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Flashcards in Water,steam and Sterilisation Deck (55):
1

What is meant by good water supply?

1. Good quality council water.
2. Chorinated as long as possible
3. Pre-filteration
4. Un-chlorinated is kept moving
5. UV txt

2

What is good design to prevent deadlegs?

Can be defined as not more than 6 diameters in length.
Design of location of user points
Limit add ons
Prevent sub loops
Heat exchangers
Design of valves and pumps
Standby equip

3

How to reduce deadlegs

Self draining
Regular flushing
Frequent sanitisation

4

Describe water system validation?

Per PDA tech rep2
A basic reference used for the validation of high purity water systems is the Parenteral Drug Association Technical Report No. 4 titled, "Design Concepts for the Validation of a Water for Injection System."



The introduction provides guidance and states that, "Validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce microorganisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function." Therefore validation no challenge organism for water system



In the review of a validation report, or in the validation of a high purity water system, there are several aspects that should be considered. Documentation should include a description of the system along with a print. The drawing needs to show all equipment in the system from the water feed to points of use. It should also show all sampling points and their designations. If a system has no print, it is usually considered an objectionable condition. The thinking is if there is no print, then how can the system be validated? How can a quality control manager or microbiologist know where to sample? In those facilities observed without updated prints, serious problems were identified in these systems. The print should be compared to the actual system annually to insure its accuracy, to detect unreported changes and confirm reported changes to the system.



After all the equipment and piping has been verified as installed correctly and working as specified, the initial phase of the water system validation can begin. During this phase the operational parameters and the cleaning/ sanitization procedures and frequencies will be developed. Sampling should be daily after each step in the purification process and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be drawn e.g. if a hose is usually attached the sample should be taken at the end of the hose. If the SOP calls for the line to be flushed before use of the water from that point, then the sample is taken after the flush. At the end of the two to four week time period the firm should have developed its SOPs for operation of the water system.



The second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in conformance with the SOPs. The sampling is performed as in the initial phase and for the same time period. At the end of this phase the data should demonstrate that the system will consistently produce the desired quality of water.



The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOPs over a long period of time it will consistently produce water of the desired quality. Any variations in the quality of the feedwater that could affect the operation and ultimately the water quality will be picked up during this phase of the validation. Sampling is performed according to routine procedures and frequencies. For Water for Injection systems the samples should be taken daily from a minimum of one point of use, with all points of use tested weekly. The validation of the water system is completed when the firm has a full years worth of data.



While the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system. First, there must be data to support the SOPs. Second, there must be data demonstrating that the SOPs are valid and that the system is capable of consistently producing water that meets the desired specifications. Finally, there must be data to demonstrate that seasonal variations in the feedwater do not adversely affect the operation of the system or the water quality.



The last part of the validation is the compilation of the data, with any conclusions into the final report. The final validation report must be signed by the appropriate people responsible for operation and quality assurance of the water system.

5

Describe a typical water system

Chlorination: extra chlorination - improve microbial control
Active carbon treatment: removes chlorine long life - gerneates carbon fines - bac build up after chlorine removal
Sand/media Filtration: Removes organic Long life
Softening: remove calcioum and Mg cations - prevent scaling - regenerate resins + microbial build up
Deionisation: regenerate with HCL and brine;
Ultrafiltration
Reverse osmosis: remove particles, bacteria, pyrgens, organics >200nmwt - not an absolute filter
Ozone or UV sanitisation
Distillation
Distribution system

6

Purified water

Prepared from portable water
Purified by: Distillation + ion exchange + any other suitable method
Uses: initial wash IV eqiupment and containers; final wash and product formulation (N/S); preparation for WFI
Specification: 4.3 mSv/cm at 20 deg; 0.5mg/L TOC, 100cfu/mL, 0.1ppm heavy metal; nitraces 0.2ppm

7

Highly Purified Water

Since Jan 2001- same as WFI except endotoxin requirement
Prepared from portable water
Double pass RO in combination with either/or ultrafiltration/deinoisation
Use: final rinse sterile non-parenteral products
Use: initial rinse of containers/closure for sterile product

8

Water for injection

Prepared from portable water/purified water
Prepared by: Distillation (EP); RO or distillation (USP)
Use: Formulation of parenterals
Use: Final washing of equipment and containers for parenterals manufacture
Spec: 1.1mS/cm at 20 deg; 0.5mg / L TOC; 0.2ppm nitrates; 0.1 heavy metal; 0.25IU/mL endotoxin; 10cfu/100mL (sample 200mL)

9

What are the differences in USP and EP water reqirements?

Testing strategy for conductivity
Different req for conductivity
USP same conductivity limt for PW and WFI
Diff sample vol

10

Storage and distribution of water

Basic design principles: (Tanks)
totally draining, tall, thin
Sterilising vent filter
Sanitary bursting disc/vacuum and pressure relief
Sanitary level switching/control
All surfaces wetted with flowing water
WFI+PW: 316L stainless steel
Basic design principles: (Pipes)
Min/zero deadlegs
internal velocity - 1-3m/s
Completely drainable
Sanitary instrumentation
Sanitary pump design
No filtration present
UV sanitisation
Materials of construction

11

Water system URS and qual

URS:
water quality
Regulatory requirement
Source water
Daily demand
Demand (max)
Circulating temp 80 deg
offtake points (hot)
offtake points (30 deg)
FS: (how is the URS to be achieved?)
Water system DQ:
Water system IQ:
Check list approach:
sys vs design spec
Correct components
correct tagging?
Correct material of construction?
Satisfacotry welding?
Slope ok?
Instrument calibration
Filter integrity tests
Water system OQ:
Correct function of all individual sub sys i.e. pump + heat exchangers
Correct function of control loops
i.e. flow rates, temp control; vessel level control; deioniser regeneration; RO sanitisation; conductivity base water rejection; Computerised sys control; water quality
Water system PQ:
Documented - confirm - total system reliable - within URS
1. Intensive monitoring
All off-take and sampling points
All parameters
10 days - daily
2. Relaxed monitoring
Rotate off-take and sampling points
Rotate parameters
different days
different times of days
20 days
3. Intesntive monitoring
All off-take and sampling points
All parameters
10 days - daily
Through out: temp control; flow rates; regeration

12

Why is it necessary to control quality of steam in an autoclave?

Mechanism of kill: Sensible heat 1 calorie / gram + Laten heat 540 cal per gram at point of condensation
Condensation/latent heat - critical latent heat only release at phase changes - near phase boundary
Steam needs to be dry and saturated
Superheated steam (abv phase boundary): needs to drop temp to phase boundary before latent heat can be released
Wet steam: droplets of water - reduce condensation efficiency + wet loads
HTM2010 limit: Non-condensable gase 3.5%; Dryness fraction >0.9
On commission, changes and yearly interval
Micro: EU - only when steam directly contact container or closure (porous load) + SIP + condensate to cool

13

What are the main autoclave equipment design considerations?

Withstand steam pressure - 2-3bar absolute
Valve to allow steam in and one to remove condensate
Drain valve: thermostatic - open when cool
EU: two separate temperature probes - one control temp of the cylce - second one provide fully independent record
Controlling prove - in the drain (coolest part)
Monitoring probe - in the load/chamber
EU: air detector esp for porous load

14

What are the design considerations of a porous load?

Contains: machine parts, filters, tubing, rubber stoppers + garments
Wrapped to protect from re-contamination
Air removal important - allow steam penetration
Vacuum air removal + vacuum/pressure steam pulsing - facilitate air removal and steam penetration
Load design to help: avoid long length tubing + separate complex assemblies + reducing wrapping
If probe in load: slow to come up to the temp compared with temp in chamber (BSEN285 - 30 sec)
Air dectector no sensitive to detect air trapped in load
Bowie-Dick test - pack of folded towels - uneven colour - incomplete air removal
Alternative to Bowie-Dick: The Lantor Cube (3M) + DART + The Brons TST pack
UK: run one of these tests as the first cycle each day
Chamber leak test: once a week (<1.3mBar/min at 50mBarA)
SIP: special case - porous load

15

What are the cycle design consideartion of a non-porous load?

No direct steam contact required
Heat transfer from container to liquid contained
No vacumm pulse required - gravity displacement
Ensure load is cooled before opening - explosion
Over pressure - add air to balance pressure
Water spray - speed up cooling
Fan installed to ensure air and steam mix

16

What is an overkill approach?

Pharmacopoeias specified condition: 121 deg for 15 min; 134 deg for 3 min
Expected to kill large population of most resistant organisms
No further justificaiton required

17

What is a bioburden approach?

Used for materials with limited thermal stability
Critical to control pre-sterilisation bioburden
Ensure cycle deliver suficient lethality - adequate sterility assurance
F0 > 8 min

18

How would you validate an autoclave?

IQ:
Confirm compliance with design spec
i.e. material of construction + slope of pipelines and drains
OQ: (Functionality)
Measuring devices - temp + press
Control system and alarms
Ancillary equipment i.e. vacuum pumps
PQ:
EU: focus mainly on physical / US: focus on BI studies
1. Temperature distribution study
Empty and loaded chamber
12 tempature probes: corners, centre, drain, inlet, baffle plates etc
Probes are in free space - i.e. mounted on a trolley/scaffold
Temp measured independently: superheat / cool spots
2. Penetration study
Demo sterilising conditions achieved in the load itself
Fluid loads: in container, 2/3 down in the centre (slowest to heat)
Probed continers in various locations i.e. conerners, centre, drain, monitorin probe position as well as cool spots
Show: slowest to heat parts achived the req temp for the time specified
Diff sizes containers: largest ands mallest should be studied
Consider variable load pattern + difference in product i.e. viscosity
Porous load: position probe at hard to remove air positions
Placement of probe should not provide pathway for steam/air
Calibrate temp probes before and after use
Repeat studies three times - pass on consecutive rungs
BI:
Innoculate product with organisms
Porous load: use strips
Geobacillus stearothemophillus: D121 value = 1.5 to 3 min

19

What are the considerations in autoclave operation and control?

Adhere to validated patterns
Max + min load for fluid but not porous load
SOP + Drawing + photo
Orientation of load important: buckets/bottles should be up side down on a rack
Link cylce parameters to relevant loads
Record autoclave cycles with log book
Maintain calibration
Review of cycle records: chagnes in heat up and cool down phases are charateristics - changes may indicate malfunction
Use of MTR (master temperature record)
Investigate any deviation
Annual revalidation single empty and load run

20

What are the main sources of endotoxins?

Raw materials:especially of plant and animal origin; TVC may not pick up debri of dead G-ive bacteria
Water: habitat of wide variety of G-ive organisms
Portable water can contain G-ive bac
Dechlorinate - good for pseudomonas
G-ive colonise moist environment i.e. drans, open gulleys, traps on equipmetn and undrained pipes, washing and cleaning equpment, disinfectant solutions

21

What are the ways of removing and destroying pyrogens?

Remove by washing with pyrogen free water
Ultrafiltration
Moist heat - totally ineffective
Dry heat most common
Acid base hydrolysis
Oxidation using HPV
Distillation
RO
Electrostatic attraction to charged media

22

What are the critical parameters to dry heat sterilisation?

BP: 160 deg for 2 hrs
No pharamacopoeia depyrogenation cycles: BP >220 deg USP >250deg
For oven: 200 deg 60min or 250 deg 30 min
For tunnel: 300 deg 5 min or 320 deg 3 min
Expect 3-log reduction in bacterial endotoxin
2nd order kinetics

23

What is the design of a heating tunnel for depyrogenation?

In-feed drying area
sterilising section
Cooling area
HEPA air over pressure - balance between two clean rooms

24

How do you qualify a dry heat oven?

IQ; OQ; PQ
IQ:
Review Equipment specifications (pressure gauges + Timing devises + Temperature recording devices)
Review structural installation specifications (levelling + insulation + sealing)
Review of utility requirement (Electrical + Pneumatic + HVAC)
OQ:
Establish consistent operation
Instrument calibration
Electircal logic
Cycle set point adjustability
Door interlocks
Gasket integrity
Vibration analysis
Lourve balance ability
Lower rotation
Blower rpm
Heater elements
Room balance
HEPA filter integrity
Verification of thermodynamic characteristics: Heat up time + Temp overshoot + heat distribution + temp drift + period of cycle
Process validation:
Equipment mapping + loaded chamber heat distribution and penetration studies
Bacillus atrophaeus (type of B.subtillus)

25

What are the other sterilisation methods apart from dry/moist heat and filtration?

Radiation: Gamma rad + electron beams + UV + Vis light + microwave
Chemical: EtO + HPV + formaldehyde

26

Tell me about sterilisation process using Gamma radiation (Cobalt 60)

Penetrate water depth equivalent of 30cm
Half life: 5.25 yrs = 10% yearly loss
Conveyer belt system
Cycle: 1-3 hours

27

Tell me about seterilisation process using electron beams (linear accelerators)

Electron beam genereated in an accleeration chamber
Narrow beam - 1cm width
Shallow penetration
short exposure time
Most need to pass through twice to get even dose

28

How is radiation doses measured in sterilisation by radiation?

Use dosimeter - strips of perspex of known optical density
Compare increase of optical density by spectrophotometer - colour change proportional to dose exposed
Sterilisation dose of 25kGy
Rare to use BI: Bacillus pumilus - D value of 3kGy
3 dosimeter in each container for gamma radiation

29

What are the critical factors to be controlled in EtO sterilisation?

Temp: 40-50 deg
RH: 33%
EtO conc: typically 250-1000mg/L
Bioburden
Time

30

How is EtO sterilisation different from other sterilisation method?

No preset protocols in Pharmacopoeias
BI used with every cycle
Kill depends on physical diffusion of the gas and water vapuour into the article or container to be sterilised

31

Describe a EtO sterilisation cycle

Load the chamber
Vacuum drawn to remove air
Heat the load to the required temp
Add water to achieve desired level of RH - allow to equilibriate
Admitt EtO gas - start hold time
Additional EtO may be reuqired to maintain conc
Circulate EtO with fan
Vacuum drawn to remove EtO
Purge with air
Quarrentine to allow residual EtO to diffuse out of the product
At least 10 strips of baccilus subtilus in load

32

What are fitlers made of?

Cellulose acetate
Acrylic polymers
Nylon
PTFE (polytetrafluorethylene)

33

What are the ways to manufacture filter?

Stretched under controlled conditions to yield pores or voids (PTFE + polypropylene)
Radiation etching (poly carbonate) + remove with strong alkaline solution

34

What are the two types of fitration action?

Seiving + entrapment (majority)

35

Describe bacterial challenge test on filter

Brevundimonas diminuta
B.diminuta 10^10 to 10^12 orgs/cm2
correctly harvest + monodispersed
Suspend product or surrogate (if product affect b diminuta)
Surrogate: non-toixic, similar to product - justify
Construct worst case scenario: pressure + flow rate + max use time + max number of sterilisation cycle + temp + effect of hydralic shock
Correlate bacterial challenge test to a filter integritty test value

36

Describe the bubble point test

Wet/saturate filter with appropriate fluid.
Pressure to about 80% of the expected bubble point per manufacturer
Slowly increase pressure until point where continuous bubble flow
If lower than expected then fail
But fail could imply temp too high membrane was not properly wetted or surface tension of fluid differs from recommended fluid

37

Describe the diffusive/forward flow integrity test

Wet membrane
remove excessive liquid
Gas and pressurise the upstream side to 60-80% of bubble point
atm pressrue maintained on the down stream side
rate of pressure decay is measured

38

How often would you carry out filter integrity test?

Tested in situ for each batch, both before and after filtration and afer any steam sterilisation step
Other less critical filters Rx Ax: autoclave vent + freeze drier vent filter + fermentation vent filter + WFI storage vessel

39

How does freeze drying work?

At pressure below 6mBar and temperature raised at constant pressure - ice - vapour (sublimation)
Can be used for heat labile and oxygen sensitive products
Low residual moisture level

40

What are the main stages of freeze drying?

Shelf loading: 5 deg +/- 3 ; 1-2hrs; 1 bar
Shelf freezing: 5 deg to -40deg over 1-2hr 1bar
Primary drying: Sublimation of water ice - 12-72hrs; 1-5bar
Secondary drying: Desorption of bound water; for 6-24 hrs; 0.01mbar
Container sealing: 25-30 deg; Nitrogen; 1bar

41

Describe media fills

Design to assess overall microbiologicla vulnerability of aseptic process
Product replaced by nutrient media - support microbial growth
Media fill replicate routine aseptic process as far as practicable
Filled and sealed containers are incubated
If positive growth - integrity of process breached
Media fill along cannot validate aseptic process
Media fill: Good process desing + well designed and maintained equipment and facility + good operator technique + EM control

42

How often would you carry out media fill?

Initial validation at start up: 3 consecutive
Each process + each line 6/12 per shift
Consider worst case: size of filling team + smallest at fastest speed + largest units at slowest speed

43

How many units should be included in a media fill?

Number of units filled - sufficient to enable a valid evaluation
Small batches: equial to the batch size with no growth
10000 units: 1 growth - investigate + 2 growths - revalidation and investigation

44

What do you understand by parametric release?

System of release that gives assurance that the produc tis of the intended quality based on info collected during the MFG process & compliance with GMP
Validation + Hazard analysis + IPC + GMP = Parametric release
Ref: Notes for guidance on parametric release
Ref: Annex 17

45

Where would parametric release apply?

Terminal Sterilised in final container - method follow EP require for steam, dry heat or ionising radiation

46

General considerations of parametric release?

only eliminate sterility testing
Data to demo process
only apply to TS in final contianer
Sterilisation methods: as EP (steam, dray heat and irradiation)
unlikely to apply to new products
Risk analysis should be performed (FMEA): risk of releaseing non-sterilised products
Good history of GMP compliance
Sterility assuranc engineer + microbiologist on site
Routine monitoring of sterilisation method - demo that initial validation applicable to routine load
Review repair/modification not compromised validated state
PPM up to date before each run
System to control bioburden
Sterilisation reocrds checked by 2 independent system
batch release: checks of PPM, repairs, modifications, calibraiton and load pattern validated load
If parametric release is in operation - non-compliances cannot be overruled by a pass of sterility test
Meausre to prevent mix up
Change control review by sterility assurance personnel

47

What is a sterility assurance system?

Sum total of the arrangement to assure the sterility of the products
Product design
EM control
Sterilisation process
Bioburden control
Sterile/non-sterile segregation
Closure/container integirty
The quality system: Validation, calibration, training, error prevention, change control, engineering aspects, FMEA, procedures, checks

48

What are the main factors that affect pulmonary deposition of drug?

Inertial impaction
Gravitational settle mentand sedimentation
Diffusion

49

What are the main ingredients of a MDI formulation?

API - micronised
Adjuvant - ethanol
Surfactants - aid suspension + valve lubrication
Propellants - HFA

50

What are the relevant IPC in MDI manufacturing?

Weight control - raise lower punch - scrape off blade
Function test
crip control
water bathing or heat tunnel

51

What are the release testing in MDI manufacturing?

ID: drug, propellants, adjuvants
Fill weight/number of doses
Moisture content
Drug content
Adjuvednt content
Valve delivery
Dose delivered: ex valvae or actuator
Dose delivered through life
Respirable dose: Anderson or TSI
Impurity and degradation products
Particle size: Malvern and microscopy
Foreign particulates
Microbial tests
Leakage

52

What are the main methods of sanitation in a pharmaceutical water system?

Thermal method:
periodic/continuous 75-80 deg at the coldst point
Limited to heat incensitive systems + does not remove biofilm
Effective in the reduction of micro + easy to validate
Chemical method:
Peracetic acid/H2O2
Need to remove added chemical
Ozone preferred: 0.01-0.02mg/L for 5min - 6 log reduction
Oxidises and reduces TOC
Toxic potential + oxygenation of water - product risk
Physical:
UV at 254nm
UV inhibits reproduction
Not very effective - use in combination with other methods
Prevent biofilm formation:
Continously run + no dead legs
Periodically/permanetly sanitised
Thoroughly monitored

53

What is D value?

Exposure time required to achieve 1 log reduction of total population at a given temp/concentration
Resistant organisms - larger D value

54

What is Z value?

Z value: increase in temp requred to achieve 1 log reduction of D value (Thermal resistant plot

55

What is F value?

Equivalent cycle time at steady state conditions - wrt lethal effect
F0 = equivalent time in minutes at 121 deg
F0 needs to be at least >8