3 - Process Validation 89-2-16

Validation Master Plan
:
Part 3: Process validation
Amir Mehdizadeh, Ph.D.
December 14, 2017 Process Validation 1

Dr. Mehdizadeh

VMP :
CV :
PV :
EQ :
AMV :
:
:
HVAC
:
:

Dr. Mehdizadeh

Process validation
-1
Principle
.
Scope -2
How to write Protocol for
PV General -3
process validation in non-
sterile products 4. Prospective validation
5. Concurrent validation
6. Retrospective validation
How to write Protocol for
Revalidation -7
sterile products
8. Change control

Dr. Mehdizadeh

Introduction on Process Validation

Dr. Mehdizadeh
Process validation
Introduction

GMP 4 )GMP
.(
Validation is an essential part of good manufacturing practices
(GMP).

.
It is, therefore, an element of the quality assurance programme
associated with a particular product or process.

Dr. Mehdizadeh
Process validation
Introduction
:

Quality, safety and efficacy must be designed and built into the product.
.
Quality cannot be inspected or tested into the product.

.
Each critical step of the manufacturing process must be validated.

Dr. Mehdizadeh

: 1975 1980

.
Sterility Test
.
Extension

Dr. Mehdizadeh
FDA
FDA

Project FDA Site Non-FDA Site
Sterile Facility 10-15% 8-10%
Non-Sterile Facility 5-8% 4-5%

Dr. Mehdizadeh
Process validation
Introduction
) (

.
Other steps in the process must be under control to maximize the
probability that the finished product consistently and predictably meets all
quality and design specifications.

.
Validation of processes and systems is fundamental to achieving these
goals.

Dr. Mehdizadeh
Process validation
Introduction
It is by design and validation that a manufacturer can establish
confidence that the manufactured products will consistently meet
their product specifications.

Dr. Mehdizadeh
:
:Documentation associated with validation includes
SOP
Standard operating procedures (SOPs)

Specifications
VMP
Validation master plan (VMP)

Qualification protocols and reports

Validation protocols and reports.

Dr. Mehdizadeh

The implementation of validation work requires considerable
resources such as:
: -1
.
Time: generally validation work is subject to rigorous time schedules.
: -2
.
Financial: validation often requires the time of specialized personnel
and expensive technology.

Dr. Mehdizadeh

: -3
.
Human resources validation requires the collaboration of experts from
various disciplines
: :

(e.g. a multidisciplinary team, comprising QA, QC, R&D, engineering,
manufacturing and other disciplines, depending on the product and
process to be validated).
Dr. Mehdizadeh

Collaboration of experts

Budget

GMP
Meticulous and careful planning
December 14, 2017 Validation Master Plan 14

Dr. Mehdizadeh
Validation
Manager
Validation
Representatives
Qualification Process Cleaning Computer Analytical M External

Team Validation Validation Validation Validation Validation
Team Team Team Team Representative

Dr.
Validation Team Members
Validation Manager
Quality Assurance Manager
Member from production
)Members from Engineering (Utilities

Member from Maintenance
HVAC
)(

Dr. Mehdizadeh
Planning For
Validation

.
All validation activities should be planned according to a pre-written ,
pre-approved and pre-authorized schedule.

. VMP
The key elements of a validation program should be clearly defined
and documented in a VMP or equivalent documents.
.VMP
VMP should be a summary document which is brief, concise and
clear.
Dr. Mehdizadeh
VMP
VMP & Process Validation
: VMP
The VMP should contain data on at least the following:
1) validation policy;
2) organizational structure of validation activities;
3) summary of facilities, systems, equipment and processes to
be validated;
4) documentation format: the format to be used for protocols &
reports;
5) planning and scheduling;
6) change control;
7) reference to existing documents.
Dr. Mehdizadeh
Process validation
-1

.
Process validation provides documented evidence that a process is
capable of reliably and repeatedly rendering a product of the
required quality.

.
The principles of planning, organizing and performing process
validation are similar to those for qualification.
Dr. Mehdizadeh
Process validation

)(

.
Process Validation is the means of ensuring, and providing
documentary evidence that processes(within their specified
design parameters) are capable of repeatedly and reliably
producing a finished product of the required quality.
Dr. Mehdizadeh
Process validation
-1

.
The requirements and principles outlined in these recommendations are
applicable to the manufacture and packaging of non-sterile
pharmaceutical dosage forms.

.) (
They cover the initial validation of new processes, subsequent validation
of modified processes and Re-validation.

Dr. Mehdizadeh
Process validation
-1

.
It should be done in accordance with process validation
protocols;

.
data should be collected and reviewed against predetermined
acceptance criteria, and reflected in process validation reports.
Dr. Mehdizadeh

Setting Limits
Marketing authorization limits

Stability or shelf life specifications (USP specification)
Release specification
Validation limits
Marketing authorization limits

based on stability specifications
Batch release limits
Validation limits

Dr. Mehdizadeh
Process validation
Scope -2
2-1
2.1 These guidelines describe the general aspects of process
validation for the manufacture of non-sterile finished products.

Dr. Mehdizadeh

Validation of non sterile products
Suspensions Syrups
Capsules Non sterile products Creams
Ointments
Tablets

Dr. Mehdizadeh
Process validation
Scope -2
2-2

)
.(
2.2 Normally process validation should cover at least the critical
steps and parameters (e.g. those that may have an impact on the
quality of the product) in the process of manufacturing a
product.

Dr. Mehdizadeh
Process validation
General -3
3-1
VMP
3.1 The policy and approach to process validation should be
documented, e.g. in a validation master plan, and should include the
critical process steps and parameters.

Dr. Mehdizadeh
Process validation
General -3
3-2
. qualification
.OQ IQ
3.2 Process validation should normally begin only once qualification of support
systems and equipment is completed.

.
In some cases process validation may be conducted concurrently with
performance qualification, PQ.

Dr. Mehdizadeh
Risk
Design Qualification
Analysis
Revalidation
Installation Qualification
Operational Qualification
Monitoring
Maintenance Performance Qualification
Change Control
HV AC
Water Treat ment System
Cleaning Analytical Method Process Computer

Validation Validation Validation Validation
Validation Report
29
Process validation
General -3
3-3
)
.(prospective validation
3.3 Process validation should normally be completed prior to the
manufacture of finished product that is intended for sale
(prospective validation).

( )
Process validation during routine production may also be
acceptable (concurrent validation).
Dr. Mehdizadeh

Process validation
-4
Prospective validation

Dr. Mehdizadeh
Process validation
-4 Prospective validation
4-1 )
(

.
4.1 Critical factors or parameters that may affect the quality of the
finished product should be identified during product development.
P.2.3.2
.
3.2.P.2
Dr. Mehdizadeh

Process validation & MAA

Dr. Mehdizadeh


Dr. Mehdizadeh


Dr. Mehdizadeh


Dr. Mehdizadeh

The Impact Spectrum
Parking Facilities No How we design

Impact and choose
Elevators
to use these
Office A/C systems can affect
their impacts!
Chilled Water Indirect
?Impact e.g. an autoclave
BMS could have
different impact
Production HVAC levels for:
a)Product
Autoclave sterilization
Direct
Pure Water Impact b)Decontamination
c)Lab Media

Dr. Mehdizadeh
Process validation
Prospective validation -4

To achieve this, the production process should be broken
down into individual steps,

.
and each step should be evaluated (e.g. on the basis of
experience or theoretical considerations).

Dr. Mehdizadeh


Dr. Mehdizadeh
Dr. Mehdizadeh
Recycle Bin
?Reprocessing
??! Reworking

Dr. Mehdizadeh

QRM is not a Single Process
Start
Process-
step
Risk
Decision identification
Feedback
procedure
Risk
Sub-Sub- Sub- analysis
process process
Start
Start
.Etc
End
End
End 42
December 14, 2017
Process validation
4-2
worst-case challenge .
4.2 The criticality of these factors should be determined through
a worst-case challenge where possible.

Dr. Mehdizadeh

Quality Risk Management (QRM)

ICH- Q9

Dr. Mehdizadeh
ICH Q9
?Why was ICH Q9 needed
QRM

Desired
State
)
(
To move from fire fighting to management of risk

ICH Q9

QRM
QRM
Where QRM can add value

Dr. Mehdizadeh

Q10 Q8 Q9
Q8, Pharmaceutical Development
Q9, QRM, Quality Risk Management, QRM
Q10, Pharmaceutical Quality Systems

Dr. Mehdizadeh

...
The new paradigm
risk-based
concepts and
principles
Q8
Q9 Q10
Dr. Mehdizadeh

...
The new paradigm
Pharmaceutical Development (Q8)
Changed
Past: Data transfer / Variable output
Paradigm Present: Knowledge transfer / Science
based / Consistent output
Quality Risk Management (Q9)

Past: Used, however poorly defined
Present: Opportunity to use structured
process thinking
Pharmaceutical Quality Systems

Q10
(Q10)
Q8
Q9
Past: GMP checklist

Future: Quality Systems across product
life cycle
December 14, 2017 48
Q10 Q8 Q9
Process
Understanding Process Process
Understanding Understanding
CMC CMC
regulatory
regulatory
Oversight CMC CMC
regulatory
(Submission)
oversight regulatory
Oversight
(Submission)
oversight CMC
regulatory
oversight
cGMPcGMP
regulatory
regulatory
oversight Q8 cGMPcGMP
regulatory
regulatory
oversight Q10 cGMP
regulatory
(Inspection)
oversight
& (Inspections)
oversight
& oversight
Companys
Quality system
Q9 Companys Q9 Companys
Quality system
Quality system
Post
Approval
approval
Change Continuous
PAC to
PAC to Improvement
change
(PAC)
Continuous
Continuous
Risk
Ris Improvement Risk
Improvement
(perceived
(P/R)& real) Risk
k
December 14, 2017 49

Risk from Manufacturing site How Q9 interacts with Q8 and Q10
Q10 Pharm. Quality Systems

High
envision
Low Q8 Pharmaceutical Development
Low Product / Process Risk High

50

How Q9 interacts with Q8 and Q10
Opportunities to impact
risk using quality risk
Design management Q9
Process
Materials Manufacturing
Facilities
Distribution
Patient
Q8 Q10
FDA 21 GMP
FDAs 21st Century GMP Initiative
: FDA
- 1
Q10
Q9 QRM

1- FDA seeks to integrate quality systems and risk management
approaches into the existing programs and encourages adoption of
modern and innovative manufacturing technology.

Dr. Mehdizadeh
FDA 21 GMP
-2
FDA
GMP

2- intended to enhance the integration of pre-approval review
and cGMP programs and achieve more consistent application
across agency organization components.

Dr. Mehdizadeh
FDA 21 GMP
- 3

QRM
3- use existing and emerging science and analysis to ensure that
limited resources are best targeted to address important quality issues,
especially those associated with predictable or identifiable health risks.

Dr. Mehdizadeh
FDA 2004
FDA announcement 27 Sep. 2004
:

desired state
current state

FDA


Dr. Mehdizadeh

Risk Management is Universal
Company
Strategic Risks Operational Risks Financial Risks Compliance Risks
Competitor Company Shareholder

Patient Harm
Advantage Viability Harm
ICH Q9 Impact

Dr. Mehdizadeh

Managing the risk of drug product use
Medication or Device
Known Side Effects Product Defects
Error
Avoidable Unavoidable
ICH Q9
Efficacy Quality
Safety Preventable
Adverse
Events
Unexpected Injury or
Consequences Death
Public Health
Dr. Mehdizadeh

Need to be determined

Need to be monitored during validation

.
May affect the quality of the product

Dr. Mehdizadeh

Risk Analysis

Method to assess and characterize the critical parameters in
the functionality of an equipment or process

.
The evaluation of the risk to quality should ultimately link back
to the protection of the patient

Dr. Mehdizadeh

Risk
Probability Harm
severity
Combination of the probability of the occurrence of the harm and the
severity of that harm
Harm

Harm

ICH Q9 Quality Risk Management

Dr. Mehdizadeh
Dr. Mehdizadeh

QRM
:
Medical devices, ISO 14971
Food, HACCP
lagged

Implementation is patchy
QRM

It is often not fully integrated with rest of the Quality System

Dr. Mehdizadeh

:Risk Management is NOT about

.
making do with insufficient time, money, or people,

.
providing an excuse not to do the right things,

deciding what to do based on what might be observed during an
inspection.
Dr. Mehdizadeh

:Risk Management is NOT about

Risk Management does NOT provide an excuse to be out of
compliance with applicable regulations.

Dr. Mehdizadeh

:Risk Management IS about

knowing our manufacturing processes (and business),

understanding whats truly important,

not spending time on a low risk activity, process, event, or system
.
Because It Just Doesnt Matter!
Dr. Mehdizadeh

:Risk Management IS about

.
focusing our money, time, energy, and people on the things that
are really important; i.e.,

focusing our efforts and resources on the things that provide
quality assurance to our customers (patients).

Dr. Mehdizadeh

:

; demonstrate that we understand what is important about our business

; have a documented, approved rationale for our decisions

.
be proud to share these with regulatory agencies because they demonstrate
our knowledge and logical thought processes.

Dr. Mehdizadeh

Quality Risk management, QRM

We have to do our Risk management properly.

Poor Risk Management will not impress regulators.

At best, they will think we do not know whats really important.

Dr. Mehdizadeh

Quality Risk management, QRM

If we dont know whats trivial, how can we know whats
important?
.
If everything is critical, nothing is critical.

Dr. Mehdizadeh

Q9, Quality Risk management, QRM

A rational approach has to begin with the question

.
What is the impact on the patient?
: 21
ICH Q9, Quality Risk management, QRM

FDAs 21st Century GMP initiative

Dr. Mehdizadeh
Q10 Q8 Q9
Guidelines on
Quality
Expert Working
Groups (EWG) Chemical and
pharmaceutical QA
Safety
In vitro and in-vivo pre-

clinical studies
Efficacy
Clinical studies in human

Multidisciplinary
Dr. Mehdizadeh
Dr. Mehdizadeh

?What is Risk Management
Risk Identification
Risk
Assessment
Risk Analysis Risk

Management
Risk Control Risk

Control
Post Production
Information

Dr. Mehdizadeh
Initiate
Quality Risk Management Process
Risk Assessment
Risk Identification
Risk Analysis
Risk Evaluation
Risk Management Tools

Risk Communication
unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Output / Result of the

Quality Risk Management Process
Risk Review
Review Events

Dr. Mehdizadeh

)Risk Priority Number (RPN
= Severity x Probability x Detectability

RPN

Dr. Mehdizadeh

A picture of the life cycle
= Risk Priority Number

Probability x Detectability x Severity
Refers to
Refers to
Refers to
past today future time
Dimensions of a risk based approach
.
Parameters
for
evaluating risks
hi
gh
probability
m
ed
iu
m
ty
ili
ab
lo
w
ct
te
de
ri s
k severity
78

Failure Mode Effects Analysis (FMEA)
Failure Mode Effects & Criticality Analysis (FMECA)
SxO Criticality
10 10
Occurrence Probability
Severity of Effect
9 9 1
8 8 2
7 7 3
6 6 SOD
S O 4 SxOxD
5 5 or Risk
5
4 4 Number
6
3 3 *Detection
7
2 2 8
1 1 9 Higher detection ability*
10 .lowers risk score

Dr. Mehdizadeh
FME(C)AIntermediate Tool
RT
A
CH
LE
P
M
SA
80
Risk Assessment Classification

Frequency
Severity Rarely Occasional Frequent
High
Injury, recall Moderate Major Critical
Medium
Complaint Minor Moderate Major
Low
Cosmetic defects No Risk Minor Moderate

Dr. Mehdizadeh
Increasing Probability
Severity and Probability Risk
of Occurrence
High
Risk
Mediu
m Risk
Low
Risk
Increasing Severity of Harm/Consequence

Dr. Mehdizadeh
Qualitative Risk Estimation
N LY
E O
A BL
L ET Probability of Occurrence
MP
SA Health
Very Very
Severity Scale Low Low Medium High High
Death Medium Medium High High High
Hospitalization LowA B
Medium High Risk
Medium High High
Acute Illness Low Medium

Medium Medium High High
Risk
Low
Worry Low Low Low CMedium Medium
Risk

Dr. Mehdizadeh
Dr. Mehdizadeh
ICH Q9
ICH Q9 Table of contents
1. Introduction
2. Scope
3. Principles of Quality Risk Management (QRM)
4. General Quality Risk Management Process
5. Risk Management Tools
6. Integration of QRM process into industry & regulatory operations
7. Glossary
8. References
Annex I: Potential opportunities for conducting QRM

Dr. Mehdizadeh
Dr. Mehdizadeh
ICH Q9 -2
Scope .2

This guideline provides a framework that may be applied to all
aspects of pharmaceutical quality, including:
development
manufacturing
distribution

Dr. Mehdizadeh
Q9 applies across the lifecycle
.
Research
Preclinical
Phase
Clinical
Phases
Launch
Manufacturing
& Distribution
GLP Safety
GCP Efficacy
GMP Quality
GDP ICH Q9
88
-3
Principles of Quality Risk Management .3

Two primary principles:
-1

1. The evaluation of the quality risk should ultimately link back to the
potential harm to the patient.
QRM - 2
.
2. The level of effort, formality and documentation of the QRM
process should be commensurate with the level of risk.
Dr. Mehdizadeh
:

Concept: Link Back to Patient Risk
Opportunities to impact
risk using quality risk
management
Design
Process
Materials Manufacturing
Facilities
Distribution
Patient

Dr. Mehdizadeh
Dr. Mehdizadeh
-5
Risk Management Tools .5

/

Failure Mode Effects Analysis (FMEA)
Failure Mode Effects & Criticality Analysis (FMECA)
Fault tree analysis (FTA)
Hazard Analysis of Critical Control Points (HACCP)
Hazard Operability Analysis (HAZOP)
Risk Ranking and Filtering
Preliminary Hazard Analysis (PHA)
Supporting statistical tools

Dr. Mehdizadeh
HACCP
I.5 Hazard Analysis and Critical Control Points (HACCP)

HACCP

.
HACCP is a systematic, proactive, and preventive tool for assuring
product quality, reliability, and safety.
HACCP

.
It is a structured approach that applies technical and scientific principles
to analyze, evaluate, prevent, and control the risk or adverse
consequence(s) of hazard(s) due to the design, development, production,
and use of products.
Dr. Mehdizadeh
HACCP 7
-1

(1) conduct a hazard analysis and identify preventive measures
for each step of the process;
-2
(2) determine the critical control points;
-3
(3) establish critical limits;

Dr. Mehdizadeh
HACCP 7
- 4
(4) establish a system to monitor the critical control points;
- 5
).
(
(5) establish the corrective action to be taken when monitoring
indicates that the critical control points are not in a state of control;
(6) establish system to verify that the HACCP system is working
effectively; (Inspection, supervision, training, validation)
(7) establish a record-keeping system. (Documentation)

Dr. Mehdizadeh
6- Integration Of Quality Risk Management Into
Industry And Regulatory Operations
Annex II: Potential Applications for Quality Risk Management

II.1 Quality Risk Management as Part of Integrated Quality Management
II.2 Quality Risk Management as Part of Regulatory Operations
II.3 Quality Risk Management as Part of development
II.4 Quality Risk Management for Facilities, Equipment and Utilities
II.5 Quality Risk Management as Part of Materials Management
II.6 Quality Risk Management as Part of Production Validation
II.7 Quality Risk Management as Part of Laboratory Control and Stability
Studies
II.8 Quality Risk Management as Part of Packaging and Labelling Design of
packages

Dr. Mehdizadeh
ICH Q9

Implementation of Q9 can help identify weak links

Dr. Mehdizadeh
QRM
Integrating QRM into product life cycle
Gain experience
:Analyse root cause ?Failure) Risk of(
Continuous Manufacture
improvement
Quality Risk
Management
Improve it (QRM) Do, what you say
Update Approval
information
Say, what you do

Dr. Mehdizadeh
Q9
Q9 Implications
QRM

Companies can choose whether to use formal quality risk
management

.
If used it should enable regulators to adopt a more flexible
approach to their oversight of a site

Dr. Mehdizadeh
Q9
Q9 Implications

.
It will be acceptable to continue to use informal approaches to
managing risk

.
Quality risk management is likely to become best practice
over time

Dr. Mehdizadeh
Q9
Q9 Implications
QRM
Significant risk management knowledge gap

Both in industry and regulatory authorities
ICH
ICH EWG plan to produce training guidance
MOH
. QRM
Industry and regulatory authorities will need to initiate programs to
Educate broadly on quality risk management

Dr. Mehdizadeh
Q9
Q9 Implications

QRM
Train a cadre of experts who can facilitate implementation of
the risk management process
MOH QRM

.
Quality Risk Management provides a useful process that
enables both industry and regulators to focus on what is
important for patients.

Dr. Mehdizadeh

Conclusion
QRM
.
Integration of Quality Risk Management into existing systems and
regulatory process will take time.
Q8, Q9 & Q10 ICH

21
.
ICH Q8, Q9 & Q10 together will enable the pharmaceutical community
to move towards the desired state for 21st century quality
management.
Dr. Mehdizadeh

Tablet compression variables

)
(
Fill volume
Pre- and compression force
Turntable speed
Dwell time
Granule size and feed
Ejection force, lubrication

Dr. Mehdizadeh

Tablet compression parameters

Mass
Hardness
Moisture
Friability
Disintegration
Dissolution
Thickness
Dr. Mehdizadeh

Tablet coating variables

Spray rate

Inlet and outlet air temp
Coating weight
Distance of nozzle and bed

Dr. Mehdizadeh

:Controllable causes of variation may include
Temperature, humidity
Variations in electrical supply
Vibration
Environmental contaminants
Light
Human factors
Variability of materials
Wear and tear of
equipment
Dr. Mehdizadeh

) ( Chopper
Impeller

Dr. Mehdizadeh

Determining critical control point
Particle size distribution of the active(s)
Blending time for the powder
Granulating time and speed; amount of granulating fluid and

binder concentration
Drying time final moisture content, granule particle size

distribution
Granule active content and homogeneity, blending time of

external phase

Dr. Mehdizadeh

Determining critical control points
Process step Operation IQ/OQ/PQ requirements
Measure humidity with IQ/OQ

XIII calibration instrument Training
humidity meter
operation, records for
cleaning, care technician
XIV Weigh granulate - balance IQ/OQ
and maintenance
calibration
XV Sieve 3/
sieve with sieve type 1
5 I Q/OQ/PQ
XVI Blend Cleaning Critical Cleaning, and Blend
3/5 validation control uniformity required to be
mixer (speed 1, 1 minute)
granulate point established during validation
XVI Blend 2 mixer (speed 1, 30
with 3/5 seconds)
granulate
XVIII Critical Decision as to whether to

Weigh granulate
control compress or not based on
point expected yield and actual yield

Dr. Mehdizadeh
Using Risk to Govern Qualification Effort
General Principle
High
Direct
Impact
Not Acceptable Enhanced Effort
By Regulators Value Added
Risk
Value Added Not Value Added
Low
No
Impact Low High
Effort, Formality, and Documentation

Dr. Mehdizadeh
Process validation

. :
SOP
facilities )
(

sample size

Dr. Mehdizadeh
Process validation
product performance characteristics
attributes to be monitored

Dr. Mehdizadeh
Process validation
.

.

Dr. Mehdizadeh
Process validation

failure investigation
root cause analysis
corrective action .
Change Variation
rationale
documented.
Dr. Mehdizadeh
Process validation
same size
full-scale production.

assumptions .
Dr. Mehdizadeh
Process validation
Reliable, repeatable, under control
At least first 3 consecutive batches - repeatable
Must investigate failures
The rationale should be documented if experimental method is

changed
document deviations, decisions and reasoning
Does not improve processes
Should not validate bad processes

Dr. Mehdizadeh
Process validation
Extensive testing
various stages

.
:
Extensive tests: viscosity, rheology, particle size distribution,
compresibility, flowability, angle of repose, contact angle,
volume of settlement

Dr. Mehdizadeh

Oral Solid Dose OSD

Homogeneity in blending the key to quality!
Sampling strategy

Sample sites, label, container
Storage of sample
Sample thief

Dr. Mehdizadeh
Extensive tests & sampling

Dr. Mehdizadeh
Process validation
Solid dose mixing (2)
In situ analysis
Methods of analysis
Statistical analysis
inter-batch
intra-batch
within-sample

Dr. Mehdizadeh
Process validation
: /

.

Dr. Mehdizadeh
Process validation

) (
.

Dr. Mehdizadeh

.Results in the report that includes, e.g
process description including details of critical steps

detailed summary of the results obtained from in-process and final
testing, including data from failed tests
raw data
any work done in addition to that specified in the protocol (SOP)
any deviations from the protocol (SOP) with an explanation
a review and comparison of the results with those expected
formal acceptance or rejection of the work by the team or persons
designated as being responsible for the validation, after completion
of any corrective action or repeated work

Dr. Mehdizadeh
Process validation

SOP
.
Actions
OOS .

Dr. Mehdizadeh
Process validation
GMP
marketing authorization .

Dr. Mehdizadeh

:Conclusion and recommendation
Made on the basis of the results obtained
Incorporated into the batch manufacturing and batch packaging

documents and/or SOPs for routine use
Limits and frequencies of testing and monitoring should be

specified. Actions in case of OOS
If validation batches are to be sold :
manufactured under GMP conditions
Compliance with the marketing authorization

Dr. Mehdizadeh
Good validation practice
Good Validation Practice

.

.

under control.

Dr. Mehdizadeh
Process validation
Finalization of validation process
Final report required
Summarize all results
Conclusion required: Is the process valid
Final report should be reviewed and approved by
the validation team
authorized person
Dr. Mehdizadeh
Process validation
-5 Concurrent validation

routine production

.

authorized personnel .

.

.
validation
report .
Dr. Mehdizadeh
Process validation
-6 Retrospective validation
Retrospective validation
historical data

.

exceptional preferred
cases .
Dr. Mehdizadeh
Process validation
-6 Retrospective validation

indication
immediate future .

Dr. Mehdizadeh
Process validation
-7 Revalidation

standard processes using conventional equipment

under control.
:

SOP

Dr. Mehdizadeh
Process validation
-8 Change control

.
:
) (

)
(

)
(

Dr. Mehdizadeh
Process validation
Change control -8
Changes that require revalidation

Software changes; Controllers
Site changes; Operational changes
Change of source of material
Change in the process
Significant equipment change
Production area changes
Support system changes

Dr. Mehdizadeh
Process validation
Change control -8
Change control
Must be a review procedure for validated processes
From time to time changes may be necessary
Documented change control procedure needed
Like for like" changes do not require re-validation

Dr. Mehdizadeh
Validation
Prospective validation
SUMMARY
Concurrent validation
Revalidation
Retrospective validation
Change control

Dr. Mehdizadeh

Validation
Group Session

critical steps

.

List the critical equipment

required to be qualified

Dr. Mehdizadeh


Dr. Mehdizadeh

Process Validation
Sterile Pharmaceutical Products

Dr. Mehdizadeh
GMP
GMP Requirements for Sterile Products
Objectives
GMP

To review basic GMP requirements in the manufacture of sterile
pharmaceutical products

To review air classifications for activities related to the
manufacture of sterile products

Dr. Mehdizadeh
GMP

To review the different types of sterilization methods

To review quality assurance aspects in the manufacture and
control of sterile products

Dr. Mehdizadeh
GMP
GMP
Additional rather than replacement

:
The emphasis of all the extra requirements for sterile production is
to minimizing risks of contamination
microbiological
particulate matter
Pyrogen
Dr. Mehdizadeh
GMP

.
This is because sterile products are administered to
particularly sensitive parts of the body, whether intravenously
or intramuscularly as an injection, as an eye ointment or as a
wound dressing.

Dr. Mehdizadeh

General Considerations for Sterile Production

Production in clean areas, Appropriate standard of cleanliness,
.
Filtered air supplied
.
Airlocks for entry
Personnel and/or equipment
Materials

Dr. Mehdizadeh

General Considerations for Sterile Production
:
Separate areas for operations
- 1
1- component preparation (containers and closures)
-2
2- product preparation,
-3
3- Filtration and filling,
-4
4- Thermal sterilization, etc.
Dr. Mehdizadeh

Premises, Sterile Production
Design

Avoid unnecessary entry of supervisors and control personnel.

.
Operations observed from outside

Dr. Mehdizadeh

:
Smooth, impervious, unbroken
Minimize shedding and accumulation of particles, MO
Permit cleaning and disinfection
No un-cleanable recesses, ledges, shelves, cupboards,
equipment
Sliding doors undesirable
False ceilings sealed

Dr. Mehdizadeh


.
Proper installation of pipes and ducts, no recesses, no
unsealed openings
B A
.
Sinks & drains avoided, (excluded in Grade A and B areas)

Dr. Mehdizadeh

:

Where installed, design, location, maintenance
.Trap
Effective cleanable traps
.Air break
Air breaks preventing backflow

Dr. Mehdizadeh


Changing rooms

Designed as airlocks

Effective flushing with filtered air

Separate rooms for entry and exit desirable

Hand washing facilities

Dr. Mehdizadeh


Interlocking system for doors

Visual and/or audible warning system

Use filtered air supply to maintain pressure cascade
15 10
Pressure differential approximately 10 to 15 Pascales

Zone of greatest risk immediate environment
Dr. Mehdizadeh

:
Pathogenic, highly toxic, radioactive materials
Pressure cascade may be different
Decontamination procedures air, equipment, garments
Qualification including airflow patterns
No risk to the product
Warning system to indicate failure in air supply
Pressure indicators results regularly recorded
Restricted access e.g. use of barriers

Dr. Mehdizadeh

Sterile Production
Equipment
Conveyer belts
Effective sterilization of equipment
Maintenance and repairs from outside the clean area
If taken apart, re-sterilized before use
Use clean instruments and tools
Planned maintenance, validation and monitoring
Equipment, air filtration systems, sterilizers, water
treatment systems

Dr. Mehdizadeh

Sterile Production
WFI
Water treatment plants and distribution system
Design, construction, maintenance
Operation and design capacity
Testing programme
Water for Injection (WFI)
Produced, stored, distributed prevention of growth of
microorganisms
Constant circulation at temperature above 70, or not
more than 4 degrees Celsius

Dr. Mehdizadeh

Sterile Production

Environmental Monitoring - I

Microbiological

Air samples

Surface swabs

Personnel swabs

Dr. Mehdizadeh

Sterile Production

Environmental Monitoring - II

Physical

Particulate matter

Differential pressures

Air changes, airflow patterns

Dr. Mehdizadeh

Sterile Production

Environmental Monitoring - II

Clean-up time/recovery

Filter integrity

Temperature and relative humidity

Airflow velocity
Dr. Mehdizadeh

Sanitation

Frequent, thorough cleaning of areas necessary
Written programme
Regular monitoring to detect resistant strains of MO .
Chemical disinfection
Monitoring of disinfectants and detergents
Dilutions
Clean containers, stored for defined periods of time
Sterilized before use, when used in Grade A or B areas

Dr. Mehdizadeh

Sanitation
Monitoring of clean areas

Monitoring of personnel and surfaces after critical operations
Frequent monitoring in areas where aseptic operations are
carried out
Settle plates, volumetric air samples, surface sampling
(swabs and contact plates)
Sampling methods should not contaminate the area
Results considered when batch release is done

Dr. Mehdizadeh

Sterile Production
Sanitation
Limits of detection established
Alert and action, and monitoring trends of air quality
Table 1. Limits for microbial contamination (Information only)

Dr. Mehdizadeh

Personnel in Sterile Production
Minimum number of personnel in clean areas

Especially during aseptic processing
Inspections and controls from outside
Training to all including cleaning and maintenance staff
Initial and regular
Manufacturing, hygiene, microbiology
Special cases
Supervision in case of outside staff
Decontamination procedures (e.g. staff who worked with
animal tissue materials)
Dr. Mehdizadeh

High standards of hygiene and cleanliness

Periodic health checks
No shedding of particles
No introduction of microbiological hazards
No outdoor clothing
Changing and washing procedure
No watches, jewellery and cosmetics

Dr. Mehdizadeh


Grade D
hair, beard, moustache covered
Protective clothing and shoes
Grade C
Hair, beard, moustache covered
Single or 2-piece suit (covering wrists, high neck), shoes
no fibres to be shed
Grade A and B
Headgear, beard and moustache covered, masks, gloves
No shedding of fibres, and retain particles shed by operators

Dr. Mehdizadeh


. C B
Outdoor clothing not in change rooms leading to grade B and C
rooms
Change at every working session, or once a day (if supportive data)
Change gloves and masks at every working session
Disinfect gloves during operations
Washing of garments separate laundry facility
No damage, and according to validated procedures

Dr. Mehdizadeh

Sterile Production
Two categories of manufacturing operations:
Terminally sterilized
prepared, filled and sterilized
Aseptic preparation
some or all stages

Dr. Mehdizadeh

Manufacture of sterile preparations
Classification of clean areas

Manufacturing operation in an appropriate environment
cleanliness level
Minimize risks particulate and microbiological contamination
product and material
Meet classification "at rest"
(i.e. "completed installation, equipment installed and
operating, but no operating personnel present").

Dr. Mehdizadeh

Manufacture of sterile preparations
For sterile pharmaceutical preparations:

Grade A
Local zone, high risk operations, e.g. filling, aseptic connections
Usually UDAF systems used
Grade B
Background environment to grade A (in case of aseptic
preparation and filling)
Grade C and Grade D
Clean areas for less critical operations

Dr. Mehdizadeh

Air Classification System

Dr. Mehdizadeh

To reach Grade B, C and D, the number of air changes should

be appropriate to the size of the area, number of personnel,
equipment present
Minimum of 20 air changes per hour
Clean up time about 15-20 minutes
Good airflow pattern in the area
HEPA-filtered air
Suitable methods to determine particulate matter and micro-
e.g. EU, ISO, Japan, USA

Dr. Mehdizadeh

Control particulate during operation

Monitoring during operation
Alert and action limits for particulate and MO
Action taken when exceeded
Area grades should be proven (e.g. validation runs, media
fills, environment, time limits based on microbiological
contamination/bioburden found)

Dr. Mehdizadeh
Sterile Production
Airborne particulate classification

Dr. Mehdizadeh
Sterile Production
Processing
Minimise contamination all stages including before
sterilization and during processing
No unsuitable materials, e.g. live microbiological organisms
Minimize activities
staff movement controlled and methodical
avoid shedding of particles
Temperature and humidity comfortable
Containers and materials in the area

Dr. Mehdizadeh

Validation should not compromise the processes

Aseptic process validation: Sterile media fill (broth fills)
Simulate actual operation intimate as closely as possible
Simulate worst expected condition
Use appropriate medium/media
Sufficient number of units - e.g. equal to batch size (small
batches)
acceptable limit
investigations
Revalidation: periodic and after change
New processing procedures validated
Revalidation after significant changes
And regular intervals
Dr. Mehdizadeh
Sterile Production
Processing
Water sources, water treatment systems and treated water
Monitored regularly
Chemicals
Biological contamination
Endotoxin
Water specification
Records of results and action taken

Dr. Mehdizadeh
Sterile Production
Processing
Components, bulk product containers and equipment
fibre generation
no recontamination after final cleaning
stage properly identified
sterilized when used in aseptic areas
Used in clean areas, passed through double-ended sterilizers or
use triple wrapping
Gas used to purge solution or blanket a product passed
through a sterilizing filter
Dr. Mehdizadeh
Processing
Sterile Production
Bioburden monitored
Products: Before sterilization
Working limits established
Solutions to be filtered before filling (especially LVP)
Pressure release outlets hydrophobic microbiological
air filters
Starting materials microbiological contamination should be
minimal
Monitored as per specification

Dr. Mehdizadeh
Processing
Sterile Production
Time intervals: Components, bulk containers, equipment

Washing and drying and sterilization; and sterilization and use
As short as possible
Time limit validated
Time intervals: Product
Start of preparation of solution and sterilization (filtration)
As short as possible
Maximum time set for each product

Dr. Mehdizadeh

Sterilization
Methods of sterilization
Moist or dry heat
Irradiation (ionizing radiation)
Sterilizing gaseous agents (e.g. ethylene oxide)
Filtration with subsequent aseptic filling
Whenever possible: Terminal sterilization by heat in their final
container - method of choice

Dr. Mehdizadeh

Sterilization
Sterilization
Validation
All sterilization processes
Special attention when non-pharmacopoeia methods are used
Non-aqueous or oily solutions
Before the method is adopted its suitability and efficacy
demonstrated with desired conditions:
All parts of the load
Each type of load
Physical measurements and biological indicators (where
appropriate)
Verified at least annually and after change
Records maintained
Dr. Mehdizadeh

Sterilization
Sterilization
For effective sterilization:
Whole of the material subjected to the treatment
Biological indicators:
Additional method of monitoring
Storage and use, quality checked through positive control
Risk of contamination

Dr. Mehdizadeh

Sterilization
Sterilization
Differentiation between sterilized and not-yet-sterilized
products
Each basket/tray or other carrier, properly labelled
Name of material
Batch number
Sterilization status
Use of autoclave tape
Sterilization records for each run approved as part of the
batch release procedure

Dr. Mehdizadeh

Terminal Sterilization

Sterilization by heat

Sterilization by moist heat

Sterilization by dry heat

Sterilization by radiation

Sterilization by gases and fumigants

Dr. Mehdizadeh

Sterilization by heat
Recording of each cycle, e.g. time and temperature chart
Temperature: validated coolest part
Check from second independent probe
Additional chemical or biological indicators
Heating phase: Sufficient time for the whole load
Determined for each load
Cooling phase: After sterilization cycle
Precautions to prevent contamination
Sterilized cooling fluid/gas

Dr. Mehdizadeh

Sterilization by moist heat (heating in an autoclave)

Water-wetable materials only, and aqueous formulations
Temperature, time and pressure monitored
Temperature recorder independent of the controller
Independent temperature indicator
Drain temperature recorded from this position
Regular leak test when vacuum is part of the cycle
Material allows for removal of air and penetration of steam
All parts of the load in contact with steam
Quality of the steam no contamination

Dr. Mehdizadeh

Sterilization by dry heat

For non-aqueous liquids, dry powders
Air circulation in the chamber
Positive pressure in chamber to prevent entry of non-sterile air
HEPA filtered air supplied
When removing pyrogens, challenge tests
validation (using endotoxins)

Dr. Mehdizadeh

Sterilization by radiation
Suitable for heat-sensitive materials and products
confirm suitability of method for material
ultraviolet irradiation not acceptable
Contracting service ensure validation status, responsibilities
Measurement of dose during procedure
Dosimeters independent of dose rate
quantitative measurement
number, location and calibration time-limit
Biological indicators only as additional control
Radiation sensitive colour discs

Dr. Mehdizadeh

Sterilization by radiation (2)

Information forms part of the batch record
Validation to cover effects of variation in density of
packages
Handling procedures to prevent misidentification of
irradiated and non-irradiated materials
Each package to have a radiation-sensitive indicator
Total radiation dose administered within a predetermined
period of time

Dr. Mehdizadeh

Sterilization by gases and fumigants

Only when no other method is suitable
e.g. ethylene oxide, hydrogen peroxide vapour
Validation: Also prove the gas has no damaging effect on product
Time and conditions for degassing (specified limits) - residue
Direct contact with microbial cells essential
Nature and quantity of packaging materials
Humidity and temperature equilibrium
Monitoring of each cycle with biological indicators
time, pressure
temperature, humidity and gas concentration

Dr. Mehdizadeh

Sterilization by gases and fumigants (2)

Post-sterilization storage controlled manner
Ventilated conditions
Defined limit of residual gas
Validated process
Safety and toxicity issues

Dr. Mehdizadeh


Dr. Mehdizadeh


Dr. Mehdizadeh

Aseptic processing and sterilization by filtration
Aseptic processing
Objective is to maintain the sterility of a product, assembled
from sterile components
Operating conditions so as to prevent microbial contamination
What do you think are the aspects that require careful
attention?

Dr. Mehdizadeh

Aseptic processing (2)

Careful attention to:
Environment
Personnel
Critical surfaces
Container/closure sterilization
Transfer procedures
Maximum holding period before filling

Dr. Mehdizadeh


Dr. Mehdizadeh


Dr. Mehdizadeh

Sterilization by filtration
Through a sterile filter of 0,22 m or less, into previously

sterilized containers
remove bacteria and moulds
not all viruses or mycoplasmas
Consider complementing with some degree of heat treatment
Double filter layer or second filtration advisable, just before
filling - no fibre shedding or asbestos filters
Filter integrity testing immediately after use
also before use if possible

Dr. Mehdizadeh

Sterilization by filtration (2)
Validation to include
Time taken to filter a known volume
Pressure difference to be used across the filter
Significant differences to be noted and investigated, recorded
in batch records
Integrity of gas and air vent filters checked after use, other
filters at appropriate intervals

Dr. Mehdizadeh

Sterilization by filtration (3)
Same filter not used for more than one working day, unless
validated
No filter interaction with product, e.g.
removal of ingredients
releasing substances into product

Dr. Mehdizadeh

Quality Control of Sterile Production
Samples for sterility testing should be representative

From parts of the batch, most at risk
Aseptic filling at beginning and end of batch filling, and
after interruptions
Heat sterilized coolest part of the load
Sterility of the batch ensured through validation
Validated sterilization cycle
Media fill
Sterility test procedure as per pharmacopoeia, and validated
for each product
Batch processing records, sterility testing records,
environmental records should be reviewed

Dr. Mehdizadeh

Quality Control of Sterile Production
Endotoxin testing for injectable products

Water for injection, intermediate and finished product
Always for large volume infusion solutions
Pharmacopoeia method, validated for each product
Failure of the test investigation
Corrective action

Dr. Mehdizadeh

Finishing of Sterile products
Containers closed by means of validated methods

Samples checked for integrity
Maintenance of vacuum (where applicable) checked
Parenteral products inspected individually
Visual inspection under suitable and controlled conditions:
illumination and background
eyesight checks of operators
allowed frequent breaks
Other methods:
validated, and equipment performance checked at intervals
results recorded

Dr. Mehdizadeh

Validation of Aseptic Process

Dr. Mehdizadeh

Validation of Aseptic Processing

Not possible to define a perfect sterility assurance level for aseptic
processing

( )
Process is validated by simulating the manufacturing process using
microbiological growth medium (media fill)

Dr. Mehdizadeh


Process simulation includes formulation (compounding),
filtration and filling with suitable media using the same
processes involved in manufacture of the product

Dr. Mehdizadeh


.
modifications must be made for different dosage forms e.g.
lyophilized products, ointments, sterile bulks, eye drops filled
into semi-transparent/opaque containers, biological products

Dr. Mehdizadeh


Media fill program should include worst case activities
.
Factors associated with longest permitted run (e.g. operator fatigue)

.
Representative number, type, and complexity of normal interventions,
non-routine interventions and events (e.g. maintenance, stoppages,
etc)

Dr. Mehdizadeh


Worst case activities (cont)

Number of personnel and their activities, shift changes, breaks,
gown changes

.
Representative number of aseptic additions (e.g. charging
containers, closures, sterile ingredients) or transfers
Dr. Mehdizadeh


Aseptic equipment connections/disconnections

Aseptic sample collections

Line speed and configuration

Dr. Mehdizadeh

Worst case activities

Weight checks
Container closure systems
Specific provisions in processing instructions
.
Written batch record documenting conditions and activities
.
Should not be used to justify risky practices

Dr. Mehdizadeh

Duration
Depends on type of operation
BFS, Isolator processes - sufficient time to include manipulations
and interventions
For conventional operations should include the total filling time Size
5000 - 10000 generally acceptable or batch size if <5000
For manually intensive processes larger numbers should be filled
Lower numbers can be filled for isolators

Dr. Mehdizadeh

Frequency and Number

Three initial, consecutive per shift
Subsequently semi-annual per shift and process
All personnel should participate at least annually,
consistent with routine duties
Changes should be assessed and revalidation carried out
as required
Line Speed
Speed depends on type of process

Dr. Mehdizadeh

Environmental conditions

Representative of actual production conditions (no. of personnel,
activity levels etc)
HVAC
no special precautions (not including adjustment of HVAC)

if nitrogen used for overlaying/purging

Dr. Mehdizadeh

Media
.
Anaerobic media should be considered under certain
circumstances

.
Should be tested for growth promoting properties (including
factory isolates)

Dr. Mehdizadeh

Incubation
35-30 20-25

If two temperatures are used, lower temperature first

Inspection by qualified personnel.
.
All integral units should be incubated.

Dr. Mehdizadeh

.
Should be justification for any units not incubated.

.
Units removed (and not incubated) should be consistent with
routine practices (although incubation would give information
regarding risk of intervention)

Batch reconciliation
Dr. Mehdizadeh

Interpretation of Results
. 5000
When filling fewer than 5000 units:
.
no contaminated units should be detected
1

.
One (1) contaminated unit is considered cause for revalidation,
following an investigation
Dr. Mehdizadeh

10000 5000
When filling from 5000-10000 units

One (1) contaminated unit should result in an investigation, including
consideration of a repeat media fill

Two (2) contaminated units are considered cause for revalidation,
following investigation

Dr. Mehdizadeh

10,000
When filling more than 10000 units

.
One (1) contaminated unit should result in an investigation

.
Two (2) contaminated units are considered cause for revalidation,
following investigation

Dr. Mehdizadeh

Interpretation of Results
QC

) .
.
Media fills should be observed by QC and contaminated units
reconcilable with time and activity being simulated (Video may
help)
.
.
Ideally - no contamination.
Any contamination should be investigated.
Dr. Mehdizadeh


Any organisms isolated should be identified to species level
(genotypic identification)
Invalidation of a media fill run should be rare

Dr. Mehdizadeh

Batch Record Review

.
Process and environmental control activities should be included in batch
records and reviewed as part of batch release
IPQC
.
In-process and laboratory control results

.
Environmental and personnel monitoring data
Dr. Mehdizadeh

HVAC WFI HEPA
.
Output from support systems(HEPA/HVAC, WFI, steam generator)

Equipment function (batch alarm reports, filter integrity)
. :
Interventions, Deviations, Stoppages - duration and associated time
.SOP
Written instructions regarding need for line clearances
.
Disruptions to power supply

Dr. Mehdizadeh


Dr. Mehdizadeh

3 - Process Validation 89-2-16

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Validation Master Plan

December 14, 2017 Process Validation 1

December 14, 2017 Process Validation 2

December 14, 2017 Process Validation 3

Introduction on Process Validation

December 14, 2017 Process Validation 4

December 14, 2017 Process Validation 5

December 14, 2017 Process Validation 6

Project FDA Site Non-FDA Site

Sterile Facility 10-15% 8-10%

Non-Sterile Facility 5-8% 4-5%

December 14, 2017 Process Validation 8

December 14, 2017 Process Validation 9

It is by design and validation that a manufacturer can establish

confidence that the manufactured products will consistently meet

their product specifications.

December 14, 2017 Process Validation 11

December 14, 2017 Process Validation 12

December 14, 2017 Validation Master Plan 14

Qualification Process Cleaning Computer Analytical M External

December 14, 2017 Validation Master Plan 15

December 14, 2017 Validation Master Plan 16

December 14, 2017 Process Validation 21

Marketing authorization limits

Marketing authorization limits

Batch release limits

December 14, 2017 Process Validation 23

2.1 These guidelines describe the general aspects of process

validation for the manufacture of non-sterile finished products.

December 14, 2017 Process Validation 24

Capsules Non sterile products Creams

December 14, 2017 Process Validation 25

December 14, 2017 Process Validation 26

3.1 The policy and approach to process validation should be

documented, e.g. in a validation master plan, and should include the

critical process steps and parameters.

December 14, 2017 Process Validation 27

December 14, 2017 Process Validation 28

Cleaning Analytical Method Process Computer

December 14, 2017 Process Validation 31

December 14, 2017 Process Validation 33

December 14, 2017 Process Validation 34

December 14, 2017 Process Validation 35

December 14, 2017 Process Validation 36

Parking Facilities No How we design

December 14, 2017 Process Validation 37

December 14, 2017 Process Validation 38

December 14, 2017 Process Validation 39

December 14, 2017 Process Validation 41

December 14, 2017 Process Validation 43

Quality Risk Management (QRM)

December 14, 2017 Process Validation 44

December 14, 2017 Process Validation 45

December 14, 2017 Process Validation 46

Quality Risk Management (Q9)

Pharmaceutical Quality Systems

Past: GMP checklist

Q10 Pharm. Quality Systems

Low Q8 Pharmaceutical Development

Low Product / Process Risk High

December 14, 2017 Process Validation 52

December 14, 2017 Process Validation 53

December 14, 2017 Process Validation 54