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4 types Process Validation,Pharmaceutical.FDA 2019

Validation is the established documents evidence or proof which provides a high degree of assurance that a specific method can systematically manufacture a product that meeting its preset specification and quality attributes. Process validation is also a part of the validation, which is explained below.

Introduction to pharmaceutical validation:

Process validation in a pharmaceutical flowchart.
Process validation in a pharmaceutical flowchart.

Validation is a concept evolving continuously since its first informal appearance in the United States in 1978.

However, concepts of validation were first introduced by Ted Byers and Bud Loftus within the middle 1970s to enhance the standard of prescribed drugs.

The first validation activities targeted the processes concerned with creating these products; however, they quickly unfolded to associated processes and environmental management, media fill, equipment sanitizing, and pure water production.

As per guidelines, validation is an act of demonstrating and documenting any Procedure, Process, and activity that can systematically cause the expected results.

It includes the qualification of systems and equipment. The goal of the validation is to confirm that quality is maintained at every step and not simply tested at the last stage, as per the validation process.

The importance of validation in pharmaceutical

Validation plays an essential role in pharmaceutical in:

Quality assurance: In daily routine, product quality can not be assured by testing because of the limitation of sample availability and finished product testing.

For reduction in Cost: Due to the validation process decreased the number of sampling and testing procedures, less product rejection and retesting results in cost shaving.

More prolonged the life of equipment if operating as per given manufacturer’s specifications.

Compliance: Validation is essential according to cGMP compliance.

Responsible departments for validation

  • Site validation committee: To develop site master plan with prepare, execute, and studies the master plan.
  • Manufacturing departments: For the preparation of a batch.
  • Quality assurance: To approve the protocol, documentation procedure, report, and compliances.
  • Quality control: For testing according to protocol and generate reports.

The Responsible Authority for validation executes

  • Head of Quality assurance
  • Head of Quality control
  • Head of a Production
  • Head of Validation

Types of validation

Different types of validations in pharmaceutical are:

  1. Process validation
  2. Equipment validation
  3. Facilities validation
  4. HVAC system validation
  5. Cleaning validation
  6. Analytical method validation
  7. Computer system validation

Process validation:

Process validation is a demand of current (GMPs) for finished pharma (21CFR 211) and of the GMP rules for medical devices (21 CFR 820) and so applies to the manufacture of each drug product and medical device.

process validation flow chart

Process validation is the analysis of data collected throughout the design and manufacturing of products to ensure the process is consistently produced as per the given standard.

The purpose of process validation is to ensure high-quality products with consistency. Regulatory authorities like EMA and FDA have published guidelines that link to process validation.

According to the Food and Drug Administration, product quality assurance comes from careful and general attention to various vital factors, including choice of quality elements and materials, good product and method design, and (statistical) management of the method through in-process end-product testing.

Guidelines describe the process validation into three stages:

Process design: Process design is the collection from the development stage to analyze the commercial manufacturing process. The collected information analyzes for the established benchmark for quality and production control.

Process qualification: This process is designed to find a result of the process that can meet the determined capability to reproduce commercial manufacturing output. During this, all critical quality parameter is taken into account to ensure product quality.

Continued process verification: It is an ongoing monitoring process that ensures all production stages are under control.

Types of process validation?

Process validation types depend on the time of validation is performed relative to production; validation can be classified into four types:

  1. Prospective validation
  2. concurrent validation
  3. Retrospective validation
  4. Revalidation

1.Prospective validation:

Prospective validation is carried out during the development stage (Also called premarket validation). Prospective validation results help in finding the risk analysis on the production process. It is divided into different steps and analyzes critical points during the product manufacturing stages, such as mixing time, RH, and temperature.

Process validation is carried out for the manufacturing process when;

  • For the introduction of New Products in the manufacturing facility.
  • If there is a significant change in the manufacturing process and the impact of the changes, e.g., leak test failed due to sealing problems in blister.
  • Minimum of the first three consecutive production scale batches after process stabilization shall consider this validation.
Criteria for prospective validation?
  • Three prospective validation batches should be the same parameters.
  • Process parameters shall be identical for these three batches.
  • The first batch shall be dispatched after completion of third batch manufacturing, testing, and review of results.

If after the first batch there is required to change some parameters of the manufacturing process, then follow these criteria,

  • Take three batches with revised parameters and do not consider the first batch to this validation.
  • Consider 2nd, 3rd, and fourth batches as prospective validation batches, which have identical parameters.
  • A change shall be made through the proper change control system.
  • The first validation batch shall be released for sale and distribution after manufacturing, testing, and review of all three batches.
  • Results of all three batches shall be within acceptable limits.

2. Concurrent validation:

Concurrent validation is carried out during the regular production stage. It has based on a complete examination of the process based on prospective validation.

The first three production scale batches must be monitored very carefully as possible.

Concurrent validation is carried out when;

  • A new product has been prospectively validated in a manufacturing facility.
  • There is no change in the manufacturing process, and the impact of change in the manufacturing process and changes is not significant.
  • If there is a change in supplier of raw material in the existing production formula.

Examples of in-process testing are:

  • pH Value
  • Tablet Hardness
  • Weight Variation
  • Dissolution Time
  • Content Uniformity
  • Viscosity or Density
  • Colour uniformity
  • Particle Size Distribution
  • Average Unit Potency

3. Retrospective validation:

Retrospective Validation is based on historical and testing data of previously manufactured batches. It includes trends analysis complied and the extent to which the process is within the permissible range of the process parameters.

Using either computer-based data or manual method. The following method is to perform validation( retrospective validation).

  • Collect data from previously completed batches.
  • Organize all data sequences wise, i.e., batch manufacturing and expiry date.
  • Ten to twenty-five baches or more are used for this purpose, preferably processed over no longer than 12 months and reviewed together.
  • Batch rejected during routine quality control is not included in this review.

4. Revalidation:

Revalidation is needed to assure that Modification within process environments, whether introduced intentionally or unintentionally, does not adversely affect the process characteristics and product quality.

Revalidation is needed when:

  • After any change having a bearing on product quality.
  • Periodical revalidation.
  • Change in batch size.
  • Change in facility and plant.


Validation is related to the process

Qualification related to system/equipment.

Eg. validation for the sterilization process, autoclave must be qualify.

Qualification and types of Qualification.

Qualification: is the requirement for validation before the start of the process. Qualification includes the following.

Design qualification (DQ): Design qualification is a design demonstration according to GMP compliance, and all details are mentioned in the user requirements specification(URS).

  • Product and requirements
  • Process and operation requirements
  • Operating ranges
  • GMP, Operation and safety requirements

The principle of design should be such as to achieve the objectives of GMP concerning equipment. Mechanical drawings and design features provided by the manufacturer of the equipment should be considered for examination.

Component qualification (CQ): CQ has developed a new term in 2005. the main aim is to ensure ancillary components are manufacturing to the correct design criteria, including secondary packing materials like cartons, shipping case labels, and insert.

Installation qualification: must be applied to new or changed facilities, systems, and instrumentality. The following main points should be included in the installation qualification.

  • Checking of installation of equipment, piping, services, and instrumentation.
  • Collection of supplier’s operating working instructions and maintenance requirements and their calibration requirements.
  • Verification of materials of construction
  • Sources of spares and maintenance.

Operational Qualification (OQ): Operational Qualification must include the following:

  • Testing developed from the knowledge of the processes systems to cover upper and lower limits, and Sometimes these are called ‘worst case’ conditions.
  • Calibrate measuring device
  • Operation and cleaning procedure
  • OQ report preparation

Performance qualification (PQ): After completing IQ and OQ, the following successive Qualification that must be completed is PQ. PQ should include the following:

  • Testing using production materials, substitutes, or simulated products. These can be developed from the knowledge of the process and facilities, systems, or equipment.

Validation master plan (VMP):

The validation master plan must be summarized before to described the whole things in projects. These are the following point to be included in a protocol that is followed by all pharmaceutical industries.

  • Introduction
  • Methodology
  • Qualifications (IQ, OQ, PQ)
  • Personnel
  • Schedules
  • Preventive maintenance
  • Change control
  • Procedure
  • Documentation
  • Appendix

VMP Should state who is responsible for the validation:

  • Preparation of VMP
  • The protocol and SOPs
  • Validation work
  • Report and documentation and its control
  • Approval and authorization of validation protocol
  • Report on all stages of the validation process
  • Tracking system
  • The need for training in support of validation

What next after validation master plan, the following steps is validation protocol contents, following is the points to be considered during the preparation of validation protocol:

Validation master plan (VMP):

The validation master plan must be summarized before to described the whole things in projects. these are the following point to be included in a protocol that is followed by all pharmaceutical industries.

  • Introduction
  • Methodology
  • Qualifications (IQ, OQ, PQ)
  • Personnel
  • Schedules
  • Preventive maintenance
  • Change control
  • Procedure
  • Documentation
  • Appendix

VMP Should state who is responsible for the validation:

  • Preparation of VMP
  • The protocol and SOPs
  • Validation work
  • Report and documentation and its control
  • Approval and authorization of validation protocol
  • Report on all stage of the validation process
  • Tracking system
  • The need for training in support of validation

What next after validation master plan, the next steps is validation protocol contents, following is the points to be considered while preparation of validation protocol:

Validation protocol:

Following are the contents required for validation protocol:

  • General information
  • Objective
  • Background/Prevalidation Activities details of development and technique transfer (from R&D or another site) activities to justify in-process testing and controls; any previous validations.
  • List of equipment and their qualification status
  • Facilities qualification
  • Process flow chart
  • Manufacturing procedure narrative
  • List of critical processing parameters and critical excipients
  • Sampling, tests, and specifications
  • Acceptance criteria

Nowadays, software tool validation is also an essential aspect of the validation process.

Today’s medical devices regulations concentrate on managing software tools, and nowadays, there are dozens of applications for accounting tools to email tools.

The first step of any scenario is to assess the software tool for its impacts on medical devices. If it will affect the “quality of device,” then validation is also needed.

Consider that software tool needs to manage the quality system including CAPAs, complaints, NCs, requirements, and risk come under this category.

This is all well and good if you have insight and knowledge in the object you are validating. However, in most cases, especially for the off-the-shelf software tools, the user sees them only as black boxes.

Setting up a comprehensive validation for a software tool without knowing its internal mechanism is a challenging task; not much for what you know, instead of for what you do not.

It is challenging to develop tests for unknown boundaries and unclear algorithms. Moreover, generally, this ends up in vital gaps within the validation coverage.

Recently, computer code tool developing corporations have started providing pre-validated computer code and validation packages for the medical device market.

The device is a priceless product for the manufacturer. It allows to demonstrate compliance using the expertise and knowledge of the developer(s); due to their knowledge of the internal processes of the tool, they can put together a relatively lean protocol that adequately challenges the product.

Caution: it is best practice (if not expected by regulatory bodies) to repeat at least part of the validation protocol in-house to confirm the results of the pre-validation provided by the developer. It is unlikely that you will be able to adequately control your software tool providers (read: audit them) to rely on their internal activities solely.

This article covers the following question asked by interviewers:

  • Types of validation in pharmaceuticals?
  • What are process validation and its types in pharmaceuticals?
  • Why is process validation required?
  • Validation master protocol contents in pharmaceuticals
  • How do validate the process?
  • What is the software tool validation?
  • What are the Qualification and their types?
  • Tell me about IQ, CQ, IQ, OP, and PQ?

2 thoughts on “4 types Process Validation,Pharmaceutical.FDA 2019”

    • No, there are no such Guidelines for this.but you have to add it (time Frame) in periodic revalidation in protocol with proper justification.


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