In the complex world of biopharmaceutical development, Chemistry, Manufacturing, and Controls (CMC) activities are critical yet often fraught with challenges. Just-Evotec Biologics offers a suite of innovative solutions designed to mitigate these risks, with their J.MD™ Molecular Design service standing out as a key player in this arena.

The Role of J.MD™ Molecular Design

The J.MD™ Molecular Design service is part of Just-Evotec Biologics’ comprehensive J.DESIGN™ platform, which integrates advanced computational tools and high-throughput methodologies to streamline the development process. This service focuses on selecting an optimal lead and optimizing the molecular design of biologics to ensure manufacturability, stability, and efficacy from the earliest stages of development.

Evaluating Early Team Supply Material

One of the primary ways J.MD™ helps derisk CMC efforts is by evaluating early team supply material produced in stable pools. This early biophysical characterization is crucial for identifying potential issues that could arise later in the development process. By addressing these issues upfront, Just-Evotec Biologics helps partners avoid costly and time-consuming setbacks.

Derisking the CMC Journey

The CMC journey involves numerous stages, from initial development to production-scale manufacturing. Each stage presents unique challenges that can impact the overall success of a biopharmaceutical product. Just-Evotec Biologics’ J.MD™ service helps derisk this journey in several ways:

1. Predictive Computational Tools: The Abacus™ tool within the J.MD™ toolbox uses predictive algorithms to assess the manufacturability and stability of different molecular variants. This allows for the selection of lead candidates with optimal properties, reducing the risk of failure in later stages¹.
   
   
2. High-Throughput Screening: By leveraging high-throughput screening methods, J.MD™ can rapidly evaluate multiple variants, accelerating the development timeline and ensuring that only the most promising candidates move forward².
   
   
3. Integrated Development Approach: The J.MD™ service is part of a larger, integrated approach that includes cell line development, process optimization, and continuous manufacturing. This holistic approach ensures that all aspects of the CMC process are aligned and optimized for success³.
   
   
4. Regulatory Support: Just-Evotec Biologics also provides comprehensive regulatory support, helping partners navigate the complex landscape of biopharmaceutical regulations. This support is crucial for ensuring that products meet all necessary standards and can be brought to market efficiently⁴.

Conclusion

In summary, Just-Evotec Biologics’ J.MD™ Molecular Design service plays a pivotal role in derisking CMC efforts for biopharmaceutical partners⁵. By evaluating early team supply material, leveraging predictive computational tools, and integrating a comprehensive development approach, J.MD™ helps ensure that the CMC journey is as smooth and successful as possible. This not only saves time and resources but also increases the likelihood of bringing effective and safe biopharmaceutical products to market.

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References

1. Just-Evotec Biologics’ Abacus™ tool 
2. High-throughput screening methods
3. Integrated development approach
4. Regulatory support
5. Derisking CMC efforts for biopharmaceutical partners

In the dynamic world of biopharmaceuticals, cost efficiency is a critical factor, especially for start-up companies navigating the complex landscape of drug development. Continuous biomanufacturing is an innovative approach that has garnered significant attention for its potential to significantly reduce the cost of commercial biologics. Less often discussed, however, is the potential for continuous biomanufacturing platforms for first-in-human (FIH) clinical trials. This method not only streamlines the production process but also offers substantial savings during the manufacture of material intended for early phase antibody development, making it an attractive option for emerging biotech firms.

What is Continuous Biomanufacturing?

Continuous biomanufacturing is a process where the production of biopharmaceuticals occurs in a seamless, ongoing manner, as opposed to traditional batch manufacturing, which involves discrete, separate production cycles. This continuous approach leverages advanced technologies and automation to maintain a steady flow of production, ensuring consistent quality and efficiency.

Cost Efficiency in Early-Stage Clinical Trials

One of the most compelling advantages of continuous biomanufacturing is its ability to produce large quantities of biopharmaceuticals in a single run. This is particularly beneficial for early phase clinical trials, where the initial supply can often be enough to cover subsequent Phase 2a and Phase 2b clinical studies. Here’s why emerging biopharmaceutical companies benefit:

1. Elimination of Additional Batches: Traditional batch manufacturing often requires multiple production runs to meet the demands of Phase I and II clinical trials. Each additional batch incurs significant costs, including raw materials, labor, and quality control. Continuous biomanufacturing, however, can produce a large enough supply in one go, eliminating the need for these extra batches.
   
   
2. Consistent Quality: Continuous processes are designed to maintain a high level of consistency and offer more levers to tightly control critical quality attributes than fed-batch processes. Supplying multiple clinical trials from the same lot of material ensures a perfect level of consistency which is crucial for regulatory approval and patient safety, further streamlining the development process.
   
   
3. Time Savings: By producing all necessary material in one continuous run, companies can significantly reduce the overall time required to manufacture the material they need for clinical trials. They avoid the challenge of finding available slots in their CDMO’s production schedule. This accelerates the overall timeline for clinical trials, allowing for faster progression through the development pipeline.

Financial Impact for Start-Ups

For start-up companies, the financial implications of continuous biomanufacturing are profound. The cost savings from eliminating additional batches can amount to millions of dollars. These funds can then be redirected towards other critical areas of drug development, such as:

1. Research and Development: Investing in the discovery of new drug candidates and innovative therapies.
   
   
2. Clinical Trials: Expanding the scope and scale of clinical trials to gather more comprehensive data.
   
   
3. Regulatory Compliance: Ensuring that all necessary regulatory requirements are met efficiently and effectively.
   
   

Learn More

From Batches to Brilliance: The Benefits of Continuous for Commercial Manufacturing

As we covered in the first blog of this series,  biotherapeutics sponsor companies face numerous challenges in process development and manufacturing. This largely comes down to the overwhelming reliance on fed-batch processes in the biologics industry, which bring lengthy production timelines, process risks, and supply chain vulnerabilities. These issues contribute to the high cost structure of biologics and limit the accessibility of these vital therapies worldwide.

Continuous manufacturing is a rapidly emerging alternative production process to fed-batch processing. Biological products are produced in an uninterrupted flow, resulting in a steady and consistent output of product. This approach addresses many of the challenges with fed-batch systems, including: 

• Reduced process costs and lower cost of goods manufactured (COGM)
• Scalability and adaptability to fluctuating demands
• Fewer process and scalability risks

Read on as we explore these benefits of continuous manufacturing for commercial manufacturing, describing how they can address the high cost structure associated with biologics, and help to meet the rising global demand for these life-saving therapies. 

Cost reduction

Continuous manufacturing can reduce the COGM by up to 75% compared to traditional fed-batch processes (1), while also achieving 10-fold higher productivity (Figure 1). 

Figure 1: Productivity of a fed-batch process compared with a continuous approach. 

This is partly achieved through workflow automation, which minimizes labor costs while improving production efficiency (Figure 2). Additionally, compared with fed-batch units that require large facilities to store product intermediates, continuous operations are highly intensified and have a much smaller facility footprint, further reducing operational costs. Continuous operations also enable manufacturers to optimize resource use and reduce waste, leading to additional cost savings. 

Figure 2: Unit operations and labor resources needed to run a continuous process compared to traditional fed-batch process

Scalability and adaptability

A continuous approach allows for a much more agile process, driven by greater scalability and adaptability. For instance, J.POD^® biomanufacturing facilities from Just – Evotec Biologics support throughput from less than 10 kg to over 2,000 kg per year of protein-based biologics including mAbs and biosimilars. Production can be rapidly scaled up by increasing bioreactor numbers and extending run times with intensified continuous manufacturing technology. This enables manufacturers to adjust production levels quickly in response to market demand. 

Figure 3: How Just – Evotec Biologics’ platform steady-state intensified continuous manufacturing process can be scaled

Reduced risk

Continuous manufacturing reduces risks by ensuring consistent product quality. A DoE approach can be used to fine tune product quality attributes (PQAs) during development and advanced monitoring in production can maintain process consistency. This consistency is crucial for reducing regulatory risks and ensuring the efficacy and safety of biologics. 

This innovative manufacturing approach also enhances supply chain and financial security. With a smaller facility footprint and reduced operational costs, the financial risk for sponsor companies is substantially reduced. The modular design of facilities like J.POD allows for rapid deployment and scaling, mitigating geopolitical disruptions and financial risks associated with traditional fed-batch processes.

Making the transition is easier than you think. Explore the benefits and the process in more detail in our whitepaper

Unravelling the blueprint for success 

Transitioning to continuous manufacturing for commercial supply, in modular facilities like J.POD, offers a robust, cost-effective, and adaptable solution to address the unmet demand for biologics globally. Yet despite the clear benefits of continuous manufacturing, many manufacturers have yet to make the transition from fed-batch systems. This is often due to a lack of understanding of regulatory uncertainties, deployment pathways, and process development activities. 

Just – Evotec Biologics leverages over a decade of expertise in continuous manufacturing to help clients convert their fed-batch processes to its continuous manufacturing platform ready for commercial production. Commercial supply runs with its continuous manufacturing platform can be performed within one of its J.POD biomanufacturing facilities. These modular, scalable facilities are designed to offer the following benefits: 

• Maximized yields and cost efficiency – J.POD facilities utilize intensified continuous perfusion culture supporting high cell densities and product yield. The facilities also minimize operational costs through workflow automation, intensified bioprocessing, optimized resource use, and more.

• Rapid deployment and advanced agility – J.POD facilities are built using modular cleanroom pods that can be swiftly deployed and assembled. This design allows for flexible and scalable manufacturing capacity, enabling the facility to adapt quickly to changing production needs.

• Risk resilience – With established facilities in the US and Europe, J.POD mitigates the risk of geopolitical or supply disruptions. These facilities are standardized in design and operation, allowing for seamless process transfer between sites. 

Discover the full benefits of J.POD facilities 

References

1. Garcia, F.A. and Gefroh, E. Reducing biopharmaceutical manufacturing costs through continuous processing in a flexible J.POD® facility. Drug Discovery Today. (2023); 28 (7): 103619. https://doi.org/10.1016/j.drudis.2023.103619 

The Biologics Bottleneck: How Conventional Manufacturing Technologies Limit Access

Over the past two decades, biotherapeutics, particularly monoclonal antibodies (mAbs), have transformed the therapeutic landscape for a range of prevalent health conditions, from autoimmune diseases to cancers. It’s also been estimated that some 7,000 rare disease indications could be addressed with biotherapeutics ⁽¹⁾. However, while biologics have shown remarkable efficacy in clinical settings, access to these therapies remains a significant challenge globally.

Most biologics developers rely on fed-batch systems for bioproduction. However, this approach brings several key challenges that create risks and inefficiencies in the production pipeline, including:

• High manufacturing costs
• Difficulty in adapting to demand
• Expensive and risk-prone commercial development process

In this blog, we’ll explore these major factors influencing the supply and access of commercial biologics, before highlighting how adopting a continuous manufacturing approach can address these challenges.

Challenges in biotherapeutics supply and access

High manufacturing costs

Fed-batch manufacturing involves discrete unit operations where production occurs in separate, sequential steps. Each step must be completed before the next one begins. This means large volumes of intermediates must be stored, which requires a substantial facility footprint.

Running these large-scale facilities is expensive and contributes to the high costs of manufacturing. Additionally, fed-batch processes often require significant manual input, needing large teams of operators for their execution, increasing costs further. As a result, fed-batch facilities run at a higher operational cost compared with continuous bioprocessing units.

Difficulty in adapting to demand

It’s challenging for biologics developers to accurately predict the take-up and global demand for a biologic, especially during early production phases. If demand is too low, it can lead to sponsors paying out for idle manufacturing capacity. Should demand be higher than forecasted, sponsors run the risk of underproduction, causing shortages and patients going without medicines.

Further adding to this problem, fed-batch processes rely on large-scale stainless-steel units for commercial supply that are expensive and time-consuming to build. This creates inflexibility, bringing difficulties in adapting fed-batch units to fluctuating demands. This scenario was experienced by the developers of rheumatoid arthritis therapy Enbrel^®. During times of increased demand, such as when new indications were approved or patient populations grew, inability to rapidly scale up production of their fed-batch process caused serious supply constraints ⁽²⁾. 

Expensive and risk-prone commercial development process

Fed-batch biomanufacturing processes face significant risk when it comes to scaling up production, especially for sponsors moving from clinical trials to commercialization. This can limit the ability of manufacturers to meet global demand.

Fed-batch processes must be scaled up by a factor of 5 to 20-fold in order to meet commercial demand, because of the inefficiency of the process.

Scaling up in this way creates the following risks:

• The large-scale process might not replicate the smaller-scale process performance
• Product quality attributes (PQAs) might change at increased scale
• A limited number of large-scale facilities exist worldwide, causing major supply issues during increased production demands

A better approach to biologics manufacturing

Biologics provide life-saving treatments, but access and supply have been limited due to their high cost structure, inflexible production processes, and unpredictable demand. Continuous manufacturing addresses these challenges by offering a more agile, cost-effective, and stable production process.

This approach involves raw materials being continuously fed into the bioprocessing system, while products are continuously yielded. By automating workflows and maintaining a steady state of operation, companies can improve scalability, adaptability, productivity, and consistency. Companies that have started their clinical journey with a fed-batch process should consider converting to a continuous manufacturing platform before commercialization to take advantage of these benefits.

Learn how continuous manufacturing can slash biologics production costs by 75 %

To maximize manufacturing outcomes, opt for an industry-leading partner like Just – Evotec Biologics. Partners can benefit from cutting-edge continuous manufacturing technologies, well-established process development systems, and state of the art J.POD facilities.

Learn more about Just – Evotec Biologics’ continuous manufacturing solutions and how they can benefit your biomanufacturing needs

References

1. Chediak L. I have a rare disease. This is my hope for the future of medicine. World Economic Forum.

2. Gellene D. Immunex says Enbrel shortage worse than anticipated. Los Angeles Times. 

Just- Evotec Biologics is pioneering a new era in biomanufacturing. Transitioning to our intensified continuous production before manufacturing at commercial scale can drive value creation in a late-stage manufacturing process. Additionally, as we offer a short feasibility study, this is a low-risk method for evaluating the benefits our workflow can bring, without impeding development timelines.

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Targeting RNA represents a paradigm shift for drug discovery. The ability to seek out and destroy, or modify, a faulty RNA template, before the toxic protein has even been made, has only recently begun to be harnessed for the benefit of patients. 
At the time of writing, 21 Oligonucleotide drugs have been approved for human use, with an exponential increase in clinical trials and development projects involving this new modality. 
There exist several different mechanisms of action for Oligonucleotide drugs, all of which are transient and reversible and do not lead to alteration of patient DNA, unlike Gene therapy. 

Antisense Oligonucleotides harness endogenous systems already existing within a cell to achieve their purpose, with the only limitation being accessibility of the target tissue.
Once bound with great specificity to its RNA target, a short synthetic Oligonucleotide can trigger degradation, upregulation of the translated protein, or alteration of a splicing event leading to a correctly folded protein. Longer Oligonucleotides can fold into 3 dimensional shapes called Aptamers with similar target affinities and applications as antibodies, and shorter Oligonucleotides can act as MicroRNA   mimetics or antagonists to alter multiple targets or pathways concurrently with subtle but broader effect. 

The precision of an Oligonucleotide and its ability to correct a faulty RNA produced by an error in the genetic code, lends itself to applications in the fields of rare disease therapeutics and toxic gain of function mutations. The field of Oligonucleotide therapeutics is developing to address this as a whole and to pioneer a new preclinical and regulatory path that could be adapted for these unique disease biologies to make this type of therapeutic innovation more accessible. 

Evotec is a leader in integrated end-to-end Research and Development and has built substantial drug discovery expertise and technical capabilities that can drive new innovative and diverse modalities into the clinic. In addition, Evotec has developed a deep internal knowledge base in key therapeutic areas including neuroscience, pain, immunology, respiratory, women’s health, aging, fibrosis, inflammation, oncology, metabolic and infectious diseases. Leveraging these skills and expertise, Evotec successfully delivers on superior science-driven discovery and development alliances with pharmaceutical and biotechnology companies.

The global interest in this new modality area has led to high demand in Oligonucleotide synthesis and related chemistry applications, from modified Oligonucleotides to conjugates and complex formulations. 
Evotec offers Oligonucleotide research and development capabilities as well as ligand and linker chemistry expertise to support projects from discovery through to development.

In particular, since 2015 the discovery chemistry group is equipped with MerMade 48X synthesizers (Biosearch Technologies, see Fig. 1) with associated purification, post processing and QC platforms (at the Evotec sites of Toulouse and Verona, see Fig 2), while the development team, since 2022, is equipped with a Cytiva ÄKTA oligosyntTM synthesizer associated to the ÄKTA pureTM 150 and ÄKTA flux 6 purification platforms and with a Virtis Lyophilizer at Evotec’s state-of-the-art Verona site (see Fig. 3 to Fig. 6).
	Figure 1: Biosearch MerMade 48X	Figure 2: Agilent Preparative HPLC for purification
	Figure 3: Cytiva ÄKTA oligosyntTM	Figure 4: Cytiva ÄKTA pureTM 150
	Figure 5: Cytiva ÄKTA flux 6TM	Figure 6: SP Virtis Advantage Pro Lyophilizer
	Figure 7: UPLC with a Thermo ScientificTM Orbitrap ExplorisTM 120 mass spectrometer for oligonucleotides characterization

This fully integrated suite of capabilities allows for the synthesis, purification, isolation, and quality control of complex modified Oligonucleotides (ASOs, siRNAs, etc) on a scale from milligrams up to 25 g (up to 12 millimoles). The objective is to support Oligonucleotide drug discovery and development projects from the earliest phases of discovery, such as the generation of screening libraries, up to the selection of a preclinical development candidate followed by manufacture and release of material to support initial preclinical development studies. 

All these activities are supported by an experienced Oligonucleotide chemistry team operating across two sites and at different scales, to ensure flexible support for projects with highly efficient information and process transfer.
Evotec capabilities also include expert analysts for Analytical Development and QC, capable of developing and validating the analytical procedures needed for a full characterization and routine testing of Oligonucleotide drug substances up to and including IND enabling studies. In addition, Evotec’s support can encompass the release of preclinical batches according to regulatory requirements, including stability and formulation studies.

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.

Our experts are just a click away! 

Reach out to us today

Don’t miss our educational webinar series on “Oligonucleotides Therapeutics: Discovery to Development”

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With high attrition rates of mAbs in early phase clinical trials, it is becoming increasingly challenging for biopharmaceutical companies to rapidly deliver high quality therapeutic mAbs using conventional antibody screening and fed-batch bioprocessing methods. This is why new Quality by Design (QbD) approaches such as using in silico AI and ML platforms to discover and optimize mAb sequences, high-throughput screening, and continuous intensified manufacturing processes such as those used at Just- Evotec Biologics are critical for enabling a paradigm shift in reducing attrition rates.

As detailed in this article, optimizing mAb design, using automated, miniaturized screening, and minimizing time in culture can deliver high-quality mAbs for FIH trials in rapid response times of around 12 months. In the future using this approach could expand access to life changing treatments, as well as support a rapid response to global health emergencies.

Learn More

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^TM 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

Download the Presentation

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.

Download our whitepaper