Process validation: A scientific event of process justification

Process validation: A scientific event of process justification

Process validation is a demonstration and verification of the science that goes into developing a process, and should be viewed as a significant accomplishment in the science and art of process development, says J Ramnivas

A key component to successful process validation of synthetic chemical processes for the manufacture of Active Pharma-ceutical Ingredients (APIs) is developing a comprehensive validation program.

Many skills and tools are required for process validation. One has to integrate the tools for process validation in a systematic, step-by-step approach on how to validate a new process, how to interpret ISO and FDA validation; how to validate changes to a process and how much testing is necessary to validate a process or machine.

Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimise energy consumption or equipment use, need not be included in the process validation. Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.

Process validation is arguably the most important event that occurs during a product’s process lifetime. Too many companies view process validation as a tedious event that takes time, money, effort, and is only needed to satisfy the FDA. Although born as a result of regulatory considerations, process validation should be viewed as a scientific event. That is, process validation is a demonstration and verification of the science that went into developing a process, and should be viewed as a significant accomplishment in the science and art of process development.

Process validation is a requirement of the current Good Manufacturing Practices (cGMP) Regulations for finished pharmaceuticals, 21 CFR Parts 210 and 211, and of the GMP Regulations for Medical Devices, 21 CFR Part 820, and therefore, is applicable to the manufacture of pharmaceuticals and medical devices.

Several firms have asked FDA for specific guidance on what FDA expects firms to do to assure compliance with the requirements for process validation.

Below given are the process validation policy expectations:

  • Documented experimental results

  • Standardised grades of materials

  • Identification of critical process parameters

  • Process development reports

  • Master batch records/change control etc

  • Process flow diagrams

  • Scale-up summary report

  • Impurity characterisation

  • Consistency of batches

  • Technology transfer

  • Process improvement evaluation

  • Process monitoring and trending

  • Validation master plan

  • Development of process validation protocol

  • Execution of process validation

  • Preparation of process validation report

  • Change control/revalidation

Protocol development for process validation

Detailed protocols for performing validations are essential to ensure that the process is adequately validated. Process validation protocols should include the following elements:

  • Identification of the process to be validated

  • Identification of device(s) to be manufactured using this process

  • Objective and measurable criteria for a successful validation

  • Length and duration of the validation

  • Shifts, operators, equipment to be used in the process

  • Identification of utilities for the process equipment and quality of the utilities

  • Identification of operators and required operator qualification

  • Complete description of the process

  • Relevant specifications that relate to the product, components, manufacturing materials, etc

  • Any special controls or conditions to be placed on preceding processes during the validation

  • Process parameters to be monitored, and methods for controlling and monitoring

  • Product characteristics to be monitored and method for monitoring

  • Any subjective criteria used to evaluate the product – Definition of what constitutes non-conformance for both measurable and subjective criteria

  • Statistical methods for data collection and analysis

  • Consideration of maintenance and repairs of manufacturing equipment

  • Criteria for revalidation

If the API for an application under review is already used in other approved or marketed dosage form products, and is being made by substantially the same process and scale as for the application under consideration for approval, the inspection should cover full process validation data and activities (including conformance batches), unless covered during a previous inspection of the API manufacturer.

If the API for an application under review is a new molecular entity or is being manufactured by a process substantially new in design or scale to the site of manufacture, approval of the dosage form incorporating the API is not to be delayed by the performance of initial conformance batches for the

API. However, the inspection team is to audit and assess any available process validation protocols, activities, data and information whether or not completed, and report to the firm any deficiencies.

The ongoing monitoring of manufacturing processes is the key element in maintaining a life cycle approach to validation. After the process validation (three validation lots) is completed and the results indicate a process is in a state of control, an ongoing process monitoring program should be implemented.

The routine process-monitoring program should include all input elements of the critical process control parameters and the resulting output elements including in-process and final release test specifications.

A properly developed process will have the validation data supporting both the process control parameters (input) and specifications (output) upper and lower limits. These input and output values should be trended and summarised on a routine basis.

The results of the trending data should be addressed in the final annual report. The trended data should include any product failure investigation reports, out of range process control parameters, and in-process and final product release specification, equipment, and process change control documents.

The writer is a Senior Manager, Quality Assurance and Regulatory Affairs, Tonira Pharma Limited. Email: