Stage 2 is referred process qualification, which includes pharmaceutical drug products at a stage prior to commercialization or prior to submitting a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA).  In this stage, it must be demonstrated that the process for manufacture of a drug product is consistent and can produce drug products that are compliant with the Food and Drug Administration’s requirements for filing.

This stage includes two elements.  The first element focuses on facility design and equipment installation and maintenance while the second includes process performance qualification (PPQ).[1]  Some prerequisites to facility design and equipment installation and maintenance includes validation and qualification of analytical methods, approved standard operating procedures (SOPs) for process validation, implementation of preventive maintenance program (PMs), cleaning validation of equipment, and process specific GMP training.  In structuring a PPQ, CPPs and CQAs must be defined, justified, and documented.  Other process performance qualification activities must be controlled by an approved protocol that includes the scope, strategy, testing, sampling plan, and acceptance criteria. This study is conducted at a manufacturing site, according to a site validation master plan.  Additional strategies are explored below.

Process Qualification Study Strategies: [2]

A strategy needs to be developed for every qualification study and it must be based on deep process understanding gained from the manufacturing experience. Some elements to consider include:

1. Number of Batches: The protocol should include three consecutive batches, with the results summarized in the final process qualification report.

2. Material Selection:  Selection of more than one lot of API and critical raw materials should be used during process qualification (especially if the API or critical raw materials are not dissolved or distributed in solution). Based on the selection of these materials, a process should be designed to validate the robustness of the process.

3. Equipment Selection: The process must be qualified on all equipment intended to be used in the manufacture of the product. For equipment determined as being equivalent, qualification on one piece of equipment is sufficient.

4. Design Space/Parameters Ranges:  For products that have an established design space, the process qualification should be executed at specified conditions within the design space. For conditions that are high risk, high and low parameter ranges should be considered for the process qualification.

5. Process Re-qualification:  Process re-qualification may be required if, for example, a significant deviation from desired process performance is uncovered through stage 3 continued process verification.  The process re-qualification studies should bridge back to the original or pivotal clinical biobatch.

Process Qualification Testing:[3]

Process qualification testing should be based on the established CPPs and CQAs and the control strategy and risk assessments, which characterize the product quality and process consistency.

CPP Monitoring:  Defined critical process parameters should be monitored and reported in the final qualification report.

• For processes that have a processing fluid (e.g., granulation), microbial testing and hold times will need to be established. For processes where critical ingredients are added as a part of the processing fluid, testing related to the critical ingredient (e.g., assay) at make-up and at the end of hold time should be considered.

• For processes involving lubricated granulation, blend uniformity testing must verify that the active ingredient has been distributed throughout the blended bulk uniformly. To determine unit-dose equivalent (1-3x) blend uniformity of the active ingredient on the final, blend samples should taken from the blender. For combination products, all APIs need to be tested for blend uniformity while respective blenders need to be tested for bilayer tablets.

• For the manufacture of compressed tablets or capsules, during the compression operation a sampling plan should be adopted with around ten evenly spaced intervals throughout the batch processing. After the compression machine is set-up, location one should include the first salable dosage units and location ten should contain the last salable dosage units while location two through nine should be evenly spaced across the lot.  For a process using a double sided machine, both the sides of the machine should be sampled at each location. For the manufacture of combination or bilayer tablets, ample samples should be obtained to properly evaluate all API specific tests.  Specific to bilayer tablets, samples should be taken to evaluate both layers.

• For the manufacture of film coated tablets, random location sampling should be taken of representative samples. For application of functional membranes, testing should be performed on samples taken from each film coating pan load. For nonfunctional coats, samples may be divided among the film coating pan load.

Acceptance Criteria:

The manufacture process must be validated and reported within the regulatory filing, batch records and final validation report, including all the appropriate specification and procedures (e.g., selected CPPs and release requirements). Any deviation must be investigated and addressed in the validation report.

Each of the processing steps can be analyzed by evaluating the process control charts (based on three sigma limits) and the historical process capability charts.  These charts should be evaluated for nonrandom systematic behavior.  Ultimately, for all initial process qualification, a comparison must be made to the dissolution profile performed on the biobatch or pivotal reference batch.  A batch may be excluded if a nonprocess related assignable cause, like mechanical failure, has been identified.

Statistical Analysis:

Intra-batch and inter-batch variability should be examined from data collected during process qualification through the analysis of process control charts and process capability charts.

Once a product has completed performance qualification, process validation continues through implementation of continued process verification.  This verification includes monitoring operating procedures, preventive maintenance and calibration programs, deviation investigations, annual review, and change control procedures. Any changes to the process must be evaluated through the process change request system and procedures for process change control to determine the impact to on-going process validation.  A list of intermediate tests for nonsterile solid dosage forms (tablets and capsules) are compiled in Table 1.

Stage 2 process qualification is conducted at the manufacturing site, which is usually a far distance away from product development/process development facilities. Therefore, another important piece of the process validation includes technology transfer to manufacturing facilities. Technology transfer includes detailed process fit, manufacturing readiness, and an execution phase. Process qualification falls under the execution phase.

Continued Process Verification (Stage 3)[4]

The goal of continued process verification (CPV) is “continual assurance that the process remains in a state of control (validated state) during commercial manufacture.”[5] Once a process has gone through process qualification, an ongoing program to collect and analyze product and process data that relate to product quality is necessary. The objective of the on-going process verification program is to understand the sources of variation, its impact on the process and product attributes, and finally to devise a way to control the variation. The knowledge gained through stage 3 of continued process verification provides ongoing assurance that a product remains in a state of control.

In summary, QbD is not a mandated requirement, however, any pharmaceutical company that instills the QbD approach in their DNA of product development (process design, process qualification, and continued process verification) will come out ahead in their value curve, since we live in an increasingly science-driven regulatory environment in 21st century — where compliance and quality have been essential elements of competitiveness and quality drug products. Hopefully these tips and strategies will support you in designing and validating a quality manufacturing process.