The word parenteral comes from Greek and means outside the intestine (para=outside and enteron=intestine). In fact, when it comes to parenterals, we are referring to those dosage forms that are administered directly into the bloodstream using a hypodermic needle, avoiding going through the gastrointestinal tract. Using parenteral filling equipment, parenteral solutions are placed in containers such as vials, syringes, or ampoules.
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Keeping it up to standards – achieving sterility and pyrogen-free solutions
Like any pharmaceutical dosage form, parenterals must meet pharmaceutical quality standards to be considered safe for their intended use. Two main requirements for parenteral solutions are to be sterile and free from pyrogenic contamination. Processes include sterilizing of equipment and containers using sterile filterers and autoclaves or radiation, and depyrogenation, which uses depyrogenation tunnels to remove bacterial endotoxins and other pyrogens.
To ensure that sterility is achieved, methods such as direct inoculation, membrane filtration, bacteriostasis/ fungistasis (B/F), and vaporized hydrogen peroxide (VHP) ingress testing are used. These methods test the samples for any presence of aerobic and anaerobic microorganisms, assess the possible growth of microorganisms, and validate sterility results.
For pyrogen testing instead, there are a number of methods. One of them is the monocyte activation test (MAT). This method mimics human immune reaction by incubating monocytes with the test sample. If pyrogens are present, monocytes are activated and produce inflammatory molecules, cytokines, responsible for the reaction. These are detected using an immunological assay involving specific antibodies and an enzymatic color reaction.
The most common method for endotoxin testing is bacterial endotoxin testing (LAL test – limulus amoebocyte lysate test). This is an assay based on the lysate of amoebocytes from the horseshoe crab blood which reacts with bacterial endotoxins in a coagulation reaction. This method has a high sensitivity for the quantification of endotoxins but it does not detect non-endotoxin pyrogens.
Formulation challenges when making parenterals: from excipient compatibility to pH value
In addition to being sterile and pyrogen-free, parenteral preparations may need excipients that are biocompatible. These excipients are selected for their appropriate use such as making parenteral preparations isotonic with the patient’s blood to prevent hemolysis or damage to cells and tissues. They can be used to adjust the pH level of the solution and maintain product stability and solubility. Other functions include providing adequate antimicrobial properties for multidose preparations.
Solubility and stability of the substance must be consistent throughout the shelf-life of the parenteral solution. For poorly soluble substances, you can use co-solvents, surfactants, or a solubility enhancer. The pH value is another critical aspect of parenteral preparations, which should be as close to physiological levels (between 3.0 to 9.0) to avoid tissue damage when the substance is injected into the body. This is why a pH buffer may be necessary to adjust the pH level of the substance. Note that large volume preparations (greater than 100 mL) should not contain a pH buffer as blood provides a buffer effect that could compete with the injected product.
Parenteral filling equipment in an aseptic environment
Parenterals are filled in ampoules, vials, syringes, cartridges, bottles, and bags. The entire process must be done under aseptic environment conditions to avoid contamination in which producers need to sterilize containers before the filling process. Isolators are placed around filling machines to separate the processing area from the environment combined with an automated sanitization system using hydrogen peroxide to decontaminate the area.
Parenteral filling equipment uses different technologies. One such technology is blow-fill-seal which is based on forming the container from heated polymer, filling it immediately after cooling and sealing it without involving contact with another product part. Another technology is closed-vial, based on the concept of using a sterile closed container. It is filled by a needle piercing the stopper and dispensing the liquid. After filling, the stopper is resealed using a laser.