Stage 3 - Process Validation: Measuring what matters · FDA (& EU) Process Validation Stages Stage...

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Stage 3 - Process Validation: Measuring what matters

Trevor Schoerie - PharmOut


A quote….

“The company that fails is the company that comes to us and says “Just tell us what to do and we will do it.”

“The company that succeeds is the company that says to us “Here is what we did and why we think it is appropriate.”

Dr. Phillip Minor

National Institute of Biological Standards and Control

A science and risk based approach


What the current GMPs say

PIC/S, EU GMPs

§1.1 v. all necessary controls on intermediate products, and any other in process controls and validations are carried out.

CFR 211.110(a)

Sampling and testing of in-process materials

and drug products.

To assure batch uniformity … in-process materials…. Such control procedures shall … monitor the output and to validate… responsible for causing variability…


What the current GMPs say – EU/PIC/S

§1.2 ii. critical steps of manufacturing processes and significant changes to the process are validated;

§1.2 iii. all necessary facilities for GMP are provided including:

a. appropriately qualified and trained personnel; people*

b. adequate premises and space; environment*

c. suitable equipment and services; machines*

d. correct materials, containers and labels; materials*

e. approved procedures and instructions; methods*

f. Suitable storage and transport;

*fishbone (+measurements)


What the current GMPs say - FDA

CFR 211.110(a)

…. such control procedures shall include, but

are not limited to, the following, where appropriate:

1. Tablet or capsule weight variation;

2. Disintegration time;

3. Adequacy of mixing to assure uniformity and homogeneity;

4. Dissolution time and rate;

5. Clarity, completeness, or pH of solutions.


Lifecycle concept, but QbD is at the start of the product lifecycle, i.e. product design, R&D

FDA Process Validation - 3 stages

1. Process Design (QbD & DOE)

2. Process Qualification

3. Continued Process Verification

FDA Process Validation?


EU GMP Guide Annex 15 “Qualification & Validation”

Concurrent Validation

• May be acceptable in exceptional circumstances "where there is a strong risk – benefit to the patient"

Traditional Approach

• Produce a number of batches under routine conditions, confirming reproducibility

Continuous Process Verification

• Science-based control strategy

Hybrid Approach

• The “Traditional Approach” and “Continuous Process Verification” together


EU GMP Guide Annex 15 “Qualification & Validation

Design Space


Focus of FDA Process Validation Guideline

Variable or variability - Mentioned 19 times

Control - Mentioned 62 times

Statistics - Mentioned 15 times

What is the goal?

Inputs and OutputsFishbone Model


FDA (& EU) Process Validation Stages

Stage 1 – Process Design: The process is defined during this stage based on knowledge gained through development and

scale-up activities.

Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

Identify sources of Variability

Control of Variability

Monitoring Variability - remains “in control”


LifecycleLe

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Time / Product & Process Knowledge

ProcessDesign

PV(PPQ)

CommercialManufacturing

Could vary

based on approach Variability

Estimate Established

Post Periodic Review Signal

Change introduced /

CAPA

PAT Implemented

Monitoring

QC Testing

Control Strategy is dynamic over the lifecycle


3 Stages - Generic Acetriptan Tablets

Define the Quality Target Product Profile

(QTPP)

Identify the CQAs

Define Process Steps & CPPs

Create a Control Strategy

Stage 1

Implement the Control Strategy

Qualify Facility, Utilities,

Systems and Equipment

Process Validation

(PPQ)

ContinuedProcess

Verification

Stage 2

Stage 3Science and Risk-based Approach at

all Stages of Lifecycle


Quality Risk Management (QRM)

Begin the QRM Process

Risk Identification

Risk Analysis

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Assessment

Risk Control

Output of the QRM Process

Review Events

Risk Review

QRMTools

Risk C

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nICH Q9

Product & Process Development


Initial RA of the formulation variables

DP CQAsDrug

SubstancePSD

MCC/ Lactose

Ratio

CCS Level TalcLevel

Mag. Stearate

Level

AssayMedium Medium Low Low Low

Content UniformityHigh High Low Low Low

DissolutionHigh Medium High Low High

Degradation Products Low Low Low Low Medium

High Risk is unacceptable. Further investigation is needed to reduce the risk.

Medium Risk is acceptable. Further investigation may be needed in order to reduce the risk.

Low Broadly acceptable risk. No further investigation is needed.


Design of Experiments (DoE)

• A designed experiment allows understanding of how input variables are related to output variables

• Experimental units are units to which one treatment is assigned or applied

• Input variables are called factors-controlled independent variables whose levels are set by the experimenter

• Levels of a factor are the settings that are tested in an experiment

Input Process Output


Defining CPPs

Process Variable

Can variable be

controlled?

NO

Process Performance

Attribute

Product Quality Attribute

OR

Process Input

YES

Potential Impact to

CQAs?

NOYESPotentially

a CPPPotentially NOT a CPP

Risk Assessment.

CPP?

YESCritical Process Parameter

NO

Key Process Parameter

Non-Key Process Parameter

OR


Equipment & fixed process parameters used in the formulation studiesProcess Step Equipment

Pre-Roller Compaction Blending and Lubrication

4 qt V-blender • 250 revolutions for blending (10 min at 25 rpm)

Roller Compaction and Integrated Milling

Alexanderwerk WP120 with 25 mm roller width and 120 mm roller diameter • Roller surface: Knurled • Roller pressure: 50 bar • Roller gap: 2 mm • Roller speed: 8 rpm • Mill speed: 60 rpm • Coarse screen orifice size: 2.0 mm • Mill screen orifice size: 1.0 mm

Final Blending and Lubrication

4 qt V-blender • 100 revolutions for granule and talc blending (4

min at 25 rpm) • 75 revolutions for lubrication (3 min at 25 rpm)

Tablet Compression 16-station rotary press (2 stations used) • 8 mm standard round concave tools • Press speed: 20 rpm • Compression force: 5-15 kN • Pre-compression force: 1 kN


Tablet Compression Process Development

Effect of Main Compression Force, Press Speed and Ribbon Relative Density:

• Compression force and press speed (related to dwell time) can affect numerous quality attributes including hardness, disintegration, dissolution, assay, content uniformity, friability, weight variability & appearance.

• The density of the ribbon following roller compaction may also impact the compressibility and compactability of the granules which would then impact tablet hardness & dissolution.



A 23 full factorial DoE with three centre points was performed to understand the effects of these parameters on tablet quality attributes

Factors: Formulation VariablesLevels

-1 0 +1

A Main compression force (kN) 5 10 15

B Press Speed (rpm) 20 40 60

C Ribbon relative density (no units) 0.68 0.75 0.81

The press was run at the speed of the specified DOE for at least five minutes prior to any sampling. Tablet samples were then pulled at the beginning, middle and end of each run (except one Batch which was sampled every 20 min).



• The results obtained from the development work identify acceptable ranges

• Feeder frame paddle speed (8-20rpm)

• Press speed (20-60rpm)

• The data also allows potential In-Process Controls to be identified for the compression step:

Test Frequency Limits

Individual tablet weight (n =10) 30 min 200.0 mg ± 10.0 mg

Composite tablet weight (n =20) 30 min 4.00 g ± 0.12 g

Hardness (n = 10) 30 min Target: 8.0-10.0 kP Limits: 5.0-13.0 kP

Thickness (n = 10) 30 min 3.00 mm ± 0.09 mm

Disintegration* (n = 6) 3 x per run NMT 5 min

Friability* (sample weight = 6.5 g) 3 x per run NMT 1.0%


Scale-Up from Lab to Pilot Scale and Commercial Scale

• Scale-up information is usually limited at the time of submission.

• The principles of scale-up should be detailed as part of a planned approach.

• It is the firm’s discretion to submit scale-up data such as actual process verification information at the time of submission for a complex drug product which has a high risk of scale-up failure.

Scale Batch Size Units

Development (Lab) 5Kg 25,000

Pilot (Exhibit) 50Kg 250,000

Commercial (Proposed) 150Kg 750,000


Scale-Up of the Roller Compaction & Integrated Milling Process

Several process parameters to consider when scaling up to a larger, wider roller. The strategy employed should be documented.

• Roller Gap, Roll Force or Roll Pressure

• Screw Speed and Roll Speed

• Mill Screen Size and Mill Speed

Scale Model Roller width (mm)

Roller diameter

(mm)

Roller Gap (mm)

RollerPressure

(bar)

Mill screen orifice (mm)

Lab WP120 25 120 1.2-2.4 20-77 1.0

Pilot WP120 40 120 1.8 50 1.0

Commercial WP200 75 200 2.0-2.4 31-121 1.0


Initial Risk Assessment of the Manufacturing Process

DP CQAsPre-RC

Blending & Lubrication

Roller Compaction

MillingFinal

Blending &

Lubrication

Compression

AssayLow Low* Low Low* Low

Content UniformityLow Low Low Low* Low

DissolutionLow Low Low Low Low

Degradation Products Low* Low* Low* Low* Low*

High risks identified during developmentScientific knowledge & understanding gained Appropriate controls developed to reduce risk to an acceptable level documented

*The level of risk was not reduced from the initial risk assessment


Other items for consideration

Container Closure system:

• Round white opaque HDPE bottles with an induction seal liner and child resistant (CR) closure

• Labelled for storage at 25°C with excursions permitted to 15-30 °C

Microbiological Attributes:

• An accelerated stability study of the exhibit batch demonstrated that the drug product has low water activity and is not capable of supporting microbial growth. Routine testing of tablets unnecessary


Control Strategy

• Built up based on previous knowledge and the outcome of extensive product & process studies

• Investigation of material attributes and process parameters that were deemed high risk to the CQAs of the DP during initial risk assessment

• Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) were determined

• Acceptable Operating Ranges were identified

• All variables that were deemed high risk are included in the control strategy

• Can be further refined as process knowledge increases over time

Create a Control Strategy




Risk Identification

Risk Analysis

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Assessment

Risk Control


Review Events

Risk Review

QRMTools

Risk C

om

mu

nicatio

nICH Q9

Control Strategy Development


Control Strategy Examples

Factor Attributes or

Parameters

Range Studied

Actual data for the exhibit batch

Proposed range for

commercial scale

Purpose of control

Raw Material Attributes

Acetriptan particle size distribution*

d90 10-45 μm 20 μm 10-30 μm To ensure in vitro dissolution, in vivo performance and batch-to-batch consistency

d50 6-39 μm 12 μm 6-24 μm

d10 3.6-33.4 μm 7.2 μm 3.6-14.4 μm

Talc, Grade D04

Particle size distribution

> 75μm: NMT 0.2%

> 75μm: 0.1%

>75μm: NMT 0.2%

To ensure batch-to-batch consistency

*Critical input Material Attributes (CMA)


Control Strategy Examples

Factor Attributes or

Parameters

Range Studied

Actual data for

the exhibit batch

Proposed range for

commercial scale

Purpose of control

Pre-Roller Compaction Blending and Lubrication In-Process Controls

Blend uniformity*

Blend to endpoint: < 5.0% RSD (In-line NIR method) In-line NIR method is used for endpoint determination to ensure BU is met consistently

Tablet Compression Process Parameters

Rotary press Feeder frame paddle speed

8-20 rpm 15 rpm 8-20 rpm To ensure all tablet CQAs are met consistently

*critical process parameter (CPP)


Stage 2 Process Qualification

• Demonstrate that the process is capable of reproducible commercial manufacture

• It should be completed before product is released commercially

• Two parts to this Stage:

Design & Qualification

of FSE

Process Performance Qualification

Product that meets predetermined quality

attributes


Process Validation

• Demonstrates the validity of the process design and the suitability of the process control strategy

• At full-scale (commercial manufacture)

• Provides confidence (documented evidence) that systems of monitoring, control and SOPs in production are capable of detecting and compensating for potential sources of process variability over the product lifecycle

• The number of PV batches to be produced should be justified


Knowledge vs # of PV batches

Prior Knowledge Process Design

Prior Knowledge

PV

Process Design PV

Comprehensive Prior Knowledge may support fewer PV batches

Limited Prior Knowledge may require more PV batches


Stage 3 (a) and (b)How many PPQ batches?

This depends on the risk and the following elements could be applied to make the decision:

Rationale and experience-based justifications

Based on Target Process Confidence and Target Process Capability

Based on expected coverage




Risk Identification

Risk Analysis

Risk Evaluation

Risk Reduction

Risk Acceptance

Risk Assessment

Risk Control


Review Events

Risk Review

QRMTools

Risk C

om

mu

nicatio

nICH Q9

Continual Improvement


Maintenance of the Validated State

• “Continued Process Verification”

• Change in the validated state of the process could impact product

• Monitored via:

• Change Control

• Periodic Monitoring

• Data Trending Review

• Calibration and PM

• Knowledge of operational parameters (Control Strategy) and Design Space (if applicable)


Thank you for your time.Questions?

Trevor Schoerie

[email protected]

www.pharmout.net

Executive Consultant

Stage 3 - Process Validation: Measuring what matters · FDA (& EU) Process Validation Stages Stage...

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Transcript of Stage 3 - Process Validation: Measuring what matters · FDA (& EU) Process Validation Stages Stage...