Water,steam and Sterilisation Flashcards
What is meant by good water supply?
- Good quality council water.
- Chorinated as long as possible
- Pre-filteration
- Un-chlorinated is kept moving
- UV txt
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
How to reduce deadlegs
Self draining
Regular flushing
Frequent sanitisation
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.
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
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
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
