Process Validation of Legacy Products

This presentation is compiled by “ Drug Regulations” a
non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
3/31/2016 1

 This presentation is compiled from freely
available resources like the websites of FDA,
EMA, WHO and ISPE.
 This presentation is based on a discussion paper
published by ISPE titled “ Process validation Life
cycle implication for legacy products”
 “Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
 Visit http://www.drugregulations.org for latest
3/31/2016 2
Drug Regulations : Online
Resource for Latest Information

◦ This presentation
 Examines challenges related to the implementation of
PV Lifecycle concept to legacy products.
 Identifies common issues related to the appliation of
Life cycle concept
 Discusses potenial reposnes to various scenarios
3/31/2016 3
Drug Regulations : Online Resource for Latest
Information

◦ Following topics will be discussed and presneted
 Current validation Lifecycle expectation for legacy
products
 Strategies for assessing and prioritizing requirements
for legacy products
 Expectation for revalidating a modified legacy product
 Expectation for revalidating an unmodifed legacy
process based on exisitng PV gaps
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 The concepts in this presentation are based on following
assumptions
◦ Legacy products were previously validated.
◦ These products are currently marketed
◦ Are typically in life cycle stage
 Ongoing Process Verification ( OPV)
 Also known as Continued Process verification ( CPV)
 Original process was validated meeting the predicate rule
requirements
 A Pharmaceutical Quality System is in place.
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 Active Pharmaceutical Ingredients
 Drug Products
 Large and small molecules
 All routes of synthesis and dosage forms
 Principles used and applied comply with
understood and accepted International GMP’s
 Third party manufacturers and Contract
Manufacturing
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 Concepts and Principles focus on
◦ Establishing a validated state
◦ Maintaining a validated state
 Organizational Strategies will be based on
◦ Product Risk
 Dosage form , criticality of clinical effect
◦ Product History
 Available data , Quality History, Manufacturing Experience
◦ Prioritization of products requiring remediation
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 This presentation will not discuss the new
Lifecycle approach per se.
 For this the reader can refer our earlier
presentations on this topic
◦ Process Validation: FDA & EU Requirements: (Click here for presentation)
◦ Process Performance Qualification. ( Click here for presentation)
◦ Continued Process Verification ( click here for presentation)
◦ New EU requirements for Qualification & Validation ( Click here for presentation
)
◦ WHO guidance on validation of Non sterile Pharmaceuticals ( Click here for
presentation)
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 Updated process validation guidance of FDA ,
EMA and WHO discusses 3 phase validation
 This is based on Process knowledge and
Quality Risk Management
 Aligned with principles of ICH Q 8, Q 9 and Q
10.
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 Lifecycle Stages
 Process Design :
◦ The commercial manufacturing process is defined during this stage based on
knowledge gained through development and scale up activites
 Process Qualification
◦ The process design is evaluated if the process along with supporting equipment and
facility is capable of reproducible commercial manufacturing.
◦ This includes manufacture of initial validation lots- Process performance qualification
 Ongoing Process Verification:
◦ Post commercial phase
◦ Ongoing assurance during routine production that the process remains in a sate of
control
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 Ongoing Process Verification:
◦ Is a two phase stage
◦ Initial monitoring of new or redesigned products
 Less historical data or process experience
 Monitored more intensely
◦ Reduced level monitoring as statistical confidence builds
up.
 Initial Phase called as Enhanced OPV
 Routine OPV
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 Prioritization of perceived gaps should preclude remediation
 In some cases comprehensive assessment of product may be
available
◦ Annual Product review
◦ Past site inspection readiness efforts
◦ Recent audits
 These assessments may be used to support GAP/ Risk
assessment
 Output from these assessment should formally be documented
as supporting documentation
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 The principles used in the approach
presented here will conform to general Risk
Assessment principles
◦ Evaluation of risk to quality should be
 Based on scientific knowledge
 Ultimately link to the protection of patient
◦ The level of effort , formality and documentation
should be commensurate with level of risk.
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 Flow chart in next figure ( Fig 1) depicts a two
part decision tree
 Top of the chart illustrates original evaluation
 This is followed by process specific
evaluation
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 Evaluate current validated state of each
product
 Evaluation should be based on the ability to
demonstrate a state of process control at any
time.
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 The validated state of each commercial
process depends on following factors:
◦ Ongoing monitoring programme ( OPV) which
 monitors appropriate attributes & variables
 Provides data to demonstrate ongoing process control
◦ Timely review of OPV to assure control with actions
& adjustments as indicated by quality signal
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 The validated state of each commercial process
depends on following factors:
◦ Sufficient documented process knowledge
 Critical Quality Attributes
 Critical Process Parameters
 Development reports
 Process justification studies
 Technical analysis
 Process experience
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◦ Sufficient documented process knowledge
 This should provide
 Adequate rationale for changes to process , investigation
of non conformances,
 Maintain adequate control
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◦ Effective Change Management
 Is it in place since original or most recent revalidation
 Does PV documentation reflect current process
◦ Does P V documentation meet GMP and regulatory
requirements effective at the time of PV
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 Based on this assessment there can be two
scenarios
1. Quality system indicates positive answers for above
questions
 This indicates that product validation life cycle is in place
 Routine monitoring can continue by adjusting levels of
sampling and testing indicated by events and trends over
time.
3/31/2016 23
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 Based on this assessment there can be two
scenarios
2. Quality system indicates GAPS in procedures ,
requirements for one or more products
 Indicates need for remediation
 Additional actions before implementing OPV
3/31/2016 24
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 Before implementation of the PV Life cycle
remediation plan ensure that
◦ Quality System Infrastructure is in place
◦ Quality work culture is in place
◦ Support for documentation, training and other
quality systems is in place
3/31/2016 25
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 Some of the items for consideration for
evaluation of legacy products for compliance
adequacy are given in Table 1in next slides
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 Expectation of Quality System Management (
QMS) Include
◦ Set requirements for Life Cycle
◦ Allow flexibility to operate in multiple global
markets
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QMS) Include
 Standard Operating Procedures
◦ Technical Product ownership & product expertise
◦ Statistical requirements
◦ Data handling and review
◦ Quality Oversight & Management Review
3/31/2016 32
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QMS) Include
 Site procedures , validation plans and Quality
systems like Deviation management, change
control periodic product review may require
updating to include lifecycle approach
3/31/2016 33
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QMS) Include
 Automated systems for data trending
especially for high product volumes
3/31/2016 34
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 Prepare detailed site specific plans once
polices and procedures are updated
 The implementation of Lifecycle approach can
be a multi phase multi year approach
 Plan should be developed to bridge the gap
between current and desired state
3/31/2016 35
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 The plan should include
◦ Schedule for implementation
◦ Prioritization of products based on
 Volume of product in the market
 Number of patients served
 Product criticality ( Life saving product)
 Product shortages
 Regulatory authority
3/31/2016 36
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◦ Prioritization of products based on
 Process Quality history
 ( % batches rejected, total complaints,)
 Total GMP deviations ( Critical , major , minor)
 Planned process changes
 Total change controls opened since last PV
 Manual / High risk control strategies
 Status of exiting PV documentation package
 Amount of ongoing monitoring data collected for a given product
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◦ Procedure for updating plan based on new
knowledge or events
◦ Handling of products to different standards
3/31/2016 38
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 The next steps in the process are
◦ Gap & risk assessment for individual process
validation packages
◦ Alignment with revised Quality System Expectations
◦ Identification of Appropriate Remediation
 The steps are summarized in the next slide
Figure 2
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 The remediation plans can be divided into two broad categories
◦ Plans that may require actual process change including risk control
strategy improvements
◦ Plans that do not require actual process change
 Changes should be implemented thorough change management
system and associated risk management activity.
 Critical impact changes should be identified and controlled
 See Table 1 earlier for PV program requirements
3/31/2016 41
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 Table No.2 given in next slides outlines
potential PV package Gaps for individual
processes.
3/31/2016 42
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 Poor or Missing Development Documentation
◦ Many legacy products are developed before ICH Q 8(R2)
◦ Before harmonized definition of CQA and CPP
 Firm is not expected to perform missing or
missed aspect of development work
 What is expected is to supplement related
documentation for established and well
controlled legacy products
3/31/2016 45
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 To manage product life cycle in the long term
it is necessary to understand the links
between the parameters and product
attributes.
3/31/2016 46
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 CQA’s and associated CPP’s can be
established based on
◦ Current and historical product and process data
◦ Characteristic attributes of the dosage form
 Discovery & development based on QbD is
typically not required for legacy products
3/31/2016 47
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 However following is necessary
◦ Identification of Product Quality Attributes directly
related to Drug safety and efficacy
◦ Process parameters that need to be controlled to
assure that those attributes meet specifications
◦ Demonstration of the adequacy of the process
control strategy
◦ Validation of the process
3/31/2016 48
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◦ Tracking and trending of release and critical in-process
testing results to demonstrate process control
◦ Well controlled legacy processes do not require
additional characterization unless OPV reveals need for
improved controls
◦ In such situations risk assessments can be useful in
determining the relative criticality of parameters,
materials, or other items being modified.
3/31/2016 49
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◦ Evaluating actual deficiencies in control strategy as
reflected in test data, complaints and process deviations
◦ Above can indicate work necessary to understand and
improve control strategy
◦ Such process improvements do not drive revalidation per
se
◦ They are triggers for process improvements and then
followed by PPQ to establish effectiveness of actions.
3/31/2016 50
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 Final category of Gaps could be
◦ When legacy packages do not conform to predicate
rules effective at the time of PV execution
◦ Other significant compliance issues
 This may require repeating or supplementing
initial validation simply to improve available
GMP evidence of validation
3/31/2016 51
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 In such cases revalidation utilizing PPQ plans
and protocols meeting current expectations is
recommended.
 However subsequent period of enhanced
monitoring may not be required since the
process itself has not been changed
3/31/2016 52
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 Important
 To understand how critical is a given parameter
or attribute to patient safety and product efficacy
 To document the rationale for above
 In absence of this Release specification can
considered to be critical as a conservative
method of attribute selection
3/31/2016 53
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 Important
 Process parameters that must be controlled
to assure that these release specifications ar
met can be considered to be CPP”s
3/31/2016 54
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 With capable process performance & in
absence of compliance gaps
◦ Trending of critical manufacturing batch data on
ongoing basis can be a routine OPV program
◦ OPV continues till product is modified, improved or
discontinued.
◦ Level of sampling , testing and other monitoring
activities should be adjusted based on quality data.
3/31/2016 55
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 Common question
 What is the relationship between OPV and
Annual Product Review ( PQR in EU)
 Is there redundancy between these two
related activities
3/31/2016 56
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 21CFR Part 211.180(e)
◦ Requires firms to maintain written records of data for
evaluating at least annually the need for changes or
improvements to specifications, manufacturing or
control procedures.
◦ “Included in the quality standard for each drug product
and drug product specifications or manufacturing or
control procedures” is the results of statistical analysis
of process capability supporting a statistical significant
confidence statement.
3/31/2016 57
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 FDA has on several occasions said that complying
with CFR 211.180 (e) does not necessarily satisfy
expectation of ongoing monitoring.
 Modern Quality Science does not advocate once a
year review of process
 Life cycle concept simply provides statistical
tools for process evaluation
3/31/2016 58
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 Revalidation of Legacy Products
◦ Due to process change
◦ Compliance/Documentation improvement
◦ Number of issues beyond process change
◦ See Table 3 in next slides
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 Applies to legacy products
 Assess products & processes and determine gaps
 Apply Life cycle approach
 Goal is same as new products
 Understand impact of various sources of variability on product
quality
 Implement control strategy to manage variation
 Generate documented evidence verifying applicable control
strategy
 Ensure robust process control
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 Products need not be revalidated for the sake of
complying with the life cycle approach in the
absence of missing data or control issues
 Remediation is related to deficiencies
 Evaluate the level of routine sampling and testing
 Identified gaps may lead to additional PV activity
 There is no need that a firm reverse engineer well
controlled legacy processes
3/31/2016 63
Information

 This presentation is compiled from freely
available resources like the websites of FDA,
EMA, WHO and ISPE.
 This presentation is based on a discussion paper
published by ISPE titled “ Process validation Life
cycle implication for legacy products”
 “Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
 Visit http://www.drugregulations.org for latest
3/31/2016 64
Drug Regulations : Online
Resource for Latest Information

Process Validation of Legacy Products

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