PARENTERAL PRODUCTS: PARENTERAL PRODUCTS MANJUL PRATAP SINGH & ANITA SINGH KAILASH INSTITUTE OF PHARMACY & MANAGEMENT, GIDA, GORAKHPUR 09628373561 K.I.P.M. GIDA, GORAKHPUR, U.P. DEFINATION:: DEFINATION: Parenteral refers injectable route of administration. It derived from Greek words Para ( Outside ) and enteron ( Intestine ). So it is a route of administration other than the oral route. This route of administration bypasses the alimentary canal Pyrogens, fever-producing substances are primarily lipid polysaccharide product of metabolism of microorganism; they may be soluble, insoluble, or colloid. K.I.P.M. GIDA, GORAKHPUR, U.P. Parenteral Dose Forms: Parenteral Dose Forms Parenteral preparations must be sterile free of microorganisms To ensure sterility, parenterals are prepared using aseptic techniques special clothing (gowns, masks, hair net, gloves) laminar flow hoods placed in special rooms K.I.P.M. GIDA, GORAKHPUR, U.P. Advantages of the Parenteral Route: Advantages of the Parenteral Route The IV route is the fastest method for delivering systemic drugs preferred administration in an emergency situation It can provide fluids, electrolytes, and nutrition patients who cannot take food or have serious problems with the GI tract It provides higher concentration of drug to bloodstream or tissues advantageous in serious bacterial infection IV infusion provides a continuous amount of needed medication without fluctuation in blood levels of other routes infusion rate can be adjusted to provide more or less medication as the situation dictates Drug action can be prolonged by modifying the formulation. K.I.P.M. GIDA, GORAKHPUR, U.P. Disadvantages of the Parenteral Route: Disadvantages of the Parenteral Route Traumatic injury from the insertion of needle Potential for introducing: Toxic agents Microbes Pyrogens Impossible to retrieve if adverse reaction occurs injected directly into the body Correct syringe, needle, and technique must be used Rotation of injection sites with long-term use prevents scarring and other skin changes can influence drug absorption K.I.P.M. GIDA, GORAKHPUR, U.P. Routes of Administration of parenteral products: Routes of Administration of parenteral products Various types of route of administration of parenteral products are: Intradermal injection Subcutaneous (Hypodermis) injection Intramuscular injection Intravenous injection Intra-arterial injection Intracardiac injection Intrathecal injection Intracisternal injection Peridural injection Intra- articular injection Intracerebral injection K.I.P.M. GIDA, GORAKHPUR, U.P. Subcutaneous Injections: Subcutaneous Injections Given at a 45-degree angle 25- or 26-gauge needle, 3/8 to 5/8 inch length No more then 1.5 ml should be injected into the site to avoid pressure on sensory nerves causing pain and discomfort Administer medications below the skin into the subcutaneous fat outside of the upper arm top of the thigh lower portion of each side of the abdomen not into grossly adipose, hardened, inflamed, or swollen tissue Often have a longer onset of action and a longer duration of action compared with IM or IV injection K.I.P.M. GIDA, GORAKHPUR, U.P. Intramuscular Injections: Intramuscular Injections Care must be taken with deep IM injections to avoid hitting a vein, artery, or nerve In adults, IM injections are given into upper, outer portion of the gluteus maximus large muscle on either side of the buttocks For children and some adults, IM injections are given into the deltoid muscles of the shoulders Typical needle is 22- 25 gauge ½- to 1-inch needle IM injections are administered at a 90 0 angle volume limited to less than 3 ml K.I.P.M. GIDA, GORAKHPUR, U.P. Intravenous Injections or Infusions: Intravenous Injections or Infusions Fast-acting route because the drug goes directly into the bloodstream often used in the emergency department and in critical care areas Commonly used for fluid and electrolyte replacement to provide necessary nutrition to the patient who is critically ill Intravenous (IV) injections are administered at a 15- to 20-degree angle K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Intra-arterial injection Intracardiac injection Intrathecal injection These are given into the subachonoid space the surround the spinal cord. This route is used for spinal anesthesia. These are given into the heart muscle or ventricle at the time of emergency only. The inaction are given directly in to the artery K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Intracisternal injection These are given in b/w first & second cervical nerve. Used for CSF for diagnostic purpose. Peridural injection These are given in b/w the dura matter & inner aspect of vertebra. Used for given spinal anesthesia. Intra- articular injection These are given in into the articulating ends of bones in a joint. Used for lubricating the joints. Intracerebral injection These are given into the cerebrum. K.I.P.M. GIDA, GORAKHPUR, U.P. Official types of injections: Official types of injections Injection: Liquid preparation there are drug substance or drug solution thereof e.g. insulin injection USP. For injection: Dry solid that upon addition of suitable vehicles yield solutions confirming in all respect to the requirements to the injection. e.g. Cefuroxime injection USP. Injectable emulsions : Liquid preparation of drug substance dispersed in a suitable emulsion medium. e.g. Propofol USP. Injectable suspension: Liquid preparation of solid suspended in a suitable medium. e.g. Methyl Prednisolone Acetate Suspension USP. For injectable suspension: Dry solid that upon addition of suitable vehicle yields preparation confirming in all respect to the requirements for Injectable suspension. e.g. Imipenem and Cilastatin injectable suspension USP. K.I.P.M. GIDA, GORAKHPUR, U.P. General requirements of parenteral preparations: General requirements of parenteral preparations Stability Sterility Free from Pyrogens Free from foreign particles Isotonicity Specific gravity Chemical purity K.I.P.M. GIDA, GORAKHPUR, U.P. Formulation of parenteral products: Formulation of parenteral products In the preparation of parenteral products, the following substances are added to make a stable preparation: The active drug Vehicles Aqueous vehicle (e.g. water for injection, water for injection free from CO 2 ) Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil) Adjuvants Solubilizing agents (e.g. Tweens & polysorbates) Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol) Buffering agents (e.g. citric acid, sodium citrate) Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol) Chelating agents (e.g. EDTA) Suspending, emulsifying & wetting agents (e.g. MC, CMC) Tonicity factor (e.g. sodium chloride, dextrose) K.I.P.M. GIDA, GORAKHPUR, U.P. PREFORMULATION FACTORS: PREFORMULATION FACTORS It is study about physical & chemical properties of drug substance prior formulation is called as preformulation. They are pH /pka Solubility Thermal/heat effect Dissociation constant Compatabilty studies- FTIR / DSC Oxidation & reduction particle size K.I.P.M. GIDA, GORAKHPUR, U.P. pH and pKa SOLUBILITY PROFILE: pH and pKa SOLUBILITY PROFILE pKa Determination: The Henderson – Hasseslebach equation provides an estimate of the ionized and un ionized durg concentration at a particular pH. For acidic drugs , pH = pKa + log (ionized drug) / un-ionized drug) For basic drugs , pH = pKa + log (unionized drug / ionized drug ) Buffers, temperature, ionic strength and cosolvent can affect the pKa value. Potentiometric titration offers maximum sensitivity for compounds with pKa values in the range of 3-10. K.I.P.M. GIDA, GORAKHPUR, U.P. SOLUBILIZATION: SOLUBILIZATION Solubilization is increased by co solvent addition. E.g.- propylene glycol solubilize drug molecules by disrupting the hydrophobic interactions of water. More non polar the solute greater is the solubilisation achieved by co solvent addition K.I.P.M. GIDA, GORAKHPUR, U.P. THERMAL/HEAT EFFECTS : THERMAL/HEAT EFFECTS Drugs which are unstable to heat requires refrigerative storage or lyophilisation (these products must be used within short periods) If it is endothermic ---> ∆H is + ve increase in temp ---> increase in drug solubility If it is exothermic ---> ∆H is – ve increase in temp ---> decrease in drug solubility For determining ∆H ln S= - ∆H /RT + C S=molar solubility at temperature, T=temperature in Kelvin, R= gas constant K.I.P.M. GIDA, GORAKHPUR, U.P. Particle size: Particle size FINE PARTICLE CHARACTERISATION Very imp. Property and here smallest particle should be tested to facilitate homogeneous sample preparation. Coulter Counter Technique To check particle size and particle volume BET (BRUNAUER, EMMET, TELLER) NITROGEN ADSORPTION APPARATUS Measurement of surface area SEM( SCANNING ELECTRON MICROSCOPY) to check surface morphology K.I.P.M. GIDA, GORAKHPUR, U.P. Oxidation & reduction: Oxidation & reduction Adding oxygen to form an oxide ( oxidation ) or 2H 2 + O 2 -> 2H 2 O Removing oxygen ( reductio n). Due to oxidation , shelf life reduces - changes in color - Potency of drug becomes less So antioxidants are used to prevent oxidation e.g sodium bisulphate , sodium metabisulphate K.I.P.M. GIDA, GORAKHPUR, U.P. Processing of parenteral preparation: Processing of parenteral preparation Following steps are involved in the processing of parenteral preparation: Cleaning of containers, closures & equipments Collection of materials Preparation of parenteral products Filtration Filling the preparation in final container Sealing the container Sterilization Evaluation of the parenteral preparation Labeling & packaging K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: 1. Cleaning of containers, closures & equipments: Thoroughly cleaned with detergents with tap water distilled water finally rinsed with water for injection. Rubber closures are washed with 0.5% sod. pyrophosphate in water. 2. Collection of materials: All raw material of preparation should be collect from warehouse after accurate weighed. Water for injection should be Pyrogens free. 3. Preparation of parenteral products : The parenteral preparation must be prepared in aseptic conditions. The ingredients are accurately weighed separately and dissolved in vehicle as per method of preparation to be followed. 4. Filtration: The parenteral preparation must be filtered by bacteria proof filter such as, filter candle, membrane filter. K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: 5. Filling the preparation in final container: The filling operation is carried out under strict aseptic precautions. 6. Sealing the container: Sealing should be done immediate after filling in aseptic environment. 7. Sterilization: For thermostable substances the parenteral products are sterilized by autoclaving method at different temp. & pressure. 10 lb pressure (115.5 0 C, or 240 0 F) for 30 minutes 15 lb pressure (121.5 0 C, or 250 0 F ) for 20 minutes 20 lb pressure (126.5 0 C, or 260 0 F) for 15 minutes Heat sensitive or moisture sensitive material are sterilized by exposure to ethylene oxide or propylene oxide gas . 8. Evaluation of the parenteral preparation: The following tests are performed in order to maintain quality control: 1. Sterility test 2. Clarity test 3. Leakage test 4. Pyrogen test 5. Assay 9. Labeling & packaging K.I.P.M. GIDA, GORAKHPUR, U.P. Evaluation of Parenteral products: Evaluation of Parenteral products Sterility testing Particulate matter monitoring Faculty seal packaging or leakage test Pyrogen testing LAL test Assay or drug content uniformity K.I.P.M. GIDA, GORAKHPUR, U.P. Sterility testing: Sterility testing DEFINITION: Sterility Testing: It is a procedure carried out to detect and conform absence of any viable form of microbes in or on pharmacopeia preparation or product. PRINCIPLE : Sterility testing only shows that organisms capable of growing in selected conditions are absent from the fraction of batch that has been tested. If the microorganism are present in the product can be indicated by a turbidity in the clear medium. OBJECTIVE OF STERILITY TESTING: For validation of sterilization process. To check presence of microorganisms in preparation which are sterile. To prevent issue of contaminated product in market. K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: STEPS INVOLVED IN STERILITY TE TESTING Sampling Selection of the quantity of the product to be used Method of sterility testing i ) METHOD 1 Membrane filtration method ii) METHOD 2 Direct inoculation method Observation and interpretation Must be carried out under aseptic condition . K.I.P.M. GIDA, GORAKHPUR, U.P. Sampling: Sampling The sample must be representative of the whole of the bulk material & a lot of final containers. MAINLY FOLLOWED BY TWO RULES: A fixed percentage of the final container are selected. A fixed number of container are taken independent of the lot or batch size. According to Indian Pharmacopoeia following guidelines for determining the minimum number of items are: K.I.P.M. GIDA, GORAKHPUR, U.P. Selection of the quantity of the product to be used: Selection of the quantity of the product to be used Selection of the quantity of the product to be used for sterility testing depends mainly on the volume or weight in the container. K.I.P.M. GIDA, GORAKHPUR, U.P. Method of sterility testing : Method of sterility testing Membrane filtration method (METHOD 1): Membrane filtration Appropriate for : (advantage) Filterable aqueous preparations Alcoholic preparations Oily preparations Preparations miscible with or soluble in aqueous or oily (solvents with no antimicrobial effect) All steps of this procedure are performed aseptically in a Class 100 Laminar Flow Hood K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Membrane filter 0.45 μ porosity Filter the test solution After filtration remove the filter Cut the filter in to two halves First halves (For Bacteria) Second halves (For Fungi) Transfer in 100 ml culture media (Fluid Thioglycollate medium) Incubate at 30-35 0 C for not less then 7 days Transfer in 100 ml culture media (Soyabeans-Casein Digest medium) Incubate at 20-25 0 C for not less then 7 days Observe the growth in the media Observe the growth in the media K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Suitable for samples with small volumes volume of the product is not more than 10% of the volume of the medium suitable method for aqueous solutions, oily liquids, ointments an creams Direct inoculation of the culture medium suitable quantity of the preparation to be examined is transferred directly into the appropriate culture medium & incubate for not less than 14 days. Direct inoculation method (METHOD 2): K.I.P.M. GIDA, GORAKHPUR, U.P. Observation and results: Observation and results Culture media is examined during and after at the end of incubation. The following observations are possible: No evidence of growth Pass the test for sterility . There is evidence of growth Re-testing is performed same no. of sample, volume & media as in original test No evidence of growth Pass the test for sterility. There is evidence of growth isolate & identify the organism . Re-testing is performed with twice no. of sample if: No evidence of growth Pass the test for sterility. There is evidence of growth Fail the test for sterility K.I.P.M. GIDA, GORAKHPUR, U.P. Particulate matter monitoring: Particulate matter monitoring Particulate matter is defined as unwanted mobile insoluble matter other than gas bubble present in the product. If the particle size of foreign matter is larger than the size of R.B.C.. It can block the blood vessel. The permit limits of particulate matter as per I.P. are follows: Source of particulate matter: Intrinsic contamination: The material which are originally present in the parenteral solution e.g. Barium ions leach in parenteral & react with sulphur ions in the product to form barium sulphate crystals. Extrinsic contamination: The material which comes from the environment e.g. Shedding of material from cloth, body, & cotton, paper, rubber, tissue etc. K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Methods for monitoring particulate matter contamination: Visual method Coulter counter method Filtration method Light blockage method Identification of particulate matter: Microscopy X-ray powder diffraction Mass spectroscopy Polarized light spectroscopy Scanning electron microscopy (SEM) K.I.P.M. GIDA, GORAKHPUR, U.P. Faculty seal packaging / leaking testing: Faculty seal packaging / leaking testing The sealed ampoules are subjected to small cracks which occur due to rapid temperature changes or due to mechanical shocks. Vials & bottles are not suitable for this test because the sealing material used is not rigid. Filled & sealed ampoules Dipped in 1% Methylene blue solution Under negative pressure in vacuum chamber Vacuum released colored solution enter into the ampoule Defective sealing K.I.P.M. GIDA, GORAKHPUR, U.P. Pyrogen Testing: Pyrogen Testing Pyrogen = “Pyro” (Greek = Fire ) + “gen” (Greek = beginning ). Fever producing , metabolic by-products of microbial growth and death. Bacterial pyrogens are called “Endotoxins”. Gram negative bacteria produce more potent endotoxins than gram + bacteria and fungi. Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in cell-free bacterial filtrates Stable to at least 175 o C ; steam sterilization ineffective Water soluble; monomer unit of LPS can be 10,000 Daltons (1.8 nm) so endotoxins can easily pass through 0.22μm filters Sources: Water (main), raw materials, equipment, process environment, people, and protein expression systems if using gram negative bacteria. K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Biological properties of endotoxin Pyrogen elevate the circulatory levels of inflammatory cytokines which may be followed by fever, blood coagulation, hypotension Low doses of Pyrogen: asymptomatic inflammation reaction Moderate doses: fever & changes in plasma composition High doses: cardiovascular dysfunction, vasodilation, vasoconstriction, endothelium dysfunction, multiple organ failure & finally death. Sources of pyrogen Equipment Containers (Glass , plastic , metal) Solvent Solute K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Elimination of pyrogens Dry heat sterilization : For glass wares, metal equipments, powders, waxes, oils, heat stable drugs 650 o C temp - 1 min 250 o C temp - 30 min 180 o C temp - 240 min Ultra filtration Reverse osmosis : RO membrane is composed of cellulose acetate phthalate/ polyamide Distillation Ads orption method K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Principal: Rabbits are used to perform this test because their body temp increases when pyrogen are introduced into their bodies by parenteral route 3 healthy adult rabbits of either sex, each weighing NLT 1.5 kg are selected Do not use any rabbit having a temp higher than 39.8 o C Showing temp variation >0.2 o C between two successive reading in the determination of initial temp Sham test is performed within 7 days of actual test Animal showing temp increase over 0.6 o C should be removed from pyrogen testing K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Method : Dissolve the subs being examined in, or dilute it with a pyrogen free saline solution Warm the liquid being examined to approx. 38.5 o C temp before injection The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body weight Withhold water during test Clinical thermometer is inserted into the rectum of rabbit to record body temp 2 normal reading of rectal temp are should be taken prior to the test injection at an interval of half an hr & its mean is calculated- initial temp The solution under test is injected through an ear vein Record the temp of each rabbit in an interval of 30 min for 3 hrs The difference between initial temp & maximum temp is recorded- taken as response K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Interpretation of results K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Bacterial endotoxin (LAL) test ) To detect or quantify endotoxins of gram- ve bacterial origin Reagent: amoebocyte lysate from horseshoe crab (Limulus polyphemus or Tachypleus tridentatus). The name of the test is also Limulus amebocyte lysate ( LAL ) test Mechanism of LAL Test: The test is based on the primitive blood-clotting mechanism of the horseshoe crab enzymes located with the crab's amebocyte blood cells endotoxin Initiation of an enzymatic coagulation cascade proteinaceous gel K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Test performance (short) Avoid endotoxin contamination Before the test: interfering factors should not be present equipment should be depyrogenated the sensitivity of the lysate should be known Test: equal Volume of LAL reagent and test solution (usually 0.1 ml of each) are mixed in a depyrogenated test-tube Incubation at 37°C, 1 hour remove the tube - invert at (180°) observe the result pass-fail test K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: LAL test Three different techniques: The gel-clot technique - gel formation The turbidimetric technique - the development of Turbidity after cleavage of an endogenous substrate The chromogenic technique - the development of color after cleavage of a synthetic peptide- chromogen complex Advantages of LAL test Fast - 60 minutes vs. 180 minutes Greater Sensitivity ,Less Variability Much Less False, Positives ,Much Less Expensive Alternative to Animal Model, cheaper, particularly useful for: Radiopharmaceuticals and cytotoxic agents Blood products Water for injection K.I.P.M. GIDA, GORAKHPUR, U.P. Production facilities of parenterals: Production facilities of parenterals The production area where the parenteral preparation are manufactured can be divided into five sections: Clean-up area Preparation area Aseptic area Quarantine area Finishing & packaging area K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Clean-up area: It is not aseptic area. All the parenteral products must be free from foreign particles & microorganism. Clean-up area should be withstand moisture, dust & detergent. This area should be kept clean so that contaminants may not be carried out into aseptic area. Preparation area: In this area the ingredients of the parenteral preparation are mixed & preparation is made for filling operation. It is not essentially aseptic area but strict precautions are required to prevent any contamination from outside. K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Aseptic area: The parenteral preparations are filtered, filled into final container & sealed should be in aseptic area. The entry of personnel into aseptic area should be limited & through an air lock . Ceiling, wall & floor of that area should be sealed & painted. The air in the aseptic area should be free from fibers, dust and microorganism. The High efficiency particulate air filters (HEPA) is used for air. UV lamps are fitted in order to maintain sterility. K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Quarantine area: After filling, sealing & sterilization the parenteral product are held up in quarantine area. Randomly samples were kept foe evaluation. The batch or product pass the evaluation tests are transfer in to finishing or packaging area. Finishing & packaging area: Parenteral products are properly labelled and packed. Properly packing is essential to provide protection against physical damage. The labelled container should be packed in cardboard or plastic container. Ampoules should be packed in partitioned boxes K.I.P.M. GIDA, GORAKHPUR, U.P. Lyophilization or freeze drying: Lyophilization or freeze drying Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes; Freezing, Primary drying (sublimation), and Secondary drying (desorption). K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: The advantages of Lyophilization include: Ease of processing a liquid, which simplifies aseptic handling Enhanced stability of a dry powder Removal of water without excessive heating of the product Enhanced product stability in a dry state Rapid and easy dissolution of reconstituted product Disadvantages of Lyophilization include: Increased handling and processing time Need for sterile diluent upon reconstitution Cost and complexity of equipment K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: The Lyophilization process generally includes the following steps: Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI). Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive filter. Filling into individual sterile containers and partially stoppering the containers under aseptic conditions. Transporting the partially stoppered containers to the lyophilizer and loading into the chamber under aseptic conditions. Freezing the solution by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or pre-freezing in another chamber. Applying a vacuum to the chamber and heating the shelves in order to evaporate the water from the frozen state. Complete stoppering of the vials usually by hydraulic or screw rod stoppering mechanisms installed in the lyophilizers . K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: There are many new parenteral products, including anti- infectives , biotechnology derived products, and in-vitro diagnostics which are manufactured as lyophilized products. Additionally, inspections have disclosed potency, sterility and stability problems associated with the manufacture and control of lyophilized products. K.I.P.M. GIDA, GORAKHPUR, U.P. PowerPoint Presentation: Thank you for listening me……… K.I.P.M. GIDA, GORAKHPUR, U.P.