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Drug Solutions Podcast: 

Pharmaceutical packaging must advance to adapt to new, complex modalities

Out-of-the-Box Packaging Advancements

From Theory to Reality: Automating Process Development

Drug Digest: 

The Importance of Appropriate Supplier Oversight

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The European Medicines Agency (EMA) announced on June 14, 2024 that the agency’s Pharmacovigilance Risk Assessment Committee (PRAC) is evaluating potential risks associated with the painkiller metamizole. PRAC is also researching the possible risk of secondary cancers developing in patients who are treated with chimeric antigen receptor (CAR) T-cell medicines.

According to EMA, concerns that measures put in place to minimize the risk of agranulocytosis in the painkiller metamizole might not be adequate. Drugs containing metamizole are authorized in the European Union, varying from country to country, for treating moderate to severe pain and fever. These medicines have a known side effect, agranulocytosis, where a sudden drop in white blood cells occurs. Agranulocytosis is a rare or very rare side effect that may lead to serious, and possibly fatal, infections. There are measures set by EU countries to minimize the risk; however, PRAC is looking into the effectiveness of these measures.

Regarding CAR T-cell medicines, PRAC states that patients receiving these treatments should be monitored for the rest of their lives for secondary cancers. New cancers, different from the original malignancy, may develop after treatment with CAR T-cell medicines.

PRAC came to this conclusion after reviewing data from 38 cases of secondary malignancies of T-cell origin in approximately 42,500 patients. “Tissue samples were tested in half of the cases, revealing the presence of the CAR construct in 7 cases. This suggests that the CAR T-cell medicine was involved in disease development. The secondary malignancies of T-cell origin have been reported within weeks and up to several years following administration of CAR T-cell medicines. Patients treated with these medicines should be monitored life-long for new malignancies,” EMA stated in a press release (1).

Product information, which has advisory information about secondary malignancies, will be updated to include new information about T-cells. PRAC is discussing direct healthcare professional communication about CAR T-cell medicines and will inform professionals about its new conclusion.

There are six approved CAR T-cell treatments in the EU: Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta. They treat a range of blood cancers.

In November 2023, FDA in the United States announced it was investigating the risk of T-cell malignancy following CAR T-cell immunotherapies (2). “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action,” FDA states on its website. “The initial approvals of these products included postmarketing requirements (PMRs) under Section 505(o) of the Federal Food, Drug, and Cosmetic Act (FDCA) to conduct 15-year long term follow-up observational safety studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment.” The agency also said that patients of these treatments should be monitored for life for new malignancies.

EMA. Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 10-13 June 2024. Press Release. June 14, 2024.

FDA. FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T Cell Immunotherapies. Nov. 28, 2024. 

https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous

Articles

PRAC is reviewing the risk of secondary malignancies in patients treated with CAR T-cell medicines. 

EMA Reviews Risks of CAR T-Cell Medicines and Painkillers

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

Red and white blood cells and in the vein | Image Credit: © Tatiana Shepeleva - stock.adobe.com

Global healthcare company, Grifols, announced on June 17, 2024 that its subsidiary Biotest has garnered its first FDA approval with the intravenous immunoglobulin (Ig) therapeutic, Yimmugo, which Grifols hopes to launch commercially in the United States in the second half of 2024 (1). FDA notified Biotest of the approval in a letter dated June 13, 2024 (2).

According to a press release from Grifols, Yimmugo was introduced in Europe at the end of 2022 and is being produced at a new, FDA-certified facility in Dreieich, Germany. This location was also previously approved for production and marketing throughout Europe.

Grifols cites a “growing demand for plasma-derived medicines” such as Yimmugo to treat primary immunodeficiencies (PIDs), meaning when a portion of the body’s immune system is missing or not functioning properly.

The Immune Deficiency Foundation further defines PIDs as a group of conditions, in excess of 450, which are considered rare, chronic, and disruptive to the immune system. They are also known as inborn errors of immunity (3).

Roland Wandeler, president of the Grifols Biopharma Business Unit, emphasized in the company’s press release the need for continued development of therapeutics for PIDs.

“The addition of Biotest’s Yimmugo to our strong portfolio of intravenous and subcutaneous immunoglobulins provides another innovative treatment option for patients with primary immunodeficiencies who rely on these essential medicines in their daily lives,” Wandeler said.

Two other plasma proteins being developed under the Biotest nameplate are currently in late-stage development for future clearance in the US and other worldwide markets. One is a fibrinogen concentrate (FC) for treatment of acquired fibrinogen deficiency; this would be the first FC approved for this indication in the US, according to Grifols (1). The other, trimodulin, is a polyvalent Ig to combat community-acquired and severe community-acquired pneumonia.

Grifols acquired Biotest in 2022 and called it “a strategic transaction that will contribute to expanding and diversifying Grifols’ plasma supply; strengthening its operations and revenues in Europe, Middle East and Africa; and supporting the company’s economic performance” (4). The acquisition increased the company’s available plasma-derived therapies and its fractionation capacity to more than 20 million liters of plasma annually.

“The Biotest acquisition is a fundamental milestone in our transformation plan, and is fully aligned with our growth strategy—strengthening our global plasma capacity, expanding our product portfolio in order to benefit more patients, complementing our innovation efforts with high value-added projects, and accelerating our presence in new markets,” said Víctor Grífols Deu, co-CEO of Grifols, at the time of the acquisition (4).

Grifols. Grifols’ Biotest Receives FDA Approval for Innovative Yimmugo® Immunoglobulin to Treat Primary Immunodeficiencies. Press Release. June 17, 2024. 

grifols.com/en/view-news/-/news/grifols-biotest-receives-fda-approval-for-innovative-yimmugo-immunoglubulin-to-treat-primary-immunodeficiencies

fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yimmugo

primaryimmune.org/understanding-primary-immunodeficiency/what-is-pi

Grifols. Grifols Completes the Acquisition of Biotest: A Strategic and Transformational Transaction to Accelerate Growth and Innovation. Press Release. April 25, 2022. 

grifols.com/en/view-news/-/news/grifols-completes-the-acquisition-of-biotest-a-strategic-and-transformational-transaction-to-accelerate-growth-and-innovation

Yimmugo, which was introduced in Europe at the end of 2022, could be on the market in the US within months.

FDA Approves Immunoglobulin Therapeutic to Treat Primary Immunodeficiencies

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Ascidian Therapeutics, a biotechnology company developing treatments by rewriting RNA, announced on June 18, 2024 that it has signed a licensing agreement with Roche to collaborate on the discovery and development of RNA exon editing therapeutics to treat neurological diseases (1). The collaboration will combine RNA exon editors with Roche’s next-generation central nervous system (CNS) delivery capabilities. Ascidian enables precise post-transcriptional editing of genes by editing exons at the RNA level.

As part of the agreement, Ascidian will receive an initial payment of $42 million with up to $1.8 billion in research, clinical, and commercial milestone payments, including commercial royalties. The partnership will allow Ascidian to create internal and collaborative programs within the neurology area. Roche will receive exclusive, target-specific rights to Ascidian’s RNA exon editing technology and will perform certain preclinical activities. Roche will also be responsible for further clinical development, manufacturing, and commercialization.

“Roche is known and respected worldwide for their expertise in complex neurological diseases, and I am proud of the scientific rigor and quality of the work done at Ascidian that has led to this partnership,” Michael Ehlers, MD, PhD, president and chief executive officer of Ascidian Therapeutics, said in a press release. “The potential of treating disease by large-scale exon editing of RNA is vast. We look forward to working with the Roche team to develop first-in-class RNA exon editing medicines for multiple neurological diseases, with a mission and passion to relieve suffering and improve lives.”

“Our partnership with Ascidian is an opportunity to harness advanced RNA exon editing technology, which has the potential to deliver transformative one-time therapeutics by editing multiple whole exons at the RNA level with a single treatment,” James Sabry, MD, PhD, global head of Pharma Partnering at Roche, said in the release.

In May 2024, Ascidian presented preclinical data that enabled the clearance of an investigational new drug (IND) application through Phase I/II testing for its RNA exon editor, ACDN-01, at the American Society of Gene & Cell Therapy (ASGCT) annual meeting in Baltimore, Md. FDA granted ACDN-01 Rare Pediatric Disease Designation as well as Fast Track Designation.

“ACDN-01 is the only clinical-stage therapeutic targeting the genetic cause of Stargardt disease, and we look forward to sharing the preclinical data that led to its IND clearance, along with the plans for the first-in-human trial,” said Ehlers in a press release (2). “ACDN-01 is designed to overcome challenges that have long kept Stargardt disease out of reach and to provide persistent therapeutic benefit with one dose. Our progress with ACDN-01 speaks to its therapeutic potential in Stargardt disease and the broader promise of our RNA exon editing platform to significantly expand the possibilities of RNA medicines.”

Ascidian Therapeutics. Ascidian Therapeutics Enters Collaboration with Roche for Discovery and Development of RNA Exon Editing Therapeutics Targeting Neurological Diseases. Press Release. June 18, 2024. 

https://ascidian-tx.com/wp-content/uploads/2024/06/Ascidian-Roche-Partnership-Press-Release_06.18.24.pdf

Ascidian Therapeutics. Ascidian Therapeutics to Present Preclinical Data for RNA Exon Editor, ACDN-01, Supporting an Open IND for Phase 1/2 Clinical Testing at ASGCT 2024 Annual Meeting. Press Release. April 25, 2024. 

https://ascidian-tx.com/wp-content/uploads/2024/04/FINAL-ACDN-01-ASGCT-2024-Curtain-Raiser_4.25.24.pdf

The research collaboration and licensing agreement will focus on the discovery and development of RNA exon editing therapeutics.

Roche and Ascidian Therapeutics Collaborate on Treatments for Neurological Diseases

Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Nadia Sellami, PhD, global segment lead for gene and cell therapy at PacBio interview

The Benefit of Long-Read Sequencing in Gene Therapies

At the American Society of Gene and Cell Therapy (ASGCT) conference in Baltimore, Md. in May 2024, 

® sat down with Nadia Sellami, PhD, global segment lead for gene and cell therapy at PacBio, about the benefits of long-read sequencing in cell and gene editing.

According to Sellami, long-read sequencing detects information that short-read sequencing cannot capture. “And in contrast to other long-read sequencing methods, it has higher accuracy while maintaining the same read length,” she says in this video interview. “So, for example, you can see long indels that you might get from gene editing. You can sequence the entire AAV [adeno-associated virus] molecule, ITR [inverted terminal repeat sequence] to ITR. You can sequence plasmids. You can sequence full length mRNA [messenger RNA] and so many more sequencing applications.”

DNA sequencing is important for the design, production, and quality of gene therapies, says Sellami. Click the video box above to view the full interview.

For more coverage from the 2024 ASGCT conference, visit PharmTech.com’s 

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Videos

Nadia Sellami, PhD, global segment lead for gene and cell therapy at PacBio, talks about long-read sequencing for cell and gene editing in a video interview. 

Joe Petroziello is Executive Vice President, Head of Global Medical Affairs & Corporate Development at MJH Life Sciences.

Gabi Hanna, MD, CEO and co-founder of Lamassu Pharma. 

In the realm of drug development, the industry puts a great deal of emphasis on centering the patient experience. As a result, it is imperative that drug developers consider how they translate scientific and medical knowledge into actionable insights that support the patient journey. To delve deeper into this topic, 

 sat down with Gabi Hanna, co-founder and CEO of Lamassu Pharma, to talk about the company’s beginnings, as well as its novel small molecule MDM2 inhibitor that activates P53 to control cancer growth.

Starting with the inception of Lamassu Pharma and the corporate focus, can you tell us about initial clinical indications?

 The company was founded in 2018 by three founders who are physicians and scientists. We focused on addressing unmet needs and translating scientific knowledge to patient care. When we started, there was a lot of knowledge but few options for conveying it to patients. That was the big gap we tried to bridge. I'm the director of the drug development center at Duke University. The second co-founder, Rabi Hanna, MD, is the director of pediatric oncology at the Cleveland Clinic. The third co-founder, Greg Palmer, PhD, is the associate director for the Duke Cancer Institute. With our experience, we had the basic knowledge to achieve our goal and maintain a focus on science while also remaining patient centric.

Our first project involved partnering with Mayo Clinic in 2019 to develop a treatment for acute pancreatitis. In just a few years, we advanced it to Phase I, partnered with another group, Arrivo BioVentures, completed Phase I successfully, and are now in Phase II. Two years ago, we partnered with the European company Adamed. We developed a very novel oncology platform focused on wild-type P53, which potentially can target 50% of all cancers. P53 is perhaps the most important gene regulating cancer; in fact, it's called the "guardian of the genome." Our therapy, a small molecule MDM2 inhibitor, activates P53 to control cancer growth.

What's the trajectory in sarcoma? Where are you in terms of development, and when will you initiate the clinical trial?

 The MDM2 inhibitor can potentially target up to 50% of cancers. We are focusing on sarcoma, a field in which treatment has not changed in ~30 years. We received investigational new drug (IND) approval from the United States Food and Drug Administration (FDA), and we have a novel therapeutic protocol agreed upon by the FDA. Our leading site is the Cleveland Clinic, so it will be a multi-site study that first starts with the Cleveland Clinic and lead to expansion. There is a consortium we will expand to, but we will begin with the acceleration phase, treating the first few patients at the Cleveland Clinic with our strategic partners leading the trial. We expect to have the first patient treated within the next two months.

Will this be a traditional dose-escalation study to find the optimal dose in Phase I?

 Yes. The approach will be traditional but also innovative. The FDA has allowed us, given the significant unmet need, to use a smaller group of patients to escalate the dose more quickly. Typically, dose escalation starts at a low, safe dose and gradually increases to find the best dose. However, this can be ethically challenging for cancer patients who might receive sub-optimal doses initially. The FDA is helping us by allowing a smaller patient group to escalate quickly. We will start with one patient to find the optimal dose faster, benefiting sarcoma patients who have limited treatment options.

Are you envisioning running the study entirely within the company, or will you potentially partner with pharmaceutical companies?

 We do not use contract research organizations (CROs). We run the trials directly due to our expertise, experience, and network. As mentioned, we come from academia, with scientific and practical backgrounds. We already have partnerships with the National Cancer Institute (NCI) and the National Institutes of Health (NIH). We have direct knowledge and collaboration with principal investigators and scientists. We've run CROs before, so we have the team to manage the trial directly. This approach serves patients best, accelerates development, and allows us to react in real time to any issues, which is crucial given that we are treating very sick patients.

We manage direct patient care with the principal investigator (PI) and the hospital. Our goal is to advance the drug to NDA approval. If we find a good partner along the way, we will partner, but we are not planning to conduct a study and then wait for a partner. However, like with our acute pancreatitis program, if we find a good partner, such as Arrivo BioVentures, we will collaborate. We are open to partnering in oncology at any stage if we find a suitable partner.

Other companies have studied the MDM2 pathway. What makes your approach different? Is it the P53 wild-type aspect?

That's correct. We consider our approach as more of a third-generation solution, addressing some of the safety issues seen before. There's no approved MDM2 inhibitor drug currently. One advantage of coming into this area later is learning from previous lessons, identifying potential pitfalls early, and testing whether we can overcome them. The disadvantage is that we are a bit behind, but we believe our asset could potentially be best in class. Our in-house testing shows it to be more potent and to have a better safety profile.

Additionally, P53 MDM2 represents a significant market. Targeting 50% of all cancer patients is a huge opportunity, with room for multiple routes if proven efficacious and safe. Sarcoma is one of the biggest unmet needs, with over 90% of sarcoma patients having P53 wild-type. Because it's a smaller market, with around 13,000 patients in the US, development can be faster. It falls under the rare oncology category. As a smaller company, we focus on early proof of concept before tackling larger cancer types. Scientifically and ethically, it is good to address the biggest unmet needs first. Starting strategically with the biggest unmet needs and smaller, more controllable studies allows us to expand to larger cancer treatments later.

In terms of clinical development priority, given that you're already in Phase II, would pancreatitis be your lead indication with cancer following that?

These are two different categories. We partnered with Arrivo BioVentures for pancreatitis, but they are not involved in the cancer aspect. Pancreatitis is inflammation, while cancer is a separate focus.

Tell us about the leadership team at Lamassu Bio and the growth trajectory in terms of expanding the team. How many full-time employees do you have right now?

We intentionally keep the team small to maintain direct oversight and efficiency. We aim to have three to four assets maximum, keeping the group small and focused. We work closely with universities and rely on outsourcing. We do have more than 10 but aim to keep it under 20. This smaller size allows for direct interaction and fewer hierarchical levels, enabling faster decision-making and problem-solving, especially when treating very sick cancer patients. We prioritize patient care over company interests, adhering to our ethical code.

Do you have any additional thoughts on the future directions of the company?

We are in discussions to bring in more partners and assets, particularly in oncology. We are expanding our team to manage trials directly and are also expanding to Canada, specifically Montreal, where we have established a partnership with McGill University. Our focus will be on oncology and direct management.

Gabi Hanna, MD, CEO and co-founder of Lamassu Pharma talks about a novel oncology platform and the link between science and patient care. 

Lamassu Pharma Bridges Scientific Knowledge and Patient Care

Dave Bearss, PhD, CEO, Halia Therapeutics. 

During BIO International Convention 2024, CEO Dave Bearss, PhD, of Halia Therapeutics, discussed the biopharmaceutical company’s progress in inflammation drug discovery. Founded in 2017, Halia Therapeutics supports the discovery and development of novel therapies to improve the lives of patients with inflammatory disorders and neurological diseases. 

Bearss discussed the clinical pipeline, upcoming announcements, and study readouts that others in the industry should look forward to, and personal thoughts regarding the industry’s focus on caring for patients with, or at risk for, chronic inflammatory diseases and neurodegeneration.

What is the current state of myelodysplastic syndromes (MDS) and inflammatory pain? What are your expectations, looking into the future clinical pipeline?

 It's been a busy year and an even busier summer. We’ve got a ton of good things going on. We have fully enrolled our post-procedural information study, meaning the evaluation of inflammatory pain after surgery. We are going to report the results of that study very soon. This is a randomized, placebo-controlled, blinded study. It will be the very first NLRP3 targeted drug to have randomized Phase II data reported out, so we are excited about this. We're excited to see what that data looks like. We are optimistic that there’s a positive signal there.

We started with a focus on MDS because we know the NLRP3-related inflammatory pathway is the driver of that disease and here we can sample the affected tissue. It's hard to do that in the brain, lung, liver, or heart. You can't. However, we can take bone marrow pretty easily and watch what happens from baseline. The reason why we started here is because we can read out results quickly and show that the drug is affecting biology in the way we expect.

We provided an update at EHA, the European Hematology Congress (2024). We've treated 16 people so far in that study, and we have 26 people in screening right now. And so, the study has really picked up. There are 40 patients total, planned to be in the study. We hope to have them all enrolled this year (2024). 

After four months of therapy, we want to look at hematologic improvement, marrow improvement, and quality of life. One of the challenges associated with MDS is that patients feel terrible all the time. In addition to being terribly anemic, they have active inflammation throughout their body, in their marrow. Because of this, they have cytokines constantly being pumped out. 

Having the capabilities to lower these, we should be able to make people feel better. So, we're very encouraged. I’d like to add that this is an open label study, so we can watch what's happening. So far, the longest patient on the study has been on it for six months. We started the Phase 2 study in December, so we're just analyzing the marrow from the first few individuals right now. This summer, we’ll have several more. We are hoping to get good objective responses.

For this specific indication a few drugs have been approved more recently, but they haven't really made an impact on the disease. We hope that we will be able to share something with the potential to modify the history of the disease and put people in a different place. We continue to generate data in the lab ourselves, and with collaborators that suggest that this pathway is the driver for these bone marrow failure disorders and anemia, more broadly. 

People don't realize how common anemia is. A lot of people walk around anemic and don’t realize that they are. In fact, most of anemia is not because they're iron deficient. Our body is efficient at absorbing and recycling iron. Most anemia is the result of inflammation.

Anemia of chronic disease, or anemia of chronic inflammation is a very common condition that is difficult to treat. Patients just learn to cope and live with the condition. The condition is associated with patient age, because we all have more chronic inflammation as we get older. In fact, the condition is very common. Almost one-quarter of the world's population has anemia. Some of that is transient, but a lot of it is chronic and impacts patients for a long time.

In addition, there’s a phenomenon called clonal hematopoiesis that no one ever speaks about and is not well understood. When we're young, our blood is produced by lots of different stem cells and clones in our body. As we age, a single clone actually starts to produce most of our blood. There are sensitive techniques available to help analyze this.

As we get older, our hematopoiesis shifts and that shift is driven by inflammation. Inflammation in the bone marrow can prevent the differentiation of normal hematopoietic stem cells. Those precursor cells there give rise to myeloid and erythroid cells, and platelets that come from a progenitor cell in the bone marrow. When you have inflammatory signaling in the marrow, it can block that differentiation.

I tell people the marrow is the hardest working tissue in our body. We have billions of blood cells. Our tissue is working like crazy. We have to have blood. Your body will find a way to fix whatever needs to be fixed. This is done by selecting mutations to overcome suppression. 

Obviously, having mutant blood cells doesn't sound like a positive thing, and it's not. And as patients age, mutations can accumulate in your marrow. They don’t necessarily lead to cancer, although they can. But they can increase the risk for the development of other diseases. If there are mutations found in a person’s white blood cells that were derived or were selected to overcome inflammation, those white blood cells are not normal anymore.

Halia Therapeutics headquarters in Lehi, Utah. 

What clinical data readouts can we expect over the course of the next 12 to 18 months?

 We’ll have the formal readout on the post-surgical information study by the end of this summer (2024). We’ll publish and present that data. That will be the first placebo-controlled randomized study for our program.

The MDS trial is actually a two-stage design. The initial stage will be analyzed this summer. The trigger to initiate an expansion study will be dependent upon seeing a certain level of responses in the first stage. We'll have that readout this summer as well.

We also have some other exciting data in other areas that we'll be releasing this summer. We have already publicly stated, but we'll announce the first patient treated on a new program that targets Alzheimer disease (AD). We're approaching AD very differently, and we are looking at high-risk populations—people who are APOE4 positive. APOE4 has been well established. It’s not a rare marker. In fact, 20-30% of the population has at least one APOE4 mutation or allele, and 2-3% of the population has two. Patients who are double positive have more than a 90% risk of developing AD. 

And our entire company, Halia Therapeutics, was founded on a genetic observation. We discovered a way to protect people who have APOE4 from developing AD. Through a human genetics study, we found another mutation that protects against this risk. And so, we have a clinical program, following up on that observation, that we’ll announce results on next month.

We've got a rapid development strategy for that in APOE4-positive patients who are pre symptomatic, so we're going to try to prevent AD, which is cool. Waiting and then trying to treat late-stage AD is a bad idea, right? You can't unscramble scrambled eggs. Once you have too much neurodegeneration, it’s hard to come back from that. A lot of great work has been done getting imaging endpoints and biomarker strategies validated and even FDA approved, and we believe we can leverage those tools to look at high risk populations and show they have changes pre-symptomatically, before they have cognitive effects. We already know their brain chemistry is starting to change. 

So, we're looking at people over age 50 who are double positive APOE4 and already shows signs of being on the on the path to AD, and are exploring the potential to take them off this path to AD. The human genetic experience says that we should be able to do this. There is another mutation that we found in a protein, RAB10. If we can inhibit RAB10 function, we can block the progression of AD down that pathway, specifically in people who are APOE4 positive. We’re very excited about this.

We are always looking for new, non-invasive ways to monitor symptoms of disease and to objectively track things. One of the big challenges in studying CNS disorders is a lot of the data is subjective. We’ve been looking to see if there are more objective ways to do this. In fact, we have a partner, Canary Speech, in Utah who has been developing specific vocal biomarkers, or speech biomarkers. It turns out that how we talk is indicative of a lot of things that are happening physiologically, especially things in our brain. We can measure things such as how much pain somebody's in. You can talk to physicians who, based on clinical experience, can pinpoint whether a patient is faking their symptoms based on certain cues. 

With help from Canary Speech, we’ve been training algorithms using speech biomarkers. In a 30 second recording, we can pick up over 2500 biomarkers that are reproducible and can distinguish between different disorders. We can assess for cognitive decline, depression, anxiety, etcetera. Maybe we can apply these to pre symptomatic patients and identify issues earlier than normal cognitive tests would detect symptoms.

When we consider the future and shifts toward digital capabilities like telemedicine, it’s been challenging. Physicians haven’t had the tools to help manage patients appropriately via a virtual call. But if you could put patients into a virtual waiting room and have them speak to an algorithm and then look at the data to assess pain levels, anxiety levels, etcetera, now physicians have something they can work with. So, we think there’s a future there. We are trying to get better at giving people tools to be able to monitor this stuff. And especially for things related to the brain, I think this all makes perfect sense.

 Even though the field has had a couple of approvals in the AD space, I don’t believe anyone thinks those are game changers, in terms of altering cognitive decline. I think everybody accepts the notion that we must get out in front of these diseases and determine how to prevent them. I’ve been reading statistics and we’re an aging population. Our birth rate has been declining for decades but the population is living longer. 

We have made some advances to help prolong life, but the problem with life prolongation is corresponding chronic conditions. I just read a statistic that if you add just one year of general health to the entire world's population, it is worth trillions of dollars to the economy. This is something we should all be thinking more about.

We all joke that nutrition and regular exercise is the answer to everything. In reality, there is a role, especially for patients with genetic predispositions or those who are predisposed to metabolic disorders or neurological disorders, to supplement healthy habits with interventions, and early. This has already been demonstrated. Statin therapy is probably one of the most successful examples. 

In regards to statin therapy, we had a biomarker that we could measure early, we had a drug that we could tie to that, and we've made an impact. It’s one of the reasons why we're living longer, right? The drug can be taken at a pretty low dose and has very few adverse effects. Right now, GLP-1 inhibitors are a perfect example. Everyone is excited about the potential for weight loss, but the long-term effects are exciting. It's not just weight loss. You're restoring a metabolic defect. We spoke earlier about the immune system. 

The immune system is actually very sensitive to the environment that those immune cells find themselves in and the nutrients they have available to them. The oncology world has been excited about taking the break off the immune system, but the gas of the immune system is the nutrients. If there are too many or too few, the way the immune system responds to certain signals is altered. 

Metabolic syndrome certainly affects what our immune system does. We're starting to see, already, some of the long-term benefits of these GLP-1 drugs aren't necessarily tied directly to weight loss but, instead, are tied to the restoration of metabolic function and can normalize the immune system. Even for Parkinson disease, a recent readout highlighted that GLP-1 drugs have demonstrated alleviation of symptoms. That's a game changer. We’re looking forward to releasing some data on targeting inflammation and using GLP-1.

What does the future hold for Halia Therapeutics?

 It’s very interesting. Right now, pharma is changing. We, as a field, are considering swinging the pendulum back, the other direction, to focus on some of the big problems we are facing, instead of only focusing on niche issues. At the start of my career, when statin therapy first began making an impact, stakeholders in the industry were very excited about the “big problems.” 

And then, the focus shifted to personalized medicine and isolation of small, more specific patient populations. Obviously, we've made progress and great advances, but I really like where we're headed. Let’s look at big stuff again and go after the big problems.

Novel approaches against chronic inflammation could potentially prevent certain inflammatory diseases and neurological conditions.

Pushing Boundaries to Revolutionize Chronic Inflammation Therapy

Considerations in Pharmaceutical Facility Design

The Pharmaceutical Technology Group spoke with John Bertagnolli, vice-president of Commercial Operations, at the 2024 CPHI North America event, about what it takes to create a new pharmaceutical facility. According to Bertagnolli, the building of greenfield facilities by contract manufacturing organizations (CMOs) is a new trend in the outsourcing industry. “It's usually an aging … pharma-owned, Big Pharma-owned facility [that is] repurposed as a contract manufacturing organization, or an existing company has … other parts of it built on so that they can do different parts of contract manufacturing,” Bertagnolli says.

He points to three milestones that CMOs should meet when building a new facility: completion of the facility, completion of the first aseptic process simulation (APS), and regulatory approval and manufacture of the first product. “[W]hen we're talking about the APS, it's what used to be referred to as the media fill, but [FDA] has put some much … tighter bounds around what they call aseptic process simulation. And because of that, it truly is the final exam for a facility to say, yes, we know we can manufacture sterile product to the correct level that would meet [FDA] requirements. [I]n the case of building a brand-new greenfield site, that also means that you've done all of the characterization of the site from a microbiological perspective, so that you know how all the monitoring is done, that all of the utilities have been established and validated, and you have data to make sure that they're doing exactly what they should be doing.”

Click the video above to watch the full interview. CPHI North America occurred May 7–9 in Philadelphia.

John Bertagnolli, vice-president of Commercial Operations at Selkirk Pharma, discusses considerations when building and scaling up pharmaceutical facilities, including contamination control and aseptic processing challenges.

Considerations in Pharmaceutical Facility Design (CPHI North America 2024)

Feliza Mirasol is the science editor for 

Purolite, Ecolab’s resins business, and Repligen launched a new protein A chromatography resin, DurA Cycle, for large-scale purification processes in June 2024. The companies introduced the new product at BIO 2024, which occurred on June 3–6 in San Diego, Calif.

The new resin is designed for the large-scale commercial manufacturing of monoclonal antibodies (mAbs) and represents the latest addition to Purolite's toolbox. In the past 18 months, Purolite launched two other new resins that address purification challenges related to the increasingly complex drugs progressing through the industry pipeline.

“The launch of DurA Cycle chromatography resin underscores Ecolab’s 100-year heritage of innovation and ongoing investment in Purolite, reaffirming our commitment to the bioprocessing industry. This new resin enables biologic developers to increase manufacturing efficiencies, reduce their cost of goods, and accelerate the delivery of innovation to the clinic,” said Srini Paluri, senior vice-president and general manager at Purolite, in a June 3, 2024, company press release.

This latest resin launch follows Purolite’s earlier investment in a new bioprocessing production facility in Landenberg, Pa. The Landenberg expansion includes the construction of resin production facilities, cleanrooms, laboratories, and new office space. There is also additional space available at the site for future expansion. This site will be Purolite’s fourth location in Pennsylvania and its sixth manufacturing facility globally. The Landenberg site is expected to significantly expand production capacity and to add more than 150 skilled jobs in the area over the next five years (1).

The Landenberg facility will produce high-quality agarose chromatography resin for the downstream purification of mAbs and recombinant proteins. It will also support the purification of new modalities such as cell therapy, gene therapy, and messenger RNA-based therapeutics. With the expanded production capacity offered by the Landenberg site, Purolite expects to better support innovators worldwide with purification resin capabilities that increase yield, optimize productivity, and reduce time-to-market (1).

The Landenberg facility complements Purolite’s Wales, UK-based facility by providing manufacturing capabilities across two world regions. The earlier manufacturing expansion in the UK site is expected to triple Purolite’s production capacity of innovative resins (2).

“The bioprocessing industry is seeking partnerships that can effectively address the most complex challenges in biologic manufacturing. Our collaboration with Purolite, an Ecolab Company, advances industry progress by delivering cutting-edge solutions that meet these demands. Together, we are paving the way for the future of bioprocessing,” said Ralf Kuriyel, vice-president of R&D, Repligen, in the press release.

1. Purolite. Purolite Grows Bioprocessing Production Capacity with New US Manufacturing Facility. Press Release, June 6, 2023.
2. Purolite. Purolite's New State-of-the-Art Facility Marks Innovative Bioprocessing Manufacturing Expansion. Press Release, Oct. 13, 2022.

Ecolab Life Sciences and Repligen have launched a new affinity resin, DurA Cycle, for large-scale biologics manufacturing.

New Affinity Resin Launched by Ecolab Life Sciences and Repligen for Biologics Manufacturing

Krizia M. Karry, PhD, ishead of Global Technical Marketing, Pharma Solutions, BASF.

Brian Carlin is president and owner of Carlin Pharma Consulting LLC.

Nigel Langley, PhD, MBA, is global technical director at Gaylord Life Sciences and Immediate Past Chair, IPEC- Americas.

R. Christian Moreton, PhD, is vice-president of pharmaceutical sciences at Finnbrit Consulting and a member of Pharmaceutical Technology’s editorial advisory board.

David Schoneker is president, Black Diamond Regulatory Consulting, LLC

Katherine L. Ulman is president of KLU Consulting.

Joseph Zeleznik is technical product director, IMCD US

An essential factor to consider when developing a robust continuous manufacturing (CM) process is the impact that inherent excipient and API physicochemical variations can have on the drug product performance, CM unit operations, or CM process as a whole.

This paper examines the key information needed for excipients and their potential impact on CM processes. Much of this information is derived from several presentations made at a 

 (PQRI) workshop entitled, “Managing Excipient and API Impact on Continuous Manufacturing”, held virtually on May 17–18, 2022 (1).

CM involves continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from an interconnected manufacturing process in which two or more-unit operations are directly integrated. While many excipients have been continuously manufactured for decades, the use for pharmaceutical drug products, particularly oral solid dosage (OSD) forms, is relatively new. Knowing how excipient physicochemical properties impact CM, whether as a whole or in individual unit operations, needs to be understood to implement a rigorous control strategy and ensure a robust CM process. Not every excipient will have a direct impact on the overall process but may affect individual unit operations to some degree.

Most regulatory guidelines apply only to APIs and drug product manufacture but not excipients (e.g., International Council for Harmonisation [ICH] Q13 [2]). However, regulators and other organizations are discussing what impact excipients may have on CM and what controls or understanding are needed to ensure success in the development and manufacture of pharmaceutical products through continuous processes. One example is International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and how the various IPEC guides may assist in understanding the role of excipients in CM.

CM is also gaining traction in the manufacture of biologic drug substances and their dosage forms. Many biologics are liquids intended for injection and excipient considerations for CM of liquid biologic drugs are quite different than for OSDs. This article will focus on CM for OSDs.

CM offers efficiency, cost-effectiveness, and real-time quality control in a reduced footprint compared to traditional batch manufacturing. However, this shift from batch-based to continuous production hinges on one critical factor: understanding and controlling the material properties of the raw materials involved.

A growing body of knowledge is being developed on this topic for CM of liquids, semisolids, and OSDs. The majority of FDA- and European Medicines Agency (EMA)-approved commercial CM drug products are OSDs, particularly tablets, manufactured via direct compression or twin-screw granulation platforms.

The following sections focus on highlighting the importance of characterizing raw materials and understanding their variability for manufacture of OSDs. General considerations based on unit operations and specific case studies are provided.

Why are material properties so important? 

The impact of raw material properties on process performance and drug product quality has been extensively studied. Understanding this impact does not automatically translate to robust processes and products. Control strategies to accommodate the impact of raw material variability should minimize the number of alarms and process interruptions and give robustness and consistent product quality.

For continuous manufacturing of OSDs, the following are three major reasons why it is important to proactively evaluate the impact of raw material properties:

 Variations in material properties can impact product critical quality attributes (CQAs) such as drug release, potency, and ultimately, patient safety.

 Predictable material properties reduce the risk of mass flow deviations from their set point, minimizing alarms and process downtime, and maximizing process and process analytical technologies (PAT) model robustness. Robust models require less updates and, if used for real-time release, reduce downtime and supply chain disruptions.

 Tailoring process parameters based on material properties (e.g., via design spaces) can improve efficiency, yield, and overall cost-effectiveness (faster return on investment [ROI]) of the manufacturing platform.

Powder properties that impact unit operations in CM. 

CM, when optimized, allows for enhanced predictability and control. Understanding the impact of raw material variability on process performance will allow for the design of a control strategy that ensures continual high drug product quality. A comprehensive list of all the material properties that can impact formulation and process development of liquids, creams, gels, and OSDs, is outside of the scope of this article. To date, most CM approvals have been for OSDs. The following is a list of the material properties to consider for manufacturing pharmaceutical tablets or capsules:

Particle size distribution can impact flowability, cohesion, mixing dynamics, blending time, and granulation torque.

Bulk density needs to be considered in feeder design. Light, fluffy powders are more difficult to feed and compress, and may require pre-blending steps before incorporation in a continuous process line.

Surface area and morphology properties can influence electrostatics or tribocharging, tablet ejection force, drug dissolution, and film coating effectiveness.

Flowability and cohesiveness (inverse correlation) determine powder handling, feeding configurations, mass flow alarms and noise/smoothing averages, blending efficiency, pre-compression parameters, and others. A shift in excipient or API cohesion can impact its flowability and thus how efficiently it fills screw flights. These differences can require new feed factor calibrations (grams delivered per revolution) and control parameter tuning on screw speed to reach the mass flow setpoints. Additionally, poor flowing blends can introduce increased tablet and capsule weight variability and thus impact overall assay. Paradoxically, a free-flowing blend can also segregate more easily as it moves downstream to the tablet press or capsule machine and flood the dies wherein increased tablet weight variability is the system response.

Compressibility refers to changes in powder volume as an effect of applied normal force. Excipients with higher compressibility are generally more cohesive (they can function as binders) and are sensitive to shear. Increased head pressure when charging material into the feeder hopper (refill) will increase powder packing and, for highly compressible materials, this can lead to bridges and densification in the screws, ultimately negatively impacting mass flow variability. Refill limits and charging systems (manual vs. pneumatic, for example) should be designed with material compressibility in mind.

Moisture content impacts blend hold time (potential for microbiological contamination), powder flowability, tribocharging, tableting properties, and drug product stability.

Characterization technique considerations. 

Performance-related properties—the physical characteristics of excipients that may impact performance and drug product manufacturability—are generally not comparable due to multiple, non-standardized methods. Formulators are then required to test these as part of product development and include the results in risk assessments and regulatory submissions that contain the product knowledge and history.

For example, particle size distribution can be determined by laser diffraction or sieve analysis, and other techniques. Flowability can be described based on Hausner Ratio, Carr’s Index, Angle of Repose, or powder rheometry. Considering that there are multiple ways to test an attribute, the details of the method are as important as the results to allow comparability.

Having standardized methods offer several benefits:

Data comparability enables consistent comparison of data across different labs, sites, and batches.

if methods are standardized, sites can share a raw material database with known interactions with their unit operations (process performance) and drug product quality. This would allow for a prediction of process and product robustness, such that precise adjustments to process parameters like refill limits and blending speeds can be tuned based on factors like compressibility and flowability. This ensures consistent product quality throughout continuous production.

Improved communication and collaboration—standardized data creates a common language for communication among scientists, engineers, and regulators. This can allow for faster technology and product transfer amongst company sites, and clear communication from the user to the excipient supplier and vice versa in cases of investigations.

Reduced costs and risks—accurate and comparable data minimizes the need for extensive re-testing and troubleshooting, leading to cost and full-time equivalent (FTE) savings, and reduced risk of production delays associated with inconsistency in raw material behavior.

The successful implementation of CM in the pharmaceutical industry relies heavily on the reliable assessment of raw materials—both excipients and API. Inconsistency in raw material properties can have a domino effect, impacting process stability, product quality, and ultimately, patient safety. Standardizing characterization techniques can mitigate these risks and ensure successful CM implementation.

Impact of material properties and variability on continuous manufacturing

To understand excipient variability, it might be helpful to understand several factors. Excipients, particularly those that are naturally derived or quarried and refined, often have complex multicomponent compositions. Changes in seasonal growing conditions, for example, may result in varying composition, even if only slight, which could impact physical and/or functional properties. Unlike many pharmaceutical products, excipients are sometimes manufactured on a metric ton scale, often by CM. This leads not only to batch-to-batch variability (inter-batch variability), which is often monitored, but also excipient intra-batch variability, or package-to-package variability. While a well-designed, robust continuous process for drug product can manage excipient variation that might otherwise adversely affect process, product quality, or performance, understanding slight variations within an excipient (or API) batch can assist in designing a robust CM process.

Raw material properties, both physical and functional, can impact process behavior due to the particle–particle interactions taking place throughout the equipment train. Using a quality-by-design (QbD) approach to understand material attributes and their impact on the process and product can facilitate better product robustness. Individual ingredients should be characterized for their intended role in a formulation in addition to how the interactions among ingredients impact the CM process and product quality. For example, understanding segregation tendency during manufacture may help with ingredient selection before moving forward with process design. By understanding the critical material attributes, and modeling one or more continuous process designs, the best outcome can be achieved.

Excipient variability can also lead to changes in the PAT signal and consequent analysis. PAT feedback is critical in implementing an adequate control strategy and ensuring a robust CM process.Without a defined control strategy with PAT input, process drift could lead to product or process failure, affecting yield. Assessing the effect of material changes on residence time distributions and from there on, establishing actionable system responses to disturbances are key to ensuring consistent product quality and process performance. Given the limitations of material introduction into the continuous process, excipient performance then assumes greater importance in CM.

CM provides the ability to isolate non-conforming material without compromising the batch in its entirety. CM also mitigates much of the tech transfer risk associated with traditional batch manufacturing, primarily through elimination of scale-up. However, CM by itself does not mitigate raw material risk. Formulation design should be guided by the finished product CQAs regardless of whether the product is manufactured continuously or batch-wise. CM reduces the process degrees of freedom relative to batch manufacturing, but not the impact of raw material variations.

The output from a continuous manufacturing run is variable, dependent on run time, in contrast to the fixed output from a batch process, which is dependent on equipment size. The ICH Q13 guideline includes an example of a CM tablet noting that “the continuous process verification approach, coupled with appropriate regulatory action for reporting manufacturing changes, was used to validate run time extensions beyond current experience” (2). Excipient selection should consider potential risks from extended running, such as fouling of tooling.

Excipients should not need tighter specifications in CM than in batch processing. The process should be designed such that any transient disturbances associated with raw material variability are averaged out according to the residence time distribution of the CM process. Excipient variability may be more visible due to PAT, as the smaller working volumes in CM allow better temporal and spatial correlation with excipient variability.

In CM, the significance of a disturbance is a function of its magnitude and duration. The robustness of CM is demonstrated by the example in the ICH Q13 guideline where a disturbance of ±20% lasting less than 90 seconds would not cause the drug concentration in the blend to exceed the 90–110% label claim (see 

). Similarly, for a ±5% disturbance of 300 seconds or 5 minutes, the product would still meet label claim. 

It is likely that CM will provide more insight into excipient impact especially if the greater amount of PAT data associated with CM can be subjected to multivariate analysis. The IPEC QbD guideline (3) provides methods for the categorization and control of excipients.

Key information is needed for excipients and their potential impact on continuous manufacturing processes.

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