6 Common Pitfalls To Parenteral Drug Development
Pharmaceutical injectables, commonly referred to as parenteral drug products or parenteral drugs, have been rising in popularity over oral formulations. One of the reasons for the rapid increase in injectables over pills or tablets is that injectable drug administration has a higher bioavailability for the administered active pharmaceutical ingredient (API), where API is the part of the drug formulation that has a therapeutic effect on the body. Higher bioavailability of the API means that less drug is required to have a therapeutic effect for a patient. Less patient drug administration results in lower risk and severity of side effects for patients. Less API also decreases the production costs of the drug per treatment. Thus, there are both biological and monetary benefits to parenteral medications when it comes to bioavailability. Below are six essential elements of parenteral drug development to consider before creating a parenteral formulation for your API. Drug solubility, drug pharmacokinetics, parenteral route of administration, drug stability, and other considerations for parenteral drug development will be covered in this article.
#1: Route of Administration
Popular routes of administration for parenteral products are injections within the vein, underneath the skin, within the skin, within the muscle, and within the joints. The parenteral dosage form created during parenteral drug development (e.g., a solution, a suspension, an emulsion) will determine the routes of administration that are possible. Thus, it is imperative to know how you would like to administer the drug and what dosage forms are available to know whether or not a parenteral version of your product is feasible. Conversely, the desired route of administration will place requirements on the formulation. For example, if you would like to create an intravenous drug, you could not use a suspension for your drug formulation due to the danger of insoluble particles blocking capillaries. Instead, either a solution or microemulsion would be used for an intravenous administration. Suspensions, while dangerous for intravenous applications, are preferred for subcutaneous or intramuscular administration. Further, each route of administration has individual requirements. Drugs administered subcutaneously require strict attention to tonicity adjustment, whereas intravenous administrations do not. Additionally, injections intended for intraocular, intraspinal, intracisternal, and intrathecal administration have stricter safety standards for formulation tonicity, component purity, and endotoxins because of the sensitivity of the tissues encountered during the injection.
#2: Drug Pharmacokinetics
Only intravenous or intra-arterial drug administration can avoid drug absorption, distribution, metabolism, and excretion effects encountered in other modes of administration. Thus, it is crucial to consider the pharmacokinetics of your medication based on the route of administration you choose. For example, an intramuscular drug administration may require a higher amount of the active drug substance to achieve a therapeutic effect than an intravenous route. The impact of the different pharmacokinetics must be assessed for the higher oral drug rate and lower intravenous drug rate individually to determine safety, how long the drug is in the body, and the minimum effective dosage needed for a therapeutic effect. Some drugs have rapid pharmacokinetic profiles and require a delayed-release mechanism so that the active ingredient stays in the body long enough to have a therapeutic effect. For parenteral products, the drug’s delayed release may be achieved by including complexing agents or viscosity-inducing agents in the drug product formulation to retard drug dissolution and transport.
#3: Drug Solubility
Suppose a drug is insoluble in water at the required therapeutic dosage. In that case, the formulation will require a cosolvent or a solute that will allow a therapeutic concentration of the drug to remain in the solution. When simple approaches to drug solubility (such as pH adjustments, cosolvents, complexing agents, and surface-active agents) do not work, a dispersed system will be needed to obtain a therapeutic dosage in liquid form. Examples of dispersed systems are emulsions and suspensions.
#4: Drug Stability
Drugs must be stable in whatever formulation they are administered until the expiration date marked on the packaging. For most oral drugs, stability is proven on a scale of years. In contrast, stability for parenteral drugs in their liquid forms may be much shorter (on the scale of weeks or months). If a particular API has significant degradation problems in solution, a freeze-dried formulation will be created to improve product expiry and safety. These freeze-dried formulations will then be reconstituted prior to injection. Products that are sensitive to temperature will need to be shipped and stored at appropriate temperatures. Packaging for temperature-sensitive products will take additional consideration (materials used, container sizing, etc.) and require product safety data to prove product expiry under these conditions. The amount of drug that is stable in solution may also impact product packaging. For example, a drug that is only stable at a low concentration but requires a higher therapeutic dose will need to be delivered at a higher liquid volume than a drug that is stable at a high concentration. In some cases, additives will be used to support the stability of the injectable product.
#5: Compatibility of Drug with Potential Formulation Additives
Drugs and certain excipients are incompatible. Further challenging the drug product development process, drug-excipients can be incompatible with one another. Thus, pre-screening is needed to ensure that adding one additive to your drug product does not create a different problem for the stability or safety of the finished drug product. Even stabilizers (buffers and antioxidants) act differently depending on the drug and the drug additives present. For example, a stabilizer could chemically stabilize drug B in solution but also cause chemical degradation reactions of other additives. Sometimes the excipient itself isn’t causing the degradation, but rather an impurity (such as peroxide) could be causing the degradation. Thus, careful regulation of raw materials during pre-screening is imperative to accurate results during drug product development.
#6: Desired Type of Packaging
Selecting packaging involves selecting your product’s size, shape, materials, colors, labeling, and branding. Packaging is strategically chosen based on marketing preferences, competition, and product stability requirements. If you know the type of packaging you would like early in product development, compatibility of your product’s ideal packaging materials with your product’s formulation can be ensured.
Summary
Overall, there are six key elements to consider when developing a parenteral drug formulation. These six pharmaceutical development keys are the route of drug administration, drug pharmacokinetics, drug solubility, drug stability, drug additive compatibility, and product packaging. The route of drug administration informs some of the pharmacokinetics of the drug. The pharmacokinetics, solubility, and stability of the drug often inform the additives used in the formulation. And product packaging, if determined early, is based around product marketing strategies. As you navigate the complexity of parenteral product development, know that contract manufacturing organizations, like MycoScience, can support you with their specialized resources and expertise to save time and money with your R&D product development, syringe filling, vial filling, and regulatory testing.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
