Sterility and Cleanliness in Drug Formulation - Essay Example

The Implication of Sterility and Cleanliness in Drug Formulation It seems common sense to say that when drugs are prepared, prescribed and taken, they must be of the highest standards possible. This includes being of an agreed and consistent formulation , but also that it be clean, and sterile where this is a necessity, as in when intravenous medications are concerned ( FDA, Summary of USP*797, 2003) . Sterility is an absolute term which means the absolute freedom from viable organisms ( Sanghavi, slide 2, 2011). The fact that using parenteral methods circumvents the body’s natural defence systems, such as the skin and mucus membrane makes it necessary that solutions used be sterile. The liquids used therefore need to be hermetically sealed. Intravenous Formulations and Their Use Preparations for injection intravenously can be aqueous or non-aqueous and usually consist of sterile solutions of salts essential to the body such as potassium, sugars such as dextrose, or suspensions of drugs in water or other physiological acceptable vehicles. Using this method has many advantages as the medications do not have to go through the digestive system, but go straight into the circulatory system. It is possible to select exact does and rates of absorption which can be administered quickly, even if the patient is unable to eat or drink, or to retain what is taken, if for instance they are nauseous, in a coma or undergoing general anaesthesia. There are however disadvantages at the bed side, in that skilled personnel are needed, needles and narrow blood vessels are involved, and in some people the blood vessels can be quite fragile, and others may find the whole idea of needles difficult. The Encyclopaedia of Pharmaceutical Technology (2007) says that the majority of problems involved are due to safety issues related to infection and thrombosis and the fact that particular techniques and equipment are needed, and of course this requires staff who can use such equipment and techniques. Manufacture Because these medications are going directly into the circulatory system, and so will be carried rapidly and without interruption to the various body organs, it is vital that they do not introduce bacteria and viruses into the body as this is likely to produce overwhelming infection and fatalities. It follows therefore that an aseptic environment is a necessity for manufacture, and this also requires skilled and experienced staff if the required asepsis is to be maintained throughout the factory process and then onwards to the point of use. Whatever type of solution is to be made it must be of the correct osmotic pressure. If the liquid is hypertonic the extra pressure would cause red blood cells to become compressed. If it were below pressure, hypotonic, then the red blood cells will swell and may burst. The pH value must be properly preserved and the fluid securely packaged and sterile, as well as being made up to the correct formulation. All of these must be maintained until use. In order to ensure that a solution is isotonic various compounds are added in the correct amounts to isotonic solutions under sterile conditions. These amounts are calculated either by taking into consideration its gram-molecular concentration, that is the number of moles of a solution contained within 100 grams of a solvent, or by allowing for the freezing point depression of each type of solution. The isotonic state is achieved when the gram molecular percentage concentration is 0.03%. Packaging of Intravenous Solutions The packaging chosen, most often plastic or glass, and should be suitable to provide protection and to retain its chemical and physical permanence. It should provide a convenient, controllable and safe method of delivery. In the long term however packaging can become a source of microscopic particulate contamination, and so to the degradation of the product, as these particles can leach into the solution contained and then can be absorbed. Glass packaging The glass used is of three types. Type one glass is relatively expensive. It is made up of silicon dioxide and is resistant to extreme acidic and alkaline conditions, and is therefore the preferred type of glass to use for parenteral medications. Even this high quality glass may require surface treatment to remove surface leachates. For this agents such as ammonium sulphate or silica dioxide are used. If Type 2 glass is used it requires treating with sodium sulphide or sodium sulphite in order to neutralise any alkaline oxides present on it surfaces. Type II glass is made of soda-lime glass but is treated with sodium sulphite or sulphide to neutralize surface alkaline oxides. It is often used for large volumes of injectable solutions and in other cases of smaller volumes it is used if the pH is 7.0 or lower. The third grade glass is used only to store dry powders or oily solutions. Plastic Containers As long ago as 1974 Cooper described how various types of plastic that could be used, and went on to describe possible problems. This was the time when compounds began to be dispensed in plastic rather than glass containers. He saw the advantages of plastic as being economic, but also those of functionality. They are lighter in weight than glass containers , and are of course less likely to be smashed. The summary of USP*797 ( FDA 2003) explains how risks of contamination vary according to whether sterile needles are used to transfer compounds, but also how many compounds are being combined at one time. Risk of contamination increases if mixing takes place over a very extended period, or if administration takes place over a period of several days, especially if the ambient temperature is between 25 and 40 degrees Celsius. Also if it is necessary to evacuate air when adding sterile drug products there can be increased risk. The plastics used can be very flexible or can be rigid, depending upon what is required. Problems include what to do with empty containers; as well as the possibility of permeation i.e. moisture gases and light which can cause changes within the contents. Cooper (page 12, 1974,) describes a number of plastics and how likely these are to be cause deterioration over time this would have to be extreme however before sterility is compromised. Compounding Personnel It is the responsibility of compounding personnel, both technicians and pharmacologists to make up and to dispense sterile forms of the exact medications described. This means that the solutions must be pure, free from any type of contaminant ( American Society of Health, 2014), which places high levels of responsibility upon staff, both as individuals and as a working team. It is known that having fluids which are not sterile can lead to patient fatality ( Sachs, 2011). There is an obvious need for staff to have appropriate training ; to be competent; to be regularly assessed, and to have particular responsibilities ( Sachs, page 90, 2011). They need to have in place several documents known as SOPs, that is Standard Operating Procedures, which set out in step by step instructions, the exact methods to be used when receiving , testing , including for the presence of pyrogens, compounding in correct and consistent formulations , storing, transporting and dispensing ingredients and medications. Staff need to be capable of carrying out such things as testing particulate matter using such methods as the Light Obscuration Particle Count Test or the Microscopic Particle Count test ( Patel, undated , slide 23). These methods and SOPS need to include such things as reporting adverse situations. They require regular reviewing as to their continued appropriateness, especially if new packaging or ingredients or methods were coming into use. Staff numbers must be as few as possible , and they must be in good health and should be aware of the need to report such things as sore throats or other possible sources of infection. They should wear uniforms which are easy to clean, such as that made of Dacron. They must wear hats and masks as needed and boots made from washable materials such as plastic or rubber. Facilities Sachs ( page 19, 2011) says that these should be cleaned and maintained and there should be systems in place to monitor procedures , and to test products. There should be safety rules covering such things as spills, accidental exposures and injuries, as well as rules about such things as storage and transport, and environmental monitoring. Administration and managements procedures also need to be decided upon. A quality assurance programme is very important, and should include action plans to correct any problems. Also important is the maintenance and calibration of any equipment, and sourcing materials from the most suitable sources. Patel ( undated) ) lists a number of ways in which preparations should be evaluated, including for sterility, pyrogen testing and the containment and closure of containers. These pyrogens, which can result in severe illness or even death in patients, are defined byPatel ( undated) as :- Pyrogens are very small, water-soluble, heat-resistant lipopolysaccharides that cannot be destroyed by typical steam-sterilization cycles or removed by 0.2-µm membrane filters. Prevention rather than elimination is the key for pyrogen removal. It follows that there must be controls upon staff, of documentation, of equipment and the facilities ( Sanghavi, slide 12, 2011) They can be removed by a process of distillation . Glass is sterilized by using dry heat at temperatures of 250°Cand above to destroy pyrogens). If rubber closures are used these can be steam sterilised, but this will not kill pyrogens. Instead closures are depyrogenated by cleaning and rinsing them using water which is pyrogen-free. Any chemical raw materials used in parenteral formulations require crystallization using suitable solvents or pyrogen-free water. Sterilisation is a complicated process as individual ingredients in a formula, the container and the closure all need to be sterilised before they are combined. The product cannot be sterilised once it is in its sealed container , which means that the combining of ingredients, the filling and final sealing must be carried out in a controlled environment of very high status. Sanghavi ( Slide 18, 2011) describes the environmental conditions required, including such things as space planning and the traffic flow of personnel and products. This covers such things as restricting access and having access to areas requiring high levels of cleanliness be done only by using such facilities as changing rooms ( Sanghavi Slide 26, 2011) He suggests (Sanghavi, Slide 20 , 2011) that a larger volume continuous operation is more advantageous than a smaller batch producing operation, but admits that this could make it more difficult to assure quality control . Sanghavi ( Slide 28 , 2011) goes on to describe necessary changes of air, the use of filters and the maintenance of maintaining higher air pressure where needed to minimise airborne contaminants entering from outside. Wall should be free from any cracks, epoxy paint is needed and counter surfaces should be made from easily cleaned stainless steel. Conclusion Giving medications parentally is quite commonplace in the 21st century, but this should not lead to complacency about sterility and patients safety. Training and vigilance is required at all times, as are procedures to ensure continued quality with regard to such things as contamination and its results. This will then lead on to successful and safe dispensing. References American Society of Health–System Pharmacists, 2014, ASHP Guidelines on Compounding Sterile Preparations , American Journal of Systematic Pharmacology 71 pp 145-66, [Online ] Available at [Accessed 15th March 2015] Cooper, J., 1974, Plastic Containers for Pharmaceuticals - Testing and Control, WHO, [Online] Available at FDA, Summary of USP*797, 2003, Pharmacopeial Form – Volume 29, Patel, V., undated, Evaluation of Injectable Preparations, Power Point, Department of Pharmacy, University of Hertfordshire. Sachs, G., 2011, Microbial contamination of parenteral contamination - How could it happen? Journal of Parenteral Enteral Nutrition, Volume 35 p 452 Sanghavi, S., 2011, Manufacturing Layout Equipment, Power point, Available at http://www.slideshare.net/swapnil_pharmacist/parenteral-preparation-equipments-and-layout [accessed 16th March 2015 ] The Encyclopaedia of Pharmaceutical Technology, 2007, cited in The History and Use of Parenterals, [Online] Available at http://intranet.tdmu.edu.ua/data/kafedra/internal/pharma_3/l [Accessed 16th March 2015] Read More

The pH value must be properly preserved and the fluid securely packaged and sterile, as well as being made up to the correct formulation. All of these must be maintained until use. In order to ensure that a solution is isotonic various compounds are added in the correct amounts to isotonic solutions under sterile conditions. These amounts are calculated either by taking into consideration its gram-molecular concentration, that is the number of moles of a solution contained within 100 grams of a solvent, or by allowing for the freezing point depression of each type of solution.

The isotonic state is achieved when the gram molecular percentage concentration is 0.03%. Packaging of Intravenous Solutions The packaging chosen, most often plastic or glass, and should be suitable to provide protection and to retain its chemical and physical permanence. It should provide a convenient, controllable and safe method of delivery. In the long term however packaging can become a source of microscopic particulate contamination, and so to the degradation of the product, as these particles can leach into the solution contained and then can be absorbed.

Glass packaging The glass used is of three types. Type one glass is relatively expensive. It is made up of silicon dioxide and is resistant to extreme acidic and alkaline conditions, and is therefore the preferred type of glass to use for parenteral medications. Even this high quality glass may require surface treatment to remove surface leachates. For this agents such as ammonium sulphate or silica dioxide are used. If Type 2 glass is used it requires treating with sodium sulphide or sodium sulphite in order to neutralise any alkaline oxides present on it surfaces.

Type II glass is made of soda-lime glass but is treated with sodium sulphite or sulphide to neutralize surface alkaline oxides. It is often used for large volumes of injectable solutions and in other cases of smaller volumes it is used if the pH is 7.0 or lower. The third grade glass is used only to store dry powders or oily solutions. Plastic Containers As long ago as 1974 Cooper described how various types of plastic that could be used, and went on to describe possible problems. This was the time when compounds began to be dispensed in plastic rather than glass containers.

He saw the advantages of plastic as being economic, but also those of functionality. They are lighter in weight than glass containers , and are of course less likely to be smashed. The summary of USP*797 ( FDA 2003) explains how risks of contamination vary according to whether sterile needles are used to transfer compounds, but also how many compounds are being combined at one time. Risk of contamination increases if mixing takes place over a very extended period, or if administration takes place over a period of several days, especially if the ambient temperature is between 25 and 40 degrees Celsius.

Also if it is necessary to evacuate air when adding sterile drug products there can be increased risk. The plastics used can be very flexible or can be rigid, depending upon what is required. Problems include what to do with empty containers; as well as the possibility of permeation i.e. moisture gases and light which can cause changes within the contents. Cooper (page 12, 1974,) describes a number of plastics and how likely these are to be cause deterioration over time this would have to be extreme however before sterility is compromised.

Compounding Personnel It is the responsibility of compounding personnel, both technicians and pharmacologists to make up and to dispense sterile forms of the exact medications described. This means that the solutions must be pure, free from any type of contaminant ( American Society of Health, 2014), which places high levels of responsibility upon staff, both as individuals and as a working team. It is known that having fluids which are not sterile can lead to patient fatality ( Sachs, 2011).

There is an obvious need for staff to have appropriate training ; to be competent; to be regularly assessed, and to have particular responsibilities ( Sachs, page 90, 2011).

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