1 6 th cph assessment training workshop may 2014 wondiyfraw worku, assessor process validation
TRANSCRIPT
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6th CPH assessment training workshopMay 2014
6th CPH assessment training workshopMay 2014
Wondiyfraw Worku,
Assessor
Process validationProcess validation
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Talk pointsTalk points Objectives of review of quality(CMC) data- reminder
Process validation, definition and current approaches
Role of dossier assessment in process validation
Risk assessment as part of process validation
Validation scheme: Monitoring and Sampling
Specific topics: Blend uniformity and validation of compression step
Process validation: other dosage forms
Process validation commitment
Retrospective validation
Summary: How to review protocol and report
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ReminderReminder
Objectives of assessment of quality partTo provide the highest assurance that all production
batches (unit doses) will be consistently efficacious as the clinical batch(es)
To reduce risk to safety via the highest assurance of acceptable and consistent quality of the product and its components
Process validation
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Process validationProcess validationThe collection and evaluation of data, from the process
design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA)
Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO)
The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.(EMA)
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Process validationTraditional vs new paradigm
Process validationTraditional vs new paradigm
Post approval
changes/change
controls/risk analysis
Development- Basic
Process validation- 3
batches
Pilot batch manufacturing
Enhanced-Development and
process qualification
Control Strategy
Continuous and extensive monitoring of CQAs and CPPs for each production
batch
ICH Q9 and Q10
ICH Q8, QbD
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Latest guidelinesLatest guidelinesFDA, January 2011 WHO, Revised Annex 7 of
WHO GMP guide (draft for comment)
EMA, February 2014
Continuous process verification (CPV)
Continuous process verification (CPV)
Alternative approaches: -Traditional approach-Continuous process verification-Hybrid approach
Process design and Initial validation (process qualification- PPQ) are initial phases of CPV
Process design and initial validation (initial process verification) are initial phases of CPV
CPV protocol to be supported by extensive development information and lab or pilot scale data. Executed on each production batch
No mention of number of batches for initial process performance qualification/validation (rather must be justified based on overall product and process understanding)
Mentions data on at least three pilot or production batches collected as part of process design
Number of batches specified for traditional approach- minimum of three production batches unless other wise justified
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Types of process validation and dossier requirements
Types of process validation and dossier requirements
Prospective validation Concurrent validation Retrospective validation
Protocol reviewed and accepted, Product PQD; OR Protocol executed before submission or PQ
Protocol reviewed and accepted, Product PQD
Protocol does not need to be submitted
Execute and finalize process validation on the first three production batches
Execute and finalize process validation on the first three production batches
Prepare product quality review report on already manufactured production batches
Commercial batches to be released only after satisfactorily conclusion of process validation on three batches
Each validation batch can be validated and released.Applicable for low demand products (such as NTDs, orphan drugs or other seasonal products)
Applicable for submissions meeting criteria for established products as described in Annex 4, TRS 970
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Process validation- Role of assessment Process validation- Role of assessment
Design qualification
Operational qualification
Performance qualification
Process validation
GMP
Dossier
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Process validation phasesProcess validation phases
Pre-validation phase
Protocol Preparation
Information from product
development studies
(identification of critical attributes)
Information from
primary/clinical manufacturing
(scale up information)
Process risk assessment information
(identification of critical
steps)
Validation phaseProtocol execution
Post valdn phase:Review of process, deviations, failures,
need for improvement,
scale up etc…
Includes demonstration of
content uniformity of the clinical batch
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Risk assessmentRisk assessment
Part of process development and protocol preparation Risk matrix- usually as part of process development
• Critical quality attributes (CQA) vs processing stages, e.g. dissolution vs granulation
• CQA vs critical process parameters, e.g., dissolution vs kneading time Failure mode analysis- usually as part of process validation
To identify critical attributes, processes and parameters Informed validation
To establish control strategy
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Example: risk matrix for low dose capsule (CQA vs process stages)
Example: risk matrix for low dose capsule (CQA vs process stages)
Sifting/sizing blending lubrication Capsule filling
Assay Low Medium Medium Medium
Content uniformity
High High High High
Dissolution Low Low High Low
Stability Low Low Low Low
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Process steps to be validated Process steps to be validated
All steps that are generally considered critical (medium and high risk steps) should be monitored/scrutinized by summarizing actual process parameters applied and observations
recorded• e.g. sifting stage, wet and dry granulation stages
observations serve as feedback for future refinement of process parameters
In addition, where feasible, sampling and testing should be performed
• e.g. drying, mixing steps, compression, filling• results measure effectiveness and consistency of the immediate as well
as preceding steps- e.g. final blend characteristics are mainly shaped by wet/dry granulation process
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Validation scheme- exampleValidation scheme- exampleProcessing steps Critical parameters Validation scheme
Dispensing Weight checks Monitored
Sifting Mesh size Monitored
Wet Granulation and drying Amount and addition rate of granulating agent, mixing speed, time, as well as sequence of events
Monitored, Drying uniformity to be tested
Dry Granulation Slugging /compaction parameters
Monitored only or Monitored and sampled?
Blending mixing speed, time Monitored; Blend uniformity to be established
Lubrication mixing speed, time Monitored; Blend uniformity from mixer and bulk container
Compression Initial set up parameters,speed, applied pressure,
Monitored; Several samples to be sampled and tested for IPQC parameters
Fluidized bed coating Spray rate, inlet and product temp, etc…
Monitored; appearance, weight gain and full testing
Primary packaging, protocol requested on case by case basis
Sealing temperature, speed Monitored; leak test
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Monitoring- Example:Compaction
Monitoring- Example:Compaction
Any comment vis à vis the difference between BMR set range and actual applied inputs?
BMR Set parameters
Batch 1 Batch 2 Batch 3
e.g. of parameters
Cycle 1 Cycle 2 Cycle 1 Cycle 2 Cycle 1 Cycle 2
Roller speed (RPM)
8-15 10 10 10 10 10 10
Roller pressure (Bars)
40-60 41-42 42-43 41-43 41-42 41-42 41-43
Vertical feed screw (RPM)
50-100 75 75 75 75 75 75
Horizontal feed screw (RPM)
10-20 15 15 15 15 15 15
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Example: Monitoring and sampling:Drying
Example: Monitoring and sampling:Drying
Monitoring Set parameter Observation
Batch X Batch Y Batch Z
Inlet temperature 60+/-10oC 62-65 52-63 52-60
Outlet temp 29-44 31-47 28-36
Total drying time (min) (for information)
65 65 80
Sampling and testing
Spec Batch X Batch Y Batch Z
Location 1 0.75-2.25% 1.54 1.53 1.70
Location 2 1.94 2.01 1.80
Location 3 2.03 1.30 2.05
Location 4 1.89 1.87 2.20
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Blend uniformityBlend uniformity
Early check for content uniformity of the final dosage form
Uniform blend with good flow
and compressibility characteristics
Compression with optimum
conditions
Tablets meeting criteria for
uniformity of dosage units
Note: Blend uniformity is a routine test for low dose products (i.e. active load <=5% or 5mg)
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Blend uniformity- Sampling location and method
Blend uniformity- Sampling location and method
Sampling location -usually predetermined as part of qualification of the mixer (i.e. mostly GMP issue)
But, in the dossier, we at least check if periphery, center positions and various other positions are considered
Samples from each location are usually taken in triplicate
Samples should also be taken from the blend container- to evaluate impact of transfer
important for low dose products and particularly for DC processed blend
Sampling should be done consistently and in away that does not disturb the bulk blend state – such aspects (e.g. type of sampling thief used) are better addressed at the time of inspection
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Blend uniformity- Sample sizeBlend uniformity- Sample size
What is an acceptable amount for samples taken at each location?
Normally 1-3 time of the FPP unit dose weight
C. Morten, PIAT programme, University of Manchester
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Blend uniformity- acceptance criteriaBlend uniformity- acceptance criteria
Commonly used criteria Individual assays: 90.0-110.0% of label claim, RSD NMT 5.0%
Less common Individual assays:90.0-110.0% of the mean value, RSD NMT 5.0%
• In this case, setting mean = 95.0-105.0% of the label claim appears reasonable
Rarely (in case of very low dose products) Individual assays: 85.0-105.0% of the label claim/mean value, RSD: NMT
5.0% May be acceptable provided that uniformity of dosage units is
satisfactorily demonstrated on tablets/capsules manufactured from blend lot with close to limit blend uniformity results
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Sampling and testing plan- Lubrication- exampleSampling and testing plan- Lubrication- example
missing parameter?
Do you agree with the acceptance
criteria?
Sample location
Sample size Sample analysed
Tests Acceptance limits
Lubrication 10 position from Octagonal blender and blend container
850-2550mg in triplicate
10 Individual samples
Blend uniformity
Mean: 95.0-105.0%, individual: 90-110%, RSD: NMT 5%
Samples from top, middle and bottom
50gm Composite samples
Complete analysis as per routine blend spec
As per blend spec
Particle size distribution, bulk and tapped density
For informationWhat are the
minimum tests we expect to see in
blend spec?
Acceptable?
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CompressionCompression
Good compression outcome is a measure of (it depends on):-Granule/powder mix properties
• bulk and tapped density-granulation• particle size and particle size distribution-granulation• moisture content- drying• extent of lubrication- lubrication time
Machine and tooling attributes• appropriate selection and adequate lubrication of punches
and dye • machine speed• applied compression pressure
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Compression – Sampling frequency and sizeCompression – Sampling frequency and size
depends on the length of the run time/ batch sizewe expect frequent sampling than the normal IPQC
frequencythe number of tablets/capsules taken should be
greater than those taken during a normal IPQC sampling
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Compression- Challenge studiesCompression- Challenge studies
Certain variations in compression speed and hardness than the target set points may happen what would be the impact of such
variations? speed affects dwell time- which
intern affects several tablet parameters (thickness, hardness, as well as weight variation)
Therefore, robustness should be demonstrated
C. Morten, PIAT programme, University of Manchester
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Extensive sampling- example(there are several other approaches)
Extensive sampling- example(there are several other approaches)
IPQC testing schedule Normal production batch Validation batches
48 station machine, batch size of 170,000 tabs, target speed 25rpm
Group weight and appearance, every 30 minutes; others every 1 hour (at least 3 times)
About 300 tabletsAbout 300 tablets
All in process parameters at start, middle and end of compression (different hopper fill levels)
-About 360 tablets
Additional samples at high, low speed; at high and low hardness levels
- About 480 samples
Total number of tablets sampled
300 tablets 1140 tablets
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How to demonstrate consistency?How to demonstrate consistency?
3 sigma process
e.g. 4 sigma process
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Process validation-oral solutionsProcess validation-oral solutions
Validation focuses on mixing time and conditions to clear solution, if deemed
relevant • bulk liquids: pH, specific gravity, clarity of solutions;
assayfilling process
• filled units:- Volume/Wt variation and as per FPP specs
Protocol with commitment is acceptable at the time of review
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Process Validation- Oral suspensionsProcess Validation- Oral suspensions
Focuses on API micronization processes (if applicable) colloidal milling process (as applicable), homogenization filling
• Viscosity, fill volume/weight variation, • Other critical attribute that may be affected by filling process?• Other parameters as per FPP spec including, PSD, pH, dissolution,
Protocol with commitment is acceptable at the time of review
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Process validation- sterile productsProcess validation- sterile products
Products mfd by Terminal sterilization
Products mfd by Aseptic processing
Container and component sterilization and depyrogenation
- Depyrogenation by tunnel depyrogenator (e.g. ampoules) or washing (e.g. rubber stoppers, plastic bottles)
- Depyrogenation by washing- for stoppers, seals, accessories*
- Validation of steam sterilization – for stoppers, seals, accessories*
- Dry heat sterilization and depyrogenation- for glass vials or ampoules*
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Process validation- sterile products-ContdProcess validation- sterile products-Contd
Products mfd by Terminal sterilization
Products mfd by Aseptic processing
Product sterilization Terminal sterilization bySteam sterilization, radiation or ETO (as applicable)*
Filter validation (as part of dev’t pharm)
Process simulation - Media fill
Full batch processing (other aspects of the mfg process, e.g. valdn of bulk prepn, filling and sealing quality)
3 production batches mfd at proposed scale
3 production batches mfd at proposed scale (commitment may also be accepted).
*validation should be on three runs to demonstrate reproducibility.
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Dissolution profile comparison with clinical/BE batch- solids and suspensions (as part of process validation) Dissolution profile comparison with clinical/BE batch- solids and suspensions (as part of process validation)
A good check point to verify performance relative to the biobatchAll validation batches should be profiled in the routine
media on 12 units, using time points as used for biobatch
Comparison with historical biobatch profile, with calculation of f2 (as necessary), should be performed and results discussed
Check if the protocol includes adequate instruction/provision
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Matrixing/bracketing approachMatrixing/bracketing approach
Multiple strengths of same product (common blend)until stages of final granules: 3 consecutive batches of the
common blend (instead of 3 separate blend batches for each strength)
compression: 3 consecutive batches of each strength
Primary packaging of tablet/capsule productsblistering of hygroscopic or moisture sensitive products
however should always be individually validated
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Process validation- commitmentProcess validation- commitment
As described in Annex 4, TRS 970, applicants are not expected to have process validation data before PQIn this case satisfactory PV protocol (PVP) and
appropriately worded commitment are essential PVP or signed commitment letter should clearly
indicate the need for prospective validation as finalized on three consecutive production batches, unless other wise justified.
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Retrospective validation for established productsRetrospective validation for established products
Generally acceptable if condition described in Annex 4, TRS 970 (generic guide), are met.
Tries to demonstrate process effectiveness and consistency via trend analysis:extent of deviationsextent of OOS or OOTextent of batch rejectionextent of product complainsextent of changes/ improvements introducedSee Appendix 2 of Annex 4, TRS 970
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Review of protocol- main aspects to checkReview of protocol- main aspects to check Scope of the validation (type, batch size, reason)- do they reflect the
planned validation? Highest batch size to be validated?
Major equipments identified (in line with BMR) and a provision for recording their Q status included?
Reference to current master production record included?
Summary of critical steps identified? is this convincing ?
Monitoring and sampling plan provided?- Do you agree with the steps monitored/sampled?
Sampling schedule, schematics, tests and acceptance criteria, as well as current specification codes included ? Are these acceptable?
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Review of protocol- main aspects to check-contdReview of protocol- main aspects to check-contd
For solid orals: final blending, compression/encapsulation, coating stages must be adequately sampled and tested. Are these being reflected?
Blend uniformity: Sampling schemes and blend uniformity acceptance criteria specified? Are these acceptable?
Compression/encapsulation at lower, target and upper speeds included?
Provision for performance of dissolution profile testing and comparison with the biobatch included?
Appropriate commitment (prospective validation on first three consecutive batches mentioned) provided?
Protocol reference and version number included in QIS?
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Review of validation reportReview of validation report
Is the reported data relevant for the proposed manufacturing process and scale
equipment used, process parameters applied
All critical steps adequately monitored/sampled?
Level of sampling and size are acceptable?
All results within acceptable limits? Particular trend?
Deviations appropriately evaluated and discussed?
Is the overall process in sufficient control? Is there any thing that should be improved or refined for future production batches
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Thank you, Questions?