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Medium-Molecule APIs are considered to have a molecular weight of approximately 500 to 2,000. Since the molecular weight of organic synthesis APIs is below 500, and that of APIs produced by microbial or animal cell culture is around 150,000, the former are called Low-Molecule APIs and the latter High-Molecule APIs. The intermediate ones are referred to as middle molecular weight APIs. Medium-Molecule APIs are broadly divided into peptide pharmaceutical APIs and nucleic acid pharmaceutical APIs.
Types and Characteristics of Medium-Molecule APIs
Peptide Pharmaceutical APIs
Peptide pharmaceutical APIs are obtained by synthesizing peptides through solid-phase or liquid-phase reactions that bond 20 types of amino acids. The synthesized peptides need to have the structure of the active sites of proteins that are usually generated in the body. Generally, the peptides are often cyclic to make them less susceptible to degradation and modification.
Nucleic Acid Pharmaceutical APIs
Nucleic acid pharmaceuticals make use of nucleic acids such as DNA and RNA, which carry genetic information, in medicinal applications. Since nucleic acid pharmaceuticals can be manufactured with synthetic techniques similar to those used for small molecule pharmaceuticals, they can be produced at a lower cost compared to high molecular weight APIs. Moreover, they can target molecules like mRNA and miRNA, which cannot be targeted by either small or high molecular weight pharmaceuticals.
Manufacturing Facilities for Middle Molecular Weight APIs ~Key Points in Construction~
Laboratory Scale Facility Adaptation
During the drug discovery phase of APIs, trial production uses test tubes and Erlenmeyer flasks. This is the so-called laboratory scale, or beaker scale. At this scale, commercially available test equipment is often installed, and the facility (including building, HVAC, sanitary, and electrical systems) must be designed to accommodate these devices in a user-friendly configuration, taking into account HSSE (Health, Safety, Security, Environment) considerations.
Adaptation for Clinical Trial Drugs and Pilot Plants
To manufacture pilot plants or clinical trial drug plants at the level of several kilograms to tens of kilograms, compliance with GMP is necessary. Especially for the multi-production of formulations whose safety and other aspects have not been confirmed, it is crucial to logically assemble and construct a system addressing various measures such as cleanroom structure, HVAC systems, equipment cleanability, and containment of highly active substances.
Chemical Hazard Adaptation
Paradoxically, the targets of middle molecular weight APIs, which are a new technology, often have high pharmacological efficacy. This is because APIs with low pharmacological efficacy have a poor return on investment. As a result, middle molecular weight APIs often require measures against chemical hazards. Regulations for these chemical hazards are independently established by each country, making global compliance challenging.
Hazardous Materials Adaptation
Since middle molecular weight APIs are produced by chemical synthesis, a large volume of solvents is used. Consequently, the manufacturing facility must comply with the Fire Service Act as a hazardous materials manufacturing site or a general handling site. Specifically, structures like hydrogenation rooms must be designed to withstand explosion pressures, and features like venting shafts must be installed to release explosion pressures. Coordination with fire authorities is necessary for these measures, so reliable design by knowledgeable and experienced engineers is required.
Cleaning Adaptation
For middle molecular weight APIs, where amino acids or nucleic acids are bonded stepwise, reaction tanks are often reused. There is a concern that reaction residues may adversely affect subsequent reactions. Thus, cleaning between processes and campaigns is important.
Continuous Production
Middle molecular weight APIs, like low and high molecular weight APIs, are beginning to explore continuous production techniques to improve production efficiency. Specifically, techniques such as continuous-flow hydrogenation reactions and membrane concentration are being adopted. To achieve continuous production, quality management through Quality by Design (QbD) and inline monitoring via Process Analytical Technology (PAT) are key points.
Scale-Up
From the drug discovery phase to clinical trials and market launch, scale-up progresses from beaker to bench (collectively sometimes referred to as kilo lab) to pilot to launch to commercial scale. Ensuring product quality and production efficiency during this scale-up process is a key point.
Strengths of CM Plus
①Engineering + CM Method
The CM method is a project management system that integrates the client’s perspective with designers to operate and manage projects transparently, ensuring success from the aspects of QCD (Quality, Cost, Delivery) + EHS (Environment, Health, Safety). Professionals, including Construction Managers (CMr) who specialize in management, work on behalf of the client.
At CM Plus, we conduct engineering (design) in-house. We have engineers who are well-versed in manufacturing processes, equipment and facilities, construction, and manufacturing support facilities (such as electrical systems, HVAC, and utilities). This allows us to oversee the entire facility from the initial planning stages, enabling the construction of integrated and cohesive layout facilities.
②Comprehensive Coordination of Production Equipment and Building Facilities
With a focus on designing from the production process perspective, we execute designs that start from the internal aspects like building production equipment lines, layouts, and internal flow/logistics, leading to the creation of API (Active Pharmaceutical Ingredient) factories that are in harmony with the production system. Our planning extends to the intangible aspects of the production system as well.
Our team consists of project managers and professional engineers experienced in factory construction across various fields. This allows us to manage the overall project schedule comprehensively, including not only the building and production support facilities but also providing support for the procurement, production management, and coordination of delivery plans of production equipment.
Services provided by CM Plus
Business Concept
We listen to our clients’ requirements and create deliverables such as a list of key equipment, PFD (Process Flow Diagrams), and conceptual layouts to visualize the investment image. Based on the created deliverables, we calculate an approximate investment amount to support investment decisions (Feasibility Study, F/S).
Conceptual Design
In the basic planning (concept design) phase, we compile the client’s requirements and requests through discussions and document them as a User Requirement Brief (URB). We also calculate an approximate project cost based on the contents of the URB.
Basic Design
In the basic design phase, based on the contents of the URB, we create the necessary drawings and specifications for effective solicitation. Specifically, in the process design, we produce PFDs, P&IDs (Piping and Instrumentation Diagrams), data sheets, time schedules (OTS), and equipment specifications required for plant design. We also organize regulations and standards related to facility design and construction, government applications, and environmental conditions, support setting up the project’s master schedule and overall execution plan, and assist with preparations and support for prior coordination with relevant government agencies and utility providers.
Procurement
In the purocurement phase, to build an optimal execution system tailored to the project’s characteristics, we study the order and service divisions and prepare solicitation specifications and procurement specifications based on these considerations. We then solicit quotations from construction companies. We support the client in selecting a construction company by conducting technical evaluations and quotation assessments on the proposals presented by the construction companies and summarizing them in a report.
Detailed Design / Production Management
In the detailed design and manufacturing management phase, we perform design supervision to ensure the construction company and production equipment suppliers reflect the URB, basic design documents, and various regulations in their designs and that progress is on schedule.
Construction and Installation Phase
In the construction and installation phase, we perform construction supervision to ensure that the construction company reflects the URB, URS, detailed design documents, and various regulations in their work, and manage the quality of facilities and equipment. Additionally, a construction manager will reside on-site to manage construction status, progress, and changes from the client’s perspective.
Trial operation
To carry out high-quality and efficient qualification, we provide services that suit the client’s needs, reducing their burden by supporting the creation of a validation master plan and risk assessment from the planning stage and creating protocols for Qualification (DQ, IQ, OQ, PQ), and supporting the execution phase.
Facility Operation
Related Projects
Related Contents
Useful Information
Please refer to the articles related to active pharmaceutical ingredients and medium molecules on our information dissemination site, “GMP Platform”.
“How to Build a Pharmaceutical Factory: Towards Project Success”
“How to Build a Pharmaceutical Factory: Special Edition”
We have published a book in English. Please refer to this news.
