Workshop on process validation
CMC Strategy Forum Europe 2013
EBE Process validation satellite session Pragues, 06/05/2013
Kowid Ho
Scope / background
Process evaluation/validation of biotechnology derived proteins used as active substance in the manufacture of medicinal products (i.e. scope of Q6B)
Address data requirement for process validation/evaluation for submission of a marketing authorisation application or variation.
Process Validation can be based on a traditional or enhanced approach to process development.
Traditional and enhanced approaches are not mutually exclusive.
A company can use either a traditional approach or an
Process validation biotech drug substance General concepts
Objective:
To establish scientific evidence that a process is capable of consistently delivering a quality drug substance.
Will justify the manufacturing process described in S2.2
More consistency in data submission and assessment
Data expected:
Process evaluation (small and/or full scale)
Process verification (full scale) or continous process verification
+/- Continued process verification
Process evaluation
Process evaluation studies:
should provide evidence that, when operating in accordance with conditions described in process description, the complete manufacturing process and each step/operating unit have been appropriately designed to obtain a product of the intended
quality.
should include
the evaluation of the ability of each step to obtain output of desired quality at small and/or full scale as appropriate.
the results, demonstrating that when operating in
accordance with the defined controls for material attributes and process parameters, the process is able to deliver
Process evaluation
Where appropriate, evaluation of selected step(s) operating in worst case and/or abnormal conditions (e.g. cumulative hold time, spiking challenge) could be performed to support or demonstrate the robustness and the capability of the process to deliver product of the intended quality in these conditions.
In some cases, these activities could be built into process verification studies.
Depending on the level of evidence provided to demonstrate the high performance of the step(s) and the relevance of experimental model with regards to the final process, these studies could leverage data
requirements for process verification (e.g. reduced number of batches) and/or control strategy (e.g. alternative approach to end product testing).
Process evaluation: main data to support PAR?
Process verification
Process verification studies should confirm that the final manufacturing process (i.e. full scale commercial process) performs effectively and is able to produce a drug substance or intermediate meeting its predetermined controls and acceptance criteria.
Process verification data (e.g. process step results, batch analyses) should be presented in the MAA on an appropriate number of batches (to confirm consistency) produced with the commercial process and scale
Process verification studies should normally be completed and included in the Marketing Authorisation Application. In some circumstances, concurrent validation could exceptionally be considered.
As an alternative approach, continuous process verification could
Continued process verification
Subsequent to successful process validation activities for MAA
Monitor product quality and process performance to ensure that a state of control is maintained throughout the commercial part of the product lifecycle.
To be performed in compliance with EU GMP
Presentation of continued process verification program in MAA to support process validation?
Include extended control system performed at appropriate
frequency, in accordance to internal limits ? acceptance limits ?
Include protocols covering aspects that will be verified on an ongoing basis? Periodicity?
Continued vs Continuous Process Verification
Continous Process Verification
Continued (/ongoing?) Process Verification Aim - Initial demonstration and/or
maintenance of a state of control
- maintenance of a state of control - Lifecycle management
Frequency - uninterrupted - timely manner
- resumed after interruption / periodic
- could be built into Continuous PV Testing/Monitoring - Not limited to CPP and CQA
- Include process performance Enabler - PAT tools (MSPC, in-line
control…)
- Extensive process knowledge
- GMP compliance
- Control strategy during product lifecycle (ex. design space
Controls included in PV studies
Controls (e.g. quality attribute, performance indicator, process parameter, controls implicit in the design of the process): normally go beyond the routine control system performed during routine production.
What is the Industry understanding of process performance indicators/parameters for the upstream and downstream processes? Would these terms differ from consistency indicators/parameters?
[Range tested]
Impact on CQA No demonstrated
impact on CQA
Process Parameter
CPP
Larger range to be tested or consider as potential CPP
[Range tested] > [Target ranges]
[Target ranges] ≥ [Range tested]
Non-CPP
[Range tested] >> [Target ranges]
potential CPP
Culture steps
Evaluation of cell culture steps:
From the introduction of the starting material in the manufacturing process (e.g. thaw of the WCB) up and beyond production level,
Demonstration of capability of consistently delivering inoculates, harvest(s), and ultimately a drug substance of appropriate quality.
Considering the complex matrices during cell culture and harvest steps, the evaluation/validation could, in part, rely on the analysis of drug
substance and/or intermediates obtained at a later stage of the process.
Include control of:
specific cell traits or indices (e.g. morphological characteristics, growth characteristics (PDL), cell number, viability biochemical markers,
immunological markers, productivity of the desired product, oxygen or glucose consumption rates, ammonia or lactate production rates),
operating conditions (e.g. time, temperatures, agitation rates, working volumes, media feed, induction of production, end of culture).
End fermentation / initiation of harvest(s): appropriately defined and evaluated.
For multiple harvests:
evidence that the quality of the product (e.g. yield, content, post translational modifications such as glycosylation, HCP, DNA) are consistent throughout the harvesting steps, or variability
appropriately managed by pooling strategy.
Culture steps
Verification of consistency of the process parameters/product quality attributes covering
Includes all culture steps under defined manufacturing conditions
Process parameters and Performance indicators in accordance to proven acceptable ranges
Complete duration of the fermentation process (including entire process time for continuous fermentation)
appropriate number of consecutive runs
For multiple harvests: confirmation that it will not have an impact on the quality and consistency of drug substances batches
Continued Verification could include:
Stability (storage) of cell banks ?
Stability of frozen intermediate ?
Controls related to change in raw materials ?
Culture steps
Should genetic stability of the cell line be considered as a performance indicator to be part of the validation of the upstream process?
Process parameters and quality attributes to be tested?
Should qualification of biological raw materials and other raw materials be addressed in the guideline and documented in the dossier?
What performance indicators should be considered for the validation of a continuous perfusion process?
How to verify reliability/predictability of small-scale models for the upstream and downstream processes?
Equipment
Information about key equipment (cell culture bottles, bags, fermeters) used, should be provided. This typically includes information on size and material.
Disposable single use equipment.
assess the suitability of the systems used.
full scale equipment has to be used.
various batches of disposable systems should be used in order to assess their impact on the product quality.
When used for media preparation and/or harvesting: their potential impact on the yield and quality of the active material should be studied
Multifacility production
Additions of alternative sites:
frequently occurring.
new site is rarely identical to the approved process (e.g. include adaptations and/or optimisations)
Local adaptations:
Normally accepted provided appropriate comparability data are shown. (e.g. different filters with same porosity)
how far can this be stretched? (e.g. different scale, conditions, raw materials, centrifugation vs filtration)
Alternate process
Cannot be ruled out that may give rise to slightly different purity/impurity profile
risk of drift with future changes
How to manage and validated differences between sites?
Purification
Evaluation:
Capacity of the purification procedures to obtain the desired product and to remove product and process-related impurities (e.g. unwanted variants, host cell derived proteins, nucleic acids, carbohydrates, viruses).
Quality of process intermediates (i.e. appropriate purity/impurity profile for the given stage)
Requires adequate analytical methods
For selected step(s):
e.g. steps for which high impurity or viral clearance are claimed
operating in worst case and/or abnormal conditions (e.g.
cumulated hold times, spiking challenge) performed to document the robustness
Purification
Evaluation:
Depending on the level of evidence provided: could leverage some process validation and/or control strategy data
requirements.
Process conditions (e.g. column loading capacity, column regeneration and sanitisation, flow rate, length) should be appropriately evaluated.
Performance parameters/indicators (e.g. yield, chromatographic profiles)
Pooling strategy and impact on drug substance consistency
Columns life time:
Demonstration of appropriate performance and integrity (e.g. clearance, collection of intended variants, leaching).
small scale studies: appropriate to estimate and set the maximum number of cycles at the time of MAA,
Hold times
Reprocessing
Purification
Verification:
Quality of process intermediates (i.e. appropriate purity/impurity profile for the given stage)
Process parameters and Performance indicators in accordance to proven acceptable ranges
Continued Verification could include:
Control of performance and integrity of operating units (e.g.
purification column) ?
Running period and periodic control of quality attribute(s) for which RTRT is done ?
Cumulative studies ?
Reprocessing?
Reprocessing
Reprocessing: introduced back into the process by repeating a step (e.g. filtration) that is part of the established manufacturing
procedure.
Limited to occasional process excursions.
The reason of the failure should be understood and should not impair the quality of the product.
Could be allowed only under appropriately defined conditions.
Should be described in the MAA.
Validation data expected, demonstrating that the reprocessing step(s) do not impact the quality of the active substance.
What are Industry views on the information to be documented in the dossier in relation to reprocessing? Is it always restricted to an
exceptional event (e.g. mechanical failure of equipment)?
Process validation for process development following traditional vs enhanced approach
Same objective:
To establish scientific evidence that a process is capable of consistently delivering a quality drug substance.
Data expected:
Process evaluation
Process verification or continuous process verification
+/- Continued process verification
Process validation for process development following traditional vs enhanced approach
Process Evaluation: higher expectations
Systematic approach using enablers (eg multivariate analysis, PAT tools, DOE, appropriate models including statistical model)
Demonstrated relationship between input/conditions (e.g. material attributes, process parameters) and output (e.g. CQA, Performance indicator)
Robustness demonstrated for selected steps (up to complete process), covering sufficiently large ranges
Demonstration of the suitability and predictability of scale down models (e.g.
qualitative, quantitative, scale dependence)
Demonstration that working within design space delivers a quality drug substance.
What additional studies would you consider in an enhanced approach versus a traditional approach?
How to evaluate and verify reliability/predictability of small-scale models for the upstream and downstream processes?
How to demonstrate validation of adaptive processes (e.g. with feed forward/feed back loops)?
Process validation for process development following traditional vs enhanced approach
Process Verification:
Compliance of complete process results to control strategy (including IPT and batch analysis) on appropriate number of batches
manufactured at target
Alternative: continuous process verification
Science and risk based, real time approach
Controls of process performance and product quality in a timely manner (e.g. PAT tools)
To be established upon accumulation of sufficient PV database?
Continued process verification could include:
Verification in part performed on an ongoing basis after MA if proper
EVALUATION VERIFICATION CONTINUED PROCESS VERIFICATION EVALUATION VERIFICATION CONTINUED PROCESS VERIFICATION
TRADITIONAL APPROACH ENHANCED APPROACH
Data to be submitted in MAA
Workshop on process validation
Closing remarks
Process validation biotech drug substance General concepts
Objective:
To establish scientific evidence that a process is capable of consistently delivering a quality drug substance.
Will justify the manufacturing process described in S2.2
More consistent data submitted and assessed
Data expected:
Process evaluation (small and/or full scale)
Process verification (full scale) or continous process verification
+/- Continued process verification
Process validation biotech drug substance General concepts
Issue with terminology
Process
Characterisation: to design intended process
Evaluation: for the process representative of final process
Verification: full scale +/- at target
Continued Verification
Process PERFORMANCE indicators/parameters vs
CONSISTENCY indicators vs KEY PERFORMANCE indicators
Differenciation between input and output?
[Range tested]
Impact on CQA No demonstrated
impact on CQA
Process Parameter
CPP
Larger range to be tested or consider as potential CPP
[Range tested] > [Target ranges]
[Target ranges] ≥ [Range tested]
Non-CPP
[Range tested] >> [Target ranges]
potential CPP
Expected to be included in process validation studies
Impact on Performance
indicators
No impact on Performance indicators
Process validation biotech drug substance General concepts
Justification of PAR
Mainly based from evaluation data?
Excursion from PAR: GMP issue?
Justification of NOR
Mainly based from verification data?
Continued vs Continuous Process Verification
Continous
Process Verification
Continued (/ongoing?) Process Verification Aim - Initial demonstration
and/or maintenance of a state of control
- maintenance of a state of control
- Lifecycle management Frequency - uninterrupted
- timely manner
- resumed after interruption - periodic
Testing/Monitoring - Not limited to CPP and CQA - Include process performance Enabler - PAT tools (MSPC, in-line
control…)
- Extensive process knowledge and
understanding
- GMP compliance
- Control strategy during product lifecycle (ex. design space verification)
MAA Submission - Included in the MAA - Prospective proposal
- May be described in MAA
Process validation biotech drug substance General concepts
Non-CPP measures included:
Markers of process consistency
Only if non redundant or indicator status?
Material and intermediate attributes linked to CQA outcomes
Indirect or indicator parameter or attributes demonstrating drift or loss of control
Multi-signal/multi-parameter probes
30 Agence nationale de sécurité du médicament et des produits de santé
Upstream
Genetic stability of the cell line
Done prior to validation
Already captured in Q5s
Process parameters and quality attributes to be tested
Inputs: can be varied; eg Process parameters
Outputs
CQA
Performance indicators (cell density, viability)
Consistency indicator ?
“Indicator”: more appropriate for output?
Criticality continuum… where to draw the line?
Controlled within narrow range?
For early warning sign?
Upstream
Multi-harvest approach
Strategy company dependent
Need to cover complete harvest
Performance indicators for the validation of a continuous perfusion process
Indicators and QA not that different from discontinuous fermentation
Upstream & Downstream
Qualification of biological raw materials and other raw materials
Difficult to incorporate different lots in to validations studies
Evaluation to be performed to analyze potential variability
Risk based approach
“Critical Raw Material” need to be identified?
Test frequency
Depends on process and product understanding, overall control strategy…
Less understood : More testing
For non release assay: demonstrated fit for purpose
Upstream & Downstream
Single use
Risk assessment
impact on performance and QA; eg could be handled as high risk raw material for upstream
attention on extrables/leachables
Quality of the bags (eg sterility of bags) covered by vendor qualification?
Same principles for downstream and upstream
Upstream & Downstream
Multifacility
List of difference + justification
How far can be stretched? Difficult to draw the line
Purpose and outputs still the same?
Risk assessment on potential impact / comparability exercise
PV to be done
Upstream & Downstream
Scale Down Models (SDM)
Incomplete representation but needed !
Description and justification of inputs, design and outputs
Can explore large ranges
Outputs:
Product quality attributes > Performance indicators > Other characteristics
SDM should match large scale at target
Statistical approach: difficult to conclude with limited number of full scale batches
Non-equivalence & offsets
"a question of confidence…“
Downstream
Reprocessing
Extraordinary
Reprocess step does not impact product quality
Root cause clearly identified and does not impact product quality
Mainly limited to re-filtration or re-concentration steps
Adaptive process and feed back loops
No real example of product quality directly measured in the process; future?
Downstream
Hold times:
Long vs short time storage
Often, storage of intermediates is impractical at small scale
Cumulative studies of DS bulk:
if stored > weeks; impact on DP stability to be assessed
If stored > months unreasonable, could take years
Intermediate hold
Cummulating unlikely; unreasonable?
Program to be included in Continued PV?
Downstream
Pooling intermediate
Intemediate of specified quality
Homogeneity ensured by mixing studies
Option to be described in dossier
Enhanced/QbD approach
Additional studies for enhanced approach
Mixture; PV approach likely to be a continuum from tradition to enhanced
More integrated approach
including Non-clinical and clinical aspects
Describe and manage influence of CPP on CQA
Control of materials (RM, intermediates…)
SDM
Flexibility…
Considered as an OUTCOME rather than the AIM of enhanced
EVALUATION VERIFICATION CONTINUED PROCESS VERIFICATION EVALUATION VERIFICATION CONTINUED PROCESS VERIFICATION
TRADITIONAL APPROACH ENHANCED APPROACH
Data to be submitted in MAA
Closing remark
Continuous discussions…
to be continued…
Thanks you all !!!
Workshop on process validation
Closing remarks
Kowid Ho
Process validation biotech drug substance General concepts
Objective:
To establish scientific evidence that a process is capable of consistently delivering a quality drug substance.
Will justify the manufacturing process described in S2.2
More consistent data submitted and assessed
Data expected:
Process evaluation (small and/or full scale)
Process validation biotech drug substance General concepts
Issue with terminology
Process
Characterisation: to design intended process
Evaluation: for the process representative of final process
Verification: full scale +/- at target
Continued Verification
Process PERFORMANCE indicators/parameters vs
CONSISTENCY indicators vs KEY PERFORMANCE indicators
Differenciation between input and output?
Process performance indicators and parameters that don’t impact CQA’s do not need to be included as regulatory commitments in the MAA?
Point that will require further discussion…
[Range tested]
Impact on CQA No demonstrated
impact on CQA
Process Parameter
CPP
Larger range to be tested or consider as potential CPP
[Range tested] > [Target ranges]
[Target ranges] ≥ [Range tested]
Non-CPP
[Range tested] >> [Target ranges]
potential CPP
Process validation biotech drug substance General concepts
Justification of PAR
Mainly based from evaluation data?
Excursion from PAR: GMP issue?
Justification of NOR
Mainly based from verification data?
Continued vs Continuous Process Verification
Continous
Process Verification
Continued (/ongoing?) Process Verification Aim - Initial demonstration
and/or maintenance of a state of control
- maintenance of a state of control
- Lifecycle management Frequency - uninterrupted
- timely manner
- resumed after interruption - periodic
Testing/Monitoring - Not limited to CPP and CQA - Include process performance Enabler - PAT tools (MSPC, in-line
control…)
- GMP compliance
- Control strategy during
Process validation biotech drug substance General concepts
Non-CPP measures included:
Markers of process consistency
Only if non redundant or indicator status?
Material and intermediate attributes linked to CQA outcomes
Indirect or indicator parameter or attributes demonstrating drift or loss of control
Multi-signal/multi-parameter probes
Shear forces, gas exchange rates, column-ligand density, non- critical attribute abundance or quality
Upstream
Genetic stability of the cell line
Done prior to validation
Already captured in Q5s
Process parameters and quality attributes to be tested
Inputs: can be varied; eg Process parameters
Outputs
CQA
Performance indicators (cell density, viability)
Consistency indicator ?
“Indicator”: more appropriate for output?
Upstream
Multi-harvest approach
Strategy company dependent
Need to cover complete harvest
Performance indicators for the validation of a continuous perfusion process
Indicators and QA not that different from discontinuous fermentation
Upstream & Downstream
Qualification of biological raw materials and other raw materials
Difficult to incorporate different lots in to validations studies
Evaluation to be performed to analyze potential variability
Risk based approach
“Critical Raw Material” need to be identified?
Test frequency
Depends on process and product understanding, overall control strategy…
Upstream & Downstream
Single use
Risk assessment
impact on performance and QA; eg could be handled as high risk raw material for upstream
attention on extrables/leachables
Quality of the bags (eg sterility of bags) covered by vendor qualification?
Same principles for downstream and upstream
Upstream & Downstream
Multifacility
List of difference + justification
How far can be stretched? Difficult to draw the line
Purpose and outputs still the same?
Risk assessment on potential impact / comparability exercise
PV to be done
Upstream & Downstream
Scale Down Models (SDM)
Incomplete representation but needed !
Description and justification of inputs, design and outputs
Can explore large ranges
Outputs:
Product quality attributes > Performance indicators > Other characteristics
SDM should match large scale at target
Statistical approach: difficult to conclude with limited number of full scale batches
Non-equivalence & offsets
"a question of confidence…“
Depend on the intended use
Ideal should include off-target; doable for downstream? Could be done for upstream?
Could be leverage by proper control strategy / continued PV
Downstream
Reprocessing
Extraordinary
Reprocess step does not impact product quality
Root cause clearly identified and does not impact product quality
Mainly limited to re-filtration or re-concentration steps
Adaptive process and feed back loops
No real example of product quality directly measured in the
Downstream
Hold times:
Long vs short time storage
Often, storage of intermediates is impractical at small scale
Cumulative studies of DS bulk:
if stored > weeks; impact on DP stability to be assessed
If stored > months unreasonable, could take years
Intermediate hold
Cummulating unlikely; unreasonable?
Program to be included in Continued PV?
Downstream
Pooling intermediate
Intemediate of specified quality
Homogeneity ensured by mixing studies
Option to be described in dossier
Enhanced/QbD approach
Additional studies for enhanced approach
Mixture; PV approach likely to be a continuum from tradition to enhanced
More integrated approach
including Non-clinical and clinical aspects
Describe and manage influence of CPP on CQA
Control of materials (RM, intermediates…)
SDM
Flexibility…
Considered as an OUTCOME rather than the AIM of enhanced approach for regulators
Also depends on data and knowledge shared
EVALUATION VERIFICATION CONTINUED PROCESS VERIFICATION EVALUATION VERIFICATION CONTINUED PROCESS VERIFICATION
TRADITIONAL APPROACH ENHANCED APPROACH