1. 6th CPH assessment training workshop May 2014
Process validation
Wondiyfraw Worku,
Assessor
6th CPH assessment training workshop May 2014

2. Talk 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

3. Reminder Objectives of assessment of quality part Process validation
To 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

4. Process validation
The 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)

5. Process validation Traditional vs new paradigm
ICH Q8, QbD
Development- Basic
Enhanced-Development and process qualification
Pilot batch manufacturing
Post approval changes/change controls/risk analysis
Process validation- 3 batches
Continuous and extensive monitoring of CQAs and CPPs for each production batch
Control Strategy
ICH Q9 and Q10

6. Latest guidelines FDA, January 2011
WHO, Revised Annex 7 of WHO GMP guide (draft for comment)
EMA, February 2014
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

7. 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
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

8. Process validation- Role of assessment
Operational qualification
Design qualification
Performance qualification
Process validation
Dossier
GMP

9. Process validation phases
Includes demonstration of content uniformity of the clinical batch
Pre-validation phase
Protocol Preparation
Information from primary/clinical manufacturing (scale up information)
Process risk assessment information (identification of critical steps)
Validation phase
Protocol execution
Information from product development studies (identification of critical attributes)
Post valdn phase:
Review of process, deviations, failures, need for improvement, scale up etc…

10. Risk 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

11. Example: risk matrix for low dose capsule (CQA vs process stages)
Sifting/sizing
blending
lubrication
Capsule filling
Assay
Low
Medium
Content uniformity
High
Dissolution
Stability

12. 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

13. Validation scheme- example
Processing steps
Critical parameters
Validation scheme
Dispensing
Weight checks
Monitored
Sifting
Mesh size
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
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

14. Monitoring- Example: Compaction
BMR Set parameters
Batch 1
Batch 2
Batch 3
e.g. of parameters
Cycle 1
Cycle 2
Roller speed (RPM)
8-15 10
Roller pressure (Bars)
40-60
41-42
42-43
41-43
Vertical feed screw (RPM)
50-100 75
Horizontal feed screw (RPM)
10-20 15
Any comment vis à vis the difference between BMR set range and actual applied inputs?
Normally, the protocol should require validation of the BMR range, but once validation is executed either the BMR set up parameters should be revised to reflect the validated range or set point or new validation should be done.

15. Example: Monitoring and sampling: Drying
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 80
Sampling and testing
Spec
Batch X
Batch Y
Batch Z
Location 1 %
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

16. Blend 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)

17. 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

18. Blend 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

19. Blend uniformity- acceptance criteria
Commonly used criteria
Individual assays: % of label claim, RSD NMT 5.0%
Less common
Individual assays: % of the mean value, RSD NMT 5.0%
In this case, setting mean = % of the label claim appears reasonable
Rarely (in case of very low dose products)
Individual assays: % 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

20. Sampling and testing plan- Lubrication- example
Sample location
Sample size
Sample analysed
Tests
Acceptance limits
Lubrication
10 position from Octagonal blender and blend container
mg in triplicate
10 Individual samples
Blend uniformity
Mean: %, individual: %, 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 information
What are the minimum tests we expect to see in blend spec?
Do you agree with the acceptance criteria?
missing parameter?
Acceptable?

21. Compression 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

22. Compression – Sampling frequency and size
depends on the length of the run time/ batch size
we expect frequent sampling than the normal IPQC frequency
the number of tablets/capsules taken should be greater than those taken during a normal IPQC sampling

23. Compression- 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

24. 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 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

25. How to demonstrate consistency?
i.e, in sigma process, the whole area within +/-3 of SD will be within spec limit, while in case of 4 sigma, +/4 SD of the curve area is within spec limit (and in this case Cpk is roughly equal to 1.33).
3 sigma process
e.g. 4 sigma process

26. Process validation-oral solutions
Validation focuses on
mixing time and conditions to clear solution, if deemed relevant
bulk liquids: pH, specific gravity, clarity of solutions; assay
filling process
filled units:- Volume/Wt variation and as per FPP specs
Protocol with commitment is acceptable at the time of review

27. Process 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

28. Process 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*

29. Process validation- sterile products-Contd
Products mfd by Terminal sterilization
Products mfd by Aseptic processing
Product sterilization
Terminal sterilization by
Steam 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.

30. 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 biobatch
All 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

31. Matrixing/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 products
blistering of hygroscopic or moisture sensitive products however should always be individually validated

32. Process validation- commitment
As described in Annex 4, TRS 970, applicants are not expected to have process validation data before PQ
In 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.

33. Retrospective 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 deviations
extent of OOS or OOT
extent of batch rejection
extent of product complains
extent of changes/ improvements introduced
See Appendix 2 of Annex 4, TRS 970

34. Review 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?

35. Review 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?

36. Review 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

37. Thank you, Questions?