TOT Water for Pharmaceutical Use - Part 1.ppt

Water | Slide 1 of 25 2013

Water for Pharmaceutical Use

WHO Technical Report Series No 970, 2012. Annex 2


GMP Principle & Target AVOIDING

“MIX UP” & “CROSS CONTAMINATION”

Supplementary Training Modules on Good Manufacturing Practice

GMP Approach

“Systematic & SCIENTIFIC WAY” & “RISK ASSESMENT” with Patient Safety

Main Orientation


Objective

General principles, water system requirements and uses

Water quality specifications

Application of specific types of water to processes and dosage forms

Water purification systems, storage and distribution

Operational considerations

Inspection of water systems



Introduction

Look at information on specifications of Water for Pharmaceutical Use (WPU)

Which Quality of water to be used in production and control– APIs, finished products, etc.

GMP for design, installation, operation of systems

Supplementary to general GMP guidelines

See also other guidelines, pharmacopoeia, etc.


1.1.1 – 1.1.2


Additional guidelines

WHO Guideline for Drinking water quality (WHO)

Water and steam systems (ISPE)

Bioprocessing Equipment Standard (ASME – BPE 2000)

European Pharmacopoeia, United States Pharmacopeia, International Pharmacopoeia

Inspection of Utilities (PIC/S)


1.1.3


Principles

Like any starting material, production of water should conform to Good Manufacturing Practice (GMP) norms

Potential for microbial growth

Systems must be properly validated / qualified

Water for parenteral use should not be contaminated with pyrogens or endotoxins

Specifications and periodic sampling and testing required



Why purify raw water?

Although reasonably pure, it is always variable due to seasonal variations, regional variation in water quality

Must remove impurities and control microbes to avoid contaminating products

Treatment depends on water’s chemistry and contaminants, influenced by, e.g. rainfall, erosion, pollution, dissolution, sedimentation, decomposition



Contaminants of water (1)

There is no pure water in nature, as it can contain up to 90 possible unacceptable contaminants

Contaminant groups:

– Inorganic compounds

– Organic compounds

– Solids

– Gases

– Microorganisms




Problem minerals

Calcium, magnesium, copper, aluminium, heavy metals, arsenic, lead, cadmium, nitrates

Iron, manganese, silicates, carbon dioxide

Hydrogen sulfide

Phosphates




Microorganisms – Biofilm formation

Protozoa– Cryptosporidium– Giardia

Bacteria– Pseudomonas– Gram negative, non-fermenting bacteria– Escherichia coli and coliforms



Biofilm formation

1. Free-swimming aquatic bacteria use polymucosaccharides to colonize surfaces

2. Complex communities evolve which shed microcolonies and bacteria



Background to water requirements and use Water is the most widely used substance / raw material

Used in production, processing, formulation, cleaning, quality control

Unique chemical properties

– Able to dissolve, absorb, adsorb, suspend compounds and contaminants

Different grades of water quality available

See also EMEA "Note for guidance on the quality of water for pharmaceutical use"


1.2.1


Background to water requirements and use (2)

Control quality of water during production, storage and distribution

Contaminants, microbial and chemical quality

Microbial contamination risk and concern

Water is used on demand

– not like other materials where sampled and tested, and THEN used. Thus no batch or lot release before use. It has to meet the specification "on demand" when used

– Micro test results require incubation periods therefore results later after already used


1.2.2


Background to water requirements and use (2)

Microbial control is a high priority

Microbes may proliferate (production, storage and distribution)

System design, periodic sanitization and other measures

Different grades of water quality (dependent on its use)


1.2.3. – 1.2.4.


General Principles of water systems

Design, installation, commissioning, qualification / validation, operation, performance and maintenance to ensure reliable, consistent production of water of required quality

Prevent unacceptable microbial, chemical and physical contamination during production, storage and distribution

Operate within design capacity

Quality Assurance involved in approval of use after installation and maintenance work, or changes


2.1. – 2.3.


Water system requirements (2)

Regular monitoring of:

Water quality– Chemical and microbiological– Endotoxin level where relevant

System performance, storage and distribution systems

Records of results, trends and action taken

Validated sanitization procedure followed on a routine basis


2.4. – 2.5.


Water quality specifications

Presentation of water processed, stored and distributed in bulk. (Not applicable for patient administration)

Specifications in pharmacopoeia include different types of water

Drinking water / potable water

Bulk Purified water (BPW)

Bulk Highly Purified Water (BHPW)

Bulk Water for Injection (BWFI)


3.


Drinking water / potable water

Must comply with specification (WHO, ISO and national or regional agencies) – regular testing needed

Supplied under continuous positive pressure

Defect free plumbing system to prevent contamination

Could be from public water supply system or natural sources

Source water quality influences the treatment required


3.2.1., 3.2.3., 3.2.6.


Drinking water:

Natural sources could include springs, wells, rivers and lakes

Treatment includes desalinization, softening, removal of specific ions, particle reduction and antimicrobial treatment.

3.2.2

Water for Pharmaceutical UseWater for Pharmaceutical Use


Bulk Purified Water (BPW)

Prepared from potable water (as minimum quality feed)

Meet pharmacopoeia specification - chemical and microbial purity

Alert and action limits (determined)

Protected from recontamination

Protected from microbial proliferation

RO/EDI


3.3.1.


Bulk Highly Purified Water (BHPW)

Prepared from potable water (as minimum feed)

Specification only in the European Pharmacopoeia

Same quality standard as WFI (microbiological and limit for endotoxins)

Prepared by combination of methods including double reverse osmosis (RO) plus ultrafiltration (UF) and deionization (DI)

Protect from recontamination and microbial proliferation


3.4.1. – 3.4.3.


Bulk Water for Injections (BWFI)

Prepared from potable water source treated further, or PW

WFI is not sterile and is not a final dosage form

WFI is an intermediate bulk product

According to The International and European Pharmacopoeias – final purification step should be distillation

To meet pharmacopoeia specification for chemical and microbial purity (including endotoxin)

Alert and action limits


3.5.1 – 3.5.4.



Water used for different stages of:

– Washing, preparation, synthesis, manufacturing, formulation

Which grade of water is suitable for a particular stage?

– As required by national authority

– Consider nature and intended use of intermediate or finished product

– Stage in process where water is used

Let's look at types of water and indicate their use


4.1. – 4.2.



BHPW – preparation of products when water of high quality (i.e. very low in

microorganisms and endotoxins) is needed

BWFI– manufacture of injectable products for dissolving or diluting substances or

preparations during the manufacturing of parenterals– manufacture of sterile water for preparation of injections– final rinse after cleaning of equipment and components – preparation of steam


4.3. – 4.5.


Complete the table


UseWhich type of water?

Preparation of injectable products?

Final rinse of equipment after cleaning

?

Final rinse of equipment and components that come into contact with injectable products

?

?HPW

?Potable water


Water purification systems: So far:

Principles for pharmaceutical water systems

Water quality specifications– Drinking-water, Bulk purified water, Bulk highly purified water, Bulk water for

injections

Specific types of water for processes and dosage forms

General considerations for water purification systems

Next slides focus on water purification, storage and distribution systems



Water for Pharmaceutical

Use

Part 2 Water purification,

storage and distribution




Objectives

To examine the basic technology and requirements for:

Water purification systems

Storage and distribution requirements

Sanitization


5. - 6.



Manufacturer to select appropriate method of purification

Appropriate sequence of purification steps

Influenced by, e.g.

– Water quality specification

– Feed water quality

– Reliability and robustness of treatment system

– Supplier support, maintenance and operation costs


5.1.1 – 5.1.2.


Water purification systems (2)

Influenced by, e.g.

– the final water quality specification

– the quantity of water required by the user

– the available feed-water quality and the variation over time (seasonal changes)

– the availability of suitable support facilities for system connection (raw water, electricity, heating steam, chilled water, compressed air, sewage system, exhaust air)


5.1.1 – 5.1.2.


Water purification systems (3)

Influenced by, e.g. (cont.)

– sanitization method

– the reliability and robustness of the water-treatment equipment in operation

– the yield or efficiency of the purification system

– the ability to adequately support and maintain the water purification equipment

– the continuity of operational usage considering hours/days, days/ years and planned downtime

– the total life-cycle costs


5.1.1 – 5.1.2.


Water purification system considerations:

Location of the plant room; temperatures

Leachates and adsorptive contact materials

Hygienic or sanitary design

Corrosion; leakage

Proliferation of microbiological organisms, cleaning; sanitizing

Capacity and output requirements

Instruments, test and sampling points


5.1.3


Water purification system considerations (2)

Physical considerations:

Ability to collect samples

Space available for the installation

Structural loadings on buildings

Adequate access for maintenance

Regeneration and sanitization chemicals.


5.1.4


Pre-treatment steps

Primary filtration and multimedia filter

Coagulation or flocculation

Desalination

Softening



raw water in

« S” trap to sewer

Water is kept circulating

To water softener & DI plant

Pretreatment – schematic drawing

cartridgefilter

5 micrometers

activatedcarbon

filter

spray ball

break tank

air break to draincentrifugal pump

air filter

floatoperated

valvesand filter

excess water recycledfrom deioniser



Water pre-treatment complex in a pre-treatment room



brine and salt tank

brine

"hard" waterin

zeolite water softener-exchanges-Ca and Mg for Na

drain

"soft" water to deioniserby pass valve

Water Softener – schematic drawing



Chlorine removal (Activated-carbon (AC) filtration or bisulphite)

AC removes chlorine but bacteria can then grow

AC filtration can remove organic impurities

Bisulphite leaves sulphate residues but is antimicrobial



Production of drinking water

Derived from raw water source (e.g. well, river, reservoir)

Processes may include:– desalinization; filtration

– softening; disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection)

– iron (ferrous) removal

– precipitation

– reduction of concentration of specific inorganic and/or organic materials


5.2.1 – 5.1.2.


Drinking water (2)

Routine monitoring of quality – cover environmental, seasonal or supply changes

Additional testing when change in the raw water source, treatment techniques or system configuration

Trend review– When quality changes significantly, but is still within specification, the direct

use as a WPU, or as the feed-water to downstream treatment stages, should be reviewed and the result of the review documented


5.2.3. – 5.2.5.


Drinking water (3)

Producing drinking water through an "in-house" system requires well documented system configuration and water quality monitoring

Change control approved by QA

Storage of water:

– no degradation, ensure turnover, routine testing

"indirect impact system" – qualification not needed


5.2.6. – 5.2.8.


Drinking water (4)

System design allows for draining and sanitization

Closed storage tanks:– With protected vents– Allows for visual inspection– Draining and sanitization possible (also pipework)

Control microbiological contamination of sand filters, carbon beds, water softeners. Measures include:

– back-flushing, chemical or thermal sanitization and frequent regeneration, continuous waterflow


5.2.10. – 5.2.11.


Drinking water (5)

When supplied in bulk or by tanker – identify problems and risks

Risk control:– Vendor assessment

– Authorized certification activities

– Acceptability of delivery vehicle

Similar as other starting materials


5.2.9.


Production of Purified Water (PW) (1)

Use appropriate, qualified

methods to produce PW.

Includes: Ion exchange,

Reverse Osmosis,

Ultrafiltration and/or

EDI and distillation


5.3.1.

raw water

High pressure

Feedwater

underpressure

Reje

ctw

ater

Sem

i-perm

eab

lem

emb

rane

Perm

eate

water

drain or recycle

Low pressure

Purified water


Factors to consider in URS for PW: – feed-water quality (and variation over seasons) and water-

quality specification;

–quantity of water required;

–sequence of purification stages and energy consumption;

– extent of pretreatment needed;

– performance optimization;

– appropriately located sampling points;

–appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity, pH and total organic carbon.


5.3.2.


Production of Purified Water (2)

Ambient temperature PW systems are susceptible to microbiological contamination – especially when static and periods of low or no demand

Evidence of effective controls

Sanitization at different stages of purification

If agents are used – proof of removal


5.3.3


Production of Purified Water (3)

Controls may include:

Maintain minimum flow at all times

Control temperature in the system e.g. < 25 °C

Provide ultraviolet disinfection

Use components that can periodically be thermally sanitized

Chemical sanitization (e.g. ozone, hydrogen peroxide and/or peracetic acid) – and thermal sanitization at > 70 °C


5.3.4.


Production of Highly Purified Water (HPW)

Produced by double-pass reverse osmosis coupled with ultrafiltration or by any other appropriate qualified purification technique or sequence of techniques.

Same principles as for Purified Water


5.4.1. – 5.4.2


Branch

Branch

2nd stage buffer tank

Cartridgefilter 1 µm

Second stage RO cartridge

First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank.

1st

stag

e re

ject

co

nce

ntr

ate

Air breakto sewer

Second stage reject water goes back to first stage buffer tank

Second stage RO watermeets Pharmacopoeia

standards Outlets or storage

1st stage buffer tank

Water from softener or de-ioniser

Water returns to 1st stage buffer tank

Typical 2-stage RO schematic

Hygienic pump

First stage RO cartridge

High pressure pump



Production of Water for Injections (WFI)

Distillation is preferred technique – also in some Pharmacopoeia

Factors to consider in design:– Feed water quality– Required water quality specification and quantity of water– Optimum generator (size and variable control to prevent

frequent start/stop)– Blow-down and dump functions– Cool-down venting (to avoid contamination ingress)

Similar principles as for PW


5.5.1. – 5.5.3


Water storage and distribution systems

This section applies to WPU systems for PW, BHPW and BWFI

The water storage and distribution to work in conjunction with the purification plant to ensure delivery of water of consistent quality to the user points, and to ensure optimum operation of the water purification equipment


6



6.

What are the main components in a water storage and distribution

system?


Water must be kept

circulating

Spray ball

Cartridgefilter 1 µm

Air breakto drain

Outlets

Hygienic pump

Optionalin-line filter

0,2 µm

UV light

Feed Water from

DI or RO

Heat Exchanger

Ozone Generator

Hydrophobic air filter& burst disc


Typical water storage and distribution schematic


General

PW usually stored in a vessel for subsequent use

Storage and distribution system is a key part of the whole system

Should be appropriately designed

Configured to prevent microbial proliferation and recontamination of the water (PW, BHPW, BWFI) after treatment

Online and offline monitoring to ensure that the appropriate water specification is maintained


6.1.1. – 6.1.3


Contact materials

Materials that come into contact with WPU should be appropriate

Includes: – pipework– valves and fittings– seals– diaphragms and – Instruments


6.2.1. – 6.2.2.


Contact materials – Considerations (1)

Compatibility

Prevention of leaching

Corrosion resistance

Smooth internal finishing

Jointing

Unions and valves


6.2.2.



Compatibility– Temperature and chemicals, operation, rest and sanitization

Prevention of leaching– Non leaching – operation and sanitization

Corrosion resistance– SS316L, cleaning and passivation

Smooth internal finishing


6.2



Jointing– Smooth. Controls (welder qualification, set-up, work session

test pieces, logs, visual inspection reports

Unions and valves– Sanitary design (no threads)

Materials– E.g. SS316L, polypropylene, PVDF


6.2


System sanitization and bioburden control

Systems in place to control proliferation of microbes

Techniques for sanitizing or sterilization

Consideration already during design stage – suitable materials of construction.

Validated procedure

Special precautions if water not kept > 65 degrees Celsius


6.3.1. -.6.3.2.


Storage Vessel requirements

Design and size important

Capacity– Buffer capacity (generation and use); operate continuously,

avoid inefficiencies due to frequent on and off cycles– Sufficient for short-term reserve in case of failure

Contamination control consideration– Headspace (kept wet with spray ball / distributor device)– Nozzles (no dead zone design)– Vent filters (type, testing, use of heat)– Pressure relief valves and burst discs (sanitary design)


6.4.3



Storage Vessel Considerations and components


Requirements for water distribution pipework

General considerations

Temperature control

Circulation pumps

Biocontamination control techniques


6.5.


General considerations

Continuous circulating loop

Control proliferation of contaminants

No filters in loops or at user points

Circulation pumps – sanitary design– Stand by – no stagnant water


6.5.1.1. – 6.5.1.2.; 6.5.3.


Temperature control

Heat exchangers should not be source of contamination

– Double tube plate or double plate and frame or tube and shell configuration preferred

– arranged in continually circulating loops or sub-loops to avoid static water

– Where cooling is done – for minimum periods of time


6.5.2.1. – 6.5.2.3., 6.5.3


Biocontamination control techniques

Sanitization (chemical or thermal) - production and distribution – and include:

Continuous turbulent flow circulation

Shortest possible length of pipework

Isolated from adjacent hot pipes


6.5.4..2


Biocontamination control techniques (2)

Minimized deadlegs (NMT 3D)

Pressure gauges separated

by membranes

Use of diaphragm valves

Sloped and fully drainable


6.5.4.2





What type of valves are these?


Biocontamination control techniques (2)

There should be no dead legs

Water scours dead leg

Dead leg:Measured from the ID pipe wall to centre line of the point-of-use valve where significant stagnation potential exists

Dead leg section

Flow direction arrows on pipes are important

Sanitary Valve

D



The growth of microorganisms can be inhibited by:

UV radiation

Maintain system <25°C or > 65°C

Periodic and routine sanitizing of the system e.g. with:

– water > 70 °C)– superheated hot water or clean steam– chemicals e.g. ozone


6.5.4.2.


Water for Pharmaceutical

Use

Part 3: Operational

considerations




Objective of this part is to discuss the operational considerations of water systems including:

Start up and commissioning

Qualification and validation

Continuous system monitoring

Maintenance

Water system review


7.


Commissioning

Planned, well defined, well documented commissioning can help to ensure appropriate qualification and validation

Includes

– setting to work and system set-up

– controls and loop tuning

– System performance parameters

If commissioning is part of qualification – then appropriate level of documentation and compliance with VMP


7.1


Qualification

WPU, BPW, BHPW, BWFI are "direct impact, quality critical“ systems

Should be qualified and be subjected to DQ, IQ, OQ, PQ

DQ: Design review influenced by source water and required water quality

IQ: Installation verification of the system

OQ: operational qualification


7.2


Qualification (2)

This presentation will focus on PQ– PQ demonstrates consistent and reliable performance of the

system

Three phase approach - over extended period

Proves reliability and robustness

Include tests on source water (drinking water quality)


7.2


Phase 1.

Daily sampling (or continuously monitor) of incoming feed-water

Cover two weeks of intensive monitoring

System should operate continuously without failure or performance deviation

Water is not used for finished pharmaceutical product (FPP) manufacturing during this period


7.2


The testing approach in Phase I:

Chemical and microbiological testing – follow a defined plan

Include incoming feed-water daily to verify its quality

After each step in the purification process

Each point of use and at other defined sample points

Develop appropriate operating ranges

Develop and finalize operating, cleaning, sanitizing and maintenance procedures


7.2


The testing approach in Phase I:

Demonstrate product water of the required quality and quantity

Use and refine SOPs (operation, maintenance, sanitization and troubleshooting)

Verify provisional alert levels

Develop and refine test-failure procedure


7.2


Phase 2.

Follows Phase 1– further two week test period with intensive monitoring using refined SOPs

Sampling scheme generally the same as in phase 1

May use water if commissioning and Phase 1 data “okay”

Phase 2 to show:– consistent operation within established ranges;

– consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs


7.2


Phase 3.

Normally over one year after the satisfactory completion of phase 2

Water can be used for FFP manufacturing

Objectives of phase 3 include– to demonstrate reliable performance over an extended period– to ensure that seasonal variations are evaluated

The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2


7.2


Continuous system monitoring

After completion of phase 3 – do a system review

Then implement a routine monitoring plan (based on results from phase 3)

A combination of on-line monitoring and off-line sample testing with qualified alarm systems

Verify that the water met the pharmacopoeia and in house specification


7.3.1. – 7.3.2.


Continuous system monitoring (2)

Parameters to be monitored include:– flow, pressure, temperature, conductivity and total organic carbon,

physical, chemical and microbiological attributes

Offline samples taken from points of use or dedicated sample points (where points of use cannot be sampled)

Water samples to be taken in the same way as when water is taken for use in production. (A suitable flushing and drainage procedure followed)

Data analysed for trends – RCA and CAPA


7.3.1. – 7.3.3.


Maintenance

A controlled, documented maintenance programme covering:

Defined frequency for system elements; a calibration programme

SOPs for tasks; control of approved spares

Maintenance plan and instructions

Review and approval of systems for use upon completion of work

Record and review of problems and faults during maintenance


7.4


System reviews

Regular intervals by a team (from engineering, QA, microbiology, operations and maintenance) and cover:

– changes made since the last review– system performance– reliability– quality trends– failure events– investigations– out-of-specifications results from monitoring– changes to the installation– updated installation documentation– log books and status of the current SOP list


7.5.1.


System reviews (2)

For new / instable / unreliable systems, also review:

The need for investigation

Corrective actions and preventative actions (CAPA)

Qualification (DQ, factory acceptance test (FAT), IQ, site acceptance test (SAT), OQ, PQ) or equivalent verification documents

The monitoring phases of the system


7.5.2.


Summary

In Parts 1, 2 and 3 – we looked at:

Water requirements and uses– general principles for pharmaceutical water systems– water quality specifications– application of specific types of water to processes and dosage forms


Water storage and distribution systems– Operational considerations

In Part 4 discuss approaches to inspection of water systems





Part 4:

Inspection of water purification systems


I start with:

As much as I learn, as much as I don’t know




The Angle point of This Training session :

cGMP Compliance, QA & Inspector Perspective for Water

System

instead of Technical Construction perspective


GMP Principle & Target AVOIDING

“MIX UP” & “CROSS CONTAMINATION”


GMP Approach

“Systematic & SCIENTIFIC Based” & “RISK ASSESMENT” with Patient Safety

Main Orientation



Chapter 4Pretreatment

Options

Chapter 1Introduction Chapter 10

Commissioning and Qualification

Chapter 9Instrumentation &

Control

Chapter 8Storage and Distribution

Systems

Chapter 11Appendix

Chapter 2Key Design

Philosophies

Chapter 7 Pharmaceutical

Steam

Chapter 6Final Treatment

Options: Water For Injection (WFI)

Chapter 5Final Treatment Options: Non-Compendial &

Compendial Purified Water

Chapter 3Water Options and

System Planning


Introduction

To understand:

The nature of producing pharmaceutical water is to minimize or eliminate potential source of contamination

It must be demontrated tahat all pharmaceutical waters (non-compendial US Pharmacopeia (USP) monograph compendial waters) can be produced consistenly to spesification

USP covers 2 compedial water qualities (USP PW and USP WFI) and non compendial water

Key Design & PhilosophiesKey Design & Philosophies


Introduction

To understand:

The nature of producing pharmaceutical water is to minimize or eliminate potential source of contamination

It must be demontrated tahat all pharmaceutical waters (non-compendial US Pharmacopeia (USP) monograph compendial waters) can be produced consistenly to spesification

USP covers 2 compedial water qualities (USP PW and USP WFI) and non compendial water

Key Design & PhilosophiesKey Design & Philosophies


CPP

To understand:

Critical parameters are defined as those parameters that directly affect the product Quality.

Ex: since microbial quality cannot be diretly monitored in real time, the parameters relied upon to control microbial growth are normally considered as CRITICAL. These may include temp, UV intensity, ozone concentration, circulating system under positive pressure, etc. The rest compendial water properties mandated in the official monograph obviously

constitute critical parameters

Water system inspection techniques and approaches





Objectives

To understand:

The specific requirements when inspecting water systems, including associated documentation

Water system inspection techniques and approaches



Prepare an aide-memoire for items to inspect (1)

May include: Schematic drawing review

Changes to system since installation

Sampling procedure and plan

Specifications, results and trends

Out-of-specification results

Annual system review

Deviations


8.


Prepare an aide-memoire for items to inspect (2)

Results of system performance monitoring

Out of limit results, failure investigations and alarms recorded

Sanitization procedures and records

Maintenance and repairs logs/records

Instrument calibration and standardization

Qualification and validation including DQ, IQ, OQ, PQ

Requalification when appropriate, etc.


8.


Where to start:

What is the water to be used for?

– sterile products

– non-sterile products, e.g. oral liquid products, external applications

– solid dosage forms

– washing and rinsing

Start: Document review – site verification – followed by additional document review



Verification:

Start with document review (e.g. schematic drawing of the system, "water quality manual" if available, system review)

Review qualification reports, then change controls (in case of changes – and requalification if appropriate)

Do on site verification (system in accordance with the drawings, no leaks, calibration etc.)

Start with source water supply

Then pre-treatment and treatment systems



Documentation should reflect information on: (1)PipelineValves (non-return type)Breather pointsCouplingsPipe slopeVelocitiesSampling pointsDrain points InstrumentationFlow rates



Documentation should reflect information on: (2)Specification for each system element Standard procedures for use System changesRoutine and non-routine maintenance Investigations and corrective action Validation studiesChemical and microbiological specificationsSampling instructionsTest proceduresResponsible persons Training requirements



On site review and verification for raw water

Storage may be required prior to pre-treatment

Check material of construction of tank

– Concrete, steel are acceptable but check corrosion

– Plastics or plastic linings may leach

Check the suitability of the cover

– To keep out insects, birds and animals

Check disinfection practices



On site review and verification (e.g. PW):

Start with source water supply – follow whole system "loop"

Walk through the system, verifying the parts of the system as indicated in the drawing

Review SOPs "on site" with the relevant records, logs, results

Verify components, sensors, instruments

Inspect the finishing, state, calibration status, labels, pipes, tanks etc as discussed in previous parts of this module



Water treatment system inspection (1)

Checks may include: – dead legs– filters – pipes and fittings– Ionic beds– storage tanks– by-pass lines



Water treatment system inspection (2)

Checks may include: – pumps– UV lights– sample points– reverse osmosis– valves– heat exchangers– Instruments, controls, gauges, etc.



Other checks (1)

Material of construction

Weld quality

Hygienic couplings

Passivation procedure and records

Air breaks or “Tundish”



Other checks (2)

Pipes and pumps

– hygienic couplings

– welded pipes

– hygienic pumps

– hygienic sampling points

– acceptable floor

– no leaks



Staining on water storage tanks

Corrosion on plates of heat exchangers indicates possible contamination

Other checks (3) Check condition of equipment



Other checks (4) Maintenance records, maintenance of pump seals and O rings



Air filters

Integrity testing

Sterilization and replacement frequency

Check burst discs

Other checks (5)



Other checks (6)

Temperature-compensated conductivity meters

Influence of plastic pipe adhesive on TOC

Non-condensable gases in pure steam



Other checks (7)

UV light – monitoring performance and lamp life and

intensity

Validating ozone dosage

Specifications for acids, alkalis for DI and sodium chloride

for water softener

“Normally open” and “normally closed” valves



Documentation review may include:

Qualification protocols and reports

System review

Change control request (where applicable)

Requalification (where applicable)

QC and microbiology test results and trends, OOS and OOT

Procedures and records



Sampling (1)

Review the sampling procedure (SOP) with a sampling plan

(user and sampling points)

Sample integrity must be assured

Sampler training

Sampling point , sample size, sample container and label

Sample transport and storage

When is the test started?

Test method – is the filtration method used? Which media?



Sampling (2)

Verify compliance with the procedure and plan

Ensure that samples were taken and not skipped

Review trends

Alert and action limits, 2 sigma

OOS, OOL, OOT results

Investigations and CAPA



Testing

Review method verification

Chemical testing

Microbiological testing

– test method

– types of media used – preferred R2A

– How was the media sterilized – validated procedure

– incubation time and temperature

– objectionable and indicator organisms

– Manufacturer’s specifications



Suggested bacterial limits (CFU /mL)

See PharmacopoeiaSampling location Target

Alert Action

Raw water 200 300 500

Post multimedia filter 100 300 500

Post softener 100 300 500

Post activated carbon filter

50 300 500

Feed to RO 20 200 500

RO permeate 10 50 100

Points of Use 1 10 100



Pyrogens and endotoxins

Where required, verify testing for pyrogens and endotoxins

“Pyrogen” : When injected into mammals – will give rise to fever

Endotoxins are pyrogenic, come from Gram negative bacterial cell wall fragments

Detect endotoxins using a test for lipo-poly-saccharides (LPS)– rabbit test detects pyrogens– LAL test detects endotoxins

Ultra-filtration, distillation and RO may remove pyrogens



I N C O R R E C T W A T E R T R E A T M E N T P L A N T

Group Session

You are given a schematic drawing of a water system to discuss. List any problems you identify and discuss their solutions



M O D I F I E D W A T E R T R E A T M E N T P L A N T

Group Session



Group Session


1.Integrity test for vent filter of PW storage tanks and WFI storage tanks have been done (total 4 storage tanks), but it can not be ensured the link and match of the filter integrity report against the filter/housing filter itself. No ID filter/housing on integrity report

2.

Vent filter handling is stated on doc SOP ENG-UT/MSO/LS/032, It is not mentioned whether the integrity tested filter (with pass integrity test status) will be re-used for the next certain period or replaced with the new one.If it is prolong used, the cycle of usage should be identified, controlled, justified and documented

3.Integrity test of vent filter is executed for every 6 months, last testing was June 2014.There is no test integrity record for Jan 2014 (the previous 6 month prior to June 14)

4.

Integrity test report of vent filter is complied with singles page. It is not attached in proper form, so the potential to page missing. There is no approval from checker, just approved by single operator. Double approved Quality team (QA) is really recommended since this is product quality direct impact


Group Session


5.Observation on Raw water plantThere is no marking of acceptance criteria pressure Magnehelic Some marking of water direction flow is missing and half was blur

6.The monitoring time for recording 10 micron filter in DRW installation is not mentioned. SOP ENG-15/MSO/LS/026

7.

Documentation of Monitoring system of DRW filter is not equipped by acceptance criteria so that operator know whether it is meet spec or OOS. Marking of acceptance criteria pressure on Magnehelic is not in placeSome piping direction was found in Blur condition, can not see clearly

8.The pressure monitoring of DRW Filter 08/DRW-F-234 was OUT OF ORDER STATUS. Out of order label was in place, but its filtration system was still used for filtering process as feed water to PW generator


Group Session


9Log book filter monitoring ENG-UT/FOR/086 are equipped with star marking. The issue was happen on recurrences mode from 1-20 Oct 2014. On that issue, there is no documented investigation for closing the issue

10. Alert limit of conductivity on PW generator has not yet establishedThe control data just using action limit only.

11.Alert limit or action limit of PW quality (etc: conductivity) is not conected to proper sound/light alarm to Room supervisor or out side area of water system room

12.All calibration labels including probe sensor, display, pressure transmitter, temperature sensor of PW Generator/Christ Osmotron are over due

13.Challenge of password level authorization on PW Generator Osmotron was done during observation. It didn’t represent any pass world level in place. All people during inspection can enter osmotron PLC system using the same password. While the SOP has already been available

14.

SOP of cool loop sanitation has been available, defined frequency is every 3 months using Hydrogen peroxide.The record of the last 3 months has not yet shown to the auditor. The evidence of residual H2O2 is not documented


Group Session


9Log book filter monitoring ENG-UT/FOR/086 are equipped with star marking. The issue was happen on recurrences mode from 1-20 Oct 2014. On that issue, there is no documented investigation for closing the issue

10. Alert limit of conductivity on PW generator has not yet establishedThe control data just using action limit only.

11.Alert limit or action limit of PW quality (etc: conductivity) is not conected to proper sound/light alarm to Room supervisor or out side area of water system room

12.All calibration labels including probe sensor, display, pressure transmitter, temperature sensor of PW Generator/Christ Osmotron are over due

13.Challenge of password level authorization on PW Generator Osmotron was done during observation. It didn’t represent any pass world level in place. All people during inspection can enter osmotron PLC system using the same password. While the SOP has already been available

14.

SOP of cool loop sanitation has been available, defined frequency is every 3 months using Hydrogen peroxide.The record of the last 3 months has not yet shown to the auditor. The evidence of residual H2O2 is not documented


Group Session


15.Label of Out of Order is not using registered label

16.Inconsistency on numbering Sampling point.

17.

Period 1-14 Oct 14, record of UV intensity meter is OOS (just reached 6%).There is no documented DVR/investigation/similar adequate doc provided.Request more info: need to investigate whether any RISK assessment in place in respect to product quality since the UV is DIRECT impact CPP controlled device to eliminating Ozon

18.

Challenge test to control performance of AUTHOMATIC TLV Valve placed in production (user point) during OZON process process is not in placeThe related risk assessment in respect to any unperformed AUTHOMATIC TLV is not provided.The qualification just done on annual basis. There is no guaranty for months before re-qualification

19.Acceptance CRITERIA of Ozon concentration prior to be used by production has not established yet

20.There is no record for ensuring of OZONE contacted time is not less than 3 hours as per required by SOP ENG-UT/MSO/LS/009.It is recommended to develop study for effective OZONE contacted time


Group Session


21.Sampling point no. 17 is not equipped by proper sampling valve, the position of sampling point is not within looping system which represent PW looping condition

22.Probe conductivity of multi steel water for producing WFI was not calibrated

23.

Recommendation:The velocity of PW distribution is not in line with HAS and Local FDA requirements. 3000 liter/hours is not enough for providing turbulence flow during distribution.A risk assessment needs to be develop if the manufacturer still used their own spec


Group Session


2The timing for introducing concentrated chlorination solution has not defined yet (SOP ENG UT/SOP/PM/030. This condition has to describe chlorine concentration, initial tank condition before adding the concentrated chlorine in respect to target dose since there is no testing of residual chlorine after treatment of chlorination itself

3Daily monitoring of industrial RO unit is not equipped by acceptance criteria so that conclusion (pass/fail) of that monitoring cannot be taken. It is important data for taking further improvement. This unit is belong Darmawan’s control

4The usage of 20 micron’s filters can not be traced back since there is no documented link data due to details profile of used filter such batch no, lot no, type and other related info since there is no testing of incoming filter, CoA is just used for filter quality justification

5

1. SOP ENG UT/SOP/PM/026, monitoring of DRW filter 20 micron’s filters, 12/1 2014 has ∆ 0,2 Pa while the acceptance requirements is ˃ 0,3 pa

2. There is no appropriate column for describing ∆P on before and after filtration (DRW) so that the operators calculate by themselves without proper documentation. The record of individual filter is in place


Group Session


6There are no measurement devices to ensure the filtration performance of 1 µ filters. So on that reason, there is no performance monitoring record of that particular filtersThe frequency of filter changes are also not defined impacted by above reasons

7There is no qualification label in PW generator unit.It is suggested to perform re-qualification after usage of some period of time

8 Cold loop system:UV intensity meter is not recorded, the same issue is also happen for UV working hours

9There is no in place technique to check the turbulence of PW inside of distribution piping. The appropriate flow meter is not in place

10Alert limit and action limit of conductivity are in place but the operator can change such water CQAs and CPPs without getting authorization from related manager. Password management needs to re-change the password and re-training


Group Session


11

The cold loop report ENG- UT/FOR/PM/026 has not yet approved by QA but the PW itself has been distributed into production area.QA approved is required as per established SOP since this is CRITICAL step which needs quality people decision. The related form has been established

12Challenge test of main distribution valve after cold sanitation is not in place. There is no adequate system to ensure that the valve is always working properly while its valve is not equipped by the periodic qualification.

13

Venting filters on storage tank:The usage of 0,2 micron’s filters can not be traced back since there is no documented link data due to details profile of used filter such batch no, lot no, type and other related info since there is no integrity testing of incoming filter, CoA is just used for filter quality justificationThe sequence activities for handling of filter change filters has considered cross contamination issues, but the SOP has not up dated yet as per the actual handling


Group Session


14The sequence of QC sampling time and PW distribution sanitation time is not representing worst case condition, since it is only show the best case condition. QC sampling is in Tuesday while sanitation is Sunday

15Ozone meter for checking residual ozone is not in place, but the operator use other system for ensuring there is not residual ozone inside of PW. After ozonization, the PW is drained, but there is no record & evidence in place for ensuring that the PW tank is empty before refill the new PW


Group Session


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TOT Water for Pharmaceutical Use - Part 1.ppt

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