Overview of intermediates & fine chemicals & more on CDMOs for the development & manufacturing of these products, from clinical to commercial scale.
Q1. What are pharmaceutical intermediates?
Pharmaceutical intermediates are chemical compounds which form the building blocks of active pharmaceutical ingredients (APIs). Pharmaceutical intermediates are produced as by-products during the production of an active pharmaceutical ingredient (API).
Both active pharmaceutical ingredients (APIs) and intermediates belong to the category of fine chemicals. The main difference between the two is that the active pharmaceutical ingredient (API) is an active product that has been completely synthesized, and the intermediate is a product at a certain place in the synthesis route.
While active pharmaceutical ingredients (APIs) exhibit pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, or prevention of diseases, intermediates are materials produced during the synthesis of APIs, which can only be turned into API by further molecular change or refinement.
Pharmaceutical intermediates, veterinary drug intermediates, and bulk drug intermediates are various types of drug intermediates. Drug intermediates are hygienically formulated using high-grade raw materials and they are used in the pharmaceutical industry. Pharmaceutical intermediates are also used for research and development purposes by pharmaceutical and biopharma companies.
While synthesizing active pharmaceutical ingredients (APIs), the pharmaceutical intermediates are exploited as chemical composites. They act as a building block in producing APIs, are involved in process development and validation to deliver quality assurance, and may help in decreasing the cost of high quality medicines.
As per a report published by Mordor Intelligence, the pharmaceutical intermediates market is anticipated to grow with a CAGR of nearly 5.3%, during the forecast period from 2018 to 2026. Consequently, organizations around the world need to work together to supply everything from starting materials to advanced API intermediates for the production of both branded and generic drugs.
Most pharma companies, contract development and manufacturing organizations (CDMO), contract research organizations (CRO) and contract manufacturing organizations (CMO ) which act as pharmaceutical drug intermediate manufacturers operate at near-full manufacturing capacity, producing a wide range of API intermediates and drugs to keep up with ever-growing demands.
Working with a CRO, CMO, CDMO for intermediates allows drug companies to benefit from a long-term partnership with an experienced team offering specific skills, equipment and technical resources that are not available internally, resulting in a robust supply chain from clinical supply to commercial scale, reduced risks and optimized costs.
Q2. How do fine chemicals differ from specialty chemicals?
Fine chemicals are single, pure and complex chemicals that are only produced in small amounts by multipurpose plants. Alternatively, fine chemicals are defined as inorganic or organic molecules produced in kilogram to multi-ton quantities by conventional or biotechnological chemical processes in plants across the world.
Most manufacturing firms, such as a CRO, CDMO, or CMO, produce chemicals in bulk using standardized reactions. Fine chemicals, on the other hand, are produced by a limited number of companies. The developing and manufacturing process of fine chemicals is complex and usually subject to multi-step synthesis.
Fine chemicals, to sum up, have to be combined with other substances to create products. They are also much more expensive to produce than bulk chemicals, due to their complexity and changing chemistries. These products end up in the specialty chemicals market. The specialty chemicals market includes high-value products that are produced in small quantities.
Fine chemicals are used as starting materials for specialty chemicals, particularly pharmaceuticals, biopharmaceuticals and agrochemicals. For instance as active ingredients in biocide formulations, as additives for plastics and coatings, or as active ingredients in cosmetics and toiletries. Some are also used as intermediates in the manufacture of liquid crystal displays, and so on.
As the name implies, specialty chemicals are manufactured for more specialist uses, and as a consequence are produced on a much smaller scale. Furthermore, they are sold based on functionality. Such products are temperature and pressure-sensitive thus the process, as well as storage conditions, need to be adhered to accordingly.
Typical specialty chemicals include additives and active ingredients. They may also include high value, low volume, ultra high purity chemicals used as intermediates for bio-pharma or high tech processing.
An organization such as a CRO, CMO, or CDMO experienced in the above-mentioned compounds and which functions as pharmaceutical drug intermediates manufacturer may offer fine chemical manufacturing services as well as the production of specialty chemicals from clinical supply to commercial scale.
Q3. How does flow chemistry help in the efficient and safe synthesis of APIs and intermediates?
The concept of flow chemistry defines a very general range of chemical processes that occur in a continuous flowing stream, conventionally taking place in a reactor zone. Flow chemistry is also known as continuous flow or plug flow chemistry. The process offers potential for the efficient manufacture of chemical products including the efficient and safe synthesis of APIs and intermediates.
Flow technology was introduced to pharmaceutical manufacturing in the early 2000s, when academic scientists started to develop a flow system for active pharmaceutical ingredients (APIs) and intermediate synthesis.
Over almost two-decades of development, flow chemistry has evolved from a novel synthesis concept to a powerful and versatile platform for the continuous manufacturing of APIs and intermediates with high productivity, a small manufacturing footprint, and reduced costs and waste.
In flow chemistry, reactants are combined by pumping fluids, including solutions of reagents, through tubes at known rates. The relative proportions of the reactants are controlled by their concentrations and relative flow rates. The advantages of this method over conventional batch reactions are the higher surface to volume ratio, easier heat and mass transfer resulting in more efficient reactions, and easier control and scale up.
Continuous operation makes it possible to minimize reaction volumes as the quantity of unstable reaction mixture in the continuous reactor at a given time is greatly reduced compared to a conventional batch process, thereby reducing safety risks. Furthermore, flow chemistry allows only a small amount of hazardous intermediate to be formed at any instant.
Flow chemistry is also characterized by a gain in chemical efficiency. Continuous flow reactors allow for tighter residence time distribution than batch reactors and enable excellent reaction selectivity. The rapid diffusion mixing avoids the issues found in batch reactors and high surface area to volume ratio enables almost instantaneous heating or cooling and therefore ultimate temperature control.
These factors contribute to minimizing secondary reactions and the formation of impurities. The quality of the product is correspondingly improved and the environmental footprint of such processes is reduced drastically.
Flow chemistry’s benefits in terms of safety, reagents consumption, and efficiency, now make it possible to conduct difficult reactions and to produce intermediates and APIs. Given all of these advantages, it is not surprising that continuous processing is emerging as one of the techniques that can significantly impact the synthesis of API intermediates. Flow chemistry is now part of the CDMO landscape and is considered as an essential technological asset for controlling sensitive chemical reactions.
Some Other Advantages of Flow Chemistry:
- Flow reactors can be easily and safely pressurised. This allows reaction temperatures well above the normal boiling point of the solvents providing reaction rates 1000 times faster than under reflux conditions.
- Testing a range of reaction variables is far faster in flow processes and less substrates and reagents are required.
- Because of precise control over variables and the ability to safely execute reactions over a wider range of reaction conditions, overall yield is improved, while impurity levels are minimized.
- It is safer for manufacturing organic intermediates and APIs under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk.
Q4. Which are the leading pharmaceutical CDMOs for intermediates and fine chemicals?
Pharmaceutical innovators are today relying more and more on Contract Development and Manufacturing Organizations (CDMOs) for the clinical and commercial production (i.e. commercialization) of their APIs and intermediates, fine chemicals, specialty APIs, etc.
Some leading pharmaceutical drug intermediates manufacturers offering CDMO services for APIs and intermediates from clinical supply to commercial scale are noted in detail below.
Pfizer CentreOne - CDMO Services for APIs and Intermediates (Including Specialty APIs)
Pfizer CentreOne, a global contract development and manufacturing organization (CDMO) and a leading supplier of intermediates and specialty APIs, offers development and manufacturing services for fine chemicals and intermediates. It therefore functions as a CDMO for intermediates and APIs.
Aozeal Certified Standards - Reference Standard Materials (RSMs) & Intermediates
Aozeal Certified Standards (AOCS), Inc. is a high-tech bio-pharmaceutical company specialized in the manufacturing and supply of intermediates and other pharmaceutical reference standard materials (RSMs). It is one of the leading manufacturers of reference standard materials (RSMs) such as drug working standards, drug impurity standards, drug metabolites and stable isotope labelled compounds.
PMC Isochem - Clinical and Commercial Production of APIs and Intermediates
PMC Isochem offers custom development and manufacturing of fine chemical intermediates (cGMP or non cGMP), active pharmaceutical ingredients (APIs), polypeptide excipients and amino acid based biopolymers for drug delivery solutions. It also has process development and validation services as part of its service capabilities. It offers the clinical and commercial production or commercialization of intermediates, APIs, excipients and polymers. PMC therefore provides CDMO services for APIs and intermediates and can thus function as a CDMO for intermediates.
Minakem - CDMO for Small Molecules, Fine Chemicals, HPAPIs, APIs and Intermediates
Minakem is a CDMO for intermediates, fine chemicals and active pharmaceutical ingredients (APIs). Minakem offers a combination of innovative development and manufacturing solutions through a wide range of flexible assets, specialized technologies, and advanced process development and validation capabilities for the synthesis of APIs and intermediates as well as HPAPIs at all production scales.
Curia - Fine Chemical Manufacturing Services
Curia serves a variety of specialty markets such as pharmaceuticals, agriculture, cosmetics, oilfields, detergents, lithography, coatings, liquid crystals, metal treatment and fuel cells via the fine chemical manufacturing services they offer. Curia’s drug substance and drug product manufacturing capabilities encompass launch through mature commercialization.
Clearsynth Labs Limited - CDMO for Small Molecules
Clearsynth functions as a CDMO for small molecules and offers small molecule manufacturing services. Chemically manufactured small molecules are the classic active drug substance that continues to be the "engine of growth" in the pharmaceutical industry.