Sterile Dosage Forms Lecture 1 PDF

Sterile Dosage Forms Salma Essam, PhD Department of Pharmaceutics Faculty of Pharmacy Alexandria University Parenteral Introduction drug Advantages & limitations delivery Routes of administration Pharmaceutical re...

Sterile Dosage Forms Salma Essam, PhD Department of Pharmaceutics Faculty of Pharmacy Alexandria University Parenteral Introduction drug Advantages & limitations delivery Routes of administration Pharmaceutical requirements Classification of parenterals Parental dosage forms Excipients & additives Containers & packaging Quality control testing  Ophthalmic Introduction drug delivery Ocular routes & pharmacokinetics Pharmaceutical requirements Excipients & additives Pharmaceutical dosage forms Containers & packaging Quality control testing References Allen, L., & Ansel, H. C. (2013). Ansel's pharmaceutical dosage forms and drug delivery systems. Lippincott Williams & Wilkins. Aulton, M. E. (2002). Pharmaceutics, The science of dosage forms designs, 2nd eds. Churchill Livingstone, New Delhi, 205-221. Banker, G. S., Siepmann, J., & Rhodes, C. (Eds.). (2002). Modern pharmaceutics. CRC Press. Remington, J. P. (2006). Remington: the science and practice of pharmacy (Vol. 1). Lippincott Williams & Wilkins.  Intended learning outcomes (ILOs) By the end of the course, you should be able to: Identify the main principles of formulation, development, sterilization, packaging and quality control testing of pharmaceutical sterile drug products. Emphasize the principles for calculation and manipulation of parenterals and ophthalmic preparations. Parenteral drug delivery  Introduction Parenterals: Introduction Definition Parenteral route: It is derived from the Greek words para (outside) and enteron (GIT). Theoretically, it denotes routes of administration other than the GIT route. Practically, it refers to the injectable route of administration. Parenterals: Introduction USP definition Parenteral articles are preparations intended for injection through the skin or other external boundary tissue or implantation within the body, rather than through the alimentary canal, to allow the direct administration of the active drug substance(s) into blood vessels, organs or tissues. Advantages & limitations Parenterals: Advantages & disadvantages Advantages It offers a predictable effect and nearly complete bioavailability. It bypasses the oral absorption barrier and avoids first pass metabolism, low oral bioavailability and high variability. Also, it offers a high degree of flexibility of dose adjustment. Many drugs are available only as parenteral dosage forms. These include most protein and peptide drugs (insulin), some antibiotics and many anticancer compounds. Parenterals: Advantages & disadvantages Advantages It can be used when a rapid drug onset of action is desired, as in emergencies. Intravenous (IV) injection delivers the drug directly into the circulatory system, whereas peak blood levels may not be achieved for one to two hours after a drug is administered orally. It is used when the patient is uncooperative, unconscious, or unable to accept or tolerate oral medication. Fluids for hydration and electrolyte replacement can also be administered this way (IV). Parenterals: Advantages & disadvantages Advantages It may be chosen to provide a highly localized effect, when the injection route accesses a particular anatomical area or organ system. Examples of this include the injection of drugs, such as steroids, into joint spaces (intra-articular injection), intra-ocular injections to treat eye diseases or intraspinal injections. Parenterals: Advantages & disadvantages Advantages Many medicines are administered parenterally because of drug instability: it would be rapidly broken down in the GIT and would thus become inactivated before it could be absorbed into the circulatory system. Parenterals: Advantages & disadvantages Disadvantages Most patients would prefer other routes of administration to parenteral route, which can be painful or stressful (some patients suffer from needle phobia). An incorrect drug or dose is harder or impossible to counteract when it has been given parenterally (particularly intravenously), rather than orally. From a manufacturer’s point of view, it is often simpler and much cheaper to prepare non-sterile medicines such as tablets or liquids. Routes of administration Parenterals: Routes Major routes Other routes Intradermal (ID) Intraarticular/ Intravenous (IV) intrasynovial Intramuscular (IM) CNS Intraarterial Subcutaneous (SC, sub-Q) Intracaridac Intraocular Parenterals: Routes Intravenous (IV) This delivers the drug directly into a vein to the blood stream to provide a rapid and predictable clinical effect. Most drugs that are administered parenterally are given intravenously. Nearly all drugs can be administered via IV route. Parenterals: Routes Intravenous (IV) Location: The basilic and cephalic veins on the back of the hand and dorsal forearm are the best peripheral veins for IV therapy. Volume: Ranges from 0.5 or 1 mL for an intravenous injection, up to several liters for an intravenous infusion. Parenterals: Routes Intravenous (IV) Advantages: IV drugs provide rapid onset of action compared with other routes of administration, and because drug absorption is not a factor, optimum blood levels may be achieved with accuracy and immediacy not possible by other routes. Because of the rapid dilution in the circulating blood and the general insensitivity of the venous wall to pain, the IV route may be used to administer irritating drugs. Parenterals: Routes Intravenous (IV) Limitations: thrombus formation The main hazard of IV infusion is thrombus formation. A thrombus is a blood clot formed within the blood vessel, usually because of slowing of the circulation or an alteration of the blood or vessel wall. It can be induced by the catheter or needle touching the wall of the vein or when the drug is irritating to the biologic tissues. Parenterals: Routes Intravenous (IV) Limitations: thrombus formation Once such a clot circulates, it becomes an embolus, carried by the blood stream until it lodges in a blood vessel, obstructing it and resulting in a block or occlusion referred to as an embolism. Such an obstruction may be a critical hazard to the patient, depending on the site and severity of the obstruction (pulmonary embolism). Parenterals: Routes Intravenous (IV) Types of IV injections IV push IV bolus IV infusion When the drug is injected When larger volumes When a small rapidly, typically in less (100–1000 mL) are volume is injected than 30 seconds in injected over a longer over a short emergency situations (in period (minutes to period of time (1 case of allergic hours) at a constant to 5 minutes). reactions). rate. Parenterals: Routes Intravenous (IV) Why infusions? The drug will enter the circulation at a much slower and controlled rate which can be adjusted to what is required, for example during and after surgery. Parenterals: Routes Intravenous (IV) Why infusions? The problem with infusion is it takes a few hours to achieve a steady state. It is often best to start with a bolus injection to cover the first few hours before the infusion achieves its steady level. Parenterals: Routes Intravenous (IV) Why infusions? By altering the infusion rate, it is possible to titrate the dose against the effect required, e.g. controlling blood pressure Slow IV infusion of a drug product is useful to avoid side effects, such as chemotherapeutic agents for cancer therapy. Parenterals: Routes Intramuscular (IM) Injections are made into the striated muscle fibers that lie beneath the SC layer Nearly all drugs can be administered via IM route Parenterals: Routes Intramuscular (IM) Location: Most commonly: the buttock (gluteal), lateral thigh (vastus lateralis) or shoulder/upper arm (deltoid) muscles. Volume: Ranges from 0.5–2 mL and up to 4 mL (in divided doses to be given in the gluteal region). Parenterals: Routes Intramuscular (IM) Advantages: The IM route of administration is second only to the IV route in rapidity of onset of systemic action, with a normal onset of action from 15 to 30 minutes. It provides effects that are less rapid but generally longer lasting than those obtained from IV administration. Parenterals: Routes Intramuscular (IM) Limitations: The major clinical problem arising from IM injections is muscle or neuron damage or abscess. The injury normally resulting from faulty technique, rather than the medication. Parenterals: Routes Subcutaneous (SC, sub-Q) Injections are made in the fat layer/adipose tissue under the dermal skin layer IM injections have a slower onset of action than by the IM or IV routes (rapidity: IV> IM > SC) Drugs administered via this route include insulin, heparin and epinephrine, among others. Parenterals: Routes Subcutaneous (SC, sub-Q) Location: The outer upper arm, the anterior thigh (upper legs), or the lower abdomen. The site of injection is usually rotated when injections are frequently given, as with daily insulin injections. Volume: Ranges from 0.5–2 mL Parenterals: Routes Subcutaneous (SC, sub-Q) Limitations: Irritating drugs and those in viscous suspension are not suitable for SC injection, they may produce change in skin appearance or abscess and may be painful. Small injection volume often puts limitations on the drugs that can be administered by this route. Parenterals: Routes Intradermal (ID) Injections are made into the skin layers between the epidermal and dermal layers Absorption from the intradermal injection site is slow. It is limited to injection of materials to detect hypersensitivity or allergic reactions for diagnostic purposes or desensitization. Parenterals: Routes Intradermal (ID) Location: the anterior forearm. Volume: only about 0.1 mL up to 0.2 mL Parenterals: Routes Injection techniques (IV, IM & SC) Parenterals: Routes Intraarticular (IA) Injections are made into the synovial fluid of joint cavities such as the knee. This route of injection produces a local effect, typically to treat arthritic conditions or sports injuries. Drugs like morphine, local anesthetics, steroids or NSAIDs are given this way Parenterals: Routes CNS Intrathecal (IT)/intraspinal Injections are administered through the lumbar sac between the vertebrae of the spine into the cerebrospinal fluid (CSF) in the subarachnoid space between the arachnoid mater and the pia mater, the two innermost protective membranes surrounding the spinal cord. Parenterals: Routes CNS Epidural Injections are made into the epidural space between the dura mater (the outermost protective membrane covering the spinal cord) and the vertebrae. Parenterals: Routes CNS Intrathecal vs epidural routes Intrathecal administration is delivered directly into the CSF while epidural administration diffuses through the dura into the CSF, and thus epidural has a slower onset of action. Epidural route is commonly used for spinal anaesthesia, for example during childbirth. Intrathecal route can also be used for spinal anaesthesia. Also, drugs like antibiotics to treat meningitis or anticancer agents. Parenterals: Routes Desired rate of onset of action: (IV vs. IM vs. SC) Location of drug action (intraarticular, intraocular, CNS,...) Injection volume: The volume of drug injected is lower for SC than for IM or IV routes. Considerations for route selection Parenterals: Routes Tissue irritability: Injection of an irritant drug is likely to be more painful by the IM than the SC route due to higher blood flow and sensory innervations in the muscles. On the other hand, IV shows less pain. Considerations for route selection  Pharmaceutical requirements Pharmaceutical requirements Absence of Sterility pyrogens/ endotoxins Isotonicity Clarity  “ Sterility Pharmaceutical requirements Sterility Sterilization, as applied to pharmaceutical preparations, means destruction of all living organisms and their spores or their complete removal from the preparation. All parenteral preparations are sterile preparations. The requirement for sterility is vital as the method of administration of these products bypasses the body’s natural defense barriers. Pharmaceutical requirements Sterility Steam Dry Radiation heat Sterilization methods Gas Filtration Pharmaceutical requirements Sterility Steam It is usually the method of choice if the product can withstand it. Most pharmaceutical products are adversely affected by heat and cannot be heated safely to the temperature required for dry heat sterilization. Pharmaceutical requirements Sterility Steam In general, it is applicable to pharmaceutical preparations and materials that can withstand the required temperatures and are penetrated but not adversely affected by moisture: Aqueous solutions in sealed containers, such as ampoules, are readily sterilized by this method. Bulk solutions, glassware, surgical dressings, and instruments. Pharmaceutical requirements Sterility Dry heat It is generally employed for substances that are not effectively sterilized by moist heat: Oils, fats, glycerin, oleaginous preparations and any preparations not penetrated by moisture Exposed powders Glassware and surgical instruments Pharmaceutical requirements Sterility Filtration It depends on the physical removal of microorganisms by adsorption on the filter medium It is used for heat-sensitive solutions. Pharmaceutical requirements Filtration: limitations Sterility Medicinal preparations sterilized by this method must undergo extensive validation and monitoring because the effectiveness of the filtered product can be greatly influenced by the microbial load in the solution being filtered. Macromolecules, such as proteins and peptides, may be damaged by filtration due to shear stress. Formulation might affect filter integrity and clogging. In addition, some filters adsorb drug. Pharmaceutical requirements Gas Sterility The great penetrating qualities of ethylene oxide gas make it a useful agent in certain special applications. It is used for sterilization of: Medical and surgical supplies and appliances such as catheters, needles, and plastic disposable syringes in their final plastic packaging just prior to shipment. Certain heat-labile preparations of enzyme, certain antibiotics, and other drugs, after testing for the absence of chemical reaction. Pharmaceutical requirements Sterile starting materials & Before process manufacture equipment Aseptic During processing manufacture technique Sterility of the Terminal Post- final product sterilization manufacture Pharmaceutical requirements Sterility Before manufacture Raw materials may be exposed to radiation or ethylene oxide for this purpose. Filtration should be employed to reduce the bioburden in water. Pharmaceutical requirements Sterility During manufacture Use of special aseptic technique during manufacture that minimizes the possibility of contamination from human or extraneous material: Manufacturing area is maintained bacteria-free by: Use of ultraviolet lights and a HEPA (high efficiency particulate air) filtered air supply The disinfectant solutions are filter sterilized because they may, themselves, be a source of contamination with resistant organisms. Pharmaceutical requirements Sterility During manufacture Since human beings are frequently the principal source of microbial contamination in the manufacturing environment, their health, hygiene, clothing and training may all have an impact on product contamination. Sterile manufacturing equipment, such as flasks, connecting tubes, and filters. Pharmaceutical requirements Sterility Post-manufacture Terminal sterilization post-manufacture is essential, preferably in final marketed sealed containers. The method is determined largely by the nature of the preparation and its ingredients. The resulting product must pass a test for sterility as proof of the effectiveness of the method and the performance of the equipment and personnel. Pharmaceutical requirements The required ingredients to be Before manufacture dissolved in water-for-injection (or other solvents). Solutions are filtered and During manufacture aseptically transferred to the final containers. Flow chart for Post The product is sterilized, parenteral manufacture preferably by autoclaving, and tested for sterility. solutions preparation “ Absence of pyrogens/endotoxins Pharmaceutical requirements Absence of pyrogens What are pyrogens/endotoxins? These substances are bacterial products that may be released from certain types of bacteria (Gram negative) when they are alive, or after they die (during sterilization). They may therefore be present in sterile products as a by-product of the sterilization process which kills the bacteria during manufacture. Pharmaceutical requirements Absence of pyrogens Pyrogenic response: Pyrogens, when present in parenteral drug products and injected into patients, can cause fever, chills, pain in the back and legs, and malaise. In the seriously ill patient, shock-like symptoms and hypotension that can be fatal. Response depends on the patient condition, count of pyrogens and the route of administration (most hazardous?) Pharmaceutical requirements Absence of pyrogens Source of pyrogens: Water is the main source of pyrogens. This is because Pseudomonas, a gram-negative bacterium, grows readily in water. Other sources of endotoxins or pyrogens are raw material, processing equipment, and human contamination. Pharmaceutical requirements Absence of pyrogens Parenteral preparations must be practically free from endotoxins and pyrogens. Removal of pyrogens, once present, from a drug product is impractical without adversely affecting the drug product. They are very stable. They are not destroyed by autoclaving They are water soluble, will pass through 0.2-μm filters. Pharmaceutical requirements Absence of pyrogens Pyrogen control Raw water should be appropriately treated to render it free from pyrogens, such as water-for-injection (WFI) and used for compounding the product or rinsing product contact surfaces such as tubing, mixing vessels, and rubber closures. Pharmaceutical requirements Absence of pyrogens Pyrogen control Rubber stoppers must undergo washing, thorough rinsing with WFI, prompt sterilization, and protective storage to ensure adequate pyrogen control. Plastic containers and devices must be protected from pyrogenic contamination during manufacture and storage. Pharmaceutical requirements Absence of pyrogens Depyrogenation: dry heat Endotoxins can be destroyed by dry heat (250°C for 45 min, for 650°C for 1 min or 180°C for 4 hr) for: Glassware and containers A product from nonsterile starting material that can withstand the heat of 200°C Depyrogenation: other methods Ultrafiltration Reverse osmosis Adsorption Thank you