Compliant Formulation Development The

Key to Successful Pharma Development

Obergeri, May 4th 2012

Dr. R. Rogasch

Regulatory Requirements in Formulation Development

EU Scientifc Guidance Documents EMA (Clinical, CMC, Procedural)

EP7 General Chapters, Monographs
US FDA Guidance Documents (Clinical, CMS, Procedural)
USP General Chapters and Methods (Dissolution Method Development, IVIVC
requirements, Statistical Methodology)
ICH Q8/Q9/Q10

Regulatory Requirements in Formulation Development

EU Scientifc Guidance Documents Formulation Development

IMP Procedure (pre-clinical data, dossier submission requirements, clinical studies)
CMC requirements (specifications, stability data, pre-process validation)
Bioequivalence or Biowaiver approach

Regulatory Requirements in Formulation Development

EU EP7 requirements Generic Drug Development - Legal status of monographs

Monographs are official standards

The Convention on the Elaboration of a European Pharmacopoeia makes the texts of the
Ph. Eur. mandatory in all signatory parties
The pharmaceutical legislation in the European Union
makes monographs obligatory standards
(2001/83/EC, 2001/81/EC)
Monographs may be accepted as suitable standards
even when not obligatory

Regulatory Requirements in Formulation Development

EU EP7 requirements Generic Drug Development - example

Do Ph. Eur. specifications apply throughout shelf-life?

A: Yes, specifications apply until time of use for raw materials and throughout period of
validity for preparations

B: No, Ph. Eur. requirements are for release only

From ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout D: Pharmacopoeial Requirements, Kuala Lumpur, July 2010

Regulatory Requirements in Formulation Development

EU EP7 requirements Generic Drug Development - example

Do Ph. Eur. specifications apply throughout shelf-life?

A: Yes, specifications apply until time of use for

raw materials and throughout period of validity for Preparations (EP7, general notices)

B: No, Ph. Eur. requirements are for release only.

Implications : EP7 mongraph specifications (impurities) are shelf life indicating !

From ICH Quality Implementation Working Group - Integrated Implementation Training Workshop
Breakout D: Pharmacopoeial Requirements, Kuala Lumpur, July 2010

ICHQ8/9/10 Paradigm in Formulation Development

Disclaimer
The information within this presentation is based on the
ICH Q-IWG members expertise and experience, and
represents the views of the ICH Q-IWG members for the
purposes of a training workshop.

QRM as part of development

To assess the critical attributes of

Raw materials
Solvents
Active Pharmaceutical Ingredient (API)
Starting materials
Excipients
Packaging materials

To establish appropriate specifications, identify critical

process parameters and establish manufacturing controls

ICH Q9
8

II.3: QRM as part of development

To decrease variability of quality attributes:
reduce product and material defects
reduce manufacturing defects

To assess the need for additional studies

(e.g., bioequivalence, stability)
relating to scale up and technology transfer
To make use of the design space concept
(see ICH Q8)

ICH Q9
9

Key Steps for a product under Quality by Design (QbD)

Pharmaceutical
Development
Prior Knowledge (science, GMP,
regulations, ..)
Product/Process Development
DOE : Design of Experiment

Quality Target
Product Profile
CQA : Critical
Quality Attribute
CPP : Critical
Process Parameter

QTPP : Definition of intended use & product

Potential CQA (Critical Quality Attribute) identified &

CPP (Critical Process Parameters) determined
Design to meet CQA using Risk Management &
experimental studies (e.g. DOE)
Link raw material attributes and process parameters
to CQAs and perform Risk Assessment Methodology

QRM principle apply at any stage

Risk Management

Product/Process Understanding

Opportunities

Design Space (DS), RTR testing

Control Strategy

Marketing Authorisation

Quality System PQS

Technology Transfer
PQS & GMP
Local Environment

Commercial Manufacturing
Batch Release
Strategy
Continual
improvement

Quality Unit (QP,..) level support by PQS

Manage product lifecycle, including

continual improvement

10

P2 of CTD as part of a regulatory submission

EXAMPLE

In line with Quality Risk Management ?

11

P2 of CTD as Quality Risk Management process ?

Initiate
Quality Risk Management Process

Formulation & Process design

Risk Assessment
Risk Identification

Risk Analysis

Process understanding

Risk Evaluation

Product release Concept

Regulatory strategy

Risk Communication

Process control Concept

unacceptable

Risk Control
Risk Reduction

Risk Acceptance

Output / Result of the

Quality Risk Management Process
Risk Review

Review the submission

Review Events

12

Risk Management tools

Manufacturing Concept

Target Product Profile

Drug substance properties; prior knowledge

Proposed formulation and manufacturing process Research

Formulation understanding Operation

Re-evaluation and confirmation

Determination of
Cause Effect relationships
(Risk Identification with subsequent Risk Analysis)

Phase 1

Risk-based classification
(Risk Evaluation)

Parameters to investigate (e.g. by DOE)

(Risk Reduction 1. proposal; 2. verified)

Product and process

FORMULATION
characteristics on the
DESIGN SPACE
final drug product
Phase 2

CONTROL
STRATEGY

Process understanding
Re-evaluation and confirmation

Developm.

Development

PROCESS
DESIGN SPACE
BY UNIT OPERATION
Review events

13
Launch

Phase 3

EXAMPLE

Responsibilities in regulatory operations

Initiate
Quality Risk Management Process

Industry
Team focused

Risk Assessment
Risk Identification

Risk Analysis

Risk Evaluation
Risk Communication

Internal consultation
Stakeholder involvement

Risk Control
Risk Reduction

Risk Acceptance

Risk Management tools

unacceptable

Output / Result of the

Quality Risk Management Process

B) Inspectorates

A) Reviewers

Risk Review
Review Events

14

Formulation Strategies for Phase I/II Clinical Programs

General Outline
The overall sequence for DP development for each phase/clinical trial can be summarized as
follows:
Define the best formulation, with the choice of excipients based on maximizing the physical
and chemical stability of the API
Ensure the formulation provides the desired in vitro release of drug
Conduct pharmacokinetic studies in animals, if models are available that are known to
predict clinical responses.
Define the best manufacturing process for DP
Place the final DP prototype on accelerated stability in intended packaging
Conduct GMP manufacture and packaging of clinical DP
Generate batch release data and certificate of analysis (CoA) for clinical DP
Initiate an accelerated stability program for clinical DP (batch made at full scale)
Submit supporting formulation and analytical data as part of the regulatory filing to request
approval (i.e., from the FDA, EU, etc.) for using the DP in a clinical study
15

Formulation Strategies for Phase I/II Clinical Programs

General Considerations Oral Dosage Forms
Material Property Assessment

API (solubility, Polymorphism XRD etc.)

PSD (DLS, LLD)
Morphology (SEM)
Compound Dissolution
Flow/cohesion
Powder compaction
Hardness, tensile strength, brittel fracture index
Excipient/API interactions
Degradation Pathways

16

Formulation Strategies for Phase I/II Clinical Programs

General Considerations Oral Dosage Forms
Bioavailability Enhancement

API (solubility enhancement)

PSD (micronization)
Solubility Screening, w/o partition
Precipitation inhibition (API/surfactant/polymer combinations)
Amorphous Dispersions (solid solutions, dispersion in polymer matrix)
Coatings (multi-particulates in capsules)
Lipid Systems (fat-matrix, SEDDS, SMEDDS, liposomal carrier)

17

Formulation Strategies for Phase I/II Clinical Programs

IR-Oral Dosage Forms

Capsule, Tablet (IR dosage forms)

Direct compression
Dry Granulation
Wet Granulation
Tabletting/Capsule Filling
Film Coating
Hot Melt Extrusion

18

Formulation Strategies for Phase I/II Clinical Programs

CR - Oral Dosage Forms
Capsule, Tablet (CR dosage forms)

Matrix
Multiparticulates
Soft Gel Capsules
Liquid filled Capsules
Fuctional Film Coating
Hot Melt Extrusion
Osmotic Systems
19

Formulation Strategies for Phase I/II Clinical Programs

Solid Orals - Excipients
Solid Orals

Formulation Excipients

Excipient type

Materials

Brittle fillers

Lactose
Calcium phosphate, dibasic

10%-95%

Imparts hardness and strength to

tablets

Ductile fillers

Mannitol
Microcrystalline cellulose Starch

10%-95%

Imparts compressibility and tensile

strength to tablets

Binders

Hydroxypropyl cellulose (HPC)

HPMC
Povidone

5%-10%

Provides strength in dry and wet

processing of powders

Lubricants

Magnesium stearate Stearic acid

Glyceryl behenate

Less than 2%

Prevents sticking of formulation to

processing surfaces

Disintegrants

Sodium starch glycolate

Croscarmellose sodium Crospovidone

Less than 5%

Aids in breakup of tablets or

granules in aqueous media

Controlled
release/matrix

HPMC
Polyethylene oxide
Polyvinylpyrrolidone (PVP)

10%-95%

Tailors drug release rate

Glidants

Fumed silica
Talc

Less than 1%

Improves powder flow and prevents

static charging

Capsules

Gelatin
HPMC
Polysaccharides

1%-5%

Unit dose to contain powders or

controlled release pellets

Approximate
ranges (%)

Function

20

Formulation Strategies for Phase I/II Clinical Programs

Solid Orals - Excipients
Solubilizers, dispersants,
precipitation inhibitors

Poloxamer 407
SLS
Cyclodextrins
HPMC and acid derivatives
HPC

0.5%-5%

Improve solubility and wettability of

hydrophobic drugs and improve
bioavailability

Chemical stabilizers

BHT/BHA
Citric acid

Less than 1%

Mitigate chemical degradation,

oxidation

Taste masking agents

Sucrose
Aspartame
Mannitol
Flavors

1%-5%

Hide unpleasant drug taste, essential for

chewable formulations

Colorants

Titanium dioxide, Iron oxides, Dyes and

lakes

Less than 2%

Cosmetic appearance, marketing

Coating ingredients Film

polymers

HPMC
Cellulose acetate , Ethylcellulose,
Polymeric acrylates

1%-30%

Cosmetic or controlled release coatings

21

Formulation Strategies for Phase I/II Clinical Programs

Solid Orals - Excipients

Plasticizers, Anti-tack
agent

Glycerol triacetate, Fatty acid salts,

esters, Polyethylene glycol,
Talc

Less than 1% Less

than 0.5%

Improve processability, Prevent

sticking

22

Formulation Strategies for Phase I/II Clinical Programs

Parenteral Dosage Forms

Parenteral/injectable Solutions (lyophilization)

Colloidal Suspensions (peptides, proteins)
Emulsions
Liposomal Systems
Suspensions

23

Formulation Strategies for Phase I/II Clinical Programs

Liquid Orals/Parenterals Excipients
Excipient type

Materials

Approximate
ranges (%)

Function

Diluent

Water
Vegetable oils
Polyethylene glycol
Propylene glycol

50%-90%

Main solubilizing/suspending
vehicle for all
components

Cosolvents

Ethanol
Polyethylene glycol
Propylene glycol
NMethylpyrrolidone

20%-50%

Helps with poorly aqueous

soluble drugs

Buffering agents

Sodium chloride Sodium

acetate Sodium
phosphate (and
corresponding
acids) Sodium
hydroxide

Enough for
adjusting to
desired pH

Maintain pH for optimum

solubility, and comfort
for injectable
formulations

Bulking agents

Sodium chloride
Hydroxypropyl
methylcellulose
(HPMC)
Mannitol Dextrose

Less than 10%

Maintain osmolarity for

parenterals, adjust
viscosity, mechanical
stability for lyophilized
cakes

24

Formulation Strategies for Phase I/II Clinical Programs

Oral Liquid/Parenteral - Excipients
Solubilizers/surfactants

Hydroxypropyl-betacyclodextrin
Sulfobutyletherbeta-cyclodextrin
HPMC
Polaxamer 407
Sodium lauryl sulfate
(SLS)
Phospholipids
Cremophors
Labrasol
Vitamin E TPGS

Less than
5%

Improve drug solubility,

emulsification,
suspension of drug
particles, prevent
precipitation

Chelating agents

Edetate sodium (EDTA)

Citric acid/citrate

Less than
1%

Bind metal impurities to

prevent
complexation and
reactions

Preservatives

Benzyl alcohol Methyl/

propyl parabens
Benzalkonium
chloride Thimerosal

Less than
2%

Prevent microbial growth

Chemical stabilizers

Butylated
hydroxytoluene/anisole
(BHT/BHA)
Citric acid/citrate

Less than
2%

Antioxidants, free radical

scavengers

Flavoring/tastemasking

Sucrose, aspartame
Peppermint oil,
flavors

Less than
2%

Sweeteners Masking of
drug tast

25

Project Case Study

Disclaimer
The information within this presentation is based
on the ICH Q-IWG members expertise and experience,
and represents the views of the ICH Q-IWG members
for the purposes of a training workshop.

26

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

27

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.

28

Case Study Organization

29

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
http://www.nihs.go.jp/drug/DrugDiv-E.html

Alignment between API and drug product

API Particle size and drug product dissolution
Hydrolytic degradation and dry granulation /direct compression

30

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

31

Technical Examples

Process focus

Quality attribute focus

API
- Final crystallization step

- Particle size control

- Blending
- Direct compression

- Assay and content uniformity

- Dissolution

Drug Product

API
Crystallization

Blending

Compression

Real Time
Release testing
(Assay, CU, Dissolution)

32

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
Experiments

Design
Space

Control
Strategy

33

Batch
Release

QbD Story per Unit Operation

QTPP
& CQAs

Process
Variables

Design of
Experiments

Design
Space

Quality
Risk Management

Control
Strategy

Batch
Release

Illustrative Examples of Unit Operations:

API
Crystallization

Blending

Compression

Real Time
Release testing
(Assay, CU, Dissolution)

34

Introducing API and Drug Product

35

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

36

Quality Target Product Profile (QTPP)

Safety and Efficacy Requirements

Characteristics / Requirements

Translation into
Quality Target Product Profile (QTPP)

30 mg

Identity, Assay and Uniformity

Subjective Properties

No off-taste, uniform color,

and suitable for global market

Appearance, elegance, size,

unit integrity and other characteristics

Patient Safety chemical purity

Impurities and/or degradates

below ICH or to be qualified

Tablet

Dose

Patient efficacy
Size Distribution (PSD)

Particle

Chemical and Drug Product Stability:

year shelf life (worldwide = 30C)

Acceptable hydrolysis degradate levels at release,

appropriate manufacturing environment controls

PSD that does not impact bioperformance or pharm

processing

Acceptable API PSD

Dissolution

Degradates below ICH or to be qualified and no

changes in bioperformance over expiry period

Hydrolysis degradation & dissolution changes

controlled by packaging

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.

37

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
formation
& removal of
impurities

Distillative
Solvent Switch

Removes water, prepares API

for crystallization step

Semi Continuous
Crystallization

Addition of API in solution and

anti-solvent to a seed slurry

Centrifugal Filtration Filtration and washing of API

Rotary Drying

Drying off crystallization solvents

38

Tablet Formulation

Pharmacopoeial
or other
compendial
specification

39

Drug Product Process

API and Excipients

Amokinol
D-mannitol
Calcium hydrogen phosphate hydrate
Sodium starch glycolate

Lubricant
Magnesium Stearate

Blending

Lubrication
Compression

Coating
HPMCMacrogol 6000
titanium oxide
iron sesquioxide

Film coating
40

Overview of API and Drug Product

Case Study Elements
Representative Examples from the full Case Study

41

Overall Risk Assessment for Process

Example from Case Study

Process Steps

in vivo performance*
Dissolution
Assay
Degradation
Content Uniformity
Appearance
Friability
Stability-chemical
Stability-physical

42

Packaging

Coating

Compression

Blending

Manufacture
Moisture Control

Drug Product
Rotary Drying

CQA

Distillative
Solvent Switch
SemiContinuous
Crystallization
Centrifugal
Filtration

* includes bioperformace of API, and

safety(API purity)

Coupling
Reaction

known or potential impact to CQA

additional study required

Aqueous
Extractions

Drug Substance

known or potential impact to CQA

current controls mitigate risk

Lubrication

no impact to CQA

Overall Risk Assessment for Process

Process Steps

in vivo performance*
Dissolution
Assay
Degradation
Content Uniformity
Appearance
Friability
Stability-chemical
Stability-physical

43

Packaging

Coating

Compression

Blending

Manufacture
Moisture Control

Drug Product
Rotary Drying

CQA

Distillative
Solvent Switch
SemiContinuous
Crystallization
Centrifugal
Filtration

* includes bioperformace of API, and

safety(API purity)

Coupling
Reaction

known or potential impact to CQA

additional study required

Aqueous
Extractions

Drug Substance

known or potential impact to CQA

current controls mitigate risk

Lubrication

no impact to CQA

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

44

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

45

Risk Assessment:
Particle Size Distribution (PSD) Control

Parameter

IM

Unit Operation

PA
C
PR T
OB
De .
tec
t

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

Crystallization

Feed Temperature

1 5 1

Crystallization

Water content of Feed

1 5 5

Crystallization

Addition Time (Feed Rate)

9 5 9

Crystallization

Seed wt percentage

9 5 5

Crystallization

Antisolvent percentage

1 1 1

Crystallization

Temperature

9 5 9

Crystallization

Agitation (tip speed)

9 5 5

Crystallization

Seed particle size distribution

9 1 1

Crystallization

Feed Concentration

1 1 1

Comments

RPN

Prior knowledge (slowness of crystallization kinetics) ensures that the

hot crystallizer feed will be well dispersed and thermally equilibrated
5
before crystallizing. Hence no impact of feed temp variation on
crystal size.
Prior knowledge (solubility data) shows that small variations in water
25
do not affect crystalliation kinetics.
Fast addition could result in uncontrolled crystallization. Detection of
405 short addition time could occur too late to prevent this uncontrolled
crystallization, and thus impact final PSD.

To be investigated
in DOE

225

Prior knowledge (Chemical Engineering theory) highlights seed wt

percentage variations as a potential source of final PSD variation

Yield loss to crystallization already low (< 5%), so reasonable

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
405 high since no possible corrective action (such as, if seed has been
dissolved)
Prior knowledge indicates that final PSD highly sensitive to Agitation,
225
thus requiring further study.
Seed PSD controlled by release assay performed after air attrition
9
milling.
1 Same logic as for antisolvent percentage
1

46

Options for Depicting a Design Space

Seed wt%

Oval = full design space represented

by equation
Rectangle represent ranges

Simple, but a portion of the design

space is not utilized
Could use other rectangles within oval

Pressure

Exact choice of above options can be

driven by business factors

Temperature

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

47

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

48

Design Space / Control Strategy

Parameter controls & Testing

Particle Size

Crystallization

Temperature

Particle Size

Crystallization

Feed Time

20 to 30C

Example from Case Study

Control between 23 and 27C

5 to 15 hours Control via flow rate settings

Quality system should ensure
1.1 to 2.5 m/s changes in agitator size result in
change to speed setting

Particle Size

Crystallization

Agitation

Particle Size

Crystallization

Seed Wt%

1 to 2 wt%

Hydrolysis
Degradate

Distillation /
Crystallization

Water Content

< 1 vol%

Controlled through weigh scales

and overcheck
Control via in-process assay

Particle size will be tested in this example, since the result is included
in the mathematical model used for dissolution.
49

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

50

Drug Product Direct Compression Manufacturing

Process
Example from Case Study

Focus of
Story
Lubrication

51

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
Drug
substance
particle size

Moisture
content in
manufacture

Blending

Lubrication

Compression

in vivo performance
Dissolution
Assay
Degradation
Content uniformity
Appearance
Friability
Stability-chemical
Stability-physical
- Low risk
- Medium risk
- High risk

52

Coating

Packaging

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

53

Predictive Model for Dissolution

Example from Case Study

A mathematical representation of the design space

Prediction algorithm:
Diss = 108.9 11.96 API 7.55610-5 MgSt 0.1849 LubT
3.78310-2 Hard 2.55710-5 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 result

92.8
(88.494.2)

90.3
(89.0-102.5)

91.5
(90.5-93.5)

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

54

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

55

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

56

Example from Case Study

Blending Process Control Options

Decision on conventional vs. RTR testing

57

Process Control Option 2

Example from Case Study

Blend uniformity monitored using a process analyser

Plateau may be detected using statistical

test or rules

Feedback control to turn off blender

Company verifies blend does not
segregate downstream
Assays tablets to confirm uniformity
Conducts studies to try to segregate API

0.045
mean spectral standard deviation

On-line NIR spectrometer used to

confirm scale up of blending
Blending operation complete when
mean spectral std. dev. reaches
plateau region

0.04

0.035

Pilot Scale
Full Scale

0.03

0.025
0.02

0.015

Plateau region

0.01

0.005
0
0

32

64
96
Number of (block
Revolutions
of Blender
Revolution
number)

Data analysis model will be provided

Plan for updating of model available
Acknowledgement: adapted from ISPE PQLI Team
58

128

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)

59

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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Iterative risk assessments

High Risk
Initial QRA
PHA

Beginning

FMEA

Design
Space

Medium Risk

FMEA

Control
strategy

Low Risk

FMEA

API
Crystallization

API PSD

API PSD

API PSD model

Blending

Blend
homogeneity

Blending time

Blending time
Feedback control

Lubricant

Lubricant
amount

Mg stearate SSA

Lubrication time

Lubrication time

Lubrication time

Hardness

Pressure

Pressure

Content
uniformity

Tablet weight

Automated
Weight control

Lubrication

Compression

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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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