Implementation of ICH Q8, Q9, Q10

Product Development:
Case Study Overview

International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human Use
 ICH Quality Implementation Working Group - Integrated Implementation Training Workshop

Product Development: Case Study Overview

Outline of Presentation
• Key Steps for Quality by Design
• Case Study Organization
• Introducing API and Drug Product
- Discussion of concepts of Quality Target Product Profile,
processes, composition

• Description of API & Drug Product process development

- Discussion of illustrative examples of detailed approaches from
the case study

• Batch release

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Key Steps
Product for a product
Development: under
Case Study Quality by Design (QbD)
Overview
Pharmaceutical Quality Target
Development QTPP : Definition of intended use & product
Product Profile

Prior Knowledge (science, GMP,

regulations, ..) CQA : Critical Potential CQA (Critical Quality Attribute) identified &
Quality Attribute CPP (Critical Process Parameters) determined
Product/Process Development
CPP : Critical Design to meet CQA using Risk Management &
DOE : Design of Experiment Process Parameter experimental studies (e.g. DOE)

Link raw material attributes and process parameters

QRM principle apply at any stage Risk Management to CQAs and perform Risk Assessment Methodology

Product/Process Understanding Opportunities Design Space (DS), RTR testing

Control Strategy Marketing Authorisation

Quality System PQS

Technology Transfer Commercial Manufacturing

PQS & GMP Batch Release Quality Unit (QP,..) level support by PQS
Local Environment Strategy

Continual Manage product lifecycle, including

improvement continual improvement
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Product Development: Case Study Overview

Purpose of Case Study

• Illustrative example
- Covers the concepts and integrated implementation of
ICH Q8, 9 and 10
- Not the complete content for a regulatory filing

Note: this example is not intended to represent the

preferred or required approach.

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Product Development: Case Study Overview

Case Study Organization

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Product Development: Case Study Overview

Basis for Development Information

• Fictional active pharmaceutical ingredient (API)
• Drug product information is based on the ‘Sakura’
Tablet case study
- Full Sakura case study can be found at
[Link]
• Alignment between API and drug product
- API Particle size and drug product dissolution
- Hydrolytic degradation and dry granulation /direct
compression
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Product Development: Case Study Overview

Organization of Content

• Quality Target Product Profile (QTPP)

• API properties and assumptions
• Process and Drug product composition overview
• Initial risk assessment of unit operations
• Quality by Design assessment of selected unit
operations

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Product Development: Case Study Overview

Technical Examples
Process focus Quality attribute focus

• API - Final crystallization step - Particle size control

• Drug Product - Blending - Assay and content uniformity

- Direct compression - Dissolution

API Real Time

Blending Compression Release testing
Crystallization
(Assay, CU, Dissolution)

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Product Development: Case Study Overview

Process Step Analysis

• For each example
- Risk assessment
- Design of experiments
- Experimental planning, execution & data analysis
- Design space definition
- Control strategy
- Batch release

QRM Design of Design Control Batch

Experiments Space Strategy Release

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Product Development: Case Study Overview

QbD Story per Unit Operation

QTPP Process Quality

& CQAs Variables Risk Management

Design of Design Control Batch

Experiments Space Strategy Release

Illustrative Examples of Unit Operations:

API Real Time
Blending Compression Release testing
Crystallization
(Assay, CU, Dissolution)

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Product Development: Case Study Overview

Introducing API and Drug Product

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Product Development: Case Study Overview

Assumptions
• API is designated as Amokinol
- Single, neutral polymorph
- Biopharmaceutical Classification System (BCS) class II – low solubility &
high permeability
- API solubility (dissolution) affected by particle size
- Degrades by hydrolytic mechanism

• In vitro-in vivo correlation (IVIVC) established – allows dissolution to be

used as surrogate for clinical performance

• Drug product is oral immediate release tablet

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Product Development: Case Study Overview

Assumptions & Prior Knowledge

• API is designated as Amokinol
- Single, neutral polymorph
- Biopharmaceutical Classification System (BCS) class II – low solubility &
high permeability
- API solubility (dissolution) affected by particle size
- Crystallization step impacts particle size
- Degrades by hydrolytic mechanism
- Higher water levels and elevated temperatures will increase degradation
- Degradates are water soluble, so last processing removal point is the
aqueous extraction step
- Degradates are not rejected in the crystallization step
• In vitro-in vivo correlation (IVIVC) established – allows dissolution to be
used as surrogate for clinical performance
• Drug product is oral immediate release tablet
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Product Development: Case Study Overview

Quality Target Product Profile (QTPP)
Safety and Efficacy Requirements
Translation into
Characteristics /
Tablet Quality Target Product Profile
Requirements
(QTPP)
Dose 30 mg Identity, Assay and Uniformity

No off-taste, uniform color, Appearance, elegance, size,

Subjective Properties
and suitable for global market unit integrity and other characteristics

Acceptable hydrolysis degradate levels

Impurities and/or degradates
Patient Safety – chemical purity at release, appropriate manufacturing
below ICH or to be qualified
environment controls

PSD that does not impact

Patient efficacy – Acceptable API PSD
bioperformance or pharm
Particle Size Distribution (PSD) Dissolution
processing

Chemical and Drug Product Degradates below ICH or to be qualified

Hydrolysis degradation & dissolution
Stability: 2 year shelf life and no changes in bioperformance
changes controlled by packaging
(worldwide = 30ºC) over expiry period

QTPP may evolve during lifecycle – during development and commercial manufacture - as new knowledge is
gained e.g. new patient needs are identified, new technical information is obtained about the product etc.

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Product Development: Case Study Overview Example from Case Study

API Unit Operations

Coupling Reaction Coupling of API Starting Materials

Removes unreacted materials. Done

Aqueous Extractions cold to minimize risk of degradation

Understand Distillative Removes water, prepares API

formation Solvent Switch for crystallization step
& removal of
impurities Semi Continuous Addition of API in solution and
Crystallization anti-solvent to a seed slurry

Centrifugal Filtration Filtration and washing of API

Drying off crystallization solvents

Rotary Drying

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Product Development: Case Study Overview

Tablet Formulation

Pharmacopoeial
or other
compendial
specification

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Product Development: Case Study Overview

Drug Product Process

API and Excipients
Amokinol
D-mannitol Blending
Calcium hydrogen phosphate hydrate
Sodium starch glycolate
Lubricant
Magnesium Stearate Lubrication

Compression
Coating
HPMC ， Macrogol 6000
titanium oxide Film coating
iron sesquioxide

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Product Development: Case Study Overview

Overview of API and Drug Product

Case Study Elements

Representative Examples from the full Case Study

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Product Development: Case Study Overview Example from Case Study

Overall Risk Assessment for Process

Process Steps

CQA

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Product Development: Case Study Overview

Overall Risk Assessment for Process

Process Steps

CQA

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Product Development: Case Study Overview

API Semi-Continuous Crystallization

• Designed to minimize hydrolytic degradation
(degradate below qualified levels)
- Univariate experimentation example
- FMEA of crystallization process parameters
> High risk for temperature, feed time, water level
- Test upper end of parameter ranges (represents
worst case) with variation in water content only and
monitor degradation
- Proven acceptable upper limits defined for above
parameters
Note that in this case study, the distillative solvent switch prior to
crystallization and crystallization itself are conducted at lower
temperatures and no degradation occurs in these steps
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Product Development: Case Study Overview

API Semi-Continuous Crystallization

• Designed to control particle size
- Multivariate DOE example leading to predictive model
- FMEA of parameters using prior knowledge
>High risk for addition time, % seed, temperature,
agitation
- DOE: half fraction factorial using experimental
ranges based on QTPP, operational flexibility & prior
knowledge
- Design space based on predictive model obtained by
statistical analysis of DOE data
• Particle size distribution (PSD) qualified in formulation
DOE and dissolution studies
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Product Development: Case Study Overview

Risk Assessment:
Particle Size Distribution (PSD) Control
What is the Impact that ------------- will have on PSD? 1) minimal 5) moderate 9) significant
What is the Probability that variations in ------------ will occur? 1) unlikely 5) moderately likely 9) highly likely
What is our Ability to Detect a meaningful variation in --------------- at a meaningful control point? 1) certain 5) moderate 9) unlikely

PR T
De .
t
C
OB
Unit Operation Parameter

tec
Comments

PA
RPN

IM
Prior knowledge (slowness of crystallization kinetics) ensures that the
hot crystallizer feed will be well dispersed and thermally equilibrated
Crystallization Feed Temperature 1 5 1 5
To be investigated
before crystallizing. Hence no impact of feed temp variation on
crystal size.
Crystallization Water content of Feed 1 5 5 25 in DOE
Prior knowledge (solubility data) shows that small variations in water
do not affect crystalliation kinetics.
Fast addition could result in uncontrolled crystallization. Detection of
Crystallization Addition Time (Feed Rate) 9 5 9 405 short addition time could occur too late to prevent this uncontrolled
crystallization, and thus impact final PSD.
Prior knowledge (Chemical Engineering theory) highlights seed wt
Crystallization Seed wt percentage 9 5 5 225
percentage variations as a potential source of final PSD variation
Yield loss to crystallization already low (< 5%), so reasonable
Crystallization Antisolvent percentage 1 1 1 1 variations in antisolvent percentage (+/- 10%) will not affect the
percent of batch crystallized, and will not affect PSD
Change in crystallization temperature is easily detected, but rated
Crystallization Temperature 9 5 9 405 high since no possible corrective action (such as, if seed has been
dissolved)
Prior knowledge indicates that final PSD highly sensitive to Agitation,
Crystallization Agitation (tip speed) 9 5 5 225
thus requiring further study.
Seed PSD controlled by release assay performed after air attrition
Crystallization Seed particle size distribution 9 1 1 9
milling.
Crystallization Feed Concentration 1 1 1 1 Same logic as for antisolvent percentage

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Product Development: Case Study Overview

Options for Depicting a Design Space

• Oval = full design space
represented by equation
Seed wt

• Rectangle represent ranges

- Simple, but a portion of the
%

design space is not utilized

- Could use other rectangles
Pressure

within oval
• Exact choice of above options
can be driven by business
Temperature
factors

Large square represents the ranges tested in the DOE.

Red area represents points of failure
Green area represents points of success.

• For purposes of this case study, an acceptable design space based on ranges was chosen

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Product Development: Case Study Overview

Options for Expanding a Design Space

• Why expand a Design Space?
- Business drivers can change, resulting in a
different optimum operating space

• When is DS Expansion possible?

- Case A: When the original design space
was artificially constrained for simplicity

Seed wt%
Temperature

- Case B: When some edges of the design

space are the same as edges of the

Seed Wt%
knowledge space
Temperature

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Product Development: Case Study Overview

API Crystallization:
Design Space & Control Strategy
• Control Strategy should address:
- Parameter controls
- Distillative solvent switch achieves target water content
- Crystallization parameters are within the design space
- Testing
- API feed solution tested for water content
- Final API will be tested for hydrolysis degradate
- Using the predictive model, PSD does not need to be
routinely tested since it is consistently controlled by the
process parameters

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Product Development: Case Study Overview Example from Case Study

Design Space / Control Strategy

Parameter controls & Testing
Particle Size Crystallization Temperature 20 to 30ºC Control between 23 and 27ºC

Particle Size Crystallization Feed Time 5 to 15 hours Control via flow rate settings

Quality system should ensure

Particle Size Crystallization Agitation 1.1 to 2.5 m/s changes in agitator size result in
change to speed setting

Controlled through weigh scales

Particle Size Crystallization Seed Wt% 1 to 2 wt%
and overcheck
Hydrolysis Distillation /
Water Content < 1 vol% Control via in-process assay
Degradate Crystallization

Particle size will be tested in this example, since the result is included
in the mathematical model used for dissolution.

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Product Development: Case Study Overview

Drug Product
• Immediate release tablet containing 30 mg Amokinol

• Rationale for formulation composition and process

selection provided

• In vitro-in vivo correlation (IVIVC) determination

- Correlation shown between pharmacokinetic data and
dissolution results
- Robust dissolution measurement needed
- For a low solubility drug, close monitoring is
important
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Product Development: Case Study Overview Example from Case Study

Drug Product Direct Compression

Manufacturing Process

Focus of
Story
Lubrication

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Product Development: Case Study Overview Example from Case Study

Initial Quality Risk Assessment

• Impact of Formulation and Process unit operations on
Tablet CQAs assessed using prior knowledge
- Also consider the impact of excipient characteristics on the
CQAs substance
Drug Moisture
content in Blending L ubrication Compression Coating Packaging
particle size manufacture
in vivo performance
Dissolution
Assay
Degradation
Content uniformity
Appearance
Friability
Stability-chemical
Stability-physical

- L ow risk
- Medium risk
- High risk

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Product Development: Case Study Overview

Drug Product CQA – Dissolution Summary

• Quality risk assessment
- High impact risk for API particle size, filler, lubrication and
compression
- Fillers selected based on experimental work to confirm compatibility with
Amokinol and acceptable compression and product dissolution
characteristics
- API particle size affects both bioavailability & dissolution
• Multivariate DOE to determine factors that affect dissolution
and extent of their impact
• Predictive mathematical model generated
- Confirmed by comparison of results from model vs. actual dissolution
testing
• Possible graphical representations of this design space
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Product Development: Case Study Overview Example from Case Study

Predictive Model for Dissolution

A mathematical representation of the design space
Prediction algorithm:
Diss = 108.9 – 11.96 × API – 7.556×10 -5 × MgSt – 0.1849 × LubT –
3.783×10-2 × Hard – 2.557×10 -5 × MgSt × LubT
Factors include: API PSD, lubricant (magnesium stearate) specific
surface area, lubrication time, tablet hardness (via compression force)

Confirmation of model
Batch 1 Batch 2 Batch 3

Model prediction 89.8 87.3 88.5

Dissolution testing 92.8 90.3 91.5

result (88.4–94.2) (89.0-102.5) (90.5-93.5)

Continue model verification with dissolution testing of production material, as needed

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Product Development: Case Study Overview

Dissolution: Control Strategy

• Controls of input material CQAs
- API particle size
- Control of crystallisation step
- Magnesium stearate specific surface area
- Specification for incoming material
• Controls of process parameter CPPs
- Lubrication step blending time within design space
- Compression force (set for tablet hardness) within design space
- Tablet press force-feedback control system
• Prediction mathematical model
- Use in place of dissolution testing of finished drug product
- Potentially allows process to be adjusted for variation (e.g. in API
particle size) and still assure dissolution performance
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Product Development: Case Study Overview

Drug Product CQA -
Assay & Content Uniformity Summary
• Quality risk assessment
- Potential impact for API particle size, moisture control, blending, and
lubrication
- Moisture will be controlled in manufacturing environment
• Consider possible control strategy approaches
- Experimental plan to develop design space using input material and
process factors
- In-process monitoring
• Assay assured by weight control of tablets made from
uniform powder blend with acceptable API content by HPLC
- Blend homogeneity by on-line NIR to determine blending endpoint, includes
feedback loop
- API assay in blend tested by HPLC
- Tablet weight by automatic weight control with feedback loop

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Product Development: Case Study Overview Example from Case Study

Blending Process Control Options

• Decision on conventional vs. RTR testing

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Product Development: Case Study Overview Example from Case Study

Process Control Option 2

Blend uniformity monitored using a process analyser
• On-line NIR spectrometer used 0.045
to confirm scale up of blending 0.04

mean spectral standard deviation

• Blending operation complete 0.035
when mean spectral std. dev. 0.03
Pilot Scale
Full Scale
reaches plateau region 0.025
- Plateau may be detected using 0.02
statistical test or rules
0.015
• Feedback control to turn off 0.01
Plateau region
blender 0.005
• Company verifies blend does 0
not segregate downstream 0 32 64 96 128
Revolution (block number)
Number of Revolutions of Blender
- Assays tablets to confirm
uniformity Data analysis model will be provided
- Conducts studies to try to Plan for updating of model available
segregate API Acknowledgement: adapted from ISPE PQLI Team

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Product Development: Case Study Overview

Tablet Weight Control in Compression Operation

Conventional automated control of Tablet Weight using feedback loop:

Sample weights fed into weight control equipment which sends signal to filling
mechanism on tablet machine to adjust fill volume and therefore tablet weight.

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Product Development: Case Study Overview

Batch Release Strategy

• Finished product not tested for assay, CU and dissolution
• Input materials meet specifications and are tested
-
API particle size distribution
-
Magnesium stearate specific surface area
• Assay calculation
- Verify (API assay of blend by HPLC) X (tablet weight)
- Tablet weight by automatic weight control (feedback loop), %RSD of 10 tablets
• Content Uniformity
- On-line NIR criteria met for end of blending (blend homogeneity)
- Tablet weight control results checked
• Dissolution
- Predictive model using input and process parameters calculates for each batch
that dissolution meets acceptance criteria
- Input and process parameters used are within the filed design space
- Compression force is monitored for tablet hardness
• Water content
- NMT 3% in finished product (not covered in this case study)
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Product Development: Case Study Overview

Drug Product Specifications

• Use for stability, regulatory testing, site change, whenever RTR testing is not
possible
• Input materials meet specifications and are tested
- API PSD
- Magnesium stearate specific surface area
• Assay calculation (drug product acceptance criteria 95-105% by HPLC)
- Verify (API assay of blend by HPLC) X (tablet weight)
- Tablet weight by automatic weight control (feedback loop)
- For 10 tablets per sampling point, <2% RSD for weights
• Content Uniformity (drug product acceptance criteria meets compendia)
- On-line NIR criteria met for end of blending (blend homogeneity)
- Tablet weight control results checked
• Dissolution (drug product acceptance criteria min 85% in 30 minutes)
- Predictive model using input and process parameters for each batch calculates whether dissolution
meets acceptance criteria
- Input and process parameters are all within the filed design space
- Compression force is controlled for tablet hardness
• Water content (drug product acceptance criteria NMT 3 wt% by KF)

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Product Development: Case Study Overview

Iterative risk assessments

High Risk Medium Risk Low Risk

Initial QRA Design Control

PHA
Beginning FMEA Space FMEA strategy FMEA

API
API PSD API PSD API PSD model
Crystallization

Blend Blending time

Blending Blending time
homogeneity Feedback control

Lubricant Lubricant
Mg stearate SSA
amount
Lubrication
Lubrication time Lubrication time Lubrication time

Hardness Pressure Pressure

Compression
Content Automated
Tablet weight
uniformity Weight control

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Product Development: Case Study Overview

Conclusions
• Better process knowledge is the outcome of QbD
development
• Provides the opportunity for flexible change management
• Use Quality Risk Management proactively
• Multiple approaches for experimental design are possible
• Multiple ways of presenting Design Space are acceptable
- Predictive models need to be confirmed and maintained
• Real Time Release Testing (RTRT) is an option
- Opportunity for efficiency and flexibility
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