Susan Haigney

Quality Considerations in Changing Excipient Providers

Ask the Expert June 2024

Changing excipient providers is not as simple as it may seem. The surge of complex therapeutics makes it even more complicated, according to Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. “I would go visit them and look at their culture and what they're doing in the way of change control and how their QMS is handled, because that is going to be critical to securing your supply chain with this new excipient provider,” Schniepp says.

According to Siegfried Schmitt, vice president, Technical at Parexel, excipient providers are inspected by regulators and require audits to be performed by the company purchasing the ingredients. “And there are various ways of performing an audit. Of course, it doesn't always have to be on site, in person. It can also be, for example, [a] questionnaire [sent to the supplier], and you hope you get something filled in truthfully. You can perform online searches. Many excipient providers have very good reputations and standings in industry, and some also provide audit reports or certifications from independent companies like EXCiPACT,” Schmitt adds.

Click the video above to watch Sue and Siegfried answer the question: “My company is looking at changing our excipient provider for our therapeutic pipeline, what quality issues should we consider when choosing the grade of our excipients and what should we ask of our new provider?”

 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. 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. We hope you enjoy the discussion!

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates and a member of 

Siegfried Schmitt is vice president, Technical at Parexel and a member of 

Videos

In the premiere episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss the challenges involved in changing an excipient supplier. 

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 United States Pharmacopeia (USP) announced on June 13, 2024 that it is collaborating with the African Union Development Agency (AUDA –NEPAD), the Africa Centres for Disease Control and Prevention (Africa CDC), the Association of African Universities (AAU), and the Federation of African Pharmaceutical Manufacturers Associations (FAPMA) to advance access to medicines and vaccines. USP grant-free access to the 

United States Pharmacopeia–National Formulary

) and USP’s education training library to all stakeholders in Africa, including regulatory authorities, laboratories, academic institutions, and manufacturers.

The new initiative will support African-led efforts, such as CDC’s New Public Health Order and AUDA-NEPAD's Pharmaceutical Manufacturing Plan for Africa, to increase the production of medical products. The initiative also builds on USP’s efforts to expand access to medicines in Africa through the organization’s direct investment, along with donors such as the US Agency for International Development. These efforts have included capacity building with 39 African manufacturers and 33 African regional and national regulatory authorities.

“Africa’s over-reliance on pharmaceutical imports created unacceptable supply chain vulnerabilities and delays during the COVID-19 pandemic,” said Jean Kaseya, MD, director-general of Africa CDC, in a USP press release (1). “We are committed to working with partners [such as] USP to build African manufacturing capacity to ensure that never happens again.”

“Development and growth of the pharmaceutical and vaccine manufacturing sector in Africa is critical to building sustainable and equitable access to health products in Africa,” said Symerre Grey Johnson, director for Human Capital and Institutional Development of AUDA-NEPAD, in the release. “With the actualization of the African Medicines Agency coupled with the African Free Trade Agreement and high-level commitments made by the African Union and numerous heads of states, the enabling conditions are primed for this sector to grow.”

“The growth of pharmaceutical manufacturing in Africa hinges on a dynamic and robust workforce,” said Olusola Oyewole, PhD, secretary-general of the Association of African Universities (AAU), in the release. “The development of a well-trained human resource pool with access to essential resources, such as those provided by USP, is crucial for educating tomorrow’s workforce, and transforming the continent’s pharmaceutical ecosystem.”

“Quality, including the adoption and scale up of accepted quality standards, must be at the heart of Africa’s expanding pharmaceutical sector,” said Emmanuel Mujuru, chairperson of FAPMA, in the release. “These resources will help African manufacturers move ever closer toward a thriving, quality-focused African pharmaceutical industry.”

The collaboration was announced at the inaugural meeting of USP’s Africa Regional Chapter. The Africa Regional Chapter brings together perspectives and expertise to identify priority issues. USP’s regional chapters will provide a forum for stakeholders to collaborate to advance pharmaceutical manufacturing and other priorities. There are more than 5000 quality standards in the 

for both chemical and biologic drugs, APIs, and excipients, therefore providing a comprehensive source for quality standards.

USP. African Institutions and USP Announce Free Access to Resources to Support Production of Quality Medical Products in Africa. Press Release. June 13, 2024.

Articles

A new initiative will advance access to quality medicines and vaccines in Africa.

USP and African Institutions Provide Free Access to Pharma Production Resources

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

The German government, in 2022, awarded a contract to WACKER, a contract manufacturer, and CordenPharma, a contract development and manufacturing organization, to produce and supply vaccines to prepare for potential future pandemics (1, 2). On June 19, 2024, WACKER and CordenPharma announced that their joint consortium entered the pandemic-readiness state on June 1, 2024 after the expansion and qualification phase. The consortium now enters the stand-by phase for a minimum of five years.

The two companies have taken measures to be able to produce 80 million vaccine doses a year under a short timeframe. A fee will be paid to the two companies to keep their capacity and expertise available for at least five years; the German government will request specific messenger RNA (mRNA) vaccines should a need develop.

Vaccines will be jointly produced by WACKER and CordenPharma with production occurring mostly in Germany. WACKER will produce plasmid DNA (pDNA), active pDNA, and lipid nanoparticles at its site in Halle, Germany, which was expanded to accommodate production over the past two years to include a new mRNA Competence Center.

CordenPharma will manufacture custom and standard lipids for the consortium at their Frankfurt, Germany and Chenôve, France sites. Aseptic fill/finish and packaging will be done at CordenPharma’s Caponago, Italy facility. To meet demand, the company invested in expansions in new lipid purification capacity and capabilities using supercritical fluid chromatography (SFC) and new compounding and freezing equipment. Both companies have also strengthened production security and supplier networks.

“We have expanded our Halle site into a Competence Center for mRNA production,” said WACKER CEO Christian Hartel, in a press release (3). “WACKER has invested over 100 million Euros in this expansion and created over 100 highly qualified jobs. Our expertise in making mRNA and LNPs [lipid nanoparticles] will contribute to the fight against future pandemics. Together with CordenPharma, we are proud to serve the German government in its pandemic preparedness plans.”

“Obtaining the official confirmation of pandemic readiness by the German government is a major milestone for CordenPharma,” said Michael Quirmbach, CEO of CordenPharma Group, in the release. “I am extremely proud of our teams across the CordenPharma sites involved in establishing and delivering our pandemic readiness plan on schedule. We are now ready, together with our partner WACKER, to manufacture end-to-end mRNA-based vaccines for the German government and other customers.”

At the time the contract was awarded, Hartel commented in a press release (1), “We are happy that our expertise in making mRNA vaccines will contribute to the fight against future pandemics. Together with CordenPharma, our partner, we will produce vaccines for Germany should the need arise.”

“WACKER and CordenPharma jointly cover the entire manufacturing chain for mRNA vaccines, which we will supply to the German government if needed. We are proud to contribute to supply security in Germany,” Quirmbach added (1).

CordenPharma. CordenPharma and WACKER to Produce mRNA Vaccines for Germany When Needed. Press Release. April 11, 2022.

CordenPharma. CordenPharma & WACKER Prepare for mRNA Vaccine Production. Press Release. June 14, 2022.

WACKER. WACKER & CordenPharma Enter Pandemic Readiness on 1 June 2024 After Successful Expansion & Qualification. Press Release. June 19, 2024.

The companies have completed the expansion and qualification phase and now enter a stand-by phase for five years.

CordenPharma and WACKER Consortium Enters Pandemic Readiness

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

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

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

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

The PharmTech Group spoke with BIOVECTRA's director of Business Development, Nucleic Acid Modalities, Jessica Madigan

Flexibility in Outsourcing Models

Outsourcing pharmaceutical manufacturing and development processes can provide pharmaceutical companies with financial flexibility, according to Jessica Madigan, director of Business Development, Nucleic Acid Modalities, at BIOVECTRA. The PharmTech Group spoke with Madigan after the BIO International 2024 Convention to learn more about the flexibility outsourcing models can provide.

“At BIOVECTRA, we offer flexible pricing models that can help companies manage cash flow and financial risks,” said Madigan. “[Pharmaceutical companies can reduce] capital investments by leveraging the infrastructure and specialized equipment that is already onboarded at CDMOs [contract development and manufacturing organizations]. This can be especially important for startups and small biotechs. … it allows them to direct the resources to their other business areas, rather than building up infrastructure and investing in specialized equipment.”

Madigan details the five different models her company provides, including a dedicated facility model what includes an entire building or facility reserved for the customer. Fractional ownership of a facilities with other customers is also available. “That way, we can [leverage] essentially a platform manufacturing process or a similar platform manufacturing process across several clients, that offers flexibility of capacity between those different partners, and allows a lower entry into a larger capacity.”

Click on the video above to watch the full interview. BIO 2024 occurred on June 3–6 in San Diego, Calif.

The PharmTech Group spoke with BIOVECTRA's director of Business Development, Nucleic Acid Modalities, Jessica Madigan, about the concept of flexibility in outsourcing and the 2024 BIO Convention.