Parenteral drug products—those that are intended to be directly introduced to the circulatory system of the patient via injection or infusion, rather than oral dosage via the alimentary canal—must be manufactured under sterile conditions in order to meet pharmaceutical quality standards as described in pharmacopeias.
They must also be safe for the end user. The first stage of ensuring quality standards and safety of use are aseptic manufacturing conditions. For parenteral liquid manufacturing, this often means manufacturing within a sterile equipment train in which the entire process is carried out under aseptic conditions.
However, aseptic filling alone doesn’t guarantee that the end product will be free of pyrogens and that drug substances will be compatible with both excipients and containers. For those considerations, more specific quality checks are required.
Parenteral liquid manufacturing requires CMOs to monitor and ensure compatibility within parenteral products.
Compatibility, in this case, means that the drug product will still work as expected when it is dosed, but also that it is safe, free of impurities, and absent any pyrogens. Each of these have their own concerns and conditions.
For instance, ensuring that parenteral products are pyrogen free requires either a depyrogenation process in manufacturing, and/or the use of pyrogen free ingredients at every stage of the manufacturing process—including active pharmaceutical ingredients and excipients.
Parenteral liquid products should also be clear and exempt of visible (or sub-visible) particles. This means that the drug substance itself should be compatible with any excipients without forming new impurities or degrading the active pharmaceutical ingredient.
Emulsions and aqueous dispersions should show no evidence of phase separation at any point in either the manufacturing process or the product’s shelf life. The parenteral product should also retain its full potency.
Active pharmaceutical ingredients should be soluble during the entire shelf life of the product. If the product is a suspension, any sediment contained within it should be dispersed if the product is shaken, and in every instance the entire product should contain a balanced amount of ingredients and should ensure a correct dosage when the product is withdrawn and injected.
Compatibility of containers is also a significant consideration for parenteral liquid manufacturing.
Parenteral liquid products require compatibility with all the elements contained in the liquid product itself—excipients and active ingredients alike—but compatibility with containers is equally vital.
For instance, containers need to be composed of materials that are neither leachable nor absorbable. That is to say, the parenteral liquid product should not leach chemicals or other elements from the container, and the container should not absorb any of the drug product.
Chemical reactions between active pharmaceutical ingredients, excipients, or solvents and the containers in which the parenteral product is manufactured or stored can introduce impurities or dilute the efficacy of the product, and so must be avoided at every stage.
These are just a few of the compatibility and formulation issues that must be addressed in parenteral liquid manufacturing.
In order to ensure that the parenteral product is both safe and effective for its intended use, its pH must be maintained both for the stability of the drug substance and for its efficacy. Achieving the right pH helps to ensure that the drug product is shelf stable and effective for its intended use.
When making large batches, as is often the case with liquid parenteral manufacturing, maintaining pH in the entire batch is of utmost importance. These products should also not contain pH buffers, because the buffer effect in human blood can compete with any pH buffers to negatively impact the effect of parenteral products.
As mentioned, pH is important to drug stability, but it isn’t the only factor that affects stability during formulation. If drug substances are unstable, impurities can form within the parenteral product during its shelf life.
Stability must be maintained not just during manufacturing, but the product must be manufactured in such a way that it will remain stable for the duration of its intended shelf life. This is especially important when manufacturing products that cannot undergo lyophilization.
Some parenteral products require the inclusion of stabilizers such as mannitol and cysteine. Regardless of how stability is maintained, however, the concentration of the final product should be such that it remains steady for the entire duration of its shelf life. Whether it is injected immediately after manufacturing or near the end of its shelf life, the concentration of each part of the formulation should remain the same.
For all of these factors, and at every stage of the manufacturing process, parenteral liquid products should be monitored and selected for ideal compatibility, stability, and efficacy of the specific product in question.
Some products are compatible with specific containers, where others may not be. Certain sterilization processes are appropriate for some products and not for others. Some solvents, excipients, and so on may interact unacceptably with some active pharmaceutical ingredients.
In every case, decisions must be made at each stage of the parenteral manufacturing process that are appropriate to the product and that help to ensure stability, efficacy, safety, and compatibility for the product both during manufacturing and for the duration of the product’s shelf life.