PROCESS VALIDATION
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. This guidance describes process validation activities in three stages.
Effective process validation contributes significantly to assuring the drug product quality. The basic principle of quality assurance is that a drug product should be produced that is fit for its intended purpose. This principle incorporates the understanding that the Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished-product inspection or by only testing.
Alignment with ‘Product life cycle’ Approach:
The ICH publishes guidelines on quality, safety, efficacy and multidisciplinary topics. Quality guidelines Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) are directly referenced in the new FDA guideline.
The FDA has also referenced the ASTM E2500, where the focus has shifted from validation of individual parts of a process, to a collective ‘process validation’ effort that takes a more holistic view of process, highlights the GxP critical parts of the process and focuses efforts and resources on the most critical aspects.
The new guidance has been aligned with this concept, giving the following three-stage approach to process validation:
- Stage 1 – Process Design
- Stage 2 – Process Qualification
- Stage 3 – Continued Process Verification.
Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on the knowledge gained through product development and scale-up activities.
The intent of this stage is to design of a process that suitable for routine manufacture that will consistently deliver product that meets its critical quality attributes.
Typical activities involved in the process design are:
- A combination of product and process design (Quality by Design)
- Product development activities
- Experiments to determine process
- parameters, variability and necessary controls
- Risk assessments
- Other activities required to define the commercial process Design of Experiment testing
Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Typical activities involved in the process qualification stage are:
- Facility design
- Equipment & utilities qualification
- Process Performance qualification (PPQ)*
- Strong emphasis on the use of statistical analysis of process data to understand process consistency and performance.
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Typical activities involved in the continued process verification stage are:
- Proceduralised data collection from every batch.
- Data trending and statistical analysis Product review
- Equipment and facility maintenance, Calibration
- Management review and production, staff feedback
- Improvement initiatives through process experience
A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that result in products with the desired quality attributes. Manufacturers should:
- Understand the sources of variation.
- Detect the presence and degree of variation
- Understand the impact of variation on the process and ultimately on product attributes
- Control the variation in a manner commensurate with the risk it represents to the process and product.
PROCESS DESIGN:
Process design is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
Building and Capturing Process Knowledge and Understanding:
Product development activities provide key inputs to the process design stage, such as
- The intended dosage form,
- The quality attributes
- General manufacturing pathway.
The functionality and limitations of commercial manufacturing equipment should be considered in the process design, as well as predicted contributions to variability posed by different component lots, production operators, environmental conditions, and measurement systems in the production setting. However, the full spectrum of input variability typical of commercial production is not generally known at this stage. Laboratory or pilot-scale models designed to be representative of the commercial process can be used to estimate variability.
Design of Experiment (DOE) studies can help develop process knowledge by revealing relationships, including multivariate interactions, between the variable inputs (e.g., component characteristics or process parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product). Risk analysis tools can be used to screen potential variables for DOE studies to minimize the total number of experiments conducted while maximizing knowledge gained. The results of DOE studies can provide justification for establishing ranges of incoming component quality, equipment Contains Nonbinding Recommendations parameters, and in-process material quality attributes.
It is essential that activities and studies resulting in process understanding be documented. Documentation should reflect the basis for decisions made about the process. For example, manufacturers should document the variables studied for a unit operation and the rationale for those variables identified as significant. This information is useful during the process qualification and continued process verification stages, including when the design is revised or the strategy for control is refined or changed.
Establishing a Strategy for Process Control:
Process knowledge and understanding is the basis for establishing an approach to process control for each unit operation and the process overall. Strategies for process control can be designed to reduce input variation, adjust for input variation during manufacturing (and so reduce its impact on the output), or combine both approaches.
Process controls address variability to assure quality of the product. Controls can consist of material analysis and equipment monitoring at significant processing points. Decisions regarding the type and extent of process controls can be aided by earlier risk assessments, then enhanced and improved as process experience is gained.
FDA expects controls to include both examination of material quality and equipment monitoring. Special attention to control the process through operational limits and in-process monitoring is essential in two possible scenarios:
- When the product attribute is not readily measurable due to limitations of sampling or detect ability (e.g., viral clearance or microbial contamination) or
- When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified.
PROCESS QUALIFICATION
During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture.
This stage has two elements:
(1) design of the facility and qualification of the equipment and utilities and
(2) process performance qualification (PPQ).
Design of a Facility and Qualification of Utilities and Equipment:
Proper design of a manufacturing facility is required under part 211, subpart C, of the CGMP regulations on Buildings and Facilities. It is essential that activities performed to assure proper facility design and commissioning precede PPQ. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. These activities necessarily precede manufacturing products at the commercial scale.
Qualification of utilities and equipment generally includes the following activities:
- Selecting utilities and equipment construction materials, operating principles and performance characteristics based on whether they are appropriate for their specific uses.
- Verifying that utility systems and equipment are built and installed in compliance with the design specifications (e.g., built as designed with proper materials, capacity, and functions, and properly connected and calibrated).
- Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under load comparable to that expected during routine production. It should also include the performance of interventions, stoppage, and start-up as is expected during routine production. Operating ranges should be shown capable of being held as long as would be necessary during routine production.
CONTINUED PROCESS VERIFICATION
The goal of the third validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal. Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control.
An ongoing program to collect and analyze product and process data that relate to product quality must be established. The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.
Variation can also be detected by the timely assessment of defect complaints, out-of-specification findings, process deviation reports, process yield variations, batch records, incoming raw material records, and adverse event reports. Production line operators and quality unit staff should be encouraged to provide feedback on process performance. We recommend that the quality unit meet periodically with production staff to evaluate data, discuss possible trends or undesirable process variation, and coordinate any correction or follow-up actions by production.
Data gathered during this stage might suggest ways to improve and/or optimize the process by altering some aspect of the process or product, such as the operating conditions (ranges and set-points), process controls, component, or in-process material characteristics. A description of the planned change, a well-justified rationale for the change, an implementation plan, and quality unit approval before implementation must be documented. Depending on how the proposed change might affect product quality, additional process design and process qualification activities could be warranted. Maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a process remains in control. Once established, qualification status must be maintained through routine monitoring, maintenance, and calibration procedures and schedules.