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PROCESS VALIDATION
ROCHAPON WACHAROTAYANKUN, PH.D.
Topic
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Key References
PIC/S and EU GMP Annex 15: Qualification and Validation (Effective date 01 October 2015)
WHO/BS/2015.2253 : WHO GMP for Biological Products Proposed replacement of: TRS 822, Annex 1
US FDA Guidance for Industry -Process Validation: General Principles and Practices ,
January 2011
ICH Q7
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Definition of Process Validation (1/2)
ICH Q7
Guideline on process validation for finished products - information and data to be provided
in regulatory submissions EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1
PIC/S and EU GMP Annex 15: Qualification and Validation (Effective date 01 October 2015)
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Definition (1/2)
Quality, safety, and efficacy are designed or built into the product.
Each step of a manufacturing process is controlled to assure that the finished product
meets all quality attributes including specifications.
Assures consistency of production process
Demonstrates the capability of the commercial manufacturing process
to give a high degree of assurance of obtaining medicinal products
meeting the required quality attributes of safety, purity, and efficacy on
a continued basis.
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…a meaningful process validation program based on the
assumption that “quality cannot be adequately assured merely by
in-process and finished-product inspection and testing”
Offers assurance that a process is reasonably protected against
sources of variability that could affect production output, cause
supply problems, and negatively affect public health”.
Proves that in spite of changes in operational parameters through
the necessary scale up of the production process, including new
facilities and equipment, the product characteristics will not vary.
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Lifecycle Approach : from R&D through clinical trials to
commercial scale
“process validation should not be viewed as a one-time event but
rather as an activity that spans the product lifecycle linking product
and process development, validation of commercial manufacturing
process, and its maintenance during routine commercial production”
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Knowledge and Risk based approach
Scientific Knowledge
Product Process
ICH Q8-11
PV Stage II
• Process description
• Process characterization • Definition of Operational Parameters • Change control
• Raw/ starting materials at commercial scale • Revalidation
• Extractables ,Leachables • Manufacturing of Consistency Lots program
• Seed bank • Manufacturing of Clinical Phase
• Cell lines, Cell bank Material • Continual
• Analytical methods • Bracketing, Family and Matrix monitoring
• Validation of production steps or Validation Approach
unit operations • Documentation Requirements
• Personnel Training and Qualification PV Stage III
• Process Technology Transfer
• Legacy products
• Design and Execution of Process
PV Stage I Validation Studies US FDA’s Continued
• Deviations Management Process Verification
• Final report
US FDA’s Process design
US FDA’s Process
Qualification *
Quality Risk Management applied
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CPP, CQA, Control strategy
Control strategy:
A planned set of controls, derived from current product and process understanding that
ensures process performance and product quality. The controls can include
parameters and attributes related to active substance and finished product materials
and components, facility and equipment operating conditions, in-process controls,
finished product specifications, and the associated methods and frequency of
monitoring and control. (ICH Q10)
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Quality Risk Management: applied through Life
cycle
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From Stephan Krause,
Medimmune, 201313
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Process development, commercial
manufacturing capabilities, and the
quality system must be integrated in
order to achieve effective and compliant
commercial operations
Rochapon W. Validation of Production Processes for Vaccines for WHO Prequalification: Compliance Expectations (Draft) 14
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Common Sequence of
Process Validation Activities
(based on PDA´s Common
Timing of PV Enablers and
Deliverables to Validation
Stage Activities)
Concurrent validation
Validation carried out in EXCEPTIONAL CIRCUMSTANCES, justified on the
basis of significant patient benefit, where the validation protocol is executed
concurrently with commercialisation of the validation batches.
Retrospective validation
Existing process(es) in use but no formally documented process validation
- Not acceptable
Traditional approach
Prospective Process Validation
Normally performed when the pharmaceutical development and/or process
development is concluded, after scale-up to production scale and prior to
marketing of the finished product.
statistically sound number of PV batches,
No. of batches depends on Process variability, complexity of the process/ product
and experience of manufacturer but should generally be a minimum of 3 batches.
PV protocol includes Critical Quality Attributes, Critical Process Parameter and non
CQA, non CPP to be monitored, etc.
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Continuous process verification approach-
An alternative approach to Traditional process validation in which
manufacturing process performance is continuously monitored and
evaluated. (ICH Q8)
May be applicable for product developed by Quality by design (QbD),
Continuous process
Required scientific control strategy,
Involve monitoring of critical processing steps, and end point testing
of current production, to show that manufacturing process is in state
of control
Hybrid approach
Apply Traditional and Continuous verification approach for different
steps
PIC/S EU GMP :Annex 15
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Design space verification
Normally developed at laboratory or pilot scale.
During scale-up, commercial process is conducted and validated in a specific
area of the design space, defined as the target interval or Normal Operating
Range (NOR).
During product lifecycle, moving from one area to another within the design
space (i.e. change in the NOR) may represent higher or unknown risks not
previously identified during initial establishment of the design space.
For this reason and depending on how the design space was originally
established and how the process was validated, there will be situations where it
will be necessary to confirm the suitability of the design space and verify that all
product quality attributes are still being met in the new area of operation within
the design space.
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Other requirements prior to PV
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On-going Process Verification
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Manufacturing processes requiring validation
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Process Validation :
What to validate and when?
may include:
specific addition sequences,
mixing speeds,
time and temperature controls,
limits of light exposure,
containment and cleaning procedures.
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§ 2.3.3 Prospective studies
Aseptic Process Validation:
Prospective studies
Product Prospective
IQ/OQ of new simulation process
or renovated validation with
facilities studies
original product
(Media Fills)
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§ 2.3.4 Concurrent validation
Aseptic Process Validation:
Concurrent validation
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§ 2.3.5 RE-VALIDATION
Formulation
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