Validation in Pharma Manufacturing

Introduction

This article includes the guidelines which can be utilized under defined circumstances but appropriate decisions can be taken by scientific justification

Scope

This document can provide guidance to validation issues for sterile and non sterile dosage forms and biologicals.

Purpose

These guidelines tend to indicate what is expected to be covered by fabricators, packagers but doesn’t encompass all the intended factors as they can vary according to different drug products. These guidelines can be applied on general level for establishing a comprehensive approach to validation

General

Product parameters like quality, safety, and efficacy should be considered by evaluating quality materials or components, product design, process design, control of various processes and in –process control and testing of end product.

Phases of Validation

The activities in accordance with the validation studies are classified into three phases

Phase I/ Pre Validation or Qualification Phase

This phase includes all activities relating to product research & development, formulation, scale up studies, pilot batch studies, stability conditions, technology transfer to commercial scale batches, handling & storage of in process & finished dosage forms, equipment qualification, installation qualification, operational qualification, master production documents, process capability.

Phase II/ Process Validation Phase

This phase verifies that established limits of critical process parameters are valid. It ensures that satisfactory products are not mentioned under worst conditions

Phase III/ Maintenance Phase

This phase requires frequent process review relating to documents, validation audit reports so they are no deviations or failures or modifications to production process. This phase further ensures that all sops have been followed including change control procedures.

Validation Protocol

Validation protocol is a written plan depicting how validation should be conducted along with their test parameters, product specifications, equipment used in production and packaging and final end decision points on test results.

If the validation protocol is changed or modified then the change should be justified and documented.

The validation protocol should be duly signed with date and numbering and it should include the following

• Objective, scope of validation
• Team involved in Validation with their qualifications & responsibilities
• Type of validation – prospective/ concurrent/ retrospective/ revalidation
• Batches number and selection which are included in validation study
• Equipment used should be listed with their normal and worst case operating parameters
• IQ, OQ outcome for critical equipment
• Calibration requirements for all measuring devices
• Critical process parameters and their respective tolerances
• Processing steps with their copy of master documents for product
• Sampling – stages, methods, plan and sampling points
• Statistical tools used in analysis of data
• Training requirements for processing operators
• Specifications for raw materials/packing materials/ test methods
• Charts or any forms, sheets used in documenting results
• Format for presenting results, documenting conclusions and study results approval

Validation Master Plan

Validation master plan is the document which gives company’s philosophy, intention and approaches for establishing performance adequacy.

The management should agree on validation master plan and in accordance with authorized standard operating procedures

It should provide an overview of entire validation operation, organizational structure, content and planning.

All the activities relating to validation like critical technical operations in accordance with product and process controls within a company should be validated

It should be clear, concise, brief and should refer to policy documents, validation protocols, reports and SOPs. The format and content should include the following

• Validation policy, scope, schedule, location
• Organizational structure -  responsibilities of personnel
• Description of plant/ process/ product – inclusion and exclusion criteria and extent of  validation
• Validation approach, matrix format including products, processes, systems to be validated
• Actual status and future perspective of revalidation activities
• Key acceptance criteria
• Documentation format
• SOP’s reference
• Time plan for each project and sub project of validation

Types of Validation

i) Prospective Validation – It involves establishment of documented evidence of what a system does or what it purposes based on plan. It is done before distribution of a new product

ii) Retrospective Validation – It involves establishment of documented evidence of what a system does or what is its purpose based on the review and analysis of available information. It is done on already distributed product based on production, testing and control data.

iii) Concurrent Validation -   It involves establishment of documented evidence of what a system does or it purposes on the information generated while implementing system.

iv)Revalidation – revalidation is done when changes in packaging, formulation, processes, equipment occurs which could alter product effectiveness or product specifications.

When changes in critical component, facility, plant, change in batch size or any batches that fail to be according to specifications of product or process

Change Control – It is a formal system where appropriate personnel from concerned departments review the changes that are prone to affect the validated status.

The change is addressed and documented accordingly.

A request for change should be made initially in formal manner with a form and signature

Based on the request the impact of the change on quality of the product is defined as either as minor or major change

If there is no impact on product quality then it can be implemented by owner with appropriate documentation

Minor changes can be done in short period and efficiently with the help of standard changes list approved by quality department

In case of major change quality department should be involved and a thorough action plan should be made.

After the plan is approved by the quality department it can be implemented.

Emergency cases should be defined by the organization and the change request can be formalized after replacement

Personnel

The validation team is to define progress and approve the documentation generated. This team would include the following members

Production Manager – incharge of manufacturing batches and review of protocols and reports

QC Manager – Analysis of the collected samples

QC Executive – Sample collection and Submission to QC

Maintenance Manager – Provides support for utilities and engineering

Production Executive – Protocol preparation and manufacturing of validation batches

QA Manager – Protocol authorization and preparation of summary report

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