1 1PharmaceuticalUtilitiesrev PDF

ETIF 2008
Costa Salguero Centre - Buenos Aires - Argentina

24 October 2008
Pharmaceutical Utilities,
current regulation,
qualification and validation
Giovanni Bini
Contents
Pharmaceutical Utility Systems
Systems Design & Validation Approach
A validation approach example: WFI distribution system
Normative References
The design phases
• User Requirements Specifications
• Functional Specifications
• Design Specifications
The Validation phases
• Design Qualification
Commissioning
The Validation phases
• Installation Qualification
• Operational Qualification
• Performance Qualification
2
Pharmaceutical utility systems
Each pharmaceutical (but also cosmetics, food,

chemical…) industry’s manufacturing process uses
several support system with different functions and
generated and distributed with centralized installations.
These systems are not necessarily designed and
customized for users of a single production facility, but
often serve an entire factory or part of it.
3
The most common systems of this type are:
• Process waters (different types)
• Cooling and/or heating fluids (steam, water, brain,
diathermic oil, etc)
• Air conditioning (HVAC systems)
• Compressed air, nitrogen
• Burning gas
• Process gas (CO2, O2, etc)
• Drinking and sanitary water
• Fire-fighting water
• Vacuum
• Various kinds of waste system (rainwater, medical,
process, biological, gas, etc.)
• Electric power
4
A good working of these systems ensures efficiency of production.
For example, the sudden lack of steam might impair a heating phase
(e.g. during a synthesis reaction) or a sterilization cycle, with the risk
of compromising an entire batch of production. The lack of vacuum
might block a filtering or drying process, causing damage to the
product.
An accurate preventive maintenance program of the systems can limit

such incidents and subsequent blocks of production.
5
The production support systems used in pharmaceutical

industry can be classified in three categories as follow:
• process systems (direct impact system)

• process support systems (indirect impact
system)
• utility systems (non-impact systems)
6
Process systems (direct impact systems)
They are:
• in direct contact with the product;
• in contact with those materials which will later be

transformed in the product or will be in direct
contact with it.
For example, process water (water for injections, purified or drinking

water) are generally considered as direct process systems.
7
They are always considered critical because they are actually or

potentially in direct or indirect contact with the product.
They must be designed and constructed considering the needs of
product quality and to prevent any contamination to the product
itself.
Incorrect design and/or construction methods may leave residues on
the inner surface of equipments or pipes that can cause
contamination of the distributed fluid and, consequently, of the
product.
For these reasons, it is often important to have a high degree of
surface finishing, or specific methods of construction (e.g. welding),
or cleaning and keeping systems that can provide the necessary level
of protection against contamination.
8
From a GMP point of view, support systems that meet the definition
of " process systems ", should be considered as real raw materials.
Due to the fact that process systems can directly, indirectly or
potential affect product quality, the same degree of control of the
production process should be applied to them, and they must be
qualified according to the classic approach of validation.
It is also important to check the qualitative aspects of the material
that comes to points of use (usually consisting of a fluid), since any
chemical or microbiological contaminants impurities would be found in
final or intermediate products, and compromise quality.
9
Process support systems (indirect impact systems)
They directly support process operations, but have no

contact with the product or with materials that will be
transformed into product.
Some examples of support systems for the process: cooling and
heating fluids that exchange heat with process materials through a
surface (heat exchange jacket applied to reactors, tanks, dryers, etc...
shell and tube, double pipe, plate exchangers, etc…)
The solutions used for equipment and/or machine washing (CIP
systems - Cleaning in Place or manual systems for washing) are
generally considered process support systems, except those used for
the final rinsing that are considered as process fluids.
10
Process support systems (indirect impact systems)
The process support systems are not generally considered critical

In these systems, in general, the qualitative aspects of the fluid have
no relevance. Instead the physical features available at point of use
(temperature, pressure, flow, etc..), and availability for the needs of
process in contemporary condition of use with other points of use
have more relevance.
From a GMP point of view, system availability to users has relevance,
while the qualification of plant and functional aspects of the system
follow the Good Engineering Practices (GEP), which are based mainly
on the proper design and a comprehensive "commissioning" of the
system (drawings "as built", tracking changes, testing, SOPs, etc.).
11
Utility systems (non-impact systems)
• They are not in contact with the product or material

that will then be transformed into product;
• They are not customized systems to specific users
but distributed with general networks serving all the
users of the factory;
• They deal with side effects of an industrial production
such as waste disposal.
Examples of service systems are the systems of drinking water,
sanitary water, electricity.
12
Utility systems (non-impact systems)
Typically, such systems did not impact on the product

quality and, therefore, are never considered critical.
In this case also, the qualification of the plant and
operating systems follows the good engineering practices
(GEP).
Electricity can instead have a critical role (e.g., Loss of
data or interruption of production processes).
In these cases the supply to its customers critical points is
ensured by appropriate systems (automatic back-up
generators, un-interruptible power systems), that are able
to overcome possible discontinuity of supply from the
distribution network.
13
EU GMP volume 4
Annex 15 - “Qualification and Validation”(2001)
ISPE Baseline Engineering Guides

Vol. 5 -“Qualification and Validation”(2001)
PIC/S
PI 006/2 - “Recommendations on VMP, IQ and OQ, non sterile
process validation, cleaning validation”(2004)
FDA
“General Principles of Process Validation”(1987)
14
Qualification and Validation of the manufacturing and process systems,

facility and equipment is intended as the documented verification that
they, as installed, comply with the approved design, operate within the
approved functional specification and are consistently able to perform
the scopes they has been intended for.
Consequent by above definition, GxP Critical System Qualification and

Validation Execution could be performed only if correct and
exhaustive Design has been done, aimed to define documented and
approved intended use, scope, operative range, not only for the system
itself but also for system’s component, building characteristic and
installation.
15
The Design Phases
THE DESIGN OF THE MANUFACTURING SYSTEMS / WATER DISTRIBUTION
FOR PHARMACEUTICAL USE SHOULD BE STRUCTURED UPON THE GOOD
ENGINEERING PRACTICES (GEP), UPON THE THREE PHASES:
Document that defines in a clear, precise and concise way

what the user wants the system to do: conditions,
User Requirements
Specifications starting specs, functions that must be performed; specs
as outcomes; environmental conditions in which the
system operates and eventual constraints
Document that defines a system and/or its

Functional components in terms of functions that must be
Specifications performed and or services that must be attached
to the system itself to satisfy the URS
Documents describing the building details

Design and the specs of installation of the system,
Specifications on the basis of which the system itself will
be built
16
Planning for Validation
2. All validation activities should be planned. The key elements of a

validation programme should be clearly defined and documented in
a validation master plan (VMP) or equivalent documents.
3. The VMP should be a summary document which is brief, concise and
clear.
4. The VMP should contain data on at least the following:
(a) validation policy;
(b) organisational structure of validation activities;
(c) summary of facilities, systems, equipment and processes to be
validated;
(d) documentation format: the format to be used for protocols and
reports;
(e) planning and scheduling;
(f) change control;
(g) reference to existing documents.
(EU GMP - Annex 15 – Qualification and Validation)

17
The Validation Phases
9 DESIGN QUALIFICATION = DQ
9 INSTALLATION QUALIFICATION = IQ
9 OPERATIONAL QUALIFICATION = OQ
9 PERFORMANCE QUALIFICATION = PQ
18
User Requirements Performance

Specifications Qualification
Functional Operational
Design Installation
Design System build

Qualification & Commissioning
Qualification
Design phases phases
19
A validation approach example:
Water for Injection distribution system
20
Water for Injection distribution system Validation
USP 31
Monograph <1231> - “Water for Pharmaceutical Purposes” (2008)
FDA
“Guide to Inspections of High Purity Water Systems” (1993)
ISPE Baseline Engineering Guides

Vol. 4 & APPENDIX -“Water and Steam Systems”(2001)
ISPE Best Practice Guides

“Commissioning and Qualification of Pharmaceutical Water and Steam
Systems” (2007)
21
The Design Phases

User Requirements Specifications
WATER FOR PHARMACEUTICAL USE MUST NOT INTRODUCE IN THE

PRODUCTS ESTRANEOUS ELEMENTS THAT COULD CONTAMINATE IT
OR REACT WITH IT
The purification processes (pre treatments and final purification) must

produce water of the required quality
&
The storage system and the distribution of the water for pharmaceutical
use must not alter the quality of the water in the points of use.
22
The Design Phases

User Requirements Specifications
9 Flow-rate, quantity and frequency of the samples at points of use
9 Location of the points of use
9 Temperature of use in the points of use
9 GMP requirements recommended by normative or guidelines:
• Distribution system in loop
• Limitations of the dead legs
• Minimum speed of the water
• Materials in contact with water
• Sanitization system
• Surface finishing
• Typology of the equipment and accessories of piping
• Junction typology
• Welds
• Sampling points
• Drainage
23
The Design Phases

Functional Specifications
9 Circulation flow and maximum simultaneously samplings
9 Storage volume
9 P&I scheme of the system (equipment, instruments, regulation
loop, control system)
9 Dimensioning of the main equipment
9 Piping track
9 Specs of the materials
9 Functional specs of the equipment and of the instruments
9 Piping specs
9 Functional specs of the control system (sequences, operator
interface, printings, videos, access, security, audit-trail, etc..).
9 Application of the GMP requirements from the norms and the
guide-lines.
24
The Design Phases

Functional Specifications
Preliminary P&ID
25
The Design Phases

Design Specifications
9 Building drawings of the main equipment

9 Selection of the equipment and standard instruments
9 Piping dimensioning
9 Building piping sketches (welds position, sloops)
9 P&I scheme for building
9 Implementation and customization of the software
9 Etc…
26
The Design Phases

Final P&ID
27
The Design Phases

Final P&ID
28
The Design Phases

Isometric Sketch
29
The Design Phases

Isometric sketch
30

User Requirements
Specifications
Functional 9 OPERATIONAL QUALIFICATION = OQ

Specifications
Design (EU GMP - Annex 15 – Qualification and Validation)
Specifications
Design
Qualification
31

European GMP – ANNEX 15 ed.June2001
“The first element of the validation of new facilities,

systems or equipment could be design qualification (DQ)”
(punto 9)
“The compliance of the design with GMP should be

demonstrated and documented”
(punto 10)
32

EXAMPLE
URS Level Requirements for drainage
FS Level Slopes towards the lowest points
DS Level Sketch Test
33

Isometric sketch for the slope verification

34
The Commissioning Phase
Once the design has been qualified and approved, it is being carried out
to its completion the phase of commissioning starts:
Activities (verifications, tests, set point operations,
calibrations, startups) that have the aim of put the system
under conditions to operate in a conform way to its scopes.
Most of these activities can be “used” for the following phases of

qualification, but they must be performed and documented according to
the cGMPs.
Particularly in the phases of startup, the acceptance of the (FAT, SAT)

can allow good synergies to be used in the qualification phases.
35

Commissioning activities
• Verification of the system conformity upon the specs and the purchase order
• Supplier documentation collection, control and adequacy verification
• FAT and SAT non conformities resolution verification
• As-Built drawings (P&ID, electrical schemes, isometric sketches, etc...) on
field verification
• Verification of the system components upon the cGMP requirements
• Initial calibration of the critical instrumentation
• Operators’ training
• Operational tests of the components (engines, sensors, controllers)
• Functional test of all the operative range of the system (reliability and
stability of the system functions)
• Set-ups, PID control algorithms, thresholds, etc. Optimization
• Design documentation updating, changes documenting
• Alarms and interlocks tests
• Control system I/O test
• Operational sequences test
• Etc…. 36
The importance of the “as built” drawings

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.
Rif.: FDA Guide to Inspections of High Purity Water Systems (1993)
37

Installation Qualification
Design Installation
38

Verifications
Compliance with installation and startup procedures.
Supplier manuals.
Certifications.
Drawings «as built»: P&ID – electric schemes – isometric sketch– etc….
Tagging of all the system components, of the instruments and of the support
utilities.
Availability of the samples point
Identification of the critical instrument and the formalization of a periodic
calibration control program.
Standard Operating Procedures (SOP) for the use of the system, for its
cleaning, its maintenance, the calibration of the critical instruments, etc., (at
least in draft).
List of the critical spare parts.
Significant characteristics of the system, and of its significant components
with the recording of the principal data (manufacturer, type, model, serial #).
39

Tests to be performed during system installation
9 Tracks and Slopes
9 Materials in contact with water
9 Welds
9 Passivation
9 Boroscopic inspections
The documentation collected in this phase is inserted in the report of

Installation Qualification:
9 Building sketches as-built
9 Certifications of the materials that come in contact with water
9 “Welding book”, welding procedures, welding samples, identification of the
used orbital weldings.
9 Procedure and certificate of passivation
9 Documentation of the boroscopic inspections
40

Operational Qualification
Functional Operational
41

Objective
To guarantee that the system is adequate to serve different

user points, satisfying the needs of the process from the
quantity point of view (Flow-rate, temperature, pressure,
etc…) and from the quality point of view (chemical- physical
and microbial characteristics).
42

Verification and tests
Approved SOPs must be available (at least in draft: following the results of
the CQ tests it is possible that is evidenced the need to include adequate
corrections applied to the SOPs following the workflow for the approval).
Utilities (clean steam, industrial steam, cooling water, compressed air,
electric energy, etc...) must be completely operative and able to
maintain the established supplying specs (temperature, pressure,
quantity, electric power, etc.).
Critical Instrument for the control of the system and that used for the
OQ tests must be calibrated in compliance to the procedures approved
and referable to the Metrology recognized Institution.
Analytical Methods as a support for the tests as in the OQ protocol
must be available and duly qualified.
43

Verification and tests
Control system verification tests :
• I/O Signals
• Alarms
• Operation sequences
• Interlocks
• Power fail and system re-start up
• Passwords
• Functionality of the operator interface
• Printouts and video images
• Audit trail
• Functioning of the loops/regulation algorithms, etc.
Flow rate at the points of use.
Water speed in the loop (choosing the worst case, e.g. in the return pipe
under conditions of maximum sampling)
Temperature in the distribution loop and at points of use.
Sterilization cycle verification and temperature mapping.
44

Tests to be performed during the SAT
Many tests included in the OQ protocol can be extracted, if executed and

documented in the right way, from the tests and the verifications of SAT.
Particularly:
9 Test of the control system

9 Test of the flow-rate and of the speed velocity
9 Loop and points of use temperatures during operation.
9 Sanitization cycle verification and temperature mapping.
45

WFI – Temperature mapping during Steam sterilization test:
• In case we want to perform
Thermocouple the test in a less invasive way
we can insert probes
Coating of externally to the pipes.
insulating • It exists a thermo gradient
material between the internal part and
the exterior of the pipe
responsible of a heat flow
exchange: the use of an
Tri-clamp appropriate external insulation
connection system can reduce the
o-ring temperature losses on the
external side but cannot
Steam flow eliminate it.
46

Performance Qualification
User Requirements Performance

47

Objective
To verify and give documental evidence that the system can supply
water to the user points, in a continuous and reproducible way,
under the working conditions detailed in the operating procedures,
at the operation temperature and respondent to the qualitative
specs (chemical – physical and microbial) already set, maintaining
the values of the critical parameters of functioning of the system
within the pre established values.
The tests must include all the cases of variability of the factors that can
have a potential influence on the water quality (i.e. those induced by
seasonal cycles) and/or taking into consideration situations of worst-case
for the performance of challenge tests.
48

Verifications and test
Systems of critical utilities that have been qualified.

SOPs for the operation and the maintenance of the system
approved in a final form.
Critical Instruments, for the control of the system and that used
for the PQ test, calibrated in accordance to the procedures
approved and referable to a metrology recognized institution (NAT).
Analytical Methods for the tests included in the PQ protocol
qualified
49

Verifications and test

Test of maximum simultaneously sampling.
Verification test of microbial quality water maintenance Test
(optional or to be associated to other quality tests).
Test to verify the efficacy of the sanitization system (with the
biological indicators or other challenge systems – optional).
Water quality at the sampling points.
50

WFI - Steam sterilization test:
Thermocouple In order to create a “worst
Scotch tape case” challenge to verify the
Spore strip effectiveness of the sanitization
Pergamine coating cycle, spore strips, normally
coupled in thermocouples, are
sometimes used.
This practice is not
tri-clamp recommended, because of
joint the contamination risk for the
o-ring entire loop in case of a strip
Steam flow
rupture:
"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."
FDA - Guide to Inspections of High Purity Water Systems (1993)
51

The PQ quality testing plan for a WFI System should provide three successive phases,
as recommended in the FDA Guide to Inspections of High Purity Water Systems, (1993).
First phase of PQ quality testing

“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 objective is to demonstrate that the system is able to supply to the

users water meeting the appropriate specifications
52

Performance Qualification recommended Program for a WFI production and
distribution system
Second phase of PQ quality testing

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.
FDA Guide to Inspections of High Purity Water Systems, 1993
53

Performance Qualification recommended Program for a WFI production and
distribution system
Third phase of PQ (Monitoring phase)
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.
54

Performance Qualification for a production and distribution system
Recommended Procedure for a WFI system
Validation 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.
55

Performance Qualification for a production and distribution system
Sampling rules
1 Samples should be taken directly from the point of use.
2 From the taps where the sampling is being performed (or from a dedicated port
placed upstream or downstream of the point of use).
3 If a single point is being used for multiple applications, i.e. on the transfer
piping the sampling must be performed at the end of the pipe.
4 If the pipes are sanitized once a day (or after a pre-determined time delay) the
sampling must be performed before the pipes sanitization cycle.
5 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.
6 Record the hour the sampling has been performed.
7 Suggestion to sample the same point at different times.
“The Worst Case criterion must always be respected”
56
Thank you for your kind attention
giovanni.bini@ctpsystem.com
57

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ETIF 2008

Costa Salguero Centre - Buenos Aires - Argentina

Each pharmaceutical (but also cosmetics, food,

A good working of these systems ensures efficiency of production.

An accurate preventive maintenance program of the systems can limit

The production support systems used in pharmaceutical

• process systems (direct impact system)

• in contact with those materials which will later be

For example, process water (water for injections, purified or drinking

They are always considered critical because they are actually or

Process systems (direct impact systems)

They directly support process operations, but have no

The process support systems are not generally considered critical

• They are not in contact with the product or material

Typically, such systems did not impact on the product

ISPE Baseline Engineering Guides

Qualification and Validation of the manufacturing and process systems,

Consequent by above definition, GxP Critical System Qualification and

Document that defines in a clear, precise and concise way

Document that defines a system and/or its

Documents describing the building details

2. All validation activities should be planned. The key elements of a

(EU GMP - Annex 15 – Qualification and Validation)

(EU GMP - Annex 15 – Qualification and Validation)

User Requirements Performance

Design System build

ISPE Baseline Engineering Guides

ISPE Best Practice Guides

The Design Phases

WATER FOR PHARMACEUTICAL USE MUST NOT INTRODUCE IN THE

The purification processes (pre treatments and final purification) must

The Design Phases

The Design Phases

The Design Phases

The Design Phases

9 Building drawings of the main equipment

The Design Phases

The Design Phases

The Design Phases

The Design Phases

The Validation Phases

Functional 9 OPERATIONAL QUALIFICATION = OQ

The Validation Phases

European GMP – ANNEX 15 ed.June2001

“The first element of the validation of new facilities,

“The compliance of the design with GMP should be

The Validation Phases

URS Level Requirements for drainage

FS Level Slopes towards the lowest points

DS Level Sketch Test

The Validation Phases

Isometric sketch for the slope verification

The Commissioning Phase

Most of these activities can be “used” for the following phases of

Particularly in the phases of startup, the acceptance of the (FAT, SAT)

The Commissioning Phase

The Commissioning Phase

The importance of the “as built” drawings

The Validation Phases

The Validation Phases

The Validation Phases

The documentation collected in this phase is inserted in the report of

The Validation Phases

Systems of critical utilities that have been qualified.