to reduce cross-contamination and 51.223 kg). With this approach, the in-line dilution, single-use powder and particulate risks (2). This operation can manufacturer can quickly dispense the liquid formulations can help reduce take anywhere from 25 to 32 working material to make a buffer of a known facility footprint, labor hours, and the hours per material handled to produce concentration. This method also elimi- overall cost of goods. one batch of a buffer. Along with the nates any on-site powder kitting process time involved, there are many other steps while reducing hours required per POWDER-HANDLING challenges with this process (3): buffer batch to almost a third of the PROCESS IMPROVEMENTS • Intrusive physical sampling of typical process. A typical powder-handling process at a powder raw materials requires rapid An equally effective approach lets biomanufacturing site starts with raw material usage post-sampling to a manufacturer make efficient use of material testing (of each lot or identity comply with regulatory guidance. a supplier’s standard, modular-weight tests). Following the raw material test- • The physical properties of powders system. Products can be provided in ing process, powders are weighed and require extensive cleaning of predefined weights—100 kg, 25 kg, or dispensed into a separate container classified prep areas to prevent 1 kg, for example—for each buffer or (e.g., intermediate bulk container [IBC], cross-contamination. salt component in a ready-to-dispense bags), and kitting and buffer compo- • Many powders have properties format. This method, ideal for sites nent storage are done in a storage area. that cause them to clump or cause that make several products with fre- This process requires proper recording static holdup, increasing the labor quent schedule changes, offers more and tracking of buffer component kits required per batch and the risk of flexibility to make buffers on-site. A until the subdivided materials can be dis- potential safety incidents. small subdivision process is still AUTHORS THE OF COURTESY ARE FIGURES

18 BioPharm International July 2020 www.biopharminternational.com Upstream Processing

Table I. Summary and comparison of ready-to-dispense options.

Man-hours Hydration Cost Receiving Sampling steps Weighing steps needed per steps savings material 1. Transfer drum to sampling 1. Weighing of material into area intermediate container Mixing in 2. Wipe down and open drums 2. Manual powder addition into tanks Traditional drum single-use 3. Samples drums to make a 30 hours None handling or stainless- composite sample steel tanks 4. Submit sample to quality control (QC) 1. Selection of pre-weighed bag + small subdivision step into 1. Remove tailgate samples intermediate container or directly Mixing in Modular direct into tank single-use dispense bag 12 hours Moderate or stainless- handling 2. Rapid ID (identification) of 2. Semi-automated or automated material using Raman and powder addition into tanks steel tanks release for use (manual addition also possible)

1. Remove tailgate samples 1. No subdivision step Mixing in Custom-weight single-use 2. Semi-automated or automated direct dispense 2. Rapid ID of material using 9 hours High powder addition into tanks (manual or stainless- bag handling Raman and release for use addition also possible) steel tankh

required to support the precise weigh- • Chemical nature of solid cases indicate a dispensing tolerance ing of solids in the sub-kilogram scale. (anhydrous, hydrated salt, close to 100% for some common raw Overall, the modular weight system hygroscopicity) materials (Table II). can reduce the working hours needed • Physical nature of solid (pellet, A powder delivery system that per buffer significantly as compared to granule, fine powder) supports non-contact, rapid identifi- the traditional approach. • Compressibility and flowability cation methodologies, such as Fourier- Pre-weighing processes can be used (bulk density, Hausner ratio) transform infrared spectroscopy with single-use powder delivery pack- • Safety (hazardous solids, (FTIR) and Raman spectroscopy, can aging. This packaging is filled in a minimum ignition energy for fine streamline the incoming testing of the controlled environment with traceable powders) powders and reduce the risk of con- trusted weight stickers, ensuring accurate • Dissolution rates (affects the tamination (Figure 2). The availabil- weights delivered into a buffer tank. This speed of dispensing and hence ity of a side sample of the material can packaging method can improve overall bag port size) further help streamline process steps, process efficiency, regulatory compliance, • Others (static nature, stability, mitigate risk, and ensure all quality and and buffer quality. compatibility with plastics). regulatory requirements are met. A manufacturer should consider the Field studies gathered where the powdered materials used in single-use packaging was in use assess the accu- ADVANCES IN LIQUID delivery systems, examining the materials’ racy of the product delivered into the HANDLING PROCESSES properties, including: production systems. Data for such The adoption of premade liquid buf- Table II. Dispensing accuracies of typical products in a direct-dispense system (3, 4). fers and buffer concentrates into biomanufacturing has been limited up to Typical weights Dispensing Amount retained this point to simple cleaning buffers, Buffer raw material used in accuracy due to static such as caustic solutions and other bio-manufacturing hazardous products that have envi- Potassium phosphate 25 kg, 50 kg, and 99.917 % 0.083% ronmental health and safety (EH&S) monobasic 100 kg concerns, such as hydrochloric acid. 10 kg, 25 kg, and Glycine 99.926 % 0.074% High shipping costs may have lim- 50 kg ited the ability to extend the use of 25 kg, 50 kg, and Dextrose 99.804 % 0.196% this technology with other materials. 75 kg Improvements in equipment and sin-

www.biopharminternational.com July 2020 BioPharm International 19 Upstream Processing

Figure 2. A powdered raw material delivery system that supports non- based on the size of the facility and contact, rapid identification methodologies, such as Fourier transform infrared the capital cost required. Nevertheless, spectroscopy (FTIR) and Raman spectroscopy, can streamline incoming quality the overall technology can generate control testing and reduce the risk of contamination. significant process improvements in downstream buffer preparation. Hydrated buffers and salts can enable continuous processing.

Deploying liquid handling systems can require planning and analysis to assess suitability for a specific operation because liquid raw materials have several challenges compared to powders. Several parameters are critical to consider when developing buffer concentrates as raw materials and when using them, such as: • Stability of essential product parameters over time (pH, conductivity, assay; critical for Figure 3. In-line dilution system schematic. chromatography) • Bioburden and endotoxin (critical for growth-promoting solutions) • Densities and viscosities of concentrates (critical to ensure accurate flow and pump sizing) • Safety (hazardous solutions can pose a challenge at large scales) • Corrosive nature of solutions (can affect extractable and leachable profiles of single-use systems and tanks) • Freezing points and temperature stability of solutions (necessary to gle-use system technologies, however, (Figure 3) and in-line conditioning mitigate issues post-shipping). have made this option more appealing. systems/buffer stock blending systems A simple failure mode and effect Hydrated buffers and salts in bio- using single-component concentrates analysis (FMEA) can guide such eval- manufacturing can help enable con- have also made the use of these buffer uation and implementation options. tinuous processing while eliminating concentrates economically viable. Stability studies on these buffer concen- issues related to powder handling. Recently, the BioPhorum trates following International Council Sterile-filtered solutions of complex 1X Operations Group (BPOG) conducted for Harmonization of Technical buffers or buffer concentrates are now an economic analysis of the use of liq- Requirements for Registration of more feasible due to the availability of uid handling systems and buffer con- Pharmaceuticals for Human Use (ICH) single-use containers ranging in vol- centrates (1, 5). The report highlights Q7 guidelines (6), extractable and leach- umes from 200 L to 1000 L. Advances operational savings from using concen- able profiles using BPOG guidelines on related to in-line dilution systems trated stock solutions along with a buf- using multicomponent concentrates fer stock blending system. Savings vary Contin. on page 47

20 BioPharm International July 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 Downstream Processing

Eliminating Residual Impurities Starts with a Strategic Plan Identifying the source, assessing the risk, and removing residual impurities requires a strategic approach.

CYNTHIA A. CHALLENER

esidual impurity testing is essential to ensure the quality it enables risk-based residual impurity control and minimizes and safety of pharmaceutical products, but it can be the need for residual impurity testing. R particularly challenging with biologics because there are so many potential sources of impurities, from the media NUMEROUS RISK FACTORS and host cells to misfolded or aggregated product to down- Residual impurities in biopharmaceutical processes can be traced stream purification reagents and process equipment. A risk- back to raw materials or can form during upstream or down- based approach to identifying potential residual impurities is stream processing steps and upon storage. They can be derived important for understanding any risks to the product quality from the host cell or the product itself, media components, and potentially the patient. It also allows the development of surfactants, virus inactivation agents, inorganic or organic con- an optimal process with a suitable control strategy and test taminants from permanent and single-use process equipment, methods in a timely fashion. the pharmaceutical formulation, and/or a breach of sterility. “A The implementation of a risk-based strategy for the test- strategy for the control of residual impurities has to consider risk ing of residual impurities, meanwhile, offers the potential factors that are specific to each of these process- or product-re- to significantly reduce the amount of testing needed while lated impurities,” asserts Michael Jahn, group head of forensic still meeting regulatory requirements and ensuring patient chemistry at Lonza. safety. It does require, however, a thorough understanding of This quantity and heterogeneity of possible impurities is the process combined with appropriate control strategies to perhaps the single biggest factor influencing the development minimize the impurities that may be present at the end of the production process (drug substance and drug product). While CYNTHIA A. CHALLENER, PhD, is a contributing editor to building a knowledge base on residual impurities requires BioPharm International. investment, that investment pays off in the long term because angellodeco/Stock.Adobe.com

22 BioPharm International July 2020 www.biopharminternational.com Host Cell Protein (HCP) Immunoassays and Role of Mass Spectrometry in Identification of HCP Impurities in Downstream Samples

ON-DEMAND WEBCAST Aired: Tuesday, June 16, 2020 Event Overview A well-developed and broadly reactive HCP ELISA remains a gold standard method effectively used during the purification process to ensure removal of HCPs and to demonstrate Presenter process consistency and final drug substance purity. Regulatory guidelines require that sponsors use orthogonal methods for demonstrating antibody coverage to individual HCPs and provide a comprehensive assay qualification package to ensure the HCP ELISA is fit for purpose. In this webcast, we will discuss: • Advantages and limitations of HCP Immunoassays • How immunoaffinity chromatography and mass spectrometry (MS) methods can be integrated with ELISA for a comprehensive characterization of HCP impurities Eric Bishop Vice-President, Research & Development • When to use MS during process development and in clinical Cygnus Technologies and commercial manufacturing

Key Learning Objectives Moderator • Methods for HCP antibody coverage analysis • Enrichment of HCPs by immunoaffinity chromatography and identification by Mass Spec is a powerful orthogonal method to ELISA enabling full understanding of those HCPs that are present in the product and could potentially impact patient safety and drug stability • Incorporation of immunoaffinity chromatography and MS methods into HCP analytics early in the project ensures the Rita Peters best possible clinical outcome Editorial Director BioPharm International Who Should Attend • Bioprocessing Scientists • Process Engineers • Quality Control • Analytical Development Managers and Directors • Analytical Development Directors

Sponsored by Presented by

For questions or concerns, email [email protected] Manufacturing

Overcoming Operational and Regulatory Challenges in Autologous Cell-Therapy Facilities Manufacturers must address scale-out challenges for commercial manufacturing.

FRANCESCA MCBRIDE

lthough only a few cell-therapy treatments have regu- administered to patients via a leukapheresis process, and prod- latory approval, recent years have seen a sharp increase ucts are not sterile filtered or terminally sterilized prior to filling. A in the number of treatments in development, many Process operations and room classification, therefore, must take are now moving rapidly from late clinical stage to commercial- into consideration the requirement for sterile processing, with ization. Most approved autologous (i.e., patient-specific) cell process operations driving the room classification. therapies are being produced for small numbers of patients in laboratory facilities. To support the accelerating commercializa- Product testing tion of autologous cell-therapy products and to provide wider Numerous in-process and final-product release methods must access to these innovative treatments globally, cell-therapy man- be applied to cell therapy products to verify that the process can ufacturers are increasingly scaling out production. produce the products within the desired critical quality attributes. Many cell therapy products are fragile preparations that must be OPERATIONAL CHALLENGES shipped and applied to a patient rapidly. There are various operational challenges that production facil- This time pressure means that standard product release ities face. The following sections discuss how these challenges testing procedures are not feasible. In particular, sterility test- are being addressed in a rapidly evolving environment. ing often cannot be completed before patient treatment. This

Sterile processing FRANCESCA MCBRIDE is director of Regulatory Compliance at The manufacture of cell therapy products must address the Jacobs, [email protected]. requirements for sterile processing. Cell therapy products are Siarhei/Stock.Adobe.com

28 BioPharm International July 2020 www.biopharminternational.com Manufacturing

unique challenge in cell-therapy manu- • Antibody and viral vector preparation providing that each patient product is facturing requires tighter environmental (ISO 7/Grade B with an ISO 5/ located on a separate shelf. and handling controls to greatly reduce Grade A biosafety cabinet [BSC]) The production of autologous prod- the risk of sterility failure. • Expansion, including antibody and uct in a launch or commercial manu- viral vector addition (ISO 8/Grade C) facturing facility setting has expanded Batch variation • Harvest (ISO 8/Grade C) to large ballroom/single room design Additionally, each dose of a cell therapy • Filling and LN2 freezing (ISO 8/ process suites with more than six sta- product is a single batch and is derived Grade C if functionally closed or tions for cell expansion. All process from a different source. Although the cell ISO 7/Grade B with an ISO 5/ operations are functionally closed, with type will be the same for a given thera- Grade A BSC) limited to no use of biosafety cabinets. peutic approach, the cells from different • Preparation for shipment to patient Expansion may occur in either incuba- patients will still behave differently when (not classified). tors, with each patient product located cultured. Source material will contain a Support operations include quality on a separate shelf, or in rocker biore- variety of cell types with varying growth control/quality assurance (QC/QA) actors, with each dedicated to a single and differential capacity. Therefore, the laboratories, warehousing, and utilities patient. All connections made to the duration of cell expansion and the overall generation/supply. rocker bioreactors are through ster- cell product manufacturing timeframe for An additional challenge facing cell ile tube-welding aseptic connections, each batch may vary. therapy facility operators is the fact that enabling the ISO 8/Grade C room clas- key process equipment used for cell ther- sification. Separate process suites are Scale out apy operations, such as cell washer, cell provided for isolation, cell expansion/ The scale-up of autologous cell therapy counter, cell separation, cell selection, and harvest, for antibody and viral vector manufacturing does not result in the controlled rate freezing, is not standard preparation, and for filling. If the pro- use of larger equipment, but rather, the equipment typically used in the produc- cess if fully closed, filling may be per- increased handling of small, laboratory- tion of therapeutics and vaccines. formed in the expansion/harvest suite. scale equipment. Therefore, to increase This equipment is new to the good There is a need for a greater focus the manufacturing capacity of the cell manufacturing practice (GMP) manu- on the ballroom design to mitigate the therapy facility, the facility and operations facturing environment and will require risk of mix-up and contamination. A require “scale out,” which requires the a robust validation and generation of full evaluation of the flow of apheresis, introduction of additional stations and/or procedures for operation and control. in-process and final product, samples, suites to support cell therapy manufactur- Additionally, this equipment is new to solutions, raw materials/consumables, and ing for an increased number of patients. the regulatory agencies and may result waste should be performed. in a more detailed review to confirm In general, there is limited to no flow FACILITY DESIGN the use in cell processing. Primarily, cell of process equipment, nor the provi- Cell therapy processing involves multiple therapy equipment is benchtop design sion of an equipment wash area because operation and process steps that can be with an internal process control sys- single-use process systems are primar- performed in different room classifica- tem for operation, and connections and ily used that are received pre-sterilized. tions, based on the open versus closed transfers between the process equip- Regulatory preference is for the flows process steps being performed. The pri- ment and steps are manual. in and flows out operations of the pro- mary operations may include: Additionally, the design and lay- cess suites to be unidirectional. Therefore, • Receipt, inspection/verification of out of early-phase clinical autologous airlocks for material in and out and per- patient cells (not classified) manufacturing facilities is different sonnel in and out should be provided. • Kitting of supplies for each stations from late-phase clinical and commer- Dynamic pass-throughs may be provided (controlled not classified [CNC] cial manufacturing facilities. The pro- for the transfer of in-process product, transfer to ISO 8/Grade C) duction of clinical cell therapy product final product, and samples. • Liquid nitrogen (LN2) freezing is typically done in a single lab limited The need to define a biosafety bound- (CNC) to one or two biosafety cabinets that ary is driven by the use of viral vectors • Isolation/separation of cells (ISO 8/ allow for simultaneous production of and, as appropriate, the processing of Grade C) two patient products at a time (one human cells. The classification of the viral • Solution preparation (ISO 8/Grade C in each biosafety cabinet). All open vector, the process operations performed, with local protection) manipulations are performed in the and the rooms where the handling of the • Thawing, cell wash, and media biosafety cabinet and the products may viral vector occurs must be considered to addition (ISO 8/Grade C) be expanded in a common incubator, determine if the processing requirements

www.biopharminternational.com July 2020 BioPharm International 29 Manufacturing

must be good large scale practice (GLSP) • Provision of multiple dynamic pass expansion. Dynamic pass-throughs are or biosafety level (BSL) 1, 2, or 3. throughs for the transfer of supplies provided for the transfer of the antibody Handling of BSL2 or higher from staging into the classified and viral vector into the cell therapy suite. viruses requires provision for waste kitting area Multiple stations for different oper- decontamination. BSL2 allows for the • Classification of the kitting area the ations within the cell therapy suite transfer of contained waste to exter- same as the process suites to which include six for initiation, 10 for expan- nal facilities either on-site or off-site the supplies are transferred sion, and three for harvest. At the for waste decontamination. BSL3 • Classified kitting area for the final completion of harvest, if the cell count requires waste treatment prior to exit- sanitization and placement of supplies is appropriate, patient product is filled ing the biosafety boundary. into individual containers that can be into bags via closed addition and trans- Typically, viral vectors are purchased sealed and staged for transfer to the ferred for freezing. from contract manufacturing organiza- process suite. The design of each process suite took tions and, therefore, only require limited Provision of a common kitting area into consideration the need for required processing prior to addition. In gen- minimizes the sanitization procedures segregation at each station to prevent risk eral, viral vector processing in the cell that would need to be performed in of mix-ups, utilization of closed process- therapy facility is limited to thawing, the airlock for transition of the sup- ing to prevent product contamination transfer to syringe/addition device, and plies into the process suite, because and cross-contamination, use of closed addition to the cells during expansion. only a final, overall sanitization of the processing to support classification of the Due to the high demand for viral vec- external kit container needs to be per- process suite as ISO 8/Grade C, in-pro- tors, cell therapy facilities are consider- formed in the airlock. cess testing, staging of materials within ing that they be manufactured in-house, each station, and unidirectional flows in which raises the need to provide separate CASE STUDY and out of the suites. suites with the appropriate biosafety clas- As an example, a client’s US-based autolo- QC laboratory space is located on the sification and design controls. Dynamic gous manufacturing facility provides space second floor of the facility. All waste is pass-throughs may be provided to enable to produce both late-stage clinical and placed in closed containers and is trans- transfer of the prepared viral vectors into commercial cell therapy products. The ferred out of each suite via separate the cell processing suite. facility is a multiproduct cell therapy facil- waste airlocks to the waste holding area. Media and buffers required for cell ity with initial focus on chimeric antigen Waste is transferred offsite for treatment. therapy manufacturing may be pur- receptor T-cell (CAR-T) manufacturing. Separate rooms are provided for in-pro- chased preformulated or prepared within All open batch manipulations occur cess product freezing and final product the facility. A common solution prepa- within BSCs located in ISO 7/Grade freezing, all in liquid nitrogen freezers. ration area may support multiple cell B rooms, and all processes utilize sterile, therapy processing suites. Single-use sys- single-use equipment. All other process- REGULATORY CHALLENGES tems are commonly used for the prepara- ing occurs in ISO 8/Grade C cleanrooms. Because autologous cell therapy man- tion of media and buffer solutions. The The primary manufacturing process ufacturing facilities are new and differ bags of media and buffers are transferred operations consist of isolation and freez- from the more traditional monoclo- into the process suites for addition to the ing, thaw, initiation and transduction, nal antibody (mAb) therapeutics and product during processing. expansion, harvest, and freezing. Support vaccine manufacturing facilities, cell Kitting areas are provided for the operations include materials receipt, solu- therapy facility operators need to give preparation of materials and consum- tion preparation, kitting, apheresis receipt, consideration to a presentation to the ables as they transition from the ware- product shipping, and QC testing. regulatory agency during the early house to each process suite. A common The facility has five, independent cell phase of the design process. practice is to prepare a single kit for process suites; all are accessed from a Typically, presentations to FDA for each station in the process suites. In common CNC corridor. Each suite has a Type C meeting involves submitting relation to kitting, best practices in unidirectional, in-and-out airlocks for a written report that fully describes the these facilities involve provision for: materials and personnel. Process sup- products, operations, and facility and • A common staging area in a CNC- port suites within three of the cell ther- defines key questions that the manufac- classified area adjacent to the kitting apy suites support the preparation of turer requires regulatory feedback on as area for the transfer of supplies antibody and viral vectors. part of their review and facility drawings. from the warehouse and removal Viral vector preparation is limited to The Type C meeting can provide strong of external wrappings and initial thaw and open transfer to appropriate confidence that the design is acceptable sanitization of materials devices for transduction/addition to cell or identify what risks or changes should

30 BioPharm International July 2020 www.biopharminternational.com Manufacturing

be considered. Key aspects that have been Additionally, the international regula- the relevant regulatory agency during the defined by FDA in Type C meetings for tory requirements that apply to the man- early phase of the design process. This both clinical and commercial manufac- ufacture of cell therapy products include proactive engagement will ensure that turing cell therapy facilities include: guidance from FDA (1–4), EMA (5), the manufacturer will receive a detailed • Preference for unidirectional flows and the National Institutes of Health (6). review from regulators and that all key through the facility issues are addressed. In turn, this review • Segregation of viral vector STAYING AHEAD OF provides strong assurances that the preparation from other operations OPERATIONAL AND design is acceptable or can identify risks • Separate areas for processing/ REGULATORY CHALLENGES or what changes should be considered. in-process testing from QC The operational and regulatory chal- laboratory testing lenges facing cell therapy operators are REFERENCES 1. CFR Title 21, Current Good • Consideration for the risk of product numerous and complex. These include Manufacturing Practices, Parts quality from multiple patient stations the need for sterile processing and for 600 and 610 (April 2020). 2. FDA, Guidance for Industry. cGMP for in a common room. cell therapy products to be shipped Phase 1 Investigational Drugs (July 2008). Within FDA, manufacturing of and applied rapidly. Adding a layer of 3. FDA, “Current Good Tissue Practice for cellular therapies is reviewed in the complexity is the fact that testing often Human Cell, Tissue, and Cellular and Tissue-Based Product Establishments; Division of Cell and Gene Therapies in cannot be completed before patient Inspection and Enforcement,” Final Rule, the Office of Cellular, Tissue, and Gene treatment, which requires tighter envi- Federal Register, 69 FR 68611-68688. Therapies, and there are two separate ronmental and handling controls. Also, 4. FDA, Guidance for Industry. Sterile Drug Products Produced product review branches, one for cell as equipment is new to the GMP man- by Aseptic Processing – Current therapies and one for gene therapies. ufacturing environment, it requires Good Manufacturing Practice Within the structure of the European validation and regulatory review, while (September 2004). 5. EC, Eudralex Volume 4: Good Medicines Agency (EMA), the from a design perspective there is a Manufacturing Practice Guidelines, Committee for Advanced Therapies need for a greater focus on the ballroom “Guidelines on Good Manufacturing Practice Specific to Advanced Therapy (CAT) plays a central role in the scientific design to mitigate the risk of mix-up Medicinal Products,” (Brussels, 2017). assessment of advanced therapy medicines. and contamination. 6. CDC, Biosafety in Microbiological It provides the expertise that is needed to From a regulatory perspective, cell and Biomedical Facilities, 5th Edition (December 2009). ◆ evaluate advanced therapy medicines. therapy manufacturers should present to

ISPE’s Facility of the Year Awards recognize innovative biologic manufacturing facility designs.

Several biologics facilities were announced as category vertically integrate by co-locating early-phase clinical winners in the annual Facility of the Year Awards (FOYA) manufacturing with the site’s existing large-scale program of the International Society for Pharmaceuti- commercial manufacturing (1). cal Engineering (ISPE) (1). Sanofi was awarded the Facility of the Future Category Bristol-Myers Squibb won the Project Execution award for its Sanofi Digitally Enabled Integrated Category award for its Multi-Product Cell Culture (MPCC) Continuous Biomanufacturing Facility in Framingham, Project in Cruiserath, County Dublin, Ireland. The project MA. The facility uses single-use systems for its transformed and expanded an existing API site into a continuous upstream and downstream processing and biologics drug substance manufacturing campus (1). buffer and media preparation and distribution. Digital Architecture, engineering, construction management, integration includes process control, data collection, and turnover services for the project were provided and analytics. Fully electronic batch records enable by Jacobs (2). The facility is designed as a flexible, review and release by exception (1). multi-product manufacturing operation and is now References in commercial operation, having recently received 1. ISPE, “2020 ISPE Facility of the Year Awards Win- regulatory approval from both FDA and the European ners Announced,” Press Release, April 7, 2020. Medicines Authority (2). 2. Jacobs, “Jacobs’ Designed and Built, Multi-Product Pfizer won the Facility Integration Category for its Cell Culture (MPCC) Facility Wins International So- clinical manufacturing facility in Andover, MA. The ciety for Pharmaceutical Engineering ‘Facility of the project relocated clinical-scale capacity from Missouri Year Award’,” Press Release, June 24, 2020. to Massachusetts in order to expand clinical biological drug substance manufacturing capacity and to — the Editors of BioPharm International

www.biopharminternational.com July 2020 BioPharm International 31 Analytics

Analytical Assays Determine Biosimilar Product Quality Appropriate analytical assays are needed to determine and ensure that biosimilar critical quality parameters are on track.

FELIZA MIRASOL

etermining product quality is a critical measure of a identified from analysis of the innovator?” says Shakespeare, proposed biosimilar product. Appropriate analytical who points out that the use of orthogonal methods provides D methods are needed to assess quality as well as for a host of information on the product that is critical for applying quality control (QC). One of the key challenges ensuring the quality. in developing or selecting an assay to determine biosimilar “There are a number of challenges facing biopharma pro- product quality is determining which critical quality attri- duction, and their impact (overall production, development butes (CQAs) are the most important for a given stage of timelines, cost, etc.) can be more significant for companies the drug development lifecycle, notes Stephen Shakespeare, developing biosimilars,” includes Madia. “One challenge product manager, Sartorius. in particular is the drive for improving process efficiencies. “For example, a binding assay may be more relevant Biosimilars are considered to be cost-effective alternatives during clone selection than a mechanism-of-action-bioassay, to expensive biologics. There is a significant pressure placed which would be more suited for the final stages of develop- on reducing production costs through improved manu- ment,” Shakespeare says. facturing processes to improve yields without introducing Titer is another critical process parameter, and to ensure product variation that might require additional processing final product quality, it is necessary to measure the product or testing.” concentration throughout a bioreactor run, adds Laura The tradeoffs between time and cost are particularly Madia, sales and marketing manager at IDEX Health & important when developing biosimilars given the limited Science. development time, Madia continues, saying that “biosimi- Another point of consideration is the kind of information lars do not benefit from the same patent protection as novel that is required from the assay. “Is it selective and specific biologics so there is typically more pressure on prices imme- for the product? Does it address the CQAs that have been diately after approval.” Foster/Stock.Adobe.com Caleb

32 BioPharm International July 2020 www.biopharminternational.com Analytics

ASSESSING THE ASSAY mize any potential downstream issues Manufacturers, meanwhile, are con- Another question to consider is what are with delivering consistent quality prod- tinuing to implement liquid chroma- the most effective assays currently used uct,” Shakespeare states. tography–mass spectrometry (LC–MS) to test for biosimilar product quality? There are situations where a pro- techniques for investigating glycan struc- When assessing a biosimilar, Shakespeare cess depends on a quick measurement ture, verifying sequences, analyzing intact explains, it is critical to take what he to move forward, Madia remarks. mass, and analyzing post-translational calls an orthogonal approach to looking “Measuring titer is not considered sim- modifications of the innovator and of bio- at antibody fragment (Fab) binding and ple nor quick. Titer is often run on a similar candidates, Shakespeare adds. “By fragment crystallization (Fc) binding high-performance liquid chromatogra- introducing simple and affordable kits, using a variety of techniques. phy (HPLC) in the QC lab due to the manufacturers are getting greater instru- “In Fc functional assays, for example, high level of skill required for method ment resolution, improvements in soft- antibody-dependent cellular cytotoxicity development and day-to-day opera- ware processing and databases, and fast (ADCC) can be addressed in numerous tion. It is not uncommon for upstream sample preparations,” he explains. ways using peripheral blood mononuclear process development or manufacturing “In a similar vein, the ongoing cells (PBMCs) or natural killer (NK) cells teams to wait 24 hours or longer to see reduction in particle size to < 3 µm in isolated from blood. Meanwhile, reporter the results of a HPLC titer analysis ultra-high-performance liquid chroma- gene assays can be validated for submis- because they had to send it to a sep- tography (UHPLC) columns continues sion to the regulators. The sensitivity arate lab,” Madia explains. As a result, to enable reduced run times and higher of each of these methods provides key titer is often underutilized or batched throughput while maintaining peak reso- information on the quality of the prod- for retrospective insights, rather than lution,” Shakespeare also adds. uct at different stages of development,” using titer for real-time decision mak- Having an innovative new product that Shakespeare notes. ing, Madia points out. measures titer on demand is also a bene- He adds that there is an array of meth- ficial advancement, Madia adds. Drawing ods, from enzyme-linked immunosorbent INNOVATIONS IN on experiences with the Tridex Analyzer assay (ELISA) and flow cytometry to sur- ANALYTICAL TECHNIQUES (IDEX), Madia highlights how innova- face plasmon resonance (SPR), that can Since the manufacture of the first biosim- tive technology can enable development be used to determine Fab binding. ilars, there have been many innovations and facilitate experimentation by provid- Another example of an orthogonal in analytical techniques and practices. In ing trend data quickly and easily. With approach is the use of size exclusion and recent years, for example, high through- the trend data, it may be possible to deter- ion exchange analytical methods, which put (HTP) flow cytometers (e.g., iQue mine product loss during the evaluation can show differences in aggregation/frag- screener, Sartorius) have enhanced the of filtration options or to monitor break- mentation and charge profile, respectively. speed with which data can be gener- through with a new piece of equipment. These attributes can be important when ated, Shakespeare highlights. HTP flow “Ultimately, a full analysis will be required assessing the stability and safety of a bio- cytometry, coupled with live cell imaging as part of the product acceptance, but by similar, Shakespeare says. (e.g., Incucyte, Sartorius), enhances the eliminating options early, it is only neces- Understanding the innovator bio- breadth of information that is collected sary to run a full analytical evaluation on logic is also critical to understanding and allows for more informed decisions to the strongest candidates,” Madia says. the CQAs of the biosimilar product, be made faster, he explains. Shakespeare also notes. Understanding Other recent analytical innovations MINIMIZING RISK the innovator CQAs allows the biosimilar include capillary electrophoresis tech- The most common application for anti- developer to determine the quality tar- niques, which have replaced slab gel tech- body titer is in determining concentration get product profile (QTPP) design space. niques, resulting in assays that have high in the bioreactor tank at the end of a cell Design-of-experiment software (e.g., resolution, are highly reproducible, and culture run, Madia emphasizes. Once a Umetrics software, Sartorius) enables bio- are applicable to a wide range of pro- process moves to production, current ana- manufacturers to monitor the production tein molecules—not just immunoglobu- lytical tools are too large or complex to be process and track whether certain biosim- lins and biosimilars. “The use of capillary co-located near the tank or in the manu- ilar CQAs are drifting, allowing them to isoelectric focusing (cIEF) and capillary facturing suite, she explains. respond accordingly. electrophoresis sodium dodecyl sulfate “During the crucial transition from “Being able to monitor different (CE–SDS) techniques are now almost upstream to downstream purification, aspects of a biosimilar production in universally applied for CQA determina- manufacturing teams require the final real-time, such as binding and function, tion, stability studies, and lot release test- enables you to control CQAs and mini- ing,” Shakespeare says. Contin. on page 47

www.biopharminternational.com July 2020 BioPharm International 33 Analytics

Detecting Microbial Contamination in Bioprocessing Safeguarding against microbial contamination requires rapid detection and innovative technology.

FELIZA MIRASOL

uarding against microbial contamination remains a “All three exist within upstream and downstream bio- challenge for biomanufacturers, particularly in the pharmaceutical manufacturing and present difficulties to G purification steps of protein therapeutics. From the safeguarding against microbes. Controls are required to limit integrity of filtering processes to the aseptic fill/finish of the the introduction of microbes from cell lines, raw materials, end product, each step must be optimized to prevent con- packaging, environment, equipment, utilities, workflow, and tamination as well as remove microbial contaminants. personnel,” Lopolito says. Despite there being established validated cleaning processes, However, a reduction in personal interaction with product there still remains demand for higher purity and increased ste- through isolators and restricted access barrier systems, as rility assurance in biopharmaceutical production. This means well as more efficient cleaning and disinfection programs, biomanufacturers may be required to reassess their procedures significantly limits the introduction of extrinsic microbes and technologies as effective microbial contamination control Lopolito adds. “The key is to understand the microbial in biomanufacturing is a critical requirement. hazards throughout each process step and to continuously strive to reduce the highest risk items. The risks may be SAFEGUARD AGAINST CONTAMINATION compounded as the equipment and facilities age,” he notes. Safeguarding against microbial contamination faces inherent challenges in all stages of biomanufacturing because THE NEED FOR ASSAY DETECTION the manufacturing environment is conducive to microbial Analytical assays are a critical tool for detecting micro- growth, consisting of three critical conditions—moisture, bial contaminants as well as identifying them. Traditional nutrients, and other favorable factors, such as temperature, methods, such as bioburden testing and viable testing using pH, and osmolarity, points out Paul Lopolito, technical ser- contact (RODAC) plates, settle plates, and swabbing, ade- vice senior manager at STERIS. quately demonstrate microbial control, says Beth Kroeger, Gorodenkoff/Stock.Adobe.com

34 BioPharm International July 2020 www.biopharminternational.com Analytics

technical service senior manager, idation or process validation to prove ASSAY INNOVATIONS STERIS. Newer microbial detection the process is robust enough to clear Innovations in analytical assays and methodologies with rapid results, how- any microbial issues,” Kroeger adds. bioprocessing technologies offer better ever, are becoming more reliable. In Kroeger also recommends that items capabilities for maintaining a sterile some instances, organoleptic means entering the cleanroom and, ultimately, bioprocessing environment. “There has may detect contamination even before the Grade A/B area should be dou- been progress in single-use disposable the quantitative results are available, ble wrapped in a protective barrier and technology and development of con- Kroeger asserts. sterilized by autoclave, irradiation, or tinuous manufacturing systems, which An example of the benefits of inno- other similar means. In addition, as the reduce or eliminate operator interac- vative microbial detection technology items move from a controlled non-clas- tion and cross-contamination between is maintaining a visual examination of sified area to an aseptic processing area different products,” Lopolito says. the cell culture during a passage, or in or Grade A/B area, a layer of protective Additionally, there have also been bioreactor monitoring, and not relying wrap may be removed, or the wrapped developments in viable/non-viable par- solely on automation for cell counts item may be disinfected. Disinfection ticulate monitoring systems. “These with instrumentation. “Operators should include the use of a sporicidal alternative rapid microbial tests have should still be able to identify contam- agent that is sprayed on the items, or been difficult to integrate within the ination well before a sample is iden- by wiping the outer wrap as an item environmental monitoring programs tified as contaminated based on cell moves from one area to a stricter clas- because the industry standards have characteristics, culture conditions, and sified area via material airlocks (MALs). been based on older methodologies, growth attributes, such as oxygen con- “Typically, it is a combination of and direct correlation between new sumption and dissolved oxygen levels,” removal of barrier wrapping and wip- and traditional methods is difficult,” Kroeger explains. ing to transfer the materials into the Lopolito elucidates. Meanwhile, in addition to isolating aseptic processing area. Large data sets Further, regulatory agencies and the process or use of restricted access such as pressure, humidity, temperature, corporate initiatives encourage the barrier systems (RABS), the process and environmental monitoring should use of rapid methods for faster deci- itself should be safeguarded. This can be trended with the use of more auto- sion making and to prevent loss of be accomplished by having robust sys- mated environmental monitoring tech- product. “Perhaps this rapid tech- tems and procedures in place for con- niques to aid in timely risk assessments nology may be used to detect control of raw materials used in the process, regarding the process and the product,” tamination and divert potentially materials entering the cleanroom, Kroeger states. contaminated media to waste rather equipment design, and personnel train- “Equipment maintenance is also a than feed in a bioreactor, or to alert of ing and management, notes Kroeger. crucial practice to ensure reliability. a change in environmental conditions “A material review board should Routine maintenance activities, such that would be unfavorable to process- approve raw materials used in the as passivation and derouging, may be ing,” Kroeger says. process and establish suitable micro- necessary to keep equipment in opti- In terms of future innovation, there bial specifications. Raw materials mal condition and not contribute to is always a need for fast and reliable should be assessed during process microbial contamination. Advances prescreening test methods for vari- validation using multiple lots and/or in formulated alkaline detergents and ous microbial and chemical hazards. bioburden results if the specification acid detergents can also be effective The control strategy often involves is anything other than 0 colony-form- in microbial and biofilm removal. In screening or evaluating all materials ing unit (cfu)/mL. If the process addition, integration of equipment introduced, testing for the absence or capability is not able to remediate a from vendors within the aseptic area quantity of microbes, and designing microbial challenge, it is better to find has advanced over the past 10 years, critical process, such as equipment that out in cleaning or process valida- providing more options and effectual cleaning or facility disinfection, to mit- tion and not during routine manufac- connections versus the sterile welds of igate the risk. Thus, the need for fast turing,” Kroeger explains. the past,” Kroeger emphasizes. and reliable prescreening is crucial. “An example of this is chromatog- “Finally, operators should be trained “Effective use of prescreening tools raphy resin. If the specification on the periodically in aseptic technique and on may expedite results and reduce over- certificate of analysis is < 100 cfu/mL basic microbial control with an under- all testing. Positive prescreening test and lots having 0 cfu/mL are tested, standing of how contamination can results may then be confirmed using ensure a lot that challenges this speci- enter the environment and the prod- traditional test methods,” Lopolito fication is included in the cleaning val- uct,” Kroeger adds. concludes. ◆

www.biopharminternational.com July 2020 BioPharm International 35 Quality/Regulations

Succeeding With OOS and Root-Cause Investigations Investigating the root causes of OOS conditions, product defects, and batch failures requires a systematic, thorough approach.

JAMES P. STUMPFF

nvestigations, deviations, complaints, and laboratory inves- to pharmaceutical manufacturers in 2019 for inadequate tigations are critical to assessing the compliance of a com- responses to quality failures (3). Regulatory citations offer I pany’s quality systems. Deficiencies in the timeliness and insights into failures that many pharmaceutical manufactur- thoroughness of these investigations can jeopardize a compa- ers make when it comes to investigations. Consider an FDA ny’s compliance status with potentially serious consequences. warning letter (4) issued in 2013. FDA inspectors cited the This article describes a challenging biopharmaceutical inves- company for inadequate investigation of critical deviations tigation into a quality control (QC) test deviation. In this and batch failure. The company had manufactured a number case, thorough evaluation involving a multidisciplinary team of lots of an API for more than one year, but six of those determined root cause, suggesting strategies that pharmaceuti- lots were severely contaminated with the bacterium, Bacillus cal companies can use to probe beneath the surface to improve thuringiensis, and a number of other microbes including laboratory investigations and overall quality systems. Acinetobacter radioresistens. Although contamination levels had exceeded the compa- REQUIREMENTS FOR INVESTIGATIONS ny’s action limit, FDA inspectors found, the manufacturer Whenever product defects, batch failures, process deviations, did not thoroughly investigate the root causes of the con- or out-of-specification (OOS) situations come up, regu- tamination, and did not assess the potential impact on final latory agencies require that pharmaceutical manufacturers product, including the ability of its manufacturing process to determine the root cause of those problems, using quality clear any non-host cell contamination. risk-management and other methods (1,2). Corrective and preventive actions must be taken in response to investiga- JAMES P. STUMPFF, RPH, is principal consultant with Parexel tions, and their effectiveness monitored and assessed. As International, [email protected]. shown in Table I, FDA issued 264 Form 483 citations littlewolf1989/Stock.Adobe.com

36 BioPharm International July 2020 www.biopharminternational.com Quality/Regulations

Solving Pharma’s Quality Unit Identity Crisis: 483s and Warning Letters Point to Inadequate Quality Oversight

Warning letters, notes, and data from regulatory in- Table I. Top 10 problem areas (Source: FDA). spections offer important insights into areas where FDA 483 US Code of Federal Regulations pharmaceutical manufacturers can improve quality Observations (CFR) Section control and assurance (1–3). An analysis of FDA current 2017– March 2020 good manufacturing practices (CGMPs) inspection cita- CFR Title 21, 211.22–Responsibilities of 738 tion data for finished drug products from 2017 through quality control unit March 2020 highlights negative patterns and suggests CFR Title 21, 211.160–Laboratory 674 ways to reduce risk and improve compliance. An ex- controls: general requirements amination of warning letters issued from 2017–2019, CFR Title 21, 211.192–Production 527 as well as 2020 warning letters, suggest a shift in reg- record review ulatory focus during the COVID-19 pandemic. Overall, CFR Title 21, 211.67–Equipment 512 data suggest the need for senior executives to better cleaning and maintenance define the goals and missions of quality departments CFR Title 21, 211.68–Automatic, 428 and to improve overall staffing and support. mechanical, & electronic equipment. FDA data show that between 2017 and 2020 (Figure 1), CFR Title 21, 211.100–Written 424 the average monthly number of FDA 483 observations procedures; deviations. trended downward from 241 in 2017 to 204 in 2018 CFR Title 21, 211.165–Testing and 368 and 173 in 2019. The lowest monthly numbers were release for distribution observed in January 2019 (83) and December of 2019 CFR Title 21, 211.166–Stability testing 313 (90), while the maximum number of observations in a CFR Title 21, 211.42–Design and single month, 360, was observed in March 2017. 308 construction features Figure 1. FDA Form 483 citation trends, 2017–2020 (Source: FDA). CFR Title 21, 211.194–Laboratory records 302

400 2017 2018 delineating responsibilities of quality control, contrib- 2019 350 2020 uted the most (71%). CGMPs require that manufacturers

300 have clear quality unit responsibilities and procedures in writing. The second most-cited section was CFR Title 250 21, 211.160, which discusses general requirements for 200 laboratory control.

150 Of facilities were cited by FDA in 2019 for 21 CFR Pafrt211.22 deficiencies, 64% also received a higher 100 number (>5) of 483 observations, highlighting that 50 weakness in a quality unit’s responsibility and its scientific 0 capability can be a business risk. Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 483 Citations A review of warning letters issued by FDA’s Center for Drug Evaluation and Research (CDER) from 2017– Observations totaled 2889 in 2017, 2453 in 2018, and 2019 showed the number of cGMP compliance-related 2087 in 2019. The average number of observations warning letters for finished drug product sites went received per site was 4.4 in 2019, compared with 4.7 down in 2019. In the second quarter of 2020, CDER was in 2018 and 4.9 in 2017. The first quarter of 2017 saw posting many warning letters, primarily to websites, 757 observations—the highest number recorded for “unapproved and misbranded products related to during this time period—while the fourth quarter of coronavirus disease 2019 (COVID-19).”, The number 2019 showed 409, the lowest number. The top 10 FDA of warning letters for 2020 numbers may not reflect a 483 observations during 2017–2020 and the specific typical year’s course. However, inspection data may be US Code of Federal Regulations (CFR) sections seen as a reminder that strong quality departments are involved, are summarized in Table I. It is interesting crucial to reducing compliance risks. to note that the quality unit’s direct functions and References responsibilities — Par ts 211.22, 211.160, 211.192, 1. FDA, “Warning Letters and Notice of Violation Letters to Pharma- 211.100, 211.165, 211.166, and 211.194—made up 73% ceutical Companies,” www.fda.gov. of the top 10 observations. 2. FDA, “Inspection Observations,” www.fda.gov. Within the most cited section, CFR Title 21, Part 211.22, 3. FDA, “Inspection Citation Dataset,” www.fda.gov. subsection (d), which pertains to failures in clearly —Ajay Pazhayattil is an independent consultant. SIDEBAR FIGURE AND TABLE COURTESY OF THE AUTHOR BASED ON FDA DATA.

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Table I. FDA 483 citations in 2019 due to insufficient investigation (Source: FDA). TIMELINES AND Number of Regulation Issue Regulator comments LAB INVESTIGATIONS citations Regulations and guidance documents There is a failure to thoroughly review [any unexplained do not specify a set timeframe for com- 21 Code Investigations of of Federal discrepancy] [the failure of a batch or pleting OOS, root cause, and other discrepancies, 167 Regulations any of its components to meet any of investigations, although many compa- 211.192 failures (CFR) its specifications] whether or not the nies use the 30 business days specified batch has been already distributed. in the Barr Laboratories legal decision Written records of investigations of 1994 (6) as a guideline. Currently, into [unexplained discrepancies] Written record [the failure of a batch or any of its it normally takes companies anywhere 21 CFR 211.192 of investigation 34 components to meet specifications] from 30 to 45 days to complete an incomplete do not [always] include the OOS or other investigation in the phar- conclusions and follow-up. maceutical industry. Written records are not [always] When an OOS occurs, it must made of investigations into No written record be investigated in the laboratory. 21 CFR 211.192 [unexplained discrepancies] [the 26 of investigation Requirements for conducting labo- failure of a batch or any of its components to meet specifications]. ratory investigations have been set by the United Kingdon’s Medicines and Investigations of [an unexplained discrepancy] [a failure of a batch or Health Care Products Regulatory Extent of any of its components to meet any Agency (MHRA) and FDA. Most discrepancy, of its specifications] did not extend 21 CFR 211.192 22 companies aim to complete the initial failure to [other batches of the same drug Phase I lab investigation within 10 days. investigations product] [other drug products that may have been associated with the Phase I of the investigation is specific failure or discrepancy]. commonly conducted by QC labora- Drug product production and tory personnel and management, and control records, are not [reviewed] commonly includes the completion Quality control [approved] by the quality control of a checklist and an interview with 21 CFR 211.192 unit review of unit to determine compliance with 15 the analyst who performed the work. records all established, approved written procedures before a batch is Generally, this interview should occur released or distributed. as soon as possible to ensure that he or she recalls clearly what occurred during Instead, regulators found, the com- lowed during an OOS event or other the analysis. Phase II of the investiga- pany had responded to the problem by product or process failure. In 2019, for tion typically involves additional per- increasing its use of a sporicidal agent example, European Medicines Agency sonnel (e.g., from QC, quality assurance in its clean rooms but did not even (EMA) regulators cited a manufacturer [QA], and manufacturing departments) attempt to verify the effectiveness of the for inadequate corrective action and and expanded investigations. During sporicidal treatment or cleaning proce- preventive action (CAPA) and SOPs this stage, sampling procedures, sample dures before resuming API production. (5). Although the company’s CAPA management and the manufacturing Subsequently, the company per- plan met regulators’ requirements in batch record will be reviewed. formed additional tests, which it used to some areas, it did not address the han- The following case study, which justify releasing the API for additional dling of OOS events, and failed to describes an actual OOS investigation, processing. However, it failed to assure respond adequately to two important demonstrates the right way to approach the absence of other contaminants. In problems that regulatory inspectors the challenge of determining root cause short, the company had failed to iden- had found at the facility. and taking appropriate corrective action. tify underlying root causes of these Regulators then determined that In this case, an established biolog- problems, and, thus could not correct the company’s SOPs for investigating ics manufacturer that produces both them or demonstrate that it could pre- OOS conditions were not sufficiently liquid and lyophilized products, had a vent them from recurring in the future defined. SOP descriptions were not deviation occur after using an estab- Other regulatory citations show the clear and complete, they found, so that lished bioburden test, membrane filtra- importance of clear and complete stan- they could not ensure that OOS situation, for final fill load sampling. The dard operating procedures (SOPs) that tions would be adequately handled in manufacturer had used this method spell out the steps that must be fol- the future. without incident for years. According

38 BioPharm International July 2020 www.biopharminternational.com Quality/Regulations

to procedure, the specification for the nation had not been introduced during during the bioburden test. This was a final fill load sample had been set at ≤1 bag assembly. An interview with the first-time event despite many years of colony forming units (CFU)/10 mL. QC analyst then confirmed that the bioburden testing with the established However, 3 CFU/10 mL was observed bioburden test had been performed procedure and personnel. QC analysts in the trypticase soy agar media incu- correctly, according to the procedure. To and supervisors had not recognized the bated in an anaerobic condition. The complete investigation into root cause, deficient gowning procedure. microorganism was identified as the SOP for the bioburden tests was The usual checklist and analyst inter- Propionibacterium sp. reviewed, including gowning and asep- view failed to identify the root cause. tic procedures in the biosafety cabinet. QA does not typically conduct routine PINPOINTING ROOT CAUSES This is where the problem was found. oversight of laboratory operations as A laboratory investigation report As it turned out, the procedures did not they do for aseptic manufacturing oper- was initiated, and the investigational require face covering, which could allow ations. QA internal audits had not iden- tests and retest were performed using contamination to take place. tified this deficiency either. Phase II of remaining sample and retained sample. The exposure of the operator’s face the investigation involved more, and a There was no microbial growth in either likely occurred during the test when more diverse group of, specialists, who sample. To confirm that results of the the operator adjusted safety googles. brought their knowledge to the inves- retest were credible (the retest had been Thus, the most probable root cause tigation. They reviewed the manufac- performed more than 195 hours after for the bioburden test OOS result was turing process and event, which led to sampling), a hold-time study for 195 found to be a deficient gowning proce- the hypothesis that the most likely root hours was performed. However, this dure. Phase II investigation tests were cause was sample contamination. study failed to recover results, and was run as follows: Lab procedures were reviewed again declared invalid. Because there were • Re-performing the hold-time with the additional investigational staff no confirmed laboratory errors and the study to confirm the hold time for involved, and the root cause identified. investigational test result was not valid the retest result. The hold time for Finally, a PowerPoint presentation was due to hold-time study failure, a devia- 195 h could not be confirmed, so prepared to make this investigation easy tion was initiated. the retest could not be validated. to explain to the regulatory authorities. In this type of situation, the entry of • Simulating the sample-hold condi- A number of lessons were learned any microorganisms into the sampling tion study to reproduce the stored from this event. For one thing, supervi- process is most likely to occur, either conditions before the sample sors and QA should spend time watch- during the procedure (when the sampling was tested. In this case, recovery ing critical operations in the lab just as bag and ultrafiltration/diafiltration [UF/ of the microorganism was main- they do in production. DF] pool bag are assembled) or as a result tained. The microbial hold-time It was also determined that of inadequate sampling procedures. study (168 h in 2–8 °C condi- multi-disciplinary teams should be Review of relevant SOPs confirmed tions) did not allow the recovery used for investigations and internal that sampling procedures had been of contaminated microorganisms, audits and QA staff included in Phase properly established. Also, considering but in a short period of storage, I investigation for OOS investigations. that the microorganism involved was Propionibacterium sp. could be The use of isolators should also be a human- derived anaerobic bacteria found through the bioburden tests. considered, to further reduce the like- and that the closed manufacturing pro- • Performing a QC operator moni- lihood of sample contamination occur- cess strictly prevented the process from toring study to test three QC ana- ring in the future. coming in contact with the outside lysts, including the first tester to environment, it was difficult to say that determine whether microorgan- REFERENCES 1. EU, EudraLex Volume 4, Chapter 1, the microorganism had been introduced isms could have been introduced Pharmaceutical Quality during production. during the test. System (Jan. 31, 2013). Fishbone root-cause analysis ruled The identical microorganism 2. US CFR Title 21, Part 211.192 (Government Printing Office, Washington, DC) 162. out personnel, equipment, the envi- (Propionibacterium sp.) was found from 3. FDA, “Inspection Observations,” ronment, material or measurement as the same analyst. Only Staphyloccus sp. www.fda.gov. potential root causes of the deviation. were found from the other analysts, so 4. FDA, Warning Letter, CMS #352798, March 22, 2013. The four operators who had performed contamination could have been due 5. EMA, Inspections Data, eudragmdp. the sampling were interviewed, and it to the microorganism from the QC ema.europa.eu, accessed June 10, 2020. was determined that the sampling had operator. The procedure was revised 6. United States vs. Barr Laboratories, ◆ been done properly and that contami- to include the wearing of a facial mask 812 F. Supp. 458 (D.N.J. 1993).

www.biopharminternational.com July 2020 BioPharm International 39 Operations

Minimizing Contamination During Biopharma R&D The right approach to biological safety cabinets, and collaboration between engineers and those who will operate the equipment, is crucial to preventing cell-culture contamination.

DAVID PHILLIPS ell-culture contamination is a common challenge process. This article summarizes the key criteria for assessing facing cell-culture laboratories, with consequences BSC performance so that it prevents contamination. C that range from minor to devastating. Every effort must be made to protect the integrity of cell cultures, both for THE IMPLICATIONS OF the experiments that are being performed in the laboratory, CELL CULTURE CONTAMINATION as well as to prevent problems later on, downstream. When The wide variety of potential biopharmaceutical contaminants selected and designed correctly, biological safety cabinets and their sources show just how vulnerable cell-culture (BSCs) play a critical role in protecting cell cultures, laboratories are. Contaminants may be classed as biological laboratory personnel, and the environment. (e.g., bacteria, fungi, mycoplasma, viruses), chemical (e.g., Selecting a BSC requires careful consideration of many endotoxins, detergent wash residue, trace concentrations of factors, including the performance criteria important to the metal ions, chemical disinfectants), or physical (e.g., fluorescent laboratory in which it will be used, and the service support and ultraviolet light, radiation, vibration) and can be introduced that the vendor will provide following installation. In recent in a variety of ways (e.g., as airborne particles, infected cell years, BSC technology has improved significantly, and vendors lines, contaminated water, or during routine maintenance or are offering more features that allow users to make better operating procedures) (1). Some contaminants require a very decisions, such as enhanced monitoring features (e.g., interfaces proactive approach to detection and management, such as that provide a visual depiction of airflow in real time) to help operators maintain an aseptic laboratory environment. DAVID PHILLIPS is senior global product technology specialist for However, the efficacy of a BSC is only as strong as its Thermo Fisher Scientific’s Clean Air division. weakest link in a complex and multi-faceted operating ryanking999/Stock.Adobe.com

40 BioPharm International July 2020 www.biopharminternational.com Operations

regular quarantine and testing to help an integrated approach. Best practices used. For example, some laboratories avoid the introduction of mycoplasma- from the quality control field must be require additional connections for the infected cell lines. The type, extent, and applied to reduce or eliminate variation BSC interior, such as power and data, or frequency of contamination determine in output. In practice, this requires piped-in media such as combustible gas. the severity of the consequences, which examining every movement and As cramped conditions compromise drain resources, whether time, samples, process and taking steps to support the processes and contamination protection, or reagents. Repeating work and consistent execution of those processes. laboratories with extensive equipment reinvesting in those resources exacerbate For example, designated spaces might assets would benefit from larger BSCs. losses, and subsequent experiments be marked out for specific items in a While the most common width of a typically become more costly as supply tray, so the operator can quickly BSC is approximately four feet, other additional precautions are incorporated confirm that he or she has everything sizes can accommodate smaller spaces, into their procedures. However, these required to perform the task at hand. more equipment, or environments in costs pale when compared with the It is easy to underestimate the benefits which two people work concurrently in long-term implications of undetected of these simple steps, but there are one space. contamination, where misidentified cell significant benefits to supporting In addition to performance criteria lines and erroneous data can compromise the consistent execution of precise and monitoring features, safety is reproducibility and lead to paper processes. Simplified workflows help another important component to retractions (2). limit operator distractions, which is consider. Laboratories working with Contamination control is complex and particularly important to maintaining volatile chemicals or gases may require challenging, particularly when laboratory an aseptic environment. the installation of a canopy/thimble environments are constantly changing, Traditionally, the industry has connection to the top of their BSC, with various components being replaced relied heavily on regular BSC testing to allow exhaust to be directed to a based on seasonal changes in building and certification following purchase designated channel. Specialized BSCs ventilation requirements. Efforts to and installation in order to respond are available for those who must protect cell cultures and experiments to gradual filter loading. With earlier contain dangerous substances, such as must, therefore, be multidimensional and models, the gradual build-up of those preparing hazardous drugs. thorough, and BSC use is no exception. contaminants captured in the filter BSCs protect the product, environment, would result in a subsequent reduction INFRASTRUCTURE and operator through two primary in air velocity, compromising the REQUIREMENTS mechanisms of containment: precise BSC’s ability to capture contaminants. To ensure optimal airflow, filters control of airflow and high efficiency Design efforts have been directed and other systems must be validated filtration, which purifies the air that at overcoming this threat to precise and shown to function as vendors enters the BSC, maintaining an air airflow and improving monitoring claim they do. BSC testing and barrier between operators and their work. systems. Modern BSC design features certification must be performed at High efficiency particulate air (HEPA) include: the prototype stage in a recognized filters remove microscopic particles from • Fan and filter systems that validation laboratory and then again the air, which is then recirculated within automatically adjust fan speed to at the manufacturing factory where the BSC and discharged elsewhere, compensate for filter loading the cabinet will be used. This practice depending on the design—into the room • Improved filter design, reducing increases the likelihood that the BSC or a building’s exhaust system. In Class II the incidence of leaks found in will remain effective in preventing cell- Type A2 BSCs, the most common class, certification tests culture contamination, because it will approximately 70% of the air is recycled • Airflow alerts that signify to the permit any design or manufacturing and pushed back into the BSC work area; operator if air velocity moves issues to be flagged early. Once the the remaining 30% is exhausted through above set thresholds BSC is installed in a laboratory, testing the HEPA filter. • Screens that clearly communicate and certification will be implemented whether a window needs to be by specially trained inspectors whose INTEGRATED repositioned or if the air barrier is experience and skills are regularly APPROACH NEEDED keeping room contaminants out. assessed, before use and then at least In addition to understanding airflow When selecting a BSC, it is annually thereafter. dynamics, the use of BSCs to prevent important to consider the specific Prototypes of each BSC design contamination involves the thoughtful processes and applications in the are assessed according to NSF/ANSI application of scientific knowledge and laboratory in which the cabinet will be 49 (National Science Foundation/

www.biopharminternational.com July 2020 BioPharm International 41 Operations

American National Standards Institute actions directly influence airflow Processes within the BSC should 49) (1), an internationally recognized and the movement of contaminants. be optimized by a process designer standard that assesses quality, Taking an active approach to BSC together with an operator or technician compliance, and safety. Assessment operation, the operator should that will be performing the required examines a wide range of parameters, arrange for regular certification of processes. The process designer must including equipment design, the cabinet and ensure he or she develop a clear understanding of construction, performance, product and has understood the test results— what is needed for the laboratory’s environmental protection, reliability, in particular, those which might operations and procedures and create a durability, cleanability, noise level and require that procedures be altered or detailed process workflow so that every illumination control, vibration control, improved (3). This active approach operating step has been optimized. and electrical safety (2). must be intertwined with various Activities, equipment, and resources Once the individual BSC arrives elements of expertise, including should be arranged so the workflow in the laboratory, it must be certified the physical operation of the BSC sequence can be followed consistently on site and periodically thereafter machinery, interpretation of alarms, using aseptic best practices. to ensure it is operating as required and an understanding of the controls, Streamlining workflows reduces and that it functions well within displays, and principles of operation. the room for error and reliance on that specific laboratory. Although Often, problems with BSCs arise the operator’s attention and should be a thorough assessment process from incorrect assumptions and poor used to examine every aspect of the can help assure that the BSC will practices. In some cases, staffers process. For example, in the case of perform properly, the responsibility may not realize the consequences of decontaminants, the process designer for performance and cell culture actions, such as silencing an alarm, would consider the type, bottle size, protection ends with the buyer. which can prevent understanding of and frequency of preparation required Following design validation and risks, preventing identification of any to meet lab needs. In the end, system performance verification at the underlying root causes of potential efficacy is only as strong as its weakest manufacturing facility and periodically contamination. Other examples link, and robust manufacturing, at the laboratory, the performance of poor practices include failing to validation, installation, and service of the BSC and level of cell culture arrange materials optimally within infrastructure is the foundation protection will largely depend on the BSC, and too many quick and required for effective laboratory correct use by system operators. unnecessary movement of hands and contamination control. arms near the equipment, which call OPERATOR REFERENCES for limiting the number of times users 1. NSF, NSF/ANSI Biosafety Cabinetry COMPETENCE IS KEY reach in and out of the BSC. Another Certification, nsf.org (2020). 2. C.K. Lincoln, M.G. Gabridge, Method Competent and knowledgeable frequent cause of problems is failing Cell Biology 57, 49–65 (1998). BSC operators are critical to to wipe down the cabinet’s interior 3. S. Horbach, W. Halffman, PLOS ◆ contamination control, because their surfaces before commencing work. One, 12 (10) (2017).

Investigating an OOS in a Biosafety Cabinet

Determining the root cause of out-of-specification However, when the standard operating procedures (OOS) and other problems requires a careful, deduc- for bioburden testing were reviewed, problems were tive approach and a clear understanding of processes. found with gowning procedures in the lab, which A case study presented by Parexel Principal Consultant allowed microbes to enter the process stream when Jim Stumpff (see feature on p. 36) also emphasizes the a CQ operator adjusted his safety googles. In this need for multidisciplinary expertise. The study exam- case, Stumpff writes, quality assurance staff had not ines an OOS event that occurred in a biosafety cabinet suspected gowning procedure problems because at one biopharma company. The problem occurred they focused on manufacturing, and did not routinely during bioburden testing and final fill load sampling monitor lab operations. Phase 2 of the lab investigation via membrane filtration. Higher than specified levels of into root cause, which involved a more diverse group of the bacterium, Propionibacterium sp., were detected. specialists, allowed the reason for the deviation to be The test had been used for years without incident. found and addressed. Risk analysis had ruled out personnel, equipment, the — Agnes Shanley environment, material, or measurement as root causes.

42 BioPharm International July 2020 www.biopharminternational.com Outsourcing

Contractors Balance Increased Demand During COVID-19 The COVID-19 pandemic has created a rise in demand for R&D and a shift in focus for some contract organizations.

SUSAN HAIGNEY

he first half of 2020 will be remembered for the rapid president, commercial marketing and customer solutions at spread of the SARS-CoV-2 novel coronavirus. As the West Pharmaceutical Services, some trends have been observed, T bio/pharmaceutical industry raced to develop vaccines including delays in clinical trials themselves, development pipe- and treatments, drug companies looked for ways to balance line reprioritization, and finding new ways to connect to patients. the demands for pandemic-related research and develop- Wilbert Frieling, corporate senior vice president, global dis- ment, while maintaining ongoing development projects for covery services at Charles River, has seen the shift in focus to diseases and conditions. COVID-19 treatments push work to contract research orga- The urgency of new research programs, combined with nizations. “This boost of directly COVID-related work has altered work environments due to social distancing require- been absorbed by the flexibility and capacity inherent to CROs. ments, made contract service providers a viable option for many As volume in the market fluctuates, CROs are able [to] easily bio/pharma companies. These contract research organizations accommodate increases of work in a short time frame. Also, of (CROs), contract development and manufacturing organizations course, during this time, other work hasn’t stopped. So, we’ve (CDMOs), and contract manufacturing organizations (CMOs) made a concerted effort to accommodate new projects while also faced the challenge of managing existing workloads, chang- maintaining existing programs for other indications,” says Frieling. ing needs of clients, as well as rapid turnaround to address Some non-essential clinical study visits stopped or were pandemic concerns. Impacts of the pandemic on the contract delayed during the pandemic because of patient reluctance services industry—as well as the response—has been varied. to travel and local restrictions, says Michael Brooks, president, Covance Clinical Development and Commercialization R&D, CLINICAL TRIALS, AND COVID-19 Solutions. “The business has experienced customer-initiated trial While the long-term impact of the pandemic is too early to delays, limitations and access to certain trial sites, and interrup- weyo/Stock.Adobe.com understand or predict, says Cindy Reiss-Clark, senior vice tions to the supply chain,” says Brooks.

www.biopharminternational.com July 2020 BioPharm International 43 Outsourcing

But Brooks also sees a healthy bio- The urgency of new their customers’ products. “For example, pharma drug development market. “In well before the COVID-19 outbreak, fact, COVID-19 is likely to strengthen research programs Catalent announced that it was to spend the fundamentals of drug development $200 million to expand capacity for bio- operations to enable more effective use of made contract logics drug substance in Madison, WI, data insights, digital solutions, and better and fill/finish capabilities in Bloomington, patient engagement,” Brooks states. “As service providers IN. Such investments are now helping to countries and regions begin to reopen, accelerate availability of manufacturing we expect impacted non-COVID-19 a viable option for capacity,” he says. clinical trials to resume, potentially with more focus on decentralized trial solu- many bio/pharma OPERATIONS ADJUSTMENTS tions, which can include digital capabil- The pandemic has changed the way ities and mobile nurses/phlebotomists. companies. many companies in the pharmaceutical These trials reduce the need for patients industry conduct business. Contract orga- to travel, which for many is a burden to Inhalation specialist, Vectura, has seen nizations and suppliers have been adjust- trial participation.” an increase in formulation and analytical ing their practices as they also protect services during the pandemic, according their employees, with many implement- DEVELOPMENT AND to Mark Bridgewater, chief commercial ing remote processes. MANUFACTURING INCREASES officer, Vectura, including an increase in “We have been impacted in our abil- Contract manufacturers are also seeing demand for dry powder inhaler and pres- ity to support our customers with tradi- an impact. CDMO Recipharm has seen surized metered-dose inhaler expertise tional face-to-face meetings, so we have an increase in demand for the produc- and technology platforms, he says. embraced technology to stay connected tion of antibiotics to treat secondary The pandemic’s impact on the com- virtually. Because West is a global orga- infections in COVID-19 patients, says pany’s overall business has not been as nization, our manufacturing operations Erik Haeffler, vice-president, manufac- great as anticipated, however, Bridgewater and supply chain efforts are aligned with turing services and head of sustainability. explains. “Recruitment to clinical trials local government guidelines,” says Reiss- “To meet this demand, we are working was initially impacted, but we are seeing Clark. “We continue to work closely with hard to ensure our facilities can con- a move back towards normality. Priorities our customers to mitigate any impacts to tinue to operate while at the same time have, of course, changed to meet the our ability to deliver goods and services. protecting the safety of our employees,” immediate needs of patients, but it is To date, we have had minimal disruption he says. The company is manufactur- amazing how robust our society has due to the pandemic.” ing antibiotics in four facilities, taking proven in dealing with the COVID-19 Catalent has restricted visitor access to steps to increase the safety stock of impact. The industry’s resilience has been the company’s facilities, limited employee API and raw materials, evaluating shift truly outstanding.” travel, and implemented remote working. patterns for existing team members, Catalent, which has facilities in China, “But the pandemic has proven again that and recruiting more personnel where Italy, and other areas affected by the ‘necessity is the mother of invention’, and needed. “Our safety protocols have also pandemic, took steps to track the pan- we are trying new things every day,” says undergone enhancement, with addi- demic and interpret how it may affect Berger. “For example, we have rolled out tional risk assessment undertaken and the company’s business by setting up a new wearable camera technology to over the introduction of workflow adjust- dedicated management team. “We have 30 facilities in just weeks, enabling our ments to maximize social distancing,” also had to respond quickly, innovating customers to do virtual plant visits and says Haeffler. and adjusting our processes and ways audits, collaborating with us in a very He expects the demand has reached of working to help vaccine innovators innovative, secure, and interactive man- its peak, however, and hasn’t seen an around the world to move their COVID- ner, as well as allowing our sites to bring impact on the company’s normal oper- 19 projects forward with greater speed, together expertise and support from the ations because their manufacturing of enabling the ingenuity, technology, and global network.” beta-lactams and cephalosporins occurs manufacturing expertise and passion of Charles River has moved to a vir- in dedicated plants. “While there have our people to come through,” says Elliott tual model when working with clients. been necessary changes to how our Berger, vice president and chief marketing “Before the pandemic, there was still a business is operating in terms of safety officer, Catalent. Proactive investments lot of personal contact, in-person project and distancing, our broader business made by the company have helped to discussions, and on-site audits. Now, we plans continue as normal,” he says. mitigate the impact of the pandemic on are leveraging all types of virtual con-

44 BioPharm International July 2020 www.biopharminternational.com Advertorial Product & Service Innovations

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Copy NO INDENT company picture here Body Copy NO INDENT Body Copy NO INDENT Services/InnovationsBody Copy NO INDENT Body Copy NO INDENT CatalentBody Copy Biologics NO INDENT supports the Body development Copy NO of INDENT biopharmaceuticals, and offers the following services: Body• Dev Copyelopment NO INDENT Body Copy NO INDENT Body• Man Copyufacturing NO INDENT Body Copy NO INDENT Body• Fil Copyl/finish NO INDENT Body Copy NO INDENT Body• Pac Copykaging NO INDENT Body Copy NO INDENT BodyOneBio Copy Suite NO can INDENT reduce timelines, Body Copyrisk, and NO complexity, INDENT Body• Ana Copylytical NO services. INDENT Bodyand draws Copy upon NO Catalent’s INDENT proven Body trackCopy record NO INDENT of Bodyprogressing Copy biologicNO INDENT drugs to Body market, Copy which NO includes INDENT over FacilitiesBody Copy NO INDENT Body Copy NO INDENT Body35 commercially Copy NO approvedINDENT products. CatalentBody Copy is headquartered NO INDENT in Somerset,Body Copy New NO Jersey, INDENT and its For advanced biopharmaceuticals, Catalent biologicsBody Copy business NO INDENT has operations Body in Copy both North NO INDENT America CellSubhead & Gene TherapySubhead is a full-serviceSubhead partner for andBody Europe. Copy NO INDENT Body Copy NO INDENT adeno-associatedSubhead2 Subhead2 virus (AAV) Subhead2 vectors and CAR-T BodyBiologics Copy NO development INDENT and manufacturing is immunotherapies,Body Copy NO INDENT with deep Bodyexperience Copy in NO viral INDENT vector undertaken at sites in Anagni, Italy; Bloomington, scale-upBody Copy and NOproduction. 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July 2020 BioPharm International 45 Outsourcing

nections for meetings, as well as virtual have to think about the total supply doses in a few months. This flexibility site audits. By these means, we have chain and capacity to make the doses and willingness to work in new and stayed close to our clients and contin- required for herd immunity. Everyone collaborative ways makes a big differ- ued to fulfill their needs,” says Frieling. will be needed.” ence,” he says. The company is also examining their According to Brooks, the pandemic Catalent is helping pharma and processes for working with suppli- has created a stronger relationship for biopharma partners prepare for antic- ers. “Our procurement team has been Covance and its clients, finding com- ipated demand by offering outsourced monitoring any changes very closely mon ground with the goals of patient capacity to complement in-house and helped significantly in sourcing safety and data integrity. “This has capabilities, Berger says. “To illus- the required supplies to keep the busi- also been true of regulators, and we trate this, we are currently helping a ness going. This combination of stay- have seen remarkably productive col- customer to prepare for large-scale ing close to our clients and managing laborations,” he says. “In addition, we commercial manufacturing of a vac- our supplies allowed us to continue to are collaborating with sites on critical cine candidate for COVID-19 in deliver for our clients,” he says. patient safety considerations, evaluat- Bloomington, and we are partnering Recipharm is also using a virtual ing the use of Covance and third-party with a leading clinical-stage messenger model, providing virtual access to its technology to help research sites more RNA (mRNA) medicines and vac- facilities so customers can audit and effectively manage trial activities, and cines company in Madison to sup- inspect their services. “This initiative have deployed enhanced solutions port the expected manufacture of an will allow our customers to virtually for clinical trials and research sites to mRNA vaccine candidate against the experience our facilities and capabil- lessen the burden on patients, investi- SARS-CoV-2 coronavirus,” Berger ities, while simultaneously satisfying gational sites, and healthcare providers.” says. their need to review the robustness Frieling believes that outsourcing of our processes. While we are con- companies can play a key role in bat- FUTURE IMPACT tinuously monitoring the impact of tling the pandemic. “By beginning to The pandemic will drive an increase COVID-19 on all our worldwide outsource research programs, the indus- in the outsourcing of biologics devel- operations, we are also working hard try reduces their necessity for constant opment, at least in the short-term, to maintain our number one priority, on-site support, and places that require- says Haeffler, noting that “as vaccine which is to uphold our responsibilities ment on outsourcing partners, who are production increases, considerable to all our customers,” says Haeffler. equipped and capable to carry out those manufacturing capacity is going to be “Clearly, there has been no physical activities anyway, with expertise across required to meet the ambitious annual interaction,” says Bridgewater. “Due drug development. An increased reli- capacity targets for 2021 that are in diligence and audits have been virtual ance on outsourcing with a geographic the region of 1 billion doses.” or paper based. There has been a level spread will allow the biopharma indus- Short-term growth created by the of innovative resilience that people and try to better continue research under pandemic will increase as the devel- companies have adopted to continue to extreme circumstances like we’ve expe- opment, testing, and manufacturing of drive business forward.” rienced with COVID-19,” he says. these products ramps up, Haeffler says. “We think the industry has now He also believes there will be a future COLLABORATION realized that we have to realistically impact to the industry. “Spurred by DURING A PANDEMIC assess capabilities and gaps and work the current crisis, the bio/pharmaceu- With the health crisis creating an closely together to move projects for- tical industry is also likely to see long- all-hands-on-deck situation, a col- ward,” says Berger. “Catalent has gone term adjustments that will result in laborative approach between health to the extent of risking starting work increased measures being put in place authorities, regulators, pharmaceuti- before contracts were finalized and to handle the threat of future pandem- cal companies, and contractors will be signed, we have repurposed capacity ics,” he explains. “I would expect to necessary to develop and manufacture and equipment between programs, we see greater focus on the development effective and safe treatments. “I believe moved to purchase equipment avail- of more collaborative relationships, as it will take strong partnerships and able on the secondary market for the well as an increase in pharmaceutical a holistic approach to expertise and new programs outside the usual bud- companies looking for partners that resources in order to develop, man- geting and procurement cycle. We have can offer the rapid and flexible end- ufacture, and fill the vaccines for also created innovate contracting mod- to-end development and production distribution around the globe,” says els to account for those ‘at risk’, and processes necessary to speed products Reiss-Clark. “Planning is key. We if approved, we will need millions of to market in crisis situations." ◆

46 BioPharm International July 2020 www.biopharminternational.com Upstream Processing — Contin. flexibility and de-risking the supply ACKNOWLEDGMENTS from page 20 chain. The authors would like to thank the following people at Avantor for con- single-use components, and bioburden CONCLUSION tributing to the data used in this article: and endotoxin specifications on vali- Buffer and media preparation are vital Jungmin Oh, Tom Lee, Calvin Cheah, dated processes to manufacture these components of the mAb manufactur- and Andrew Kalinovich. concentrates are some of the necessary ing process, requiring significant efforts REFERENCES critical quality items. and time. Innovative approaches com- 1. BioPhorum Operations Group, They can ensure compliance with prising pre-weighed, ready-to-dispense “An Economic Evaluation of Buffer quality and regulatory requirements solid packaging systems, ready-to-use Preparation Philosophies for the Biopharmaceutical Industry,” and proper functioning of the pro- diluted buffers, and ready-to-use buffer BioPhorum.com, December 2019. cesses. Harmonization between ven- concentrates with in-line dilution or con- 2. N. Deorkar, “Enhancing Cleanroom QC and Efficiency Through dor test methods and raw material data ditioning systems can significantly help Direct Dispense Technology,” management will enable the real-time streamline bioprocessing operations. CleanroomTechnology.com, Oct. 11, 2017. release of buffer stocks and reduce Improving the efficiency and productiv- 3. Private communications/internal data 4. W. Hesselink, et al., “Implementation the risk of noncompliance. Reduced ity of buffer preparation and delivery oper- of Single-Use Powder Delivery Systems in-house testing will also allow for ations can significantly improve the overall in Continuous Bio-Manufacturing Processes: A Case Study,” PharmaiQ. increased on-site effectiveness. performance of mAb manufacturing. The com, accessed June 5, 2020. The added costs will be for the stor- most suitable approach will depend on 5. BioPhorum Operations Group, age of these premade stocks and their the manufacturing operation’s type, size, “NIIMBL-Biophorum Buffer Stock Blending System: a More Advanced management. In some cases, buffer and required flexibility. Continuing inno- Concept for Buffer Manufacturing,” vendors are addressing these storage vations in single-use technologies, process BioPhorum.com, December 2019. 6. ICH, Q7 Good Manufacturing and management issues by also offering analytical technologies, and in-line dilu- Practice Guide for Active local current good distribution practices tion will offer the potential for further Pharmaceutical Ingredients, Step 4 storage facilities, providing additional significant benefits in the future. version (ICH, Nov. 10, 2000). ◆

Analytics — Contin. from page 33 exchange on a UHPLC as well as by between the biosimilar and the innovator using cIEF on a capillary electrophoresis biologic, and that these discussions occur titer data in order to load the purifica- instrument. Both techniques will show prior to moving on to the next stage of tion columns. Once the tank is emptied the difference in charge profiles between biosimilar drug development. and the filtration step is complete, pro- the innovator and biosimilar, but when a BioAgilytix supports a single assay duction stops. Product is put in a hold- manufacturer is gathering evidence of the approach, such as an ADA assay or anti- ing tank while the team waits for results. biosimilarity of their molecule compared genic assay, to support biosimilar develop- Eliminating downtime while waiting to the innovator, there is strength in using ment. When developing an ADA assay, for titer could shave hours or days and multiple techniques that incorporate dif- the company advises building it in a sys- can also reduce the risk of moving prod- ferent instruments,” Shakespeare says. tematic, stepwise manner. This will sup- uct between areas. Using real-time titer Meanwhile, BioAgilytix, a bioanalyt- port the build-up of knowledge needed to streamline this transition can make ical lab service provider, encourages bio- to instill confidence in the assay’s ability a real impact at manufacturing scale,” similar developers to engage with their to detect antibodies against the biosimilar Madia says. chemistry, manufacturing, and controls and the innovator biologic. To that end, (CMC) team because it is important to the focus should be on reducing the risk REGULATORY ASPECTS discuss the analytical characterization of for potential variability and developing a In May 2019, FDA proposed a draft both the biosimilar and innovator bio- meaningful interpretation of data derived guidance for the development of biosim- logic and note any observed differences. from the assay (2). ilars (1) in which it outlines comparative The company has pointed out that differ- analytical studies for determining quality ences observed in an anti-drug antibody REFERENCES 1. FDA, Draft Guidance for Industry: criteria. The guidance itself recommends (ADA) assay, for example, “may reflect Development of Therapeutic Protein using orthogonal techniques and not rely- previously undiscovered analytical dif- Biosimilars: Comparative Analytical ing on one analytical method when ana- ferences between the biosimilar and the Assessment and Other Quality-Related Considerations (CDER, CBER, May 2019). lyzing biosimilars, notes Shakespeare. originator” (2). It is advisable that a dis- 2. T. Lester, “Questions on Immunogenicity “For example, consider analyzing cussion be held with regulatory author- Testing for Biosimilars Answered: Part 1,” the charge profile of a sample using ion ities if there are unexplained differences www.bioagilytix.com, Feb. 18, 2020. ◆ www.biopharminternational.com July 2020 BioPharm International 47 PRODUCT SPOTLIGHT

Pump Tubing System Lightweight Flow Controller AdvantaPure’s GORE The new Masterflex Flow STA-PURE Pump Controller from Cole-Parmer Tubing systems can measures, controls, and now overmold into logs fluid path information any manifold tubing after receiving input from assembly as its pump a flow sensor and then element. Designed for modifies the speed of the optimal performance pump to support a set flow in peristaltic pumps, rate or dispense volume. the system is made The device is designed for with platinum-cured silicone rubber and ePTFE for a the 33501-series Masterflex fluid transfer product that uses overmolding technology ultrasonic flow sensors and works with all Masterflex pumps. to provide a smooth contact surface for fluid flow. The flow controller is lightweight and lets users select the The tubing system can also lessen the risk of tubing size of the ultrasonic flow sensor connected to the controller ruptures in pumps, withstand operating pressures via an LED color touchscreen. Users also have the option up to 100 psig, maintain consistent flow rates, lower to choose from two separate modes: continuous flow or spallation, and support sterile fluid processing. volume dispense mode. In continuous flow mode, the flow controller varies the output to the to the pump to maintain the flow rate set point. In volume dispense mode, the device AdvantaPure runs the pump at a designated flow rate until the volume set www.advantapure.com point has been pumped, then it stops the pump operation.

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48 BioPharm International July 2020 www.biopharminternational.com Ask the Expert

Ask the Expert — Contin. place, as tools and technology vary for such a comparison. Whichever from page 50 considerably across organizations. It audit model is selected, it should is recommended to prepare a check- be based on a documented risk such as electronic quality manage- list with minimum requirements, assessment, and standard audit ment systems (e.g., to view stan- such as Internet upload and down- procedures should be developed in dard operating procedures [SOPs], load speeds, for each technology, and advance of the audit. deviations, electronic batch to share this checklist in advance records, video recordings from the with the sites to be audited. REFERENCES operational area, etc.). It is also important to consider 1. EMA, “Update to Guidance on As part of the audit preparation, in advance not only the feasibil- Regulatory Expectations in the Context of COVID-19 Pandemic,” Press Release, it is important to ensure that all ity of each type of audit, but its April 20, 2020. involved parties have suitable and respective benefits and limita- 2. FDA, Medical Device Single Audit compatible technological means in tions. Table I provides an example Program (MDSAP), FDA.gov. ◆

Table I. Benefits versus limitations of remote versus in-person audits. In person audit Virtual audit Activity Pro Con Pro Con Body language more Agenda and contents Body language can be Persons not on location None difficult or not possible to planning meeting observed. can participate. observe • May require visa. • May face travel • No travel required restrictions. • Saves time Allows for cultural • Requires free meeting • No restrictions on who Travel to site/logistics None interaction space. can participate • Available space • No need for physical may limit number of meeting space participants. Dependent on available Conduct of the meeting technology • Presenting the agenda Body language can be None None None and talking points observed. Individuals unable to Dependent on people be on location can Participants commit to showing up on time, • Timing and attendance None participate (includes attend. virtual meetings can be persons who cannot easily overlooked. obtain a visa). • Number of participants principally unlimited. Does not require physical • Difficulty to attract Body language can be Number of participants access and thus no risk attention. • Participation observed. typically limited. to environment (e.g., to • Body language cleanrooms) more difficult or not possible to observe. • It is easy to get distracted. Looking up for a No contamination issues Depending on the sound Potential contamination confirmatory view around pen and paper quality, it may be difficult • Taking notes issues with bringing pen (checking the note) is being brought into the to hear and catch all and paper into the area easy. area comments. • Control over meeting Quick word with anyone Likely a strictly adhered to None None progress attending is easy. agenda Ability to break into Not possible to break into smaller groups to discuss Too many small groups smaller groups to discuss • Spontaneity None and resolve issues and forming and resolve issues and challenges challenges It is difficult to conceal It is easier to conceal • Transparency None None items from the auditors. items from the auditors. Budget N/A Can be costly Minimal N/A

July 2020 www.biopharminternational.com BioPharm International 49 Ask the Expert

Performing Remote Audits

During the Pandemic Siegfried Schmitt, It is important to consider the feasibility, benefits, vice president and limitations of each type of audit in advance. technical, Parexel.

In light of the COVID-19 pandemic, many Similarly, FDA announced postponement of Q: of our planned on-site audits can no lon- both foreign and domestic inspections, except ger be performed for the foreseeable future, and those deemed mission critical, and the agency is there is a need to replace these by remote (desktop) now relying on off-site monitoring and the com- audits. Under what circumstances can such remote mitment of companies to quality in the absence audits be considered equivalent to on-site audits? of in-person regulatory oversight. For medical Regulatory agencies around the world devices, FDA has published a “Remote Auditing A: are facing the same challenge of decid- Pilot Program” document outlining a volun- ing when inspections can be performed remotely tary pilot program for remote auditing of pro- and when they must be performed in person. cesses, the Medical Device Single Audit Program Each respective agency has its own guidelines, but (MDSAP) as part of the audit of a medical device across the board, they all rely on the fundamental organization (2). An important aspect of this principle of a risk-based approach to compliance. pilot is the use of technology that facilitates In April 2020, the European Medicines Agency remote audits, including: (EMA) updated its guidelines to allow for qual- • Videoconferencing ity personnel to conduct remote audits when • Web -based meeting systems with screen shar- on-site audits are not possible, noting that, “… ing capability on-site audits as well as remote audits can be con- • Teleconferencing in conjunction with e-mail sidered, after agreement with the investigator and • Smart glasses or optical mounted head displays if the audits are assessed as essential, e.g., triggered • Secure fileshare repositories audits with the purpose of investigating serious • Rem ote ‘read only’ access to automated systems, deviations from the trial protocol or from the applicable legislation” (1). Contin. on page 49

Regulators Work to Coordinate Pandemic Response

On May 14, 2020, the International Coalition of underpowered clinical trials and observational Medicines Regulatory Authorities (ICMRA) held studies that compete for essential resources a virtual meeting with international regulators and patients and may not generate sufficient to discuss policy issues and regulatory require- data. The need for regulatory requirements ments in relation to the COVID-19 pandemic. for COVID-19 studies was determined, and The meeting was conducted to align global it was agreed that further guidance on the regulations and approaches to clinical trial management, drug supply issues, and pharmaco- prioritization of clinical trials and on serology vigilance during the pandemic (1). was needed to harmonize efforts. The use of master protocols for clinical trials Reference around the world to accelerate development and 1. EMA,” Global Regulators Work Towards Alignment approval of COVID-19 treatments and vaccines on Policy Approaches And Regulatory Flexibility was discussed. Regulatory considerations During COVID-19–update #2,” Press Release, May regarding exploratory clinical trials and pivotal 18, 2020. studies with investigational or repurposed medicines for the treatment of COVID-19 —The editors of BioPharm International were discussed. Concerns were raised about freshidea - Stock.adobe.com - freshidea

50 BioPharm International www.biopharminternational.com July 2020 Automated Inspection Technologies for Vial and Syringe Fill-Finish

ON-DEMAND WEBCAST Register for this free webcast at: www.biopharminternational.com/bp_p/fill_finish Aired: Wednesday, June 24, 2020

Event Overview As the bio/pharma industry develops new container delivery solutions, greater understanding and control of primary container quality is needed. Deterministic technologies that Presenter provide a more reliable test measurement can be leveraged to automated inspection platforms. Vials and prefilled syringes create challenges that call for deploying alternative technologies and inspection methods.

This presentation will cover various challenges and pitfalls of specific applications and solutions to assure reliable container closure integrity (CCI). Scientific case studies will establish criteria for successfully deploying a next- Oliver Stauffer generation automated CCI inspection technology. CEO PTI Key Learning Objectives • How to evaluate your container and product classes against available CCI test technologies Moderator • Technology capabilities and how they can be leveraged for automated CCI assurance • Solution and pathways to navigate the next generation CCI quality requirements Who Should Attend • Technical specialists within the parenteral Feliza Mirasol pharmaceutical field, focused on lab space, fill-finish Science Editor and all container/packaging operations BioPharm International

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BioPharm.indd 1 6/23/20 3:15 AM