Susan Haigney

AAPS PharmSci 360 2024: Flex Manufacturing

As a preview of what’s to come at this year’s AAPS PharmSci 360, being held Oct. 20–23, 2024 in Salt Lake City, UT, 

® sat down with Anna Jenks, director of Pharmaceutical Operations for Merck & Co., Inc. (known as MSD outside of the United States and Canada) in Rahway, NJ, USA to talk about her 

 for the conference and the benefits of utilizing flexible manufacturing.

“Flexible manufacturing really relates to the industry and the needs of the industry,” says Jenks in the interview. “I think, from [a] historical facility standpoint, oftentimes we build fixed facilities that are harder to change. Flexible manufacturing looks at what we need now, but also is looking at what we need in the future, and even recognizing we don't know everything that we need, and we need to be able to change in the future when that need comes.”

At Merck & Co., Inc., Rahway, NJ, USA, Jenks states that they are focused on using flex manufacturing in clinical stage manufacturing but are looking to also apply it to commercial manufacturing.

“The clinical manufacturing has a short-term turnaround,” Jenks says. “Oftentimes, you see many short campaigns that are on days to weeks timeframe[s] and need fast switchover from one to the next, whereas the commercial manufacturing oftentimes has low, longer timeframes. So, you're looking, in a few years, [at] what kind of process train might be needed, and how are those retrofits going to occur. So the needs of flexible manufacturing might be slightly different, but the concepts definitely apply.”

Click the above video to watch the full interview.

 AAPS PharmSci 360 is being held Oct. 20–23, 2024 in Salt Lake City, UT.

Videos

Pharmaceutical Technology sat down with Anna Jenks, director of Pharmaceutical Operations for Merck & Co., Inc. in Rahway, NJ, USA to talk about her prologue presentation for AAPS PharmSci 360 2024.

Science laboratory test tubes, laboratory equipment | Image Credit: © BillionPhotos.com - © BillionPhotos.com - stock.adobe.com

On Sept. 26, 2024, FDA announced that the agency has approved Bristol Myers Squibb’s (BMS) Cobenfy (xanomeline and trospium chloride) capsules to treat schizophrenia in adults. The approval is significant because it is the first treatment for schizophrenia that targets cholinergic receptors. The standard treatments target dopamine receptors.

The approval was based on results from two identical studies; both were five-week studies that were randomized, double-blind, placebo-controlled, and multi-centered. Study participants were adults diagnosed with schizophrenia according to DSM-5 criteria.

“The primary efficacy measure was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at week 5. The PANSS is a 30-item scale that measures symptoms of schizophrenia. Each item is rated by a clinician on a seven-point scale. In both studies, the participants who received Cobenfy experienced a meaningful reduction in symptoms from baseline to Week 5 as measured by the PANSS Total Score compared to the placebo group,” FDA stated in the press release (1).

According to FDA, symptoms of schizophrenia include “hallucinations, difficulty controlling one’s thoughts, and being suspicious of others.” Patients may also have cognitive problems and difficulty with social interactions. Schizophrenia impacts approximately 1% of Americans and is one of the 

 of disability worldwide (2). Schizophrenia also poses a greater risk of death at a young age.

“Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a person’s quality of life,” said Tiffany Farchione, MD, director of the Division of Psychiatry, Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, in a press release. “This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed.”

“Today’s landmark approval of our first-in-class treatment for schizophrenia marks an important milestone for the community, where after more than 30 years, there is now an entirely new pharmacological approach for schizophrenia—one that has the potential to change the treatment paradigm,” said Chris Boerner, PhD, board chair and chief executive officer at BMS, in a company press release (3). “As we reenter the field of neuropsychiatry, we are dedicated to changing the conversation around serious mental illness, beginning with today’s approval in schizophrenia.”

“For people living with schizophrenia, it's often difficult to find a treatment that works for them. Having a variety of treatment options gives patients and healthcare providers the tools to help manage this serious condition,” said Gordon Lavigne, chief executive officer of the Schizophrenia & Psychosis Action Alliance, in the BMS press release (3). “People living with schizophrenia want and deserve more. Today's approval provides a new option as people with schizophrenia move forward with proper support to rebuild their lives.”

“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” said Rishi Kakar, MD, chief scientific officer and medical director at Segal Trials and investigator in the EMERGENT program, in the press release (3). “The approval of C[obenfy] is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, C[obenfy] offers a new option to manage this challenging condition.”

Cobenfy, however, may cause urinary retention, and should not be prescribed to patients with urinary retention, according to FDA. There is also the possibility of increased heart rate, decreased gastric movement, or angioedema (swelling) of the face and lips. Liver damage is also a risk and, therefore, the drug is not recommended for patients with liver impairment. Patients with moderate to severe renal impairment should also avoid the drug as it is substantially excreted by the kidneys.

Common side effects include nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, increased heartbeat, dizziness, and gastroesophageal reflux disease.

FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia.

 Press Release. Sept. 26, 2024.
2. NIMH. Schizophrenia. NIMH.NIH.gov (accessed Sept. 27, 2024). 

https://www.nimh.nih.gov/health/statistics/schizophrenia


3. BMS. US Food and Drug Administration Approves Bristol Myers Squibb’s COBENFY (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults. Press Release. Sept. 26, 2024.

Articles

The new mechanism of action targets cholinergic receptors instead of the standard dopamine receptors.

FDA Approves Schizophrenia Treatment that Targets Cholinergic Receptors

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - © Artur - stock.adobe.com

The European Medicines Agency (EMA) announced on Sept. 26, 2024 that its Committee for Medicinal Products for Human Use (CHMP) has recommended that the marketing authorization for the sickle cell disease (SCD) drug, Oxbryta (voxelotor), be suspended. EMA stated in the press release that this is a precautionary measure as emerging safety data are reviewed (1). Sickle cell disease, according to EMA, is a genetic disease that produces an abnormal form of hemoglobin causing red blood cells to become rigid and sticky.

Data from two registry-based studies show that patients had a higher occurrence of vaso-occlusive crises (VOC) while being treated with Oxbryta. VOC are a common complication with sickle cell disease where patients experience episodes of acute pain that may lead to arthritis, kidney failure, or stroke.

The data were found during a benefit-versus-risks review of the medicine that was started in July 2024 because clinical trial data showed a higher number of deaths involved with use of Oxbryta. “In this context, the CHMP considered that, overall, these data raise serious concerns about the safety of Oxbryta; due to the increased uncertainties it therefore recommended that the authorization, marketing and supply of the medicine be suspended until all the available data have been assessed in the ongoing review,” the agency stated in a press release (1).

EMA is recommending that doctors not begin the use of Oxbryta with any new patients. Doctors should also stop treatment with those patients already using the medicine. Patients who have used Oxbryta should also be monitored for adverse events.

Pfizer, the marketing authorization holder of the medicine, is voluntarily withdrawing the medicine from areas in which is available and is discontinuing clinical trials and expanded access programs worldwide (2), stating in a press release that the benefits of the drug no longer outweigh the risks.

“The safety and well-being of patients is of the utmost importance to Pfizer, and we believe this action is in the best interest of patients,” said Aida Habtezion, chief medical officer and head of Worldwide Medical and Safety at Pfizer, in the press release (2). “Our primary concern is for patients who suffer from SCD, which remains a very serious and difficult-to-treat disease with limited treatment options. We advise patients to contact their physicians to discuss alternative treatment while we continue to investigate the findings from our review of the data.”

Oxbryta is indicated for the treatment of hemolytic anemia in patients aged 12 years and older with sickle cell disease and works by increasing oxygen affinity in hemoglobin. “Oxbryta inhibits sickle hemoglobin polymerization and the resultant sickling and destruction of red blood cells leading to hemolysis and hemolytic anemia, which are primary pathologies faced by every single person living with SCD,” Pfizer stated in the press release (2).

EMA Recommends Suspension of Sickle Cell Disease Medicine Oxbryta.

Pfizer Voluntarily Withdraws All Lots of Sickle Cell Disease Treatment Oxbryta (voxelotor) From Worldwide Markets

The agency is recommending that the market authorization for Oxbryta (voxelotor) be suspended so that emerging data may be reviewed.

EMA Suspends Sickle Cell Disease Medicine

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - © Cagkan - stock.adobe.com

Cryoport, a supply-chain service company, and SK pharmteco, a contract development and manufacturing organization, announced on Sept. 25, 2024 that the two companies are entering into a partnership to provide integrated logistics and manufacturing services to bio/pharmaceutical companies. Cryoport will support SK pharmteco by providing end-to-end cell and gene therapy services that include biomaterial collection, shipping systems, data solutions, and bioservices.

“We are delighted to be selected by SK pharmteco in supporting its manufacture of APIs and intermediates, biopharmaceuticals, and cell and gene therapies,” said Jerrell Shelton, CEO of Cryoport, in a press release (1). “Our organizations share a mission to support the life sciences by helping bring lifesaving treatments to patients. This relationship not only extends our reach to more people in need but also aligns with Cryoport’s strategic goal to further diversify and enhance our revenue streams, particularly as we continue to drive higher revenue from the support of commercial cell and gene therapies.”

Dana Cipriano, vice president, Analytical Services for SK pharmteco, added, “The cell and gene therapy industry continues to see substantial growth, and ensuring the safety and integrity of the supply chain is essential for these products. We are dedicated to our clients, and partnering with Cryoport reflects our commitment to providing the highest-quality services that are specifically tailored to meet the needs of our customers and the patients they serve.”

In April 2024, SK pharmteco also entered into an agreement with Ferring Pharmaceuticals to provide scale-up manufacturing capacity for the company’s gene therapy,Adstiladrin (nadofaragene firadenovec-vncg) to ensure long-term supply of the treatment for bladder cancer.

“SK pharmteco is proud to partner with Ferring Pharmaceuticals as a manufacturer of the breakthrough gene therapy Adstiladrin,” said Joerg Ahlgrimm, chief executive officer, SK pharmteco, in a press release at the time of the announcement (2). “Our integrated approach, incorporating customizable clinical and commercial GMP [good manufacturing practice] manufacturing solutions with comprehensive in-process testing, quality control, and lot release programs, provides unparalleled support to our partners throughout their product lifecycle and is in perfect alignment with our mission of expediting the delivery of potentially life-saving therapies to patients across the globe.”

In other company news, SK pharmteco’s facility in Swords, Ireland celebrated its 60th anniversary in August 2024 (3). The Swords facility was acquired in 2018 by SK biotek, and therefore, became the first Korean company in Ireland.

“It is an honor to commemorate 60 years of our Swords facility,” said Joyce Fitzharris, President of SK pharmteco Small Molecule, Europe, and leader of the Swords facility, in the press release. “This milestone is a testament to the unwavering dedication of our employees, who have consistently driven innovation and quality. We are committed to transforming lives through the development of life-impacting therapies, and this anniversary reflects our journey thus far.”

SK pharmteco. SK pharmteco and Cryoport Partner for Cell and Gene Therapy Logistics and BioServices. Press Release. Sept. 25, 2024.

SK pharmteco. Ferring Pharmaceuticals and SK pharmteco Enter into Commercial Gene Therapy Manufacturing Deal. Press Release. April 18, 2024.

SK pharmteco. SK pharmteco’s Swords Facility Celebrates 60 Years of Pharmaceutical Excellence. Press Release. Aug. 26, 2024.

The two companies are partnering to provide logistics and manufacturing services to biotechnology and pharma companies.

Cryoport and SK pharmteco Partner on Cell and Gene Therapies

Cell and Gene Therapy Production Facilities

Once a therapy has been discovered and proven, it has to be manufactured in order to reach patients. However, depending on the therapeutic modality, companies can be left with a difficult decision of whether or not their existing facilities will meet their manufacturing needs or whether they need a new facility entirely. Cell and gene therapies come with unique challenges that must be considered when either building a new manufacturing facility or expanding an existing one. Peter Walters, Fellow of Advanced Therapies at CRB Group, gives his insight on some of the challenges and benefits of creating new production facilities and/or expanding on what is already available.

To ensure one follows current good manufacturing practices when building a new facility for the production of cell and gene therapies, Walters stresses that one should understand the requirements by reading the European Medicines Agency (EMA) or the Pharmaceutical Inspection Co-operation Scheme (PIC/S) guidelines. “[T]hose, I think, are the most prescriptive in terms of what is expected and what is possible to do with your facility and your equipment, and the kinds of classifications [and] handling requirements required,” says Walters. “I think it's important to brush up on those, because cell therap[ies] especially have requirements that are a bit nuanced and different than a lot of other biotech—a lot going to chain of custody, a lot going to the degree of segregation that has to happen, the degree of quality control that has to happen, especially with open operations. A lot of these therapies can't be sterilized just prior to filling, and so they have to be handled with extreme care throughout the entire lifespan of their production, and so, … understanding those requirements is going to be crucial [to make] sure you've got a facility and an equipment plan and a development plan that's going to get you the whole way through to commercial.”

When it comes to using a current facility to expand a cell or gene therapy pipeline, Walters says, “I think we've seen a number of companies successfully, effectively, more or less bolt on a production facility onto their existing building, or build a small [campus], [such as] create a small building that has a spine that connects it, or something like that.

And so that way you're not really disrupting your ongoing production, but you gain the access to that office space. You gain access to the labs and the warehousing and all of that sort of shared, common support space that maybe can be leveraged across both [and] utility systems can sometimes be split between the two. [T]hat way, you can create a new production that doesn't have to come with the cost of a whole new mechanical infrastructure, and especially if we're talking about cell therapy, typically, those types of facilities have a larger air handling load sometimes, but they can be smaller clean rooms. And so, the overall load could be small, and then the rest of the utility load might be very, very low.”

Click the video above to watch Peter answer the following questions:

My company is planning new construction of a cell and gene therapy production facility. How can we ensure it meetings CGMP requirements?

How can we use our current facility to expand our cell and gene therapy pipeline?

Peter Walters is Fellow of Advanced Therapies at CRB Group.

Welcome to the Ask the Expert video series. This series is an extension of the PharmTech Group’s long-running print column in which industry experts answer common quality and regulatory questions from the industry. This new video series will expand on topic areas to include development and manufacturing concerns to help those working in the industry better understand bio/pharmaceutical requirements. Have a question you would like answered? Send it to 

, and it may appear in a future episode or print column.

In this episode of the Ask the Expert video series, Peter Walters, Fellow of Advanced Therapies at CRB Group, discusses factors to be considered in constructing a new facility for cell and gene therapy production as well as using an existing facility to expand cell and gene therapy pipelines.

In late September 2024, FDA approved two drugs for the treatment of neurological symptoms associated with Niemann-Pick disease, type C (NPC) in both adults and children. According to FDA, patients with NPC experience progressive neurological symptoms and organ dysfunction caused by changes in the NPC1 or NPC2 gene that impact the transport of cholesterol and other lipids in a cell. This is a rare genetic condition, and patients with NPC may live only approximately 13 years (1).

Miplyffa (arimoclomol), approved on September 20, is the first treatment approved by FDA for NPC and is an oral medication used in combination with the enzyme inhibitor miglustat to treat NPC symptoms in adults and children two years of age and older. FDA’s 

Genetic Metabolic Diseases Advisory Committee

 discussed the application for Miplyffa at its first meeting in August 2024 (2, 3). The approval was based on results from a randomized double-blind, placebo-controlled 12-month trial that included patients aged two to 19 years of age. Of those patients, 50 were “randomized 2:1 to treatment with weight-adjusted Miplyffa (31 to 124 mg) or placebo orally three times per day. Among these 50 patients, 39 (78%) received miglustat as background treatment in the trial.” These studies showed that Miplyffa resulted in slower disease progression compared to placebo.

“NPC is a serious disease that leads to enormous adverse impacts on patients and families. Despite extensive research efforts, there have not been approved treatments to meet the significant needs of patients,” said Janet Maynard, MD, director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine in the FDA’s Center for Drug Evaluation and Research, in a press release (1). “The first-ever approval of a safe and effective drug option for NPC will undoubtedly support the essential medical needs of those suffering.”

The second drug, Aqneursa (levacetylleucine), was approved on September 24 to treat NPC in adults and children who weight at least 15 kilograms. A randomized, double-blind, placebo-controlled, two-period, 24-week crossover study found that patients treated with Aqneursa for 12 weeks had better outcomes in the functional Scale for the Assessment and Rating of Ataxia (fSARA) compared with those that received a placebo. The fSARA evaluates “gait, sitting, stance, and speech disturbance domains of the original SARA with modifications to the scoring responses” (4).

“This is the second treatment the FDA has approved for NPC within the span of a week. Today’s action further underscores the agency’s commitment to support development of new treatments for rare diseases,” said Maynard, in a press release (4). “This approval again demonstrates the FDA’s commitment to work with the scientific community toovercome the unique challenges that may arise with rare disease drug development.”

FDA. FDA Approves First Treatment for Niemann-Pick Disease, Type C. Press Release. Sept. 20, 2024.

FDA. Updated Public Participation Information: August 2, 2024: Meeting of the Genetic Metabolic Diseases Advisory Committee Meeting Announcement. Aug. 2, 2024.

FDA. Genetic Metabolic Diseases Advisory Committee. 

FDA. FDA Approves New Drug to Treat Niemann-Pick Disease, Type C. Press Release. Sept. 24, 2024.

Two drugs, Miplyffa (arimoclomol) and Aqneursa (levacetylleucine), have been approved by FDA to treat neurological symptoms associated with Niemann-Pick disease, type C in adults and children.