Process Design and Process Validation Recommendations

Generally, early process design experiments do not need to be performed under the CGMP conditions required for drugs intended for commercial distribution that are manufactured during Stage 2 (process qualification) and Stage 3 (continued process verification). They should, however, be conducted in accordance with sound scientific methods and principles, including good documentation practices. This recommendation is consistent with ICH Q10 Pharmaceutical Quality System. Decisions and justification of the controls should be sufficiently documented and internally reviewed to verify and preserve their value for use or adaptation later in the lifecycle of the process and drug product.
Although often performed at small-scale laboratories, most viral inactivation and impurity clearance studies cannot be considered early process design experiments. Viral and impurity clearance studies intended to evaluate and estimate product quality at commercial scale should have a level of quality unit oversight that will ensure that the studies follow sound scientific methods and principles and the conclusions are supported by the data.
Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes, and a general manufacturing pathway. Process information available from product development activities can be leveraged in the process design stage. 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.
Designing an efficient process with an effective process control approach is dependent on the process knowledge and understanding obtained. 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 parameters, and in-process material quality attributes. US FDA mentioned in its guidelines on process validation that it does not generally expect manufacturers to develop and test the process until it fails.
Other activities, such as experiments or demonstrations at laboratory or pilot scale, also assist in evaluation of certain conditions and prediction of performance of the commercial process. These activities also provide information that can be used to model or simulate the commercial process. Computer-based or virtual simulations of certain unit operations or dynamics can provide process understanding and help avoid problems at commercial scale. It is important to understand the degree to which models represent the commercial process, including any differences that might exist, as this may have an impact on the relevance of information derived from the models.
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.

2. 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 pharmaceuticals 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 (§ 211.110(c)). 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. It is expected that 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:
1. When the product attribute is not readily measurable due to limitations of sampling or detectability (e.g., viral clearance or microbial contamination) or
2. When intermediates and products cannot be highly characterized and well-defined quality attributes cannot be identified.

These controls are established in the master production and control records (see § 211.186(a) and (b)(9)).
More advanced strategies, which may involve the use of process analytical technology (PAT), can include timely analysis and control loops to adjust the processing conditions so that the output remains constant. Manufacturing systems of this type can provide a higher degree of process control than non-PAT systems. In the case of a strategy using PAT, the approach to process qualification will differ from that used in other process designs.  PAT ― A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.

The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation.Also see ( process validation in pharma )
FDA guideline

 
Also see:
Process validation and its regulatory, statutory requirements.

Process Validation and Drug Quality Approach to Process Validation.

General Considerations for Process Validation and Recommendations

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