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Download our presentation from Recovery of Biological Products XX titled “Turning the crank using a hybrid continuous purification platform” from Michelle Najera, Megan McClure, Shahbaz Gardezi and Beth Larimore. 

Learn how:

1. Process intensification solutions for monoclonal antibodies, Fc-fusion proteins and bispecific antibodies t ease liquid handling pain points.
2. Our J.CHO High Expression System is delivering perfusion permeate titers of over 2 g/L/d over 25 days.
3. Continuous capture chromatography significantly enhances resin utilization
4. Two tank virus inactivation steps can be developed with bench-scale models

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The top challenges in commercial API manufacturing

Once an investigational medicinal product has demonstrated its safety and efficacy during clinical trials, the next challenge for its Sponsor is to secure a reliable supply chain for its commercial production. Understandably, commercial pharmaceutical manufacturing, including commercial API manufacturing, is a highly regulated area to ensure patients’ ongoing access to a consistently high quality of medicines that guarantees their safety and efficacy. Transitioning from a clinical pilot scale to eventually the larger plant scale required for commercial API production can be a long and arduous process.

The main challenges faced in the journey to commercialization include scaling up production, establishing and maintaining process consistency and reproducibility, and ensuring compliance with regulatory guidelines. In this blog, we explore these areas in detail, discussing how a strategic approach, robust planning, and the incorporation of innovative technologies, can help ensure your drug smoothly and successfully reaches the market.

Developing robust and scalable processes

Increasing the production of active pharmaceutical ingredients (APIs) and drug excipients from milligram to multi-kilogram quantities is arguably the biggest challenge faced in paving the way to reliable commercial pharmaceutical manufacturing. Without the adoption of strategic planning during the process development stage, unexpected issues may arise and lead to significant increases in your program timelines and costs.

Here are our top tips for effectively planning and developing robust and scalable API manufacturing processes, and achieving faster and more seamless scale-up that supports marketing approval and supply security requirements:

• Choice of starting materials – several considerations should be made when selecting the starting materials used in the manufacture of APIs and medicinal products. This includes quality, compatibility, long-term stability, affordability, safety, security of supply, and compliance with pharmaceutical regulatory guidelines. Ensuring your starting materials meet these criteria throughout the entire scale-up process, up to commercial scale, will pave the way for a safe and high-quality medicinal product.
• Choice of equipment and processing technology – where possible, scalable equipment and processing technology should be chosen in API and drug manufacturing. This will help to streamline the technology transfer process, reducing the time and costs required for process optimization and validation, and minimizing the risk of failure. Cost, availability, material compatibility, cleaning processes, and the ability to implement automation and control systems at commercial scale should be considered.
• Process development – the basis of every robust, scalable process is effective API process development. This requires the optimization of several components, including the selection of the synthetic route, and measures for process control and risk management. Scientific and risk-based approaches should be utilized to help gain an in-depth understanding of how any changes to the process during scale-up will affect the safety and quality of the product.
  
  

Read this blog for more detail on how to optimize API process development

Establishing and maintaining process consistency and reproducibility

Establishing and maintaining consistency and reproducibility during scale-up is a complex yet vital task in commercial pharmaceutical manufacturing. Increasing the vessel size and introducing any other necessary changes can drastically alter process performance and product quality. Failure to design and optimize the process to account for these differences could derail production, altering the safety, quality, and efficacy of the API.

The key to ensuring process consistency and reproducibility in commercial scale production lies in strategic planning during process development, with the use of systematic approaches that facilitate the implementation of a robust process control strategy

Implementation of systematic approaches

Several systematic approaches, such as design of experiments (DoE), quality by design (QbD), and process modeling and simulations performed with a software such as Dynochem® are used to improve knowledge of the product and the scale-up process. This includes the thorough impact assessment of any changes in processing parameters on process performance and final product quality.

DoE involves the use of factorial design to plan a series of experiments that test simultaneously variations in individual input factors. The aim of this is to gain an understanding of the individual and combined effects of parameters variability on the process performance and output. Following these experiments, mathematical models, such as response surface methodology (RSM), are used to identify the optimal set of process parameters as well as the acceptable operating envelope for the process.

DoE and process modeling and simulations can be integrated into a QbD approach, which incorporates statistical and analytical methodologies to enhance the process control strategy and build quality and risk management into the manufacturing process. This is achieved by identifying the critical process parameters (CPPs) and critical quality attributes (CQAs) that are associated with the quality, safety, and efficacy of the drug substance and excipients.

Using the QbD methodology, the determined parameters and quality attributes are used to establish a design space. For this, statistical tools are used to explore how combinations of CPPs might interact and impact on CQAs. This helps manufacturers optimize the production of APIs and drug excipients, ensuring the design of reproducible processes that minimize batch failure risks and significantly reduce batch-to-batch variability.

Click here to learn more on how to apply QbD principles to drug development and manufacturing

Adoption of advanced process control systems

The process knowledge gained from experimental modeling approaches, such as QbD and DoE, can be used to develop advanced process control systems. These commonly utilize process analytical technology (PAT), which monitors process parameters on-line in real-time.

When PAT is integrated into advanced process control systems, the analytical data may be used to make automatic system adjustments and maintain process parameters within their predefined limits. This reduces manual intervention and creates a closed-loop control system, allowing for the immediate detection of deviations in process conditions and subsequent feedback control.

By immediately correcting any deviations in the process, advanced process control systems enable real-time release testing, assuring manufacturers that the processes have remained consistent, and that the product meets quality and safety standards. By increasing efficiency and consistency, these systems also help to reduce waste, costs, and product cycle times.

Regulatory compliance

Compliance with current good manufacturing practice (cGMP) regulations is critical to ensuring the production of consistent, high-quality, pharmaceutical products. API manufacturing plants are subject to strict regulations, with complex and ever-evolving requirements, stringent quality standards, and severe consequences in case of non-compliance. To comply with cGMP guidelines, several robust management systems must be in place, including those for data integrity, process control, risk management, and supply chain management:

Data integrity

Consistent, accurate, timely, and complete records are required to provide regulators and stakeholders with the confidence that your medicinal product meets all safety and quality standards. Clarity, consistency, and conciseness of the documents must be maintained across the entire product lifecycle. The development of a robust documentation system can help manufacturers with this, establishing effective procedures for naming, authoring, reviewing, approving, updating, storing, and distributing documents.

Control strategy

There are increasing requirements for a clear, well-defined, and scientifically justified process control strategy in cGMP applications. This should include the selection and evaluation of starting materials, followed by approaches including QbD and DoE to link materials attributes and process parameters to product CQAs. These approaches are used to establish a design space and plan control measures to ensure that CQAs are met and a sound process validation methodology is implemented. Furthermore, the process control and validation strategy should be adapted to the increased production scale throughout all stages of the product’s lifecycle.

Risk management strategy

cGMP guidelines require a systematic approach to risk assessment in pharmaceutical manufacturing. This involves the process of identifying, assessing, controlling and reviewing risks based on their potential for impacting the performance of the process and the quality of the product. Risk management plays a central role in scaling up to commercial production in order to mitigate significant quality risks such as cross-contamination and minimize health and safety risks to operators, especially when handling highly potent APIs. Several tools are available for risk assessment, including failure mode and effects analysis (FMEA).

Supply chain management systems

In the pharmaceutical industry, securing patients’ access to drug supplies post-marketing authorization is a regulator’s number one priority. Regulatory guidelines are designed to cover the entire supply chain, from the supply of raw materials to be introduced in cGMP manufacturing operations through to the manufacturing, packaging, labeling, and distribution of the final product.

Digitalizing the management of manufacturing activities can enhance the visibility and efficiency of inventory management, product monitoring, and data exchange throughout the supply chain. Additionally, supply chain management systems should be designed to incorporate risk management strategies for the prediction, prioritization, and mitigation of risks of product stock-outs. This is not only essential for regulatory compliance and patient access, but it will also increase supply chain efficiency to help overcome issues such as inadequate forecasting, long lead times and build-up of working capital.

How to master commercial pharmaceutical manufacturing

The journey to commercialization can be challenging. Scaling up production while maintaining process consistency, product quality, and regulatory compliance, requires expert process development capabilities, and the adoption of innovative science and risk management methodologies. A common pitfall for the Sponsor of an innovative therapy is to under-estimate the complexity and intricacy of this enterprise, which involves the coordinated optimization of strategies for process control, risk management, data management, and supply chain management.

With ever-evolving regulatory requirements and the increasing urge to shorten drug development timelines, getting your drug to market can seem like a daunting undertaking. That’s why taking some of the pressure off your organization by outsourcing your drug development and manufacturing activities to an expert partner can be the smartest decision. This will ensure your drug is commercialized in the fastest and most cost-efficient way possible, utilizing expertise, facilities, equipment, and processes to anticipate and overcome any challenges thrown at your program with ease.

Evotec offers an integrated end-to-end solution for innovative drug R&D, with the capabilities to support all phases of your drug development program. Your projects are in safe hands with our team of expert scientists who are pioneers in QbD, process design, scale-up, and validation, operating to full cGMP within FDA, MHRA, AIFA and BfArM approved facilities.

Learn more about our API and drug product manufacturing capabilities

By leveraging intensification, minimization, and simplification in bioprocessing workflows, Just-Evotec Biologics can achieve higher productivity, better resource utilization and lower facility costs. Collectively, these benefits contribute to reducing the COGM of biotherapeutics.

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This poster describes the rapid conversion of an intensified fed-batch antibody manufacturing process to an integrated continuous biomanufacturing process using the Just-Evotec Biologics platform, resulting in several key project accomplishments: 

• Mitigation of upstream IFB challenges
• Significant productivity increase
• Short development time
• Minimal risk from changes in product quality

These results demonstrate that the rapid conversion of fed-batch processes for monoclonal antibodies to an integrated continuous biomanufacturing process can be achieved with a robust ICB platform. This supports the biotherapeutics industry’s need to quickly adapt to changing clinical and business circumstances.

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Biologics manufacturing typically uses engineered Chinese Hamster Ovary (CHO) cells to produce folded and glycosylated antibodies. Determining the optimum conditions to grow and maintain cell culture often requires considerable time and effort.

A quantitative understanding of cell metabolism through an analysis of cell culture metabolites can enable optimization growth conditions for improved titles or increased perfusion duration. Mass spectrometry is the optimum tool for metabolite measurement, however, transforming raw data into accurate quantitative measurement requires both expertise and extensive sample preparation.

In this poster we demonstrate the ability of simple sample preparation using universal calibrators and a novel machine learning algorithm to rapidly provide biological insight into bioprocessing samples taken from perfusion cell cultures.

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Continuous biomanufacturing arrives in Europe:

Nick Hutchinson, Head of Market Development at Just – Evotec Biologics, explains the benefits of this new approach, why the company’s new cGMP manufacturing facility, J.POD® Toulouse, France (EU), is the first of its kind in Europe and what this means for the industry.

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Active pharmaceutical ingredient (API) manufacturing for new chemical entities (NCEs) is a lengthy undertaking involving many complex chemical processes, including the production of intermediates and purification and isolation steps. Optimizing the manufacturing process, through rational API process design and development, is the key to enabling fast, safe, reproducible, and cost-effective API production. And with the increasing pressure on accelerating drug development while staying within budget and meeting increasingly complex and stringent regulatory requirements, optimizing the API process development workflow has never been more crucial.

However, designing and executing an effective API process development strategy is no small or easy feat. From the early phases of drug development through to commercial manufacturing, the fine-tuning of many individual steps is required to optimize and de-risk API production. This blog outlines some of the key considerations involved in successfully designing and developing an optimal commercial API manufacturing process, including the selection of the synthetic route and regulatory starting materials, the development of a highly effective process control strategy, as well as risk management methodologies, and process safety considerations.

Synthetic route selection

When designing or selecting a synthetic route, it’s important that you get it right, as the use of suboptimal, inefficient routes can drain resources and substantially increase your time to market. Indeed, changing the synthetic route at the late development stage can prove very costly and time-consuming, not least due to the regulatory constraints being faced; in the worst-case scenario, such a change can even trigger the requirement for additional in vivo studies of the drug.

A key consideration for selecting the synthetic route for any type of chemical API is efficiency. Ideally, the chosen synthetic route requires the least number of steps and results in the shortest time to market.

In this regard, scalability is a critical aspect. All chosen materials, unit operations, processing equipment, and conditions should be suitable for scale-up to enable the manufacture of both clinical and commercial scale API batches. Building robustness into the synthetic route by selecting chemical transformations for ease of scalability will help maintain high levels of reproducibility, quality, and cost-effectiveness at increasing scales. This will ultimately ensure continuity in API supply by minimizing the time and costs involved in technology transfer activities.

Additional essential considerations in API synthetic route selection and optimization include those outlined by the SELECT principle: safety, environmental impact, legal requirements, economics, control, and throughput. These principles were first proposed in a 2006 consortium of pharmaceutical manufacturers, including AstraZeneca, GSK, and Pfizer, providing a good basis for selecting or designing a robust, commercially viable synthetic route.

Starting material selection

The selection and introduction of all processing materials, including raw materials, intermediates, solvents, and reagents, will depend on the chosen synthetic route and the API. However, all materials should have well-defined chemical properties, structures, and impurity profiles.

Additionally, a thorough understanding of the selection criteria for starting materials is essential, as outlined in global regulatory guidelines, including ICH Q7 ‘Good manufacturing practice for active pharmaceutical ingredients’. This requires a risk-based approach, which entails gaining a detailed understanding of how changes in the proposed API starting materials can influence the critical quality attributes (CQAs) of the drug substance, including its impurity profile, and the consequences this may have on the medicinal product’s quality.

All starting materials should also be evaluated for their security of supply, in addition to their quality, safety, and environmental impact. It is of particular importance to develop a robust supply chain strategy for custom-made starting materials, including the evaluation and qualification of reliable suppliers.

Developing a process control strategy (PCS)

Each process involved in API manufacturing requires the definition of a unique set of process parameters, such as mixing, temperature, pressure, and time. These parameters must be adequately monitored and tightly controlled to avoid the formation of impurities and prevent inconsistencies in output quality and yield. To develop an effective PCS, several considerations should be made, including the control of input materials, and the use of quality-by-design (QbD) principles to characterize the process and develop appropriate analytical methods to be implemented for quality control.

Quality-by-design (QbD)

QbD is a systematic, rigorous, data-driven approach that should be adopted to improve process and quality control in API manufacturing. QbD relies on predefined objectives to gain a thorough understanding of process control. This starts with determining the drug’s quality target product profile (QTPP), which consists of several design specifications that ensure the product is safe to use and has the desired therapeutic effect.

Based on the definition of the QTPP for the medicinal product, the API CQAs, i.e. the measurable properties of the compound that characterize its quality, including purity, potency, particle size, and stability, are identified. Once API CQAs are defined, the manufacturing process must be thoroughly studied and characterized to evaluate the critical process parameters (CPPs), which are the variables, such as temperature, pH, agitation, and processing time, that impact process performance and consequently product quality.

Essentially, QbD involves the consideration of all materials and processing parameters that could influence product quality. By gaining a sound scientific understanding of the processes through the execution of a rational experimental design, e.g. using a statistical design of experiments (DoE) methodology, this approach enables the elaboration of a more effective control strategy. As documented in the international pharmaceutical guidelines, ICH Q8, Q9, and Q10, the QbD methodology enhances drug development by helping to reduce the risk of batch failure and improving final product quality, safety, and consistency.

Learn more about the role of QbD in drug development

Analytical method development

QbD principles can also be extended to analytical method development. The API’s CQAs provide a good basis for selecting the most appropriate analytical methods and determining their parameters. Well-designed test methods are paramount to supporting the accurate and reliable monitoring of intermediates and product quality, in line with international quality standards and regulatory guidelines.

For in-process analysis, chromatographic methods, like high-performance liquid chromatography (HPLC) and gas chromatography (GC), are commonly preferred to monitor process execution due to their accuracy and reliability. More recently, the development of process analytical technology (PAT) based on the use of in-line spectroscopic methods, such as Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and focused beam reflectance measurement (FBRM), has helped to improve process control by enabling real-time process monitoring.

When choosing the best analytical method for each process, molecule type and stability arekey considerations. These attributes drive requirements for achieving the appropriate sensitivity and robustness of each assay, including the choice of detection method, range of detection, sample preparation procedure, and analysis time, in addition to cost and ease of routine implementation.

Implementing quality risk management

Risk of failures associated with the facilities, equipment, materials, personnel, processing, product testing, and storage are inherent to API manufacturing. Effective risk management strategies are required to prevent these risks from impacting the quality, efficacy and safety of the API, and from causing costly delays. Recognizing this, ICH guideline Q9 outlines a framework for quality risk management (QRM) applied to pharmaceutical products. This is a strategic approach that involves assessing, controlling, and continuously reviewing potential risks that could occur in API manufacturing, using the following steps:

• Risk assessment – this step considers the identification of hazards, the probability of them occurring, and the evaluation of the severity of their consequences.
• Risk control – this next step consists of the use of a decision-making tool to identify and implement control strategies designed to either eliminate or reduce the probability of occurrence, and lessen the severity of the impact down to a level that assures the quality, efficacy, and safety of the product.
• Risk review – this step is essential to maintaining the effectiveness of the quality risk management framework since it is designed to incorporate the risk assessment and control activities described above while reviewing the new data and knowledge generated throughout the product lifecycle activities.

Several risk management tools are available to aid quality risk management, including failure mode effects analysis (FMEA) and its extension, failure mode, effects, and criticality analysis (FMECA). FMECA is a critical risk analysis tool derived from FMEA and used to determine the potential sources of failure during the execution of the manufacturing process, evaluating the severity and likelihood of such failure, in addition to how it can be detected before it occurs.

Process safety

The development of API manufacturing processes requires particular attention to health and safety considerations to avoid serious and potentially fatal hazards. In addition to ensuring that operators are effectively protected from direct exposure to chemicals, particularly those with high potency, the process chemist also needs to ensure that the safety of the API manufacturing process is carefully assessed and established.

The first step to developing an effective process safety strategy consists of performing hazard assessments for each processing step. These require a detailed understanding of the chemical processes involved, in addition to several other components, including the use of material safety data sheets (MSDS) to take into account specific chemical risks associated with the starting materials and API, and the consideration of any requirement for specific operator training, worker exposure control measures, and compliance with regulatory standards. Although conducting thorough hazard assessments and using these to develop safe processes is time-consuming, it is essential to manage the operational risks associated with small molecule drug development.

Key considerations and future directions for API process development

In summary, a clear API process development strategy is essential to streamline and de-risk drug development, helping your drug reach the market in the most cost and time-effective way possible. Additionally, utilizing science- and risk-based methodologies in your strategy is essential for successful API production and for demonstrating a thorough understanding of the product and the process, including how any changes in the manufacturing process will affect the safety, efficacy, and quality of the final product.

Looking to the future, the adoption of innovative technologies, such as high-throughput experimentation (HTE) and predictive process modeling, will undoubtedly change the landscape of API process development. These methods can effortlessly generate large amounts of data, aiding the prediction of how processes will respond to varied reaction conditions and scale-up configurations. These data-driven techniques will further help to improve decision-making and design more efficient, robust, and scalable API manufacturing processes.

Outsourcing your API process development With these many complex considerations, outsourcing your API process development can maximize your chances of success while taking the pressure off your drug development teams. Leveraging the scientific expertise and tried-and-tested tools and methodologies offered by a specialist partner to develop your processes will pave the way for streamlined and de-risked API manufacturing. When looking to outsource your API process development, you’re in safe hands with Evotec. The combination of our 25 years of experience in the development and manufacturing of small molecule APIs and our end-to-end shared R&D platform offers a fully integrated approach to process research and analytical development, supplying APIs for use in pre-clinical development, non-clinical use, and clinical trials, all the way through to commercial supplies.

Head to our API capabilities webpage to find out more about how we can optimize your API process development strategy, and de-risk and accelerate your drug development program.

CONTACT OUR EXPERTS

OncoResponse is a biotech company that specializes in immuno-oncology, the science of using the body’s own immune system to fight cancer. The company uses insights from patients who have exceptional responses to cancer treatments to create new therapies. OncoResponse works closely with MD Anderson Cancer Center at the University of Texas, one of the world’s leading cancer research institutes, to use a unique technology that finds and develops new antibodies that target the immune cells in the tumors.

The company’s most advanced therapy, OR502, is an antibody that blocks a protein called LILRB2 that suppresses the immune system. OR502 restores the immune system’s ability to attack the cancer cells and is currently being tested in clinical trials.

OncoResponse partnered with Just-Evotec Biologics on OR502 to develop a manufacturing process that would supply their Phase 1 clinical trials.

The partnership was kicked-off by OncoResponse providing several variants of the OR502 antibody. Just-Evotec Biologics used its Abacus™ predictive computational tool from its J.MD™ Molecular Design toolbox to evaluate the manufacturability and stability of the different variants allowing OncoResponse to select a lead candidate with optimal manufacturability properties.

Just-Evotec Biologics then developed a cell line with its J.CHOTM High Expression System to produce OR502 in its continuous biomanufacturing platform. This system utilizes CHO-K1 host cells, transposon-based expression vectors and proprietary cell culture media. The company’s scientists further developed the process and successfully scaled it up in their J.PLANT™ Seattle GMP manufacturing facility at the 500-L bioreactor scale. This allowed operational teams to manufacture material for the first-in-human trial and provide the necessary CMC data for OncoResponse’s Investigational New Drug submission to the FDA. The CMC development from ordering DNA for transfection through to the shipment of drug substance to the fill finish site took just 11 months.

In November 2023, OncoResponse announced the first person to receive OR502 has been dosed in a Phase 1/2 trial. The trial aims to test the safety, tolerability, and initial anti-cancer effects of OR502 alone and in combination with anti-PD-1 in people with advanced solid tumors. OR502 clinical studies are being conducted with support from the Cancer Prevention Research Institute of Texas (CPRIT) DP230076.

“Our launch of this trial in cancer patients shows our ongoing dedication to developing treatments that can enhance the outcomes for people with cancer,” said Clifford Stocks, CEO of OncoResponse.

Learn more on Early Clinical Supply

Continuous biomanufacturing is reducing the cost of goods of biopharmaceuticals. Achieving continuous manufacturing requires expertise in equipment design.

Download the highlights of Andrea Isby's presentation at Repligen's DSP Workshop in Estonia from May 23rd, 2024 to learn more. 

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High-throughput screening methodologies have accelerated downstream development for monoclonal antibodies by enabling parallelized evaluation of chromatographic resins across a range of conditions. However, scientists must now interpret results in a meaningful and consistent way.

Learn how Just - Evotec Biologics' Downstream Data Browser automates visualization of high-throughput datasets, fits response surface statistical models, standardizes report results from a high-throughput screening method and facilitates comparison across molecules allowing the accelerated development of continuous biomanufacturing processes.

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