Thursday, March 19, 2009


Validation is a fundamental block that supports a company commitment to quality assurance. Validation is a tool of quality assurance; it is a confirmation of the quality in equipment systems, manufacturing processes, software and testing methods. Validation confirms that products with pre-determined quality characteristics and attributes can be reproduced consistently/reproducibly within the established limits of the manufacturing process operation at the manufacturing site. Validation is required in order to move a product from development to commercial production in the product life cycle. Validation is an on-going commitment that is integral to every aspect of commercial product manufacturing.
There are 4 basic principles of quality assurance for compliance:
1) Establish and confirm quality characteristics
2) Monitor quality characteristics
3) Monitor for change and control changes
4) Documentation

Validation applies to special processes. According to cGMPs, one must validate Special Processes. A special process is one in which the quality or effectiveness of the process cannot be adequately tested or evaluated in the final product, i.e. mfg process.
Validation must occur when new products are brought to commercial production, before new products are manufactured for human use.
Validation is a terminal event to PD and demonstrates that the commercial scale manufacturing process will consistently produce a product that meets its pre-determined specifications of the developed product. Validation demonstrated consistency. This means that one must demonstrate that specied requirements are met multiple times (i.e. at least 3 replicate times). To demonstrate consistency, replicate runs must be identical. Identical means that processing parameters must fall within pre-determined limits of acceptability.

Fundamentals Elements of Validation:

1) Document validation plan and procedures
2) Establish acceptance criteria (i.e. testing parameters, limits of acceptability of the components...)
3) Demonstrate equipment systems are calibrated and operate properly.
4) Demonstrate that the process meets an established range of operation for multiple runs.
5) Demonstrate that the final product of the process meets pre-determined quality characteristics.
6) Demonstrate the ruggedness of equipment or process performance by challenging
the equipment/process at the limits of operating conditions for multiple runs.
7) Demonstrate the accuracy, precision.. of any analytical test methods.
8) Demonstrate that the validation work has been performed as planned and the outcome meets predetermined specifications and the validation work has been documented , reviewed, approved.

In lieu of validation, routine preventive maintenance programs and routine calibration may be sufficient to establish the reliability and reproducibility of simple equipment performance (i.e. calipers, balances, pH meter, pipettes, conductivity meters)

Prospective Validation means that after a product is developed, the product and its manufacturing process are validated before it is either introduced into the commercial market or used in humans. Ironically, many manufacturers are faced with validating products and processes that have been on the market for many years.
Retrospective validation means the validation of a process, a method, or equipment that has been in use for a long time or a product that has already been on the market.

Validation of Equipment and Equipment Systems

Reliability of equipment operation and performance must be assured. This assurance supports the validation of products produced used these equipment.

The following is a list of equipment requiring validation:
1) Manufacturing equipment (i.e. packaging machine, filling machines)
2) Support processing equipment (i.e. incubators, ovens..)
3) Test equipment (i.e. test stations..)
4) Utility system equipment (i.e. clean rooms, water systems, air systems..)
5) Measuring equipment (i.e. balances, pH meter, pipettes)

In general, Category I equipment are those whose reliability can be assured through calibration and preventive maintenance programs (i.e. balances, pH meter, pipettes) Category III equipment are those that will need validation (i.e. process equipment, test equipment...) Category III equipment validation is commonly performed as a 3 phase process consisting of Installation Qualification (IQ), Operation Qualification (OQ) and Performance Qualification (PQ).

Installation Qualification is the documentation of the installation of the equipment that allows for the efficient implementation of calibration and preventive maintenance programs and facilitation of the effective control of changes to the equipment over-time. IQ protocol looks like an equipment specification, listing all of its critical features. An IQ consists of :
1) "As built" drawings
2) Equipment or system requirements
3) A statement declaring the adequacy of the equipment for its intended use
4) Equipment identity characteristics
5) Utility requirements
6) Safety features
7) Reference to operator or maintenance manuals
8) Reference to vendor support services or parts suppliers

Operation Qualification is the confirmation of the adequate operation of the equipment as expected under ideal conditions. The protocol must include what will be done, how it will be done, acceptance criteria and information on how raw data is handled or processed. An OQ Protocol consists of the followings:
1) Calibration of sensors and measuring devices on the equipment or on the test equipment used.
2) Qualification of support processing (i.e. equipment cleaning, disinfection)
3) Qualification of monitoring or controlling software
4) A systematic demonstration of equipment electromechanical features and functions.
5) Qualification of test methods
6) A demonstration of cycle performance
7) A demonstration of process consistency (i.e heat distribution in an oven, fill volume uniformity on a filling machine)
8) A demonstration of safety features and reset procedures after likely events like a power failure.
The OQ protocol must be supported by SOPs on topics such as operating, cleaning, assembling and calibrating the equipment and perform routine maintenance programs.

Performance Qualification

The PQ is the heart of validation. The PQ is a confirmation that the equipment will continue to operate as expected under routine and challenged conditions of operation and that the outcome is acceptable. It is basically about challenging the equipment to confirm its operation within the established limits of operation. This run must be demonstrated repeatedly in 3 consecutive successful runs. For example, in validation a heat sealing unit with parameters for temperature, pressure and dwell time, the PQ is to demonstrate the two extremes of operation that would most likely result in a poor seal like a set of conditions for the highest acceptable temperature, highest acceptable pressure and the longest acceptable dwell time and a second set of conditions for the lowest of all parameters.

Generally, for equipment systems like a clean room, purified water system or compressed air systems, it might be appropriate to perform an IQ/OQ on system components and then a PQ on the system as a whole.

Validation Plan Format:

1.0 Purpose
2.0 Scope
3.0 Responsibility
4.0 Protocol
4.1 IQ
4.2 OQ
4.3 PQ
5.0 Acceptance criteria
6.0 Documentation requirements
7.0 References.


A process is the controlled interaction of components, equipment, environment, software and personnel to produce a product or achieve an acceptable outcome. The validation protocol simply describes a plan that demonstrates consistency in processing and confirms that all component, processing and product specifications are appropriate and attainable under ideal and challenged conditions.
There are 3 general types of processes in a medical product manufacturing facility:
1) Support process: prepares materials, equipment or environmental areas for the work of manufacturing.
2) Standard manufacturing process: standard events used to process many products.
Equipment dependent, include assembly, formulation, mixing, coating, packaging, labeling and inspection.
3) Product process: a manufacturing process that is product specific.

Process Validation Protocol Format:
1. Purpose
2. Scope
3. Responsibility
4. Process History
5. Process Description/Flow
6. Processing Variables/Controls
7. Worst case challenge and Rationale
8. Validation
8.1 Preliminary operation
8.2 Process qualification
8.3 Product qualification
8.4 Validation Acceptance Criteria
9. Process Change Control

Validation Documents:

Validation Master Plan: This document describes the overall company
commitment to validation and further defines commitments to equipment,
method, software and process validation.

Validation Protocols: Controlled documents that describe how to perform a
Specific validation work/event. They can reference SOPs, specifications and
Manufacturing records, acceptance criteria.

Validation Reports: Narrative summaries of a specific validation event referencing the validation protocol document. It summarizes the data and declare the disposition of the item validated.