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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?