Introduction

 The concept of the validation was first purposed by FDA ( Ted Byers and Bud loftus) in 1979 in
USA to improve the quality of pharmaceuticals.
 Proposed for direct response to several problems in the sterility of the Large volume parenteral.
 The first validation activities were focused on the process, but quickly spread to associated
processes including the environmental monitoring, equipment , water treatment station.
 Computer incident ( Atomic Energy of Canada Limited).
Discussion :
1. What is the Validation ?
2. What is the Qualification ?
3. What is the relationship between Qualification and Validation ?
 Validation :
 Action of proving and documenting that any process , procedure or method actually
and consistently leads to the expected results.
 Qualification :
► Documented evidence that premises, systems or equipment are
able to achieve the predetermined specifications when properly
installed , and/or work correctly and lead to the expected results.
The Relationship between validation and qualification
The Term " Validation“ is normally used for method , procedure and process.
The Term " Qualification “ is normally used for Premises, equipment and utility.
Premises Qualification : Ensures buildings are suitable for manufacturing.
Utilities qualification : Ensures utility systems e.g, water , HVAC) meets requirements.

Equipment qualification :

 Design qualification ( DQ) : Verifies equipment design ( user requirement specification )

 Installing qualification (IQ) : Verifies correct installing
 Operational qualification (OQ ) : Ensures correct operation on its operation range.
 Performance qualification (PQ) : Verifies consistence performance within defined
specifications and parameters.
 Verification VS Calibration :
 Calibration is used to determine the accuracy of an instrument according to
reference standard
 Verification is used to determine whether the equipment is operating as expected
( monitoring )
Validation process should be operate in
qualified system
The importance of Validation :
 Helps you to find and define your road map.( VMP)
 Find and define your problems during operations.
How you can defined the road map of validation activity?

Validation Master Plan

A high-level document that summarizes the manufacturer’s overall philosophy
and approach, to be used for establishing performance adequacy. It provides
information on the manufacturer’s qualification and validation work
programmed and defines details of and timelines for the work to be performed,
including a statement of the responsibilities of those implementing the plan.
Importance of Validation Master Plan
- Cover manufacturer validation policy.
- Provides information on validation organization.
- It should describe :
- Why ?
- What?
- Where?
- By whom?
- How?
- When ?
 Discussion :
 How to be assure from your product before releasing to the customer ?
 Are samples taken before releasing enough ?
 What about samples ?
 If you assure what’s make other trust you ( such as inspector teams from
different authorities ) ?
 Example : Batch size = 5000 units.
Sampled unit for analysis is destructed.

- The samples is representative if the process is validated .

‫)))) نبيع ماال نختبر و نختبر ماال نبيع‬

Process Validation :
The Collection and evaluation of data, from the process design stage
through to commercial production, which establishes scientific
evidence that a process is capable of continuously delivering the
finished pharmaceutical product, meeting its predetermined
specifications and quality attributes.

Types of process validation :

 Prospective
 Retrospective
 Concurrent
 Prospective Validation :
 Validation carried out during the development stage, on the basis of a risk analysis of
the production process, which is broken down into individual steps; these are then
evaluated on the basis of past experience, to determine whether they may lead to
critical situations.
 The validation of process by this approach leads to transfer of manufacturing process
from the development function to commercial batches. based on
pre-planned protocol.
Concurrent Validation :
Validation carried out during routine production of products intended for sale
in exceptional circumstances when data from replicate production runs are
unavailable because only a limited number of batches have been produced,
batches are produced infrequently or batches are produced by a validated
process that has been modified.
 Based on information generated during actual implementation of the
process.
 This approach involves monitoring of critical processing steps and
end product testing of current production.to show that manufacturing
process state in control.
Retrospective Validation :
 it is chosen for established products whose manufacturing process are considered
stable.
 Where in the numerical in-process and/ or end product test data of historic production
batches are subjected to statistical analysis.
 Equipment , facilities and system used in connection with the manufacturing process
must be qualified conformance with GMP requirement.
 The process validation life cycle of the product and
process
The process validation activities has three stages :
Stage 1 : Process design
Stage 2 : Process qualification.
Stage 3 : Continuous process verification .
Phases of Process Validation
How we can study the process and make it
validated ?
 Stage 1 :
 Process Design : During this Stage the commercial manufacturing process is

defined based on knowledge gained through development and scale-up activities.

 The goal of this stage : is to design a process suitable for routine commercial

manufacturing that can consistently deliver a product that meets its quality

attributes.
Stage 2 :

Process Qualification : During this Stage, the process design is

evaluated to determine if the process capable of reproducible commercial
manufacturing
 The goal of this stage :

Verify process performance qualification .
 Verify qualification of utilities and equipment.
Stage 3 :
Continued process verification : ongoing assurance is gained
during routine production that the process remains in state of control.

The goal of this stage : Verification validation state .

1- New Product :
- From stage I of process validation to stage III.

- Continued monitoring and sampling of process parameters and quality

attributes at the level established during the process qualification stage until
sufficient data are available to generate significant variability estimates.

Relation between 2 stages process design and process qualification.

Existing product :
- Routine Sampling and monitoring which is adjusted to
statistically appropriate and representative level.
- Here we covers routine monitoring with reduced sampling and
monitoring compared with the previous collected ( CPV for new
product).
- To verify the that product control strategy remains effective.
CPV Monitoring Plan ?
 Number of batches. (Mini 30 batches VOP )
 Sampling and monitoring program.( sampling points ,location, interval , no of
samples)
 CPP & CQA.( Safety, Efficacy & compliance ).
 Statistical analysis tools.
 Action tracking and escalation route.

 Note : CPV is part of APQR

Objective of process validation :
 The Process design is evaluated to show that the process is
reproducible , reliable and robust.
 The commercial manufacturing process is defined , monitoring
and controlled.
 Assurance is gained on continuous basis to show that the process
remains in state of control.
 Critical process parameter:
A process parameter whose variability has an impact on a
critical quality attribute and therefore should be monitored
and/or controlled to ensure the process produces the desired
quality.
Critical quality attribute:
A physical, chemical, biological or microbiological property
or characteristic of materials or products that should be
within an appropriate limit, range or distribution to ensure
the desired product quality.
 Approach to Identify CQAs

 Consider all product quality attributes; physical

attributes, identification, assay, content uniformity,
dissolution and drug release, degradation products,
residual solvents, moisture, microbial limits, etc.
 Identify a CQA based on the severity of harm to a
patient (safety and efficacy) resulting from failure to
meet that quality attribute.
 What is a Quality Target Product Profile (QTPP)?
 ICH Q8(R2) Definition: A prospective summary of the
quality characteristics of a drug product that ideally will be
achieved to ensure the desired quality, taking into account safety
and efficacy.
 QTPP: quality characteristics to ensure safety and efficacy

 The Quality Target Product Profile (QTPP) : provides an

understanding of what will ensure the quality, safety, and
efficacy of a specific product for the patient
What is the action required if we find deviation
in result during process qualification ?

Change Control
 Change control is an important element in any Quality Assurance system.

Written procedures should be in place to describe the actions to be taken if

a change is proposed to a product component, process equipment, process
environment (or site), method of production or testing or any other change
that may affect product quality or support system operation.
Revalidation :
 Revalidation should be raised in case of changes any of the following
(but are not limited to ):
 Changes in the master formula, methods
 Changes of raw materials (physical properties such as density, viscosity, particle
size distribution may affect the process or product)
 Change of starting material manufacturer
 Changes of primary packaging material
 Changes in the process parameter limit (e.g. mixing times, drying temperatures).
 Changes in the manufacturing process
 Changes in the equipment or instruments.
 Production area or utilities (changes in water treatment or rearrange in the
production areas)
Change in the batch size without any change in the final validated
manufacturing process steps
Documentation of Process Validation ?
 Collect all sufficient data and its evidence.
 Define a validation team and its responsibilities.
 Pre-validation Requirements :
 Preventive Maintenance for Facilities and Utilities
 Calibration of Equipment
 Cleaning Validation Equipment
 Qualification Raw Materials/Components/Test Methods
 Change Control
 Process justification
 Training operators
 Process Validation Protocol :
 Manufacturing formula
 Manufacturing plan containing batch size of product.
 process flow chart containing all manufacturing procedure from dispensing stage to
delivery to warehouse including all Process parameter

Equipment information and calibration records .
 Process criticality containing all critical process steps, process Parameter and critical
process Parameter.
 Process map containing process parameter, critical process parameter and its process
control (Check process parameter, physical examination(description,
Av. Fill wt , wt. Uniformity, PH & water content ) chemical examination
( Assay, dissolution).
 Calibration , qualification Of equipment
 Finished product specification limit.
 Equipment in the manufacturing areas containing process and critical process parameter.
 Sampling Plan contain ( manufacturing process, sampling specification (beg, mid, end),
acceptance criteria, sample size ).
 Instrument information contain ( equipment name, model, calibration & due date)
 Environmental condition ( RH, Temp) of each room.
 Standard operating procedure used for each department ( QA, QC, production)
 Risk Assessment.
 QTPP& CQA of product( Description ,fill weight, Assay , Dissolution )
 Training
 Holding time between each manufacturing Steps.
 Qualification of utilities ( HVAC, Water treatment station ).
 Stability studies
 Change control.
 Deviation.
Process Validation Report :
 The report should reflect the validation protocol :
 Approval page
 Raw materials and its supplier.
 Packaging material and its supplier
 Full results and its statistical Study
 Results of finished product specification.
 Any deviations (including abandoned studies) should be explained and
justified.
Thank You
References :
 FDA 2011
 WHO TRS No.1019 ,2019.