This document discusses validation of critical utilities in the pharmaceutical industry. It covers validation of various systems including purified water systems, compressed air systems, HVAC systems, and clean steam systems. It describes the FDA requirements for validation which includes installation qualification, operational qualification and performance qualification. It provides specifications for purified water and discusses environmental monitoring programs for validated utilities.

1. SUPPORT AND UTILITIES
VALIDATION
PRESENTED BY-
MISS VAISHALI V. DUDHABALE
M PHARM F. Y. (QAT)
GUIDED BY-
DR. SONALI MAHAPARLE
PROFESOR, DR. D. Y. PATIL COLLEGE OF
PHARMACY, AKURDI, PUNE.

2. VALIDATION
• Validation is the process of establishing documentary evidence
demonstrating that a procedure, process, or activity carried out in testing and
then production maintains the desired level of compliance at all stages.
• In the pharmaceutical industry, it is very important that in addition to final
testing and compliance of products, it is also assured that the process will
consistently produce the expected results.
• Since a wide variety of procedures, processes, and activities need to be
validated, the field of validation is divided into a number of subsections
including the following:

3.  Equipment validation
 Facilities validation
 HVAC system validation
 Cleaning validation
 Process Validation
 Analytical method validation
 Computer system validation
 Packaging validation
 Cold chain validation
Most important part in any industry is the utility available in the industry.
Hence its Qualification and Validation are one of the most important
parameters.

4. SUPPORT DOCUMENTS
• The User Requirements Specification
(URS)
• FAT/SAT
• Change Management
• Design Specifications
• Functional Specification
• Purchases Requisitions
• Turn-Over-Packages
• Vendor Manuals
• P&IDs
• Manuals

5. CRITICAL UTILITY QUALIFICATION
• Construction Qualification
During construction, document procurement and verification of construction activities,
are critical components of a successful Installation Qualification (IQ).
• Installation qualification
Full description of equipment capabilities, design features and company's specific
intended use in manufacture, Vendor, equipment ID, serial number, etc.

6. CONT.….
• Operational Qualification
Is a documented plan for the performance of inspections and tests to verify specified
dynamic attributes of a system.
• Performance Qualification (PQ) –
Is a documented plan for the execution of tests to demonstrate the effectiveness and
reproducibility of a system/process as a fully integrated functional entity.

7. VALIDATION OF PURIFIED WATER
SYSTEMS
• Purified Water is used in Aspect of GMP Manufacturing Operations
• Water Usage in Pharmaceutical Production
–Potable -EPA
–USP Purified –different types
–USP Water For Injection

8. VALIDATION OF CRITICAL WATER SYSTEMS
• FDA REQUIREMENTS: Phase 1
• All water systems should have documentation containing a system description and
accurate drawing.
• The drawing needs to show all equipment in the systems from water input to points
of use. It should also show all sampling points and their designations.
• After all the equipment and piping has been verified as installed correctly and
working as specified, the initial phase of the water system validation can begin.

9. PHASE 1
• During the initial phase the operational parameters and cleaning/sanitation
procedures and frequencies will be developed. Sampling should be daily after each
step in the purification process and at each point of use for two to four weeks.
• The sampling procedures for point of use should reflect how they are taken, e.g. use
of hose, and time for flushing. At the end of the two (2) or four (4) weeks the firm
should have developed its SOPs for operation and maintenance of the water system.

10. FDA REQUIREMENTS: PHASE 2
• The second phase of the water system validation is to demonstrate that the system
will consistently produce the desired water quality when operated in conformance
with SOPs.
• The sampling is performed as in the initial phase and for the same period . At the
end of this phase the data should demonstrate that the system will consistently
produce the desired quality of water.

11. FDA REQUIREMENTS: PHASE 3
• 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 desired quality.
• Any variations in quality of the feedwater, that could affect the operation and
ultimately the water quality, will be noticed during this phase of the validation.

12. • Sampling is performed according to routine procedures and frequencies.
• For Water for Injection systems 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
collected data for a full year.
• The FDA states that “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.

13. • 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. This last part of the validation is the
compilation of the data, with any conclusions into the final report.

14. Contaminant Specification
Conductivity USP Specifications
Endotoxin No Specifications
Bacteria 100 cfu/ml
pH 5.0 - 7.0
TOC 500 ppb
Specifications for purified water system:

15. VALIDATION OF PURIFIED STEAM SYSTEMS
• Clean Steam Usage in Pharmaceutical Production
Clean Steam Requirements
–Steam-In-Place (SIP) –tanks, transfer lines, bioreactors, etc.
–Sterilization Process –autoclaves
• Clean Steam Validation Requirements
–URS
–DQ
–IQ, OQ & PQ

16. • Clean Steam Design
–It includes Clean Steam Generator
–Distribution System
–Points of Use (Traps) –Autoclave, Reactors, etc.
• PQ Requirements
–Typically 7 –14 days depending on the complexity of
the system

17. CLEAN STEAM SYSTEM ENVIRONMENTAL
MONITORING PROGRAM
• Sample Site and Frequencies Determination
• –For Clean Steam systems samples should be before manufacturing process
i.e. SIP, autoclave, etc. and from a minimum of one point of use, with all
points of use tested bi-weekly.

18. VALIDATION OF COMPRESSED AIR SYSTEMS
• Compress Gases Usage in Pharmaceutical Production
Compress Gases Requirements
• –Preserve the Status of product
• –Drying after cleaning
• –Assist Cell Growth
• –Instrument Actuation
• –Move Fluid

19. Types Of Gases
–Clean Dry Air
–Nitrogen
–Carbon Dioxide
–Helium
–Oxygen
–Argon
CLEAN STEAM MAJOR COMPONENTS
Cylinders
•Dryer
•Manifold
•Automatic/Manual Switchover System
•Valves
•Pressure Gauges
•Filters
•Control System (Low Gases, Low Oxygen)
•Distribution System (SS or Type L copper)

20. COMPRESS GAS SYSTEMS ENVIRONMENTAL
MONITORING PROGRAM
• Sample Site and Frequencies Determination
• For compress gas systems samples should be taken daily from a minimum of
one point of use, with all points of use tested weekly.

21. VALIDATION OF HVAC SYSTEMS
• HVAC is used in Aspect of GMP
Manufacturing Operations
• Clean Room Standards
This ISO committee produces 10 new
standards documents that relate to
cleanrooms or clean zones. The nine
standards have been published: ISO 14644-
1 and -9.

22. CLEAN ROOM CERTIFICATION
• Clean Room Certification Testing
• Differential Air Flow
• Humidity/Temperature
• Supply Air Volume/Room Air
Change Rate
• Room Differential Pressures
• DOP Test of HEPA Filters
• Room Non-Viable Particulate
Counts
• Light Levels
• Noise Levels
• Recovery Time
• Unidirectional and Parallelism
• Enclosure Induction

23. HVAC SYSTEMS ENVIRONMENTAL
MONITORING PROGRAM
• Sample Site and Frequencies Determination
• Would the act of sampling at a given site disturb the environment sufficiently to
cause erroneous data or possibly cause the product to be contaminated?
• At which site would the potential of microbial contamination most likely affect
product quality adversely?
• During the PQ study which sites were highest in microbial contaminates.
• What sites would be the most difficult to clean?
• Should site selection involve statistical design or should it be based on a grid
profile?
• How often is a particular area or process used?

24. PHYSICAL, MICROBIOLOGICAL TESTING
PARAMETERS
TABLE 1-Air Classification

25. Table 2: Airborne particulate classification

26. Table 3: EU-GMPANNEX 1recommended limits for microbial
contamination

27. REFERENCES
1. Pharmaceutical validation by Chitlange