Pfizer vaccine has good results in adolescents; More vaccine capacity announced

Feds Direct J&J to Run Operations at Emergent Facility

Intensified and distributed manufacturing approaches create flexible, local capacity.

Manufacturing Outside the Box

In-vitro and in-silico tools can help predict in-vivo outcomes.

Spray-Dried Dispersion Formulation

Materials availability is a factor in vaccine production.

Supply Chain Hurdles for Vaccine Production

Strategies to Prevent Drug Shortages and Resolve Capacity Challenges

PharmTech’s Technology Forum Series

Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

For anyone who was wondering in recent weeks what was holding up FDA Emergency Use Authorization for Johnson & Johnson (J&J) to distribute vaccine produced by the Emergent BioSolutions Bayview facility in Baltimore, the reason is clear from the multiple red flags and violations at the facility cited in an April 2020 field inspection report. Even before Emergent disclosed that it had to discard 15 million doses of the J&J vaccine drug substance, FDA inspectors had uncovered multiple deficiencies and quality control issues. Journalists and investigators have disclosed additional government reports and complaints about Emergent’s operations and practices, raising multiple questions about how and why federal health officials continued to ramp up contracts with the company.

A picture of wide manufacturing violations appears in a recently disclosed 

on a site visit to Emergent’s Baltimore vaccine plant conducted from April 9, 2020 to April 20, 2020. The report describes inadequate controls for computer and records systems, disregard of established test procedures and laboratory control mechanisms, failure to investigate deviations from test methods, unclear quality control unit responsibilities and procedures, and lack of employee training on current good manufacturing practices (cGMP) practices.

Most prescient is the last observation citing deficient operations to prevent contamination or mix-ups of products by having separate or defined areas for holding rejected components before disposition. The FDA investigator noted the absence of a report on a non-conforming material held in the “reject cage,” which was needed to explain the rejection and how the material was disposed. The year-old inspection report indicates that Trump administration officials and subsequently Biden staffers were aware of the serious quality control issues at the Emergent facility, even before the discovery that millions of doses of J&J vaccine doses were, in fact, discarded due to a mix-up with vaccine ingredient being produced for AstraZeneca. Despite the serious concerns raised by FDA and other analysts, pandemic preparedness officials continued to award ever-larger contracts to Emergent for vaccine ingredient production.

that it would assume full responsibility for manufacturing its vaccine drug substance at the Emergent facility. The company is shifting operations and quality experts to the site and “significantly increasing the number of manufacturing, quality, and technical operations personnel” to work with Emergent staffers. At the same time, Emergent was instructed by the Biden administration to halt production of the AstraZeneca vaccine, offering to assist the company in identifying other facilities to handle its production.

Even so, Emergent executives downplayed the situation, emphasizing in a press release that it was receiving an additional $23 million from the Biomedical Advanced Research and Development Authority (BARDA) to improve its manufacturing operations to expand J&J vaccine production. CEO Robert Kramer 

highlighted the company’s long-standing collaboration with the federal government

 in expanding vaccine production, and that the Bayview facility remains an Emergent property. This followed an 

that its quality control checks had identified only one single noncompliant batch, and that there was nothing unusual in having to discard some material in the complex vaccine production process.

The continued award of ever-larger manufacturing contracts to Emergent reflects its political connections in Washington as well as still limited US capacity for producing large quantities of critical vaccines. J&J has imported its vaccine substance from its plant in the Netherlands and also signed an agreement for Merck to produce its vaccine and has expanded its collaboration with Catalent to ramp up production of its vaccine at its Bloomington, Ind. facility.

One result of “uneven” production from the Emergent Baltimore plant is that federal health authorities now indicate that J&J will provide less than a million vaccine doses in the coming weeks, 85% less than the expected 5 million doses a week.

Articles

Even before Emergent disclosed that it had to discard 15 million doses of the J&J vaccine drug substance, FDA inspectors had uncovered multiple deficiencies and quality control issues.

FDA Inspectors Cited Critical Problems at Emergent Facility

BeiGene, a commercial-stage biotechnology company, announced on April 7, 2021 that the China National Medical Products Administration has given the company the green light to begin manufacturing commercial supply of its approved anti-programmed cell death (PD)-1 antibody, tislelizumab, at its biologics facility in Guangzhou, China.

The 1 million-ft.2 facility currently has 8000 Lof biologics capacity approved for commercial supply, with 64,000 additional liters planning to be added to the site by the end of 2022, BeiGene said in a company press release.

“We started building this large-scale, commercial biologics manufacturing facility in 2017 to meet our expected future demand. Since that time, tislelizumab has been approved in several indications in China, included in the National Reimbursement Drug List, and licensed to Novartis in Europe, North America, and Japan,” said Xiaobin Wu, PhD, president, chief operating officer, and general manager of China at BeiGene, in the press release. “With significantly expanded capacity for tislelizumab and for other biologics in our pipeline, we are continuing our strong commitment to the quality, safety, and compliance of our products.”

The China National Medical Products Administration has given the company the green light to begin manufacturing commercial supply of its approved anti-PD-1 antibody, tislelizumab, at its biologics facility in Guangzhou, China.

China Approves BeiGene for Commercial Manufacturing at its Biologics Facility

Takeda and CSL Behring, co-founders of the CoVIg-19 Plasma Alliance, announced on April 2, 2021 that a Phase III inpatient treatment with anti-coronavirus immunoglobulin clinical trial did not meet its endpoints. The year-long collaboration of the companies in the Alliance has ended with the end of the clinical trial, but it provides a framework for future collaboration, the companies said in the press release.

According to a Takeda press release, the trial, which was sponsored and funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, intended to determine whether CoVIg-19, an investigational anti-coronavirus hyperimmune intravenous immunoglobulin medicine, could lessen the risk of disease progression when added to standard care treatment including remdesivir in hospitalized adult patients at risk for serious complications.

“While the results of this particular clinical trial are disappointing, we are proud that as an industry we proactively and collaboratively pursued this work, and that the program may contribute to a growing understanding of this challenging virus and strategies for patient care,” said Bill Mezzanotte, MD, executive vice-president, head of Research and Development and chief medical officer, CSL Behring, and co-leader of the CoVIg-19 Alliance, in the press release. “Since we embarked on this development program, and throughout the pandemic, we have learned much from our scientific research. Importantly, we learned that as an industry we have the fortitude and capability to quickly work together for the greater good of human health.”

“We are especially proud that we pooled resources, brought our plasma expertise and infrastructure together at our own cost to benefit public health and added to our understanding of a complex field. We are extremely thankful to all those who collaborated day and night for one year in testing circumstances to develop and manufacture a potential solution for COVID-19, including those organizations from outside the industry who chose to support us,” added Julie Kim, president of Plasma-Derived Therapies Business Unit, Takeda and co-leader of the CoVIg-19 Alliance, in the press release. “We express our sincere gratitude to the COVID-19 survivors who generously donated their plasma to make our work possible, the patients who graciously participated in the trial, and to the regulatory and government agencies for their partnership and flexibility to support our efforts."

A Phase III clinical trial of anti-coronavirus immunoglobulin did not meet its endpoints, concluding the year-long CoVIg-19 Plasma Alliance, Takeda and CSL Behring announced.

Plasma-Based COVID-19 Treatment Alliance Ends its Project as Trial Fails to Meet Endpoints

Merck, known as MSD outside of the United States and Canada, and Alkermes, a biopharmaceutical company headquartered in Ireland, announced on April 7, 2021 that they have entered into a collaboration and supply agreement to conduct a Phase III study to evaluate nemvaleukin alfa, Alkermes' novel investigational engineered interleukin-2 (IL-2) variant immunotherapy, in combination with Merck’s Keytruda (pembrolizumab), in patients with platinum-resistant ovarian cancer.

The combination is currently being evaluated in two 1/2 phase studies, ARTISTRY-1 and ARTISTRY-2, to determine its safety, tolerability, efficacy, and pharmacokinetic and pharmacodynamic effects, Alkermes said in a company press release.

"We are pleased to collaborate with [Merck] to evaluate nemvaleukin in combination with Keytruda in patients with platinum-resistant ovarian cancer, a patient population for which there are limited treatment options available and overall survival remains low. Importantly, there are no anti-PD-1 treatments currently approved for this tumor type," said Jessicca Rege, PhD, vice-president, head of Oncology at Alkermes. "Nemvaleukin in combination with Keytruda has demonstrated antitumor activity in heavily pre-treated patients with platinum-resistant ovarian cancer in the ongoing ARTISTRY-1 study, with durable and deepening responses observed. We look forward to initiating this Phase III study to further evaluate the potential clinical utility of this combination in this tumor type and advancing our interactions with regulatory authorities related to potential registration strategies for the combination in platinum-resistant ovarian cancer."

The Phase III study will evaluate nemvaleukin alfa, Alkermes' novel investigational engineered interleukin-2 variant immunotherapy, in combination with Merck’s Keytruda (pembrolizumab), in patients with platinum-resistant ovarian cancer.

Merck and Alkermes Collaborate on Phase III Study for Ovarian Cancer Treatment

The National Horizons Centre (NHC) in the United Kingdom has been confirmed as a National Training Centre that will deliver on-site advanced therapies and vaccine manufacturing specific practical and digital training.

NHC was announced as a preferred bidder in December 2020 to become one of the initial three centers to provide hands-on training for advanced therapy medicinal products (ATMPs) and vaccine manufacture as part of the Advanced Therapies Skills Training Network (ATSTN)—a UK-wide initiative. ATSTN has been awarded funding by the Department for Business Energy and Industrial Strategy for the delivery of training centers across the UK that will help to develop practical skills and address the growing need in vaccine and ATMP manufacturing.

The on-site training being offered by NHC will be focused on good practice (GxP) manufacturing, process development, and bioprocessing techniques. In addition to hands-on training, NHC will also create a virtual reality (VR) training facility, which will include four VR stations alongside a tutor demonstration station. The VR facility will be used in conjunction with the NHC laboratory and teaching facilities to deliver the training courses.

“The UK cell and gene industry is a great place for people to build their future. We want to see that opportunity opened up to everyone,” said Matthew Durdy, CEO at Cell and Gene Therapy Catapult, in a March 31, 2021 press release. “With its cutting-edge training facilities, the [NHC] will be an integral part of the [ATSTN’s] unique offering to anyone in the UK who wants to advance their career in advanced therapies.”

“With the rush to develop and deliver a COVID-19 vaccine, the importance of the biomanufacturing and bioprocessing sectors has never been so apparent,” added Jen Vanderhoven, director of NHC, in the press release. “We’ve worked very closely with leading figures across the bioindustry sector to ensure that each of these courses will address the requisite technical and digital needs. We pride ourselves on our ability to be responsive to the sector’s needs, so we’re very pleased to have been able to react quickly and develop these courses, which will deliver vital skills needed for vaccine manufacturing and advanced therapies and to grow this important industry.”

The training courses will be available at NHC from May 2021. Courses will cover upstream and downstream bioprocessing, analytical techniques for bioprocessing, process control and automation, viral vector manufacturing, biologics manufacturing, data integrity, computer systems validation and IT compliance, good manufacturing practice for biologics, practical proteomics, and flow cytometry for bioprocessing.

The UK's National Horizons Centre has been confirmed as a National Training Centre that will deliver on-site advanced therapies and vaccine manufacturing specific training.

National Horizons Centre to Provide ATMP and Vaccine Manufacture Training

CrystecPharma, a pharmaceutical crystal and particle engineering company, has opened a new subsidiary, Nantong Crystec Pharmaceutical R&D Co. Ltd., and research facility in Haimen City, Jiangsu Province, China.

According to a March 31, 2021 press release, the R&D center was established following an invitation to participate in the Yangtze Delta Advanced Drug Development platform—an initiative jointly funded by the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, and the Haimen government. The platform is aimed at accelerating pharmaceutical product innovation underpinned by advanced pharmaceutical excipients and drug delivery technologies. Crystec’s proprietary supercritical fluid technology, mSAS, will play a role in enabling the development of new therapeutics, creation of value-added medicines, and in the simplification of formulations and manufacturing processes.

“We are delighted to open our new facility in Haimen, a project credited to the collaborative efforts of SIMM, Chinese Academy of Sciences, and the Haimen government,” said Qun Shao, Crystec’s chief operations officer, in the press release. “This cutting-edge research facility will enhance our capacity to support clients across China and the rest of the world, and will provide opportunities to achieve rapid transition from proof of concept studies to delivering clinical material for human trials in China.”

CrystecPharma has opened a new subsidiary, Nantong Crystec Pharmaceutical R&D Co. Ltd., and research facility in Haimen City, Jiangsu Province, China.

CrystecPharma Opens New Subsidiary in China

Sterling Pharma Solutions has announced its acquisition of ADC Biotechnology, a bioconjugation development services business specializing in antibody drug conjugates (ADCs), in an April 6, 2021 press release. The acquisition follows the strategic investment by contract development and manufacturing organization (CDMO), Sterling, in December 2020.

Through the acquisition, the ADC Bio facility, which is based in North Wales in the United Kingdom, will be rebranded and become part of the Sterling Pharma Solutions international network. Combining Sterling’s experience in current good manufacturing practice (CGMP) manufacturing, quality processes, and compliance, with the expertise of ADC Bio, the companies are aiming to establish a center of excellence for bioconjugation and ADC development and manufacturing services.

Financial investment is being made to support to growth of the ADC capabilities, including expansion and development of the existing bioconjugation technical services team and analytical services team (particularly in the CGMP area). Additionally, the companies plan to create CGMP bioconjugation/ADC manufacturing at the North Wales facility in 2022.

“We are delighted to confirm the acquisition of the ADC Bio business, this investment provides us with the opportunity to offer a wider portfolio of services to our customers in the fast-growing ADC and bioconjugation market, as well as providing additional services to existing ADC Bio customers,” said Kevin Cook, CEO at Sterling Pharma Solutions, in the press release. “Integrating our HPAPI [highly potent API] capabilities with the expertise already found at Deeside means that we will also be able to offer the development and manufacture of toxin linkers. This is an exciting time for both businesses as we embark on a period of growth and diversification to ensure we always stay ahead of the next innovation. I’d like to welcome all ADC Bio employees to the Sterling family.”

Alan Raymond, executive chairman of ADC Bio, added in the press release, “This is fantastic news for our employees and our customers; targeted investment in both people and processes will allow the team to continue supporting important advances in drug development with additional services, and importantly with the additional support and experience from the Sterling team.

Sterling Pharma Solutions has acquired ADC Biotechnology, a bioconjugation development services business specializing in antibody drug conjugates.

Sterling Pharma Solutions Confirms ADC Bio Acquisition

Berkeley Lights, a US-based digital cell biology company, announced on April 5, 2021 that it has launched Opto Assure, a series of assays that provide yield and product quality data at an earlier stage in cell-line development.

According to a company press release, the first series supports direct detection of product aggregates for a faster ramp toward volume production by evaluating biotherapeutic protein quality sooner in the antibody therapeutic development process, allowing for customers to rapidly choose clonal cell lines with promising manufacturability profiles.

“We’re excited to empower manufacturers of complex therapeutics, such as bispecifics, to develop better production cell lines faster. As we build out the Opto Assure series, customers can look forward to added capabilities that further reduce resources spent on preventing product failures downstream and ensure a more efficient process,” said John Proctor, PhD, senior vice-president of Antibody Therapeutics at Berkeley Lights, in the press release.

The company has introduced Opto Assure, a series of assays that provide yield and product quality data at an earlier stage in cell-line development.

Berkeley Lights Launches Assay Series for Early Cell-Line Development Yield and Product Quality

Catalent announced on April 6, 2021 that it has expanded its strategic collaboration with Moderna by dedicating a new high-speed vial-filling line at its biologics facility in Bloomington, IN, for the manufacture of Moderna’s COVID-19 messenger RNA (mRNA)vaccine and other investigational programs in Moderna’s pipeline.

Under the terms of the expanded agreement, Catalent will provide Moderna with the filling line until June 2023 along with inspection, labeling, cartoning, and final packaging for the potential pipeline programs, Catalent said in a company press release.

The companies’ initial agreement was announced in 

 and involved Catalent providing aseptic vial filling and packaging from its Bloomington site to support production of an initial 100 million doses of Moderna’s vaccine.

“We appreciate this expanded collaboration with Catalent and the dedication of their team,” said Juan Andres, Moderna’s chief technical operations and quality officer, in the press release. “This additional fill/finish capacity will be important for not only our COVID-19 vaccine, but also potentially for other programs in our clinical development pipeline.”

“Catalent’s partnership with Moderna began in 2016, when we had only glimpsed the potential applications of mRNA and could not have guessed how pivotal mRNA would become in the fight against COVID-19,” added Alessandro Maselli, Catalent’s president and chief operating officer, in the press release. “We are proud to announce this extension of our companies’ strategic collaboration, and we look forward to further demonstrating our commercial manufacturing expertise as we help supply more vaccine doses.”

Under the terms of the expanded agreement, Catalent will provide Moderna with a new high-speed vial filling line until June 2023 along with inspection, labeling, cartoning, and final packaging for potential pipeline programs.

Catalent Expands COVID-19 Vaccine Fill/Finish Collaboration with Moderna

Determining cybersecurity risks as a result of the ongoing pandemic is necessary for pharmaceutical laboratories complying with lab data integrity practices. 

 spoke with Bob Voelkner, vice-president of Sales and Marketing at LabVantage Solutions; Matt Grulke, vice president of Research and Development, also at LabVantage Solutions; Dennis Curran, BIOVIA portfolio technical director at Dassault Systèmes; and Paul Smith, strategic compliance specialist, and Humera Khaja, software compliance program manager, both at Agilent Technologies, about the best practices for maintaining lab data integrity during the COVID-19 pandemic while combatting cybersecurity risks.

 What precautions need to be taken to protect lab data integrity and security during the pandemic?

 As organizations deploy enterprise lab information management systems (LIMS) in their laboratories to digitize their operations, data integrity features and capabilities are vital in ensuring compliance. Documenting and protecting data maintained in online systems during the pandemic is a key solution to keeping the lab working and its data safe.

 Organizations also need to continue to elevate the importance and visibility of cybersecurity. Many organizations will deploy a comprehensive cybersecurity program that includes routine training of staff on common techniques, ongoing patching of systems to address known vulnerabilities, and the continued use of tools and frameworks to prevent, detect, and minimize cyber threats.

 With many employees working remotely during the pandemic, biopharma organizations are under increased pressure to maintain the highest standards of data integrity, security, and quality. On the one hand, they are engaged in often multi-organizational, collaborative R&D initiatives to bring safe and efficacious therapeutics and vaccines to patients faster than ever. On the other hand, working remotely comes with many challenges related to accessing and sharing data securely. Increasingly, mobile teleworkers can inadvertently open the doors to bad actors who can access critical data and disrupt supply chains. As a result, organizations need to beef up their virtual private networks (VPNs) with robust system access logging. Who was in? When were they in and why? Were the activities approved, and by whom? Most importantly, organizations need to take precautions to ensure that project teams are sharing data securely. In this new, remote sharing ecosystem, is critical project data available to more people beyond just the involved project team?

 The pandemic resulted in all labs requiring the implementation of social distancing measures, as well as performing risk assessments associated with the potential impact and management of COVID-19 transmission within the lab. This constrained operations considerably, therefore, additional precautions were required to ensure that labs could continue, and to be compliant operationally with fewer lab personnel, and potentially reduced direct supervision.

Travel restrictions also limited external personnel such as service engineers from visiting labs to perform repairs, planned maintenance, and operational qualifications on analytical instruments. As a result, lab personnel may have had to perform these tasks while being remotely supervised, for example, via video link to the instrument manufacturer. With restricted service visits, it may have been necessary to utilize lab instruments outside of their scheduled maintenance or qualification tolerances, potentially impacting instrument performance and possibly data quality. Many non-essential lab staff, not able to enter their labs, were required to access lab systems remotely, which required closer attention to information technology (IT) infrastructure to ensure business continuity as well as data integrity.

Although all above mentioned actions were most likely supported by additional regulatory guidance and instructions related to the pandemic, labs may still have been exposed to unforeseen data integrity risks. To safeguard, it was essential that all deviations from standard working practices, and all controlled non-compliance with company policies, were well documented and subject to rigorous risk assessment to identify additional risks and implement additional safeguards to reduce the impact of these risks.

 Since FDA has reduced inspections, what are you seeing as the top areas of non-compliance regarding lab data integrity during the pandemic?

 To protect R&D data and avoid non-compliance with regulatory requirements during the pandemic, biopharma organizations need to pay close attention to lab procedures. Having procedures in place and following procedures can both be significant lab challenges in today’s new work environment. Organizations should assess standard operating procedures in the light of current working conditions to ensure that electronic reviews/approvals are properly structured and appropriate. This is especially important whenever paper-based organizations need to implement electronic workflows due to the pandemic. This can create a high-risk situation for regulatory violations by creating uncertainty around data.

In response to the pandemic and travel restrictions, regulators issued communications confirming the halting of on-site inspections. This initially applied only to overseas inspections but was then extended to domestic on-site inspections due to potential risks to inspectors. This triggered a move to remote and office-based inspections using secure video links. One positive to this approach has been closer pre-audit sharing of data and information prior to the virtual audit. One not so positive consequence of remote audits was reduced capacity of the auditor to apply critical thinking skills to what they found during the ‘walk-through’ of the labs. The pandemic also drove regulators to be more reliant on risk-assessments associated with a lab’s historical regulatory footprint to prioritize virtual audits.

FDA has been transparent in documenting cases of data integrity problems. When labs come to us, they either want to avoid compliance-encountering issues or need to remediate known problems. The pandemic has amplified this need as labs accelerate their digital transformation plans.

 What have been the greatest vulnerabilities that companies face regarding lab data integrity during the pandemic?

During the pandemic and ensuing lockdown, virtually all labs were forced to embrace remote working conditions. Vulnerabilities labs have faced during this time have been to the maintenance of data quality and data security, which are the essential subsets of data integrity. Organizations’ data governance programs have had to re-evaluate their IT security, data quality, and data management policies and procedures, to mitigate these vulnerabilities. Though regulatory audits were significantly reduced in 2020 due to the pandemic, regulators still expected that laboratories’ electronic data and computerized systems should remain compliant.

The pandemic also exposed that labs changed the way their employees accessed, viewed, and processed results, and other critical eRecords. Lack of trust in the results, or outputs of data analysis, could be of concern. If the data is to be considered trustworthy and of high-quality, it must adhere to the principles of data quality.

 Dealing with fully online and digital processes as compared to paper or spreadsheets requires the lab to adapt to commercial solutions and the rigor that compliance requires. Without a purpose-built LIMS solution that meets the current and future compliance needs of the regulated laboratory, labs face higher risk of non-compliance of data integrity guidelines.

 Increased electronic workflows and remote access during the pandemic gives malicious actors more opportunities to penetrate networks and compromise critical data, whether it is testing data for a batch of new vaccine or a Raw Material Certificate of Analysis documenting the material make-up of a product. With this in mind, biopharma organizations need to ensure that they are operating with robust VPNs and data backups. Biopharma organizations have already expanded their IT footprint to support home workers and hybrid workflows (e.g., lab staff onsite and supervisors, reviewers, and quality assurance [QA] offsite). They should continue to review their hardware, contingency plans, and any new, extended networks for vulnerabilities, especially if further shutdowns occur. In addition, organizations storing data in the cloud should ensure that their hosting company is following appropriate security protocols and that there is adequate redundancy built into the system. Finally, organizations should monitor their supply chains closely, as well as machines and equipment that generate data to ensure that the data is accurate and trustworthy.

Lauren Lavelle is the assistant editor for 

When referring to this article, please cite it as L. Lavelle, “Pandemic Spurs Cybersecurity Risks in Laboratories,” 

Pharmaceutical laboratories must work to maintain lab data integrity practices as the pandemic surges on and cybersecurity risks increase. 


Featured Content

Feds Direct J&J to Run Operations at Emergent Facility

Manufacturing Outside the Box

Spray-Dried Dispersion Formulation

Supply Chain Hurdles for Vaccine Production

PharmTech’s Technology Forum Series