Current Global Trends in Process Validation Webinar

Webinar
Current Global Trends in Process Validation
By
Dr. Ganesh Prasad
Q-Pharma Consulting India
Cell: +91-9848029532
www.qpharmaconsulting.net
Q_Pharma Consulting India,
1

Speaker’s Profile
• Dr. Ganesh Prasad is a Pharma consultant in India & holds a doctorate degree in
Organic Chemistry from Indian Institute of Science, Bangalore. Previously, he
worked at senior levels in pharmaceutical companies like Apotex Pharmachem
India Pvt Ltd, ICI Pharmaceuticals, Chennai and other organisations heading
QC/QA/Process functions.
• He has also worked as scientist in the US FDA laboratory at NIH campus and other
reputed institutions in USA/ Canada. He has together more than 25 years
experience in quality assurance function, research in academia and industry.
• As a consultant he has assisted many pharmaceutical companies towards
establishing cGMP standards complying with national and international standards
and submission of Drug Master Files to various global regulatory agencies and
other regulatory documents. He also conducts third party quality audits of
Pharmaceutical manufacturers on behalf of domestic and international clients. He
has conducted many public and in-house workshops and delivered invited lectures
in forums like UBM, ISPE, DIA and so on.
• Dr. Prasad is a life member of Indian Pharmaceutical Association and a former
board member of ISPE (International Society for Pharmaceutical Engineers) India
Affiliate, Hyderabad chapter.
2

Validations – Regulation history
• Sterilisation 1977
• Aseptic processing 1979
• Water Systems 1981
• Non-sterile Mfg Process 1987
• Revised PV Guidance by US FDA 2011 (January)
3

4

Only Excepients
Ideal tablet
Only API
5

‘cGMP for the 21st Century’: ICH Guidelines
6

Current Regulatory Thinking
7

Process Validation – Current Regulatory
Trend
• US FDA January 2011 Guidelines
• EMA Guidelines on Process validation (2016) and
EC guideline Eudralex Vol 4, Annex 15 (2015)
• Development and manufacturing of drug substances
(ICH Q11, QBD concept)
• Process Analytical Technology (PAT)
8

Process Validation - US FDA definition
1987:
To Demonstrate with Documented Evidence that a Specific
‘Manufacturing Process’ is Capable of Performing in a
Reliable and Consistent Manner to Deliver a Homogenous
Product Meeting Defined Quality Attributes Consistently.
Jan 2011 Guidelines:
‘Process Validation’ is defined as the collection and evaluation of
data, from the process design stage through commercial
Production, which establishes with Scientific evidence that a
Process is capable of Consistently delivering quality product.
9

Sequence to Validation – US FDA
2011 Process Development (Lab scale)
Experimental Batches
(Pilot & Plant scale)
1987
Validation of Sub-Systems
(Analytical methods, Lab instruments; Equipment Qualfn
Utility Qualfn)
Plant Validation batches
Continued Process Verification
(Commercial manufacturing)
Currentdefn
Previousdefn
Process Design
Process Qualfn
CPV
10

Basis for Current Strategy for PV
A thorough process development work in lab and pilot plant &
‘Process Knowledge’ is the basis for a successful ‘Process
Validation’
• Understand the source of variation at every stage
• Determine the presence & degree of variation
• Knowledge of impurities, its origin & removal (APIs)
• Relationships between ‘Process Variables’ and ‘Product
Quality Attributes’.
• Critical Steps & Process Parameters
• Control of variation based on ‘Risk Analysis
11

Process Validation: Current FDA Perspective
“Focusing on Process Qualification efforts without
understanding the ‘Manufacturing Process’ may not lead to
adequate assurance of Quality”
Stages of Process Validation :
1. Process Design: - Lab trials; Pilot plat trials, Tech transfer
2. Process Qualification: - a. Facility, Equipment/ Utility Qualfn.
b. Process Performance Qualification
3. Continued Process Verification: After commercial release
12

EMEA Guidelines on Process Validation
(Eudralex Vol 4, Annex 15 (2015))
• Traditional Approach
• Continuous Process Verification
- Use of multivariate statistical tool
- Use of Process Analytical Technology strategy.
• Hybrid Approach
• On-going Process Verification
(same as FDA’s ‘Continued Process Verification’)
13

QUIZ-1: Introduction and Regulatory Perspective
1. Name three ICH documents which are the basis for 21st Century cGMP and what aspects do they cover?
1. As per the new definition of Process Validation by USFDA, what is the basis for a successful validation?
Select the most appropriate answer:
i. Thorough process investigation ii. Thorough process knowledge iii. Risk management
3. Do you think the current Thinking of USFDA and European agency like EMEA on the basic concept of
validation are very different?
Chose the right answer: Yes OR No
4. As per the revised scope of process validation by USFDA, what is the 3rd stage of validation and what are
its objective?
5. As per EMEA Hybrid approach is acceptable. What does Hybrid Approach mean?
Refer page --- for answers
14

Stage -1
Approaches to Process Design
15

Process Design – Traditional Approach
Based on univariate study. Study impact of single input variable
at a time on a specific quality attribute of the product.
This will require large number of trials to provide thorough
understanding of impact of multiple input variables and CQAs.
Inter relationships between input variables and CQAs not
possible.
Provides limited knowledge and less flexibility in process
operation.
16

Process Design – QBD Approach
• Based on study of the impact of multi dimensional
combination of input variables.
• Establishes inter relationships between multiple
input variables and CQA based Design of
Experiments (DOE).
• A ‘Design Space’ is developed.
• Provides thorough understanding of process and
operational flexibility.
• Movement within design space not be considered as
‘Change’.
17

Process Design – Input Variables
Identify all process variables based on their possible
impact on Product Quality.
1. Material Attributes
- Critical raw materials / excipients/ intermediates
- In process tests, shelf life, Suppliers
2. Process Variables:
- Critical steps & Control parameters
- Impact of deviations from critical parameters
- Impurities, its origin, detection & control
3. Equipment Parameters: Equipment settings
4. Environment conditions: Ex: Air quality, Room temper & RH
18

Process Design – Scale Effect
Process Variables:
- Scale Independent
- Scale Dependent
Laboratory Scale :
- Establish ‘Scale Independent’ parameters
Pilot & Plant Scale:
- Establish ‘Scale Dependent’ Parameters
www.qpharmaconsulting.net 19

• Scale Dependent Parameters:
- Granulation amperage, Time
- Blending Time
- Drying time …etc.
• Scale Independent Parameters:
- API – Excipients Ratio
- Particle size of API, Excipients & Granules
- Granules drying temp
- Tablet compression parameters …etc
Process Parameters – Scale Effect
(Drug Product: ex: Tablets)
-----continued
20

Process Parameters – Scale effect
(APIs)
Scale Independent Parameters : Lab Scale Study
- Reaction pH, Temp, Pressure
- RM ratio, Rate of addition, Sequence of addition ..etc
- RM / IM quality attributes,
- Impurity formation & Removal
- Crystallisation Temp, Solvent ratio
- Hold time for RMs/ In-process materials/ Intermediates
RM - Raw material; IM – API Intermediates

Process Parameters – Scale effect
(APIs)
Scale Dependent Parameters: Pilot/Plant scale study
- Agitation RPM, Mixing, Extraction, Rate of heating
- Centrifuge washing
- Drying time, Blending Time …etc
- Distillation
- Safety parameters
22

Risk Approach in Process Life Cycle
23

Application of Risk Assessment in ‘Process
Validation’
To Identify:
• Critical Stages in the manufacturing process
• Critical Process Parameters (CPPs)
• Critical Material Attributes (CMA)
• Equipments requiring qualification
• Equipment settings
• Requirement of validation due to ‘Change
…etc
24

CPPs by Risk Assessment
Methodology:
Risk Assessment
- Risk identification
- Risk analysis
- Risk Evaluation
Risk Control
Risk Review
Factors: Severity
Probability
detectability
Risk assessment Tools:
Examples:
• Process flow charts, check lists
• Risk mapping
• Risk ranking and filtering
• 5-Whys
• Fault tree analysis
• FMEA
25

Limits for Critical Process Parameters:
Risk Evaluation Based on Operating Ranges
• Normal Operating Range (NOR)
• Proven Acceptable Range (PAR)
• ‘NOR’ is generally fixed tighter than the actually required
‘PAR’.
NOR (based on equipment capability)
Δ
PAR (based on process limits)
As ‘Δ’ decreases,
risk increases and
vice versa
26

Risk Ranking Matrix
Very Rare Rare Likely Very likely
Low
Medium
High
Very high Very High
High
Medium
Low
Very low
Probability
Severity
27

Risk Matrix – APIs Qualitative
S.No Process
parameter
CQA
affected
Severity Probability Combined
Risk level
Criticalit
y
1 Reaction temp RM
impurity-A
High Likely High CPP
2 Crystallisation
Temp
Impurity-B High Likely High CPP
3 RPM during
crystallisation
Particle
size
High Very Rare Low WCP
4 Crystallisation
temp
Colour Medium Likely High CPP
5 Centrifuge spin
time
LOD Medium Rare Low WCP
6 Drying Temp Moisture
content
High Likely High CPP
• CPP – Critical parameter
• NC – Non-critical parameter
• WCP – Well controlled parameterQ_Pharma Consulting India,
28

Risk Matrix : Example 2
Identification of CPP – Tablet Compression
Process parameter CQA affected **
Severity
**
Probability
Risk
Score
CPP?
1 Exepient- particle size
(minor component)
Hardness ..etc 2 1 2 NO
2 Granulation -Temp
- Time
Degradation
Homogeneity
8
8
4
4
32
32
Yes
Yes
3 Sieving – particle size Hardness ..etc 4 1 4 No
4 Drying temp Degradation 8 4 32 Yes
5 Mix with Mg-Stearate Glossyness 2 1 2 No
6 Blending:
No of revolutions
Homogeneity 8 2 16 Yes
Severity score : 1 , 2, 4, 8 Probability score : 1 , 2, 4, 8**
29

Quiz-2: Process Design
1. What is one important difference between Traditional approach and QBD approach for process design?
Chose the most appropriate answer:
i. Multivariate study Traditional approach & univariate study in QBD approach
ii. Univariate study in Traditional approach & Multivariate study in QBD approach
ii. Traditional approach means lab scale study and QBD approach means Plant scale study
2. Name at least two types of input variables to be studied during Process Design stage.
3. Provide at two examples EACH for Scale Dependent and Scale Independent process parameters in API
process and process for finished dosage forms.
4. Is risk assessment a one time study? If not, name at least two stages where it should be applied during
the manufacturing Life Cycle of the product.
5. What is the objective of risk assessment in the process validation exercise?
6. Name two Risk Assessment Tools to for assessing ‘Overall Risk’.
7. How do you calculate Risk Priority Number (RPN) in a quantitative risk assessment tool
30

Stage -2 : Process Qualification
2a. Facility /Equipment / Utility qualification
- Fit for the Purpose
- ASTM E 2500 approach (risk based)
2b. Process Performance qualification
31

Stage 2b: Process Performance Qualification
(PPQ)
- Must be completed before commercial dispatch
- By this stage, process well understood.
- Process parameters fixed based on knowledge in all stages so far.
- Effects of scale up on process parameters.
- Carried out under normal operating conditions.
- Driven by approved protocol.
- Number of validation batches required should be decided by the
validation team with justification.
How many batches to be included for validation??
32

Stage 2b: PPQ - How many batches required?
Depends on:
• Complexity of the process
• Previous experience
• Confidence generated from earlier development stages
• Three consecutive batches may be adequate if Design data
shows:
- Process has been shown to be very robust.
- Process variables can be very well controlled with
existing systems.
- Process variables are very well correlated v/s CQAs
- Product quality is controlled very well within specified
limits
Other wise, more than 3 consecutive batches will be required.
33

Types of validation
Three types of validation:
• ‘Prospective’
• ‘Concurrent’
• ‘Retrospective’
- Prospective Validation is the preferred approach.
- ‘Retrospective validation’ has been taken off from
the FDA 2011 guideline. However, ICH Q7 still
carries this type of validation.
- Concurrent validation maybe carried out in special
cases with justification.
34

Prospective Validation
• Prior to commercial dispatch
• Batches failing due to reasons unrelated to
process can be removed & fresh batch included
However, in such cases investigation should be
conducted to confirm that the cause is assignable
to design of process.
• Validation Protocol
35

Concurrent Validation
Concurrent validation may be carried out, when:
• Should be limited to exceptional cases
- Only limited number of batches possible
- Deviation in critical parameter in a validated batch
- Changes in existing validated process
• Based on extensive process monitoring, in-
process, finished product testing.
• Commitment to include future batches in the
validation program.
36

Retrospective Validation
Not a preferred approach any more.
Conducted when:
 Process well established
 Sufficient data available
 System and records in place
 Analyses of data from 10 – 30 similar batches
- May be used when: (example):
An existing non-critical parameter is identified as ‘Critical’
A limit for a quality attribute is made more stringent.
37

Planning and execution of validations
Validation Master Plan

Validation Master Plan
• Overview of entire Validation Project
• Validation Policy
• Responsibilities for key activities
• List of activities/equipment/utilities to be validated/
qualified with description
• Justification for exclusions
• Validation sequence and planning schedules
• Validation protocols & responsibility
• Revalidation requirements ?
• Large validation projects can have separate VMP
39

Planning Process validation - Protocol
Define :
1. Quality of Product
2. Manufacturing Process
(Process flow charts, Equipments, BPRs ..etc)
1. Batch Selection
2. Responsibility
3. Critical RM / Excepient Quality
4. Sampling and testing plan (In-process)
5. Critical process steps and parameters
6. Critical instruments & calibration requirements
7. Qualification of equipments/Utilities
8. Acceptance Criteria
9. Evaluation & Report Q_Pharma Consulting India,
40

QUIZ-3: Stage 2-Process Qualification
1. What are the two sub stages of ‘Process Qualification and what are they focused on?
2. During ‘Process Qualification’ stage development trials can continue. True or False ?
3. What are the criteria to decide how many batches should be selected for Process Performance Qualification?
4. Normally retrospective Validation is no longer recommended by regulators. However, Retrospective
Validation can be acceptable in special cases. Describe those two cases .
5. Concurrent Validation approach is acceptable in special cases. When this approach is selected, what is
strategy followed to validate the process.
6. What is the main objective of a Validation Master Plan
7. Name at least five sections which should be included in a validation Protocol.
41

Continue to monitor the process during routine manufacturing and
ensure that process is under control and delivers product quality
consistently.
• Continue to understand the impact of ‘INPUT’ variability on CQAs
• Develop & Manage Process Knowledge from
‘Changes’
‘Failures’
‘Inspections’ (internal / external)
• Adjustments to control strategy/ continuous improvement
• Ensure validated status of the manufacturing process throughout
Product Life cycle.
42

- Multiple ways to execute the 3rd stage
- Based on risk analysis
- Could be done in two stages.
i. Continue the study with same level of sampling and
monitoring as stage-2 for some more plant scale batches
to understand variability & provide more confidence.
ii. Establish Statistical Process Control (SPC) program to
evaluate process capability, as well as ‘Investigation of
variability’ and CAPA programs.
New Products: both ‘I’ and ‘ii’
Existing products: only ‘ii’
43

CPV – What to monitor?
• Based on the knowledge gained form stage 1 and stage 2
• Risk approach to prioritise parameters
Examples:
- Critical Material attributes
(Particle size, specific impurity in RM, RM qty ..etc)
- Critical Process Parameter Input Variables
- Critical Equipment Parameter
- Critical In-process results
- Critical quality attributes of API Impact on out put
(ex: assay, impurity, particle size) quality
44

CPV – Monitoring Tools
1. Statistical Process Control tools
- Histograms
- Control charts
- Process capability analysis (Cpk value)
2. Investigations and CAPA
- Fault Tree analysis
- Root cause analysis
- Risk –benefit analysis
- CAPA, Process improvements ..etc.
45

Summary
• The scope of validation was widened by FDA in 2011 to
include all stages beginning from Process development to
throughout commercial manufacturing.
• Three stages: Process design, Process qualification and
continued process verification.
• Hybrid approach is acceptable. i.e. combination of Traditional
& QBD /PAT approach.
• Risk assessment applied to identify critical stages and process
parameters.
• Process monitoring using statistical tools and upgradation of
process knowledge through CAPA program throughout
commercial manufacturing expected.
46

QUIZ-4: Continued Process verification
1. State at least two objectives of Continued Process Verification’ (CPV), the 3rd stage of process validation.
2. Name two sources of knowledge upgradation during commercial production.
3. What strategy would you follow to execute CPV for a new product?
4. Name two SPC tools which can be used to monitor capsule filling process in this stage.
5. What do you propose to do when CPk value for a specific parameter is found to be significantly below
acceptable limit (ex limit CPk fixed at 1.3).
6. Expanding the process validation paradigm and applying it to the biopharmaceutical life cycle from
development to commercial manufacturing.
Pharmaceutical Engg., Jan-Feb 2013, Vol 33,No 1.
47

Literature References for Reading
1. ICH Q8 (R2) :Pharmaceutical development, August 2009.
2. ICH Q9: Quality risk management, November 2005.
3. ICH Q10: Pharmaceutical quality system, June 2008.
4. FDA Guidance document 2011: Process validation – General principle and practices, Jan 2011
5. ICH Q11: Development and manufacture of drug substances, May 2012.
6. EMA guideline on process validation for finished products – Information and data to be provided in
regulatory submissions, November 2016.
7. Eudralex guideline for GMP, Vol 4, Guidelines for good manufacturing practice for medicinal products for
human and veterinary use, Annexe 15: Validation and Qualification, March 2015.
8. Continuous Verification – Providing an alternative approach to process validation
Pharmaceutical Engg., Jan-Feb 2011, Vol 31, No 1,
7. ASTM E-2500 guidance document 2007: A standard guide for specification, design & verification
of pharmaceutical and biopharmaceutical manufacturing systems and equipments.
48

Online Certification Programs Offered:
Online Certification Courses on ‘Pharmaceutical Validation Program’ offered by
Q_Pharma Consulting India.
Content of online Certification Course are given below:
• Pharmaceutical process validation
• Introduction to process development by QBD approach
• Application of quality risk management in process validation
• Qualification of pharmaceutical process equipments
• Development and validation of cleaning procedures
• Analytical method validation
For details contact:
Dr. G. Prasad
Q_Pharma Consulting India
Cell:+91-9848029532
49

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