In this interview, NewsMedical talks to Dr. James Mencel’s Guidance about Scaling Up API Processes.
Could you please introduce yourself and your expertise in the pharmaceutical industry?
I earned a Bachelor of Science in Chemistry at Fairfield University in 1979 and a Ph.D. in Organic Chemistry at Yale University in 1984 before starting my career in cardiovascular discovery chemistry at Revlon Health Care, which later became Rorer in 1986, and eventually, Rhone Poulenc Rorer (RPR) in 1990.
The focus at the time was on peptidomimetic targets, which led to the opportunity to join Process R&D and establish a peptide development function to assist both drug discovery and commercial manufacturing of peptide hormones. This role progressed within RPR to an international responsibility, resulting in a broader role supporting process development and production of various New Chemical Entities (NCEs) entering development.
In 2000, I joined Rhodia Chirex, seeing it as a chance to gain knowledge in the expanding contract API R&D and GMP production arenas. At Rhodia Chirex, I was in charge of process development, plant implementation, and GMP production for contract programs.
Working with budget-conscious clients emphasized the need to obtain every bit of information possible from each experiment and operational run. This method was crucial for improving process capacity and readiness in a timely and cost-effective manner, especially when preparing for large-scale operations and stringent requirements. This experience stands out as one of the most important in my career.
In 2006, I joined Johnson Matthey (JM) Pharmaceutical Materials as Chief Scientist, where I was responsible for commercial product manufacturing support, analytical and process development, and plant implementation for novel Active Pharmaceutical Ingredients (APIs).
My responsibilities included contributing to regulatory filings, offering technical assistance for intellectual property issues, and providing on-site technical and regulatory counsel to other business units working on building processes for commercial applications. At JM, my understanding of the CMC regulatory environment expanded greatly, informing my approach to chemical development and manufacturing going forward.
In 2012, I joined Galleon Pharmaceuticals, where I played a key role in API and medicinal product development, as well as GMP production using outsourced resources. My responsibilities also included assisting with the discovery process by profiling candidate compounds and handling the regulatory documentation for both APIs and medicinal products.
In 2016, I joined Design Space Inpharmatics as an API consultant, where I helped customers with API process development, GMP manufacturing, and regulatory document preparation.
Since joining DSI, I have continued to broaden my knowledge and gain extensive experience in the technical and regulatory aspects of chemical research and development. I have contributed to several registration filings and played an important role in several products that have recently been approved.
In your experience, how important is scaling up API processes when transitioning from laboratory development to commercial production?
The primary responsibilities of the API chemical development and plant implementation teams are to design and deliver a process, complete with analytical controls, that meets the expected demands and to efficiently implement this process to manufacture the API. This is critical at every development step and for every planned usage of the API since the proper preparation of API supplies and reaching the needed quantity and quality within the necessary timeframe is crucial.
The API, or Active Pharmaceutical Ingredient, is the crux of the development program; without it, progress is halted. In the case of generic API controlled substances, DEA quotas may severely limit trial scale-ups, making it critical that the lab-to-plant transfer succeeds on the first try, which may also serve as the initial process validation batch. Effective process creation and scale-up are therefore important for business success.
According to my experience, the chemical development and production teams are fully aware of their critical role in the drug development program and are sincerely devoted to performing their jobs effectively.
Could you provide an example from your career where expert assistance, particularly in API development and process scaling, was critical to project success?
During a recent initiative, isolating the product at a crucial stage of the API process proved extremely difficult, raising significant concerns about its scalability in commercial production. This isolation stage was particularly critical for reducing impurities since ineffective separation could jeopardize the removal of impurities from the product’s wet cake.
With expert guidance, the laboratory development team conducted a thorough review of all available information on this particular isolation step, analyzing a decade’s worth of development reports and production records.
This deep dive yielded numerous scattered but useful discoveries, which, when combined, hinted at a possible solution. Notably, a previous isolation process identified for allowing straightforward product separation also showed promise for its capability to successfully remove impurities. However, the solvents used in this historical method were not compatible with the current product preparation conditions.
Guided by expertise, the team developed a two-part, optimized approach that allowed the essential chemistry to proceed while smoothly incorporating the solvents and conditions from the historical isolation technique.
This novel strategy not only achieved the desired chemical change but also reintroduced the effective isolation and impurity-purging methods of the past. The redesigned process step has now been validated and implemented in commercial manufacturing operations.
Image Credit: DS InPharmatics (DSI)
What unique problems have you encountered when transitioning from lab-scale to plant-scale API production, and how have you dealt with these complexities?
In my experience, the chemical reaction itself is rarely the problem during process scale-up. It is crucial to note that while the conditions for developing a chemical reaction may be well-defined, the techniques used for executing it, especially with respect to product separation at useful scales, can vary. Once the reaction conditions are established, factors impacting scalability and robustness, such as the choice of solvents and catalysts, must be considered.
Problems during scale-up can arise based on the depth of understanding of the reaction and how well the entire process for the specific chemistry stage is designed for the environment in which it will be run.
Three common and critical technical challenges include combined heat and mass transfer, time dilation for large-scale operations, and behavior during product isolation. Additionally, issues may arise with the handling and charging of individual materials, which could be related to safety, the characteristics of the specific substance (e.g., hygroscopicity), and the requirements of the reaction.
To address complications in scaling up processes, understanding external requirements (such as managing oxygen or water) and verifying their feasibility at scale is important. Many operational aspects can be simulated in the laboratory, while others are more challenging. These problems vary depending on the process.
For complex scenarios, an experienced team should analyze the process collectively and design scale-up and process-stressing simulations. When evaluating the overall API process, some aspects that are acceptable or even necessary for initial small batches may need to be removed or specifically adapted for large-scale manufacturing.
Operations such as concentration to dryness and chromatographic purifications are typically prioritized for replacement early in the scale-up process. However, initial program risks and time constraints can limit the development scope before early API manufacturing. Early API manufacturing might include these operations until clinical program risks have been sufficiently mitigated to justify the more extensive chemical development necessary for their replacement.
Scaling up indicative analytical controls can also be challenging. Some approaches used in the lab to aid development may be entirely inappropriate for, or difficult to implement in, a scale-up setting.
Robust analytical support is crucial for understanding the chemistry and behavior of the product throughout the manufacturing process. Scale-up failure can result from insufficient analytical examination during process development, as well as an inability to monitor the reaction or other essential process factors for success.
What practical insights and best practices may be used to ensure a successful API scale-up process?
Achieving a successful scale-up involves several aspects, with experts presenting varying perspectives. First and foremost, calculating the expected operational size and identifying the available equipment to carry out the process is critical. This involves understanding the equipment’s capabilities. In addition, scheduling the scale-up venue and providing supporting analytical services for staffed processing (e.g., five days/12 hours, five days/24 hours) are critical factors. These aspects serve as a framework for the development effort.
The key requirement for scaling up is a comprehensive understanding of the chemical process. This extends beyond stoichiometry to the choice of solvents, reactants, and any necessary catalysts. It entails determining the essential external parameters, such as the order in which reactants are added, mixing, and temperature requirements, as well as how they are handled. Establishing appropriate analytical monitoring methods is also crucial.
The specifications for quenching the reaction mixture and performing the work-up process must be explicitly defined. The entire process for isolating the product must also be specified. In some cases, the product may not be isolated in solid or oil form but rather acquired as a solution, ready for the next chemical stage. Predefined quality criteria for intermediates upstream of the API are essential for preserving its quality. As a result, the procedure for each intermediate must meet these quality requirements.
These components serve as the basic blueprint of the intended chemical transformation process, from material input to an isolated product that fulfills specified quality standards. This procedure must be described in terms of the planned scale, available equipment, and other aspects of the scale-up environment. It is critical throughout development to observe and document any behaviors such as exotherms, thickening, foaming, color changes, precipitation, phase separation issues, and product filterability.
Observing behaviors like exotherms or phase splits can reveal the need for specific adjustments in the scaled-up process (for example, using a conductivity meter for dark-on-dark phase splits).
Alternatively, these findings may imply that the chemistry or general process for producing the specific product is not scalable in its current state. The product’s stability at various phases of the process should be evaluated through laboratory simulations that match plant conditions.
When viewing the process in a broader context, aspects such as the availability, lead time, and cost of critical materials, as well as product storage and the possibility of intersite shipping, must be analyzed and planned for. These aspects can become critical for long-term planning.
The points listed above provide a framework for determining the process parameters and adjustments required for the initial scale-up. To ensure the process’s long-term viability, individual process parameters must be studied methodically to determine those that are crucial and require specific boundaries.
Could you give some instances of how DSI’s API consulting team supports small molecule and peptide clinical development, manufacturing, and strategic API regulatory guidance?
For experienced chemical development personnel, many aspects of contemporary regulatory requirements are inherently linked to having a thorough grasp of the process, which is a necessary component of solid process development.
Effective development work should be guided by ICH guidelines such as Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), and Q11 (Development and Manufacture of Drug Substances), which emphasize the necessity of quality control throughout the process. These guidelines recommend conducting frequent risk assessments to examine the adequacy of information collected as the process progresses.
DSI’s consultants specialize in providing advice on chemical development and API manufacturing, catering to a wide spectrum of needs from pre-IND stages to post-validation commercial manufacturing. In the early stages of drug development, DSI focuses on leading toward a process and manufacturing setup capable of producing periodic, often smaller-sized batches. As the clinical program progresses, both process understanding and skills must evolve accordingly. DSI assists in gathering the essential body of information for a robust process and a thorough API regulatory filing.
Impurity control is a critical area that requires expertise: understanding the introduction or derivation of structurally related impurities, their regulatory toxicity status (per ICH Q3A(R2) or ICH M7), and their elimination throughout the chemical process is crucial for setting intermediate and API specifications. This information may highlight the need for additional targeted development of the process. Short polypeptides and peptidomimetic APIs face similar issues as small molecule APIs, such as acquiring non-natural, often chiral, amino acids.
For larger polypeptide APIs, factors such as the molecule’s chain length and expected quantities are critical, and DSI offers advice on whether to use solid-phase or conventional solution-phase synthetic techniques for large-scale production.
Early supplies for Drug Discovery or pre-IND activities, which are frequently manufactured by semi-automated solid-phase processes, purified by chromatography, and separated by lyophilization, may not be suitable for clinical supplies. Many small companies may lack the necessary expertise for large-scale preparations or to evaluate peptide CMOs and their proposals. For large-scale production, DSI helps determine whether the peptide should be produced sequentially or by preparing and linking polypeptide fragments.
To minimize racemization, coupling locations and chemistry for C-terminus activation must be carefully selected. The choice between solid and solution-phase synthesis influences the choice of amino acid side chain protecting groups and the N-terminal protection approach (e.g., t-BOC vs FMOC vs CBZ).
If the peptide API contains rings or side chain branching, the timing of their introduction is critical. Purification and isolation techniques, such as chromatography and lyophilization, need proper scale adjustments.
Developing a peptide synthesis for scale-up requires thorough analytical support to check quality factors specific to synthetic biopolymers, such as racemized centers, deletion sequences, and appropriate ring placement.
Synthetic polypeptides can have structural errors affecting in vivo conformation, making it crucial to identify erroneous species. Given their high potency, even minor structural impurities in peptide APIs can have a considerable impact on activity and may cause undesirable pharmacodynamic consequences. These quality considerations are critical for creating an acceptable peptide regulatory submission.
Can you provide an example of how DSI optimizes manufacturing processes to balance quality control and cost efficiency during API scale-up?
Cost, efficiency, and quality control are broad subjects that require careful consideration and cover entire textbooks. They address topics such as reaction chemistry, chemical processes, waste reduction, product isolation and drying, supply chain management, and manufacturing venues. At DSI, we strive to optimize cost and efficiency while maintaining quality standards. Improving throughput, chemical yields, and product quality at each stage can lead to increased efficiency and quality throughout the process.
Reducing time in equipment, which is a key cost factor, is critical. GMP plant reactors are expensive to run, and the objective is to process as much material through a reactor as possible in as little time as possible while manufacturing a high yield of suitably pure product.
Volumetric optimization is critical to process as much reactant as possible in the least amount of solvent possible. This involves decreasing quench and work-up volumes, resulting in optimized vessel loading. This is influenced by reactant solubility, as well as heat and mass transfer. Volumetric improvements can also minimize solvent distillation time, lowering processing costs and the risk of sensitive product degradation.
Focusing on the completeness of product crystallization or precipitation, as well as reducing yield losses to the wash liquors, is simple but crucial. It is important to ensure that conditions that maximize crystalline yield do not introduce impurities into the desired product.
The method and conditions of drying can also influence efficiency and quality since improper approaches can impede drying and cause degradation, while dryer unloading mechanics can alter final batch homogeneity. These fundamental components are central to optimizing cost and efficiency.
How does DSI assist drug substance manufacturers?
DSI’s API consultants play an active role throughout the process, collaborating closely with selected chemical development and GMP manufacturing contractors. If requested, we can assist API CMOs in drafting proposal requests, evaluating bids, and recommending contract awardees.
Additionally, we can help locate secondary manufacturers for intermediates or the API itself and oversee the entire technology transfer process between primary and secondary manufacturers.
At the client’s request, our experts can supervise contracted development work and API manufacturing. We are committed to understanding the chemistry and current analytical controls, using insights from previous lab or plant results to predict future manufacturing operations.
We routinely visit development and production sites to interact with the local team, create reports, and assess the contractor’s potential development, manufacturing, and analytical capabilities at the primary location, as well as gather information about affiliate sites. This engagement helps establish a relationship with the contractor’s team and provides an understanding of the process, its scale-up performance, existing infrastructure for API manufacturing, and new capabilities. The cost and availability of critical materials are also integral to our strategy to enhance API manufacturing.
We work to understand the API’s evolving needs and the projected timeframe. This informs our evaluation of the supply chain and chemical process, enabling us to determine what may be required to meet anticipated future API demand.
DSI API experts assist in designing and assessing data following pre-scale-up laboratory demonstrations. We also examine and update draft master batch records and are available to assist with the process as required, even on-site. Moreover, we review executed batch records.
We participate in post-action evaluations to extract lessons from completed scale-ups and identify any necessary steps before the next manufacturing operation, which may include long-term considerations.
In collaboration with DSI Quality specialists, the customer, and the contractor, our consultants review manufacturing-related deviations, investigations, and change controls, often in real time throughout production. Our goal is to finalize all manufacturing-related documentation necessary for product release.
How does DSI assist with drug substance regulatory affairs?
Recent regulatory guidance underscores the importance of developing a thorough understanding of the process, including quality control throughout its entirety. This understanding evolves as the process progresses.
Regulatory authorities require assurance that a chemical process can control product quality while reliably delivering products to the intended population. As a result, the ultimate aim of API chemical development is to create a robust manufacturing process that consistently operates at the required scale and produces a product that meets intended specifications and yields.
To enhance process understanding, DSI assists in designing and reviewing spike fate and purge studies, utilizing the resulting data to help define defensible specifications for purchased materials, intermediates, and the API, all of which are necessary for registration filings.
We pay close attention to current expectations regarding nitrosamines and potentially genotoxic impurities (PGIs), assessing the process’s ability to keep them within the required levels by the Agency. Once specifications are established, our API team undertakes critical process parameter studies to identify and set bounds for sensitive parameters, ensuring product quality.
The experience and data gathered from these activities form the foundation of process understanding and quality control, which is critical for Module C of the registration filing. Identifying and obtaining an Agency agreement on regulatory starting materials (RSMs) in a chemical process is a crucial CMC juncture. The DSI API team assists in selecting suggested RSMs, produces supporting arguments following ICH guidelines, and, at the client’s request, prepares RSM briefing books for the US and other authorities.
Additionally, we provide briefing books and comparability evaluations to support major process changes and the introduction of new GMP manufacturers or locations after pivotal clinical API trials have been conducted.
Upon client request, we can accompany or fully represent them at Agency CMC meetings following briefing books and meeting requests. Our API team also prepares and reviews API-related filing content for INDs, IMPDs, NDAs, sNDAs, DMFs, and MAAs and addresses reviewer questions during dossier review.
About James Mencel
A Yale educated chemist, Dr. Mencel has served the pharmaceutical industry for 40 years with practical experience in all aspects of synthetic chemistry and API development as well as early drug product formulation. In this capacity, Jim is technically proficient in several languages which serves his work with the global CMO community.
Jim joined DSI in 2016 from Galleon as an expert process chemist whose career focus has evolved toward applying principles of quality risk assessment and sound science to provide CMC guidance to all aspects of drug substance.
The Drug Substance Team assists our clients by providing strategic guidance and timely assistance ranging from the pre-IND to commercial arenas, spanning peptide and small molecule API chemical process R&D and manufacturing, and including authoring and review of regulatory documentation. Services include support for lab-to-plant transfer for cGMP clinical supply and commercial manufacturing and inter-site technology transfer. Our Drug SubstanceTeam can support your process & analytical development for API process scale-up, and cGMP API manufacturing.
About DS InPharmatics
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations, or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.
