Top 3 Stages of Pharmaceutical Validation

Pharmaceutical validation entails confirming that a medication adheres to the necessary quality criteria and specifications for its designated purpose. It is an essential part of pharmaceutical development and production, as it guarantees the safety, effectiveness, and uniformity of the drug. Additionally, validation is instrumental in refining the manufacturing process, curtailing expenses, and adhering to regulatory standards.

The pharmaceutical validation process is comprised of three main stages: process design, process qualification, and continued process verification. Each phase has its unique objectives, methodologies, and documentation.

The following sections will provide a brief overview of each stage, as well as references for further reading.

Stage 1: Validation: Process Design 

 During the process design phase, the product and manufacturing procedures are specified and optimized using scientific expertise and thorough risk assessments. The aim is to identify and assess the critical quality attributes (CQAs) of the product, determine the critical process parameters (CPPs) influencing the CQAs, and establish specifications and thresholds. It also includes choosing and confirming the suitability of raw materials, equipment, and techniques involved in the production process. 

Process Validation is exemplified in the manufacturing of a pharmaceutical drug, which must uphold safety, efficacy, and consistent quality standards for human consumption. This involves adherence to three distinct phases: 

1.  Conduct Experiments and Trials: to determine the optimal formulation and processing conditions for a medicine.

2. Identify Critical Attributes (CQA) such as potency, purity, and stability, and Production parameters like temperature, pressure, and mixing time that affect these attributes. 

3. Establishing a Specification: Determining the acceptable variability of formulation/processing and operational parameters to ensure consistent drug quality. The result is a Process Design Report (PDR) that includes the scientific rationale, findings from experiments, and statistical analysis supporting the process design.

A process design document (PDD) outlines the thought process, assumptions, and data involved in developing a process. It includes a flow diagram of the process, control strategies, and approaches for validation, which are examined and approved by relevant stakeholders prior to implementation.

Example: Process Design Validation: 

An instance of pharmaceutical process design is creating a continuous production method for an acetaminophen solid oral dosage, commonly used for pain relief and fever reduction.

This procedure entails combining the active pharmaceutical ingredient (API) with excipients, granulating the blend through a twin-screw extruder, drying the granules, milling to achieve the required size, and then pressing them into tablets using a rotary tablet press. Moreover, the process includes real-time monitoring and feedback control to maintain steady quality and efficacy of the product.

Document for Process Design would include;

-            A Process Flowchart illustrating the principal operational units, inputs and outputs, and key control points.

-            An Overview of the product Critical Quality Attributes (CQAs) like potency, purity, dissolution, hardness, and weight uniformity, along with the techniques used to assess them.

-            An Outline of the Critical Process Parameters (CPPs) like feed rate, screw speed, barrel temperature, dryer temperature, mill speed, and compression force, along with the techniques to manage these factors.

-            A Justification for choosing certain raw materials, equipment, and methodologies grounded in scholarly research, empirical evidence, and the evaluation of potential risks.

-            A Detailed Validation Strategy outlining goals, extent, standards, and procedures for confirming the setup of equipment, efficiency of the process, and quality of the product in line with regulatory norms and industry benchmarks. 

Stage 2: Validation: Process Qualification

 Process qualification is the phase in which the production process is tested and verified to reliably manufacture the product according to the predetermined quality standards. It includes two main stages: the installation qualification (IQ) and the performance qualification (PQ). 

Installation Qualification verifies that the equipment and facilities operate according to their design specifications. Performance Qualification validates that the process consistently produces products that meet predefined standards under standard and adverse conditions.

The Process Qualification Report (PQR) summarizes the results and conclusions from the Installation Qualification (IQ) and Performance Qualification (PQ) assessments. It includes process performance measurements, an evaluation of process capability, and criteria for validation approval. The PQR must be reviewed and approved by relevant stakeholders before moving on to the next stage.

During the Process Qualification stage, the pharmaceutical manufacturer conducts full-scale testing and confirmation of the production process utilizing the actual equipment and facilities designated for commercial manufacturing. It's imperative for the manufacturer to carry out installation qualification (IQ) to certify that all equipment and facilities are correctly installed and operating as required.

Additionally, the manufacturer is required to conduct performance qualification (PQ) to verify that the process consistently produces the drug in accordance with the established acceptance criteria, even under standard and challenging conditions. The outcome of the process qualification phase is encapsulated in the process qualification report (PQR), documenting the findings from IQ and PQ assessments, metrics on process performance, analysis of process capability, and standards for validation acceptance.

Example: Process Qualification

Process Qualification (PQ) is the testing and evaluation of a tablet manufacturing process that involves mixing, granulating, drying, milling, blending, compressing, and coating steps. The manufacturer would conduct Installation Qualification (IQ) to confirm that all the equipment, such as mixers, dryers, mills, blenders, presses, and coaters, are properly installed, calibrated, and functioning according to the design specifications.

The manufacturer would also perform PQ to demonstrate that the process can reliably produce tablets that meet the predefined quality attributes, such as weight, hardness, thickness, friability, dissolution, assay, and content uniformity, under normal and worst-case scenarios.

The PQR would document the results and conclusions from the IQ and PQ tests, as well as the process performance measures, process capability analysis, and validation acceptance criteria. The PQR would be reviewed and approved by the quality assurance team and other relevant stakeholders before proceeding to the next stage of validation.

Stage 3: Validation: Continued Process Verification

Ongoing process verification refers to the constant monitoring and assessment of the manufacturing process to guarantee that it continuously operates under control and can consistently produce the product according to the established quality standards.

Continued process verification entails gathering and examining data from the operation, products, and surroundings and executing corrective action and preventive action (CAPA) measures as needed. It also involves regular evaluations and revalidation to accommodate any modifications or enhancements.

This report serves as proof and gives the reasoning behind the sustained control and validation of the process. It contains details such as process performance indicators, Analysis of Process Capability, Corrective and Preventative Actions (CAPAs), and plans for Revalidation.

Continued Process Verification: At this phase, the pharmaceutical company continuously monitors and evaluates the production process to ensure it is controlled and consistently produces the drug according to established quality standards.

It is incumbent upon the producer to collect and scrutinize details about the process, product, and environment, and implement corrective and preventive actions (CAPA) as needed. Additionally, they should regularly review and revalidate to adjust to any changes or improvements.

The Continuous Process Verification is recorded in a continued process verification report (CPVR). It documents the consistent control and validation of the process, covering indicators of process performance, analysis of process capability, corrective and preventive actions (CAPAs), along with plans for subsequent revalidation. Stakeholders regularly review and approve the CPVR.

Example: Continued Process Verification

An Example of Continued Process Verification in Pharmaceutical Dosage Form is as follows. A pharmaceutical company produces an antihypertensive medication in tablet form. They've determined the critical quality attributes and process parameters, confirming these through studies which also validate their control strategy within the design space. 

To ensure consistent process performance and product quality, they utilize a continuous verification system using statistical charts and indices, while also monitoring environmental and raw material variables for any impact on quality. Through regular analysis and risk evaluations, they identify and address potential inconsistencies with corrective actions.

Updates to the process validation lifecycle are made when necessary, reflecting innovations or modifications. Documentation of this ongoing verification is captured in a report that's authorized by both the internal quality division and regulatory agencies, certifying the persistent integrity of the manufacturing process and guaranteeing product safety for users.

 

References

·       ICH Q10: Pharmaceutical Quality System.

·       Guidance for Industry: Process Validation: General Principles and Practices.

·       Continued Process Verification: An Industry Position Paper With Example Plan.

·       ICH Q8: Pharmaceutical Development.

·       Guidance for Industry: Process Validation: General Principles and Practices.

·       Pharmaceutical Process Design and Management.

·       ICH Q9: Quality Risk Management.

·       Guidance for Industry: Process Validation: General Principles and Practices.

·       Pharmaceutical Process Validation: An International Third Edition.

·  International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). 2009. Pharmaceutical Development Q8(R2).

·      Jadhav, S. B., Pisal, S. S., Paradkar, A. R., & Mahadik, K. R. (2014). Continuous manufacturing of acetaminophen granulation using twin screw granulator: influence of key process parameters on granule properties and tabletability. Drug Development and Industrial Pharmacy, 40(7), 985-994.

·       Singh, R., Sahay, A., & Reed, M. R. (2020). Process design and control strategy for continuous manufacturing of an immediate release tablet. Journal of Pharmaceutical Innovation, 15(3), 466-483.

·       Reference: FDA, 2011. Guidance for Industry: Process Validation - General Principles and Practices.