Concept of process validation in pharmaceutical industry

The process validation of formulated products (e.g., tablets, capsules, ointments, etc.) starts with a well-defined validation plan and protocol.

The validation protocol outlines the steps to ensure the process consistently produces a formulated product meeting quality standards.

It begins by identifying critical process steps and parameters (e.g., blending, granulating, tableting, etc.), conducting validation risk assessment, and considering potential adverse consequences if they are not met.

We have prepared some essential steps relevant to most process validation activities for formulated products.

a. Develop a validation master plan.

For more complex validation activities, a validation master plan, VMP, should be produced to describe the approach for each validation element.

A VMP is a strategic document that must be approved early in the project, and the scope of the elements needs to be validated.

b. Prepare validation protocol.

After you describe the elements in the validation master plan, define validation requirements for those elements in the validation protocol.

For example, qualified and calibrated facilities, systems, services, equipment, and validated testing methods.

The validation protocol should include, but not be limited to, the following:

– Detailed objectives.

– Process description.

– List of products/product strengths.

– List of processes, facilities, systems, and equipment to use.

– Summary of critical parameters and activities to evaluate.

– Number and identity of runs/batches.

– Release specification/s and list of analytical methods.

– Acceptance criteria.

– Proposed in-process controls.

– Additional testing to be carried out.

– Sampling plan and testing procedures.

– Methods for recording and evaluating results.

– Functions and responsibilities.

– Proposed timetable.

c. Identify prerequisites for process validation.

Prerequisites for process validation include, and are not limited to, the following:

– Approved master formulation, master manufacturing process instructions, and applicable standard operating procedures (SOP).

– Identified critical process parameters and critical quality attributes.

– Qualified equipment – facilities, utilities, and Computerized Systems.

– Qualified or validated supporting processes that may affect validation (e.g., Filtration, inspection, sterilization, media fills.

– Calibration of critical instruments.

– Approved specifications for finished products, raw materials, and components.

– Established in-process controls (IPC) and their decision criteria.

– Validated test methods will be required to test and release products.

– Qualified personnel will manufacture the validation batches.

d. Select validation approach

As we described earlier, the validation can be prospective, concurrent, or retrospective, depending on when it is performed concerning production.

Prospective validation must be the default method or approach for new or modified processes.

The validation protocol and the VMP (if applicable) must document the rationale and justification for using a concurrent or retrospective validation approach.

e. Worst-case and challenge tests

The process should be challenged by deliberate changes to demonstrate its robustness and define its tolerance limits.

In challenging a process to assess its adequacy, the conditions should simulate those that could be encountered during actual production.

These tests should be repeated to ensure that the results are meaningful and consistent.

Such worst-case or challenge tests should preferably be performed before manufacturing validation batches.

Typically, they are done during a validation program’s operational or performance qualification stage.

f. Determine matrixing or family approach

The general principle is to validate a manufacturing process, and the “same” process can typically be used for several related products.

Rather than developing a plan for each product manufactured by a process, you should develop a plan for that process instead.

Two general principles could be applied.

i. A “Matrix approach” generally means a plan to conduct validation on different strengths of the same product.

ii. A “Family approach” describes a plan to conduct validation on different but similar products.

Either approach must demonstrate that the process is consistent for all the strengths of products involved.

The plan should be designed to evaluate all likely sources of variation in the products manufactured by the process.

Each plan should be evaluated on a case-by-case basis.

This approach would not be applicable for significant differences in equipment or process, and each strength or product would need to be validated separately.

g. Perform validation testing

Validation tests are conducted under conditions mimicking routine manufacturing, with batch size representative of commercial scale.

Sampling and testing ensure compliance with stringent requirements, focusing on critical process steps.

Homogeneity studies are conducted as needed, with sampling plans ensuring representative samples.

Tests demonstrate physical and chemical homogeneity, with individual samples meeting acceptance criteria.

On-line or in-line monitoring may substitute discrete sampling to demonstrate homogeneity or fulfillment of acceptance criteria.

h. Validation Documentation

All documentation and raw data generated during validation activities are considered GMP documentation for retention/archiving purposes. It must be retained in a manner that permits traceability and ensures that it is readily retrievable.

We have provided a detailed list of validation documentation in the later section of the article.

i. Manage changes

You must document and manage all changes that may affect product quality and reproducibility. You must evaluate the likely impact on the process or product due to the changes.

Determine whether the change is major or minor and its impact on the validation status and stability testing.

Why do you need three batches for validation?

Your validation study needs at least three batches to provide a more accurate and unbiased representation of the validation model’s performance.

If you use a single batch during your validation study, it may not provide an accurate picture of the process’s performance, as the specific parameters and environments can influence the results of that batch.

When you use multiple batches, the validation results are more likely to represent the process performance on unseen data.

Additionally, more than one validation set should be used to reduce the chance of overfitting and give a better sense of the process’s performance.