ATMP Manufacturing Service

• Analytical development

At Molgenium, we are proud to offer a comprehensive range of services to support analytical development for our clients, particularly within the field of cell and gene therapy. Our team of experts has extensive experience in the pharmaceutical industry, and we are committed to helping our clients achieve their goals in a timely and cost-effective manner.

Our analytical development services include:

Method development and validation: We work with clients to develop and validate analytical methods for quantifying compounds and impurities in raw materials, intermediates, and finished products. Our team has experience with a wide range of analytical techniques, including HPLC, GC, MS, Flow Cytometry, ELISA, and PCR.

Stability testing: We provide support for stability testing to establish a product’s shelf-life and ensure consistency over time. Our team has experience with a wide range of products, including small molecules, biologics, and cell and gene therapies.

Quality control testing: We provide support for quality control testing to ensure that finished products meet the required specifications.

Regulatory support: We provide support for the analytical sections of regulatory submissions, including the development of analytical methods, stability studies, and quality control testing.

Case Study:

One of our clients, a biotechnology company, was developing a CAR-T cell therapy for cancer treatment. The client needed to develop analytical methods for the characterization of engineered T-cells, including quantitation of transgene expression, cell viability and purity, as well as monitoring the persistence of CAR-T cells in patient’s blood. Molgenium’s team of experts provided method development and validation services, including the development of Flow Cytometry, ELISA, and PCR methods for the characterization of the engineered T-cells. Our team also provided stability testing services to establish the product’s shelf-life and monitor the product stability during transportation and storage. Additionally, we supported the client in the analytical sections of regulatory submissions with the FDA and EMA. Our work helped the client to successfully launch the product and achieve market success.

One of the critical aspects of the development of this therapy was the establishment of appropriate product specifications for the final product. These specifications needed to ensure that the modified T cells, referred to as CAR-T cells, were of consistent quality and potency, and that they met the requirements for safety and efficacy.

Our analytical development team, consisting of experts in the field of flow cytometry, ELISA, PCR, and sequencing, designed and implemented a comprehensive analytical testing strategy for the characterization and release of the CAR-T cells.

The characterization of the CAR-T cells included the evaluation of the CAR expression and function using flow cytometry, the assessment of transgene integration and stability using PCR and sequencing, and the determination of the phenotype and viability of the cells using flow cytometry. The release testing of the CAR-T cells included the assessment of the identity, purity, and potency of the cells using flow cytometry and ELISA.

In addition to the analytical development, our team also assisted the client in developing a robust manufacturing process for the CAR-T cells. The process development included the selection of appropriate raw materials, optimization of the transduction and expansion protocols, and implementation of quality control measures at each step of the process.

The implementation of these specifications, characterized by analytical methods, and process development allowed us to provide the client with a scientifically sound basis for regulatory submissions and clinical trials, which have shown promising results in the treatment of ALL. Our team’s expertise in analytical development and process optimization, together with our client’s cutting-edge research, have played a key role in the development of a potentially life-saving therapy.

Our analytical development services help our clients to develop and validate analytical methods, establish product stability, and ensure product quality. We are committed to working closely with our clients to help them achieve their goals and bring their products to market, especially in the field of cell and gene therapy, where complex analytical methods are required to ensure the safety and efficacy of the therapy.

Molgenium’s Comprehensive Analytical Support Package for Licensure

The development and licensure of cell and gene therapy (C&GT) products require the use of robust analytical methods to ensure their safety, efficacy, and quality. The process of obtaining regulatory approval for these products can be challenging, as it involves meeting the requirements of multiple global jurisdictions simultaneously.

Molgenium, a leading provider of personalized medicine, was approached by a late-stage cell therapy client, who was preparing to file licensure applications for their product that was currently in multinational clinical trials. The client required a broad range of analytical guidance to ensure their product met the necessary regulatory standards for approval.

Molgenium offers a range of analytical support services that are tailored to meet the specific needs of each client. In this particular case, Molgenium provided analytical guidance to the client, which included a comprehensive evaluation of their C&GT product to ensure it met the necessary quality and safety standards for licensure.

• Establishment of a potency assay, including providing guidance on the overall strategy and rationale for mechanism of action, as well as method validation and assistance in drafting and reviewing related study protocols and reports.
• Establishment of other release and characterization methods, including method validation and assistance in drafting and reviewing related study protocols and reports.
• Establishment of specifications and associated acceptance criteria for raw materials, drug substance, and drug product.
• Establishment of a defined stability program for raw materials, drug substance, and drug product, including guidance on setting retest/expiry periods and data trending for shelf-life projections.
• Providing guidance on strategy and approach for comparability, and assistance in reviewing related study protocols and reports.
• Review of testing plan for delivery device suitability study.
• Drafting and/or reviewing relevant CMC sections for regulatory submissions.
• Preparation for and participation in communications with external stakeholders.

The Impact Molgenium’s analytical support services provided this late-stage program with a comprehensive understanding of the requirements for licensure in multiple jurisdictions. The client was able to make data-driven decisions on how to use their resources efficiently, ultimately accelerating their timeline towards commercialization. Molgenium’s analytical perspective also ensured that the client’s product met the necessary standards for long-term stability and safety.

• Quality control

Molgenium is a leading provider of quality control services for the biopharmaceutical industry. Our team of experienced scientists and engineers are experts in the development and implementation of analytical methods for the characterization of biotherapeutics, including gene therapies. We offer a wide range of services to support the quality control testing of these products, including:

Method Development and Validation: Our team develops and validates analytical methods for the characterization of gene therapies, including quantification of the therapeutic gene, identification and quantification of impurities, and assessment of product quality attributes such as purity, potency, and identity.

Stability Studies: We conduct stability studies to evaluate the long-term stability of gene therapies and to support the establishment of appropriate shelf-life and storage conditions.

Raw Material and In-Process Testing: We provide testing services for raw materials and in-process samples to ensure that they meet the necessary specifications and quality standards.

Product Release and Lot Release Testing: We perform testing on finished product samples to ensure that they meet the established specifications and quality standards.

Case Study: Gene Therapy

A gene therapy product being developed for the treatment of a rare genetic disorder. The product is based on a viral vector that delivers a therapeutic gene to the patient’s cells. The therapeutic gene is intended to provide a functional version of a protein that is missing or defective in patients with the disorder.

Molgenium was engaged by the sponsor to provide QC support for the development and characterization of the final product. Our team of scientists and engineers worked closely with the sponsor to develop and validate a suite of analytical methods for the characterization of the product. These methods included quantification of the therapeutic gene, identification and quantification of impurities, and assessment of product quality attributes such as purity, potency, and identity.

We also conducted a comprehensive stability study to evaluate the long-term stability of Solgenesma and to support the establishment of appropriate shelf-life and storage conditions. Our team also provided testing services for raw materials and in-process samples to ensure that they met the necessary specifications and quality standards.

Finally, we performed product release and lot release testing on finished product samples to ensure that they met the established specifications and quality standards. Through our efforts, we were able to provide the sponsor with the data and information necessary to support the regulatory filing and commercialization of the product.

As a result of our work, the sponsor was able to confidently submit the product for regulatory approval and the therapy was approved for the treatment of the rare genetic disorder.

In conclusion, Molgenium’s Quality Control services provide a comprehensive and scientific approach to the development, characterization and release of gene therapies and other biologics, thus ensuring that these products meet the necessary safety and efficacy standards. Our team’s expertise and experience in the field of gene therapy QC testing is a valuable asset to any sponsor looking to develop and commercialize a gene therapy product.

• Regulatory Compliance

At Molgenium, we understand the importance of regulatory compliance in the field of cell and gene therapy. Our team is well-equipped to provide comprehensive support for our clients’ global regulatory needs. We have established connections with current and former regulatory bodies and have supported filings across a wide range of global jurisdictions and stages of development.

Our services include regulatory strategy development to help our clients plan for long-term success while maintaining a focus on near-term realities such as resource constraints and timeline objectives. Additionally, we offer technical writing and editing support, including authorship of full documents or individual sections, review, gap analysis, and editing of existing draft documents. Our team has a diverse range of experience spanning preclinical, clinical, and marketing approval stages in various global jurisdictions.

We also provide gap analysis services, including an in-depth analysis of our clients’ current status and existing plan relative to requirements for targeted milestones, such as readiness for pre-IND, IND/CTA, BLA/MAA. Our team also organizes and leads internal preparatory sessions for regulatory meetings and frequently attends meetings with our clients to assist in effectively communicating with regulators.

Case Study:

Molgenium is a leading provider of regulatory strategy and support for cell and gene therapy products, with a particular focus on non-viral vector delivery of mRNA. In this case study, we will examine the regulatory challenges faced by a client developing a non-viral vector mRNA therapy for a genetic disease, and the strategies implemented by Molgenium to successfully navigate these challenges.

The client, a biotechnology company, had developed a novel non-viral vector platform for the delivery of mRNA encoding therapeutic proteins. The platform was based on the use of synthetic nanoparticles to protect and deliver the mRNA to target cells. The therapy was intended for the treatment of a genetic disease caused by the loss of function of a specific enzyme.

One of the major regulatory challenges faced by the client was the lack of precedent for non-viral vector mRNA therapies. The majority of mRNA therapies under development at the time were using viral vectors, and there was limited regulatory guidance for non-viral vector platforms. Molgenium worked closely with the client to develop a regulatory strategy that would address this lack of precedent and demonstrate the safety and efficacy of the therapy.

The first step in the regulatory strategy was to establish a strong preclinical development program. Molgenium helped the client to design appropriate animal models and conduct extensive toxicology and efficacy studies. These studies provided the necessary data to support the safety and efficacy of the therapy, and also established the non-viral vector platform as a viable option for mRNA delivery.

Next, Molgenium assisted the client in the preparation of an Investigational New Drug (IND) application to the US Food and Drug Administration (FDA). The IND application included extensive data from the preclinical studies, as well as a detailed description of the manufacturing process for the therapy. The FDA accepted the IND and granted clearance for the client to proceed with clinical trials.

Throughout the clinical development, Molgenium provided ongoing regulatory support to the client, including assistance with study design, data analysis and interpretation, and preparation of clinical sections of regulatory submissions. The client successfully completed a Phase I/II clinical trial, and the results demonstrated the safety and efficacy of the therapy in humans.

Based on the positive results of the clinical trial, Molgenium helped the client to prepare a Biologics License Application (BLA) to the FDA. The BLA included extensive data from the preclinical and clinical studies, as well as a detailed description of the manufacturing process for the therapy. The FDA granted the client’s BLA, and the therapy was approved for use in the United States.

In conclusion, this case study demonstrates the importance of a well-designed regulatory strategy for non-viral vector mRNA therapies. Molgenium’s expertise in regulatory affairs and ability to navigate the complex regulatory landscape was instrumental in the successful development and approval of this innovative therapy.

• CMC Development and Manufacturing Strategies

Molgenium, a leading biotechnology company, offers expert consulting services in the area of CMC development and manufacturing strategies for cell and gene therapy products. Our team of experienced scientists and engineers have extensive knowledge in the field and are well-versed in the latest regulatory requirements and industry best practices.

We understand that each product is unique and requires a tailored approach. Therefore, our CMC development and manufacturing strategies are fully integrated, smart, and customized to meet the specific needs of the product development, regulatory, manufacturing and customer needs.

Our consulting services begin with a comprehensive assessment of the current status of development or manufacturing, and then we work with our clients to plan and implement a strategy that looks forward three, five or ten years. We are dedicated to providing our clients with the most cost-effective and efficient solutions that meet the highest quality standards.

At Molgenium, we pride ourselves on our ability to deliver quality and timely results, while maintaining the highest level of customer satisfaction. If you are looking for expert consulting services in the area of CMC development and manufacturing strategies for cell and gene therapy products, please do not hesitate to contact us. We would be happy to discuss your needs and provide a proposal for our services.

CMC Development and Manufacturing Strategy for Cell Therapy and Gene Therapy Products: A Case Study

Introduction The development and manufacture of cell therapy and gene therapy products requires a high degree of expertise and attention to detail in order to ensure their safety and efficacy. CMC (chemistry, manufacturing, and control) strategies play a crucial role in ensuring that these products are manufactured and controlled to the highest quality standards. In this case study, we will examine the CMC development and manufacturing strategy for a cell therapy product and a gene therapy product, highlighting the unique challenges and considerations that must be taken into account.

Case 1: Cell Therapy Product The cell therapy product in question is a novel, autologous cell-based therapy for the treatment of a rare genetic disorder. The therapy involves the isolation of patient-specific cells, followed by genetic modification and expansion in culture. The final product is a purified population of genetically modified cells that are then re-administered to the patient.

CMC Development and Manufacturing Strategy The CMC development and manufacturing strategy for this cell therapy product was designed to ensure the consistency, quality, and purity of the final product. A key focus was placed on the development and validation of robust and reproducible methods for isolating, modifying, and expanding the patient-specific cells. The genetic modification process was also thoroughly characterized and validated to ensure the stability and expression of the therapeutic gene.

Manufacturing of the final product was performed under GMP (good manufacturing practice) conditions, with thorough documentation of the entire process to ensure complete traceability. The final product was characterized using a combination of analytical methods, including flow cytometry and PCR, to ensure that the desired cell population was obtained and that it met the appropriate quality standards.

Case 2: Gene Therapy Product The gene therapy product in question is a novel, adeno-associated virus (AAV)-based therapy for the treatment of a monogenic disorder. The therapy involves the preparation of a purified, high-titer AAV vector that is then administered to the patient.

CMC Development and Manufacturing Strategy The CMC development and manufacturing strategy for this gene therapy product was designed to ensure the consistency, quality, and purity of the final product. A key focus was placed on the development and validation of robust and reproducible methods for purifying and characterizing the AAV vector. The AAV vector production process was also thoroughly characterized and validated to ensure the stability and integrity of the vector.

Manufacturing of the final product was performed under GMP conditions, with thorough documentation of the entire process to ensure complete traceability. The final product was characterized using a combination of analytical methods, including gel electrophoresis and qPCR, to ensure that the desired vector was obtained and that it met the appropriate quality standards.

Conclusion The development and manufacture of cell therapy and gene therapy products requires a high degree of expertise and attention to detail in order to ensure their safety and efficacy. The CMC strategies presented in this case study demonstrate the importance of robust and reproducible methods for isolating, modifying, and expanding cells, as well as purifying and characterizing vectors. Furthermore, the implementation of GMP conditions and thorough documentation throughout the entire process ensures complete traceability and the quality of the final product.

Molgenium, as a leading consulting company, is well-equipped to provide expert guidance and support in the development and implementation of CMC strategies for cell therapy and gene therapy products, ensuring the safety and efficacy of these products for the benefit of patients.

• Nonclinical Development

Molgenium is dedicated to providing comprehensive nonclinical development support for cell and gene therapy products. Our team of experts possess extensive subject matter expertise in this field, allowing us to assist clients in successfully planning and executing nonclinical development programs.

One of our main services includes Preclinical/Nonclinical Strategy, where we help clients define and describe their nonclinical development plans and related safety and efficacy endpoints, with the goal of optimally supporting regulatory and clinical strategies.

In terms of Study design and oversight, we offer a range of services including:

• De novo nonclinical package design, where we work with clients to understand the intended clinical population and setting, and carefully develop a nonclinical package in a relevant model with meaningful safety and efficacy endpoints.
• Oversight of nonclinical study execution, where our in-house expertise can be deployed to oversee the execution of preclinical studies and analyze the generated data.
• Nonclinical data compilation and review, where we compile data from lab notebooks and study reports into a comprehensive tracking-and-trending database, and evaluate this data using statistical analysis software to help clients understand their nonclinical data and its trends.
• Nonclinical package gap analysis and study design, where we review existing nonclinical data packages and develop a comprehensive nonclinical/preclinical roadmap to make the data package more robust, complete, and likely to succeed in gaining regulatory agency approval.

Additionally, we also offer vendor selection services, where we work with clients to identify, appraise, audit, and recommend the most appropriate vendor(s) to successfully achieve their objectives. Furthermore, we provide technical writing services, where we write and/or review study protocols, reports, and regulatory submissions, ensuring that essential items are thoroughly and appropriately addressed and clearly communicated.

• Manufacturing support

At Molgenium, we understand the importance of utilizing advanced methods and techniques in the manufacturing process of cell and gene therapies. Our team of experienced scientists and engineers provide comprehensive support to aid in the development and implementation of efficient and effective manufacturing strategies.

One of the key services we offer is quantitative modeling, where we employ advanced mathematical models to analyze various factors such as capacity and cost, and determine the most suitable manufacturing approach for a specific program, whether in-house or outsourced. This allows for optimal capacity planning and identification of cost reduction opportunities.

Additionally, we assist in the selection of the appropriate Contract Manufacturing Organization (CMO) through our proprietary, quantitative Request for Proposal (RFP) process. Our deep knowledge of the CMO landscape enables us to solicit responses from qualified organizations, conduct audits, and evaluate responses to determine the best fit for the specific needs of the process and organization.

Furthermore, we provide oversight and support during the technology transfer process, ensuring a smooth transition of the technology to the chosen manufacturing location through the preparation of a technology transfer package, planning and execution of the transfer, and person-in-plant support.

Our team also assists in the design and construction of facilities optimized for the specific process and workflow, utilizing the latest technologies and industry standards.

In addition, we offer failure analysis services utilizing advanced techniques such as Fishbone Diagrams, Failure Modes and Effect Analysis, and statistical analysis to identify root causes of lot failures and implement corrective and preventative actions to prevent recurrence.

Molgenium is dedicated to providing the highest level of support in the manufacturing process to ensure the success of cell and gene therapy programs.

Failure Analysis in CAR-T Cell Therapy Manufacturing: A Case Study

Introduction: CAR-T cell therapy is an innovative treatment for cancer that involves the genetic modification of a patient’s own T cells to express a chimeric antigen receptor (CAR) specific to a cancer antigen. This therapy has shown remarkable results in treating various types of blood cancers, such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). However, the manufacturing process of CAR-T cells is complex and requires strict control to ensure product quality and safety.

Background: In this case study, Molgenium, a leading biotechnology company, faced an issue of high variability in the final product of CAR-T cells. Lot failures were observed during the manufacturing process, which resulted in delayed release of the product and decreased product yield. To address this issue, Molgenium implemented a failure analysis (FA) program to identify the root cause of the problem and implement appropriate corrective and preventive actions (CAPAs).

Methods: The FA program was conducted using a systematic approach, including:

• Collection of data from all relevant manufacturing processes, including raw materials, equipment, and process parameters.
• Identification of the critical process parameters (CPPs) that were found to have the greatest impact on product quality.
• Statistical analysis of the data to identify patterns or trends that may have contributed to the lot failures.
• Use of formal root cause analysis tools, such as Fishbone Diagrams, Failure Modes and Effect Analysis (FMEA), and statistical process control (SPC), to identify the underlying causes of the problem.

Results: The FA program revealed that the root cause of the lot failures was the high variability in the transduction efficiency of the CAR-T cells. This was caused by the use of an outdated transduction vector, which had a low efficiency in integrating the CAR gene into the T cells. Additionally, the variability in the transduction efficiency was found to be influenced by the quality of the raw materials, such as the T cells and transduction vector, and the environmental conditions during the transduction process.

Conclusion: The FA program conducted by Molgenium identified the root cause of the lot failures in the CAR-T cell therapy manufacturing process and implemented appropriate CAPAs to prevent them from re-occurring. These included the use of a more efficient transduction vector, stricter control of the quality of raw materials, and the optimization of the transduction process conditions. This resulted in an improvement in the product yield and a decrease in the variability of the final product, ensuring that patients receive a safe and effective treatment.