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Process validation

Wondiyfraw Worku,


6th CPH assessment training workshop

May 2014

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

 Objectives of assessment of quality part
 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

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)

Process validation
Traditional vs new paradigm
Development- QbD
Basic Development and
Pilot batch
Post manufacturing
ange Continuous and
controls/risk extensive monitoring Control
analysis Process of CQAs and CPPs Strategy
validation- 3 for each production
batches batch

and Q10
Latest guidelines
FDA, January 2011 WHO, Revised Annex 7 of EMA, February 2014
WHO GMP guide (draft for

Continuous process Continuous process Alternative approaches:

verification (CPV) verification (CPV) -Traditional approach
-Continuous process
-Hybrid approach
Process design and Initial Process design and initial CPV protocol to be supported
validation (process validation (initial process by extensive development
qualification- PPQ) are initial verification) are initial phases information and lab or pilot
phases of CPV of CPV scale data. Executed on each
production batch
No mention of number of Mentions data on at least Number of batches specified
batches for initial process three pilot or production for traditional approach
performance batches collected as part of - minimum of three production
qualification/validation (rather process design batches unless other wise
must be justified based on justified
overall product and process
Types of process validation and
dossier requirements
Prospective validation Concurrent validation Retrospective validation
Protocol reviewed and Protocol reviewed and Protocol does not need to
accepted, Product PQD; OR accepted, Product PQD be submitted
Protocol executed before
submission or PQ
Execute and finalize Execute and finalize Prepare product quality
process validation on the process validation on the review report on already
first three production first three production manufactured production
batches batches batches

Commercial batches to be Each validation batch can Applicable for submissions

released only after be validated and released. meeting criteria for
satisfactorily conclusion of Applicable for low demand established products as
process validation on three products (such as NTDs, described in Annex 4, TRS
batches orphan drugs or other 970
seasonal products)

Process validation- Role of assessment

Design Operational Performance Process

qualification qualification qualification validation



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

Example: risk matrix for low dose capsule (CQA vs
process stages)
Sifting/sizing blending lubrication Capsule
Assay Low Medium Medium Medium

Content High High High High


Dissolution Low Low High Low

Stability Low Low Low Low

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
• e.g. sifting stage, wet and dry granulation stages
 observations serve as feedback for future refinement of process

 In addition, where feasible, sampling and testing should be

• 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

Validation scheme- example
Processing steps Critical parameters Validation scheme
Dispensing Weight checks Monitored
Sifting Mesh size Monitored
Wet Granulation and drying Amount and addition rate of Monitored, Drying uniformity to
granulating agent, mixing speed, be tested
time, as well as sequence of
Dry Granulation Slugging /compaction parameters Monitored only or Monitored and
Blending mixing speed, time Monitored; Blend uniformity to be
Lubrication mixing speed, time Monitored; Blend uniformity from
mixer and bulk container
Compression Initial set up parameters, Monitored; Several samples to be
speed, applied pressure, sampled and tested for IPQC
Fluidized bed coating Spray rate, inlet and product Monitored; appearance, weight
temp, etc… gain and full testing
Primary packaging, protocol Sealing temperature, speed Monitored; leak test
requested on case by case basis

Monitoring- Example:
BMR Set Batch 1 Batch 2 Batch 3

e.g. of Cycle 1 Cycle 2 Cycle 1 Cycle 2 Cycle 1 Cycle 2

Roller 8-15 10 10 10 10 10 10
Roller 40-60 41-42 42-43 41-43 41-42 41-42 41-43
Vertical 50-100 75 75 75 75 75 75
feed screw

Horizontal 10-20 15 15 15 15 15 15
feed screw

 Any comment vis à vis the difference between BMR set range and actual
applied inputs?

Example: Monitoring and sampling:

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 65 65 80

(min) (for

Sampling and 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

Blend uniformity
 Early check for content uniformity of the final dosage form

Uniform blend
with good flow Compression with Tablets meeting
and optimum criteria for
compressibility conditions uniformity of
characteristics dosage units

Note: Blend uniformity is a routine test for low dose products (i.e.
active load <=5% or 5mg)

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

Blend uniformity- Sample size

 What is an acceptable amount for samples taken at each location?

C. Morten, PIAT programme, University of Manchester

 Normally 1-3 time of the FPP unit dose weight

Blend 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

 Rarely (in case of very low dose products)

 Individual assays: 85.0-105.0% of the label claim/mean value, RSD: NMT
 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

Sampling and testing plan- Lubrication- example

Sample Sample size Sample Tests Acceptance

location analysed limits
Lubrication 10 position 850-2550mg 10 Individual Blend Mean: 95.0-
from in triplicate samples uniformity 105.0%,
Octagonal individual:
blender and 90-110%,
blend RSD: NMT
container 5%
Samples 50gm Composite Complete As per blend
from top, samples analysis as spec
middle and per routine
bottom blend spec
Particle size For
What are the distribution, information
Do you agree with missing
minimum tests we bulk and
expect to see in
the acceptance parameter?
blend spec? criteria? density

 Good compression outcome is a measure of (it depends
 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

Compression – Sampling frequency and size

 depends on the length of the run time/

batch size
we expect frequent sampling than the normal IPQC
the number of tablets/capsules taken should be
greater than those taken during a normal IPQC

Compression- Challenge studies
 Certain variations in
compression speed and
hardness than the target set
points may happen
 what would be the impact of such
 speed affects dwell time- which
intern affects several tablet
parameters (thickness, hardness,
as well as weight variation)

 Therefore, robustness should be

C. Morten, PIAT programme, University of Manchester

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 About 300 tablets
minutes; others every 1 hour About 300 tablets
(at least 3 times)
All in process parameters at -
start, middle and end of About 360 tablets
compression (different
hopper fill levels)
Additional samples at high, - About 480 samples
low speed; at high and low
hardness levels
Total number of tablets 300 tablets 1140 tablets

How to demonstrate consistency?

3 sigma
e.g. 4 sigma
Process validation-oral solutions

 Validation focuses on
 mixing time and conditions to clear solution, if deemed
• bulk liquids: pH, specific gravity, clarity of solutions;
 filling process
• filled units:- Volume/Wt variation and as per FPP specs

 Protocol with commitment is acceptable at the

time of review

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

Process validation- sterile products

Products mfd by Products mfd by

Terminal sterilization Aseptic processing
Container and - Depyrogenation by - Depyrogenation by
component sterilization tunnel depyrogenator washing- for stoppers,
and depyrogenation (e.g. ampoules) or seals, accessories*
washing (e.g. rubber - Validation of steam
stoppers, plastic sterilization – for
bottles) stoppers, seals,
- Dry heat sterilization
and depyrogenation-
for glass vials or

Process validation- sterile products-Contd
Products mfd by Products mfd by Aseptic
Terminal sterilization processing
Product sterilization Terminal sterilization by Filter validation (as part of
Steam sterilization, dev’t pharm)
radiation or ETO (as
Process simulation - Media fill
Full batch processing 3 production batches mfd 3 production batches mfd
(other aspects of the mfg at proposed scale at proposed scale
process, e.g. valdn of bulk (commitment may also be
prepn, filling and sealing accepted).
*validation should be on three runs to demonstrate reproducibility.

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
Comparison with historical biobatch profile, with
calculation of f2 (as necessary), should be performed
and results discussed

 Check if the protocol includes adequate


Matrixing/bracketing approach
 Multiple strengths of same product (common
 until stages of final granules: 3 consecutive batches of the
common blend (instead of 3 separate blend batches for each
 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

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.

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

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?

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?

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

Thank you, Questions?