MAAC: Sterile product manufacturer Flashcards

Question

What are the potential sources of conatamination within the clean rooms?

Answer 1

* personnel * the air supply of the room/ inflow of external air * production of contaminants within the room

Answer 2

Air in cleanr rooms is typically recirculated air and a proportion of fresh in take air (this contains contaminants dispersed from people, equipment and machinary) AIr quality controls meausres include the purity of air supplied, Particulate matter of air controllled by HEPA filter, air flow pattern eithin the room, volume of air used and the relative pressure provided to the rooms

Answer 3

* high quality positively pressurised air * floors, walls and ceilings are smooth, impervious and covered * cleaning protocols (rotation of at least two disinfectants) Control of contamination relies on regulation of **production environment, equipment, solutions and personnel**

Answer 4

First, you have to identify sources of contamination and the routes of transfer to products. Then introduce new control methods and establish a monitoring schedule, including predetermined alert and action levels, with set corrective procedures. Monitoring locations must also be considered, depending on the size of the room and activities taking place. Locations should be based on the potential for direct product impact and where contamination could spread through movement of samples/equipment/personnel. When working in Clean Rooms we continuously review product contamination rate, environmental monitoring result, risk assessment, control methods and action levels. All GMP principles apply with appropriate document control system in place and appropriate training delivered (and documented!).

Answer 5

Alert level - set level which when exceeded indicate process may have drifted from normal opperating conditions, correction action not necessarily needed Action level - et level which when exceeded indicate process may have drifted from normal opperating conditions. Correction action is needed

Answer 6

1. Skin scales are the main source of contamination with 25% of skin surface shed daily (with more skin shed by males) 2. To control skin scale release we should: * limit number and movement of operators * restrict operator conversation * avoid airflow interruption by operators * ensure operators wear clean room clothing * exclude people with skin conditions

Answer 7

Skin organisms can be either resident (live on the surface of the skin) or transient (just "passing by") * 75% of people harbour pathogens in nose/ear * Males disperse up to 6 x more bacteria than females * Typical places where flora resides: palm of hand, sole of foot, centre back, back of thigh, peri-umbilical area, lower axillae (mainly Staphylococcus: S. epidermidis mainly on upper body and S. hominis on arms and legs) * Exclusion of people with colds, smokers and shedders from Clean Rooms

Answer 8

Ideal operator would be female, non-smoker, no skin disease, no colds/flu, status of carrier checked, status of shedder checked

Answer 9

**Clean room suits help to minimise the skin shedding** They are made of a specific fabric (Tyvek or ceramic terylene) preventing any particles getting out. Note the fitting at neck, wrists and ankles; head cover; shoes and lint free gloves. **Cleaning of garments** After each use garments are washed (particle free solution, followed by antibacterial rinse, then hot air drying and folded and packaged) then irradiated (suits are gamma irridated using cobalt 60)

Answer 10

* positively pressurised to prevent ingress of contaminated external air * effective at expelling particles produced within the Aseptic Suite * this is achieved with the help of HEPA filters

Answer 11

Aseptic suite needs to be greater pressure than external areas. Minium P differences: between Grade A/B and grade C = -10Pa Between Grade C and external = -15Pa

Answer 12

High Efficiency Particulate Air (HEPA) filters are essential in clean rooms

Answer 13

1. Least efficient at removing 0.3um particles 2. Exits at 0.45m/s 3. inital P diff is 150Pa across filter depth, increasing to 490Pa at the end of filters life 4. Room size, equipment and opperaotr number 5. 20 changes/hour 6. 25-35 changes/hour

Answer 14

They remove particulate and microbial contamination through pleated fibreglass paper filter. A fan is required to force the air through and maintain pressure difference. They are located at the inlet to clean rooms and alert the operators when faulty. Large particles are removed by inertial impaction, medium by direct interception and small particles by Brownian diffusion. The air-flow patters in the clean rooms are either:

Answer 15

1. Unidirectional 2. Conventional 3. Combination of both systems

Answer 16

Unidirectional (laminar flow Clean Room): * all the air moves along parallel flow lines * vertical air speed 0.3 metres per second down flow air from ceiling filters * horizontal air speed 0.45 metres per second cross flow air from wall filters * highly efficient - expensive

Answer 17

Conventional: Airflow is not unidirectional. Air enters through filters and diffusers in centre of ceiling and exits through wall ducts. The air is re-circulated and mixed with fresh inlet air each air change diluting contaminated air in room. Diffusers are fitted to the air inlet air source to direct the airflow into the room Perforated plate diffusers produce a jet flow of high quality air directly underneath the diffuser Bladed diffusers mix air released from diffusers with Clean Room air giving constant air quality in room

Answer 18

Or a combination of the two systems: Often the system of choice in pharmacy production Background air runs as non-unidirectional airflow, while the foreground air as unidirectional airflow. Vertical unidirectional air flow over work area, providing improved aseptic control Plastic curtains separate critical areas Cheaper to use yet sufficient to manufacture terminally sterilised products

Answer 19

Pyrogen free product with low particulate & micro organism contamination before heat sterilisation. Solutions are prepared in Grade C Cleanroom and packaged in Grade A Laminar Air Flow workstation with minimum Grade C background.

Answer 20

* Radial vein * Cephalic vein * Basilic vein * Median cubital vein

Answer 21

These need to be preservative free solutions for spinal injection. There shelf life is less than 6 hours after preparation. Critical that the word “INTRATHECAL” is ALWAYS written in full and the label on these products clear indicates 'FOR INTRATHECAL USE'.

Answer 22

Pre-Filled Syringes In pre-filled syringes, the injection solution is aseptically filled into sterile syringes. This means that there is a high level of sterility assurance and does not contain an antimicrobial preservative.

Answer 23

**_Advantages_** * Increased safety – reduced risk of self injection * Decreased medication errors * Increased sterility assurance – no preservative **_Disadvantages_** * Expensive/limited product availability * Potential drug uptake by plastic syringes

Answer 24

**Water** for injection is the preferred parenteral solvent for **IV and intraspinal agents** as it is physiologically compatible with tissues. Water is therefore the main component (by volume) of parenteral products, but they can also contain carbohydrates, amino acids, electrolytes, lipid emulsions and polyols. In comparison, **metabolisable oils** are used as the vehicle in **I/M injections**. Although other injection vehicles such as, emulsions, dried injections, oil injections can also be utilised. Injection suspensions are more complex to prepare than solutions and are therefore difficult to process and sterilise.

Answer 25

Production of Large Volume Parenterals Large Volume Parenterals need to be sterile, non-pyrogenic and have low particulate counts. Prior to being filled LVPs must be filtered and then heat sterilised. They are prepared & filtered in Grade C environment, then filtered via in-line membrane filter. Pre-formed plastic bag is aseptically filled in a Grade A environment and then heat sealed

Answer 26

* Glass containers * Type II glass used * Only used for products possessing high pH * PVC collapsible pouches * Used to package most infusion fluids * Semi-rigid polyethylene containers * Electrolyte, TPN, dialysis solutions

Answer 27

buffers, antioxidants, antimicrobial agents, tonicity adjusters, solubilising agents and chelating agents.

Answer 28

* The product and container can interact and therefore cause changes in the pH of the products * Acetate/citrate/phosphate buffers are used in S/C & I/M injections * pH range commercial SVPs 3 -10.5 - ideal injection pH 7.4 * At pH 9 or above, tissue necrosis may occur * At pH 3 or below, pain and phlebitis may occur

Answer 29

* Low oxidation potential * Preferentially oxidised or block oxidative chain reactions * Must not interact with the drug * Commonly used antioxidants are sodium bisulphite & sodium metabisulphate

Answer 30

* Not added to single dose products * Not used in large volume injections * Not used if drug has antimicrobial activity * Must be stable when formulated * Examples include, benzyl alcohol, chlorocresol, phenol, thiomersal

Answer 31

* Isotonic solutions have the same osmotic pressure as blood plasma * Tonicity adjusters * dextrose, sodium & potassium chloride * Injections that should be isotonic * S/C, I/M, intradermal and intrathecal

Answer 32

* Disposabal influsion pumps * Elastomeric Infusion Pumps * Spring Powered Infusion Pumps * Negative Pressure Infusion Pumps * PCA Infusion Pumps

Answer 33

Disposable Infusion Pumps can be used for the administration of chemotherapy, antimicrobials, analgesics, anaesthetics and post-operative pain control

Answer 34

**_Advantages_** * Closed, lightweight and portable * Easily concealed * Have a pre-determined flow rate/volume * Gravity independent product delivery * Limited cost * Minimal manipulation by patients **_Disadvantages_** * Low accuracy in dosage delivery * Inflexible - cannot adjust flow rate * Visual assessment of drug in unit required * Inconsistent infusion times due to fill volume, fluid viscosity, temperature, and storage * Disposable – cannot be re-used and therefore expensive if used long-term

Answer 35

* Narrow tubing restricts flow rate * temperature has little effect on tubing * tubing material is plastic e.g. PVC * Pressure forcing fluid through tubing achieved * stretched elastomer * compressed spring * pressure from a chemical reaction * pressurised gas cartridge

Answer 36

Elastomeric Infusion Pumps * Multiple layer membranes * higher pressures than single layer membranes * Advantage * Fast flow rates - ideal for narrow catheter * Disadvantage * May require special electric pump to fill reservoir

Answer 37

Spring Powered Infusion Pumps: Positive pressure spring powered pumps: * single use devices such as Springfusor * re-usable devices such as Sidekick

Answer 38

PCAs have an additional fixed volume, bolus dose reservoir that is integrated or attached to an administration line of a standard disposable pump

Answer 39

* The driving force is produced by the pressure difference in atmospheric chamber. 1. Filling Port 2. Drug Reservoir 3. Moveable Wall Plunger 4. Vacuum Chamber 5. Atmosphere Chamber

Answer 40

An isolator is a piece of kit with a series of barriers, providing a sealed working space. Isolators can be used in order to provide an aseptic product, or to protect the operator. Isolators are often used in pharmaceutical production, as they provide high quality, cost-effective product versus preparation in a clean room.

Answer 41

* mprove product quality by reducing contamination * Improve operator safety by protecting the product from the operator and the operator from the product. * Reduce operating costs * Often located in Grade D Clean room

Answer 42

They can be made of rigid or flexible film, with a rigid frame preferred as this minimises the puncture risk. Usually made of steel frame with acrylic windows, with glove ports for operators, and interlocked double doors. Separate product entry/exit ports help with sterility.

Answer 43

Isolators have separate filtered air inlet and air exhaust, passing through HEPA filters. Inside the chamber the environment is classed as Grade A, with up to 100 exchanges per hour.

Answer 44

The cabinet offers great flexibility: it can be set to either positive or negative pressure, unidirectional/non-directional/combination air flow. For aseptic work the airflow should be set to vertical unidirectional, with positive pressure.

Answer 45

Positive pressure isolator protects product from external environment, for example: production of IV antibiotics, Total Parenteral Nutrition (TPN) fluids. Negative pressure isolators protect the operator, as well as the product. This type of isolator would be used for cytotoxics & radiopharmaceuticals. The exhaust air is ducted through at least one HEPA filter plus adsorption filter e.g. activated carbon. When working with cytotoxins operator safety is the top priority, with special protocols in place (frequent glove changes, record of staff handling with product).

Answer 46

Common problems associated with isolators: * As with any sterile work, contaminants introduced to the chamber can cause issues. This could happen due to, for example a puncture in the glove. To avoid this, isolators are sterilised in between each use (rapid gassing system can achieve sterility after only 20 min!) * Operator freedom of movement is limited * Chemotherapeutic/radiopharmaceutical agents can diffuse through gloves, putting the operator at risk. * Location of isolator cabinet.

Answer 47

* all isolators have double doors * isolators must be placed in a room of a minimum grade D (with no sinks) * All tubing to be single-use and disposable * Pharmacist training and risk awareness

Answer 48

Summary of water treatment: 1. Raw water (potable water) 2. Pre-treatment process 3. Purification (first pass reverse osmosis -\> pH adjustment -\> second pass reverse osmosis). This yields purified water, which could be then further purified to produce water for injection. 4. Storage 5. Distribution

Answer 49

Purified - made from portable water and used in cough mixtures and to manufacture WFI WFI - used in injections, infusions and opthalamic products. Prepared from purified water by destilliation/ processing of purified water. UPS conductivity of 1.1 uS/cm at 20 degree C

Answer 50

Raw water contains many impurities * Gases: dissolved (oxygen and nitrogen) and reactive (carbon dioxide and ammonia). Dissolved gases damage stainless surfaces, whereas reactive ones reduce the conductivity; * Microbial contamination, often gram negative organisms producing endotoxins; * Particulate matter, including colloid particles of aluminium, iron or silica; * Organic matter, providing source of nutrients for microorganisms, contributing to steel damage when reacting with dissolved gases, and blocking reverse osmosis membranes; * Residual disinfectants, e.g. Triclosan. All of the above must be removed in order to provide an aseptic product.

Answer 51

The first step is the pre-treatment * This is a complex process involving multiple steps to target various impurities. * Chemical injection which binds impurities turning them to insoluble particles. This helps removal further down the process; * Organic scavenging and UV exposure, absorbing organic matter and killing bacteria via the UV; * Water softening to remove magnesium and calcium cations; * Filtration through an activated carbon filter to remove chlorine and other residual impurities, preparing the water for reverse osmosis treatment.

Answer 52

Purification is achieved by the process of reverse osmosis 1st reverse osmosis unit removes 95-99 % ions, with second pass further improving the purity. This yields purified water. N.B. Reverse osmosis filters units are easily blocked, so the filtration step in pre-treatment phase prevents filter blockage.

Answer 53

Raw Water to Pure Water Raw water contains many impurities Gases: dissolved (oxygen and nitrogen) and reactive (carbon dioxide and ammonia). Dissolved gases damage stainless surfaces, whereas reactive ones reduce the conductivity; Microbial contamination, often gram negative organisms producing endotoxins; Particulate matter, including colloid particles of aluminium, iron or silica; Organic matter, providing source of nutrients for microorganisms, contributing to steel damage when reacting with dissolved gases, and blocking reverse osmosis membranes; Residual disinfectants, e.g. Triclosan. All of the above must be removed in order to provide an aseptic product. The first step is the pre-treatment This is a complex process involving multiple steps to target various impurities. Chemical injection which binds impurities turning them to insoluble particles. This helps removal further down the process; Organic scavenging and UV exposure, absorbing organic matter and killing bacteria via the UV; Water softening to remove magnesium and calcium cations; Filtration through an activated carbon filter to remove chlorine and other residual impurities, preparing the water for reverse osmosis treatment. Purification is achieved by the process of reverse osmosis 1st reverse osmosis unit removes 95-99 % ions, with second pass further improving the purity. This yields purified water. N.B. Reverse osmosis filters units are easily blocked, so the filtration step in pre-treatment phase prevents filter blockage. Purified water is then distilled (or treated to an equivalent standard) to produce water for injection * Various stills can be used for water distillation process, depending on requirements: * Single effect still, producing less than 900 litres/hour * Multiple effect still, producing between 900 to 9000 litres/hour * Vapour compressor still, producing excess of 10,000 litres per hour

Answer 54

Once the water is sufficiently purified, it has to be appropriately stored to maintain its qualities. This can be achieved as **batch storage** (small volumes) or in a larger volume, **dynamic storage** surge tanks. ## Footnote **_Batch water storage_** Water is packed in unit volumes and released for use once the QC is passed. It provides maximum product accountability, but is expensive to manufacture. **_Dynamic Storage_** Allows for storage of much larger volumes, at lower cost. Freshly distilled water is mixed with water already stored in the stainless steel surge tank, with typical capacity of 316 L. Water is stored at 80oC.

Answer 55

Pyrogens are fever producing substances. The two main types of pyrogens are: * Endotoxins (high molecular weight complexes associated with outer membrane of Gram-negative bacteria. The pure endotoxin is a lipopolysaccharide (LPS)) * Exotoxins (specific protein toxins released by pathogens affecting a particular site within the human body)

Answer 56

Pyrogens can originate from microbes, as they are components of Gram-negative & Gram-positive bacteria, fungi & viruses, moulds and yeasts, but also non-microbial sources, as some steroids and plasma components also produce a pyrogenic response if injected. Pyrogen sensitivity varies with endotoxin source, ranging from 1 ng/kg for E. coli endotoxin to 50 ng/kg for P. aeruginosa endotoxin.

Answer 57

Injection of endotoxins & other pyrogens can affect thermoregulatory centres in the brain High doses of endotoxin can activate the coagulation system, alter lipid & carbohydrate metabolism, and cause platelet aggregation!

Answer 58

LPS is composed of three areas: the inner region composed of LIPID A is linked to a central polysaccharide core, a polysaccharide core is joined to O-antigenic side chains and a KDO (an eight carbon sugar joined to a core polysaccharide).

Answer 59

* solvents * medicaments * production apparatus * storage conditions prior to sterilisation T hey are thermostable, but CAN be destroyed by excessive heat (126 oC for 20 hours). Pyrogens CANNOT be destroyed by antimicrobials.

Answer 60

1. Acid-base hydrolysis, where acid separates Lipid A from components; 2. Alkaline-base hydrolysis, causing chemical & biological changes to LPS; 3. Oxidation, where mechanism of action is still unclear; 4. Dry heat, 250 oC for 30 minutes 5. Moist heat, 126 oC for 20 hours 6. Distillation, where LPS molecules are not carried into still distillate 7. Reverse osmosis, which filters out pyrogens by size exclusion.

Answer 61

Pyrogen Testing The test commonly utilised for detection of bacterial endotoxins is a Limulus Amoebocyte Lysate Test (LAL), with a detection limit of 0.5 endotoxin units per kg. LAL uses lysate of amoebocytes (American or Japanese horseshoe crab) and looks for clotting as an indication of a positive reaction. Various testing methods can be used ranging from a gel clot end point assay, turbidimetric assay (looking for change in opacity due to the formation of insoluble coagulin), or kinetic chromogenic test (colour change test, suited well for automation); All good science has to be controlled. Here we use a known endotoxin as a positive control and apyrogenic water as a negative control. Threshold pyrogenic dose is almost identical for humans and rabbits, so rabbits are the animal of choice for in vitro pyrogen testing. The "rabbit test" can identify the presence of a wide range of pyrogens and endotoxins. The detection limit for the rabbit test is 5 endotoxin units per kg. Interestingly, at doses above the threshold pyrogenic dose humans show a greater response than rabbits. Rabbit pyrogen test requires the injection of a small amount of batched test material into a rabbit's blood stream, and monitoring for temperature increases. This test is expensive, difficult and slow. Due to biodiversity, experiments on live animals are much harder to control. Testing on animals presents with numerous ethical issues, which have to be considered. Pharmaceutical industry is moving away from animal testing replacing it with alternative methods, such as monocyte activation, where possible.

MAAC: Sterile product manufacturer Flashcards

(92 cards)