Process Validation Strategy

A written program should be established and followed for validating the manufacturing processes for all APIs. Validation studies should ensure that a specific manufacturing process is capable of performing in a reliable and consistent manner and results in a homogeneous API that consistently meets predetermined specifications.

Validation should embrace steps in the processing of APIs that are critical to the quality and purity of the final API, and should include: - Definition of the API in terms of its critical quality attributes. Among the attributes that should be considered are chemical purity; qualitative and quantitative impurity profiles; physical characteristics such as particle size, bulk and tap density; polymorphic forms; moisture and solvent content; homogeneity; and microbial quality (if the product is susceptible to microbial contamination).

- Identification of process parameters that could affect the critical quality attributes of the API. Critical parameters should be determined by scientific judgement and typically should be based on knowledge derived from research, scale-up batches, or manufacturing experiences.

- Determination of the range for each critical process parameter expected to be used during routine manufacturing and process control. Data to substantiate the ranges for critical process parameters generally should be obtained from laboratory- or pilot-scale batches, unless a specific parameter can only be determined from a production-scale batch.

Examples of processing steps that could be defined by the API manufacturer as critical include: - Phase changes, such as dissolution or crystallization; - Phase separation, such as filtration or centrifugation; - Steps that cause chemical changes; - Steps that alter temperature or pH; - Mixing of multiple raw materials; and - Steps that cause changes in surface area, particle size, bulk and tap density or homogeneity.

Critical process parameters (e.g., reaction times, reaction temperatures, reactant ratios, concentrations, pressures, pH, and impurity levels) should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize 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 and is comparable to the profile determined during process development or for batches used for pivotal/toxicological studies.