How is Active Pharmaceutical Ingredient (API) Manufactured?

About API

Active pharmaceutical ingredients or APIs can be defined as the chemicals used to manufacture pharmaceutical drugs. The active ingredient (AI) is the substance or substances that are biologically active within the drug and is the specific component responsible for the desired effect it has on the individual taking it.

Any drug or medication is composed of two components. The first is the API – which is the central ingredient. The second is known as the excipient, which is the inactive substance that serves as the vehicle for the API itself. If the drug is in a syrup form, then the excipient is the liquid that has been used to make it as such.

Production Process

APIs are generally manufactured through processes that include: Biological and Chemical Processes. How is active pharmaceutical ingredient manufactured? The following is the active pharmaceutical ingredient manufacturing process.

1.Feed Handling

The first step of API production is feed handling. This step is the preparation and transport of raw materials used for subsequent reactions.

2.Reactions

After the feed materials are prepared, chemical reactions convert the feed into the API. The production of API can occur by chemical synthesis or by using biotechnology, depending on the API chemistry.

2.1 Chemical Process

In industry, typical reactors used to achieve chemical synthesis of API include batch reactors , loop reactors, and specialized batch autoclaves.

Batch Reactors

Batch reactors , can range in size from 500 liters to 16 cubic meters depending on the scale of production for the API. Since contamination is a major concern in the pharmaceutical industry , these reactors are normally made from stainless steel or glass - lined mild steel and are fitted with a manway for easy cleaning. Agitation is also used in the reactor to provide mixing and heat transfer.

Loop Reactor

A loop reactor is a variation of a continuously stirred tank reactor, which is used for gas-liquid reactions at high pressures. Of the three types of loop reactors, jet, gas lift, and propeller, the jet loop reactor is the most common in chemical synthesis.

Batch Autoclave

A batch autoclave is a special type of batch reactor that is used for high pressure reactions or for feeds that are solids or a slurry. These reactors can operate above 5,000 psi and 500°C and are normally equipped with a magnetically driven stirring system to ensure even heat exchange.

2.2 Biological Process

Bioreactions mimic reactions that occur in living organisms. An example of biotechnology used in API production is fermentation, in which a fermenter is used as the reaction vessel.

Fermenters

Fermenters can be used in API manufacturing to produce antibiotics through microbial fermentation. The process is characterized by fast growth rates, which can lead to mass and heat transfer issues. To account for this, often a stirred tank or sparged tank fermenter is used. Both of these reactors undergo aerobic fermentation and therefore can only be used in aerobic API processes. For anaerobic processes an open tank design is used since the microorganisms produce a foam covering of carbon dioxide which blocks the oxygen from the reactants.

3.Recovery

After pharmaceutical reactions occur, the exit stream can contain API, unreacted feed materials, solvents, and any additional reaction additives. Typical recovery methods to separate API from reaction byproducts are described below.

4.Distillation

Distillation is a thermal process used to separate liquid species by evaporation. Batch, flash, and fractionaldistillation columns are used in API processing.

5.Membranes

In the pharmaceutical industry, pressure-driven processes often employ membranes . One of the ways membranes are used in this industry is by direct flow filtration. This involves passing the feed solution through a membrane, where particles are retained by physical capture or absorption. These membranes are commonly available in cartridges that contain the membrane or can be found as disposable capsules.

6.Crystallization

The final API is often in the solid stage in most synthetic processes. Crystallization is a process that includes a variety of steps for solid isolation, such as cooling, evaporation, concentration, reaction precipitation, pH change precipitation, and solvent change precipitation.

7.Filtration

After a solid is produced it can be separated from the liquid by filtration. A calmic or bag filter can be used to remove small quantities of solid but for larger quantities a nutsche filter is used.

8.Centrifugation

The principle of a centrifuge is to create enough centrifugal force to push the liquid through a filter medium which separates it from the solid. Four types of centrifuge are used in API manufacturing,including the vertical axis with a top discharge centrifuge, the horizontal axis centrifuges ,the vertical axis centrifuges and the peeler discharge centrifuge.

9.Drying

After recovery of the API from reaction byproducts, the API may still be wet with reaction solvent. Dryers are used to vaporize the solvent and produce a dry powder of API. Drying the API into dry powder form can be vital to accurately dosing some pharmaceutical products, such as tablets or capsules.

Production characteristics 

1.The pharma api manufacturing process is complex.

The production process of API contains complex biological and chemical reaction processes, so it is often necessary to carry out multiple unit operations in API production, including subsequent distillation, extraction, purification and so on. Technology and equipments are also very complex.

2. The pharma api manufacturing process is of high risk.

Because the production of API requires a large number of raw and auxiliary materials, and often requires the use of more organic solvents, many of raw materials and intermediates are flammable, explosive and toxic, and the reaction process is often accompanied by high temperature or high pressure control. because of the flammability and explosive nature of organic solvents, there are often some safety risks in the operation process.

3.The pharma api manufacturing process has lot pollution and more industrial wastes.

In the production and synthesis of API, with the progress of various side reactions, there is a certain amount of waste water and waste gas, which will not only affect the quality of soil, water and ecological environment, but also cause some harm to the air and operators. At the same time, a variety of drugs should be introduced into the API workshop in the process of production, and the nature of these APIs is different, so many different kinds of pollutants will be produced after production.  

4. The pharma api manufacturing process requires a high operating environment.

In the production process, there need to be measures and areas to prevent pollution and cross-contamination, especially the production of aseptic API, at the same time, the production of API needs to meet the requirements of GMP and various laws and regulations in order to better enter the market.

5. Strict product quality requirements.

Quality is an important index related to the production of APIs. If the quality of APIs can not be guaranteed, it will directly affect the production quality of drugs.

Market Overview

The API market's outlook is positive. The growing trend toward new high-tech therapeutics, coupled with the emergence of novel and innovative delivery systems and the evolution of personalized medicines, will only serve to further emphasize the growing demand for advanced APIs. APIs are commonly referred to as bulk pharmaceuticals and usually made in places at quite a distance to where tablets, suspensions and liquids are manufactured. Today, the greatest concentrations of API manufacturers are located around Asia, specifically in India and China. This has led to more companies outsourcing API manufacturing to such places, which has the main benefit of eliminating the need to invest in highly expensive equipment and infrastructure — which can also be complicated to install and maintain.

Long-Term Outlook

The demand for drugs to treat the aging population will definitely boost the sales of active pharmaceutical ingredients that are popularly used for manufacturing drug products.Due to a growing pool of geriatrics, these regions are primarily driving the active pharmaceutical ingredient market. Improving access to health care and the growing demand for pharmaceuticals in Asia-Pacific and the rest of the world are likely to create lucrative growth opportunities for the overall market.

Regulations

Regardless of where the active pharmaceutical ingredient is made, companies must adhere to strict safety and quality standards set by the country where it will be used. So, APIs manufactured in China or India for use in the United States must still be inspected and licensed by the FDA. Similarly, if the API is intended for use in Europe, it would need to meet regulations set by the European Medicines Agency.

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