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Kirsty 3.1 > MAAC: Sterile product manufacturer > Flashcards

MAAC: Sterile product manufacturer Flashcards

1
Q

What are sterile products?

Examples

A
  • dosage forms delivered to patients outwith the alimentary canal,
  • often containing drugs that cannot be given orally,
  • examples include injections, infusions, irrigation solutions and ophthalmic products.
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2
Q

What can paretnal preperatoins be sub-divided into?

A
  • Small Volume Parenterals
  • Large Volume Parenterals
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3
Q

What are small volume parentals?

A
  • Sterile & Pyrogen free
    • Pyrogen: a substance, typically produced by a bacterium, which produces fever when introduced or released into the blood.
  • Have a volume between 1-100mL
  • Packed as single dose ampoules, multiple dose vials, pre-filled syringes
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4
Q

What are large volume parentals?

A
  • Volumes greater than 100 mL and administered by IV infusion as a single dose
  • Depending on drug stability can be used to deliver antibiotics/antivirals, cytotoxics
  • Packed as infusions, TPN, IV antibiotics, dialysis fluid
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5
Q

Where can sterile products be manufactured?

What is the difference between them?

A

The manufacture of sterile products takes place in either industrial pharmaceutical plants or hospital aseptic production units.

In hospital aseptic production, products are prepared for individual patients and no sterility testing of these products is performed. This contrasts with industrial pharmaceutical production where products are terminally sterilised and aseptically prepared.

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6
Q

Describe asecptic preperations and central intra-venous additive service?

A

Aseptic Products

  • have a limited shelf life once produced
  • they are also potentially harmful to patients and operators who prepare them e.g. agents used in chemotherapy

Central Intra-venous Additive Service (CIVAs)

a service to provide injections in a ready-to-administer form from the pharmacy, thus avoiding the necessity to prepare injections on hospital wards under non-asep tic conditions by ward-based stalf, such as nurses and junior doctors

  • This is a service that is provided in some hospitals
  • It requires access to suitable facilities i.e. an Aseptic Suite
  • Staff possess necessary skills and knowledge to prepare these products
  • Examples of intravenous additive products include: IV antibiotics, epidural infusions, saline flushes
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7
Q

Describe licence products units

A

A Licensed Unit

  • Requires a marketing authorisation (MA) or a manufacturing licence (ML) to produce a medicine for the MA holder
  • Can prepare “stock” intravenous doses
  • Expiry dates limited by product stability

Unlicensed Unit (Hospital Aseptic Units)

  • Exempt from licensing requirements provided products prepared under supervision of the Accountable Pharmacist
  • Preparation undertaken in Aseptic Suite using licensed sterile products as ingredients
  • Maximum shelf life of seven days – supported by stability data
  • Preparation of clinical trial products requires an investigational medicinal products licence (IMP)
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8
Q

What does medicaines regulations regard:

  1. Dispensing
  2. Prerperation

of aspetic products?

A
  1. supply of a finished product to a patient for its administration is dispensing
  2. manipulation of the product leading to its final presentation is preparation
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9
Q

Quality and Standards Board for Health in Scotland integrate patient safety & clinical effectiveness

A

Quality and Standards Board for Health in Scotland integrate patient safety & clinical effectiveness

responsibility of hospital chief pharmacists to ensure policies exist for aseptic ward processes.

IV fluids for patient administration should be prepared in pharmacy aseptic unit.

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10
Q

Aseptic preperation requires:

A

Aseptic preparation requires:

  • Cleanroom with vertical laminar air flow OR Type I or Type II isolator
  • Specialised operator clothing
  • Aseptic Technique
  • Validation of technique
  • Standard Operating Procedures (SOPs)
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11
Q

CLEAN ROOMS

A
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12
Q

What are clean rooms used for?

A

These are essential for the aseptic production of sterile products.

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13
Q

Where does the greatest source of contaminant in clean rooms ocme from?

A

Opperators

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14
Q

What is the cycle stages involvent from patient presentation to GP to supply of aseptic product?

A
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15
Q

What is the aseptic protocol preperation

A

Aseptic Preparation Protocol

  • Material assembly & worksheet written up
  • Pre-compounding check carried out
  • Worksheet signed & materials transferred into Grade A area
  • Aseptic dispensing procedures including In-Process check of manipulation
  • Label product, final check & release
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16
Q

Why do these processes need to occur?

A

To avoid product contamination, prevent pyrogenicity in products and maintain sterility for aseptic production

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17
Q

What can product contamination cause?

A

Small particles may:

  • Get lodged in lungs
  • Get lodged in tissues - heart, bone marrow
  • Get lodged in blood vessels - organ damage
  • Cause an inflammatory response

Large particles may:

  • Get lodged in liver or spleen
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18
Q

What can occur if proucts contain pyrogens?

A
  • Temperature rise
  • Infection
  • Septicaemia
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19
Q

What must sterility be?

BP limits?

UPS limits?

A

Sterility:

  • no viable organisms (bacteria/ fungi)
  • No or limited particular contaminants
  • Be free from unwanted chemical compounds

BP:

  • Small parental volumes must be clear and particile free

UPS:

  • 103 particles per container >25um in diameter
  • 104 particles per container >10um in diameter
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20
Q

Microbial contaminations in commercial production

A
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21
Q

Microbial contamination in hospital preperation

A
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22
Q

Who is allowed into clean rooms?

A

Only for those with authorised access

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23
Q

What is present in changing areas?

What happens in changing areas?

A
  • Tacky mat/ polymetric flooring
  • Handwashing and donning garments
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24
Q

What are clean room grades

A

Grade D (ISO 9) – minimum prep grade

Grade C (ISO 8) – sterile products prep

Grade A/B (ISO 5) – aseptic dispensing

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25
Q

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

A
  • personnel
  • the air supply of the room/ inflow of external air
  • production of contaminants within the room
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26
Q

Describe personnel contaminants

What are used to minimize this

A
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27
Q

Describe air flow control

A

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

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28
Q

what are solutions to sources of contaminants?

A
  • 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

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29
Q

How can production envitoment be regulated?

A
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30
Q

Is equipment a priamry or secondary contaminant source?

A
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31
Q

How are risks in clean rooms managed?

A

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!).

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32
Q

What is alert level and what is action level?

A

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

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33
Q
  1. What is the main source of personnel contaminant?
  2. Methods to reduce this?
A
  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
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34
Q

Skin organisms can be either resident (live on the surface of the skin) or transient (just “passing by”)

Where are pathogens often present and which are most common?

A

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
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35
Q

Ideal opperator?

A

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

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36
Q

What are suits made out of?

How are they washed?

A

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)

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37
Q

What does aspetic suite air supply need to be and how is this acheived?

A
  • 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
38
Q

What are pressure difference limits?

A

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

39
Q

PArticle limits view both slides and next cue card

A
40
Q

Particle limits view

A
41
Q

What does HEPA stand for?

A

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

42
Q

HEPA:

  1. What size of particle is HEPA least effective at removing?
  2. What speed does air exit filter?
  3. What is inital P difference across the filter and what is end P difference when filter at end of life?
  4. What does the number of air changes in a room depend on?
  5. What is the minium changes required for grade B,C,D rooms?
  6. What is common number of air changes?
A
  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
43
Q

How do HEPA filters work?

What is needed to maintain pressure difference?

Where are HEPA located?

How are particles removed?

A

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:

44
Q

What are the airflow patterns in clean rooms either?

A
  1. Unidirectional
  2. Conventional
  3. Combination of both systems
45
Q

Describe uniflow HEPA systems?

A

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
46
Q

Describe conventional airflow system

A

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

47
Q

Describe combo of both

A

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

48
Q

What grade conditions needed for terminla sterilisation products?

A

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.

49
Q

What routes of administration is there?

What is there corresponding volumes?

What are the used for?

A
50
Q

What are upper IV administration sites?

A
  • Radial vein
  • Cephalic vein
  • Basilic vein
  • Median cubital vein
51
Q

What is the shelf-life of intraspinal preperations any why?

What is it important to remember about intra-thecal injections?

A

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’.

52
Q

How are pre-filled syringes made?

A

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.

53
Q

Advantages and disadvantages of pre-filled syringes

A

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
54
Q

Describe the vehicle usage in large volume parentals

A

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.

55
Q

How are large volume parentals produced?

A

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

56
Q

Large volume parenterals can be packaged in a number of different containers, which is related to the product and how it will be administered to the patient.

What are packaging options:

A
  • 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
57
Q

In addition to the medicine and the vehicle for delivery, injectable products contain a number of other additives such as…?

A

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

58
Q
  • Why are buffers used?
  • What buffers are used?
  • What pH ranges is there and what is the ideal pH
  • What happens at the extremes of pH
A
  • 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
59
Q

Why are antioxidants used?

What is important when choosing agent?

What are commonly used agents?

A
  • Low oxidation potential
  • Preferentially oxidised or block oxidative chain reactions
  • Must not interact with the drug
  • Commonly used antioxidants are sodium bisulphite & sodium metabisulphate
60
Q

When are antimicrobals not used?

What must you make sure when using them?

What are examples?

A
  • 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
61
Q

What do isontic solutions means?

What are examples of tonicity adjusters?

What injections need to be isotonic?

A
  • 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
62
Q

For large volume parenterals there are a range of different devices that can be used to administer the product to the patient.

Examples include?

A
  • Disposabal influsion pumps
  • Elastomeric Infusion Pumps
  • Spring Powered Infusion Pumps
  • Negative Pressure Infusion Pumps
  • PCA Infusion Pumps
63
Q

What can disposabal influsion pumps be used for?

A

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

64
Q

Advantages and disadvantages of disposabal infusion pumps

A

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
65
Q

Mechanism of action of disposable infusion pumps

A
  • 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
66
Q

What makes elastometric pump different from other pumps?

What are the advantages and disadvantages of elastometric pumps?

A

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
67
Q

Spring Powered Infusion Pumps examples

A

Spring Powered Infusion Pumps:

Positive pressure spring powered pumps:

  • single use devices such as Springfusor
  • re-usable devices such as Sidekick
68
Q

Describe PCA infusion pumps

A

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

69
Q
  1. Describe how negative pressure infusion pumps work.
  2. Label the diagram
A
  • 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
70
Q

What are isolators?

What are they used for?

A

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.

71
Q

Advantages if isolators

A
  • 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
72
Q

What is the minimum air exchange rate in a cat D clean room?

  1. 10 exchanges per hour
  2. 20 exchanges per hour
  3. 50 exchanges per hour
A

2

73
Q

Describe isolator cabinants in terms of their characterisitics and what they are made off

A

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.

74
Q

Describe air control in isolator cabinets.

What grade are isolators and how many air cycles per hour?

A

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.

75
Q

What can airflow in the isolator cabinet be?

What should the airflow be for aspetic work

A

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.

76
Q

Difference between positve and negative pressure.

When would each be used?

A

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).

77
Q

What are common problems associated with isolators?

A

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.
78
Q

Requirements for isolators

A
  • 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
79
Q

What is the summary of water treatment?

A

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
80
Q

Difference between purified water and water for injection

A

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

81
Q

Raw water contiains many impurities such as…?

A

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.

82
Q

Describe the pre-treamtnet process

A

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.
83
Q

Descibe purification treatment

A

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.

84
Q

Describe the production of WFI from purified water

A

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
85
Q

What storage options are available?

Describe both

A

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.

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.

86
Q

What are pyrogens?

What are the main types?

A

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)
87
Q

When do pyrogens originate from?

What does pyrogen sensitivity vary with?

A

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.

88
Q

What can injection of endotoxins and other pyrogens lead too?

What can high doses of endotoxins cause?

A

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!

89
Q

What is the LPS composed of?

A

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).

90
Q

Pyrogens may contaminate parenteral products through a number of sources e.g…?

How can they be destroyed?

A
  • 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.

91
Q

It is important that injectable, sterile products are DEPYROGENATED, how can this can be achieved?

A
  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.
92
Q

Describe pyrogen testing

A

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.

Kirsty 3.1 (47 decks)

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