Validation

Definition: 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.The desired results are established in terms of specifications for
outcome of the process. Qualification of systems and equipment is therefore a part of
the process of validation. Validation is a requirement of food, drug and pharmaceutical
regulating agencies such as the US FDA and their gmp guidelines.

Reasons for validation:

FDA, or any other food and drugs regulatory agency around the globe not only ask for a
product that meets its specification but also require a process, procedures, intermediate
stages of inspections, and testing adopted during manufacturing are designed such that
when they are adopted they produce consistently similar, reproducible, desired results
which meet the quality standard of product being manufactured and complies the
Regulatory and Security Aspects. Such procedures are developed through the process
of validation. This is to maintain and assure a higher degree of quality of food and drug
products. "Process validation is defined as the collection and evaluation of data, from
the process design stage through commercial production, which establishes scientific
evidence that a process is capable of consistently delivering quality product. Process
validation involves a series of activities taking place over the lifecycle of the product and
process.". A properly designed system will provide a high degree of assurance that
every step, process, and change has been properly evaluated before its
implementation. Testing a sample of a final product is not considered sufficient evidence
that every product within a batch meets the required specification.
 1)Validation process for Water
Water system validation (generation and distribution) should contain three phases:
a)Phase I: investigation phase;
b)Phase II: short-term control; and
c)Phase III: long-term control.
The objective of pharmaceutical water system validation during these three phases
should demonstrate that water system is under control and producing the specified
quality of water over a long time period.

Commissioning of purified water system

Proper documentation of commissioning is an essential part of the successful validation
of pharmaceutical water system. Commissioning includes the startup of the water
system with documenting the performance of all system parameters.

Qualification
Purified water, water for pharmaceutical use, water for injection systems can directly affect the
quality of our pharmaceutical products. Hence, it should be validated. Before starting the
validation, water system qualification should be completed i.e. design qualification (DQ),
installation qualification (IQ) and operational qualification (OQ).

Phase I:
Water sampling and testing should be done for 2 to 4 weeks to monitor the water system. During
this phase, water system should operate continuously without failure. Following things should be
considered during this phase:

•  Sampling and testing of the raw water i.e. feed water should be done to monitor its quality.

•  Sampling after each step should be done daily.

•  Chemical and microbiological testing should be done as per the approved specification.

•  Operating, cleaning, sanitizing and maintenance procedures should be finalized during this
phase.

•  Ensure the production of the required quantity of water.

•  Alert and action limits should be verified after this phase.

Phase II:
A 2 to 4 week testing should be done again in phase II to monitor the water system intensively.
Sampling frequency shall remain as per the previous phase. Water can be used for manufacturing
during this phase of water validation.
The demonstration should be done that the water system is producing the required quality and
quantity of water while operated according to the relevant SOP.

Phase III:
After the successful completion of phase II, phase III runs for one year. We can use water for
manufacturing during this phase.

•  The frequency of sampling and testing should be reduced in this phase after successful
completion of phase I&II.

•  Seasonal variations are observed in this phase of validation i.e. seasonal trending shall be

done.

Validation of Process Gas Systems

Validation of process gas systems involve documenting the expected system behavior, and
verifying that the system performs as expected. This article covers the pertinent aspects of IQ,
OQ, and PQ related to process gas systems and many of the potential problem areas. The
validation of nitrogen and compressed air systems, including breathing air systems, is used as
an example which can be extended to the validation of most other process gas systems.

Design Considerations
As with any other cGMP system or equipment, we must design nitrogen and compressed air
systems so that they can be qualified. The design process begins and ends with documentation
of the point-of-use requirements for the system. A typical compressed air system consists of
the air compressor(s), driers (desiccant or refrigerated), distribution piping, and filtration
systems. A typical nitrogen system consists of either a liquid nitrogen storage tank and
vaporizer or nitrogen bottles, distribution piping and filtration systems. Breathing air systems
are becoming more commonplace as our industry increases the research and production of
potent and toxic drugs. The qualification of breathing air systems is generally similar to that of
other process gases.

Process Gas Standards

Currently, there are no universally recognized standards for the validation of process gases.
However, a group within ASTM subcommittee 48.06 is developing validation standards for the
process gases, and for the methods used to test the gases. There are several places to go for
direction on the requirements of process gas systems. Generally, process gas systems must
meet the chemical, microbial, and purity requirements of the products they will potentially
contact, and the requirements of the room into which they are exhausted, if applicable. The
USP has developed test monographs for process gases, such as medical air, nitrogen-99%,
nitrogen-75%, and oxygen. Care should be taken to consider the particular process application
before assuming that conformance to USP specifications is required. Some of these methods
are difficult to execute in the field (e.g., Nitrogen-99%), and should not be attempted unless
they are required. For microbial and particulate monitoring, the specific criteria developed in
our respective facilities for class 100,000, 10,000, 100 and so on, should be consulted. In
general, the process gas must not negatively impact the room into which it is exhausted.

Use of Final Filters

The use of the air should always be considered when deciding what type of filter, if any, is
required. Compressed air and nitrogen are often used to power equipment and motors in the
process areas. In classified (such as 100,000, 10,000, and 100) areas, where process gases
directly contact the product, final filters are advisable. Point-of-use filters should be in place, or
at least considered during PQ of the system. Many companies qualify the system without the
point-of-use filters in place to ensure system integrity even if the filter develops a leak during its
use. Filter model numbers should be documented, and controls should be established to ensure
the same filters are used over the life of the system. The manufacturer may vary, but critical
characteristics, such as filter materials, flow rate, and particulate filtration levels must be
maintained. This information can be documented in the system or equipment SOPs, or in the
maintenance management system. The filters found in the system two years after the initial
qualification must have the same critical characteristics as the filters that were originally
designed, specified, and qualified. Final filters serving class 100, or cleaner areas, should be
integrity tested.

Installation Qualification Issues

As with any cGMP system or equipment, every inch of the system should be checked to verify
conformance with as-built drawings, construction materials, valves, cross-connection to other
systems, and unused portions of the system. In any large, unused portion of the system,
adequate protection preventing fluid buildup during system shutdown, which could
compromise the microbial purity of other parts of the system, must be ensured. All alarms must
be tested, including those on the compressors and desiccant driers for the compressed air
system, on the storage tanks and vaporizer for nitrogen systems, as well as on the distribution
system itself. It is often useful to hire the service representative to conduct these test.

Operational Qualification Issues

As with any system, all critical instruments should be calibrated prior to the performance of
operational tests. Critical instruments on a process gas system are those instruments used to
measure the parameters listed in F i g u re 1. However, an instrument need not be permanently
installed for each characteristic. For example, if diversity testing is done well, the permanent
installation of flowmeter(s) should not be required. But a pressure switch used in maintaining
the minimum system pressure by turning on the lag c o m p r e s s o r, should be calibrated. The
instruments used to monitor the critical characteristics of a breathing air system should also be
calibrated. These include on-line carbon monoxide (CO), carbon dioxide (CO2), and dewpoint
monitors. CO and CO2 monitors can be easily calibrated by using standardized test gas canisters
which trigger the alarms at the appropriate levels. The manufacturer of the respective monitor
can usually provide the certified gas canisters. The gases are typically provided in
concentrations that correspond to the alert and action alarm levels. They can be easily input to
the monitor, and then flushed from the system.

Validation of electric system

It is essentially important to carry out electrical maintenance on a regular basis;
maintaining all fittings, appliances and devices in and around home. Maintenance
enhances the smooth running of all the electricity powered items in pharmaceutical
industries, while creating a safe environment that will be free from all sorts of
hazards.

Steps in Electricity Validation

Ensuring Safety

When working with electrical items, make sure to unplug the unit or turn off the
power to the specific circuit. Don't forget that water and electricity don't get along,
so make sure to unplug anything electric before cleaning. Never use a metal ladder
when performing electrical tasks.

Using of elctronics:

It's important to be smart about how you're using electronics. Avoid plugging in
too many things into one circuit, which can overload it and cause a power outage.
Be mindful of where you place small appliances and electronics, such as toaster
ovens and hair dryers. Make sure they're not under any vents that could potentially
drip on them or are too close to a source of water, such as sinks and showers.
Further, the Occupational Safety and Health Administration recommends
installing for all of the outlets in wet locations, such as kitchens, bathrooms and
laundry rooms. They're designed to turn off electric power immediately in the
event of an incident, which can be a potentially life-saving feature.

Careful about plugs, outlets and wires

Treat plugs kindly and don't force them to fit into outlets. Don't try to bend and
adjust the prongs, as this could cause an electric shock. Alternatively, if it's loose
inside the outlet, it may be time to replace the cord for a fresh plug. Replace old
outlets with new electric sockets with advanced safety features, such as built-in
surge protectors. Unplug extension cords when you're not using them to avoid an
electric and fire hazard. When you're outside, only use cords and electrical items
that are specifically for the outdoors.
If you notice any frayed wires, make sure to replace them before they cause shocks
or fires. Ideally, you should turn off, unplug and cut the power to the appliance or
item with the frayed wire. You can call a professional to help replace damaged
appliance wires. If you have just purchased an older home, you may want to have a
professional perform a full wiring inspection before doing any electrical DIY.

Schedule routine professional check ups

Electricity can be dangerous, so never hesitate to call a licensed electrician for

help. In fact, one of the most important steps in good electrical maintenance is
having a professional inspect your system at least once a year. An electrician can
check your electric panel, replace damaged wires and test circuit breakers.