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Highly complex APIs developed to treat rare and orphan diseases present big technical questions for contract developers.
The switch in emphasis in the pharmaceutical industry from the development of blockbuster drugs to therapies that treat rare diseases and smaller patient populations has led to the need for small-volume current good manufacturing practice (cGMP) API manufacturing capabilities. These APIs must meet the same regulatory requirements as larger-volume drug substances, except at smaller scale and with less-but much higher value material-available for analytical testing, and often under accelerated timelines. In addition, the APIs used to formulate these products are typically highly complex, requiring multi-step syntheses using unusual reagents. Managing multiple projects can be a challenge for contract development and manufacturing organizations (CDMOs).
CDMOs often manage at any one time numerous small-volume API development projects involving a wide range of chemicals targeting a broad array of therapeutic indications. As a result, they must deal with many different challenges simultaneously. “These molecules tend to by highly complex, and most have never been synthesized before except perhaps at small scale in the laboratory. They also typically require the application of specific, sophisticated technologies, some of which must be engineered for the first time,” says Ed Price, president and CEO of PCI Synthesis.
Practical syntheses must be developed that can be transferred to cGMP processes that consistently meet quality requirements. Even though commercial processes for these APIs involve smaller volumes than those of APIs intended for blockbuster drugs, scale-up issues must still be addressed. Understanding critical process parameters (CPPs) and their impact on critical quality attributes (CQAs) is essential to understanding the process and conducting risk evaluations for unit operations and equipment to ensure “right-first-time” technology transfer, according to Shyam Vispute, general manager of tech transfer at Neuland Labs.
Analytical methods must also be developed and validated, which can be challenging due to the complexity of the molecules. In addition, given the small quantities of high-value material being manufactured even at commercial scale, minimizing the quantity of material consumed in these activities is important. “Alternative protocols may need to be developed in some cases to allow for use of reduced quantities of these costly APIs,” Vispute says.
The complex molecules being developed as drug candidates today require sophisticated technology for their production, such as advanced chromatography systems and specialized isolation techniques like tangential flow filtration, according to Price. PCI Synthesis has seen the need for low-temperature chemistry grow significantly. “Doing cryogenic chemistry is manageable at the lab scale but is much more challenging at the 1000-gallon scale,” he says.
Often it is necessary to design suitable hardware for use in the laboratory and then transfer the technology to plant scale, according to Vispute. In some cases, existing equipment can be modified, but in others new systems must be purchased.
Scale-up and optimization of small-volume processes can be challenging because for many there is little information available in the literature. “It is essential to consider all of the various process parameters-temperature, pressure, mass transfer, etc.-upfront,” Vispute observes. Risk analyses for each unit operation-reaction and purification (extraction, distillation, crystallization, filtration, etc.), drying, and powder processing-should be conducted to avoid problems at plant scale.
Joshua Hoerner, senior director of research and development at Noramco Athens, notes, however, that solution mixing, pressure, and temperature challenges may actually be reduced on a small-volume basis due to the smaller surface areas involved.
In some cases, the batch scale, which is determined from the dosage strength of the final formulation, will impact the choice of technology used in a synthesis. When developing peptides, for example, researchers must determine whether solid-phase, solution-phase, or hybrid technology is most appropriate, according to Partha Pal, head of custom manufacturing solutions and business development for Neuland Labs.
Because most of these molecules have not been synthesized on any appreciable scale before, it is also necessary to develop practical purification strategies, according to Price. Poorly soluble compounds falling in Biopharmaceutical Classification System (BCS) classes II and IV can be particularly challenging. “Exploring all available techniques to improve solubility and bioavailability, such as employing suitable techniques to modify the physicochemical properties or increase the specific surface area of the API powder particles, is often necessary,” notes Girish Kavishwar, associate vice-president of R&D at Neuland Labs.
Some isolated intermediates and APIs may be oily liquids, which can create handling and stability challenges, according to Hoerner. “Managing active ingredients that are predominately viscous oily liquids is a significant challenge, both from a handling and stability perspective. Noramco is working on dosage form solutions to help improve the processability of such substances while also enhancing their commercial shelf-life,” he notes.
Crystalline powders, on the other hand, may have different polymorphs and crystal habits that can impact drug product manufacturing robustness and the bioavailability of the API, Hoerner adds. “Identifying and stabilizing the appropriate polymorph requires special skills and should be performed early on in the process to avoid problems late in the development cycle,” agrees Pal.
Handling cytotoxic and highly potent compounds is yet another issue. Appropriate facility and equipment design is required for handling such compounds, and appropriate disposal facilities are also required based on their occupational exposure limits. Automation of process operations is also important for reducing the exposure of operators and the environment to hazardous chemicals, according to Pal. “A process hazard analysis (PHA) should always be conducted prior to implementing a small-volume cGMP synthesis to systematically identify and mitigate hazards that arise from innate chemicals or chemical reactions,” Hoerner asserts.
One of the key technical and operational challenges associated with cGMP manufacturing of small volumes of intermediates and APIs is difficulty in obtaining reliable reaction yields and consistent quality, according to Hoerner. Noramco tackles this issue with thorough process development efforts to maximize process knowledge and understanding. In-process controls for monitoring reaction completion, crystallization, drying, and other critical steps are also used to ensure completion.
“Overall, we emphasize a company culture that focuses on the patient/customer and ensures our products are of optimal quality and produced in a safe and compliant manner,” Hoerner comments. From a technical perspective, Noramco begins at the R&D stage, selecting and developing a phase-appropriate route and evaluating critical raw material sources, reagents/solvents, equipment, and analytical controls to ensure robust delivery of cGMP material. In addition, Hoerner says that scale changes between development and cGMP supply are modeled with advanced software; process analytical technology (PAT) or advanced offline analytical technologies are applied to synthetic steps that are highly complex or have significant risk to impact product quality.
Neuland uses quality-by-design (QbD) and design-of-experiment (DoE) approaches beginning at the development stage to identify relevant process parameters and identify the design space that will have minimal variations at the plant scale, according to Vispute. Use of simulation software, such as for scale up and mixing behavior studies, allows the evaluation of equipment performance prior to actual experimentation in the plant, leading to reduced costs and development times for Neuland. PAT tools are used for real-time measurement of CPPs, such as focused-beam reflectance measurement (FBRM) probes for particle size distribution, particle vision and measurement (PVM) probes for particle shape and polymorph determination during crystallization processes, infrared (React IR , Mettler-Toledo) for monitoring the real-time progress of reactions, and near infrared (NIR) probes to perform drying profile studies for determination of desired polymorphic forms of temperature-sensitive products.
The internal protocol at PCI Synthesis places emphasis on doing a good job at building a practical process early on in a project. “Once the chemistry and analytics are locked in, if any changes are needed, a tremendous amount of work will need to be repeated. That is why it is so important to take the time upfront to choose the right raw materials (considering cost and availability), really understand the process, and build into the early stage chemistry what will be required down the road,” Price observes. Process optimization using a DoE approach allows efficient yet thorough exploration of the design space. Method development for in-process and final product testing and confirmation of process robustness and reliability at larger scale are then performed before moving to GMP production.
Small-volume cGMP chemistry is clearly an area that can pose significant challenges. “The first focus should always be on safety and compliance during manufacturing and ensuring robust production of high-quality intermediates and active ingredients,” Hoerner says. That cannot be achieved if small-volume API manufacturing is treated as a commodity business, according to Price.
“We work with many different small companies, each with its own business model, culture, internal resources, and level of experience. Each project they bring us is unique, involving vastly different raw materials, equipment, and chemistry. Flexibility and the ability to respond to the different needs of our customers and their projects are crucial to success. We must be able to bring a significant number of differing resources to bear to create custom-tailored solutions to complex problems,” Price concludes.
Vol. 42, No. 3
When referring to this article, please cite it as C. Challener, " Small Volumes, Big Challenges" Pharmaceutical Technology 42 (3) 2018.