Sterile Products PDF

1 Sterile Products Dr Laxmi Kerai-Varsani Learning outcomes 2 Discuss the types and critical components of sterile products. Discuss the role of osmotic pressure, vehicles, pH and preservation on formul...

1 Sterile Products Dr Laxmi Kerai-Varsani Learning outcomes 2 Discuss the types and critical components of sterile products. Discuss the role of osmotic pressure, vehicles, pH and preservation on formulation of sterile products. Understand the role of packaging materials for sterile products. Sterile products 3 Liquid ▪ Aqueous solutions ▪ Non-aqueous solutions ▪ Co-solvents ▪ Suspensions ▪ Emulsions Dry powder for reconstitution Semisolid ▪ Ointments ▪ Gels Product types 4 Small volume injectable (SVI) ▪ A product that is packaged in containers labelled as containing 100 mL or less Large volume injectable (LVI) ▪ More than 100 mL Small volume injectables 5 Packed in vials, ampoules, syringes, cartridges, bottles, or any other containers. Terminally sterilized or aseptically filtrated and processed. 80% or greater of all SVIs commercially available are prepared by aseptic processing. Relatively simple - composed of the active ingredient, a solvent system (preferably aqueous) and a minimal number of excipients present. Small-volume injections may be injected by ▪ IV, SC, IM (primary routes of parenteral administration) or ▪ Secondary routes such as intra-abdominal, intra-arterial, intracardiac, intrathecal. Large volume injectables 6 More than 100 mL Terminally sterilized LVIs usually involve intravenous infusion, dialysis, or irrigation fluids containing electrolytes, sugar, amino acids, blood, blood products, and fatty lipid emulsions. LVIs must be administered by intravenous administration. Components of sterile products 7 Drug Solvent Solubiliser Preservative Anti-oxidant Buffer Tonicity adjuster Diluent Critical attributes of injectable products 8 Osmotic pressure Vehicle pH Preservation Packaging Sterility test including test for Pyrogens Test for sub-visible particles Osmotic pressure/ tonicity of solution 9 Hypotonic solution: lower osmotic pressure than that of a body fluid. These solutions lead to swelling and bursting of RBCs, which in turn leads to haemolysis. Isotonic solution: same osmotic pressure as a body fluid. Ophthalmic, nasal, and parenteral solutions should be isotonic. Hypertonic solution: higher osmotic pressure than that of a body fluid. These solutions lead to shrinkage of the RBCs. Osmotic pressure 10 Colligative property ▪ Solely depend on numbers and independent of size or weight of particles. For non-dissociating solute, the osmotic pressure is directly proportional to its molality, i.e. number of moles of solute per kg of the solvent. Osmolarity and osmolality 11 Osmolarity Osmolality A theoretical quantity expressed in osmoles For a non-dissociating solute, it is equal to per L. molality of an ideal solution. Widely used in clinical practice because it Expressed as osmoles per kg of solvent expresses osmoles as a function of volume. (Osmol/kg, mOsmol/kg). Can’t be measured but is calculated from the A measure of the osmotic pressure exerted by a experimentally measured value of osmolality. solution across semipermeable membrane. Adult: 285-295 mOsm/L, Children: 275-290 Measured by properties of solution dependent mOsm/L. on number of particles such as freezing point depression. Colligative Properties Changes per mole of the solute per kg of the solvent Boiling Point Boiling Point Elevation 0.52°C EFFECT Freezing Point Freezing Point Depression 1.86°C Osmotic Pressure Osmotic Pressure Elevation 17,000 mm Hg Vapor Pressure Vapor Pressure Depression 0.3 mm Hg Method to adjust tonicity 12 The freezing point depression method is primarily used to calculate the amount of additional substance to be added to a hypotonic drug solution to render it isotonic. Isotonicity calculations using freezing point 13 depression method Refer to Parenteral Routes of Administration Lecture. The required amount of adjusting substance needed to make a hypotonic solution isotonic is given by the equation: 0.52 − 𝑎 𝑊= 𝑏 where W is the weight/volume percentage of adjusting substance in the final solution, a is the freezing point depression of unadjusted solution (i.e., freezing point depression of 1 % solution × strength in weight/volume percentage) and b is the freezing point depression of water due to 1 %w/v of adjusting substance, usually sodium chloride or glucose. Isotonicity calculations using freezing point 14 depression method 1. Calculate the amount of anhydrous glucose that should be added to make a solution containing 1.0 %w/v potassium chloride isotonic. 1.0 %w/v solution of potassium chloride depresses freezing point by 0.439˚C and 1.0 %w/v solution of anhydrous glucose depresses the freezing point by 0.101˚C. 0.52−0.439 𝑊= = 𝟎. 𝟖𝟎 %w/v 0.101 Equivalent to 0.80 g of anhydrous glucose per 100 mL to make the potassium chloride solution isotonic with plasma Isotonicity calculations using freezing point 15 depression method 2. Calculate the amount of sodium chloride that should be added to make a solution containing 1.5 %w/v lidocaine hydrochloride isotonic. 1.0 %w/v solution of lidocaine depresses freezing point by 0.338˚C and 1.0 %w/v solution of sodium chloride depresses the freezing point by 0.576˚C. 1% solution of lidocaine hydrochloride depresses the freezing point of water by 0.338 °C. Therefore, the freezing point depression of unadjusted solution = 1.5 × 0.338 = 0.507 °C. (a) 1% solution of sodium chloride depresses the freezing point of water by 0.576 °C. (b) 0.52−0.507 𝑊= = 𝟎. 𝟎𝟐 %w/v 0.576 Equivalent to 0.02 g of sodium chloride per 100 mL to make the lidocaine hydrochloride solution isotonic Isotonicity calculations using freezing point 16 depression method 3. You are approached by a doctor who wants to investigate the application of intrathecal acetylcysteine 1 %w/v for a clinical trial that he is considering running. He asks how you might formulate a 10 mL syringe. From your research, you find that the freezing-point depression of cerebrospinal fluid is 0.5770°C and that the freezing point depression value of a 1 %w/v acetylcysteine solution is 0.1135°C. You also find that you will need to add sodium chloride to the formulation to make it isotonic and that the freezing point depression value of a 1 %w/v sodium chloride solution is 0.5760°C. What mass of sodium chloride must be added to make the final product isotonic? 0.5770−0.1135 𝑊= = 0.8047 %w/v 0.5760 Equivalent to 0.8047 g of sodium chloride per 100 mL 0.08047 g of sodium chloride per 10 mL 80.47 mg of sodium chloride Isotonicity calculations using freezing point 17 depression method 4. The research division of your pharmaceutical company has synthesised a new drug. Studies suggest that 20 mg of the drug may be an appropriate dose for use in humans. For the purposes of clinical trial, you are requested to produce three hundred 1 mL ampoules, each containing 20 mg of the drug. Give the formula to prepare sufficient solution (i.e., 300 mL + 10% extra) to produce three hundred 1 mL ampoules, each containing 20 mg of drug, and made isotonic with sodium chloride. The freezing point depression of a 1 %w/v solution of drug is 0.255°C and of a 1 %w/v solution of sodium chloride is 0.576°C. The solution is made using Water for Injections BP as a vehicle. Need to give formula to produce 330 mL Drug 20 mg/ 1 mL = 2.0 %w/v Drug required for 330 mL = 6.6 g The required amount of adjusting substance required to make a hypotonic solution isotonic is given by the equation: 𝑊 = (0.52−𝑎)/𝑏 1% solution of drug depresses the freezing point of water by 0.255°C. Therefore, the freezing point depression of unadjusted solution = 2.0 × 0.255 = 0.51°C (a) 1% solution of NaCl depresses the freezing point of water by 0.576°C (b) 𝑊 = (0.52−0.51)/0.576 = 0.01736 %w/v NaCl required for 330 mL = 0.057 g Water for Injections BP to 330 mL Isotonicity calculations using freezing point 18 depression method 5. You would like to prepare 30 mL of eye drops containing 1 %w/v of pilocarpine and 2 %w/v procaine. How many mL of 0.9 %w/v sodium chloride should be used to make the above eye drops isotonic? 1% solution of pilocarpine depresses freezing point by 0.14˚C, 1% solution of procaine depresses freezing point by 0.11˚C and 1% solution of sodium chloride depresses freezing point by 0.576˚C. 1% solution of pilocarpine depresses the freezing point of water by 0.14°C, and 2% solution of procaine depresses the freezing point by 2 x 0.11 = 0.22°C. Freezing point depression of unadjusted solution = 0.14 + 0.22 = 0.36°C (a) 1% solution of sodium chloride depresses the freezing point of water by 0.576°C. (b) 0.52−0.36 𝑊= = 0.28 %w/v Equivalent to 0.28 g of sodium chloride per 100 mL 0.576 0.084 g of sodium chloride per 30 mL We have 0.9 %w/v sodium chloride solution = 0.9 g per 100 mL. We need 0.084 g. Therefore, we need 0.084/0.9 *100 = 9.33 mL of 0.9 %w/v sodium chloride.  19 Break time herts.ac.uk Critical attributes of injectable products 20 Osmotic pressure Vehicle pH Preservation Packaging Sterility test including test for Pyrogens Test for sub-visible particles Vehicle/solvent system: aqueous 21 Water for injection (WFI) USP/BP mostly used at industrial scale while sterile WFI used mainly in hospitals. Benzyl alcohol is a common antimicrobial preservative used in bacteriostatic water for injection. Type Preparation Pyrogen-free Usage Purified water USP Distillation or Ion No Pharmaceutical Solvent Exchange Water for injection (WFI) Distillation or reverse Yes* Non-sterile. Must be used within 24 h or stored at USP osmosis 80°C Sterile water for injection Distillation or reverse Yes* Same as WFI. Single-dose containers; USP osmosis reconstitution fluid for sterile powder or as a diluent for sterile solutions Bacteriostatic water for Distillation or reverse Yes* Multiple and single dose application injection USP osmosis Sterile water for irrigation Distillation or reverse Yes* 1L or larger, exempted from particulate matter USP osmosis requirement for LVI; Labelled “For Irrigation Only” * ≤ 0.25 endotoxin units per mL; EP only permits distillation as the process for producing WFI. Vehicles/solvent system: non-aqueous 22 Several SVIs also marketed as oily solutions. The oil must be of vegetable origin because of safety, purity and biocompatibility considerations. Oils for injection must meet USP requirements: ▪ Solid paraffin test (measurement of oil clarity) ▪ Saponification value: 185-200 ▪ Iodine value: 79-128 ▪ Test for unsaponifiable matter and free fatty acids. Oily solutions are prepared by separately sterilizing the solvent and the drug and then combining the solvent and drug aseptically. Terminal sterilization cannot be used for oily solutions due to lack of moisture in the product. Vehicles/solvent system: solubilizers 23 Increase the solubility of the poorly soluble drug. Minimize or even prevent drug chemical degradation by hydrolysis. Terminally sterilized using saturated steam under pressure or aseptically processed. Potential to cause lysis of red blood cells when administered intravenously. Examples of solubilizers: Liquid co-solvents: ▪ Glycerin, polyethylene glycol (300, 400, 3350), propylene alcohol, ethanol, Cremophor EL, sorbitol. Surface active agents: ▪ Polysorbate 80, polysorbate 20, Pluronic 68, lecithin. Complexing agents: ▪ β-Cyclodextrins, polyvinylpyrrolidone, carboxymethylcellulose sodium. pH control: buffers 24 The solubility of the drug in the vehicle over the shelf-life of the preparation needs to be maintained so precipitation can be prevented. Precipitation of drug and/or excipients may lead to a blockage within the capillaries. Maintaining the pH of the formulation within the range of optimum chemical stability of the therapeutic agent enhances the chemical stability of the therapeutic agent. Preservation 25 To maintain the sterility of the product during its shelf life and use. Required for multiple dosing products from the same container. The combination of antimicrobial preservative agents and adjunctive heat treatment is also used to increase assurance of sterility for products that cannot be terminally sterilized. Irritating at relatively low concentrations and usually have stability limitations. Highly toxic even at low concentrations, easily oxidizable, and their volatility can cause problems with rubber closure permeation. Examples of preservatives in SVI 26 Anti-oxidants 27 Antioxidants function by reacting preferentially with molecular oxygen and minimizing or terminating the free radical auto-oxidation reaction. Example: sodium bisulphite ▪ Oxidation-reduction potential lies in the range at which it does not preferentially oxidize too slowly or too rapidly. Other sulphurous acid salts also effective ▪ Ascorbic acid and sodium ascorbate. Combinations of antioxidants with chelating agent strengthen oxidative drug protection ▪ Most common chelating agent used in parenterals is disodium ethylenediamine tetra acetic acid (Disodium EDTA). Examples of anti-oxidants 28 Solids 29 SVIs are available as sterile dry solids. Reconstituted with a diluent, usually sterile water for injection before administration. Sterile dry SVIs are prepared using two primary methods: ▪ Freeze drying (lyophilization) ▪ Powder-filled SVIs Solids: freeze drying 30 Freeze drying: Product is aseptically filtered and filled as solution. Special slotted rubber closures are inserted partially onto the vials, which are then transferred to a freeze dryer. Freeze drying involves three primary operations: Freezing the Primary drying Secondary product drying Below eutectic temperature (for Solute bound water Frozen solvent is crystalline materials) is removed to an sublimed, a phase or glass transition acceptable product transition from a solid temperature (for moisture level for directly to a gas amorphous long-term stability. materials) Solids: freeze drying 31 On completion of the freeze-dry cycle, the partially inserted rubber closures are fully seated in the vials. The finished product contains a white or off-white sterile dry powder. Freeze-dried formulations usually contain bulking agents (e.g. mannitol). Other excipients are also added to aid in product chemical and/or physical stabilisation. Most freeze-dried vials are stable for at least 2 years at ambient conditions. Once the freeze-dried product is reconstituted, the normal shelf-life storage conditions are 24 - 72 hours. Solid: powder filled SVI 32 Sterile crystallisation Many SVI antibiotics, particularly the injectable cephalosporins, are manufactured by sterile crystallisation of the active ingredient followed by aseptically filling the sterile powder into the final container. Slurry is collected The drug is on a filter system dissolved in an (e.g., the appropriate Buchner funnel) solvent, then Crystallisation followed by filtered through a drying, milling 0.2 µm and blending membrane filter. process. Addition of sterile Critical factors: seed crystals and/or temperature, rate of adjusting the pH addition of solvent, level. adjustment of pH Addition of a sterile level, mixing rate and anti-solvent. time, and the quality of the seed crystals. Packaging 33 An integral part of the parenteral product. Provides long-term protection and maintains physical and chemical stability. As a drug delivery tool ▪ Convenient delivery of the drug product (e.g. syringes, dual chamber vials) ▪ Offer a better control of drug dosing (e.g. cartridges). A major source of particulate contamination ▪ Physical and chemical degradation of the products. Packaging constituents can leach into the product or the product can be adsorbed or absorbed. The primary types of packaging systems are glass, rubber and plastic. Packaging 34 0.5 to 1000 mL in size. Single dose container size max 1000 mL ▪ Opened aseptically and should be used once. Multi dose container size max 30 mL ▪ To reduce number of punctures for total withdrawal of doses ▪ Increased risk of contamination ▪ Antimicrobial preservative must be included and tested for antimicrobial preservative efficacy. Single dose disposable container provides greater sterility assurance and ultimately patient safety. Glass 35 Glass used for parenteral products is classified as type I, type II, and type III. Type I is the highest quality grade, composed almost exclusively of borosilicate (silicon dioxide and boric oxide), making it chemically resistant to extreme acidic and alkaline conditions. ▪ Type I glass is preferred for most parenteral products. ▪ Usually surface treated with agents such as ammonium sulfate or silica dioxide to remove surface leachates. Type II glass is made of soda-lime treated glass treated with sodium sulphite to neutralize surface alkaline oxides. ▪ Type II glass generally used for large-volume injectables and for small-volume products if the solution pH level is less than 7.0. Type III glass is untreated soda-lime glass. Type III glass can only be used for oily solutions and dry powders. Glass 36 Glass leachates ▪ Can affect solution pH ▪ Cause precipitation problems if the drug or other formulation components form insoluble salts The Glass Grains Test combined with the Surface Glass Test for hydrolytic resistance determines the glass type. Glass Grain test (refer to USP/BP for more detail) ▪ Distinguishes Type I borosilicate glass from Type II and III soda-lime glass Surface Glass test (refer to USP/BP for more detail) ▪ Determines hydrolytic resistance of inner surface ▪ Distinguishes between Type I and Type II containers with high hydrolytic resistance and Type III containers with moderate hydrolytic resistance. Rubber 37 Rubber as packaging components are used as rubber closures (vials, cartridges); rubber plungers (syringes, cartridges); and other applications (rubber septum in dual chamber vials, rubber septum for needle introduction in administration set tubing). Commonly used additives ▪ Plasticizers ▪ Fillers ▪ Vulcanizing agents ▪ Pigments ▪ Activators, accelerants, and antioxidants. Additives are sources of physical and chemical degradation problems in parenteral products. Rubber 38 Natural and butyl rubber - mostly used in SVI. Silicone and neoprene - used but less frequently. Butyl rubber has greater advantages compared to natural rubber ▪ It requires fewer additives ▪ Has low water vapour permeation properties ▪ Good characteristics with respect to gaseous (e.g. oxygen) permeation and low reactivity with the active ingredient. Rubber 39 Problems with rubber materials include ▪ Leaching of constituents into the product, ▪ Adsorption of active ingredients or antimicrobial preservatives, ▪ Coring of the rubber by repeated insertion of a needle. Siliconization of rubber closure ▪ A common practice in manufacturing to facilitate movement of the closure through stainless steel equipment on the filling lines. ▪ Silicone is incompatible with hydrophobic drugs. ▪ Excessive silicone on rubber can potentiate protein aggregation and cause precipitation problems with certain hydrophobic drugs. Plastic 40 Plastic bottles for LVIs have been used for many years. Offers cost savings, elimination of the problems caused by breakage of glass, and is more convenient to use. Can interact with the product causing physical and chemical stability problems. Less complicated than rubber formulations and tend to have a lower potential for leachability of its constituents. However, plasticizer leachates are well known with polymers such as polyvinyl chloride (PVC) containers used for LVI bags and administration devices. For other SVIs, polyolefin formulations are widely used as well as polyvinyl chloride, polypropylene, polyamide (nylon), polycarbonate, and copolymers such as ethylene vinyl acetate. Comparative compatibility properties of container 41 materials Leaching Permeation Adsorption (selective) Extenta Potential leachables Extenta Potential agents Extenta Glass Borosilicate 1 Alkaline earth and heavy metal oxides 0 N/A 2 Soda-lime 5 Alkaline earth and heavy metal oxides 0 N/A 2 Plastic polymers Low density 2 Plasticizers, antioxidants 5 Gases, water vapor, other molecules 2 High density 1 Antioxidants 3 Gases, water vapor, other molecules 2 PVC 4 HCl, especially plasticizers, antioxidants, 5 Gases, especially water vapor and other molecules 2 other stabilizers Polyolefins 2 Antioxidants 2 Gases, water vapor 2 Polypropylene 2 Antioxidants, lubricants 4 Gases, water vapor 1 Rubber polymers Natural and related 5 Heavy metal salts, lubricants, reducing 3 Gases, water vapor 3 synthetic agents Butyl 3 Heavy metal salts, lubricants, reducing 1 Gases, water vapor 2 agents Silicone 2 Minimal 5 Gases, water vapor 1 a. Approximate scale of 1 to 5, with 1 as the lowest. Does getting the correct parenteral administration site 42 matter? https://www.youtube.com/watch?v=oNCObzqSMa0 Please look at the National Patient Safety Agency (NPSA) Rapid Response Report for Using Vinca Alkaloid Minibags!! Recommended reading 43 Michael J. Akers, Drug Delivery-Parenteral route, Encyclopaedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100000368 Current British Pharmacopoeia Current United State Pharmacopoeia  44 Thank you herts.ac.uk