Validation Requirement:

 Establishing reliability of pharmaceutical water purification, storage, and distribution systems requires demonstrating control of the process through an appropriate period of monitoring and observation. Finished water is typically continuously produced and used, while product and process attributes may only be periodically assessed. The quality of bulk finished water cannot be established by only testing monograph attributes. The unit operations in the pharmaceutical water system need to demonstrate that they are in control through monitoring of the process parameters and water quality.

The advent of using conductivity and total organic carbon (TOC) to define chemical purity allows the user to more quantitatively assess the water’s chemical purity and its variability as a function of routine treatment system maintenance and regeneration. Treatment processes must also demonstrate control of microbial attributes within the overall system. Some unit operations that are needed for chemical treatment may significantly increase microbial and bacterial endotoxin levels.

Afterthat controlled by downstream unit operations. Knowledge of the treatment system processes and the effectiveness of control measures is needed to ensure that the pharmaceutical waters are acceptable for use.
Efficacy of the design, operation, sanitization, and control of the pharmaceutical water system is demonstrated through the monitoring of chemical and microbial attributes. A typical water system validation program involves an initial increased frequency of monitoring of the treatment system process parameters and sampling and testing of major process points to demonstrate the ability to produce the acceptable water and to characterize the operation of the system. This is followed by a life cycle approach of validation maintenance and monitoring.

Validation Approach
Validation is the program of documenting, to a high level of assurance, that a specific process is capable of consistently delivering product conforming to an established set of quality attributes. A validation program qualifies and documents the design,installation, operation, and performance of the system. A graphical representation of a typical water system validation life cycle is shown in Figure 3.
The validation protocol should be based on the boundaries of the water system and the critical water quality and process attributes needed to maintain consistent performance. The system boundary may stop at the point of use or may include the water transfer process. If the transfer process from the distribution system outlets to the water use locations (typically either with hoses or hard-piped equipment connections) is defined as outside the water system boundary, then this transfer process still needs to be validated to not adversely affect the quality of the water as it is delivered for use. Because routine quality control (QC) microbial monitoring is performed for the same transfer process and components (e.g., hoses and heat exchangers) as that of routine water use , there is some logic to include this water transfer process within the distribution system validation.

Validation is accomplished through the use of a structured, documented process. The phases of this process include Design Qualification (DQ)

Installation Qualification (IQ)

Operational Qualification (OQ),

Performance Qualification (PQ), and

Validation Maintenance.

The process is documented in a validation protocol. The elements may be in individual protocols for each
phase, or integrated into variations of a DQ/IQ/OQ/PQ combined document format. The protocols are formally approved quality documents. Factory Acceptance Testing (FAT), Site Acceptance Testing (SAT), and commissioning testing of the system may supplement qualification tests for IQ or OQ provided that they are properly documented and reviewed and if it can be shown that the system functionality is not affected by the transport and installation.

The user requirements for the water system should identify the design, operation, maintenance, and quality elements needed to produce the desired water type from the available source water, including its anticipated attribute variability.

The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level.
The review of the specifications, system design, components, functions, and operation should be performed to demonstrate that the system complies with GMPs and verify that the design meets the user requirements. This documented review may be performed as part of the overall design process or as a separate DQ.

Installation Qualification:
IQ protocol for a water system confirms that the system has been properly installed and documented.

This may include :

Verification of components,


Installation, and weld quality;

Documentation of the specifications for all system components present;

Inspections to verify that the drawings accurately depict the final configuration of the water system and, where    necessary, special tests to verify that the installation meets the design requirements.

Additionally, the water system is readied for operational testing, including calibration of instruments, configuration of alarm levels and adjustment of operating parameters (e.g., flow rate, pressure).

Operational Qualification:

The OQ phase consisting of tests and inspections to verify that the equipment, system alerts, and controls are operating reliably and that appropriate Alert and Action Levels are established (this phase of qualification may overlap with aspects of IQ and PQ).

During this phase of validation specific testing is performed for alarms, verifying control sequences, equipment functional checks, and verification of operating ranges. SOPs for all aspects of water system operation, maintenance, water use,water sampling, and testing, etc. should be in place and operator training completed.

At the completion of the OQ, the water system has demonstrated that the components are operational and the system is producing suitable water.

Performance Qualification:
The prospective PQ stage considers two aspects of the water system:

1.Critical process parameters and

2.Critical water attribute parameters.

These are evaluated in parallel by monitoring the water quality and demonstrating acceptable quality attributes
while demonstrating control of the process parameters . The initial PQ stage may result in refinement of process parameters to yield appropriate water quality.

Critical process parameters of PQ stage includes an increased frequency of monitoring for approximately 2–4 weeks, or sufficient time to generate adequate data to demonstrate that water meeting the appropriate quality attributes is produced and distributed. One of the reasons for this duration is that bio-film, the source of plank-tonic organisms in water samples, takes time to develop and to determine if the sanitization unit operations and processes are adequate to control microbial proliferation. The chemical control program adequacy is typically apparent in less time than it
takes to see microbial control adequacy. However, chemical purification can be compromised by poor microbial control and to a lesser degree, vice versa.

Once a level of control of microbial and chemical attributes has been demonstrated,

The next phase (Critical water attribute parameters) of PQ is to continue the frequency of monitoring for approximately 2–4 weeks at a somewhat reduced level that will still give adequate data on system performance while using the pharmaceutical water. The water may be used for manufacturing at risk, and the associated products may be released only after water quality attributes have been determined to be acceptable and this validation phase has been completed.

At the completion of this second phase, the data should be formally reviewed and the system approved for operational use.

Operational Use:
When the water system has been placed into operational use, monitoring of the water quality attributes and the system process parameters is performed at a routine frequency  to ensure that they remain with a state
of control during long-term variability from seasonal variations in source water quality, unit operation maintenance, system sanitization processes, and earlier-established Alert and Action Levels.

The water system should continue to be monitored and evaluated on an on-going basis following a life cycle approach using online instruments or samples for laboratory-based testing. The use of online instruments and process automation technology,such as conductivity, TOC, temperature, flow rate, and pressure can facilitate improved operational control of the attributes and parameters and for process release.

Manual observation of operating parameters and laboratory-based testing is also appropriate and acceptable for monitoring and trend evaluation.


The frequency of routine monitoring should be based on the criticality of the finished water, capabilities of the process, and ability to maintain product water quality trends. Monitoring may be adjusted from the initial validation monitoring program when there is sufficient data to support a change (Routine Sampling Plans).


Maintaining the validated state of control requires a life cycle approach. After the completion of the PQ and release of the water system for use, ongoing activities and programs have to be in place to maintain the validated state of control after the system has been validated and placed into service (Operation, Maintenance, and Control). This includes unit operation,calibration, corrective maintenance, preventive maintenance, procedures, manuals and drawings, standardization of instruments,process parameter and quality attribute trending, change control, deviations, corrective and preventive actions (CAPA),training, records retention, logbooks, etc.


Identification and control of changes made to unit operations and other system components, operation parameters, system sanitization, and laboratory processes or procedures need to be established. Not all changes will require validation follow up,but even minor ones, such as gasket elastomer changes could have an impact on quality attributes. The impact of the change on process parameters and quality attributes must be identified, evaluated and remediated.

This may result in a selective validation activity to demonstrate the ongoing state of control for the system and ability to maintain water quality attributes.
Certain calibration and preventive maintenance activities may be considered routine tasks if they do not impact on system operation or water quality.

Replacement of components needs to be carefully evaluated. Replacement of components using exact parts generally does not affect system operation or control. Replacement of components with ones that have the similar
functional specifications can be performed at risk with the critical specifications (e.g., material of construction, dimensions,flow rate, response factors) having been evaluated and the differences determined to be acceptable and documented within the change control system.


The water system qualification, maintenance history, calibration records, quality and process data, issues with the unit operations and any process variability, change control, and other validation maintenance data should be assessed periodically to determine impact on the state of control.
The review may result in adjustments to operating or sanitization processes, calibration or maintenance plans, or monitoring plans. This may also result in additional testing or repeating certain qualification tasks (re-qualification).

For More Pharma Updates Visit –https://pharmaguidances.com

Reference: General Information / (1231) Water for Pharmaceutical Purposes 

About Pharmaceutical Guidanace

Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field. During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube

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