Injectables

Injectables are sterile liquid drug products that are injected into the bloodstream . A high-level overview of the processes to develop the three typ es of injectables ( solutions, suspensions, and emulsions ) is described below. The active pharmaceutical ingredient (API), along with inactive ingredient s, also referred to as excipients, are mixed together and then packaged. Since the drug is injected into the body, steps to ensure sterility are incorporated throughout the process through the use of personal protective equipment (PPE), filters, environmental monitoring, and isolation of the product until usage .

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Syringe Delivering Injectable

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

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

Process Map

Injectables Production

Ingredients

The primary ingredient in injectables is purified water or a water-based solvent. For adult injectables, propylene glycol is often used as a cosolvent with water. Propylene glycol lowers the freezing point of the solution, acts as a preservative, and dissolves several APIs that are insoluble in water. The API and any excipients (additives) are the only other component s in the injectable mixture. Generally, the excipients present in an injectable are determined by the properties of the API, the desired lifetime of the medicine, and the location at which the injectable is administered. Excipients are often added to prevent aggregation and loss of form, structure, and effectiveness of the API molecules. If the medicine is to be stored for an extended period of time or will not be used immediately after production, then excipients that preserve and stabilize the API must be added.

Each API will have its own physical and chemical properties, so each will interact with excipients in differing ways. The additive thus must be carefully selected for each injectable. The producers of the injectable must use excipients that result in the desired drug behavior while also ensuring that the injectable will be able to function in the environment that it will be used in without causing harm to the human body.

Mixing

The first step to producing an injectable product is mixing the ingredients. Solutions usually only require soft mixing since the ingredients are almost always able to dissolve in the liquid solvent to become a homogeneous mixture without significant heating or mixing required. 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, in which the API is suspended and not dissolved, vary in the type of mixing needed depending on the type of formulation.

When the inject a ble cannot be produced with soft mixing, tumblers and ribbon mixers are most often used . 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 for thicker components, ribbon mixers a re often used for their ability to scrape the outside walls and induce mixing of multiple phases. A tumbler and a ribbon mixer are shown below.

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Tumbler

Ribbon Mixer

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

(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. For mixtures that will become 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 sterilized thoroughly since they are being injected straight into the body. The Food and Drug Administration’s 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 . Two additional sterilization methods are available for these situation s : sterile filtration and clean room production.


In s terile filtration , 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 solutions, since suspensions and emulsions have particles larger than most microbes, rendering the filtration useless.


The least common method of sterilization , due to its high costs, is to produce the product under clean room conditions. This means that all workers and machinery operate under certified clean room conditions, to ensure that no microbes are present at any point during the manufacturing process. The high cost involved to meet the strict regulations for clean rooms make this a method of last resort.

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

James Rivard