3.2 Quality of Sterile Medicines PDF

Preview

Summary

Case 2 – Quality of Sterile MedicinesCase Study 1: Outbreak of fungal meningitis in patients who had received steroid injections (USA, 2012) , caused by  A failure to sterilise products for the minimum amount of time necessary to ensure sterility  Orders shipped before results of sterility tests w...

Description

Case 2 – Quality of Sterile Medicines Case Study 1: Outbreak of fungal meningitis in patients who had received steroid injections (USA, 2012), caused by  A failure to sterilise products for the minimum amount of time necessary to ensure sterility  Orders shipped before results of sterility tests were returned  Hazards were found in clean rooms  Environmental sampling routinely detected contamination in the air, and on surfaces of clean rooms, and the company ignored decontamination standards Case Study 2: Outbreak of septicaemia in babies who had received Total Parenteral Nutrition (England - UK, 2014), caused by  Bacillus cereus infection was the contamination of intravenous liquid products during a single day of production  MHRA saw it as an isolated incident, and subsequently, appropriate actions were taken immediately by the manufacturer to avoid a reoccurrence

Route of administration

Max TAMC Max TYMC CFU/gor ml CFU/gor ml

Specified microorganisms absent in 1 gor 1 ml

Non-aqueous oral products

103

102

Absence of E. coli

Aqueous oral products

102

101

Absence of E. coli

Rectal products

103

102

Oral mucosal, gingival, cutaneous, nasal and ear products

102

101

Absence of Staph. aureus and Ps. aeruginosa

Vaginal products

102

101

Absence of Staph. aureus, Ps. aeruginosa and Candida albicans

Inhalation products (excluding nebulized liquids)

102

101

Absence of Staph. aureus, Ps. aeruginosa and bile-tolerant Gramnegative bacteria

Parenteral route Any route of delivery that does not involve absorption from the intestine. A sterile preparation is essential if administration through one or more layers of the skin or mucous membrane will occur. These preparations must also be pyrogen-free (something that would create fever, such as endotoxins) and contain no particulates. Injectables are used where:  A drug is ineffective through other routes, e.g. insulin is a peptide, that is degraded by low pH in stomach, and peptidases  a local action is needed, e.g. anaesthetic at dentist’s surgery  a prolonged action is required Problems with injectables:  Once administered, it is difficult/impossible to remove from the body, so in the event of overdose or severe side effects, little can be done  It is more difficult & expensive to produce these products, due to need for sterility  Patient compliance (pain, discomfort, inconvenience)  More often than not, requires trained personnel to administer; infusions, cannulate can be done at home but a nurse is required for administration Small volume parenterals (SVPs)  1 – 50 mL  Not necessarily administered IV  Not necessarily isotonic  Not necessarily at physiological pH o Blood acts as buffer Hypertonicity is where water moves out of RBCs (reversible) Hypotonicity is where water moves into RBCs (irreversible)

Large volume parenterals (LVPs)  Up to 1000 mL  IV infusion over prolonged period  Isotonic, to avoid damaging blood vessels o 0.9% NaCl or 5% dextrose

Injectables 

Intradermal – skin ~0.1 ml into corium (the more vascular layer of the skin beneath the epidermis). The usual site is anterior forearm. o Substances injected tend to be for diagnostic determinations, desensitisation or immunisation, not delivery drugs.  Intra-articular - joints  Intrasynovial - joint fluid area  Intraspinal - spinal column  Intrathecal - spinal fluid  Intra-arterial - arteries  Intracardiac - heart o

Intravenous (IV) You would inject IV when a rapid drug action is required, such as in the case of anaphylaxis/allergic reaction or if the patient is uncooperative, unconscious or unable to tolerate oral medication; drugs, fluids, electrolytes and/or nutrients can be given. Most superficial veins are suitable for IV injection but veins of forearm preferred because they are large, superficial and easy to see and enter. Both small and large volumes can be administered IV. Large volume (1000 ml) infusion containers are administered via an in-dwelling catheter. Flow rate can be adjusted according to needs of patient and tend to range from 42 – 150 ml/hour. Generally infusions must be aqueous solutions and must not precipitate; such an event can lead to pulmonary microcapillary occlusion and blockage of blood flow. Therefore oily vehicles are NOT usually used. However, IV fat emulsions e.g. intralipid are used as source of calories & essential fatty acids for patients requiring parenteral nutrition for extended periods (> than 5 days). The main 3 types of IV products are parenteral nutrition (lipid emulsions, amino acid solutions, carbohydrates), monoclonal antibodies (cancer) and large molecular weight molecules (treatment/proph’ venous thromboembolism).

Types of IV administration IV bolus or IV push 1-2 mL is given over seconds to minutes. In hospitals, a patient can be cannulated, so the drug is put into a catheter. This means that the skin is injected into only once. Drug toxicity/irritation can occur if the drug is not diluted Intermittent infusion Drug is diluted in 25-100ml of fluid, and infused over 15-60 minutes, at spaced intervals (q6h); a larger volume of fluid is needed if a drug is less water soluble. Intermittent infusion is safer than bolus, but less convenient. A secondary IV line can be added, which ‘piggybacks’ into the bag of nutrients, which avoids a second venepuncture but the primary & secondary drug solutions must not precipitate. Continuous infusion Drug added to LVP (up to 1000 mL) and slowly and continuously infused. Fluid and drug are administered simultaneously. HCPs have excellent control over drug plasma levels over long period of time, so drug toxicity/irritancy are minimised, but this requires greater monitoring. Unstable drugs can’t be used because of long run-time and can’t use with poorly soluble drugs dissolved in water miscible solvents or hydro-alcoholic solutions. Fluid-restricted patients can’t be given a continuous infusion due to large vol. of fluid given.

Subcutaneous (SC) An injection of aqueous solution or aqueous suspension (≤2ml) through the skin into loose subcutaneous tissue. The drug enters capillaries via diffusion and/or filtration. The blood supply to an area is important; the closer a good blood supply is to the injection site, the more rapid the onset of action. More capillaries provide an increased surface area for absorption. Vasoconstrictors, such as adrenaline (epinephrine), will decrease absorption and removal from injection site. Lipid soluble substances permeate at rates that vary relative to oil-water partition coefficient. Lipid-insoluble substances permeate capillary membrane at rates inversely related to molecular size (Smaller  larger).

Intramuscular (IM) An aqueous, or oily, solution/suspension (2-5ml) is injected deep into skeletal muscles (in adults, gluteus maximus is used; in children, deltoid muscle (upper arm) or mid-lateral muscle (thigh) are used) as far from major blood vessels and nerves as possible. Injuries (can include paralysis, resulting from neural damage, abscess, cyst, embolism, haematoma, sloughing of skin and scarring) are generally related to the point at which needle inserted and where medication deposited. IM delivery is used if drug is irritant when injected SC.

Steroids When injected IM route, is a sustained release because there is a of lower rate of partition from oily vehicle into aqueous environment of tissue. Examples include progesterone (using sesame or peanut oil) and testosterone enantate – the ester form of testosterone (using sesame oil). This is a depot preparation given every 2-3 weeks, and requires esterases at the injection site to cleave active drug from ‘pro’ drug. The half-life of testosterone is 1&½ hours, so esters are added. This decreases water solubility, increases oil solubility, deactivates molecule so it can’t bind to androgen receptor. The Ester is cleaved/ hydrolysed in blood, which restores –OH so can attach to receptor.

Release of steroid molecule from oily depots of long-chain esters in muscle tissue. Oil has some affinity for water and thus allows penetration of water; the ester is hydrolysed at the surface of the droplet. Muscle is quite aqueous, so steroid-ester favours oil phase (depot). It slowly moves out, and the ester is cleaved, allowing the steroid to have an effect. The rate of release is determined by the release of steroid-ester from depot. The larger the ester group, the greater affinity for oils & greater solubility in oils, which means it will remain in the depot for longer & have a longer duration of action.

The total surface area of the droplet can influence release rate and hence pharmacokinetics of the drug. Droplet dimensions and total surface area influenced by:  force of injection  viscosity and surface tension of oil phase  size of needle  environment into which it’s injected – exercise can increase plasma levels, by increasing surface area of droplet Stealth liposome injections (such as Doxorubicin HCl) consist of the drug encapsulated in stealth liposomes, for IV administration. The doxorubicin is at least 90 % encapsulated. The Stealth liposomes are protected from detection by the mononuclear phagocyte (immune) system by the coating with surface-bound methoxy Polyethylene Glycol (PEG). This is done to increase blood circulation time. These liposomes have a half-life of ~ 55 h in humans.

Implants Nexplanon is a form of progestogen only contraception; it contains etonorgestrel 68mg in each flexible rod. It is delivered by sub dermal implantation and provides effective contraception for up to 3 years (unless BMI greater than 35 kg/m2 in which case may not provide effective contraception in 3rd year).

Gliadel wafer (Polifeprosan 20) is a biodegradable polyanhydride copolymer, 1.45cm in diameter and 1mm thick. Each wafer contains a biodegradable polyanhydride copolymer (192.3mg) and Carmustine (7.7mg). It is used in patients with brain tumours. Wafer is implanted into the brain, no. of wafers implanted dictated by dose required. 8 provides recommended dose. In aqueous environment, anhydride bonds are hydrolised releasing carmustine, Carboxyphenoxypropane (eliminated by kidneys) and Sebacic acid (metabolised by liver expired as CO 2). The active drug, carmustine, diffuses into surrounding brain tissue, producing an anti-neoplastic effect by alkylating DNA and RNA. In 3 weeks more than 70 % of co-polymer degrades.

Goserelin matrix implant – Zoladex – is injected SC into upper abdominal wall with continuous release over 28 days. Goserelin is dispersed in a matrix consisting of D,L-lactic and glycolic acids coploymer. This is Used for palliative treatment of advanced carcinoma of the prostate and treatment of endometriosis & advanced breast cancer.

Needle-free delivery Intradermal, subcutaneous and intramuscular delivery of liquid or powder medication or vaccine through a nozzle via high pressure or high speed narrow stream that penetrates the skin. Most are gas powered using CO2 or N2, but some are spring powered. Powder injection delivers dry powder directly. There is no need for cold chain (refrigerated products).

These needle-free devices are expensive due to their novelty & recent application. Market should increase with:  More drugs  Increased patient awareness and acceptance  Prevention of needle-stick injuries  Lack of special disposal requirements  Standardisation of devices

Special products Any pharmaceutical product must have a marketing authorisation (MA). In the UK, the regulator is the MRHA. Licenses are needed to ensure safety, quality & efficacy. An MA stimulates the details/circumstances that a medicine can be used, such as indication, dose. A special product is an unlicensed medicine, used in unique/unusual circumstances, and is commonly made up for a specific patient. The MHRA permits the manufacture of specials in unique clinical circumstances:  different formulations may be required  nothing on the market has worked for a patient  supply and demand issues, where it is not commercially viable to constantly produce medicines, such as treatments to extremely rare conditions  babies and children The special product will usually be made by a company who have a Specials Manufacturing Licence (MS) from the MHRA, and it must comply with certain standards and keep specific records. Companies can perform limited batch manufacturing of specials. Specials are exempt from needing an MA, but they must be manufactured and supplied in accordance with prescriber specifications. For their use, a patient must fall into category of having ‘special needs’, with clear reasons as to why a licensed alternative is not clinically appropriate. Unlicensed medicine is a medicine with no MA (off-license); unlicensed use is where a medicine with an MA is used, but in a different way to the conditions stimulated in the MA. Specials are a last resort. Ideally treatment options should be followed:  Use of a licensed product within the conditions of the licence  Use of an alternative licensed product  Use of a licensed product in an unlicensed way  Use of a special Patient care is always the primary concern; all medicines should be prescribed and supplied in a safe, effective and appropriate way. Specials should always be an exception. If a prescriber has prescribed an special medication, it is good practice to double check they know it is a special. All records relating to purchase & supply should be kept. Batch manufacture of special products is used in cases of:  Common liquids for children  Ophthalmic preparations – eye drops, ointments  Many preservative-free products  Less common injectable preparations  Epidural infusions  Dermatology preparations that would be made extemporaneously  Hospital products Professional Practice Guide’s 5 principles on specials: 1. Establish the patient’s special clinical need 2. Understand patient’s experience 3. Identify a preparation and a supplier 4. Ensure effective governance is in place 5. Monitor patient and review need for the special There is no guarantee of safety and efficacy, due to the lack of robust testing of specials (as there is in licensed medicines). They have short expiry dates, and instability is common, especially if they are preservative-free. Specials are very expensive, so GPs struggle to fund them if they are used long-term.

Sterilisation In non-sterile medicines, there is a quality criteria that must be met. This criteria describes the maximum amount of colony forming units allowed in pharmaceutical products. A sterile product is one that is completely free of viable microbial contaminants.. Sterility: absence of microorganisms there can be no degrees of sterility Sterilisation: complete removal or destruction of all living organisms Sterility testing must use a validated processes, but there is no guarantee of sterility. Sterilisation isn’t an alternative to good manufacturing practices! Sterility is required when preparations are placed inside the body (injections, implants, sutures, dialysis fluids, etc) or they come into contact with broken skin and mucosal surfaces, which could lead to infection. Sterility may also be required if there is a risk of product degradation. Certain areas of the body are microbe-free. The most important of these are blood & cerebrospinal fluid. If a drug will reach any microbe-free area, it must be sterile. Ideal sterilisation methods should have the following properties:  High antimicrobial activity (giving a high Sterility Assurance Level, SAL – this is a probability that a non-sterile unit is present, usually 10-6 or 1 in a million units)  Easily controllable/measurable /understood physical conditions for microbial inactivation  Terminal sterilisation  Material compatibility  No hazard to operator  No toxic residues  Short processing time  Low cost There are two strategies one can consider when making sterile products: Terminal sterilisation - Make the product under non-sterile Aseptic manufacturing - Make the product from sterile conditions using non-sterile ingredients then sterilize it at ingredients under sterile conditions the end of the process Wherever possible, sterilisation in the final container is preferred – terminal sterilisation. Parametric release (PR) is a demonstrated control of the sterilisation process that gives assurance that the product is of the intended quality. This is based on information collected during the manufacturing process and on the compliance, with specific GMP requirements. PR may be permitted for products sterilised using certain processes, so no sterility tests are required. Quality control of sterile products is usually assured by combining process monitoring and performance criteria. It is important to determine the bioburden, monitor the environment, validate and monitor sterilisation procedures and perform sterility tests. The bioburden is the concentration of organisms in a material. During manufacture processes, the growth of microbial populations that are initially present should be restricted. Processes will usually include extreme temperatures/pH values, or expose materials to organic solvents. The SAL achieved is dependent upon the pre-sterilisation bioburden. It is better if the bioburden before sterilisation is low as:  It reduces the exposure to high sterilisation temperatures, minimising the degradation of actives and excipients  Increases probability of the product passing the bacterial endotoxins test (BET). Autoclaving does not destroy endotoxins, so a high bioburden means high endotoxin concentration.  A shorter autoclaving cycle uses less energy  To determine the bioburden of pharmaceutical products, standard microbiological methods (pour and spread plates/membrane filtration) are applied to raw materials and manufactured medicines, with adjustments if necessary.

Clean rooms Specific practices and procedures performed under carefully controlled conditions with goal of minimizing microbial contamination; most sterile manufacturing processes are performed in clean rooms. Clean rooms are self-contained facilities with dedicated ventilation systems (control of air quality, temperature and humidity). Air is filtered by High Efficiency Particulate Air (HEPA) filters. It is important that air pressure is controlled:

Clean rooms have unidirectional or non-unidirectional air flow. In unidirectional air flow (1), air flows through HEPA filters located in the ceiling/side of the room and air is extracted through perforated flooring or grilles mounted at floor level; this can be vertical or horizontal. In non-unidirectional airflow (2), HEPA filters are located in various positions and returned through opposite locations.

(1)

(2)

Floors, walls and ceilings should be made of a smooth impervious material with rounded corners, to ensure easy cleaning. Ceilings & walls should be cleaned monthly. All doors should be controlled to prevent unwanted flow of air from one area to another (by opening of doors simultaneously). There should be no shelves, window ledges or door frames, pipes or ductwork; flush fittings (where dust might settle). There should be no water sources, sinks or drains. Floors, benches, doors, chairs & cabinet exteriors should be cleaned daily for good contamination control. Hand washing facilities should be available external to changing rooms, as a wash room, with taps elbow/foot operated so clean hands do not contact unclean taps. Outside shoes should not be brought into clean rooms; only approved clean room clothing is allowed. Grading of room quality: A - Laminar air flow cabinets and isolators (high risk operations e.g. filling zone, open ampoules and vials) B - The aseptic room (for aseptic preparation and filling; the background environment for grade A zone) C - The preparation room - inner support ro...