Sterile Dosage Forms and Delivery Systems PDF

 Sterile Dosage Forms and Delivery Systems Parenterals – para (outside) and enteron (intestine) Biologicals  Sterile Dosage Forms and Delivery Systems Hypodermic morphine solution – Earliest injectable drug to receive recognition  Parenteral Prepara...

 Sterile Dosage Forms and Delivery Systems Parenterals – para (outside) and enteron (intestine) Biologicals  Sterile Dosage Forms and Delivery Systems Hypodermic morphine solution – Earliest injectable drug to receive recognition  Parenteral Preparation  are pharmaceutical dosage forms that are injected through one or more layers of skin.  the parenteral route bypasses the protective barriers of the body, thereby it must be sterile.  it is imperative then that the preparations should be pure, free from toxicity, free from contamination and free from pyrogen. Advantages: Immediate action is provided Modification of the formulation allowing the drug to be administered slowly or with prolong duration of action Therapeutic response is more readily controlled When administered by a professional can provide actual and accurate dose For drugs which cannot be administered or taken orally Disadvantages Requires aseptic technique. Results to psychological pain factor Requires a professionally trained person to administer Parenteral Routes Of Administration Injection dependent routes (Sterility Demanding Route) – limited to solutions, suspensions, and emulsions – limited volumes of formulation that can be injected – excessive injection volumes will cause pain and cell necrosis. Parenteral Routes Of Administration Injection independent routes – Intranasal – Inhalation – Ophthalmic Routes 1. Intravenous  the basilic and cephalic veins on the back of the hand and dorsal forearm are the best peripheral veins for IV therapy. 1. Intravenous the veins of the antecubital area, and some of the larger veins in the foot  Intravenous  provide the most rapid onset of action of any parenteral route  Highest bioavailability  Drugs that are too irritating for intramuscular or subcutaneous administration (e.g.,chemotherapy agents) can be given by this route.  Placement of these devices is crucial to avoid problems of extravasation or infiltration. Extravasation - pass out of vessel into the tissue, blood, lymph. Infiltration - into a substance or a cell.  Complications Thrombosis - Clotting within a blood vessel - Caused by factors: - extremes in solution pH - particulate material - irritant properties of the drug - needle or catheter trauma - selection of too small of a vein for the volume of solution injected.  Complications Phlebitis - inflammation of the vein - Caused by the same factors that cause thrombosis  Complications Air Emboli - air is introduced into the vein - a good practice is to purge all air bubbles from the formulation and administration sets before use  Complications Embolism - A complication wherein a circulating clot carried by the blood stream lodges into a blood vessel  Particulate material is generally small pieces of glass that chip from the formulation vial or rubber that comes from the rubber closure on injection vials. Although great care is taken to eliminate the presence of particulate material, a final filter in the administration line just before entering the venous system is a typical precaution. 2. Intramuscular  Intramuscular  Patients generally experience more pain via IM administration compared to intravenous administration.  considered less hazardous and easier to use than the intravenous route.  Drugs intended for prolonged or delayed absorption commonly are administered intramuscularly.  Intramuscular  Needles used for the injections are generally 2 inch to 3 inches long and are generally 20 to 22 gauge in size.  The size of the needle must be chosen based on the patient's deposits of fat.  Not more than 5 ml of a solution should be injected by gluteal region and nmt 2ml in the deltoid of the arm.  Intramuscular  Women tend to have more fat in this region than men, so the possibility of a intralipomatous injection is significant.  It is estimated that few women and about 15% of men actually receive the intended intramuscular injection because an improper needle length was used.  Complication  Abscesses  Cysts  Embolism  Hematoma  Skin sloughing  Scar formation 3. Intradermal The usual site for intradermal injections is the anterior surface of the forearm.  Needles are generally 3/8 inches long and 23 to 26 gauge.  Intradermal Drugs that are intradermally injected are agents for diagnostic determinations, desensitization, or immunization. 0.1 mL of solution is the maximum volume that can be administered (tuberculin syringe) 4. Subcutaneous into the subcutaneous tissue beneath the skin layers-usually of the arm or thigh. it can be used for both short term and very long term therapies.  Subcutaneous  The injection of a drug is made in the loose interstitial tissues of the upper arm, the anterior surface of the thigh, or the lower portion of the abdomen or the upper back  The site of injection is usually rotated when injections are frequently given.  Subcutaneous  The maximum amount of medication that can be subcutaneously injected is about 2 mL.  Needles are generally 3/8 to 1 inch in length and 24 to 26 gauge. 5. Intracardiac administration is injection of a drug directly into the heart. 6. Hypodermoclysis refers to injection of large volumes of a solution into subcutaneous tissue to provide a continuous, abundant drug supply. This route occasionally is used for antibiotic administration in children. 7. Intraspinal administration refers to injection into the spinal column. 8. Intra-articular administration means injection into a joint space. 9. Intrasynovial administration refers to injection into the joint fluid. 10. Intrathecal administration is injection into the spinal fluid; it sometimes is used for antibiotics.  Official Types of Injections 1. Injection – Liquid preparation that are drug substances or solutions thereof 2. For injection – Dry solids added with suitable vehicles. 3. Injectable emulsion – Liquid preparation dissolved or dispersed in an emulsion medium  Official Types Of Injections 4. Injectable suspension – Liquid preparation of solid suspended in a suitable liquid medium 5. For injectable suspension – Dry solids added with vehicles to make them injectable suspension Parenteral Solutions and Suspensions  Solvents or vehicles  Added substances (colorants = PROHIBITED)  Production (facilities, areas)  Specifications or standards  Containers  Labeling  Powders for reconstitution  Vehicle Components  Water is the vehicle of the greatest importance for sterile products and especially, for parenterals since it is the vehicle for all natural fluids.  It must meet the requirements for water for injection, USP.  Vehicle Components Water for Injection  Meets requirements for Purified Water USP plus the USP "Pyrogen Test"  Contain no additives  Not necessarily sterile  Used to prepare parenteral products which are then sterilized after preparation  It must not contain more than 1mg/100mL of total solids  Vehicle Components Sterile Water for Injection  Meets requirements for Water for Injection USP plus passes the USP "Sterility Test"  Contains no additives, pyrogen free (allowable 0.25 USP EU/mL)  Used to prepare parenterals - no further sterilization needed  Packaged in single dose containers not larger than 1 L  Vehicle Components Bacteriostatic Water for Injection  Sterile water with antimicrobial agents  Packaged in container not more 30 mL  For multiple dose preparation  Use for preparations administered in small doses.  “NOT USE FOR NEONATES”  benzyl alcohol – gasping syndrome  Vehicle Components Sodium chloride for Injection  sterile, isotonic  No antimicrobial agents  Approx. 154 mEq of Na and Cl per L solution  Vehicle Components Bacteriostatic Sodium chloride  Contains 1 or more antimicrobials  nmt 30 mL  “NOT FOR USE IN NEONATES”  Vehicle Components Ringer’s Injection  NaCl, KCl, CaCl2  Electrolyte replenisher and plasma volume expander  + Sodium lactate (Lactated Ringer’s)  Fluid and electrolyte replenisher and systemic alkalizer.  Non-aqueous Vehicle must not be toxic, irritating or sensitizing and must not exert any adverse effect on the ingredients of the formulation. most frequently used non-aqueous solvents are polyethylene glycol, propylene glycol, alcohol, glycerin and fixed oils. Corn oil, cottonseed oil, peanut oil and sesame oil are used as solvent for IM injection.  Characteristics  Perform its function throughout the useful life of the product.  Must be non-toxic and non-irritating.  Must not exert any adverse effect on the products, i.e., must be compatible with all the components of the formulation.  must not interfere with:  Therapeutic efficacy  Assay of the active therapeutic compound Antibacterial/Antifungal Agents The USP states that antimicrobial agents in bacteriostatic or fungi static concentrations must be added to preparation contained in multiple dose containers. Antibacterial/Antifungal Agents They must be present in adequate concentration at the time of use to prevent the multiplication of microorganism inadvertently introduced into preparation while withdrawing portion of the contents with a hypodermic needle and syringe. Antibacterial/Antifungal Agents The most commonly used agents include the two mercurials, phenylmercuric nitrate and thimerosal, the four homologous esters of p-hydroxybenzoic acid, phenol, benzyl alcohol and chlorobutanol.  Antioxidants  Oxidation is one of the pathways of degradation of which can be accelerated during thermal sterilization.  To protect a therapeutic agent susceptible to this reaction, antioxidants are required.  Antioxidants Antioxidants used in sterile products are classified into: – Reducing agents – Blocking agents – Synergist – Chelating agents – Inert gases  Antioxidants Reducing agents- antioxidants which function by being preferentially oxidized; e.g.: ascorbic acid, sodium bisulfite, and metabisulfite, sodium formaldehyde sulfoxylate, thiourea. Blocking agents- antioxidants which block an oxidative chain reaction in which they are not usually consumed; e.g.: ascorbic acid esters, butyl hydroxytoluene(BHT) and tocopherols. Synergist- compounds increase the effectiveness of antioxidants, particularly those blocking oxidative reactions; e.g.: ascorbic acid, citric acid, citraconic acid, phosphoric acid and tartaric acid. Chelating agents- those that complex with catalysts which otherwise would accelerate the oxidative reactions; e.g. ethylenediaminetetraacetic acid salts. Inert gases like nitrogen and carbon dioxide have been used to displace oxygen from solution and reduced the possibility of the oxidative changes in the formulation.  Buffers Buffers are added to maintain the required pH for many products;  a change in pH may cause significant alterations in the rate of degradation reactions  Buffers The principal buffer systems used to stabilize pH are the acetates, citrates and phosphates.  Tonicity Contributors Compounds contributing to the isotonicity of a product Reduced the pain of injection in the areas with nerve endings. Note: Buffers may serve as tonicity contributors as well as stabilizers for the pH.  Sterilization Means the destruction of all living organisms and their spores or their complete removal from any preparation  Sterilization Thermal Moist and Dry heat Chemical Radioactive Mechanical  Steam/Moist Heat Sterilization  Steam under pressure in an autoclave  Method of choice  MOA: Denaturation and coagulation 10 lb pressure for 30 mins  115.5 C 15 lb presure for 20 mins 121.5 C  20 lb pressure for 15 mins 126.5 C  Moist heat Sterilization  Autoclave – commonly used for moist heat sterilization.  Used for heat-stable materials  Bulk solutions  Glassware  Medical devices  Surgical dressings  Not for oils, fats, oleaginous preparations  Dry Heat Sterilization  Dehydration followed by slow oxidation  Objects are subjected to a temperature of at least 160°C for 120 minutes (if higher temperatures can be used, less exposure time is required).  150-170°C for not less than 2 hours  Dry Heat Sterilization  Utilizes a special oven  Used for heat-stable materials which cannot be sterilized by moist heat  Fixed oils, glycerin, various petroleum products,  Glassware  Medical devices, instruments  Sterilization by Filtration  Non thermal method based on the removal of microorganisms by adsorption on filter medium  Filters with varying pore size Millipore filter – 14 to 0.025 um 6.5 um - RBC 0.2 um - smallest bacteria 0. 025 um - poliovirus  Sterilization by Filtration  Depth filter usually consist of fritted glass or unglazed porcelain-substances that trap particles in channels.  Sterilization by Filtration  Screen filter Particulate filter remove particles of glass, plastic, rubber, and other contaminants Final Filter which may be either particulate or microbial, are in-line filters used to remove particulates or microorganisms from an intravenous solution before infusion.  Sterilization by Filtration Membrane filter  Cellulosic materials (acetate, nitrates, fluorocarbonate, acrylic polymers, polyester, PVC, vinyl, nylon, polytef)  Sterilization by Filtration  Used for small quantity of solutions  Inexpensive  Allows removal of microorganisms  Disadvantages include:  Membrane tend to be fragile  Requires validation of compatibility and integrity  Limited to small volumes  Nature of the filter  Particle size of the drug  Gas Sterilization  In this method, ethylene oxide is generally used in combination with heat and moisture  used to sterilize surfaces and porous materials (e.g., surgical dressings) that other sterilization methods may damage.  Affected by time, temperature, gas concentration, humidity  Low temperature requires longer exposure  Radioactive Sterilization  Radioactive sterilization is suitable for the industrial sterilization of contents in sealed packages that cannot be exposed to heat (e.g., prepackaged surgical components and some ophthalmic ointments).  This technique involves irradiation causing cellular destruction  Accelerated drug decomposition sometimes results.  Validation of sterility Media fills is that the growth medium will support the growth of the contaminating microbe, and this growth can be detected. Biologic indicator B. stearothermophilus – steam and gas sterilization B. subtilis – dry heat P. diminuta – membrane filtration Thermal death time - Time required to kill a particular organism under specified conditions  Pyrogen  are lipid substances associated with a carrier molecule, which is usually a polysaccharide but maybe a protein.  are fever-producing organic metabolic products arising from microbial contamination and responsible for many of the febrile reactions in patients following injection  are known synonymously as bacterial endotoxins  Pyrogen Testing Bacterial Endotoxin Test - This is a test for estimating the concentration of bacterial endotoxins - Endotoxins react with enzyme Limulus Amebocyte Lysate (LAL) forming gel-clot formation  Pyrogen Testing LAL are obtained from aqueous extracts of the circulating amebocytes of the horseshoe crab, Limulus polyphemus  Pyrogen Testing The pyrogen test using rabbit is the Quantitative Fever response test –designed to limit to an acceptable level the risk of febrile reaction in the patient to the administration, any injection, of the product concerned.  Rabbit Test Inject into an ear vein of each of three rabbits 10 mL of the product per kilogram of bodyweight, completing each injection within 10 minutes of the start of administration. Record the temperature at 30-minute intervals 1 to 3 hours subsequent to the injection.  Rabbit Test If no rabbit shows an individual rise in temperature of 0.5°C or more, the product meets the requirements for the absence of pyrogens. If any rabbit shows an individual temperature rise of 0.5°C or more, continue the test using five other rabbits. ------------ If not more than three of the eight rabbits show individual rises in temperature of 0.5°C or more and if the sum of the eight individual maximum temperature rises does not exceed 3.3°C, the material under examination meets the requirements for the absence of pyrogens. QC Micro: LAL Assay The Lysate  General Process of parenteral production procurement and selection of the components production facilities and procedure quality control packaging handling  Production A cleanroom is to be a separate room that contains laminar airflow hoods and meets certain standards of airborne particle concentration.  Clean Room Positive pressure airflow, uniform velocity Counters as stainless steel Walls and floors are non-porous (epoxy- painted), no cracks, no crevice and with rounded corners Personnel wear special suit (cover-all gowns and shoe cap, mask and gloves) Clean Rooms Classification  Clean Room Positive pressure airflow, uniform velocity Class 100 – less than 100 particles of 0.5 micron size per cubic foot – (HEPA) filter – air is filtered through a high efficiency particulate air filter, removing 99.97% of all particles 0.3 microns or larger DOP smoke test – efficiency of HEPA filters using anemometer and particle counters Vertical and Horizontal Laminar Flow hood  Filtration and Filters  Filtration is used to remove particles from solutions.  Filtration is not a "terminal sterilization" procedure as are steam (moist heat), dry heat, ionized radiation, or gas sterilization.  Filtration will sterilize the product, but after filtration, the sterile product is then aseptically combined with its packaging.  Packaging, Labeling and Storage Parenteral solutions are packaged as large volume parenteral (LVP) solutions and small volume parenteral (SVP) solutions  LVP Common uses : 1) correction of electrolyte and fluid balance disturbances 2) Nutrition 3) vehicle for administering other drugs packaged in containers holding 100 ml or more Packaged in glass bottles or plastic bags  Plastic bags Advantages over glass bottles: they do not break; they weigh less they take up less storage space they take up much less disposal space available in different sizes, the most common sizes are 250, 500, and 1,000 ml.  Plastic bags Disadvantages Adsorption of drugs into the plastic. Leaching of a plasticizer out of the plastic  Glass bottles The major advantage of glass bottles is to administer drugs that are incompatible with plastic bags. Glass intravenous bottles are packaged with a vacuum, sealed with a solid rubber closure, and the closure is held in place by an aluminum band  SVP  are usually 100 ml or less and are packaged in different ways depending on the intended use.  If the SVP is a liquid that is used primarily to deliver medications, it is packaged in a small plastic bag called a minibag of 50 - 100 ml (minibags look like small plastic LVP bags).  SVPs can also be packaged as ampules, vials, and prefilled syringes.  Ampules  sealed glass containers with an elongated neck that must be broken off.  weakened around the neck for easy breaking or if not, it must first be scored with a file  Filtration is done when using solutions from ampule.  In addition, it is useful to wrap an alcohol wipe or small piece of gauze around the top of the ampule before breaking it.  Types of Ampule  Pull seal  Tip seal  Disadvantages  Their unsuitability for multiple-dose use, the need to filter solutions before use, and other safety considerations have markedly reduced ampule use.  Vials Vials are made of glass or plastic and are sealed with a rubber stopper. Vials may be designated for single- dose or multi-dose use.  Vials Advantages:  can be designed to hold multiple doses (if prepared with a bacteriostatic agent).  easier to remove the product from vials than from ampules.  eliminate the risk of glass particle contamination during opening  Vials  Disadvantages:  The rubber stopper may become cored causing a small bit of rubber to enter the solution.  Multiple withdrawals (as with multiple-dose vials) may result in microbial contamination.  Some drugs that are unstable in solution are packaged in vials unreconstituted and must be reconstituted with sterile water or sterile sodium chloride for injection before use.  Prefilled syringes A cartridge type package, is a single syringe and needle unit which is to be placed in a special holder before use. Once the syringe and needle unit is used, they are discarded but the holder is used again with a new unit.  Ready-to-mix systems Mix – O – Vial (Pharmacia) ADD Vantage System (Abbott)  Mix-O-Vial Example: Solu-Medrol  Quality Control Aseptic technique can be defined as the sum total of methods and manipulations required to minimize the contamination of sterile compounded formulations.  Sterility Test 1.Sterility tests are intended primarily as a check test on the probability that a previously validated sterilization procedure has been repeated. 2. The USP provides two basic methods - direct introduction method and membrane filtration method. 3. A product is deemed to pass the sterility test if all media vessels incubated with product sample reveal no evidence of microbial growth (turbidity). 4. The time for incubation for sterility testing by membrane filtration is 7 days, less than that for testing by direct inoculation (14 days).  Pyrogen testing 1. The USP pyrogen test is a quantitative fever response test in rabbits. 2. A more recent test is the Limulus amebocyte lysate (LAL) test for the presence of bacterial endotoxins, i.e., the USP Bacterial Endotoxins test  Devices for Administration The basic parts of a syringe are the barrel, plunger, and tip. The barrel is a tube that is open at one end and tapers into a hollow tip at the other end. The plunger is a piston-type rod with a slightly cone-shaped top that passes inside the barrel of the syringe. The tip of the syringe provides the point of attachment for a needle *Syringes come in different sizes  IV Infusion Pumps The set contains a spiked plastic device to pierce a port on the IV container This connects to a sight or drip chamber that may be used to set the flow rate  Heparin lock is a short piece of tubing attached to a needle or intravenous catheter  Dialysis solution Dialysis – separation of substance from one another in solution by taking advantage of their differing diffusibility through membrane Peritoneal dialysis Hemodialysis  Cytotoxic Agents  These agents present an environmental hazard.  It is now known that prolonged exposure to these agents may lead to the development of cancers.  For this reason special precautions must be taken to minimize the exposure of pharmacy personnel to these agents.  These agents should be prepared in a shielded vertical flow hood, so that materials are not blown into the operators face  Radiopharmaceuticals  These agents also represent an environmental hazard and must be handled carefully.  In addition to adhering to the guidelines set forth for cytotoxic agents, one may further reduce his exposure to these agents by working with them in protective lead vial shields  Antibiotics  Due to the allerginicity of the penicillins, it is desirable to work with them in a shielded vertical flow hood to avoid environmental contamination.  When working with any of the antibiotics, it is important to remember that prolonged exposure may lead to infections of exposed areas by non- susceptible bacteria and fungi  Biologicals  are substance derived from a living organism and used for the prevention or treatment of disease.  include antitoxins, bacterial and viral vaccines, blood products and hormone extracts.  any virus, therapeutic serum, toxin, antitoxin, or analogous product employed for prevention, treatment, or cure of diseases in humans (Code of Federal Regulations)  Immunity State of relative resistance to a disease that develops after exposure to the specific disease- causing agent Natural immunity Acquired immunity  Natural Immunity Also known as innate or native immunity depends on factors that are inborn and can be classified as  Species  Racial  Individual  Immunization is the process by which an individual is exposed to an agent that is designed to fortify his or her immune system against that agent.  The material is known as an immunogen.  human immune system  expose to an immunogen in a controlled way body will then be able to protect itself from infection Edward Jenner originated vaccination procedure Dr. Raymond Parker defined a chemical nutrient medium in which cells can grow and replicate Jonas Salk developed polio vaccine - Sabin polio vaccine was developed few years later  Vaccines Substance used to produced immunization Vaccination - it refers to the use of a biologic product (a vaccine) to develop active immunity in the patient. Active immunization is where the actual microbe is taken in by a person. Antibodies are created by the recipient and are stored permanently  Active Immunization Natural active immunization - when an untreated microbe is received by a person who has not yet come into contact with the microbe and has no pre-made antibodies for defense. Artificial active immunization - where the treated microbe is injected into the person before they are able to take it in naturally. Passive immunization is where pre-made antibodies are given to a person. Immunization begins to work very quickly, but it is short lasting, because the antibodies are naturally broken down, and not stored for later use.  Passive Immunization Natural passive immunization - when antibodies are being transferred from mother to fetus during pregnancy, to help protect the fetus before and shortly after birth.  Passive Immunization Artificial passive immunization - given by injection and is used if there has been a recent outbreak of a particular disease or as an emergency treatment to poisons.  Types of Vaccines Live attenuated vaccines contain bacteria or viruses that have been altered so they can't cause disease. Killed vaccines contain killed bacteria or inactivated viruses.  Types of Vaccines Toxoid vaccines contain toxins (or poisons) produced by the germ that have been made harmless. Component vaccines contain parts of the whole bacteria or viruses.  Live attenuated vaccines usually are created from the naturally occurring germ itself. Viruses are weakened by growing them over and over again in a laboratory under nourishing conditions called cell culture. The process of growing a virus repeatedly-also known as passing serves to lessen the disease- causing ability of the virus. Examples of live attenuated vaccines include: Measles vaccine (as found in the MMR vaccine) Mumps vaccine (MMR vaccine) Rubella (German measles) vaccine ( MMR vaccine) Oral polio vaccine (OPV) Varicella (chickenpox) vaccine Inactivated (killed) vaccines  cannot cause an infection, but they still can stimulate a protective immune response.  Viruses are inactivated with chemicals such as formaldehyde. Examples of inactivated (killed) vaccines  Inactivated polio vaccine (IPV), which is the shot form of the polio vaccine  Inactivated influenza vaccine  Toxoid vaccines made by treating toxins produced by germs with heat or chemicals, such as formalin, to destroy their ability to cause illness. do not cause disease but they stimulate the body to produce protective immunity just like the germs' natural toxins.  Examples of toxoid vaccines Diphtheria toxoid vaccine (may be given alone or as one of the components in the DTP, DTaP, or dT vaccines) Tetanus toxoid vaccine (may be given alone or as part of DTP, DTaP, or dT)  Component vaccines made by using only parts of the viruses or bacteria. Examples of component vaccines: Haemophilus influenzae type B (Hib) vaccine Hepatitis B (Hep B) vaccine Hepatitis A (Hep A) vaccine Pneumoccocal conjugate vaccine  Production Extraction Chemical synthesis GENETIC ENGINEERING  Genetic engineering is the artificial alteration of the genetic composition of cells or organisms. Gene cloning is fundamental to genetic engineering.  A segment of DNA from any donor organism is joined in the test tube to a second DNA molecule, known as a vector, to form a "recombinant " DNA molecule. Thimerosal (49.6%) is the common preservative Dispensed in units of Total # of organism/ml or dose mcg of immunogen/ml or dose For toxoids – in flocculating units Biologicals are sensitive to extreme temperature These are kept in a biological refrigerator or an insulated container Diagnostic skin biologics Contains antigen Multiple Skin Antigens AEROSOLS  Aerosols Pressurized dosage forms designed to deliver drug systematically or topically with the aid of liquefied or propelled gas  Aerosols Colloidal system of very finely subdivided liquid or solid particles dispersed in and surrounded by a gas.  Advantages Minimum contamination Maximum stability Reduces the irritation and provides cooling effect Easy to control physical form: particles size and form A clean process requiring no wash-up  Two Components Product concentrate- Active drug with adjuncts like antioxidant, solvent, etc. Propellant- Gas  Classification Formulation of the product Type of the valve assembly  Container Valve Assembly Pressurized container  Tin-plated- light, inexpensive  Aluminum (canisters) – seamless, extremely strong, can withstand high pressures  Glass– preferred due to absence of incompatibilities  Container Valve Assembly Valve – expels the contents from the container; regulate the flow of product from container Actuator – provides a rapid and convenient means for releasing the contents from a pressurized container; button that activates the system. Dip tube – the tube that delivers the content.  Aerosol Assembly Valves - Must be approved by FDA Components  Ferrule or mount cap  Valve body or housing  Stem  Gasket  Spring  Dip tube  STEM - Part of the usual aerosol valve assembly that supports the actuator and delivers the formulation in the proper form to the chamber of the actuator MOUNTING CUP- Part of the usual aerosol valve assembly that is attached to the aerosol can or container and hold the valve in place.  Principle Product concentrate Propellant ------ Valve assembly  pressure of the propellant forces the liquid phase up the tube and out in the atmosphere  propellants meet the air  evaporates due to drop in pressure  leaving the product concentrate as airborne liquid droplets or dry particles, as in powders.  Propellants Supplies the necessary force to expel the product act as a solvent and diluent and has much to do with determining the characteristics of the product as it leaves the container.  Propellants Liquefiable gases – Widely used, extremely effective dispersing agents, inert and non-toxic. – Pressure within the container remains constant. – include the saturated hydrocarbons, chlorofluorocarbons, hydroflurocarbons and dimethyl ether – CFCs - Propellant 114, 12, 11 – HFCs – 134a, 152b – A ban was implemented (Montreal Agreement) by EPA, CPSC, FDA regarding the use of CFCs because of the negative impact to the ozone layer, temporary exceptions for CFCs in metered dose inhalers were granted and the use of acceptable hydrofluorocarbons  Propellants Compressed gases – include carbon dioxide, nitrogen, nitrous oxide – higher initial pressures are used with compressed gas-based systems as compressed gas tends to lose pressure over time as the product is dispensed resulting to the drop in pressure  Propellants Compressed gases – Nitrogen Inert, tasteless, odorless, insoluble – Carbon dioxide, nitrous oxide Slightly soluble  Aerosol system Two-phase › Liquid phase composed of Liquid propellant and Product concentrate › Vapor phase  Upon activation of the valve, the pressure of vapor phase causes the liquid phase to rise in the dip tube and be expelled from the container  Two Phase System Space sprays – Finely divided spray with particles not larger than 50 µm. – 2-20% AI – 80-98% propellant [85%] – 30-40 psig at 70F – Space insecticides, room deodorants, and vaporizer sprays  Two Phase System Surface coating sprays – Larger particle (50-200µm)  wet or coarse spray. – Product concentrate 20-75% – 25-80% of propellant [30-70%] – 35-55 psig at 70F – hair sprays, residual insecticides, perfumes, colognes, paints, protective coatings, and topical sprays  Two Phase System Aerated sprays – Foams, paste and creams – 6 – 10% propellant – Pet products and food products  Aerosol system Three-phase › Water-immiscible propellant › Highly aqueous product concentrate › Vapor phase  The liquified propellant has greater density and resides at the bottom and the aqueous phase floating above it.  Three Phase System Foam sprays – Liquid propellant 10-15% only emulsified with propellant [35-55 psig at 60F] – Shave creams, suntan foams  Filling Methods Cold Filling –Both the product concentrate and the propellant must be cooled to temperatures of -30F and -40F  Filling Methods Pressure filling – Product concentrate is placed in the container and the propellant, liquefied gases, is metered into the valve stem. – This is the method commonly used in pharmaceutical aerosols.  Tests Tests for leaks and weakness at 130 F Proper functioning of the valve Particles size distribution Accuracy and reproducibility using metered valve  Packaging and Labeling Packaging is part of the manufacturing process Labeling uses the shrink wrap labels or peel-away labels  Packaging and Labeling – Use warning labels whenever required – Avoid inhaling except for preparations intended for inhaling – Do not puncture or incinerate container – Storage condition: 15 and 30C – Shake before use and proper angle and distance for use are also included in the label  Inhalations – drugs or solutions of drugs administered by the nasal or respiratory route. The drugs may be administered for local or systemic effect. – drugs or combination of drugs which by virtue of their high vapor pressure can be carried by an air current into the nasal passage where they exert their effect  Sprays – aqueous or oleaginous solutions in the form of coarse droplets or as finely divided solids to be applied topically, most usually to the nasal-pharyngeal tract or to the skin. Inhalation Devices Metered Dose Inhaler – metering valves are used for potent medication is required in inhalation therapy. In this device the amount of material discharged is regulated by an auxiliary valve chamber by virtue of its capacity or dimension  Inhalation Devices Nebulizer – contains atomizing unit within a curved glass, bulb-like cylinder with a rubber bulb at the end of the apparatus  Inhalation Devices Atomizer – device used for sprays to deliver fine mist of droplets  Inhalation Devices Insufflator – or powder blower used to produce powder spray  Inhalation Devices Haleraid – a simple device, which fits over certain, makes of pressurized aerosols. The simplicity of operation makes it useful for elderly or arthritic patients  Inhalation Devices Spacer inhaler – a standard pressurized inhaler with an elongated mouthpiece. The usefulness of this device is based on the diffuse delivery of the dose of the drug and the propellant reducing the ‘cold freon effect’  Inhalation Devices Large volume inhaler – spacer attachment used for metered dose inhaler  Inhalation Devices Autohaler – a pressurized aerosol which incorporates a self-firing mechanism.  Dry Powdered Inhaler – MDI vs DPI – MDI’s energy for generating a dose relies on the device, DPI relies on energy provided by the patient’s inspiratory effort  Why a Curved Bottom? The shape strengthens the structure of the can The shape makes it easier to use up all the product  CURRENT GOOD MANUFACTURING PRACTICE cGMP AO 220 – JUNE 23, 1974  cGMP a term that is recognized worldwide for the control and management of manufacturing and quality control testing of foods and pharmaceutical products. takes the holistic approach of regulating the manufacturing and laboratory testing environment itself And an extremely important part of cGMP is documentation of every aspect of the process, activities, and operations involved with drug and medical device manufacture  GMPs are enforced – in the United States by the FDA – in the United Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA) – In Australia by the Therapeutical Goods Administration (TGA) – In India by the Ministry of Health – Philippines by FDA  cGMP Quality It is everyone’s responsibility QC function is to audit or inspect periodically the procedures, equipment, facilities (to detect NON- COMPLIANCE and to CORRECT the said deviation)  cGMP Non-compliance may result to quality variation  contamination, mix-ups and errors  product recall Recalls result to the ff disadvantages: – Lost of money – Bad publicity – Low sales – Negative effect on employees  Objectives Safe Pure Effective  Administrative Order No. 220, s. 1974 SCOPE Organization and Personnel Buildings and Facilities Equipment Components Production and Process Control  Administrative Order No. 220, s. 1974 Packaging and Labeling Control Holding and Distribution Laboratory Controls Records and Reports Returned and Salvaged products  Terminologies Active ingredient or active pharmaceutical ingredient (API) – Any component that is intended to furnish pharmacologic activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or function of the body of man or other animals.  Terminologies Batch – A specific quantity of a drug of uniform specified quality produced according to a single manufacturing order during the same cycle of manufacture.  Terminologies Batchwise control – The use of validated in-process sampling and testing methods in such a way that results prove that the process has done what it purports to do for the specific batch concerned  Terminologies Certification – Documented testimony by qualified authorities that a system qualification, calibration, validation, or revalidation has been performed appropriately and that the results are acceptable.  Terminologies Compliance – Determination through inspection of the extent to which a manufacturer is acting in accordance with prescribed regulations, standards, and practices.  Terminologies Component – Any ingredient used in the manufacture of a drug product, including those that may not be present in the finished product.  Terminologies Drug product – A finished form that contains an active drug and inactive ingredients. The term may also include a form that does not contain an active ingredient, such as a placebo.  Terminologies Inactive ingredient – Any component other than the active ingredients in a drug product  Terminologies Lot – A batch or any portion of a batch having uniform specified quality and a distinctive identifying lot number.  Terminologies Lot number, control number, or batch number – Any distinctive combination of letters, numbers, or symbols from which the complete history of the manufacture, processing, packaging, holding, and distribution of a batch or lot of a drug product may be determined.  Terminologies Master record – Record containing the formulation, specifications, manufacturing procedures, quality assurance requirements, and labeling of a finished product.  Terminologies Quality assurance – Provision to all concerned the evidence needed to establish confidence that the activities relating to quality are being performed adequately.  Terminologies Quality audit – A documented activity performed in accordance with established procedures on a planned and periodic basis to verify compliance with the procedures to ensure quality.  Terminologies Quality control – The regulatory process through which industry measures actual quality performance, compares it with standards, and acts on the difference.  Terminologies Quality control unit – An organizational element designated by a firm to be responsible for the duties relating to quality control.  Terminologies Quarantine – An area that is marked, designated, or set aside for the holding of incoming components prior to acceptance testing and qualification for use.  Terminologies Representative sample – A sample that accurately portrays the whole.  Terminologies Reprocessing – The activity whereby the finished product or any of its components is recycled through all or part of the manufacturing process.  Terminologies Strength – The concentration of the drug substance per unit dose or volume.  Terminologies Verified – Signed by a second individual or recorded by automated equipment.  Terminologies Validation – Documented evidence that a system (e.g., equipment, software, controls) does what it purports to do.  Terminologies Process Validation – Documented evidence that a process (e.g., sterilization) does what it purports to do.  Terminologies Validation Protocol – A prospective experimental plan to produce documented evidence that the system has been validated.  Personnel Qualified  healthy with an awareness of the importance of good hygiene  Buildings and Facilities Designed for easy cleaning, maintenance and freedom from congestion and traffic Adequate space for operations Adequate lighting, ventilation Adequate facilities Adequate supply of water suitable housing and space for animal care safe and sanitary waste disposal Clean room  Storage Conditions  Cold – between 2 to 8C  Freezer - -10 to -20C  Cool – between 8 and 15 C  Room temperature – 15 and 30C  Warm – between 30 and 40C  Excessive heat – any temperature above 40C RADIOPHARMACEUTICALS  Radiopharmaceutical chemical containing a radioactive isotope for use in humans, for the diagnosis, mitigation, or treatment of a disease Products should meet requirements of state agency, FDA and NRC  Related Terms Isotope – substances that have the same number of protons but have varying numbers of neutrons. Radioisotope – an isotope of an element that emits alpha, beta or gamma radiation during its decay into another element Radioactive – substance that emit energy in the form of alpha, beta or gamma rays. Naturally occurring radioactive elements include radium and uranium.  Half-life - the time required for a radioisotope to decay to 50% of its original activity. 0.69315 t1/2 = -------------- λ – λ is transformation or decay constant  Curie – the fundamental unit of radioactivity, defined as radionuclide decaying at a rate of 3.700 x 1010 nuclear transmission per second. Becquerel – the international unit of radioactivity and is equal to one disintegration per second Radioactive dose – amount of radiation absorbed by the body tissue in which a radioactive substance resides (rad)  An atom of a radioactive isotope will spontaneously decay into another element through one of three common processes: – Alpha decay – Beta decay – Spontaneous fission  Three different kinds of radioactive rays produced: –Alpha rays –Beta rays –Gamma rays  Alpha Rays Spontaneously throw off an alpha particle. An alpha particle is made up of two protons and two neutrons bound together Largest mass and charge particle Composition : identical to helium nucleus Velocity : low velocity, 1/10 the speed of light or 10,000 miles per second Penetrating power : low How to stop penetration : paper or layer of human skin Hazards to the body : not hazardous unless swallowed or inhaled  Beta Rays In beta decay, a neutron in the nucleus spontaneously turns into an electron with a negative charge, negatron, or positive electron, positrons. Composition : identical to electron Velocity : greater velocity than alpha Penetrating power : moderate How to stop penetration : wood block, aluminum plate Hazards to the body : cause damage to skin and eyes  Gamma Rays Atom actually splits instead of throwing off an alpha or beta particle  Neutron radiation Composition : high energy radiation Velocity : equal to velocity of light (3 x 1010 cm/s) Penetrating power : high How to stop penetration : several layers of blocks of Pb Hazards to the body : affect the genes causing mutations  Nuclear medicine depends on radiopharmaceuticals that decay by gamma emission. Radiopharmaceuticals are produced by the process of nuclear activation in a nuclear reactor. Uses of radiopharmaceuticals include: - diagnosis of disease or evaluation of progression of disease, evaluation of drug- induced toxicity - used therapeutically.  Diagnostic Radiopharmaceuticals are used to derive detailed description of the morphology and dynamic functioning of the various internal organs of the body. The radiopharmaceutical accumulated in an organ of interest emit gamma radiation which are used for imaging of the organs with the help of an external imaging device called gamma camera. Examples: Abscess and infection- Gallium Citrate Ga 67, Indium In 111 Oxyquinoline Appendicitis- Technetium (99m Tc) Fanolesomab Biliary tract blockage- Technetium Tc 99m Disofenin, Technetium Tc 99m Lidofenin, Technetium Tc 99m Mebrofenin Blood volume studies- Radioiodinated Albumin, Sodium Chromate Cr 51 Blood vessel diseases- Sodium Pertechnetate Tc 99m  Therapeutic Radiopharmaceuticals are radiolabeled molecules designed to deliver therapeutic doses of ionizing radiation to specific diseased sites. The concept explains that certain radionuclides possessing particulate emission such as alpha and beta radiations or low-energy, low-range electrons (Auger electrons) possess the ability to destroy diseased tissues.  Radioisotopes may be used internally or externally. – externally or as implants in sealed capsules in a tissue the dose could be terminated by removal of the sources. – internally as unsealed source the dose cannot be stopped by removal of the source.  The total dose in therapeutic applications may be calculated on the ff. basis: 1. effective half- life of the isotope 2. concentration of the isotope 3. type and energy of radiation emitted. Positron Emission Tomography (PET) A nuclear medicine medical imaging technique which produces a three- dimensional image or map of functional processes in the body. Has been employed to study cerebral physiology The technique was first developed by Michel (Michael) Ter-Pogossian, Michael E. Phelps and others at the Washington University School of Medicine in 1975.  Radioisotopes used in PET carbon-11 (~20 min) nitrogen-13 (~10 min) oxygen-15 (~2 min) fluorine-18 (~110 min) *palmitic acid-mostly used in PET imaging These radionuclides are incorporated into compounds normally used by the body such as glucose, water or ammonia and then injected into the body to trace where they become distributed. Such labeled compounds are known as radiotracers  Drug Antidote for Radiation Exposure – Prussian Blue (ferric hexacyanoferrate) Drugs used as interventional pharmaceutical drugs. – Acetazolamide – Captopril – Dipyridamole and Adenosine – Furosemide – Vit B12- Schilling’s Test  Nuclear Pharmacy is the patient-oriented service that embodies the scientific knowledge and professional judgment required to improve and promote health through the assurance of the safe and efficacious use of radioactive drugs for diagnosis and treatment. is the first specialty in pharmacy recognized by the Board of Pharmaceutical Specialties (1978)  The practice is composed of the following areas: Procurement Compounding Routine quality control procedures Dispensing and distribution Implementation of basic radiation protection procedures Consultation and education  RADIOPHARMACEUTICALS USED IN MEDICINE Albumin Microspheres Tc 99m, In 111, In 113m, Pb 203 – used for lung imaging. Chromated Cr 51 Albumin Injection - detection and quantitation of gastrointestinal protein loss and placental localization. Iodinated I 125 Albumin Injection – diagnostic aid in the determination of total blood and plasma volumes.  Iodinated I 131 Albumin Injection – diagnostic aid in the determination of total blood and plasma volumes, circulation times or cardiac output and as adjunct to other diagnostic procedures in the detection and localization of brain tumors, in placental localization and in cisternography. Iodinated I 131 Albumin Aggregated Injection – diagnostic study of the lungs (pulmonary embolism) by radioisotope scanning.  Chlormerodrin Hg 197 Injection – diagnostic aid for scanning the brain for suspected lesions and the kidneys for anatomical and functional abnormalities. Chlormerodrin Hg 203 Injection – same uses as above.  Chromic Phosphate P 32 Injection – neoplastic suppressant for palliative treatment of pleural and peritoneal effusions. Cobalt Co 60 and Iridium Ir 192 Sources – 60 Co has replaced radium, which is relatively expensive for many radiation uses of the latter element. Cyanocobalamin Co 57 and Co 60 Capsules and Solution – diagnostic aid to study the absorption and deposition of Vit. B12 in normal individuals and in patients with megaloblastic anemias.  Ferric hydroxide In 113m – diagnostic agent for lung imaging. Ferrous nitrate Fe 59 Injection – diagnostic aid for the evaluation of the kinetics of iron metabolism. Ferrous Hydroxide Tc 99m – diagnostic aid in pulmonary scintigraphy.  Fibrinogen I 125 Injection – diagnosis and localization of deep-vein thrombosis, the accumulation of fibrinogen in clots is observable by use of a radiation detector pressed to the surface of the limb. Gallium Citrate Ga 67 Injection – diagnosis of lesions of the lungs, breast, maxillary sinuses and liver by using scanning and organ-imaging techniques. A positive 67 Ga uptake is a potential indicator of certain malignancies such as lymphomas, bronchogenic carcinoma, and Hodgkin’s disease. Indium Chloride In 113m Injection – blood-pool studies, including visualization, aneurysms, and in placental scintigraphy.  Indium Hydroxide In 113m Injection – for liver, spleen and bone marrow scintigraphy. Insulin I 125 and I 131 - in vitro assay of circulating insulin either free or bound. Iodohippurate Sodium I 131 Injection – for kidney function.  Krypton Kr 81m – lung function, ventilation and perfusion and radiocardiology. Liothyronine I 125 and I 131 – in vitro evaluation of thyroid function. Levothyroxine I 125 and I 131 – study metabolism of endogenous thyroxine, supplementing other tests of thyroid function.  Oleic acid I 125 and I 131, Trinolein I 125 and I 131 – diagnostic agents for measuring fat absorption in suspected pancreatic disease and other gastrointestinal dysfunction. Pentetate Indium Trisodium In 113 Injection – diagnostic aid for brain scanning, for studies of glomerular filtration and for kidney imaging. Pentetate Indium Disodium In 111 Injection – diagnostic aid for studies of cardiac output, for cisternography, for evaluation of glomerular filtration and in renal scintigraphy.  Pentetate Ytterbium Trisodium Yb 169 Injection – for brain and kidney imaging and for cisternographic diagnosis of CSF rhinorrhea. Potassium Chloride K 42 Injection – tumor localization and studies of renal blood flow. Potassium Chloride K 43 Injection – for heart imaging.  Rose Bengal Sodium I 131 Injection – diagnostic aid (liver function), especially for differential diagnosis of hepatobiliary diseases. Selenomehtionine Se 75 Injection – scintigraphy of the pancreas and parathyroid glands. Sodium chloride Na 22 Injection – determining circulating times, sodium space and total exchangeable sodium.  Sodium chromate Cr 51 Injection – biological tracer to measure circulating red-cell volume, red-cell survival time and whole blood volume. Sodium Fluoride F 18 Injection – bone imaging, especially to define area of altered osteogenic activity. Sodium Iodide I 123, I 125, I 131 – thyroid function.  Sodium Pertechnetate Tc 99m Injection – detection and location of cranial lesion, thyroid and salivary glands, imaging placental localization and blood pool imaging. Sodium Phosphate P 32 Solution – neoplastic and polycythemic suppressant, diagnostic aid for localization of ocular tumor. Strontium Sr 85 Injection – diagnostic aid for scanning bones to detect and define lesions and to study bone growth and abnormal formation.  Technetium Tc 99m Etidrenate Injection – best agent for bone imaging. Technetium Tc 99m Iminodiacetic acid (TIDA) or Hepatobiliary Iminodiacetic acid (HIDA) – hepatobiliary imaging agent. Technetium Tc 99m Ferpentate Injection – kidney imaging. Technetium Tc 99m Pentetate Injection – brain and kidney visualization, for vascular dynamic studies for measurement of glomerular filtration and lung ventilation studies.  Technetium Tc 99m Pyrophosphate Injection – skeletal imaging agent used to demonstrate regions of altered osteogenesis. Technetium Tc 99m Sulfur Colloid Injection – diagnostic aid for liver scanning. Technetium Tc 99m Gluceptate Injection – a renal imaging agent and localization of brain, lung and gall bladder lesions.  Technetium Tc 99m sodium phosphates Injection – bone and renal imaging. Technetium Tc 99m Sodium Phytate Injection – for liver and spleen imaging. Thallium Tl 201 chloride Injection – myocardial perfusion imaging for diagnosis and localization of myocardial ischemia and infarction. Xenon Xe 133 Injection – as gas for lung imaging to detect alveolar blockage. Technetium 99M ( 99M Tc) t1/2 = 6 hrs Offers gamma photons for imaging Strontium-89 Chloride (89 Sr) t1/2 = 51 days Decays by beta emission  Yttrium-90 ( 90 Y) t1/2 = 64.2 hrs (2.68 days) pure beta-emitting radionuclide Thallous-201Chloride ( 201 Tl) t1/2 = 73.1 hrs Decays by electron capture to mercury Gallium-67 Citrate ( 67 Ga) t1/2 = 78 hrs Behaves similarly to Fe+3 ion Indium-111 Chloride( 111 In) Advantageous for immunoscintigraphy for its long half life Carbon-14 ( 14 C) t1/2 = 5730 years Sodium-24 ( 24 Na) t1/2 = 15 hrs Krypton-81 ( 81 Kr) t1/2 = 13-15 sec  Beta emission For therapeutic purposes Myocardial perfusion imaging the most common diagnostic imaging Radiopharmaceutical drugs that are used for the treatment of non Hodgkin lymphoma Bexxar