Process Validation - API

Why Process Validation is required?

 

The objective of the process validation is to establish documented evidence and it give the assurance that the process, method or system are capable to produce an API and intermediates consistently as per pre defined specification limits.

 

Who are the Responsibial for Process Validation?

The QC, QA, Production and some where Regulatory

 

Approach for Process Validation: Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes process validation activities in three stages:

 

Stage-1: Process Design: The Exhibit / Commercial batch / production batch manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.

 

Stage-2: Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible Exhibit / Commercial batch / production batch manufacturing.

Stage-3: Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

Process Design:

Process Design activity shall be carried out at R&D or Process Development Lab of company in the form of development activity for lab scale or pilot batch for API and intermediate stages. Process Design should capture the functionally, suitability and limitations of manufacturing equipments, experimental study with different lots and / or different vendor for KSM and raw materials of API and intermediate stages. Process Design should capture the yield variation, selection of vendor for KSM, determined the critical process parameters, supporting stability data of API and Intermediate stages. Based on that Batch Manufacturing Record shall be prepared for exhibt batches / Production batches.

 

Definition for Production Batch: A batch of a drug substance manufactured at production scale by using production equipment in a production facility as specified in Batch Manufacturing Record.

 

Definition for Pilot scale Batch: A batch of a drug substance manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. . The pilot scale is generally, at a minimum, one-tenth that of a full production scale.

 

Definition for Laboratory scale Batch: A batch smaller than pilot scale that is manufactured for development purposes.

 

Process Validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug should be produced for its intended use. This principle incorporates the understanding that the following conditions exist: 

• Quality, safety, and efficacy are designed or built into the product
• Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications.

When Process Validation to be performed?

 

 Process Validation shall be performed in following criteria:

1. Product to be manufactured first time in manufacturing facility.
2. Change in manufacturing area within the facility.
3. Change in manufacturing facility within the location
4. Product to be transferred from one location of other location of company or Process Development Lab to manufacturing facility. 
5. Change in route of synthesis of existing validated process
6. Change in key starting material of existing validated process
7. Change in source of key starting material of existing validated process
8. Change in unlike and critical process equipments in existing validated process (e.g Tray Dryer is replacing with Rota Cone Vacuum Dryer)
9. Change in in-put qty. of raw materials
10. Removal or addition of intermediate stage in existing validated process even though ROS (route of synthesis) remain same with existing validated process.
11. Change in purification solvents of API.
12. Change in batch size more than 10 fold of validated process

Minimum three consecutive API batches shall be selected for Prospective Process Validation. The batch size of the exhibit batch shall be less than the commercial batch size.

 

The following parameters shall be similar in selected API batches and there intermediates stages for Process Performance Qualification or Prospective Process Validation:

 

Ø  Batch Size of API and its Intermediate stages

Ø  Input qty. of Raw materials & Key Starting Materials

Ø  Source of input Raw materials & Key Starting Materials

Ø  Equipments

Ø  Manufacturing area and facility

Ø  Supporting utilities

Ø  Manufacturing Process

Ø  Evaluation specification

At the end of process validation batches (PPQ), commercial batches shall be manufactured. The batch size for commercial batches shall not exceed the 10 times from the exhibit batches. PPQ shall be considered as successful after satisfactory completion of six months stability data for Accelerated Condition (40° ± 2°C / 75% ± 5% RH) and Long Term Condition (25°C ± 2°C / 60% ± 5% RH) of selected batches.