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David W. Vincent Critical Utility Systems Page 1

6th Annual EU Validation Week

David W. Vincent

SESSION 17: Critical Utility Qualification —

HVAC and Water Systems

- Case Study

Amsterdam, Netherlands

March 17 – 19, 2015


OVERVIEW OF SYSTEM

Water System Design – Pretreatment, Purified

Water, Still, WFI Storage & Distribution System

HVAC System – Design to meet 4 Classification

(Grade D, C, B and A)

Purified Water System and HVAC Qualification

– Case Study


STORAGE, SAMPLING, TESTING

REQUIRMENTS AND QUALIFICATION

WATER SYSTEM QUALIFICATION


Qualification of Water System

• PART 1

• Water System Design

• PART 2

• Qualification and Requalification of Process Systems

• PART 3

• Monitoring - Sampling and Testing Frequencies

• PART 4

• Physical, Chemical and Microbiological Testing Parameters

• PART 5

• Testing Methods and Requirements

• Alert and Action Levels

• Documentation and Trending of Data Monitored

• PART 6

• Requalification Considerations for Water Systems


Design Specifications

• Pretreatment URS Requirements

• Feed Water Storage Tank – Potable Water/City

• Gravel Filter (Filter Mix Beds) – remove solid

contaminants

• Activate Carbon Filters - adsorb low molecular

filters to weight organic material and oxidizing additives

• Softeners the water - remove water-hardness ions

• Ion Exchange System - removing cations and

anions.

• Sanitary Valves – control the distribution water

• Process Piping – directs transfer water

• Controls – RTD, Flowmeters


Pretreatment System

feed water

To RO/EDI



• Purified Water Generation

• RO System - chemical, microbial, and endotoxin

quality improvement.

• Pre-Filter – remove larger particles

• EDI – Ion Exchange (removing cations and

anions)

• Distribution Piping – transfers purified water

• Sanitary Valves – prevent biomass from building

up

• Controls – RTD, Flowmeters, Pressure

Gauge – control the condition of the water


RO and EDI System

feed water

poits of use



• Purified Water Storage and

Distribution System

• Storage Tank – Vent Filter – Storage of H2O

• Heat Exchanger - Control Temperature

• Distribution Piping – directs H2O to POU

• UV Lamp - 254-nm wavelength for microbial

control

• Points of Use – distribute PW to local site

• Sanitary Valves

• Controls – RTD, Flowmeters


Storage Tank and Distribution Loop

feed water

poits of use


Test Items for Qualification of

Process Systems (2)• Based on this table, the qualification team determines by means of a risk-based

• approach …

– the sampling points, e.g. by answering the following questions… Which points of use are critical ?

Which points of use are system-specific ?

Is it necessary to realize a particular sampling point (due to the unattainability of the point

of use) ?

Usually, selected sampling

points include…

significant points of use

return loop

points prior to and after each

significant treatment step

storage tank


Water Systems (2)

• Pharmaceutical water - used for product compounding or final

rinsing of surfaces - exists in different (compendial) qualities

such as:



• PART 1


• PART 2


• PART 3


• PART 4


• PART 5




• PART 6



Process Systems – General

Qualification Provisions

• Qualification is required for Water Systems –

Commissioning Pretreatment, Qualification of the Purified

Water Generation/Distribution System & WFI System

• that is involved in the manufacture of APIs (beginning with the

regulatory starting materials), Drug Products or intermediates

• that may affect testing results of an API, Drug Product or

intermediate,

• that is involved in final cleaning processes,

• where the utility supplied directly contacts an API, Drug

Product or intermediate,

• where the utility supplied comes in contact with surfaces

that have direct contact with APIs, Drug Products or

intermediates,

… and, therefore, could have an impact on the quality of the API,

Drug Product or intermediate.


Prerequisites for Qualification of

Process Systems

Before beginning the qualification of a process system, the

following documentation has to be available:

• URS have been written

• System Impact Analysis and Critical Component Analysis Performed

• SAT has been executed with no deviation

• P&IDS have been redlined

• Draft Operation and Maintenance SOPs Developed

• All critical Devices Calibrated

• IQ or OQ Protocols approved


Test Items for Qualification of

Process Systems (1)• Following table outlines parameters and aspects to be checked, evaluated and tested

within the qualification study of a process system, provided that these are relevant for

the particular qualification (see following slide).


Particular Considerations for Water

Systems Qualification

• In case of water systems, the qualification process entails a three-phase

approach in order to satisfy the objective of demonstrating the reliability and

robustness of the system in service over an extended period.


Performance Qualifcation for Water

Systems (2)

• Phase 1:

– Initial phase, usually taking 2 to 4 weeks, serves to establish operating parameters

and procedures,

– Does not end until the system operates stable and within the required ranges,

– Might be shortened in case of modifications to a water system already in use.

• Phase 2:

– Short-term control phase usually taking 2 to 4 weeks, serves to demonstrate

consistent operation within the established ranges,

– Before water is permitted to be used for pharmaceutical purposes, an interim

qualification report is required, documenting the successful completion of Phase 2.

– However, water can also be used for pharmaceutical purposes during this phase,

provided that the respective batches are not released until the interim qualification

report has been finalized.


Particular Considerations for Water

Systems (3)• Phase 3:

– Long-term control phase usually taking 1 year, serves to demonstrate

continuous and consistent operation irrespectively of external and seasonal

variations.

– Physico-chemical properties, microbial counts (as well as endotoxin where

required) are monitored and evaluated at close intervals,

– Where the season affects the quality of the feed water (e.g. potable water),

sampling should be increased.

– Phase 3 ends with the preparation of the final Qualification Report.


Qualification Phase

• PART 1

• Water Systems

• PART 2

• Qualification of Water Systems

• PART 3


• PART 4




• PART 5

• Monitoring – Sampling and Testing Frequencies

• PART 6

• Particular Considerations for Water Systems


Physical, Chemical and Microbiological

Testing Parameters

TEST MODULE SPECIFICATIONS REFERENCE

Appearance Clear, Colorless Liquid Ph. Eur. and USP

Conductivity < 1.1 µS / cm (20oC) or values as per Ph. Eur.

Table

Ph. Eur. and USP

Nitrates and Nitrites Not more intense in color than reference,

corresponding to < 0.2 ppm

Ph. Eur.

Total Organic Carbon

(TOC)

< 0.5 mg / L Ph. Eur. and USP

Heavy Metals Not more intense in color than reference,

corresponding to < 0.1 ppm

Ph. Eur.

Microbial Contamination max. 10 cfu / 100 ml Ph. Eur. and USP

Bacterial Endotoxins < 0.25 EU / ml Ph. Eur.

Following table outlines testing specification for high purity water system



• PART 1


• PART 2


• PART 3


• PART 4


• PART 5




• PART 6



Monitoring – General Requirements

– Water systems undergo periodic monitoring of the specified required characteristics.

– The monitoring program is based on the

results of the qualification* work and/or

according to the results of a risk assessment.

– Monitoring is performed according to written

procedures, describing in sufficient detail the

responsibilities for sampling, the sampling sites,

and the sampling frequencies.

– Typical minimum sampling frequencies for process systems are described in slide

– Higher or lower sampling frequencies for specific processes or products are justified

according to the results of a risk assessment.


Sampling Method

– Sampling sites must be selected based on a risk evaluation and / or as result of the initial

qualification.

– Samples have to be taken from representative locations within the distribution and

processing system.

– Selection of sampling sites must not compromise the quality (e.g.: microbiological status)

of the system being monitored.

– The sampling plan has to be dynamic allowing for adjustments to sampling frequency and

locations based on system performance trends.

– When routine monitoring points are reduced or increased, the reason for the change has

to be documented.

– Sampling practice must simulate the use of a process system during manufacturing,

for example where water for manufacturing is delivered through a hose,

sampling has to be performed through this hose.


Monitoring – Typical Minimum Sampling & Testing Frequencies


Sampling Point & Point of Use

Preparation

Vessel

point of use point of use

= sampling point

sampling point

sampling point

Sampling Point & Point of Use may or may not be the same (see the diagram below):

Monitoring – Typical Minimum Sampling

& Testing Frequencies


UV

Disinfection

unit

Points of Use

Return

Storage Tank

Mixed ion

exchange bed

Particle Filter

Pump

Ventilation Filter

Particle

Filter

UV

disinfection

unit

Feed Water

Inflow




ReturnInflow




Test Methods and Method

Requirements

– All methods must be performed according to

current USP and/or European Pharmacopoeia

and, if applicable other pharmacopoeia and/or

local requirements (e.g. in case of potable water).

– All methods or culture media have to be suitable

to detect microorganisms that may be present.

The cultivation conditions, are selected to be

appropriate for the specific growth requirements

of microorganisms to be detected, for example:

• Total aerobic count can be obtained by incubating at 30 to 35 °C for not less than three

days

• Suitable culture media (low nutrient medium) is used for monitoring of water systems (30

to 35°C, at least 5 days).

– Testing of viable monitoring samples is performed under aerobic conditions unless there are indications

that the process is at risk for contamination with anaerobic microorganisms.

– It must be assured that cleaning or disinfection agents remaining on surfaces sampled does not interfere

with microbial recovery when methods using culture media are applied.



• PART 1


• PART 2


• PART 3


• PART 4


• PART 5




• PART 6



Alert and Action Level in Microbiological

Monitoring

– An Alert level in microbiological monitoring is that level of microorganisms that shows significant

differences from normal operating conditions.

– Alert levels are usually based upon historical information gained from the routine operation of the

process in a specific controlled environment.

– In a new facility, these levels are based on prior experience from similar facilities/ processes.

– Alert levels are re-examined and – if necessary – re-set at an established frequency. Trends that

show a deterioration of the environmental quality require respective CAPAs.

– An Action level is that specification level of microorganisms or particles that when exceeded

requires immediate follow-up and, if necessary, corrective action.

Common procedure of setting alter level based on a set of at least 12 months data:

95% of all results < alert level AND 5 % of all results ≥ alert level

Typically, the initial alert level is set to…

50 % of the action level (specification limit)


Alert and Action Level in

Microbiological Monitoring (2)

• Procedures when an Alert level is exceeded

– Exceeding the Alert level does not necessarily require

a definitive corrective action, but it prompts at least

documented follow-up measures, as established in

a local procedure.

– These measures include but are not limited to the following:

o Comparison with results obtained concurrently with other related sampling

points.

o Comparison with historical data from the same sampling point.

o If possible re-sampling of the affected sampling point; routine sample(s) taken

from the affected point(s) within this period can be considered as resample.


Action and Alert Level in Microbiological

Monitoring

• Procedures when an Action level is exceeded

– As soon as an Action level excursion is reported,

“immediate corrective actions” and an investigation

have to be performed as described in a local procedure.

– An evaluation of the potential impact this exceeding

has on manufactured products has to be made.

– When a definitive cause for the excursion can be determined immediately, specific

corrective actions are performed before re-sampling starts.

– Re-sampling of the affected points has to be performed immediately after the

implementation of “immediate / specific corrective actions”.

– Monitoring critical sampling points includes routine identification of

microorganisms to the species (or, where appropriate, genus) level

at least when Alert and Action Levels are exceeded.



• PART 1


• PART 2


• PART 3


• PART 4


• PART 5




• PART 6



Documentation and Trending of

Monitoring Data

All monitoring activities are documented properly (typically on form sheets which are

laid down in SOPs).

The results from critical sampling locations must be assignable to the respective

activity at the time of sampling (important in case of batch-related monitoring, i.e. the

environmental monitoring data must have a formal linkage to product release as

defined by procedures).

Monitoring data must be summarized on a periodic basis and issued to the

responsible senior management on a periodic basis (e.g. via Product Quality

Review).

Based on this summary, trends have to be evaluated and corrective action to be

defined, if appropriate.



• PART 1


• PART 2


• PART 3


• PART 4


• PART 5




• PART 6



Requalification of Process Systems

• For-Cause Requalification

• Generally, in case of changes or modifications, the same test items apply for requalification as for initial

qualification. However, based on a risk evaluation, the extent of a requalification may be reduced in comparison

to the initial qualification.

• Periodic Requalification

• The following periodic requalification

intervals apply:

• However, the regular evaluation of the

• existing documentation such as…

– monitoring data,

– quarterly reports,

– change documentation,

– logbooks,

– maintenance/servicing documentation,

– technical reports

• … equates to periodic requalification, provided that relevant

• requalification item are appropriately covered.

Process System Requalification Interval

Water for Injection Annually

Pure Steam Annually

High Purified Water Annually

Purified Water Annually

Pretreatment Every 2 years


QUALIFICATION, AND SAMPLING,

TESTING REQUIRMENTS

HVAC SYSTEM QUALIFICATION


Qualification of HVAC System

• PART 1

• HVAC System Design

• PART 2

• Qualification of Systems

• PART 3


• PART 4

• Physical, Microbiological Testing Parameters

• PART 5




• PART 6

• Requalification Considerations for HVAC Systems


Objectives

In the following slides, we will study the components

of air- handling systems in order to:

1. Become familiar with the components

2. Know their functions

3. Become aware of possible problems

HVAC


Impact Assessment

• “Direct Impact” Systems are expected to have an impact on product quality

• Indirect Impact systems are not expect to have an impact on product.– Both types of systems will require

commissioning; however, the “Direct Impact” system will be subject to qualification practices to meet additional regulatory requirements of the FDA and other regulatory authorities

– System Impact Assessment Form Direct HVAC System Template Part 1.doc

System Impact Assessment Form Direct HVAC System Template Part 1.doc


FilterSilencer

Terminal filter

Weather louvre Control damper

FanFlow rate controller

Humidifier

Heating

coil

Cooling coil

with droplet

separator

Production Room

Overview components

+

Prefilter

Exhaust Air Grille

Heater

Secondary Filter

Recirculated air

HVAC


• Weather louvre

• Silencer

• Flow rate

controller

• Control damper

• To prevent insects, leaves, dirt and

rain from entering

• To reduce noise caused by air

circulation

• Automated adjustment of volume of

air (night and day, pressure control)

• Fixed adjustment of volume of air

Components (1)

HVAC


• Heating unit

• Cooling unit/ dehumidifier

• Humidifier

• Filters

• Ducts

• To heat the air to the proper

temperature

• To cool the air to the required

temperature or to remove moisture

from the air

• To bring the air to the proper

humidity, if too low

• To eliminate particles of

predetermined dimensions and/or

microorganisms

• To transport the air

Components (2)

HVAC


Control damper for airflow

De-humidification

Filter Pressure

Gauges

AHU with fan Variable

Speed Controller

Humid room air

Air heater

Regeneration air

Humid room airAdsorber wheel Dry air

Air-handling unit

HVAC


Positioning of filters (1)

Filter in terminal position AHU mounted final filter

Production Room

+

Production Room

HEPA Filter

HEPA Filter

HVAC


Regulation of room pressure – pressure differentials

concept

Room pressure

gauges

Room pressure indication panel

HVAC


HVAC

Consider different air types, e.g.:

• Supply air

• Return air (recirculated air)

• Fresh air (make-up air)

• Exhaust air

And: Concepts of air delivery to production areas:

• Recirculation systems

• Full fresh-air systems


+

Production Room

Exhaust

air

Return air

(recirculated)

Fresh air

(make-up air)Supply

air

Air types

HVAC


HVAC



• PART 1


• PART 2


• PART 3


• PART 4

• Maintenance for HVAC Systems


A Qualification approach for HVAC systems

Key Definitions :

• DQ - Design Qualification

• IQ - Installation Qualification

• OQ - Operational Qualification

• PQ - Performance Qualification

• VMP - Validation Master Plan

• GEP - Good Engineering Practice


Qualification Risk Based

Assessment

• “Direct Impact” Systems are expected to have an impact on product quality therefore the level of validation or qualification must be determine by using Qualification Risk Based Asessment

• Qualification Level Analysis Form Direct HVAC Template Part 2.doc

• Qualification Level Analysis Results Form Direct HVAC Template Part 3.doc

Qualification Level Analysis Form Direct HVAC Template Part 2.doc

Qualification Level Analysis Results Form Direct HVAC Template Part 3.doc


A Qualification approach for HVAC Systems

A Validation Master Plan

Design Qualification

User requirement document

Installation Qualification

Operational Qualification

Performance Qualification


A Qualification approach for HVAC

Systems

Critical vs non-critical systems :

(Risk or Impact assessment)

Impact assessment

Critical component

Non-critical component

ISPE Definition: Impact assessment is the process

by which the impact of a system on product quality

is evaluated and the critical components within

those systems are identified.


Critical Components

• A critical component within a system where

the operation, contact, data, control, alarm

or failure will have a direct impact on the

quality of the product.

• Eg. Supply air fan in an AHU, HEPA filters,

HVAC control system.


Non-critical Components

• A non-critical component within a system

where the operation, contact, data, control,

alarm or failure will have an in-direct, or no

impact on the quality of the product.


System

An organization of engineering

components that have a defined

operational function.

System Boundary

A limit drawn around a system to

logically define what is, and is not,

included in the system.

System Boundary Approach


Impact Assessment

• Identify systems, and develop of system

boundaries

• Perform impact assessment for

determination of direct/indirect or no

impact systems


System Impact Assessment

• The process of evaluating the impact of the operating, controlling, alarming and failure conditions of a system on the quality of a product.


Define System Boundaries

Sample P&ID of HVAC and BAS Equipment


Component Criticality Assessment

Process

• The components within “Direct Impact”,

Indirect Impact” and in some cases “No

Impact” systems should be assessed for

criticality.



Systems

User requirement specification (URS)

What operational requirements are there ?

Required room temperatures and relative

humidities

Cleanroom classifications for the areas

Single pass or re-circulated HVAC systems ?

Room pressures / Air flow directions

GMP requirements



Systems

DESIGN QUALIFICATION (DQ)

First step in the qualification of new HVAC

systems.

It documents the design of the system and will

include :

a) Functional Specification.

b) Technical / Performance specification for equipment.

c) Detailed Air Flow Schematics.

d) Detailed layout drawing of the system.



Systems

A thoroughly executed DQ process ensures the following :

Compliance with GMP’s and other regulatory requirements.

Design meets the user requirements.

Design details facility airflow and pressure cascade philosophy.

Design takes into account process and personnel flow (cross-contamination

issues)

Design details materials of construction.

Design details safety requirements.

Full details of the intended construction prior to implementation.

Details all equipment that must be ordered.

ISPE Baseline Guide Vol.5



Systems

Installation Qualification (IQ)

The goal of IQ is to verify and document the quality,

installation and integrity of the HVAC system.

Execution of IQ protocols provides assurance that a

HVAC system is installed in accordance with the qualified

design.

IQ should highlight discrepancies between design

layouts detailed in the DQ and what has been constructed

(‘As-built” status)



Systems

IQ should include, but not be limited to the following :

a) Installation of equipment, piping, services and

instrumentation checked against current engineering

drawings and specifications

b) Collection and collation of supplier operating and

working instructions and maintenance requirements

c) Calibration of measuring instruments requirements

d) Verification of materials of construction

Ref : PIC/S Annex.15



Systems

Practical aspects of IQ :

Design drawings can be marked up and deviations highlighted.

DQ to be complete and signed off before IQ begins.

IQ protocols to be written and approved prior to implementation.

Check lists for components to be installed can be used. Items such as

fans, fan motors, cooling and heating coils, filters, temperature and

relative humidity sensors and differential pressure gauges can be included

in check lists.

Duct and pipe pressure test reports.

Filter integrity tests.

Functionality Loop checks and alarm tests for HVAC control systems.


A Qualification approach for HVAC Systems

Practical aspects of IQ (cont.) :

Calibration of measuring instruments.

Calibration of additionally used instruments.

Initial cleaning records.

Basic commissioning checks.

Maintenance requirements.

IQ process checks that the correct components are installed in the

correct location.

Materials of construction

Spare parts

Change controls


Operational control / operation within established

limits and tolerances can be demonstrated by any of

the following :

Ability to maintain temperature, relative

humidity and pressure set points.

Ability to provide air of sufficient quality

and quantity to ensure achievement of

specified cleanroom conditions.

Ability to maintain any critical parameters

stated in the DQ consistently.


Operational Qualification should include, but

not be limited to the following :

• Tests that have been developed from

knowledge of processes, systems and

equipment.

• Tests to include a condition or a set of

conditions encompassing upper and lower

operating limits, sometimes referred to as

‘worst case’ conditions.

Ref : PIC/S Annex.15


Practical aspects of OQ :

– IQ reports must be completed and signed off.

– OQ protocols to be written and approved prior to completion.

– Measurement reports are required to demonstrate achievement of critical parameters as detailed in DQ.

Eg: * Temperature measurement report

* Humidity measurement report

* Differential pressure measurement report

* Air flow direction measurement report

* Room particle count measurement report

* All drawings etc. – done in ‘as-built’ status

* All maintenance/ cleaning instructions available

* All O & M staff to be trained to use and maintain the HVAC system.



Systems

• The purpose of PQ is to verify and document

that an HVAC system provides acceptable

operational control under ‘ full operational ‘

conditions.

• PQ verifies that over time, the critical

parameters , as defined in the DQ are being

achieved.

• PQ should follow successful completion of IQ

and OQ.

PERFORMANCE QUALIFICATION ( PQ)



Systems

• Tests, using production materials,

qualified substitutes or simulated product,

that have been developed from

knowledge of the process and facilities,

systems or equipment.

• Test to include a condition or set of

conditions encompassing upper and lower

operating limits.

PQ should include , but not be limited to the following:-



Systems

• PQ tests can consist of the following :-

Air flow direction tests

Room pressure tests

Room temperature monitoring

Room relative humidity monitoring

Room particle monitoring

Microbiological monitoring

Practical aspects of PQ (cont.) :


Performance Qualification Phase

• Static State/Dynamic Monitoring

– Static State Monitoring: Normally Performed over 3

Day Period with the room in at rest condition (no

Activity)

– Dynamic State Monitoring: Normally Performed

over 3 to 5 Day Period under manufacturing

conditions occurring.



• PART 1


• PART 2


• PART 3


• PART 4



Physical, Microbiological Testing Parameters

– a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.

– b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A.

– c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis.

– d- The additional use of settling plates is optional.

– e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

•TABLE 1- Air Classification



• PART 1


• PART 2


• PART 3


• PART 4



Maintenance of HVAC systems

• The validation process should ensure that all

maintenance information is obtained prior to

the handover and use of the system.

• The validation process should ensure that

preventative and planned maintenance are

put into practice.


Maintenance of HVAC systems

• HVAC systems will not achieve the

required critical parameters.

• Correct air flows may not be guaranteed

• Correct room temperature and relative

humdity may not be achieved.

• Room cleanliness can be compromised

• Cross contamination could be promoted

instead of being prevented.

What happens when maintenance is done poorly or not

at all ?


Thank You

Question and Answers

Validation Technologies Inc. 82

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