Pharmaceutical Utility Qualification
Pharmaceutical Utility Qualification
Pharmaceutical Utility Qualification
Regulation, Qualification
and
Validation
Arvind Kumar Srivastava
Asst. Manager QA , Beta Drugs limited , Baddi
Mobile No. 9817039581 , Email ID : arvindsri82@gmail.com
Utility System
Qualification
for
The
Pharmaceutical
Industry
INTRODUCTION
the manufacturing process uses several support Utility system like Water ,
❖ The Utility System are have different functions and generated and
❖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.
❖Pharmaceutical equipment manufacturing is a highly regulated industry.
❖In pharmaceuticals, critical utilities like water and HVAC (Heating, Ventilation
and Air Conditioning) systems form the backbone of the manufacturing
process.
❖To pass inspection, utilities must pass a string of qualitative and quantitative
specifications. Different utility systems have different quality and standard
criteria, designed on the basis of inputs from relevant departments and
organizations as well as manufacturing and engineering provisions.
•Burning Gas
•Fire-Fighting Water
•Vacuum
•Electric power
PHARMACEUTICAL UTILITY SYSTEMS
For example,
The sudden lack of steam might impair a heating phase (e.g. during a synthesis
production.
The lack of vacuum might block a filtering or drying process, causing damage to
the product.
They are:
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.
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.
PHARMACEUTICAL UTILITY SYSTEMS
Process support systems (indirect impact systems)
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.).
PHARMACEUTICAL UTILITY SYSTEMS
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;
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.
References
EU GMP volume 4
Annex 15 - “Qualification and Validation”
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)
What is the Systems Design & Validation
Approach for Utility System
Qualification and Validation of the manufacturing and process systems,
as installed, comply with the approved design, operate within the approved
functional specification and are consistently able to perform the scopes they
FDA
“Guide to Inspections of High Purity Water Systems”
(1993)
➢Specifies deliveries
➢To optimize your URS, focus on the parameters for the system and the
regulations and standards that will be applicable. Including contradicting
requirements can lead to confusion, so develop clear concise requirements
that are unambiguous.
➢It is not the amount of pages that decide the quality of your URS but how
specific and easy to read and understand it is for the different groups involved
in design, manufacturing, and validation.
❖Process Requirements
➢What user points need to able to use water at the same time
➢Usage priorities if several user points need water at the same time (worst
case scenario)
➢The water quality of the system (whether it should fulfill the USP or the Ph.
Eur. monograph for PW. both, or any other pharmacopeia).
➢Materials that come into contact with WPU should be appropriate and its
Includes: pipework , valves and fittings , seals , diaphragms and Instruments
❖User Prerequisites
➢A water analysis report of the incoming water so engineering can design and
size pre-treatment of the system for optimal operation. Attach water analysis
reports from different seasons of the year so the changes in water quality can
be considered
➢Room layout with measurements for where the system will be located
➢Air break to floor drains to prevent back flow back up to the system
You should not need to specify drain-ability and slope requirements for the PW
treatment system itself. Since you will never steam sterilize it you will not have
to worry about any condensation in the lines. If the system won’t be used for a
longer time or “stored”, it would be filled with preservation chemicals and not
emptied. Note also that several components in this process are not drainable
(for instance, RO vessels and CEDI modules). Many times pre-treatment
vessels have both an inlet and outlet on the top.
❖Electrical Requirements
❖Automation/Software Requirements
The system must be provided with design documents specifying how it will
operate and the components and structure of the automation:
•Functional Specification
The program must be logically structured and must be provided with clear
comments and free of dead code.
Tests typically include:
FDA 21 CFR Part 11 requires that a water system’s software have an audit trail
capability, data storage, individual passwords, and so on. Note that a PLC
which is commonly used in water treatment systems will not have the feature
of tracking changes, store them in a log and refer to the specific user who
implemented the change and show at which time it happened.
➢Design review
➢Validation requirements
➢If the system is going to be installed in the European Union it must comply
for hot distribution systems and during hot water sanitizations. Requirements
➢Suppliers normally have a “standard” design that fulfils most regulations. Site-
❖ specification;
❖ performance optimization;
&
✓ Piping dimensioning
✓ Etc…
Design Specifications
“The first element of the validation of new facilities, systems or equipment could
documented”
The Commissioning Phase
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….
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,
• the provision for drainage of water from the vessel, when required
• construction materials
• the fitting of sanitary design bursting discs provided with external rupture
indicators to ensure that loss of system integrity is detected;
• the design and location of valves, sampling points and monitoring devices
and sensors; and
STORAGE TANKS / STORAGE VESSELS :
• the need for heat exchangers or jacketed vessels. Where these are used,
double tube sheet or double plate heat exchangers should be used, ideally
with the utility pressure less than the system pressure to minimize the risk of
contamination.
PIPINGS:
•PIPING'S ARE MADE OF SS316L EVEN SOMETIMES SS304L BASED UPON
THEAREA OF USAGE AND TYPE OF WATER.
✓Passivation
✓Boroscopic Inspections
Installation Qualification
The below mentioned documentation / reports are collected during
The Installation Qualification ------
Objective
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).
Operational Qualification
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.
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.
PERFORMANCE QUALIFICATION
Verifications and Test
❖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 to verify the efficacy of the sanitization system (with the biological
Phase I should cover a period of at least two weeks. The system should be
monitored intensively for its performance. The system should operate
continuously without failure or performance deviation. Normally, water should
not be used for FPP manufacturing during this phase.
The procedures and protocols for Phase I should cover at least the following
activities and testing approaches:
❖use and refine the standard operating procedures (SOPs) for operation,
maintenance sanitization and troubleshooting
Phase 2 should cover at least a further test period of two weeks. The system
should be monitored while deploying all the refined SOPs after the
satisfactory completion of Phase 1.
The sampling program should be generally the same as in Phase 1. The use of
the water for FPP manufacturing purposes during this phase may be
acceptable, provided that both commissioning and Phase 1 data demonstrate
the appropriate water quality and the practice is approved by QA.
Water can be used during this phase (e.g. for manufacturing and cleaning)
which has the following objectives
❖ Validation protocol :
68
Introduction
69
Compressed air is an important component of pharmaceutical
manufacturing facilities.
The application for which the compressed air will be used will dictate
the level of air quality that is appropriate for use.
70
Direct Impact Systems :
The system will produce data which is used to accept or reject the
product
The system will be a process control system that can affect product
quality and there will be no system for independent verification of
control system performance
71
Indirect Impact or No Impact Systems :
The system will not contact the product or materials that ultimately
become part of the product
The systems are generally site or building systems and are not
tailored specifically to aseptic manufacturing facilities
72
How the Compressed Air System(CAS) works?
73
Components of the CAS system
Inlet filter:
Compressor :
Compressor Controller :
74
Aftercooler :
Compression leaves the air hot and wet. The aftercooler lowers
the temperature of the air leaving the compressor and removes
water that condenses as the air cools
75
• Dryer :
• Condensate Trap :
Collects and discharges liquid that condenses out of the air stream
Integral part of aftercoolers, dryers and separators
76
Distribution Piping :
Pressure Regulator :
77
Test Functions :
1. Perform Installation Qualification
78
5. Perform a capacity test to verify that the system is capable of
supplying the required gas, pressure, and flow rate at each use
point
6. Verify that in-line filters are integrity tested. Confirm that all
documentation clearly indicates acceptable test results
80
Acceptance Criteria :
82
Method for Dew Point and Oil Content
As per Air Quality Standards ISO 8573 and Filter Standard ISO 12500 for
compressed air there are nine part to it as follows :
84
Installation Qualification (IQ)
85
Contd…
Materials of construction will vary with gas type, and must agree
with specification
Verify that the systems have been thoroughly cleaned and dried
before operation
86
Operational Qualification
87
Contd…
All use points supply the specified pressure prior to any pressure
reducing valves or equipment
88
Performance Qualification
89
Contd…
• The highest total particulate count from the five one-minute runs
must meet class 100 or EC Class A criteria
90
Contd…
91
92