Principles of the Process Validation Protocol

The document Guidance for Industry, Process Validation: General Principles should be adhered to when drafting your process validation protocol. For a copy of the draft for process validation guidance, go to:

http://www.fda.gov/cder/guidance/index.html

The Purpose of Process Validation

In addition to ensuring that a product in is compliance, process validation (PV) can add value to the process by eliminating variance, batch rejects and ultimately product recall.

While PV is compulsory, in order to remain in compliance, it can also be a cost effective addition to manufacturing. A process validation protocol is a requirement as stipulated by the Current Good Manufacturing Practices Regulations for Finished Pharmaceuticals and is therefore applicable to manufacturing of drugs. Process validation will ensure a robust product that is highly reproducible over time.

This protocol is central to the goal of documenting a process, as reliable and controlled to an auditor. The process validation protocol is not specifically concerned with the validation of equipment, environment or analytical test methods. All of these types of validation should already be completed prior to process validation.

There are many possible methods that can be used to qualify process validation. One method is to justify the extremes of all operating ranges. Once the statistical analysis is complete, using experimental design, permutations and combinations, any six sigma black belt will provide figures that will clog the manufacturing schedule with a huge number of PV batches! To alleviate this problem, data recorded and analyzed during development and scale-up phases can be used.

Methods of Process Validation

Risk Assessment

Various assumptions will be necessary in order to lock down protocol acceptance criteria and minimum batch number requirements. These assumptions must documented, assessed and justified using risk assessment.

For example, an approach in which centre-line values of the operating ranges are applied to three PV batches may be justified with the addition of development and scale-up data, by combining the information in a risk assessment.

This system can dependably lead to a strong manufacturing process that consistently produces a drug product with minimal discrepancies in quality requirements.

Factors for Planning Process Validation

Timing

The process must be validated prior to commencement of commercial manufacturing. This is called prospective validation and is defined as: validation required before the circulation of either a new drug product, or a drug that was manufactured under a revised process; in this case, the revisions may have affected the drug's attributes.

Another possibility is that a process is currently being run and is categorized as "at risk". This can occur if the initial validation was inadequate, any process changes were not validated and changes occur in regulatory requirements. In this case a retrospective validation must be performed ASAP!

A retrospective validation is the validation of a process for a drug product that is in the distribution phase and it is performed on the basis of accumulated production, control and testing analysis. This is likely to be accomplished using data gathered from previous batches.

Elements Involved in Writing a Process Validation Protocol

In order to validate a process, a validation protocol must be developed which details how the validation will be performed. It will be written in line with the site validation master plan (VMP) and will reference all relevant documents like the VMP, risk assessments, etc. The protocol will need to be signed by all relevant departments, this may include:

- Technical Support

-Development

-Engineering

-Quality Control

-Quality Assurance

-other departments as appropriate

The process validation protocol includes, but is not limited to, the following information:

-The scope and purpose of validation

-The responsibilities and functions of all organizational sections involved in validation

-Background information about the process to be validated

-A process summary which may contain details of the chemistry involved, unit operations, or flow diagrams of the process

-Safety information

-The process validation procedure which will includes associated documents like the validation master plan, and other information like sampling, hold times etc.

-All process validation studies which will include parameter ranges (specifying criticality) and acceptance criteria

-A list of key equipment to be used along with the design and type, the operational qualification (IQ/OQ) and installation

-Deviation, general attachment and signature logs

In all cases, the ultimate guide for process validation and the process validation protocol should be from the regulatory body. With which the facility maintains compliance, such as the Federal Drug Administration (FDA). There is a vast amount of literature to read on process validation and articles such as the one presented here can act point you in the right direction, to avoid aimlessly jumping into an ocean of validation information.