Biomanufacturing with GMP cell culture media: an interview with Maximilian Gert-Kleint

When referring to cell culture media being “GMP-grade” or “GMP-compliant” it signifies that the cell culture media are manufactured and controlled according to the principles of Good Manufacturing Practices (GMP). GMP is a set of quality assurance guidelines and practices that ensure the consistent production of high-quality pharmaceutical products and excipients while minimizing the risks associated with contamination, errors and deviations.

The manufacturing environment of a GMP-grade cell culture media needs to be certified by an accredited certifier, e.g., the DQS (Frankfurt, Germany). This EXCiPACT certification, based on an ISO9001 certification, is a voluntary, third-party certification scheme specifically designed for suppliers and manufacturers of pharmaceutical excipients, which are the inactive ingredients in medications or cell culture media in the case of cell and gene therapy manufacturing. The certification aims to ensure the quality and safety of these excipients, promoting GMP and regulatory compliance.

In the context of cell culture media, being GMP-compliant involves adhering to certain standards and practices during the manufacturing, testing and eventually the distribution processes. This ensures that the cell culture media are of reliable quality, safe for use and suitable for their intended purpose, which is to support the growth and maintenance of cells in a laboratory or production setting.

Several key aspects of GMP compliance for cell culture media include different process steps, beginning from quality control and testing to documentation and traceability to more broad concepts like validation, qualification, training, hygiene and facility standards. For example, the quality control of GMP-compliant cell culture media includes rigorous testing to ensure they meet specified quality standards. This includes tests for microbial contamination, endotoxin levels, pH, osmolality and nutritional content, among others. The “gold standard” for testing methods is described in the European Pharmacopoeia, which is mandatory for pharmaceutical substances, but not for cell culture media.

The traceability and documentation clearly benefit from the implementation of GMP. The ingredients and components used to formulate the cell culture media must be traceable to their original sources. This helps to ensure consistency and accountability in the manufacturing process. Comprehensive documentation of manufacturing processes, quality control procedures and testing results is essential to demonstrate GMP compliance and facilitate regulatory inspections or audits from external parties.

Another big concept for manufacturing cell culture media for the pharmaceutical industry is the implementation of a validation and qualification procedure. Manufacturing processes should be validated in their methodology and reliability. Equipment should be qualified to ensure they consistently produce cell culture media that meet predetermined specifications.

One crucial part of GMP-compliant cell culture media is the personnel and the implemented personnel training procedures because employees involved in the production of GMP-grade cell culture media should be adequately trained in GMP principles and practices, as they have to strictly cohere to these principles. In the end, however, the best compliance regulations are useless if employees don’t understand them or are unfamiliar with their application. Employees are the backbone of a compliant manufacturing environment.

In summary, when cell culture media are labeled as GMP-grade or GMP-compliant, it indicates that they have been produced in accordance with established GMP guidelines, assuring users that the media are of the high quality, safe and suitable for their intended applications, in laboratory research or biopharmaceutical production. EXCiPACT Certification of an excipient manufacturer, like PromoCell, further verifies that the manufacturer has met these GMP standards through an independent assessment process.

Cell therapy is a rapidly advancing field within regenerative medicine that involves the use of living cells to treat or potentially cure a variety of medical conditions. Manufacturing cell-based therapies involves complex processes to ensure the viability, functionality and safety of the therapeutic products. One crucial aspect of cell therapy manufacturing is the use of GMP media. The implementation of GMP-grade cell culture media does have several significant applications:

Foremost it is necessary to maintain cell viability and functionality of utilized cells. GMP cell culture media are formulated to provide an optimal environment for the growth, expansion and differentiation of therapeutic cells. These media contain carefully balanced ingredients, like growth factors, cytokines and other components essential for the cells’ survival, proliferation and therapeutic potential. The use of GMP-compliant media helps ensure that the cells remain viable, functional and capable of carrying out their intended therapeutic actions.

The second part is consistency and reproducibility over time and between batches. GMP media are manufactured under stringent quality control measures to ensure batch-to-batch consistency and reproducibility. Consistency in media composition is critical for producing uniform cell populations with predictable characteristics. This is especially important in cell therapy applications, where the therapeutic outcome depends on the consistent behavior of the administered cells.

The traceability of the raw material and documentation are key factors in a certified manufacturing environment. The production of a GMP media product involves detailed documentation of the formulation, manufacturing process, quality control tests and testing results. This documentation ensures traceability of the media components, enabling thorough investigation and resolution of any issues that may arise during cell therapy manufacturing. Traceability is crucial for quality assurance, regulatory compliance and post-production analysis.

At every step in the manufacturing process, safety and regulatory compliance should be kept in mind, as the final product might be compromised if non-compliance is detected during manufacturing. Cell culture media are produced in compliance with regulatory guidelines that prioritize patient safety. PromoCell´s manufacturing processes for GMP media are designed to minimize the risk of contamination, endotoxin presence and other potential hazards. The use of GMP media reduces the likelihood of introducing harmful substances or agents that could adversely affect patient safety during cell therapy administration.

The application of GMP-grade cell culture media culminates in regulatory acceptance and the initiation of clinical studies in humans. Cell therapies intended for clinical use must adhere to regulatory standards and guidelines. Cell culture media, manufactured in a certified environment, play a pivotal role in obtaining regulatory approvals and in facilitating the progression of cell therapy candidates through various phases of clinical trials. Overall, the use of GMP media demonstrates a commitment to producing safe and effective cell-based therapies.

For the pharmaceutical industry, scaling up and commercialization is additionally a key factor. As cell therapies move from research and development to large-scale manufacturing and commercialization, the use of GMP media becomes even more critical. GMP-compliant media are designed to support scalable production processes, ensuring that consistent and high-quality therapeutic cells can be generated for a larger patient population.

To summarize the previous points, GMP media are of paramount importance in cell therapy manufacturing because they provide the necessary controlled environment for the optimal growth and function of therapeutic cells. By adhering to GMP guidelines, cell therapy manufacturers can ensure the safety, consistency and quality of the therapeutic cells intended for patient treatment.

Using GMP-grade media, such as PromoCell’s PromoExQ media, offers several benefits in various cell culture applications, especially in the context of cell therapy, biopharmaceutical production and other clinical or regulated settings. Several aspects of implementing GMP-grade cell culture media are beneficial for the user.

First, regulatory compliance might be easier to achieve. GMP-grade media are manufactured in accordance with GMP guidelines and principles, which are recognized internationally as a quality assurance standard for the production of pharmaceuticals and excipients (cell culture media) and related products. Using GMP-grade media helps ensure compliance with regulatory requirements, facilitating the approval process for clinical trials and regulatory submissions. The consistency in product quality is also a benefit for the user, along with the resulting minimization in product variability. GMP-grade media are designed to meet the predefined quality standards and undergo quality control testing for the product release. This ensures consistent and reproducible performance of the media, leading to uniform cell growth, behavior and characteristics across different batches.

Consistency is crucial for generating reliable and predictable results in research, development and manufacturing processes. GMP-grade media help reduce variability in cell culture conditions, which can impact the reproducibility and comparability of experimental results. By providing a standardized and well-defined environment, GMP-grade media contribute to more robust and meaningful research outcomes.

The next benefit is the commitment of manufacturers to reduce the risk of contamination in their products. Our GMP-grade media are produced under controlled conditions and bottled under aseptic conditions, minimizing the risk of contamination by microorganisms, endotoxins or other impurities. Raw material is procured from qualified manufacturers and, in a risk-based concept, checked for microbial and viral contamination. This is particularly important in cell therapy and biopharmaceutical production, where even minor contamination can compromise product safety and efficacy. GMP-grade media contribute therefore to the safety of the final cell product by minimizing the risk of introducing contaminants or impurities that could harm patients.

Another benefit of traceability and documentation is that GMP-grade media come with comprehensive documentation detailing the composition, manufacturing process, quality control tests and testing results. This traceability ensures transparency and accountability throughout the manufacturing and supply chain, facilitating regulatory audits, inspections and troubleshooting. This plays a significant role in the support for translating research findings into clinical applications. This is essential for cell therapy development, where a seamless transition from preclinical studies to clinical trials is critical. Utilizing GMP-grade media ensures that the cells produced in the laboratory maintain their quality and therapeutic potential when used in patients. It is prescribed in relevant guidelines that the stability of the products should also be taken into consideration. Taking this into account, GMP-grade media are formulated and manufactured to maintain their stability and performance over extended periods. This is crucial for ensuring that the media can support the growth and function of cells during the entire cell therapy manufacturing process.

In summary, using GMP-grade media, such as PromoCell’s PromoExQ media, offers numerous advantages in terms of regulatory compliance, product quality, safety, consistency and support for clinical translation and scale-up. These benefits make GMP-grade media a valuable choice for cell culture applications in clinical, research and biopharmaceutical settings.

Cell and gene therapy manufacturers decide to switch to GMP media at different stages of their development and manufacturing processes. The decision to transition to GMP-grade cell culture media is influenced by various factors, including regulatory requirements, clinical translation, scalability, quality assurance and patient safety. Furthermore, the timing and process of switching to GMP media can vary based on the specific cell therapy, its stage of development and the manufacturer’s overall strategy. Therefore, a general overview of when and how cell therapy manufacturers might decide to make the switch can only be given.

Preclinical to Clinical Transition:

The transition to GMP-grade media often occurs when a cell therapy candidate progresses from preclinical studies to clinical trials. Regulatory agencies require that cells and products intended for clinical use must be manufactured under GMP-compliant conditions.

The manufacturer might establish GMP-compliant processes for cell culture, including the use of GMP-grade media. This typically involves adapting existing protocols or developing new documents that meet GMP and Good Documentation Practice standards. The manufacturing facility and equipment may need to be upgraded or validated to ensure compliance.

Phase-specific Transitions:

Manufacturers may switch to GMP media at different phases of clinical development (Phase I, II, III) to align with regulatory expectations and increasing patient numbers.

The transition involves implementing GMP-compliant manufacturing practices, which may include sourcing GMP-grade reagents, e.g., cell culture media, qualifying suppliers, documenting processes and implementing quality control measures.

Scale-Up and Commercialization:

When transitioning from clinical trials to commercial manufacturing, the use of GMP media becomes even more crucial for scalability, consistency and regulatory compliance.

The manufacturer will optimize processes for larger-scale production while ensuring GMP compliance. This may involve process validation, technology transfer and establishing supply chains for GMP media and other materials.

Regulatory Approvals:

Regulatory agencies require evidence of GMP compliance for market approval of cell therapies.

The manufacturer must demonstrate that GMP media have been used throughout the development, clinical trials and manufacturing processes. This involves thorough documentation, process validation and adherence to regulatory guidelines.

Process Improvement and Quality Enhancement:

Manufacturers may switch to GMP media as part of ongoing efforts to improve process efficiency, product quality and patient safety.

The decision may stem from a desire to mitigate risks associated with non-GMP media, enhance reproducibility and ensure robustness in manufacturing. The transition involves evaluating and validating new GMP media formulations.

Changed Regulatory Expectations:

If regulatory agencies update their guidelines to require GMP media for specific cell therapies, manufacturers may need to switch to GMP media to remain compliant.

Manufacturers would assess the impact of the regulatory changes on their processes, evaluate available GMP media options and implement necessary changes to meet the new requirements.

In the process of switching to GMP media, cell and gene therapy manufacturers need to carefully plan and execute the transition to ensure a seamless integration of GMP-compliant practices. This involves evaluating the impact on processes, training personnel, validating methods, qualifying equipment, documenting procedures and establishing a robust quality management system. The decision to switch to GMP media is driven by the overall goal of producing safe, effective and consistent cell therapies that meet regulatory standards and patient needs.

Utilizing GMP-grade media and associated documentation can significantly facilitate regulatory approval and accelerate the time to market for cell therapy products. Regulatory agencies, such as the US Food and Drug Administration and the European Medicines Agency, require cell therapy products to be manufactured under GMP-compliant conditions.

Using GMP-grade media and following GMP guidelines ensures that the manufacturing process meets regulatory expectations from the outset. GMP-grade media are manufactured to stringent quality standards, ensuring consistent and reproducible performance. This consistency translates to a higher degree of quality assurance that the therapeutic cells produced using GMP media will meet predefined specifications and exhibit the desired therapeutic properties. A high assurance in product quality leads to a higher level of product safety. GMP media are produced in controlled environments, bottled under aseptic conditions, minimizing the risk of contamination by microorganisms, endotoxins or other impurities.

Ensuring product safety is a fundamental requirement for regulatory approval, especially for therapies intended for human use. A GMP (facetiously: give me paper) cell culture media comes with comprehensive documentation that outlines the composition, manufacturing process, quality control tests and testing results. This documentation provides transparency and traceability throughout the manufacturing process, enabling efficient audits, inspections and regulatory submissions. This documentation itself results in a faster regulatory review. When regulatory authorities receive applications for clinical trials or marketing approval, having a well-documented GMP manufacturing process, including the use of GMP media, streamlines the review process. Regulators can more easily assess the quality and safety of the cell therapy product, which can expedite the approval timeline. A big benefit is reduced manufacturing risks, as GMP media and processes are designed to minimize the risks associated with variability, contamination and deviations in manufacturing. This reduces the likelihood of encountering manufacturing issues that could delay regulatory approval or reduce quality which both lead to product recalls.

In summary, the use of GMP-grade media and associated documentation like a Drug Master File plays a pivotal role in expediting regulatory approval and accelerating the time to market for cell therapy products. Meticulous documentation speeds up and simplifies the conduct of audits by authorities and potentially reduces the need for post-audit work that could slow down or even halt the approval process entirely. By ensuring product quality, safety and regulatory compliance, manufacturers can navigate the regulatory landscape more efficiently and bring their therapies to patients in a timely manner.

Accelerating regulatory approval and time to market means that innovative and potentially life-saving cell therapies can reach patients sooner, addressing unmet medical needs and improving patient outcomes.

Performing risk assessments when using GMP-grade cell culture media is a critical step in ensuring the safety, quality and compliance of the cell therapy manufacturing process. A detailed risk assessment, such as a failure mode and effects analysis (FMEA)-based risk assessment, helps to identify potential hazards, vulnerabilities and areas where deviations could occur, allowing manufacturers to implement appropriate mitigation strategies.

The following considerations do not guarantee completeness and each manufacturer is inherently responsible for assessing its own processes, but the fundamental points are:

Identification of critical process steps

Determine which steps in the cell culture process involve the use of GMP media. The focus should be on steps that directly impact product quality, safety or regulatory compliance, such as cell expansion, differentiation and final product formulation.

Hazard Identification

Potential hazards associated with non-GMP media usage should be identified. These hazards could include contamination, endotoxin presence, media component variability or incorrect formulation.

Risk Mitigation Strategies

Develop strategies to mitigate identified risks. These strategies may involve process improvements, enhanced quality control measures, additional testing or changes to manufacturing procedures. If you cannot change something, evaluate how this step might be controlled. Is the residual risk acceptable based on regulatory standards and your organization’s risk tolerance?

Documentation

Thoroughly assess the risk resulting in incomplete, incorrect or non-existent documentation, like manufacturing protocols or other supplemental documents. This includes hazard identification resulting from the use of non-GMP-compliant products and how this is crucial for regulatory compliance and audits.

Personnel Training

Ensure that personnel involved in the cell culture process are trained to recognize and manage potential risks associated with GMP media usage. Training helps promote a culture of risk awareness and mitigation.

Regulatory Compliance

Consider relevant regulatory guidelines and expectations for the utilization of GMP-grade media in cell therapy manufacturing. The use of products manufactured in a controlled and certified environment intrinsically enhances the acceptance rate of the final product.

By systematically conducting risk assessments, you can proactively identify and address potential issues related to GMP-grade cell culture media usage or the risk if a “non-compliant” product is used. This approach helps ensure the integrity of cell therapy manufacturing process, enhances patient safety and supports regulatory compliance.

The future of cell culture media for cell therapy applications is likely to be shaped by advancements in various fields, including biotechnology, materials science, personalized medicine, regulatory adjustments or other scientific fields, e.g., IT.

While nobody can predict the future with certainty, the Covid-19 pandemic is a prime example of how fast something can change. Despite numerous factors in this pandemic being overlooked, not only research but also society, regulatory authorities and politics can adjust to rapid changes. Anyhow, some potential trends and directions that cell culture media in the field of biomanufacturing applications might be:

In analogy to personalized medicine, personalized and customized media formulations will increasingly become a requirement. As our understanding of individual patient differences deepens, there could be a move toward personalized or patient-specific cell culture media formulations. These media could be tailored to the specific needs and characteristics of each patient’s cells, optimizing growth and therapeutic potential. The manufacturer needs to ensure that their manufacturing environment is able to adapt to these more and more customized products. The batch size might decrease, but the complexity of the formulation might increase.

The overall classification of cell culture media and their distribution in the market might change. The trend toward using serum-free and defined media will likely continue to ensure reproducibility, reduce variability and enhance safety. Efforts to develop chemically defined media that support robust cell growth and function will likely expand. This might be further facilitated using designer media products. Advances in synthetic biology and genetic engineering could enable the design of cell culture media with precise compositions, growth factors and nutrients to optimize specific cellular functions, differentiation pathways and therapeutic outputs.

A possible idea is the implementation of nutrient sensing and feedback systems. “Smart” cell culture media could incorporate sensor molecules and feedback mechanisms to monitor cell health and nutrient levels in real time. This could enable dynamic adjustments to media composition, promoting optimal growth conditions.

The incorporation of advanced biomaterials and matrices into cell culture media could provide more physiologically relevant environments for cell growth, mimicking the in vivo conditions and enhancing cell functionality.

Cell therapy manufacturing is increasingly shifting toward bioreactor-based production, so a more bioreactor-specific medium might be designed. Future media formulations might be optimized for specific bioreactor systems, promoting efficient cell expansion and culture in these environments. The increasing research capacity of stem cells might be additionally taken into account in the development of new cell culture media. Specific media for stem cell therapies could advance to better support directed differentiation into specific cell lineages. This could include media formulations that induce targeted lineage commitment with higher efficiency.

New developments in Quality-by-Design principles, which focus on building quality into the manufacturing process, could lead to the development of media formulations optimized for robust and consistent cell production. This concept might also include the integration of Artificial Intelligence into development and manufacturing processes. Cell culture media are a complex mixture of different substances, which might or might not adversely affect the cells. AI algorithms could be used to analyze large datasets to identify optimal media compositions for specific cell types, accelerating the development of novel media formulations.

A last trend includes the regulation of cell culture media and their implementation. Cell therapy applications are not yet regulated in detail like active pharmaceutical substances are. Regulatory agencies may provide clearer guidelines for GMP-compliant media and their use in cell therapy manufacturing, further promoting product consistency and safety.

It’s important to note that the above trends are speculative and dependent on ongoing scientific and technological advancements. The future of cell culture media for cell therapy applications will likely be shaped by a combination of these and other factors, ultimately contributing to safer, more effective and widely accessible cell therapies.