Top 7 Regulatory Requirements For Injectable Pharmaceuticals
Gels, ointments, lotions, and pills, oh my! Drug products come in all sorts of formulations, shapes, and sizes. However, injectable products require sterility of the drug product (dosage form) due to their route of administration. Unlike most products, injectables have increased requirements because injectable products can avoid our body’s natural skin barriers and digestive tract barriers to toxins. Keep reading to learn how these seven regulatory requirements apply to your pharmaceutical product.
Regulatory Requirement #1: Safety
Most sterile pharmaceuticals are injected directly into the body and avoid the body’s natural barriers to infection (skin) and metabolite breakdown (digestive tract). Thus, sterile injectables must be safe for the body to be exposed to at the quantity of the therapeutic dose. Even water, in large enough quantities, is unsafe to the human body. Depending on the pharmaceutically active ingredient, sterile dosage forms can be easier or more difficult than nonsterile dosage forms. This is because a limited number of additives can be used as the active pharmaceutical ingredient for sterile injectables due to the increased safety considerations. When considering drug solubility, controlled or sustained delivery, stability, and tonicity, make sure that suitable, FDA-approved additives are available for your active ingredient before moving forward with an injectable formulation. Otherwise, expect to spend additional time and money acquiring data to prove the safety of the new additives in your injectable formulation. Required safety date is often time-consuming to obtain as the Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act require most pharmaceutical preparations to be tested for safety in animals. Safety testing in animals is required as even a product that passes sterility testing, endotoxin testing, and chemical analysis can still have unexpected toxicity when injected. The FDA and USP provide instructions for safety evaluations of pharmaceutic excipients. Also, the International Pharmaceutical Excipients Council (IPEC), a regional collaboration of the United States, Europe, and Japan, covers excipient safety and public health issues connected with international trade. Over 200 national and multinational excipient makers and producers and the companies that use these excipients in finished drug dosage forms are members of one or more of the three IPEC regions.
Regulatory Requirement #2: Sterility
Achieving and maintaining product sterility are among the greatest challenges manufacturers face for injectables since most rely on aseptic manufacturing. In aseptic manufacturing environments, product processing requires excluding microorganisms from the manufacturing methods. There are many validation steps to maintain sterility. Some of these validation steps include valid sterilization procedures for all components during manufacturing of the product, a proper method for sterile aseptic filtration, maintenance of ISO-certified clean rooms, validation of aseptic processes, training and application of good aseptic practices by contract manufacturing organizations, use of antimicrobial preservatives for multiple-dose products, proper testing of container-closure integrity, and proper testing for overall product sterility.
Regulatory Requirement #3: Freedom from Pyrogenic Contamination
Pyrogens are fever-producing molecules that are primarily microbial. Microbial pyrogens are known as bacterial endotoxins. If injected at a high enough concentration, pyrogens can lead to fever, illness, and (in extreme cases) death. Limulus Amebocyte Lysate (LAL) endotoxin testing can detect and quantify bacterial endotoxins. For an injectable product to be marketed, it must be LAL tested and meet strict endotoxin limits expressed by λ. If your injectable does not meet its endotoxin limit, certain depyrogenation methods can be used to reduce endotoxins from the manufacturing and packaging of injectable products. Some of these methods are improved cleaning validations, additional depyrogenation cycles for glassware, improved pyrogen/endotoxin removal from rubber closures, depyrogenation of water systems, and use of endotoxin-free raw materials.
Regulatory Requirement #4: Freedom from Visible Particulate Matter
Visible particulate matter in a liquid implies poor product quality and safety. Ready-to-use solutions and reconstituted solutions must be free from visible particulate matter and meet criteria for subvisible particles of specific sizes. Some of the ways particulate matter can sneakily enter a product during exposure to manufacturing equipment and packaging materials, solution filtration procedures, manual manipulation by manufacturing personnel, and the addition of product solutions or additives. Additional validations for equipment cleaning, personnel training, cleanroom cleanliness, raw material sourcing and preparation, and filtration processes can support in eliminating issues with particulate matter.
Regulatory Requirement #5: Stability
All pharmaceuticals have stability requirements. They must be stable under established manufacturing, packaging, storage, and usage conditions. In addition to traditional stability, injectables need to be chemically and physically stable throughout the product’s shelf-life. Except for solubility challenges, solving stability problems occupies most product development time and effort. Injectable therapeutic peptides and proteins offer additional stability challenges. The temperature, light, pH, shear, metallic impurities, oxygen, and more must be considered to keep these biologics active with peptides and proteins.
Storing, shipping, and handling of the active pharmaceutical ingredient affect the stability of chemical therapeutics. Stability challenges compound with the mixing, filtration, filling, stoppering, and sealing of the product. Many injectable drugs are so unstable in a solution that they must be stored in a solid-state long term. Thus, lyophilization processes and maintaining stability during lyophilization add further challenges to product development. Unlike unsterile medical products, sterile dosage forms must simultaneously address stability and sterility challenges. In other words, injectables must maintain chemical stability, physical stability, and sterility throughout the entire shelf-life and usage of the product. Thus, maintaining stability in the final container-closure system while being stored, shipped, and manipulated before being administered to people or animals ends this marathon of developmental stability challenges injectable products face.
Regulatory Requirement #6: Compatibility
Most pharmaceutical formulations are ready-to-use products that do not require preparation by patients or health care professionals before administration. However, many injectables require manual preparation prior to injection. In particular, freeze-dried parenteral products must be reconstituted before use. This manual manipulation step means that the sterile, freeze-dried product must show compatibility with the diluents used for reconstitution. If the parenteral is a multi-drug infusion, pharmaceutical companies must show that the two or more drugs in the infusion system are compatible.
Regulatory Requirement #7: Isotonicity
Isotonicity, loosely translated, means “the same tone.” Human cells maintain a certain “tone” to support optimal function within the body. This “tone” is a certain biological concentration of ions, molecules, etc., that gives cells unique properties. For injectables, the most critical component of isotonicity to regulate is our cells’ osmotic pressure. Osmotic pressure differences result in water migration across cellular membranes. Osmotic pressure itself is an equilibrium pressure where no water migrates across the cell’s membrane. Solutions can be hypertonic (have a greater osmotic pressure than our cells), hypotonic (have less osmotic pressure than our cells), or isotonic (have the same osmotic pressure of our cells). Hypotonic injections can cause cells to swell to the point of bursting.
Conversely, hypertonic injections cause cells to shrink. Cell shrinkage is also known as crenation. Thus, injectable formulations should be isotonic and prevent cells from swelling or shrinking within the body. Large-volume intravenous injections and small-volume non-intravenous injections must be isotonic to avoid pain, tissue irritation, and more physiological severe reactions. Small volume intravenous injections are more forgiving and do not have to be isotonic. Small volume intravenous injections will only damage a small number of red blood cells which the body can readily replace.
Summary
Overall, sterile dosage forms are needed for injectable products. Injectables have higher requirements for safety, sterility, pyrogenicity, particulate matter, stability, compatibility, and isotonicity since they circumvent our body’s traditional barriers to toxins. Regarding safety, safety testing is often lengthy since animal testing is required. When it comes to injectables, maintaining sterility can be tricky as aseptic manufacturing conditions must be maintained. Injectables must pass a LAL test for pyrogens as well as exclude all visible and certain subvisible particles. Injectables must be compatible with any agents used for reconstitution or any drugs used in a multi-drug infusion. Stability offers a marathon of challenges from active pharmaceutical manufacture to reconstitution and end-use in patients. Injectable liquids must have the same osmotic pressure as our biological cells to prevent the swelling or the shrinking of our critical cells, tissues, and organs). Luckily, many contract manufacturing organizations can support you with passing these seven regulatory hurdles and getting your novel injectable product on the market.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
Regulatory Requirements For Injectable Pharmaceuticals. Pyrogenic contamination. Visible particulate matter.
