Jennifer Markarian is a contributing editor for 

Jennifer Markarian

Contract packaging organizations for clinical trial materials are increasingly handling biologic drugs, which are typically delivered by injection and have more stringent packaging requirements than other drug forms. In addition to the shift to biologics, the trend to direct-to-patient shipping affects how materials are packaged and makes tracking even more important. Careful consideration of primary packaging materials, kit design, and distribution is crucial for optimizing packages that balance user requirements, protection of drug product quality, and efficiency.

Pharmaceutical Technology's Biologics and Sterile Drug Manufacturing

Jennifer Markarian is manufacturing editor of 


eBook: Biologics and Sterile Drug Manufacturing, May 2021
May 2021
Pages: 44–48

When referring to this article, please cite it as J. Markarian, “Packaging Biologic Drugs for Clinical Trials

" Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook 

Articles

Contract packaging organizations packaging biologic drugs for clinical trials use technologies that meet the unique requirements of each study. 

Packaging Biologic  Drugs for Clinical Trials

Now that COVID-19 vaccines have received regulatory authorizations and vaccine manufacturers are providing a steady and increasing supply, the focus is on distributing doses. Vaccine manufacturers worked closely with cold-chain distribution experts to plan for maintaining and monitoring the cold chain for these crucial drug products. 

spoke with Mahesh Veerina, CEO of Cloudleaf, and Gisli Herjolfssonn, CEO and cofounder of Controlant, about supply-chain visibility systems for maintaining the cold chain.


eBook: Biologics and Sterile Drug Manufacturing, May 2021
May 2021
Pages: 38–43

When referring to this article, please cite it as J. Markarian, “Tracking Technologies Safeguard Vaccine Cold Chain

Supply-chain visibility systems are proving their worth in the distribution of COVID-19 vaccines and may see broader use in the future.

Tracking Technologies Guard Vaccine Cold Chain

Process analytical technology (PAT) tools collect process data that can be used for real-time process control and to increase process understanding. 

 interviewed Eamonn Garry, operations director at Optimal Industrial Automation, and Paul Gillham, innovations director at Optimal Industrial Technologies, about implementing PAT in oral solid dose (OSD) manufacturing.

 PAT provides OSD manufacturers with a data-driven, in-depth process understanding that supports accurate and responsive in-line control across all production stages, from raw material input up to the delivery of end products. Thanks to the actionable insight gained from these data, it is possible to create an intelligent as well as flexible manufacturing line that is able to address variability and meet market demands with high-quality products. PAT is therefore essential for any business seeking to implement quality by design (QbD), lean, and smart manufacturing applications.

By offering a holistic approach to manufacturing, PAT offers multiple advantages to pharmaceutical producers. First, this system is crucial for the transition from traditional quality control methods to more comprehensive and efficient quality assurance strategies. As a result, OSD producers can improve the consistency of end-product quality whilst considerably reducing the volume of off-spec materials, rejects, and reworks. Furthermore, the advanced process understanding generated by PAT enables manufacturers to continuously increase the quality of their end products by fine-tuning operating conditions.

Moreover, the information on quality that is continuously generated, analyzed, and stored offers full data traceability, which facilitates quality auditing activities to prove regulatory compliance. In practice, this provides the foundation for real-time release testing (RTRT). All these quality-oriented features also help manufacturers increase product safety, thus minimizing—if not eliminating—the risk of drug recalls.

A shared PAT infrastructure can also enhance collaboration between manufacturing facilities within an organization, improving end-product consistency and maintaining quality across the company.

In addition to increased quality, pharmaceutical companies can also benefit from more energy-efficient and resource-efficient processes. Not only do fewer off-specs and reworks result in lower waste generation and material usage, but optimum process conditions also avoid overprocessing. As a result, OSD producers can reduce their running costs, leading to substantial savings. In particular, PAT can increase operating margins by 6% for mid-sized pharmaceutical companies manufacturing small-market branded, generic, and over-the-counter OSD forms (1).

Furthermore, the reduction of reworks and overprocessing, coupled with the elimination of downtime associated with off-line quality control, play a key role in shortening production times. This [faster production], in turn, increases productivity and speed to market. For new OSD formulations, producers can take full advantage of a product’s patent life.

Manufacturers wanting to fully optimize their operations can also leverage PAT to facilitate the transition from batch to continuous processing, which can achieve even more productivity gains. For example, Vertex reported how this change in production has helped the company manufacture medicines from APIs to commercial-ready tablets in a few days as opposed to 4–8 weeks with a traditional batch process (2).

Finally, PAT-driven applications use the power of data, in line with Industry 4.0 or Pharma 4.0 concepts. Consequently, businesses have a key tool that enables them to continuously drive process improvements and intensification as well as to increase their flexibility in adapting to variability in market demands. OSD manufacturers can therefore address current market requirements while being ready to meet future needs.

 What are the challenges for installing such systems in existing lines (retrofitting)? Is this possible/practical? Or is it best for new lines?

 One of the biggest benefits of PAT is that both new and existing manufacturing lines can implement and profit from it, whether they run batch or continuous processes. Therefore, businesses adopting a PAT-driven approach do not need to build new facilities. In fact, they can leverage this framework to retrofit their plants, improving their operations.

Whether PAT is applied to grassroots or brownfield plants, it is important to seamlessly integrate the technology with the facility’s control system. Therefore, it is crucial to design and validate a well interconnected setup.

The implementation of PAT on existing manufacturing lines requires the development of a PAT environment that can be adapted to the existing infrastructure. It may also be necessary to adapt the pre-existing control system to a quality-centric control strategy as directed and orchestrated by a PAT system.

In new facilities, it is beneficial to develop the control and PAT aspects simultaneously, so that a comprehensive solution can be created that is tailored to the application. Ultimately, the creation of a PAT-driven OSD line should follow the same principles of QbD that are applied for process and quality monitoring, where quality is built into the solution from the outset.

In both cases, companies should rely on a PAT specialist, especially if they do not have expert in-house teams. The right specialist should have extensive experience in the pharmaceutical sector and a proven track record in developing customized solutions for new and existing plants. This [expertise] will ensure the creation of a suitable framework that addresses the specific needs of the OSD manufacturing plant. By collaborating with such an expert, businesses can make sure they are using a high-quality system that maximizes the benefits of PAT-driven manufacturing.

 When thinking about using PAT for automating/controlling an OSD manufacturing line, what are some of the things to consider?

 The most important element that should be considered in automated, PAT-driven OSD manufacturing lines is certainly interoperability. PAT systems are highly likely to interface with multiple systems and devices, including instruments and analyzers, programmable logic controllers (PLCs), supervisory control and data acquisition (SCADA) systems, historians and, potentially, distributed control systems (DCS). Therefore, it is crucial to select a PAT knowledge management platform for process orchestration and closed-loop control that can communicate bi-directionally with multiple automation, device, and system vendors.

For the same reasons, it is highly beneficial to select an independent PAT platform and system integrator specialist that has experience with automation products from different manufacturers, as well as in-depth understanding of PAT and how to deploy the technology effectively. By utilizing this knowledge, the specialist can select the most suitable components for an intended application as well as effectively configure devices on new or existing networks.

Another aspect that should be considered is the structure of the PAT knowledge management software used. In particular, a modular solution should be favored, as it allows specialists to conduct the installation, validation, and testing of PAT setups in different stages, which can then be unified. This ability is especially important in continuous manufacturing lines, where everything should operate in sync. In these situations, having the flexibility to develop the automation and PAT strategy for each unit operation separately enables the simplified, ‘standalone’ testing of each component before each one is successfully incorporated into a larger, comprehensive automation and PAT framework for integrated testing and subsequent use.

In addition, modularity not only simplifies the creation of a suitable PAT-led manufacturing approach, but also helps manufacturers to adopt the framework in a staged PAT strategy. Such a strategy allows progressive benefits to be gained as the technology is rolled out along the processing line. In effect, OSD manufacturers adopting this manufacturing concept can begin with a simple, smaller-scale project that would enable the business to explore PAT and the possible gains while getting accustomed to the technology.

 What types of maintenance must be performed when using these systems?

 Another key advantage of PAT is that once a suitable system has been correctly set up, the framework can operate near continuously. A well-designed PAT system can also be adjusted to support expansions, modifications, or the repurposing of existing lines and units. In addition, it can support its own optimization by using increasingly accurate and representative predictive models as more process data is analyzed. For this reason, a PAT approach embraces continuous improvement.

To realize these opportunities, a modular PAT infrastructure can be highly beneficial. In particular, it facilitates a highly flexible, extensible, and scalable PAT approach. As a result, its reprogramming or development, validation, and subsequent addition to the complete infrastructure can be simplified and streamlined.

 2, 38–50 (2007).
2. Manufacturing Chemist, “Talking continuous: Q&A with Patricia Hurter from Vertex,” 


Supplement: Solid Dosage Drug Development and Manufacturing
April 2021
Pages: s26–s28

When referring to this article, please cite it as J. Markarian, “Using PAT in OSD Manufacturing,” Solid Dosage Drug Development and Manufacturing Supplement (April 2021).

Manufacturers of oral solid dose pharmaceutical formulations need PAT tools to reduce a product’s time-to-market and increase profitability. 

Using PAT in OSD Manufacturing 

Continuus Pharmaceuticals received a $69.3 million US government contract in Jan. 2021 to build a continuous manufacturing facility for US-production of critical APIs and finished dosage forms and bring the company’s Integrated Continuous Manufacturing (ICM) technology for end-to-end production of small-molecule drugs to commercial scale. Continuus, which was launched in 2012 from the Massachusetts Institute of Technology (MIT) using technology developed at the Novartis–MIT Center for Continuous Manufacturing, currently has a functioning pilot plant at its Woburn, MA site. The new ICM facility at the site, slated to start up within two years, will be the first US current good manufacturing practices (cGMP)-certified facility for end-to-end, ICM-based production of small-molecule drugs.

The ICM technology shortens drug production time from months or years to days, which will help to mitigate shortages of critical drugs. Under the US government contract, Continuus will produce vital medicines, including medicines that have been in short supply. With additional available capacity, the company plans to manufacture generic medications as well as provide contract manufacturing services to the industry.

The ICM technology also enables distributed manufacturing, because it can produce multiple types of drugs and can be set up to be portable. The April issue of 

 will discuss this subject in further detail. 

 spoke with Bayan Takizawa, co-founder and chief business officer of Continuus, about the technology and what end-to-end continuous manufacturing offers for the pharmaceutical industry.

 What needs have been driving your work in end-to-end pharma manufacturing? Has the pandemic accelerated plans for commercialization?

 There definitely is a positive trend of increased interest in continuous manufacturing from pharma companies, both innovator and generic. We observed this before the pandemic, and were able to grow our pipeline significantly from when we first started eight years ago. There are several reasons for this rise in interest, and I will name just a few. First, several companies have successfully submitted drug applications with significant continuous manufacturing components, such as Vertex and Johnson & Johnson. Thus, there is a regulatory pathway. Second, related to the first, the US FDA and other regulators have provided guidance on the topic, and have been active in engaging companies implementing advanced manufacturing through their Emerging Technology Team at the Center for Drug Evaluation and Research. Third, US government agencies such as the Biomedical Advanced Research and Development Authority (BARDA) and the Department of Defense have been keenly aware of [US] foreign dependence on critical drugs and have been working with companies to develop advanced manufacturing capabilities at home, even before the pandemic. Drug shortages have been a problem for many years. Finally, from our own company perspective, with each successful project, pharma companies have been able to understand better the advantages of ICM. The COVID-19 pandemic highlighted our pharma supply chain vulnerabilities in a big way. As a result, I believe, many ongoing activities and planned projects were accelerated with the intent of combatting the current crisis and preparing for future events.

 What are some of the challenges you are addressing as you scale up from your pilot plant facility to the cGMP facility?

 An example of a challenge is long-term processing equipment reliability. ICM will require 24/7 operations of processing equipment, which is different from the campaign model used in batch manufacturing. To ensure that they are functioning within their respective parameter limits, we will utilize real-time monitors and employ rigorous predictive maintenance strategies and tools. Regular maintenance schedules will complement these preemptive measures, and when appropriate, we will introduce redundancy into the system.

 Can you explain the differences between the multisuite model and the mobile pharmaceuticals (MoP) model that Continuus offers?

 Both models, the multisuite and MoP, leverage ICM lines, which is the underlying technology platform. A multisuite refers to a facility that can house a number of ICM lines in the same building infrastructure, which is generally not mobile. For example, with our planned cGMP facility, we will have two different ICM lines with different throughputs that can produce both oral solid dosages and sterile injectables. ICM is especially suitable for this strategy because its manufacturing lines are much smaller than conventional batch technologies. MoPs refers to an entire ICM line located in a mobile pod that can be transported across sites. Again, this is enabled because of the small size of our manufacturing lines. With MoPs, there is tremendous flexibility to place entire manufacturing lines in facilities that contain a minimum amount of infrastructure, as the pods basically provide the environment required for cGMP manufacturing. It is important to note that multisuites and MoPs are not mutually exclusive, as a multisuite can consist of multiple MoPs. Furthermore, within the multisuites and MoPs, the individual unit operations can be quickly reconfigured in a plug-and-play fashion to produce different drugs. The bottom line is that ICM provides a lot of flexibility.

 Where you see the industry headed in the future?

 We are moving in the right direction. Most people recognize the strategic importance of developing advanced pharmaceutical manufacturing infrastructure so we will never be without the critical drugs that Americans need, especially during healthcare crises. So, I do not think this is a movement that will lose momentum. Additionally, a very important benefit is the impact on drug development. For example, with ICM, bottlenecks associated with scaling-up manufacturing across clinical phases will no longer be an issue. We would just produce for longer periods of time. In this way, life-saving drugs will become available more quickly, again, ultimately benefiting the patient. We look forward to continuing to lead this effort.

Continuus Pharmaceuticals is building the first GMP facility using integrated continuous manufacturing technology for end-to-end production of small-molecule APIs and finished dosage forms.

Building Up End-to-End Continuous Manufacturing

The United States Pharmacopeia (USP) and Phlow Corp. have collaborated to build a new laboratory that will develop test methods and standards for continuous manufacturing. This work aims to aid product development, tech transfer, and drug application filings using continuous manufacturing to foster wider adoption of continuous manufacturing by generic-drug and other pharmaceutical manufacturers.

Operated by USP, the lab will be located in the Virginia Biotechnology Research Park, which currently houses Phlow’s R&D Laboratories and Virginia Commonwealth University (VCU)’s Medicines for All Institute (M4ALL). USP, which will also use labs at its headquarters in Rockville, MD for some analytical and testing projects, is hiring scientists for the new lab in Virginia, which will be started up as soon as possible.

“Pharmaceutical Continuous Manufacturing poses several advantages over traditional batch manufacturing, especially during supply disruptions. These include the availability and use of real-time data to accelerate manufacturing scale-up and help improve medicine quality, enabling more efficient and nimble production of essential medicines and strengthening the overall supply chain,” noted Ronald T. Piervincenzi, CEO of USP, in a Feb. 22, 2021 press release (1) . “We hope that USP’s work with Phlow will help pave the way for the pharmaceutical industry to apply continuous manufacturing more broadly for the generic medicines so many patients rely upon.”

The lab is being funded in part by Phlow, as part of a four-year, $354-million contract it signed with the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) in May 2020. Phlow is leading a group of partners, including AMPAC Fine Chemicals, Civica Rx, and M4ALL, to manufacture essential medicines that are at risk of shortage in the US, including drugs for those hospitalized with COVID-19 (2). The USP lab will initially focus on continuous API manufacturing.

“Phlow’s partnership with the USP, working alongside the Virginia Commonwealth University’s Medicines for All team represents another key resource in our efforts to strengthen our supply chain for essential medicines,” said Frank Gupton, co-founder of Phlow, chair of VCU’s department of Chemical and Life Science Engineering, and CEO of the Medicines for All Institute, in a press release (1).

Early adopters have done the work necessary for good manufacturing practice (GMP)-scale continuous manufacturing of their own products, but standards could help facilitate broader use of continuous manufacturing, suggests Piervincenzi. Standards, for example, could describe what parameters to measure and how to do so. “In some cases, what you need to measure for continuous manufacturing is quite different than what needs to be measured for batch manufacturing. For example, for both batch and continuous processes, you need to check your excipients for purity and strength, but in a continuous solid-dosage drug manufacturing you also need to measure powder flow characteristics,” he explains.

USP has been working with the Center for Structured Organic Particulate Systems (C-SOPS) research group at Rutgers, the State University of New Jersey, on test methods for continuous solid-dosage manufacturing processes, such as methods for characterizing residence time distribution (RTD). Researchers are currently conducting a round robin for transferring RTD test methods from one site to another.

Another area where continuous processing differs from batch manufacturing is in how and when quality tests are performed, says Piervincenzi. In continuous manufacturing, tests will need to be performed in real-time while the process is running. In the new lab, researchers will develop new on-line, in-line, or at-line analytical methods and will compare these to conventional lab methods.

USP’s research efforts will not change the organization’s current practice of drawing upon industry experts to set standards, says Piervincenzi. For now, USP researchers are being advised by an expert panel on a less formal basis but, after test methods have been more fully developed, USP will convene expert committees to create standards.

USP is an advocate for quality standards for continuous manufacturing so that questions about quality will not prove to be a barrier to adoption of the technology, says Piervincenzi. The organization is also working to remove the potential barrier of workforce capability. USP and Rutgers have developed an interactive training course so that technical personnel can gain an in-depth understanding of the skills that are needed for continuous manufacturing for solid-dosage drugs. USP sees potential in the future for similar training programs on the VCU campus. “We’re looking at expanding capability building more broadly for industry and for regulators, both in and outside of the US,” says Piervincenzi. As he notes, getting regulators throughout the world more comfortable with advanced manufacturing technologies will be another key to eliminating current barriers to the technologies’ adoption in the industry.

1. USP, “Phlow Corp. and USP Announce Strategic Alliance Focused on Pharmaceutical Continuous Manufacturing to Increase Supply of Essential Medicines for US Patients,” Press Release, Feb. 22, 2021.

2. HHS, “HHS, Industry Partners Expand US-Based Pharmaceutical Manufacturing for COVID-19 Response,” Press Release, May 19, 2020.

USP is collaborating with Phlow to build a new lab that will develop test methods and standards to facilitate broader adoption of continuous manufacturing. 

New Lab Will Develop Standards for Continuous Manufacturing 

PCI Pharma Services, a contract development and manufacturing organization (CDMO), introduced the pci|bridge digital platform in September 2020 to make real-time inventory, production, distribution, and shipping information readily accessible to its biopharmaceutical clients. “The platform includes data for raw materials received, as well as bulk materials, storage-only products, and finished goods,” explains Morgan Brandt, director of Digital Products at PCI Pharma Services.

“The goal of pci | bridge is to not only make clients’ lives easier, but to help them get life-changing therapies to patients faster by providing efficiencies via greater transparency, accessibility, and automated communications,” says Brandt. She notes that clients appreciate the “self-serve” aspect of the platform and the customized reports. Insights from data help clients make more informed decisions.

The platform is part of PCI’s digital transformation strategy. The platform enables digitization of records by providing a document repository where electronic paperwork can be stored and accessed in one place, with signatures secured on the platform. Brandt says that cybersecurity was a focus during the development of the platform, and that cloud-based storage helps ensure data integrity.

A digital system makes real-time inventory, production, distribution, and shipping information readily accessible.