The European life sciences industry is red hot. The DACH (Germany, Austria, and Switzerland) region alone, attracted nearly 20% of Europe’s biggest life sciences investments last year (1). With this influx of cash comes the potential for commercial success and for a new generation of advanced, life-saving therapies. To unlock that potential, though, life science innovators need more—more manufacturing capacity, more flexibility, and more expertise to get their products to market faster.

The key to ‘more’ is sometimes ‘less’: less wasted effort, more value for the project owner; less fragmentation between teams, more shared expertise. These subtle shifts are the key to delivering complex, high-value facilities faster and more cost-effectively. The shifts are not easy to embrace, but they will pay off a hundredfold for teams who successfully make the transition. That means adopting a lean culture and using it to power an integrated project delivery approach (2).

The terminology of integrated project delivery

A vocabulary has been developed that turns the idea of integrated project delivery into a concrete, phase-by-phase practice, helping the benefits of the approach be leveraged in the conference room, at the jobsite, and inside the working facility (

). Embracing this vocabulary is the first step in making the cultural shift from traditional delivery methods that can no longer withstand today’s pressures to a method that’s much more capable of supporting fast-track delivery.

 to the right can feel uncomfortable. This discomfort may be particularly true in the European market, where project owners have a long tradition of compartmentalizing tasks and distributing them to different localized vendors in a highly regimented and fragmented system. Procurement teams are comfortable with the control implied by this approach, but an increasing number of companies, under constant pressure to move at warp speed, are recognizing its deficiencies.

That discomfort was revealed when CRB asked more than 500 life sciences leaders to rank their preferred project delivery method, and then to disclose their level of satisfaction with that method. The results, which are included in the 2021 Horizons: Life Sciences report (3), show that traditional project delivery ranks near the top in terms of preference, while integrated project delivery sits in last place. The reverse is true when it comes to overall satisfaction, which respondents judged based on quality, speed, and cost: integrated project delivery shoots up the rankings, while traditional methods fall dead last.

Although the survey focused on the North American life sciences market, this trend is playing out on a global scale. Companies are looking for alternatives to the approach they’ve always known to get results they’ve never seen before. But what does it look like to leave well-established but underperforming delivery methods behind, and embrace integrated project delivery?

During this phase, the project team collaborates with the owner to understand the project’s overarching ‘why’. What are the business drivers behind this project? What does the owner hope to achieve? What value does the owner expect to get for their investment?

The project team can then pressure-test this vision within the project’s cost and scheduling benchmarks. Experts from the owner’s side work with their design and construction partner to evolve, revise, and sharpen that vision until they’re certain that it’s achievable within those constraints. That early certainty becomes a commitment, which will shape all future decision-making on the project.

This phase diverges from the early stages of a more traditional project in one important way: instead of immediately developing solutions, the team starts by developing a shared understanding of the problem they’re trying to solve.

Rather than costing more time, this approach actually accelerates the overall project timeline by creating an opportunity for the client to share their knowledge, project requirements, specifications, and other variables up front. This early disclosure of critical information positions the project team for a more streamlined downstream process—no stalling while the team waits for important details, and no confusion over the project’s target scope, cost, or schedule.

The lean principle of ‘respect for people’ plays an important role across the whole integrated project delivery lifecycle, but its greatest impact is felt during this phase, which has one goal: to establish a fully integrated project team, united by a shared commitment to the project’s target value.

The first step in this phase is to onboard selected trade partners and invite them to the table alongside the project owner and manufacturing service provider. This step looks very different from more traditional approaches, in which trade partners have no influence over early decision-making, despite their specialized expertise. The chartering phase corrects this missed opportunity by soliciting that expertise from day one.

This early integration of upstream and downstream stakeholders creates a cohesive, end-to-end project team, and it invites that team to collaboratively define the project’s conditions of satisfaction. Team members are empowered to identify which deliverables will play a role in meeting those conditions and generating value. If a particular deliverable isn’t mission-critical, it’s cut from the process—even if that’s “how we’ve always done it”. Using this approach, team members can stay focused on the project’s target value without wasting effort on extraneous activities.

Early team integration has another key benefit: thanks to the cross-pollination of expert ideas and solutions from day one, the chartering phase enables early cost and scheduling certainty and maximizes the impact of lean tools like target value delivery (4). As a result, all team members are in a position to make a firm commitment to the same objective, with the understanding that all team members share the project’s risks—and its rewards.

The chartering phase drives early cost certainty

Some project teams focus on a chartering document. That’s a good first step, but we find that prioritizing on the process of chartering—rather than its deliverable—is the key to early cost certainty (

The benefits of integrated project delivery multiply as projects evolve. By this phase, they’re abundant. The challenges that snarl progress and drive costs higher during typical downstream delivery—challenges like design clashes, frequent requests for information, or supplier delays—are reduced or eliminated, thanks to the early integration and input of the cross-functional project team.

Removing these challenges is just one advantage of integrated project delivery. What this approach adds to the delivery lifecycle matters just as much. Take long-lead equipment, for example. Because the integrated project team is able to reach design certainty much earlier, they can manipulate the sequence of deliverables based on supply chain timelines and other constraints. This adds even more speed and flexibility to the project, helping to ensure on-time delivery. It also adds to the project’s quality and safety profiles, because project teams have more opportunities to shift certain construction activities from the unpredictable environment of a jobsite to the controlled conditions of an offsite manufacturer (5).

When discussing the critical role of bringing experts from across the delivery lifecycle to the table as early as possible, the indication is to bring in all experts—including the commissioning, qualification, and validation (CQV) team. Their input during early decision-making pays off here, during the turnover phase, when the integrated team is close to realizing the project’s target value but still faces the hurdle of transferring substantial knowledge, documentation, and responsibilities to the owner.

Because of the CQV team’s early input and consistent participation in the project’s evolution, this process happens smoothly and quickly under an integrated project delivery approach. Rather than waiting for the building’s physical completion, the CQV team is able to proactively maintain accurate as-built drawings, systems manuals, and other critical documents throughout the delivery lifecycle. This approach dramatically reduces the back-and-forth that’s typically necessary to organize and share building information with the facility’s operations and maintenance team, and it helps owners unlock the full value of their new asset from the very first day of operation.

Get on board with integrated project delivery

On its own, integrated project delivery is not a silver bullet. For it to generate and maximize value for project owners, it needs the support of a lean delivery team that’s fully committed to shifting away from the traditional mindset and towards a new, improved way of working. That’s where the power of integration comes to life—and it’s where tomorrow’s life sciences leaders will find the resilience, flexibility, and speed they need to survive today’s pressures.

1. J. Smith, “European Biotech Investors Cap Off Record Year in Fundraising,” News, 

, 10 Dec. 2021.
2. R. Kidmose, E. Unrau, and C. Aktar, “Accelerating Project Delivery with a Lean Alternative to DBB,” 

 33 (12) 34–36 (2021).
3. J. Bornholdt and D. Kearney, 

, CRB Horizons Life Sciences Report, pp 73–79, 16 Nov. 2021.
4. R. Little and C. Seese, “Target Value Delivery Success: 3 Best Practices to Hit the Bullseye,” Insight Feature, CRB Group, 13 July 2022.
5. D. Kearney and M. Politi, “Improve Project Performance with PPMOF Strategies,” Insight Feature, CRB Group, 13 July 2022.

, office lead, director EPCM Projects, and 

, vice president, Project Delivery Services, all at CRB Group.

Articles

Features

Integrated project delivery can fast-track delivery targets by eliminating the waste involved in traditional approaches to project set-up and execution.

Fast-Tracking Through Integrated Project Delivery

As the biopharmaceutical industry moves towards automated processes, technologies that allow biomanufacturers to predict outcomes and troubleshoot issues is becoming increasingly useful. Predictive modeling is one such technology that may be used to optimize bioreactor performance.

The issue of bioreactor control has become increasingly important because of the difficulty inherent in controlling the behavior of the living cells used in cell culture systems (1). Despite having a well-designed control scheme, a bioreactor can still exhibit poor performance. As such, an approach that includes predictive modeling can be an advantage in developing process controls for bioreactor performance.

One advantage of using predictive models is that these models enable a data-driven approach, which can assist in accelerating process development, says Tania Pereira Chilima, chief technology officer, Univercells Technologies. Chilima explains that these models allow users to gain a deeper process understanding, which, over time, helps to limit the development resources needed.

“This approach can be used in both batch and continuous processing and can perhaps be even more useful in continuous processing due to the increased number of variables to understand and control (e.g., perfusion rates). Gaining all of these data in real time allows for a faster learning curve and helps to ensure a reproducible process,” Chilima states.

Edita Botonjic-Sehic, director of Analytics at Pall, notes that predictive modeling combines tools and technology “to collect real-time process data and turn it into meaningful information for the long run”. Predictive modeling technology does this by using mathematical algorithms to turn data streams that are pulled from batch or continuous processes into meaningful and targeted assumptions.

“You can think of it like the Amazon algorithm that uses search and purchase data to make certain assumptions and suggestions. Over time, that information becomes richer,” Botonjic-Sehic explains. “When we take this approach to bioprocessing, it allows the prediction of process conditions, such as outcome of glucose feed rate during the process.”

While predictive modeling can be used in both batch and continuous processes, it is, however, currently more challenging to successfully apply to continuous processing, Botonjic-Sehic says. Companies are working to fill in the gaps with batch and continuous predictive modeling solutions that help achieve better outcomes.

Upstream challenges for modeling to solve

The upstream processing stage can be challenging. For one thing, upstream proteins are not pure and need to be differentiated, and on top of that, there are multiple attributes and parameters that need to be monitored and controlled with analytical devices to maintain process conditions, Botonjic-Sehic points out. These parameters include temperature, pressure, dissolved oxygen, pH, and critical quality attributes (CQAs)—all of which need to be part of the model.

“Multi-variant statistical tools are required to come up with the right models because of the complexity and interactions of attributes in the bioreactor; the need for the right tools to measure attributes in real time is a need, and, even when data are acquired, there is still a challenge to translate such data into meaningful information that is ultimately used for prediction,” Botonjic-Sehic states.

Analytical tools such as Raman spectroscopy are commonly used along with other complex spectroscopic techniques to allow for measuring analytes and for predicting information by using pre-determined models. Botonjic-Sehic says that the industry is making the effort to find new solutions to support better predictive modeling.

“The ability to monitor all the CQAs of cell growth using predictive models would be valuable not only in streamlining the use of glucose, nutrients, and metabolites, but also in drastically reducing overall process waste and development time. The ability to predict cell viability and titer concentration is also helpful to aim for the right amount of protein to get pushed [into downstream processing], which is a much purer product,” Botonjic-Sehic explains.

Furthermore, many advancements have been made in the bioreactor space, and Pall itself is also working on its own solutions. “The key here is modeling bioreactors from small scale forward. The ability to demonstrate feasibility early in processes will be critical to lowering costs and increasing accessibility. We need cross functional solutions that enable the measuring, monitoring, predicting, and controlling of processes,” Botonjic-Sehic says.

Predictive modeling approaches in the upstream may also impact design
innovations or accessory development moving forward.

Chilima notes that the industry has definitely seen an increased amount of process analytical technologies (PAT) being developed, for example. PAT enables automated-real time data collection. “Some of these tools also enable different types of data to be collected with a single probe, which is a real advantage. Lately we have also seen significant advances in software development with a number of tools that centralize data collection and analysis to facilitate the development of predictive models, and even digital twins,” Chilima says.

“We expect to see different types of models and approaches that take into consideration a multitude of processes,” adds Botonjic-Sehic. She notes that more work is being done in the space to offer an enabling and standardized platform approach to predictive modeling from the discovery phase through to commercial scale.

Another innovative tool that can enable predictive approaches in upstream processing is the microbioreactor. This is an area on which Univercells has been placing significant focus because microbioreactors can be used to collect an immense amount of data without significant resources, says Chilima. “When the operation of these bioreactors is automated, the costs of developing reliable predictive models can decrease significantly. Taking down the barrier of cost will facilitate more innovation in the space and continue evolving the modality spread in the industry. It is an exciting time to be in development and manufacturing,” Chilima remarks.

“This is a sweet spot for Pall,” emphasizes Botonjic-Sehic. The company continues to build out both its small- and large-scale offerings. “We recognize the industry need for flexible models that streamline development and enable efficient and reliable tech transfer. The idea is to align this flexibility with strong modeling and predictive maintenance functionality from the microbioreactor forward.”

1. S. Ramaswamy, T.J. Cutright, and H.K. Qammar, 

Feliza Mirasol is the science editor for 

Using a predictive modeling approach can help tighten up operator control over bioprocessing, which in turn can increase bioreactor output.

Using Predictive Modeling to Optimize Bioreactor Performance

Amphista Therapeutics, a biotechnology company focusing on drug discovery projects that use targeted protein degradation (TPD), announced on Oct. 6, 2022, that it had selected Domainex, a medicines research service partner, as a partner to provide integrated drug discovery services for its research programs. Domainex will provide Amphista with expertise in protein production, assay biology, and medicinal chemistry.

According to a company press release, Domainex has experience designing, synthesizing, and profiling targeted heterobifunctional protein degraders. Additionally, the company has established 

 binary and ternary complex formation assays to confirm target engagement.

“We are delighted to have been selected by Amphista Therapeutics to help them advance their portfolio of drug discovery projects, building on our previous collaboration,” said Tom Mander, CEO, Domainex, in the release. “Our skilled, multi-disciplinary, integrated team of medicinal chemists, cell biologists, biophysicists, and protein scientists will work closely with the scientific leadership team at Amphista to advance their cutting-edge protein degrading technology.”

“Amphista is expanding rapidly as we advance our growing internal TPD portfolio and our recently signed research collaborations with BMS and Merck Healthcare,” said Nicki Thompson, CEO, Amphista, in the release. “To support our planned growth, we’re also excited to expand our network of contract research collaborators and work with Domainex with their high-quality chemistry, assay biology, [and] biophysical expertise as we tap into the rich expertise in the Cambridge, UK, area.”

News

Amphista Therapeutics and Domainex will work together to develop treatments focusing on targeted protein degradation.

Amphista Therapeutics Enters Targeted Protein Degradation Partnership with Domainex

OGT, a Sysmex Group company and supplier of clinical and diagnostic genomic solutions, announced the launch of the SureSeq Myeloid Plus panel and OGT Universal Next Generation Sequencing (NGS) Complete Workflow on Oct. 5, 2022. The SureSeq is designed to detect aberration in genes implicated in various myeloid disorders, while the workflow is designed to significantly reduce hands-on-time when working with hematology, inherited, and rare disease panels.

According to a company press release, the new SureSeq panels is able to detect single nucleotide variants (SNVs), insertion–deletion mutations (indels), internal tandem duplications (ITDs), and partial tandem duplications (PTDs) within 49 genes. These genes are associated with myeloid disorders, including acute myeloid leukemia (AML), myeloproliferative neoplasms, and myelodysplastic syndrome, among others.

The product is designed to deliver coverage uniformity for low-frequency variants, even in difficult-to-sequence adenine-thymine/guanine-cytosine (AT/GC)-rich regions and regions covering ITDs and PTDs. According to the release, these are common somatic variants in AML and are often associated with poor prognosis and an aggressive form of the disease.

The NGS Workflow is designed to complement the panel, which is designed to be more amenable to automation. According to the release, the Workflow has been upgraded with improvements in copy number variant interpretation, annotation, visualization, and sample data import and display.

“Thanks to our unmatched expertise in bait design, and through partnering with leading cancer experts, we have developed a powerful tool for myeloid research with a highly efficient workflow,” said Adrian Smith, CEO, OGT, in the release. “This enables clinical researchers to quickly and confidently detect all relevant variants in one simple assay. NGS is a key area of expertise for OGT, and we have exciting plans and possibilities for the future.”

New Technology

OGT has launched the SureSeq Myeloid Plus panel and OGT Universal NGS Complete Workflow.

OGT Launches New Panel and Workflow Solutions

Thermo Fisher Scientific recently announced the DynaSpin Single-Use Centrifuge system, a centrifuge that is specifically designed to provide optimal single-use solution for large-scale cell culture harvesting. The system aims to improve and streamline the process by reducing the number of depth filtration cartridges required to complete the harvest process.

According to a Sept. 28, 2022 press release, by reducing the number of filters required for harvesting, the DynaSpin offers upwards of six-fold reduction in material requirements. This is estimated to eliminate approximately 70% of waste compared to traditional harvest systems.

“We developed the DynaSpin system with an eye on efficiently harvesting biologics at large-scale,” said Srini Paluri, vice-president and general manager, Bioprocess Equipment & Automation, Thermo Fisher Scientific, in the release. “It was critical that the solution also consider the environment while outperforming traditional harvest solutions and delivering consistent product yields to our customers.”

The DynaSpin is designed for scalability, rapid changeover, reduced downtime, and lower risk of contamination to the workflow, according to the release. It also features configurable user access, audit trail, and batch reporting.

Thermo Fisher’s new centrifuge technology is designed to enable efficient, sustainable cell culture harvesting.

Thermo Fisher Scientific Launches Large-Scale Cell Culture Harvesting Solution

Freudenberg Medical, a medical and pharmaceutical devices, components, and tubing manufacturer, announced the launch of the HeliFlex Thermoplastic Elastomer (TPE) tubing on Sept. 29, 2022. The Heliflex is a high purity TPE designed for biopharmaceutical fluid transfer applications.

According to a company press release, the HeliFlex is ideal for bioprocessing applications because it can be heat-sealed to allow for easy, fast, and safe fluid transport and transfer. Additionally, the product can be welded to existing tubing lines, is sealable, translucent, and can be used in peristaltic pumping applications.

The tubing is offered with various sterilization options, including autoclave, gamma irradiation, x-ray, and e-beam. According to the release, it is a more environmentally friendly option than silicone, as it can be recycled.

“Silicone has always been the gold standard for biopharma applications,” said David Schwass, director, Sales & Marketing Biopharm, Freudenberg Medical, in the release. “But with silicone material in short supply over the past few years, Freudenberg wanted to offer global customers another single-use tubing alternative.”

Freudenberg Medical’s Heflix TPE tubing is a high purity TPE intended for bioprocessing applications.

Freudenberg Medical Launches HelixFlex TPE Tubing 

Citius Pharmaceuticals, a late-state biopharmaceutical company, recently announced a collaboration with Haider Madhi, MD, an assistant professor at the University of Pittsburgh. The collaboration will focus on an investigator-initiated trial evaluating I/ONTAK (denileukin diftitox), a recombinant fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments, in combination with pembrolizumab, for the treatment of recurrent or metastatic solid tumors.

According to a company press release, the trial is an open label, Phase I/Ib study designed to evaluate regulatory T-cell (T-regs) cell depletion through the denileukin diftitox and pembrolizumab combination; it consists of two parts. Part I is a dose escalation study of four cohorts (3, 6, 9, 12 mcg of denileukin diftitox) that is expected to enroll 18–30 patients. Part II is a dose expansion study enrolling approximately 40 patients to evaluate the safety and tolerability of the recommended dose. Additionally, the study will investigate the alteration of the immune microenvironment within tumors and peripheral blood.

"This study will expand the body of knowledge about [denileukin diftitox] unique mechanism-of-action targeting the CD25 component of the IL2-receptor, which is present on both malignant T-cells (T-cell leukemias and lymphomas) and immunosuppressive T-regs," said Myron Czuczman, chief medical officer, Citius Pharmaceuticals, in the release. "Preclinical research in a syngeneic solid tumor mouse model shows that [denileukin diftitox] enhances anti-tumor activity and significantly extends [the] survival benefit of anti-PD-1 [programmed cell death 1] therapy. This data provides a positive signal of denileukin diftitox's potential in the immuno-oncology space.”

"Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T-cell responses against cancer result in a significant survival benefit in patients with advanced malignancies,” said Mahdi in the release. “Overexpression of PD-L1 [programmed cell death ligand 1] on tumor cells has been reported to impede anti-tumor immunity, resulting in immune evasion. The interruption of the PD-1:PD-L1 pathway combined with diminishing the suppressive effect by T-regs may represent an attractive strategy for restoring tumor-specific T-cell immunity.”

In addition to this study withUniversity of Pittsburgh, Citius is collaborating with an investigator-initiated study at the University of Minnesota. This Phase I dose-finding study is to evaluate denileukin diftitox prior to tisagenlecleucel chimeric antigen receptor-T cell therapy in patients with diffuse large B-cell lymphoma; the study enrolled its first patient in May 2021.

Citius and the University of Pittsburgh will investigate I/ONTAK in combination with pembrolizumab for treatment of recurrent or metastatic solid tumors.

Citius Pharmaceuticals Announces Clinical Collaboration with the University of Pittsburgh

PerkinElmer announced on Sept. 26, 2022 that it has launched the Cellaca PLX Image Cytometry System, a platform designed to enable researchers to assess multiple Critical Quality Attributes (CQAs) of cell samples in a single automated workflow; this includes cell identity, quality, and quantity.

The system combines image cytometer hardware, software, validated consumables, and trackable data reporting; it is designed to eliminate complex calibration procedures or intense training requirements. According to a company press release, the new offering will provide researchers expanded cell sample CQA analysis options beyond flow cytometry and staining methods, which have historically required a variety of different instruments and analytical methods. By combining these capabilities, researchers can detect multiple markers simultaneously and perform immunophenotyping and viability assays in seconds.

"Pharmaceutical companies have invested heavily in cell and gene therapy, but they struggle to assess the complex cell samples required to meet immense scientific demands and regulatory rigor across their research and manufacturing processes," said Alan Fletcher, senior vice-president, Life Sciences, PerkinElmer, in the release. "While the Cellaca PLX Image Cytometer platform is therapeutic area agnostic, it is expected to be especially beneficial for researchers working in CAR-T cell therapy who want to streamline their phenotyping of immune cells for downstream processes."

PerkinElmer has unveiled a cell analysis solution to streamline cell and gene therapy research and manufacturing. 

PerkinElmer Unveils Cell Analysis Solution

Novo Nordisk announced on Sept. 12, 2022 that it has entered a strategic collaboration with Microsoft to accelerate drug discovery and development. The collaboration will combine Microsoft’s computational services, cloud, and artificial intelligence (AI) with Novo Nordisk’s drug discovery, development, and data science capabilities.

According to a company press release, AI models arising from the collaboration will be applied to a range of use cases, two of which are currently in execution. One of the uses will be automated summarization and analysis of information from sources such as literature, patents, scientific reports, and discussion forums. The AI will be used to gain novel scientific insight. The second use aims to develop models that predict a person’s risk of developing atherosclerosis, a cardiovascular disease caused by fat build-up, cholesterol, and other substances on the artery walls. The AI will also be used to establish biomarkers of the disease.

“We are very excited about this new partnership that allows us to work closely together with key experts from Microsoft as we look to expand our digital science and AI capabilities,” said Lars Fogh Iversen, senior vice-president, digital science & innovation at Novo Nordisk, in the release. “Together, we are on a path to enable faster and scaled use of AI in drug discovery, ultimately leading to more breakthrough innovations and efficiency gain to better serve the needs of patients.”

Novo Nordisk and Microsoft are collaborating to accelerate drug discovery and development using big data and artificial intelligence. 

BioPharm International's BP Elements, October 2022