Process validation can be defined generally as a series of activities taking place over the life cycle of the product. The validation exercise establishes scientific evidence that a process is capable of robustly delivering a quality product. After 24 years the FDA modernized its process validation guidance in 2011. The changes were consistent with trends in place within the pharmaceutical industry. The views changed from validation being a point in time event to being applicable over the product life cycle. The life cycle approach to drug product management is laid down in ICH Q7.
Pharmaceutical Quality Systems
The FDA describes process validation as taking place in three stages.
- Process design
- Process qualification
- Continued process verification
Process qualification and continued process verification these stages align with the first three product life cycle phases to find an ICH Q7 Product development, technology transfer and commercial manufacture. Each phase of the product life cycle contributes to the overall understanding of process variation and control of the manufacturing process to deliver a drug product that is fit for purpose. A successful validation program ensures that the sure understand the sources of variation and the impact on the process detects the variation and controls the variation in a manner commensurate with the risk. The FDA is correlating the concepts articulated in ICH Q8 pharmaceutical development and ICH Q7 quality risk management. The validation exercise ensures critical variability is identified and controls to meet the drug product critical quality attributes (CQAS) ICH Q7 articulated the same concept in 2004 drug substances.
Phase-1 process design
The 1980 are over the days of three batches and livings on a prayer are done. Focusing exclusively on qualification efforts without also understanding the manufacturing process and allied variations may not lead to adequate assurance of quality. An integrated team approach should be used that includes expertise from process engineering, analytical chemistry, manufacturing and quality assurance. Process design is where knowledge gained through development and scale-up activities is used to define the commercial manufacturing process. The CQAS and critical process parameters CPPs are defined. The risk assessments gauged the level of process understanding robustness and control. The result is defining a control strategy that is the subject of the qualification phase two. Although the full spectrum of input variability is not known at this stage laboratory of pilot-scale models can be used to estimate variability. Considerations should include variability posed by different raw materials, operators, environmental conditions, and measurement systems. ICH principals are in full consideration ICH Q8 design of experiment studies can be used to help reveal relationships between variable inputs. Such as equipment parameters and the resulting outputs ICH Q9 risk analysis tools can be used to screen potential variables for studies. These studies in turn can be used as justification for established ranges ICH Q10 knowledge management is essential during process design. All studies resulting in process understanding must be documented.
Phase-2 Process qualification
Process qualification is the evaluation of the process to determine if it is capable of reproducible commercial manufacturing. It is a point in time event that defines a strategy for the replicate batches used in the validation study. The process qualification phase corresponds to the technology transfer phase in ICH Q10. Process qualification phase can be broken into two parts.
Part one is commissioning/qualification of the facilities, utilities, and equipment.
Part two is the process performance qualification of the manufacturing process. Commissioning ensures that the manufacturing facility, utilities and equipment is designed properly and functions as intended as defined in the user requirements specifications QRS. Qualification ensures critical aspects of the equipment utilities are installed according to the design specifications and suitable for their intended use. Process performance qualification (PPQ) combines the facility, utilities, equipment, operators, procedures and raw materials with the commercial manufacturing process. It is the part of validation most like the old approach. The manufacturer should clearly lay out in the validation protocol why the approach is appropriate. Simply relying on three batches without justification is not acceptable. The process performance qualification should demonstrate that the commercial manufacturing process performs as expected. The manufacturer must complete a successful process performance qualification before commercial distribution of the drug product.
Phase-3 continuous process verification
Continued process verification is an ongoing program to assure that the process remains in a state of control. It is related to the commercialization phase defined in ICH Q10. Product and process data should be collected and analyzed in order to verify that the quality attributes are being appropriately controlled throughout the process.
A comprehensive continued process verification program includes scrutiny of inter batch variation. The process monitoring is based on risk defined from data from the previous phases. Good process design should anticipate significant sources of variability and establish appropriate detection, control and mitigation strategies. However unexpected sources of variation may occur. In such cases the distal techniques can be used to detect a variation characterize it and determine the root cause. The risk assessments are updated and appropriate intervals as new knowledge is gained. As more data is collected the risk assessments can become more quantitative and less qualitative. The update of the risk assessments can also be timed with the annual product review since the comprehensive product and process data set is being analyzed. Data gathered during continued process verification may provide ways to optimize the process by altering operating conditions process controls or raw materials. This process enables the FDA vision of the pharmaceutical industry embracing continual improvement.