Injectables

Injectables, such as solutions, suspensions, and emulsions, are a liquid form of the active pharmaceutical ingredient that is injected into the bloodstream of the recipient. The overall processes to develop the three types of injectables are quite similar, so the general process will be described below and differences pointed out as needed. The API, along with inactive ingredients, are mixed together and then packaged. Additionally all injectables must be sterilized.

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(Copyright GEA Process Engineering Inc., Columbia, MD)

This module describes production equipment relevant to mixing, packaging, and sterilization of injectables. The Quality Control module describes additional equipment used to monitor quality parameters during this process.

Process Map

Injectables Production

Mixing

The first step to producing an injectable product is mixing the ingredients. Solutions usually only require regular mixing since the ingredients are able to dissolve in the liquid to become a homogeneous mixture. Emulsions, on the other hand, are composed of two phases of liquids, such as oil and water, and so require high shear mixing.  Lastly, suspensions, where the API is suspended and not dissolved, vary in the type of mixing needed depending the type of formulation.

Commonly used mixers include tumblers and ribbon mixers. Tumblers are used for their simplicity and ability to operate in batch operations allowing for high quality control. Effective quality control coupled with the gentle mixing cycles are highly sought after in the pharmaceutical industry. When high shear mixing is required, ribbon mixers are often used for their ability to scrape the outside walls and induce mixing of multiple phases.

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(Copyright Glen Mills, Inc., Clifton, NJ)

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(Copyright H.C. Davis Sons Manufacturing Co., Inc., Bonner Springs, KS)


Packaging


Once the product is properly mixed, the injectable is ready to be packaged into a container. Injectables are generally packaged in glass vials by pumping the mixture through needles into the bottom of the vial. The needles are slowly raised as the mixture is pumped through, to prevent splashing of the mixture out of the vial. When the mixtures are suspensions or emulsions, the holding tank usually needs to be continuously circulated to prevent settling.


Once the vials are full they are sent down the production line and a stopper and cap are added. This stopper and cap combination allows physicians to extract the injectable with a needle without having to open the vial.


Sterilization


All injectables need to be sterile since they are being injected straight into the body. The Food and Drug Administration’s, FDA, preferred method of sterilization is through gamma radiation, wherein the packaged injectable is bombarded with gamma rays for a set period of time, effectively destroying any microbes in the vial. Occasionally, gamma radiation is not feasible due to the harsh nature of the gamma rays, which might not only destroy microbes but also render the API ineffective. In these situations two additionally sterilization methods, sterile filtration and clean room production, are available.


Sterile filtration is the next best option to sterilize injectables. As the name implies, the mixture is sent through an extremely fine filter through which microbes cannot pass. The microbes are filtered out of the solution, leaving only sterilized products. This is an extremely effective method of sterilization, but it only works well with injectable solutions, since suspensions and emulsions have particles larger than most microbes, rendering the filtration useless.


The least common method, due to its high costs, is to produce the product under cleanroom conditions. This means that all workers and machinery operated under certified clean room conditions, so that no microbes are present during the manufacturing process to contaminate the product. However, due to the strict regulations for clean rooms, high cost is involved with this method of sterilization and it is avoided whenever possible.

After sterilization, injectables are tested against product specifications. The Quality Control module describes equipment relevant to this testing process.

Process Map

Injectables Production

Acknowledgements

GEA Process Engineering Inc. , Columbia, MD

Glen Mills, Inc. , Clifton, NJ

H.C. Davis Sons Manufacturing Co., Inc. , Bonner Springs, KS

References

Bennett, Bill and Cole, Graham. Pharmaceutical Production: An Engineering Guide. United      Kingdom: The Institution of Chemical Engineers, 2002. Print.

Niazi, Sarfaraz K. Handbook of Pharmaceutical Formulations. Vol. 2. CRC LLC, 2004. Print.

Development and Manufacturing of Injectable (Parenteral) Drug Products Unit. Web . “http://biomanufacturing.org/uploads/files/767606324956311286-drug-product-unit-overview.pdf”

Yuan, Y., Pfizer Inc., personal communications, 2017.

Developers

Howard Hsu