Sterile Pharmaceutical Products

Transcription

1 Sterile Pharmaceutical Products Hugo and Russell s Pharmaceutical Microbiology, 8 th Edition Chapter 22, Page Injections: May be aqueous solution, oily solution (due to poor solubility or for prolonged drug release), aqueous suspension or oily suspension. These are either aseptically produced or terminally sterilized in their final containers. Single dose injection is mandatory for some routes like spinal cord (e.g. intrathecal) and for large volume infusions. Multiple dose injections require the addition of preservative Unstable drugs may be presented as freeze dried (lyophilized) powder to be reconstituted just befor adminstration 1

2 1.1. IV infusions: Large-volume (500 ml or more) injections or drips Generally sterilized by autoclaving Examples: Isotonic soln of NaCl or glucose Plasma substituents e.g. degraded gelatin & dextrans Blood products which are collected & processed in sterile containers Total parenteral nutrition (TPN) fluids are example on large-volume IV infusions but are usually aseptically compounded 1.2. Small volume injections: Usually single-dose injections of 1-2 ml (but can be as high as 50 ml) or, rarely, multiple-dose vials of 5-25 ml Preservatives are added to multiple-dose injections Preservatives (bactericides) may not be used in injections if the total volume to be injected at one time exceeds 15 ml Also it is absolutely prohibited to include preservatives in injections of intra-arterial, intracardiac, intrathecal, subarachnoid, intracisternal & epidural injections and various ophthalmic injections (e.g. intravitreal ) because of potential long term damage to the patient Oily injections: the product is sterilized by dry heat, (preservative is practically ineffective in these!) 2

3 1.3. Freeze-dried products: Freeze drying (lyophilization): is an aseptic technique, consists of preparing the drug solution with buffers & cryoprotectants, filtering through a bacteria-proof filter, dispensing into containers, removing water in a freeze drier, then capping & closing the containers Water is removed by sublimation (conversion of ice directly to vapour state). The process consists of 3 steps: freezing, primary drying by applying vacuum to remove moisture at subambient temp, then secondary drying by heating the product to remove last traces of water Lyophilization is used for drugs with poor stability. Drugs are reconstituted into solution immediately prior to injection 1.4. Blow-fill technology: Is an aseptic process whereby the container is formed from thermoplastic granules, filled with sterile solution & sealed, all within one automatic operation The plastic granules are heat-extruded at 200 C into a tube, the two halves of the mould close around the tube & seal the base, the required quantity of sterile fluid is filled into the container which is sealed. e.g. IV solutions, small volume parenteral, ophthalmic & nebulizer solutions. The cost is lower than conventional packaging 3

4 1.5. Quality control of injections: Sterility test: As discussed in the previous chapter Pyrogen test: Pyrogen is any substance that when injected into a mammal elicits a rise in body temp While some substances produced by G+ve bacteria, mycobacteria, fungi & viruses conform to this definition, the most common pyrogens & of major significance to pharmaceutical industry are produced by G-ve bacteria (i.e. endotoxins (LPS)) LPS are able to withstand temp at 120 C for over 3 hrs, extremes of ph are required for rapid destruction Sources of pyrogens in parenterals include water (for manufacturing, cleaning, etc), raw materials, packaging components and equipment 1.5. Quality control of injections: (cont d) Pyrogen test: (cont d) Rabbit test: Pyrogens are assessed using rabbits stored at controlled conditions whose temp is monitored before and after administering the test product Limitations of this test: Repeated use of the animals will lead to endotoxin tolerance Low reactivity to the endotoxin produced by certain species e.g. legionella Many factors affect the repeatability of results: inter-laboratory factors, seasonal variation, rabbit species Radiopharmaceuticals & certain drugs may themselves elicit rise in temp. Not sensitive to detect low levels of endotoxins like that allowed in intrathecal products 4

5 1.5. Quality control of injections: (cont d) Pyrogen test: (cont d) LAL test: Called Limulus amoebocyte lysate (LAL) test or gel clot method LAL test detects endotoxins of G-ve bacteria only & not all pyrogens so it can be used even for radiopharmaceuticals LAL reagent comes from blood of freshly captured horseshoe crab (Limulus polyphemus), whose amoebocytes are concentrated, lysed and used in the test Samples of the product are incubated with LAL reagent at 37 C and, if endotoxins are present, a solid gel is formed (can be checked by inverting the test tube or measuring the liquid opacity) 1.6. Depyrogenation: Pyrogens & endotoxins are difficult to remove from products so it is better to keep components free from them rather than to remove them from the final product. Rinsing or dilution with apyrogenic fluid, eliminates pyrogenic activity. Pyrogens in glass, equipment or vials can be destroyed by dry heat sterilization at 250 C for 45 min or 650 C for 1 min or 180 C for 4hrs. These processes equate incineration. The removal of pyrogens from water for injection (WFI) may be effected by distillation or reverse osmosis. Distillation is the most reliable method. WFI is circulated at C to prevent microbial growth & endotoxin production. Pyrogen-free water can be also produced by membrane ultrafiltration with nominal M.wt. limit that is below that of endotoxin 5

6 2. Non-injectable sterile fluids : Non-injectable sterile water: Used during surgical procedures for wound irrigation, moistening of tissues, washing of surgeons gloves & surgical instruments during use. Urological (bladder) irrigation solutions: Used for rinsing of urinary tract to aid tissue integrity & cleanliness during or after surgery. Peritoneal dialysis & haemodialysis solutions: Peritoneal dialysis soln are admitted into the peritoneal cavity as a means of removing accumulated waste or toxic products following renal failure or poisoning, these should be sterile Haemodialysis soln need not be sterile but must be free from heavy bacterial contamination. 3. Ophthalmic preparations: Since there is a very poor blood supply to the anterior chamber, defense against microbial invasion is minimal; also, it appears to provide a good environment for growth of bacteria, therefore, ophthalmic preparations should be sterile Presence of pyrogens in ophthalmic preparations is not clinically significant 3.1. Eye drops: They can be sterile multi-dose eye-dropper bottles or sterile singledose plastic sachets containing ml of liquid Eye-drops for use during open-eye surgery must not contain a preservative because of their cytotoxicity. Single-dose preparations are used in this case. Thermostable eye-drops and lotions are sterilized at 121 C for 15 minutes (autoclaving) For thermolabile drugs, filtration sterilization followed by aseptic filling into sterile containers. Eye-drops in plastic bottles are prepared aseptically. 6

7 3. Ophthalmic preparations: 3.2. Eye ointments: The base is filtered when molten to remove particles and sterilized at 160 C for 2 hours. The drug is incorporated prior to sterilization if heat stable, or added aseptically to the sterile base Contact lens solutions: Cleaning solutions These are responsible for the removal of ocular debris and protein deposits, and contain a cleaning agent that consists of a surfactant and/or an enzyme product. They contain a preservative Soaking solutions (storage) These are soln for disinfection of lenses but also maintain the lenses in a hydrated state. The antimicrobial agents used for disinfecting hard lenses are those used in eye drops (benzalkonium, chlorhexidine, phenylmercuric acetate or nitrate, thiomersal and chlorbutol). 7

8 Decision tree for non -aqueous liquid, semisolid or dry powder 4. Dressings Dressings and surgical materials are used both as a means of protecting and providing comfort for wounds and for many associated activities such as cleaning, swabbing, etc. They may or may not be used on areas of broken skin. Methods for their sterilization include autoclaving, dry heat, ethylene oxide and ionizing radiation. The choice is governed by the stability of the dressing constituents and the nature of their components. 5. Implants Implants are small, sterile cylinders of drug, inserted beneath the skin or into muscle tissue to provide slow absorption and prolonged action therapy. This is based on the fact that such drugs, e.g. hormones, are almost insoluble in water and yet the implant provides a rate of dissolution sufficient for a therapeutic effect. Implants are manufactured from the pure drug made into tablet form by compression or fusion. If heat stable sterilized by dry heat, or sterilized during fusion (melting at 5-10C above melting temp) & poured in moulds 8

9 6. Absorbable haemostats A soft pad of solid material (e.g: oxidized cellulose, gelatin foam, human fibrin foam) packed around and over the wound which can be left in situ, being absorbed by body tissues over a period of time, usually up to 6 weeks. The mechanism of action of these is the ability to encourage platelet fracture 7. Surgical ligatures and sutures The use of strands of material to tie off blood or other vessels (ligature) and to stitch wounds (suture) is an essential part of surgery. Both absorbable (e.g. strands of collagen derived from the intestine of the sheep) and non-absorbable materials (metal or organic material e.g. linen, nylon, silk, that do not react with tissues) are available for this purpose 8. Instruments & equipment The suitable method for sterilization of instruments depends on the nature of the components and the design of the item. There is a wide range of instruments that may be required in a sterile condition like syringes (glass and plastic disposable), needles, giving sets, metal surgical instruments (scalpels, scissors, forceps, etc.), rubber gloves, catheters, etc. Relatively complicated equipment, such as pressure transducers, pacemakers, kidney dialysis equipment, incubators and aerosol machine parts may also be sterilized. Also artificial joints should be sterile. The choice of method depends on the physical stability of the items and the appropriate technique in particular situations. E.g, incubators necessitate a chemical method of sterilization. On the other hand, even delicate instruments like pressure transducers are now available that can withstand Mahmoud Alkawareek, autoclaving PhD 9

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