Sterile & Parenteral Preparations Overview of Sterile Preparation Formulation

Introduction The objective of formulating and compounding sterile preparations is to provide a dosage form of a labeled drug, in the stated potency, that is safe to use. This section will explore the professional standards and operating procedures that should be followed during formulation and compounding. The components, containers, and closures also are described, as well as the physiological and physical norms of preparing formulations for parenteral and ophthalmic use. Stability, incompatibility of drugs, sterilization methods, labeling, documentation, and end preparation evaluation.

Sterile dosage forms include parenteral/injectable dosage forms as well as other sterile products such as topical ophthalmic products, irrigating solutions, wound-healing products, and devices. Ideally, a sterile dosage form is absolutely free of any form of biological contamination, and, of course, is the final goal of every single unit of sterile product released to the marketplace, either commercial or clinical. Parenteral (the author prefers the term “sterile”) products must be exceptionally pure and free from physical, chemical, and biological contaminants (microorganisms, endotoxins, particles).

Seven Basic Characteristics of Sterile Product Dosage Forms Safety (freedom from adverse toxicological concerns) Sterility (freedom from microbiological contamination) Nonpyrogenic (freedom from pyrogenic-endotoxin-contamination) Particle-free (freedom from visible particle contamination) Stability (chemical, physical, microbiological) Compatibility (formulation, package, other diluents) Tonicity (isotonic with biological fluids)

SEVEN PRIMARY CHARACTERISTICS OF STERILE DOSAGE FORMS: 1- Safety Any component of an injectable product must be proven safe at the quantitative level. The safety considerations when selecting additives to combine with the active ingredient to overcome one or more problems related to drug solubility, stability, tonicity, and controlled or sustained delivery.  with a nonsterile dosage form, a excess of choice with respect to additives safe to use for administration other than by injection.  with sterile dosage forms, the requirement for safety prohibits the use of many additives that could be effective

The parenteral products pass the routine sterility test, pyrogen and/or endotoxin test, as well as the chemical analyses, and still cause unfavorable reactions when injected. A safety test in animals is essential, particularly for biological products. The FDA has published guidance for safety evaluation of pharmaceutical ingredients that is periodically updated

2- Sterility The sterility is what defines/differentiates a sterile product. The characteristic of sterility is achieved via:- valid sterilization procedures for all components during manufacturing of the product, design and maintenance of clean rooms meeting all requirements for preparing sterile products, validation of aseptic processes, training and application of good aseptic practices, use of antimicrobial preservatives for multiple-dose. valid testing for sterility of the product and maintenance of container/closure integrity.

3- Freedom from Pyrogenic Contamination Pyrogens are fever-producing entities originating from a variety of sources, primarily microbial. In sufficient amounts following injections, pyrogens can cause a variety of complications in the human body. The pyrogen called bacterial endotoxins, all marketed injectable products must meet requirements for pyrogen (or endotoxin) limits. To achieve freedom from pyrogenic contamination, like achieving and maintaining product sterility,

Depyrogenation methods include:- cleaning validation, time limitations, validated depyrogenation cycles for glassware, validated water systems validation of pyrogen/endotoxin removal from rubber closures and other items that depend on rinsing techniques, and use of endotoxin free raw materials.

4. Freedom from Visible Particulate Matter   The visible particulate matter involves product quality and perhaps safety. The solutions and reconstituted solutions are to be free from any evidence of visible particulate matter. Several factors contribute to the presence or absence of foreign particulate matter. valid cleaning methods of all equipment and packaging materials, valid solution filtration procedures, adequate control of production and testing environments, adequate training of personnel in manufacturing, testing and using sterile product solutions.

5. Stability All dosage forms have stability requirements. All dosage forms are required to be stable under predetermined manufacturing, packaging, storage, and usage conditions. Achieving and maintaining chemical and physical stability starts with the active ingredient and how it is stored, shipped, and handled. Stability challenges continue with the compounding, mixing, filtration, filling, stoppering, and sealing of the product.

Many injectable drugs are so unstable in solution that they must exist in the solid state so lyophilization processes. Maintaining stability in the final container/closure system, while being stored, shipped, and worked prior to being administered to people or animals. Sterile dosage forms also have one extra requirement related to stability and that is maintaining sterility as a function of stability. So, with sterile dosage forms, product stability includes not only chemical and physical properties, but also includes microbiological stability throughout the shelf-life and usage of the product.

6. Compatibility Freeze-dried products are released by the manufacturer, but must be manipulated by the user and/or health care professional prior to administration. The product must be reconstituted by sterile dilution, withdrawn into a syringe, and, often, then combined with another solution, perhaps a large volume infusion fluid, for administration. The sterile product must be shown to be compatible with diluents for reconstitution and diluents for infusion. Many infusions contain more than one drug, so obviously the two or more drugs in the infusion system must be compatible.

7. Isotonicity   Osmotic pressure is a characteristic of semipermeable cell membranes where osmotic pressure is the pressure where no water migrates across the membrane. Osmosis is the phenomenon where solutes will diffuse from regions of high concentration to regions of low concentration. So, if a formulation is injected that has an osmotic pressure less than that of biological cells (hypotonic), the solvent will move across the cell membranes and could cause these cells to rupture. Conversely, if the formulation injected has an osmotic pressure greater than that of biological cells (hypertonic), the solvent will move outside the cell membranes and cause these cells to shrink.

Ideally, any injected formulation should be isotonic with biological cells to avoid these potential problems of cells bursting or shrinking. It is well known that 0.9% sodium chloride solution and 5% dextrose solution are isotonic with biological cells. Why the difference in isotonic concentrations between these two common large-volume solutions?

Dextrose is a nonelectrolyte that in solution exists as a single entity; therefore, the osmotic pressure of a nonelectrolyte solution is proportional to the concentration of the solute. Sodium chloride is an electrolyte in solution that dissociates into two ionic species. Thus, the osmotic pressure dissociating into two species would be at least twice that of a solution containing a nonelectrolyte.