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process validation

Thesis project

marwa yousry

on 6 March 2017

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Transcript of process validation

 Severity

Process validation Protocol
Facility and equipments
Flow chart of Process(sequence of operation with in-process controls)
Risk assessment
Production steps
Acceptance criteria of finished product
Sampling plan, Critical steps,Test done, & Acceptance criteria
Evaluation valuation Process including according analysis procedure
Denzin (1989) Focus on interpretation and description

Plummer (1983) Focus on samplings, sources and validations

Author: Focus on the author of the research
Process Validation
Types of Process Validation
Thank you
Sampling plan
Detailed description of the investigations that are carried out for validation purposes in addition to the normal in-process controls specified in the manufacturing instructions.
-Define all critical Parameters and do the following :
■ More frequent monitoring of process parameters
■ More frequent in-process controls
■ Additional examinations, e.g. content uniformity or particle size distribution
--Additional chemical tests on all stages of process.

Critical steps,Controls, Test done, Sampling plan & Acceptance criteria
Importance of Validation:
The collection and evaluation of data from the process design stage throughout production which establishes evidence that a process is capable of consistently delivering quality product”Process validation involves a series of activities taking place over the lifecycle of the product and process.
Risk Assessment
Facility &Equipments
The manufacturing systems and equipment used must have been qualified before validation is executed.
To assure

Does the author convey an philosophical understanding of the phenomenon?

Does the author analyze a clear phenomenon to study?

Does the author use procedures? (steps)

Does the author describe the overall essence of the experience (including participants’)

Is the author reflexive about throughout the study
Process Validation
The report must be easy to read, and have a conceptual structure
Issues should be developed seriously
A sense of story in the presentation
Are quotations used effectively?
Does the report have a good edition?
Adequate attention to various contexts
Data sources are well chosen and in sufficient number
Observation and interpretation are triangulated
Does the author show empathy?
Were individuals put at risk?

- Is there a clear identification and description of case or
cases in the study?

- Are themes identified for the case?

- Are generalizations made from the case analysis?

- Reflexivity or self-disclosure of the author.
"Action of proving, in accordance with the principles of
Good Manufacturing Practice, that any procedure, process,
equipment, material, activity or system actually leads to
the expected results."EU Gmp guidline
Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality
(FDA Guideline)

Scope of validation
Process validation
Analytical method
Reduction of quality Cost
Assurance of
Internal failure cost
1. Reject.
2. Re-inspection.
3. Rework.
4. Re-test.
External failure cost :

. 1.Recall
2. Complaints.
3.Return due to Quality problem
Internal failure cost
1. Reject.
2. Re-inspection.
3. Rework.
4. Re-test.
External failure cost :

. 1.Recall
2. Complaints.
3.Return due to Quality problem

According to the FDA’s Current Good Manufacturing Practices (CGMPs)21CFR 211.110 a:
Control procedures shall be established to monitor output and to validate performance of the manufacturing processes that may be responsible for causing
in the characteristics of drug product. to assures the repeatability of the process .

Validation& Process control
The heart of GMP.

Without validated and controlled process it is impossible
to produce quality product
A retrospective validation is the validation of the manufacturing procedure for a product already in distribution based upon available production, in-process control and quality control data.
Involves the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged.
A retrospective validation should be carried out with no fewer than ten batches(10-30Batches)
Establishing documented evidence based on a review and analysis of historical data and information obtained during production of marketable products.it must includes:

Retrospective Validation
Concurrent validation is carried out during normal production.This time the in-process quality control parameter are also decides& monitor for use of regular production, final control & stability

Concurrent Validation
A prospective validation is a validation conducted prior to distribution of either a new product, or product made under a revised manufacturing process, where the revisions may affect the product quality. A prospective validation should be carried out with at least three consecutive batches. The
three batches must comply with the specifications.
Prospective Validation
After any changes bearing on product quality
 1-Changes in master formula(Drug composition)
 2-Changes in production area or utilities (water system-HVAC)
 3-Change of equipment used
 4-Extension of the ranges of critical process parameters

5-Change of material supplier
 6-Change in batch size
 7-Change of primary packaging material
 8-Transfer the process to another site
9-Changes in production process or the sequence of operations
10-Extensive maintenance measures on manufacturing machines
■11- Trends observed in IPC or quality control
■ occurrence of quality problems (e.g. OOS) during
manufacturing or quality control

Periodic Re-validation
Processes and procedures should undergo periodic critical re-evaluation to ensure that they remain
capable of achieving the intended results.
--Intervals of between two and five years

When fixing the Re-validation intervals, the following must be taken into consideration:
■ 1-The individual process risk and product risk
■ 2-The number of batches manufactured per year
Process validation Report
Product name Batch size
Production area Type of product
Status of Product Numbers of batches
Steps which be validated
Description of process

N.B :

--Batch Record master
--Finished product specification
--Test method
-- IQ/OQ/PQ reports
--all Sops & Instructions
of operation and cleaning
of all equipments used in
--All Sops & Instructions of
operation and cleaning of
instruments used in analysis

Manufacturers should ensure that the principles of process validation described in this guideline are implemented. These include and cover phases of validation during process design, scale up, qualification of premises, utilities and equipment, process performance verification and ongoing monitoring of batches manufactured for commercial supply to ensure that the process remains in a state of control.

Effective Efficient
Process as the minimum Cost
The size of batches must correspond to the recent commercial scale.
-For the purposes of risk analysis, the entire production process is divided into individual processing steps and each processing step is assessed with regard to possible failures which might occur.

RAN = Risk Assessment Number
 High risk : >100 Medium risk : 50-100
Low risk : <10


--The quality of the starting materials which are used in the process validation has a direct influence on the result of the validation.
--Validation begins with the raw materials, active pharmaceutical ingredients ,excipients.

An author should ask himself:

- Did the interviewer influence the
contents of participants’ descriptions?

- Is the transcription accurate?

- Is the analysis of transcriptions correctly
done by the author?

- Is there a general description and other
specific contents?
Does the author convey an philosophical understanding of the phenomenon?

Does the author analyze a clear phenomenon to study?

Does the author use procedures? (steps)

Does the author describe the overall essence of the experience (including participants’)

Is the author reflexive about throughout the study
Physical properties:
--Drug morphology, solubility & particle size/surface area may affects drug availability.
--The particle size, shape , and density can affect material flow and blend uniformity.
Chemical characteristics : e.g:Moisture Content,Drug impurities
--Drug impurities can affect the stability.
All difference in approved specification of raw material (active or excipients )may affect on Flow, blend uniformity, granulation solution/binder compressibility, lubricant efficiency.
--All Raw materials (Active-Excipients )
--All Packaging material (Primary- Secondry Packaging material

--Approved Supplier of
each material
Facility :
Equipments &Instruments :

--The analytical methods used must be validated.
--If not
, there is a
that a variability possibly observed during process validation
--Analytical methods need to be validated, verified, or re-validated

Flow Charts

Flowcharts are used in designing and documenting complex processes .
They help visualize what is going on and thereby help the viewer to understand a process, and perhaps also find

Acceptance criteria of finished product:
top - middle - bottom)
■ --
time, frequency or start - middle - end)
■ --

using which instrument?)
■ --
How many
g, ml or pieces per sample?)
■ --
Number of samples
How many samples

at each time?)
■ --
for what
content uniformity, determination of physical properties, residual moisture, etc.)
--Identify all
Production steps.
-- Identify all
Critical parameters
in each step :

omogeneity -
ime -
Sampling Plan
required for each step
Tests :
May be
On Spot
- or
Tests done
On Spot:
Visual inspection

E.X: -
Solution :
omogenous or not
-Recording and testing performed by visual
inspection of
_Recording and testing performed by visual
inspection of
-Recording and testing performed by visual
inspection of
-Recording and testing performed by visual
inspection of
Tests done :

-Analysis of
of active ingredient
moisture content

Acceptance Criteria of each test
Product name
Batches numbers
Batch size of each one
Time schedule

-3 Batch records of Batches validated
-All certificates of analysis of finished product
--All certificates of analysis of all raw materials used in 3 batches
-All reports & raw data of result of analysis of all samples taken
--All raw data of inspection done at each step
--IQ ,OQ,PQ of all equipments
--All Raw & Packaging material BOM dispensed in each batch


Supplier of each material
Batch number of each material

Qc number of each material
For Raw & Packaging materials
Scope :
Facility and equipments
Flow chart of Process
Production steps
Acceptance criteria of finished product
For each Batch Sampling plan, Critical steps,Test done,

Report on results
Deviations from the validation protocol
-Number of each room
-Differential pressure of each room
-Class of each one
-Code of each equipment
-Code of each instrument
-Calibration date of all equipment ,
instruments used
--All manufacturing steps Stated
--All Parameters used for each step
--Date &Time of all steps
--Duration taken for each step
-All manufacturing step from dispensing of raw material to packaging of finished product must be stated

Results Report of each Batch
--Identify samples taken
--ID of each test done
--Number of samples taken -place of them -time of them
--Tests done
--Identify Acceptance criteria , upper specification limit & lower specification limit of each test of each test
--Statical conclusion of each result
--Capability investigations
--Key performance indicator

calculating CPK Process capability
CPK is lower of CPK1 and CPK2
CPK1 =(USL-mean )/(3*STAD.)
CPK2 =(Mean-LSL )/(3*STAD.)
if CpK < 1.0 No process capability
1.0 < CpK < 1.33 Limited process capability
CpK > 1.33 Process capability
--Deviations from the requirements in the validation protocol must be justified and explained.
--Observations and all corrective action &Preventive actions
--Formal authorization or rejection of the validation by the team responsible
(after remedial actions or repeated operations have been completed)
Protocol must Contain :
Protocol must contain
Process Capable or Not ??
Key performance indicator
--Identify all critical parameters
--Divide each parameter results into Categories
e.g :For assay of Active ingredient :
95% > Excellent > 105% 92% > Good> 108% 90% > Fair > 110%

Facility &Equipments
RSD must be not more than 5
-- Results of 3 batches for each location for each test
--Calculate Mean ,STD , RSD to know variation between Batches
--Calculate process capability
Statistical conclusion on 3 Batches
Finally ,
--Validation Summary Report
--Final Situation & Conclusion
on report
Computer system Validation
Difference in Specification of Raw Materials
Validation is an essential part of good manufacturing practices (GMP).

1-Technical department, engineering department:
--Install; qualify & certify plant, facilities & equipment
--Maintenance status of facilities and machines
--Technical documentation
2-Documentation department:
--Current master production record
--Current test procedure
--Current validation master plan
■3-Planning department
--Planning of development and pilot batches
--Planning of sufficiently large time for use of facilities and machines
4-R and D:
--Design and optimize manufacturing process within design limits specification &/or requirements in other words , the establishment of process capability information

5-Quality Control&Microbiology :
Validation status of analytical methods
Approval of analytical methods
Implementation of analytical work on Samples
■Status of environmental monitoring
Microbiological assessment of Samples
6-Quality assurance
--Conduct process validation by monitoring, sampling, testing, challenging, &/or auditing the specific manufacturing process for compliance with design limits, specification, &/or requirements
--Approval of validation protocol and validation report
--Approval of product specifications
--Approval of validation batches
--Control of equipment documentation, logs, SOPs
--Change control
1-Batch production records with the results of the in-process control.
2-Certificates of analysis .
3-Reports on rejected batches, exceptional approvals, releases with restrictions.
4-Authorized testing procedure.
5-Stability data.
6-Log books for the facilities, machines and utilities.
7-Results of the environmental monitoring.
--Raw materials, major causes of product variation or deviation from specification
--In order to cover possible differences in quality between the various
approved suppliers
or even differences between batches from the same supplier in the process validation, the production of validation batches should be planned such that different batches of raw materials are used.
This is particularly important for the active pharmaceutical ingredient, but also for quality relevant excipients, for example excipients that affects the dissolution, or for (synthetically modified) natural products.
-- Performance of the machine
--The equipment is working in accordance with engineering and vendor specification.
--The equipment performance satisfies the acceptance specified within this protocol.
--Room numbers
--Labs numbers
--Class of each room &Lab
--List of equipments used in Manufacturing
--List of Instruments used in analysis
--Codes of all equipments and instruments used
Critical Steps

-Each failure is then assigned with a probability and a significance of occurrence, as well as theability to detect a failure in case the error really had occurred. There are various ways of grading
these three factors, i.e. allocating numbers and calculating the risk of each processing step
(Risk assessment)

- Risk assessment is to evaluate the critical to quality steps failure & how to control to decrease risk accompanied by each step
--All parameters of each step (e.g:duration of each step
(Interval e.g from 3-5 min ) - Time of mixing -Temp -Speed -sieve size used--parameters of granulation -parameters of preparation -parameters of filling -of compression -of coating,......)

--Controls & all Precautions must be taken for each manufacturing step to Produce qualified product
Accuracy of method:
True value

Precision of method
:Estimate reproducibility
accurately measure a SPECIFIC analyte in the presence of other components.
The PV puzzle – The 3 stages

Part of process development and protocol preparation Risk matrix- usually as part of process development Critical quality attributes (CQA) vs processing stages, e.g. dissolution vs granulation
CQA vs critical process parameters, e.g., dissolution vs kneading time
Failure mode analysis- usually as part of process validation

All steps that are generally considered critical
(medium and high risk steps)
should be monitored
by summarizing actual process parameters applied and observations recorded

Personnel, premises, utilities, support systems and equipment
should be appropriately qualified before processes are validated.
Materials, environmental controls, measuring systems/apparatus and methods
should be considered during validation.

The commercial process is defined during this stage based on knowledge gained through
process development
activities.Process design should normally cover
design of experiments

clinical manufacturing
pilot scale batches and technology transfer
Manufacturers should define:
– The number of batches for which monitoring is proposed
– The type of testing/monitoring to be performed
– The acceptance criteria to be applied
– How the data will be evaluated.
Any statistical models or tools used should be described. If continuous processing is employed, the stage where the commercial process is considered to be validated should be stated based on the complexity of the process, expected variability and manufacturing experience of the company.

Process Qualification
Continued Process Verification:
Process Design
During this stage, the process design is confirmed as
being capable
of reproducible commercial manufacturing. Including qualification of the facility, utilities and equipment.
Maintenance, continuous verification, and process improvement.
On-going assurance that routine production process remains in a state of control.
Assessed by collecting and monitoring information during commercialization
The extent and frequency of continued process verification should be reviewed periodically and modified if appropriate throughout the product life-cycle.
Process design should be
during product development.
Process design should cover aspects for the selection of materials, expected production variation, selection of in-process controls, tests, inspection and its suitability for the control strategy
Stages of qualification of equipment may include design, installation, operation and performance of equipment
three batches
have been considered the minimum number for process validation;
however, the number of batches should be based on risk assessment that includes: variability of materials, product history, where the product is being transferred from and where it will be produced

Manufacturers should define the stage at which the product is considered to be validated and the basis on which that decision was made.
It should include a justification for the number of batches used based on the complexity and expected variability of the process.

Periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement. Process trends such as the quality of incoming materials or components, in-process and finished product results and non-conformance should be collected and assessed in order to verify the validity of the original process validation or to identify required changes to the control strategy
Common Cause
Special Cause
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