In this interview, NewsMed talks to Dr. James Mencel's Guidance about Scaling Up API Processes.
Could you introduce yourself and your experience in the pharmaceutical industry?
I obtained a B.S. in Chemistry at Fairfield University in 1979 and a Ph.D. in organic chemistry in 1984 at Yale University and then began my career in cardiovascular discovery chemistry at Revlon Health Care, which later became Rorer (1986) and ultimately Rhone Poulenc Rorer (RPR, 1990).
The focus at the time was peptidomimetic targets, and that led to an opportunity to join Process R&D to start a peptide development function in support of both drug discovery and commercial manufacturing of peptide hormones. That evolved within RPR to an international responsibility and led to a broader role supporting process development and manufacturing of all types of NCEs entering development.
I moved to Rhodia Chirex in 2000, seeing that as an opportunity to gain experience in the emerging contract API R&D and GMP manufacturing arena. At Rhodia Chirex, I was responsible for process development, plant implementation, and GMP manufacturing for contract programs.
Working with budget-conscious clients underscored the importance of extracting every bit of information from each experiment and operational run. This approach was critical for enhancing process capability and readiness in a time-efficient and cost-effective manner, particularly when preparing for larger-scale operations and more stringent requirements. This experience stands out as one of the most pivotal in my career.
In 2006, I joined Johnson Matthey (JM) Pharmaceutical Materials as Chief Scientist, where I was entrusted with leading commercial product manufacturing support, analytical and process development, and plant implementation for new Active Pharmaceutical Ingredients (APIs). My responsibilities extended to contributing to regulatory filings, providing technical support for intellectual property matters, and offering on-site technical and regulatory guidance to other business units focused on developing processes for commercial applications. At JM, my knowledge of the CMC regulatory world grew tremendously and informed my approach to chemical development and manufacturing henceforth.
In 2012, I moved to Galleon Pharmaceuticals, taking on a pivotal role in API and drug product development, as well as GMP manufacturing through contracted resources. My responsibilities also included supporting the discovery process by profiling candidate molecules and managing the regulatory documentation for both API and drug products.
In 2016, I moved to Design Space Inpharmatics as an API consultant, where I have been supporting clients with API process development, GMP manufacturing, and the drafting of regulatory documents. Since joining DSI, I have continued to expand my expertise and gain comprehensive experience in both the technical and regulatory facets of chemical development and manufacturing. I have contributed to numerous registration filings and played a significant role in several products that have recently received approval.
In your experience, how crucial is the scale-up of API processes when transitioning from laboratory development to commercial production?
The core responsibilities of the API chemical development and plant implementation teams are to devise and deliver a process—complete with analytical controls—that fulfills anticipated needs and to effectively implement this process to produce the API. This is crucial at every development phase and for every intended use of the API, as the successful preparation of API supplies and achieving the required quantity and quality within the necessary timeframe is paramount.
The API, being the Active Pharmaceutical Ingredient, is the linchpin of the development program—without it, progress halts. In the realm of generic API controlled substances, DEA quotas may severely restrict trial scale-ups, making it imperative for the lab-to-plant transition to succeed on the first attempt, which might also serve as the initial process validation batch. Effective process development and scale-up are thus critical to business success.
Based on my experience, the chemical development and manufacturing teams are acutely aware of their pivotal role in the drug development program and are deeply committed to contributing their part effectively.
Could you share an example from your career where expert guidance, especially in API development and process scaling, played a pivotal role in project success?
During a recent program, isolating the product at a critical juncture of the API process proved to be exceptionally challenging, raising significant concerns for its scalability in commercial production. This isolation step was also crucial for eliminating impurities, as ineffective separation could compromise the removal of impurities from the product's wet cake. Under expert guidance, the laboratory development team embarked on a thorough review of all available information on this specific isolation step, examining a decade's worth of development reports and manufacturing records.
This deep dive unearthed several scattered but valuable insights that, although dispersed, hinted at a potential solution when pieced together. Notably, a historical isolation procedure identified as facilitating easier product separation also showed promise for its ability to expel impurities effectively. However, the solvents required for this older method were incompatible with the current product preparation conditions.
Guided by expertise, the team devised a two-part, streamlined process that allowed the necessary chemistry to proceed while seamlessly integrating the solvents and conditions from the historical isolation technique. This innovative approach not only enabled the desired chemical transformation but also reincorporated the effective isolation and impurity purge methods of the past. The revised process step has since been validated and integrated into the commercial manufacturing operation.
Image Credits: DS InPharmatics (DSI)
What specific challenges have you encountered when moving from lab-scale to plant-scale API manufacturing, and how have you addressed these complexities?
Generally, in my experience, during process scale-up, the chemical reaction itself is rarely the issue. It is important to point out that the developing conditions for the chemical reaction itself can be different from developing the process by which it is performed, with product isolation, at useful scales. However, as the reaction conditions are developed, factors that may affect scalability (e.g., selection of solvents, catalysts, etc.) and robustness should be considered.
Issues may arise during scale-up due to how well the reaction is understood and how well the overall process for the specific stage of chemistry has been developed for the environment in which the process will be run. Three common and key technical challenges are heat and mass transfer taken together, time dilation for operations at a large scale, and behavior during product isolation. There can also be challenges with how individual materials are handled and charged, some of which may relate to safety, properties of the specific material (e.g., hygroscopicity), and the requirements of the reaction.
To manage complexities in scaling up reactions, it's vital to understand external requirements (e.g., controlling oxygen or water) and ensure they're feasible at scale. While simulating many operational aspects in the lab is possible, others are more challenging. These challenges vary with the process.
For challenging cases, it's beneficial for an expert team to collectively review the process and design scale-up and process-stressing simulations. When considering the entire process of the API, some features might be tolerable or even necessary for initial small batches but must be eliminated or specially accommodated for large-scale manufacturing.
Operations like concentration to dryness and chromatographic purifications are prioritized for replacement early in scale-up development. However, initial program risks and time constraints may restrict development scope before early API manufacturing. Early API manufacturing might necessitate these operations until clinical program risks decrease sufficiently to warrant the more extensive chemical development required for their replacement.
Indicative analytical controls can also be a challenge for scale-up. Some methodologies used in the lab to aid development may be entirely unsuitable for or difficult to accommodate in the scale-up setting. Good analytical support is essential to understanding the chemistry and also the behavior of the product across the process during which it is made. Scale-up failure can occur because insufficient analytical scrutiny was applied during process development and/or because of an inadequate ability to monitor the reaction or other elements of the process that may be essential for success.
What practical insights and best practices can be implemented for a successful API scale-up process?
Achieving a successful scale-up encompasses numerous factors, with experts providing various insights. This discussion will highlight key aspects for initially scaling up a single chemical stage.
First, determining the anticipated operational scale and identifying the available equipment to execute the process is crucial. This includes understanding the equipment's capabilities. Additionally, the scheduling of the scale-up venue and the arrangement of supporting analytical services for staffed processing (e.g., five days/12 hours, five days/24 hours, etc.) are important considerations. These aspects frame the development work.
The primary requirement for scale-up is the thorough development and understanding of the chemical reaction. This goes beyond stoichiometry and the choice of solvents, reactants, and any required catalysts. It involves defining the fundamental external factors, such as the sequence of adding reactants, mixing, and temperature needs and how those are managed. Additionally, establishing suitable analytical monitoring methodology is crucial.
The specifications for quenching the reaction mixture and for the work-up process need to be clearly outlined. Additionally, the complete procedure for isolating the product must be specified. In some instances, the product might not be isolated in solid or oil form but could be obtained as a solution, ready for the subsequent chemical stage. There may also be predefined quality standards for intermediates upstream of the API that are crucial for maintaining API quality. Therefore, the process for each intermediate must fulfill these quality standards.
These components form the foundational outline of the desired chemical transformation process, ranging from the input of materials to an isolated product that meets specified quality criteria. This process must be defined within the context of the intended scale, the available equipment, and other characteristics of the scale-up environment. It's crucial during development to observe and document any behaviors like exotherms, foaming, thickening, precipitation, color changes, issues with phase separation, and the filterability of the product.
Observing behaviors such as exotherms or phase splits may highlight the need for specific accommodations in the scaled-up process (for instance, using a conductivity meter for dark-on-dark phase splits). Alternatively, these observations could indicate that the chemistry or the overall process for preparing the specific product isn't scalable in its current form. The stability of the product at different stages of the process should be assessed through laboratory simulations that mimic plant conditions.
When considering the process in a broader context, factors such as the availability, lead time, and cost of key materials, along with product storage and potentially the need for intersite shipping, must be evaluated and planned for. These elements can become crucial for long-term planning. The points mentioned provide a framework for identifying the process parameters and accommodations needed for initial scale-up. For robust, longer term use of the process, it will be necessary to systematically study individual process parameters to identify those which are critical and which require specific boundaries.
Could you provide examples of how DSI's API consulting team supports small molecule and peptide clinical development, manufacturing, and strategic API regulatory guidance?
For experienced chemical development professionals, many aspects of current regulatory expectations are inherently tied to achieving a comprehensive understanding of the process, which is a fundamental part of sound process development. Effective development work should be informed by ICH guidelines such as Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), and Q11 (Development and Manufacture of Drug Substances), which emphasize the importance of controlling quality throughout the entire process. These guidelines advocate for periodic risk assessments to evaluate the sufficiency of knowledge accumulated as the process develops.
DSI's consultants specialize in offering advice on chemical development and API manufacturing, catering to a range of needs from pre-IND stages through to post-validation commercial manufacturing. In the initial phases of drug development, DSI focuses on guiding toward a process and manufacturing setup that can produce periodic, usually smaller-sized batches. As the clinical program advances, both process understanding and capabilities must evolve accordingly. DSI then aids in accumulating the necessary body of knowledge for a robust process and a comprehensive API regulatory submission.
A key area requiring expertise is the control of impurities: 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 specifications for intermediates and the API. This knowledge might indicate the need for further focused development of the process. The considerations for short polypeptides and peptidomimetic APIs are similar to those for small molecule APIs, including challenges like the sourcing of non-natural, often chiral, amino acids.
For larger polypeptide APIs, considerations such as the molecule's chain length and the expected quantities are crucial, and DSI provides guidance on choosing between solid phase or classical solution phase synthetic methods for large-scale manufacturing.
Early supplies for Drug Discovery or pre-IND activities, often produced via semi-automated solid phase methods, purified by chromatography, and isolated through lyophilization, may not be suitable for clinical supplies. Many small companies may lack the expertise for larger-scale preparations or in evaluating peptide CMOs and their proposals. For larger-scale syntheses, DSI assists in determining whether the peptide should be synthesized through sequential coupling of individual amino acids or by preparing and coupling polypeptide fragments.
The location of couplings and the chemistry used for C-terminus activation must be carefully chosen to minimize racemization. The decision between solid vs. solution phase synthesis affects the selection of amino acid side chain protecting groups and the N-terminal protection strategy (e.g., t-BOC vs FMOC vs CBZ). If the peptide API includes rings or side chain branching, the timing of their introduction is crucial. The methods for purification and isolation, such as chromatography and lyophilization, require appropriate scale accommodations.
Developing a peptide synthesis for scale-up necessitates comprehensive analytical support to confirm quality aspects unique to synthetic biopolymers, like racemized centers, deletion sequences, and proper ring placement. Synthetic polypeptides can have structural errors affecting in vivo conformation, making detection of erroneous species critical. Given their high potency, even minor structurally related impurities in peptide APIs can significantly affect activity and might have undesired pharmacodynamic effects. These quality aspects are vital for preparing a satisfactory peptide regulatory submission.
Can you share an example of how DSI optimizes manufacturing processes to balance quality control with cost efficiency during API scale-up?
Cost, efficiency, and quality control are broad topics that warrant detailed consideration, and encompass entire textbooks. They cover aspects such as reaction chemistry, chemical processes, product isolation and drying, waste reduction, supply chain management, and manufacturing venues. At DSI, we focus on optimizing cost and efficiency while maintaining quality standards.
Improving throughput, chemical yields and product quality provided at each stage can lead to time efficiency and improved quality for the overall process. Reducing time in equipment, which is a significant component of cost, is crucial. GMP plant reactors are expensive to operate, and the goal is to process as much material through a reactor as possible in as little time as possible, with a high yield of suitably pure product.
Optimizing volumetrics is key, aiming to process as much reactant as possible in as little solvent as possible, which includes minimizing quench and work-up volumes. This leads to optimized vessel loading, influenced by reactant solubility and heat and mass transfer. Improvements in volumetrics can also reduce solvent distillation time if distillation is part of the process, reducing processing cost and the risk of degradation of sensitive products.
Focusing on the completeness of product crystallization or precipitation and minimizing yield losses to the mother or wash liquors is basic yet important. it is crucial to ensure that conditions that increase crystallized yield do not also bring out impurities with the desired product. The method and conditions of drying can also impact efficiency and quality, as improper techniques can slow drying and cause degradation, and dryer unloading mechanics can affect final batch homogeneity.
These basic elements are central to improving cost and efficiency.
How does DSI provide drug substance manufacturing support?
DSI's API consultants are deeply involved in the process. We collaborate closely with chosen chemical development and GMP manufacturing contractors. If requested, we assist in drafting requests for proposals from API CMOs, evaluating bids, and recommending contract awardees. Additionally, we can assist in identifying secondary manufacturers for intermediates or the API and oversee the entire technology transfer between primary and secondary manufacturers.
At the client's request, our consultants can oversee contracted development work and API manufacturing. We are dedicated to understanding the chemistry and existing analytical controls, leveraging insights from previous lab or plant outcomes to anticipate future manufacturing exercises.
We will visit the development and manufacturing sites to interact with the local team, develop a repport, and learn about the development, manufacturing, and analytical capabilities that the contractor may offer at the primary site. We will also solicit information about affiliate sites. This will help build a relationship with the contractor’s team and provide an understanding of what is known about the process and its performance at scale, what infrastructure is already in place for API manufacturing, and what additional capabilities can be accessed. The cost and availability of key materials will also be a focus in our planning to support API manufacturing. Concurrently, we will strive to understand the evolving needs of the API and the expected timeframe involved. This informs our assessment of the supply chain and chemical process, helping us identify what may be needed to meet anticipated future API demand.
DSI API consultants contribute to the design of and review data after pre-scale-up laboratory demonstrations. We also review and edit draft master batch records and are available as needed, including on-site, during the execution of the process. Additionally, we review the executed batch records.
We will participate in post-action reviews to extract lessons from completed scale-ups and identify any necessary actions before the next manufacturing exercise, possibly extending to longer-term considerations. DSI API consultants, alongside Quality experts at DSI, the client, and contractor, will review manufacturing-related deviations, investigations, and change controls, often in real-time during production. Our aim is to finalize all manufacturing-related documentation required for product release.
How does DSI offer support for drug substance regulatory affairs?
As previously noted, recent regulatory guidance emphasizes the importance of establishing a thorough process understanding characterized by quality control throughout the entire process lifecycle. This understanding evolves alongside the proper development of the process.
Regulatory authorities must be confident that a chemical process both controls product quality and will reliably deliver products to serve the population for which the drug is intended. Accordingly, the ultimate goal of API chemical development is a robust manufacturing process that performs reproducibly at the required scale and which generates a product that reliably meets specifications and with the expected yield.
To build process understanding, DSI helps design and review the outcomes of spike fate and purge studies and uses the resulting data to help with setting defensible specifications for purchased materials, intermediates, and the API, as will be required for registration filings.
We are very attentive to current expectations regarding nitrosamines and PGIs and monitor the ability of the process to control these to within the Agency's required levels. Once specifications are established, our API team designs critical process parameter studies to identify sensitive parameters and establish boundaries for each, ensuring product quality.
The experience and data gained from these activities form the foundation of process understanding and quality control, crucial for Module C of the registration filing.
Identifying and gaining Agency agreement on regulatory starting materials (RSM(s)) in a chemical process is a pivotal CMC juncture. The DSI API team assists in selecting proposed RSM(s), develops supporting arguments following ICH recommendations, and at client request has prepared RSM briefing books for US and other authorities.
Additionally, we prepare briefing books and comparability assessments to support major process changes and the introduction of new GMP manufacturers or locations after pivotal clinical API trials have been conducted or introductions into a validated manufacturing state.
Upon client request, we accompany or fully represent them at Agency CMC meetings following briefing books and meeting requests. Our API group also prepares and reviews API-related filing content for INDs, IMPDs, NDAs, sNDAs, DMFs, and MAAs and addresses reviewer inquiries that may arise 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.
In April 2021 we were thrilled to announce that DSI has just become part of ProductLife Group.
French-headquartered ProductLife Group (PLG) is well-known in the Life Sciences market. It has a track record of successfully managing global outsourcing programs and insourcing services for its international client base. The company is on a mission to help transform human health outcomes by optimizing regulatory affairs, safety & vigilance, and quality compliance for life sciences organizations worldwide.
The fit between our two organizations could not be more perfect. We will complement PLG's growing biotech services portfolio. US biotech sponsors recognize DSI as a leader in consulting for go-to-market strategies and RA pre-market consulting. At the same time, PLG has a strong reputation for managing end-to-end outsourcing of regulatory affairs and pharmacovigilance activities worldwide.
Our merger with PLG will harness our combined strengths, offering our clients on both sides of the Atlantic support with their developed drugs approvals and post-approvals compliance, plus advisory services on the best market strategies to deliver a rapid ROI on their development. Together we will offer our clients increased pharmacovigilance capabilities - including a QPPV; pharmacovigilance consulting; and a fully validated safety database - as well as complementary toxicology-related services; RIM/electronic document management services; and support for medical device regulatory requirements.
We see enormous potential in this new chapter for DSI and you, our clients. As a PLG company, we have the opportunity to become part of a global force in life sciences regulatory and compliance solutions and services, and we're incredibly excited to add our momentum to that effort.
Understanding Global Harmonization of Regulatory CMC within Veterinary Medicine with Tammy Newbold