TOPIC: IMPLEMENTING A QUALITY BY DESIGN PROGRAM FOR DRUG PRODUCT...

TOPIC: IMPLEMENTING A

QUALITY BY DESIGN

PROGRAM FOR DRUG

PRODUCT

DEVELOPMENT

Presenter: Steven Laurenz

Principal Consultant with Biophia Consulting

QbD Philosophy

• QbD is about connecting the molecule and the patient.

– Science-based product/process design begins with the API molecular entity and is geared to meet patient needs for pharmacotherapy which is safe, effective, convenient and of consistently high quality.

• All products are designed and developed to be of high quality; QbD provides a structured framework for developing, documenting and presenting development rationale, experience and knowledge of the formulation and the process, and to ensure manufacture of products consistently fit for patient use.

2

Steven Laurenz, MS – BioPhia Consulting, Inc.

Essential Elements of a QbD Approach

• Product quality and performance achieved and assured by design of effective and efficient manufacturing processes

• Product specifications based on mechanistic understanding of how formulation and process factors impact product performance

• An ability to affect continuous improvement and continuous “real time” assurance of quality


Summary:An Industry View of QbD: Key Scientific Elements and ‘Flow’

Target

Product

Profile

Control

Strategy

Prior

Knowledge

Product/

Process

Dev.

Product/

Process

Design

Space

Definition of

Product

Intended

Use and

pre-

definition of

Quality

targets (wrt

clinical

relevance,

efficacy and

safety)

Summary of

Scientific

Understanding of

Product and

Process.

Justification and

description of

Multi-dimensional

Space that

Assures Quality

(interrelation-ships

and boundaries of

Clinical

Relevance).

Definition of

Control

Strategy

based on

Design

Space

leading to

Control of

Quality and

Quality Risk

Mgmt.

(Process

Robustness)

Overview of

Quality by

Design key

actions and

decisions

taken to

develop New

Scientific

Knowledge,

e.g. DoE,

PAT, Risk

Assessment

and Risk

Control

Summary of

Prior

Scientific

Knowledge

(drug

substance,

excipients;

similar

formulations

and

processes).

Initial Risk

Assessment

Regulatory

Flexibility

Proposal of

Regulatory

Flexibility

based on

Product and

Process

Scientific

Knowledge

and Quality

Risk Mgmt.

(Materials,

Site, Scale

etc)

EFPIA Working Group


Benefits of a QbD Approach

– Increased regulatory flexibility

• Fewer prior approvals

• Increased production efficiency

– More robust products and manufacturing processes

• Large cost reduction potential due to fewer deviations

• Reduced risk to patients

– Improved in-line product quality

• Reduced risk to patients

• Large cost reduction due to reduced testing

– Improved alignment for development strategies across the different functional areas within the company.

– Improved R&D efficiency by increased use of prior knowledge and science/risk base approach.


Outline

•TPP & QTPP

•Early Risk Assessments

•Development Plan (Target Operational Profile}

•Design Space

•Later Risk Assessment

•Control Strategy


Target Product Profile and Quality Target Product Profile

Definitions

Target Product Profile: Summary of major characteristics of

the drug as described in the 'prescribing information',

'Summary of Product Characteristics', 'package insert', or

'label'. Includes clinical indication (including age and other

characteristics of population for which drug is approved),

dosage form, administration schedule, efficacy, safety,

stability.

Quality Target Product Profile: a prospective and dynamic

summary of the quality characteristics of a drug product that

ideally will be achieved to ensure that the required quality,

hence safety and efficacy, of a drug product is realized. It

forms the basis of design for the development of the product.


TPP Considerations:

• Dosage form and route of administration

• Dosage form strength(s)

• Therapeutic moiety release or delivery and

pharmacokinetic characteristics (e.g., dissolution;

aerodynamic performance) appropriate to the drug product

dosage form being developed

• Drug product quality criteria (e.g., sterility, purity)

appropriate for the intended marketed product


Quality Target Product Profile (QTPP)

A prospective summary of the quality characteristics of a

drug product that ideally will be achieved to ensure that

the desired quality, taking into account safety and efficacy

of the drug product.

(ICH Q8 R1 Annex)


QTPP – Factors to Consider

• QTPP starts with Target Product Profile. The QTPP translates the high-level product requirements in the TPP to quality attributes that the Drug Product must possess in order to reproducibly deliver the therapeutic benefit in the targeted label

– Drug Release: Relationship of in-vivo performance to in-vitro test, Safety/Efficacy, BE requirements

– Potency/CU: Relationship to therapeutic index

– Impurities/Degradation Products: Relationship to patient safety

– Size, Appearance, Cost: Differentiation, marketing

– Design issues associated with actual use by targeted patient population

– Packaging: Protection, compliance, convenience, cost

– Pharmacopoeial requirements, global product

• Basis for design of commercial drug product, allowing formulation scientists/DP team to establish appropriate strategies and keep efforts focused and efficient

• Provides potential critical quality attributes and foundation for risk assessment


Early Risk Assessment

QbD Risk Assessment Outline

• Overview

• Risk Assessment Central Role in QbD

• RA Deliverables

• RA Process


Overview

Quality Risk Management (ICH Q9)

A systematic process for the assessment, control,

communication and review of risks to the quality of the drug

product across the product lifecycle

Risk-based regulatory decisions

• Review

• Inspections

• Changes


Overview

Two primary principles of Quality Risk Management:

• The evaluation of the risk to quality should be based on

scientific knowledge and ultimately link to the protection of

the patient; and

• The level of effort, formality and documentation of the

quality risk management process should be commensurate

with the level of risk and stage of development


Important Terms & Definitions

Risk: Combination of the probability of occurrence of harm

and the severity of that harm

Risk Assessment: Identification of hazards and the

analysis and evaluation of risks associated with exposure to

those hazards


Early Development Risk Management Flow

Response Variables

Po

ten

cy

Dru

g r

ele

ase

Co

nte

nt

Un

ifo

rmit

y

Deg

rad

ati

on

Mic

rob

iolo

gic

al, I

D

Quality Attributes --------- Correlation of Input to Output ---------

Patient Safety (Cmax) Med High Low Low Low

Patient Safety (Food

effect)

Efficacy Med High Low Low Low

Commercialization

High

Med

Low

None

Formulation-Raw Materials

Tab

let

siz

e

Po

lym

er

leve

l

Po

lym

er

MW

Dru

g/p

oly

me

r

rati

o

Co

ati

ng

le

ve

l

HP

C l

ev

el

Oth

er

ing

red

itn

s

Po

lym

er

vari

ab

ilit

y

Quality Attributes --------- Correlation of Input to Output --------- --------- Correlation of Input to Output ---------

Potency Med

Drug release High Med Low Med High Low Low Low

Content Uniformity

Degradation

Microbiological, ID

Appearance

Stability (drug

release)

Patient / Business

Needs, relation to DP

quality

Formulation Packaging Unit Operations

Packaging

Bo

ttle

siz

e

Bo

ttle

co

un

t

Blis

ter

thic

kn

es

s


Potency

Drug release

Content Uniformity

Degradation

Microbiological, ID

Appearance

Stability (drug

release) High High High

Dis

pen

sin

g R

aw

Mate

rials

Gra

nu

lati

on

Delu

mp

ing

Dry

ing

Sif

tin

g &

Im

pact

Mil

lin

g

Ble

nd

ing

Co

mp

ressin

g

Co

ati

ng

En

cap

su

lati

on


Potency High High High

Drug release High

Content Uniformity

Degradation

Microbiological, ID

Appearance

Response Variable

Acid

pro

tecti

on

Dru

g r

ele

ase

rate

Gg

astr

ic

rete

nti

on

Gra

nu

le D

10,

D50,

D90

LO

D

Flo

wab

ilit

y

Co

mp

ressib

ilit

y

Tab

let

Hard

ness/T

hic

kn

ess

Att

riti

on

Co

ati

ng

In

teg

rity

Po

ten

cy

Formulation --------- Correlation of Input to Output ---------

Tablet size High High

Polymer level Med Med

Polymer MW Low

Drug/polymer ratio High

Coating level High High

HPC level High High High

API morphology Med Med

API size High High

SSF Med Med

PVP High High

Other ingreditns

Polymer variability Low

High

Med

Low

None

Response Variable

Packaging Mo

istu

re

up

date

Ch

an

ge

of

dru

g

rele

ase

Bottle size Med Med

Bottle count Med Med

Blister thickness High High

Response Variable

Gra

nu

le

D10

, D

50

,

D90

LO

D

Flo

wa

bil

it

y

Co

mp

res

s

ibilit

y

Tab

let

Hard

nes

s/

Th

ick

ne

s

s

Att

riti

on

Co

ati

ng

Inte

gri

ty

PK

Po

ten

cy

Unit Operations --------- Correlation of Input to Output ---------

Dispensing Raw

Materials

Granulation High High

Delumping

Drying High High

Sifting & Impact

Milling Med Med Med

Blending High

Compressing Med Med Med

Coating High High

Encapsulation

Level 1

Level 2

Level 3


Initial Risk Assessment Process

• Review QTPP

• Identify high-level product attributes important to Patient, i.e., safety

and efficacy, and to Business, i.e., manufacturability, appearance

• Identify Drug Product Quality Attributes related to high-level product

attributes, e.g., potency, stability, uniformity

• Review formulation components, process steps, and packaging

against the DP Quality Attributes

• Assess which variables are likely to have greatest impact on DP

quality (and which areas have opportunity for robustness

improvement)

• Prioritize focus areas

• Design & conduct experiments

• Outline next level of detail for areas of greatest impact

• Include mitigation plans and timing for high risk areas


Benefits of the Risk Assessment Matrix

• It considers the whole design space and how process inputs affect outputs.

• It is an efficient communication tool to achieve consensus within the CMC team and across stakeholders.

• It can be used to assign resources and to prioritize team activities.

• It can be used to communicate risk areas in project reviews.


How the Risk Assessment Links to Development Activities

Response Variable

Acid

pro

tecti

on

Dru

g r

ele

ase

rate

Gg

astr

ic

rete

nti

on

Gra

nu

le D

10,

D50,

D90

LO

D

Flo

wab

ilit

y

Co

mp

ressib

ilit

y

Tab

let

Hard

ness/T

hic

kn

ess

Att

riti

on

Co

ati

ng

In

teg

rity

Po

ten

cy

Formulation --------- Correlation of Input to Output ---------

Tablet size High High

Polymer level Med Med

Polymer MW Low

Drug/polymer ratio High

Coating level High High

HPC level High High High

API morphology Med Med

API size High High

SSF Med Med

PVP High High

Other ingreditns

Polymer variability Low

High

Med

Low

None

Compressibility

Blending Granulation

Drying Sifting and Impact Milling

Screen

Blend Time 1

Blend Time 2

Water Amount

Water Addition Rate

Nozzle

Wet massing time/power

Inlet Temperature

Max exhaust temperature

Inlet humidity

Drying endpoint

Sweco screen

Mill speed

Feed Speed

Red: Critical Process

Variable

Cause and EffectFMEA on High/Med Risk

DOE

Or

PAT

Or

Other

Control

Ongoing 2Q 2010• Advance planning

• Process development

Possible delays due to acquisition, installation, familiarization

3. Roller compaction implementation in GPO

Ongoing - 2Q 2008• Formulation/process development

• API phys prop studies

Inadequate powder flow

Possible CU failure

Interrupted/failed runs

2. Preblend processability; agglomerates; segregation; sticking/layering

Ongoing 2Q 2008• Stability studies

• Open dish studies

• Packaging selection

• DVS, water vapor transmission model

Potential stability failures at 40°C/75%RH, but

good stability expected at 25°C/60RH

1. Stability/Packaging –Conversion to trihydrate at RH above 60%,

instability observed at 40°C/75%RH in capsule formulation

1-2Q 2008

and continuing

• Assess functional attributes of Vivapur 102 for potential test/acceptance criteria

• Work with supplier to evaluate different batches

Unknown potential for variability between batches

4. Vivapur 102 MCC

TimingMitigation strategyRiskChallenge

Ongoing 2Q 2010• Advance planning

• Process development

Possible delays due to acquisition, installation, familiarization

3. Roller compaction implementation in GPO

Ongoing - 2Q 2008• Formulation/process development

• API phys prop studies

Inadequate powder flow

Possible CU failure

Interrupted/failed runs

2. Preblend processability; agglomerates; segregation; sticking/layering

Ongoing 2Q 2008• Stability studies

• Open dish studies

• Packaging selection

• DVS, water vapor transmission model

Potential stability failures at 40°C/75%RH, but

good stability expected at 25°C/60RH

1. Stability/Packaging –Conversion to trihydrate at RH above 60%,

instability observed at 40°C/75%RH in capsule formulation

1-2Q 2008

and continuing

• Assess functional attributes of Vivapur 102 for potential test/acceptance criteria

• Work with supplier to evaluate different batches

Unknown potential for variability between batches

4. Vivapur 102 MCC

TimingMitigation strategyRiskChallenge


Development Plan (Target Operational Profile (TOP))

TOP Background

• The implementation of the QbD principles will not be the same for all drug products (i.e. Defining a design space is not a regulatory requirement)

• A method to communicate how these principles will be applied is needed

• The QbD strategy for a particular project needs to be communicated relatively early in a program to ensure there is cross functional support

• A strategy needs to be defined for further QbD implementation after a product is launched


Definition

• The target operational profile acts to define what elements of QbD/QRM are considered to be essential components of the development process for a specific drug product at the time of market authorization. It is a method to communicate joint requirements thus avoiding surprises later in development


Purpose of TOP

• There may be cases were a significant upfront investment in elements of QbD, such as the extensive design of experiments needed to define a wide design space or investment in process analytical technologies (PAT), may not be appropriate

• It is important that all major divisions involved agree upon the recommended development strategy

• The TOP helps to ensure that agreement is in place


Important components

•Critical to Filing:

–What QbD components for this particular product must be defined before filing (as part of the filing strategy)

–Minimum CMC dataset that will be required to deliver successful marketing authorizationsfiling in regions of commercial interest


Important Components

•Critical to Operations

–The expected process knowledge and design space dataset that will be required to deliver a manufacturable active pharmaceutical ingredient or drug product at the commercial launch site(s)

–Agreement as to what can be developed post launch.


Important Components

• Post-approval Plans

– defines the anticipated process knowledge and design space enhancements (while not critical to initial commercialization) that are essential to meet long-term requirements for process robustness and capacity

– Process enhancements that may be deferred past commercial

launch may include Process enhancements that may be deferred

past commercial launch may include

• Manufacturing capacity expansion (technology transfer and up-scaling)

• Strategic PAT investment

• Data warehousing to support continuous manufacture/parametric

release strategies


TOP Summary

• TOP is important communication tool to describe how the QbD principles will be applied to a particular CMC project. What is the plan?

• It serves as an important tool to get strategic alignment on this implementation strategy including PAT applications, the use of prior knowledge, and post approval plans

• Components that are critical to filing, critical to operations, and post approval plans are documented


Design Space

QbD Design Space Outline

• Design Space definition

• Design Space strategies and tools

• Design Space examples


Design Space Definition

• The established range of process parameters that has been

demonstrated to provide assurance of quality

• The focus is on high and medium risk areas as defined by the

risk assessment.

• Regulatory Flexibility: Working within the design space is not

generally considered as a change of the approved ranges for

process parameters and formulation attributes, or,

• Changes within this space would not entail a regulatory

reporting requirement.

The Design Space is a quantitative understanding of how API,

Formulation, Packaging and Process parameters affect the Drug Product

Quality Attributes.


Knowledge Space and Design Space

Knowledge Space

Design Space

Normal

Operating

Ranges


Product Robustness

Process (or Process Step)

Design Space

Monitoring ofParameters

or Attributes

Process Controls/PAT

InputProcess

Parameters

Input Materials

Product (or Intermediate)

Product

Variability

Reduced

Product

Variability

Process

Variability


Tools for Design Space Definition

• Design of Experiments

– Multivariate understanding includes interactions between input variables.

– These require planning and expertise to maximize their return.

• Analytical Modeling

• PAT


Types of Experiments

• Trial and Error – While this may provide a successful result (e.g. one batch meets the TPP), it does not provide the design space or robustness that meets the intent of a QbD submission.

• One Factor at a Time – Inefficient strategy as compared with DOE and may miss the optimal design space.

• Screening DOE – Low resolution factorial designs to identify the most important factors early in the development process. Lab-scale batches.

• Refining DOE – Full factorial designs gives information about the interaction of factors and a mathematical model. Lab-scale batches.

• Optimizing DOE – Response surface designs that include non-linear effects.


DOE Application

• The DOE objective depends on your knowledge level.

• Determine responses (Quality Attributes)

• Choose Factors

• Set Levels

• Use Minitab or other statistics software package to design and analyze.

• Runs from screening experiments can be used in refining and optimizing experiments.

Screening

DOERefining

DOE

Optimization

DOE5 to 10 factors

Typically 2-level

Identify those factors which have most impact; remove those that do not.

Less information about interactions.

2 to 5 factors

Often 2-level

Learn about important interactions.

2 to 3 factors

Often 3 to 5 levels

Learn about important interactions.

Includes non-linear effects.

Provides a response surface / design space.

Trial

RunsConfirmation

Runs

Two or three additional runs to verify design space.

May use full-scale batches

Pre-DOE runs to assure that the spec can be met.

Also gives info to set levels


Models in Science

• Models are formed and used every moment just in the act of human reasoning

• Scientists take models from abstraction to the tangible by describing in mathematical form

• Types: scale, empirical, semi-empirical, mechanistic or first principles

• Useful models must be predictive!

“I can model the process” = “I understand the process”


Packaged drug product moisture uptake simulation


PAT (NIR) Enables Broad Operating Space


Blend Scale-up


Design Space Representation for a DP


Summary

• Design Space is enabled by multivariate DOE, Analytical Models and PAT.

• DOEs/PAT/modeling are driven by upstream needs

– DOEs should be performed on the smallest batch possible

– Models can be used to minimize commercial scale runs

• The comprehensive development space can be communicated quickly to other stakeholders, development partners, management and regulatory agencies.


Later Stage Risk Analysis

Process Failure Mode & Effects Analysis (FMEA)

Purpose of an FMEA

• To analyze potential failures of a design (product, process, project) by prioritizing risk based on the likelihood of each failure and its effect, including the severity of its impact

• It a risk management tool used to:

– Systematically assess the adequacy of the process controls to deliver the QA & identify design inefficiencies

– Identify potential problems before they occur

– Evaluate risk of process changes

– Identify areas requiring improvement

– Provide a structured approach for identifying what to work on first

– Aid objective-based decision making

– Identify critical input & process variables than can affect output quality

– Improve the reliability of a process


FMEA Inputs & Outputs

FMEA

Detailed

Process

MapEarly Risk

Assessmen

t

Fishbone

Diagram

Prior

knowledge

Required

process

controls to

produce an in-

spec product

Process Transfer

to the

manufacturing

area

Quality

Attributes

Process

Parameters

Controls,

Test

Methods,

PATInputs to

Risk

Control

Strategy

Actions

intended

to

prevent

or reduce

failures

Iterative lifecycle

document for

continuous

improvement

(CAPA)


BASIC RISK ASSESSMENT & FMEA

Risk Assessment 4 related questions:

Translated to the FMEA tool:

prospective

Epival 250 tablets FMEA

# Function/ StepPotential

Failure Mode

Potential Local

Effect of Failure

Potential End

Effect of Failure Se

vC

las

s Cause of Failure

Occ Prevention

Control

Detection

Control Det

Sx

O

RP

N Recommended

Action

3

Milling [Starch

Pregelatinized

Povidone]

Lubricant

contaminationFailed batch [5] Contamination [4] 5

equipment

malfunction -

lubricant leakage

1

Alarm system

PM

alarm system

operator visual

1 5 5


Risk Assessment Summary

• Flow from qualitative to quantitative tools

• Lower level parameters will be traceable to patient and business needs

• Risk Analysis is used to drive mitigation activities; it is not just a paper exercise to meet a quality requirement

• DOEs/PAT/modeling are driven by upstream needs

• Tools are sequenced to tell a logical story to regulatory agencies

• Assessment is documented to serve as communication and for filing


Control Strategy

Outline

–What is a control strategy, how to develop and implement a control strategy - Control Strategy Model


Control strategy – Q10 definition

• A planned set of controls, derived from current product and process understanding

• These controls assure process performance and product quality

• The controls can include parameters and attributes related to:

– API

– Drug product

– Materials and Components

– Facility and equipment operating conditions

– In-process controls

– Finished product specifications

– Associated methods and frequency of monitoring and control


A Control strategy can include Q8 (R)

• Control of input material attributes

– based on understanding of their impact on processability or product quality

• Product specifications

• Controls for unit operations

– that have an impact on downstream processing or end-product quality

• In-process or real-time release

– in lieu of end-product testing

• A monitoring program

– for verifying multivariate prediction models


Control Strategy Model- an approach to developing a Control Strategy

• Facilitates discussions between disciplines

• Science & risk-based approach

• Embraces product and systems (ICH)

• Link controls to CQAs

• Pharmaceutical & business requirements

• May support regulatory submission


Product: CQAs

For patient safety,

efficacy and quality

(as ICH Q8/Q6a)

Product: CQAs

For patient safety,

efficacy and quality

(as ICH Q8/Q6a)

Other Product Attributes &

Business Requirements

e.g. cost, safety,

environmental,

manufacturability

Other Product Attributes &

Business Requirements

e.g. cost, safety,

environmental,

manufacturability

Controls to Enable

Product CQAs to be met

e.g. CPPs, material

attributes & components,

equipment and facility

operation s that must be

monitored or controlled to

achieve product CQAs

Controls to Enable

Product CQAs to be met

e.g. CPPs, material

attributes & components,

equipment and facility

operation s that must be

monitored or controlled to

achieve product CQAs

Other Controls

Other parameters and

material attributes &

components, equipment &

facility operations that

must be monitored or

controlled to achieve

other product attributes &

business requirements

Other Controls

Other parameters and

material attributes &

components, equipment &

facility operations that

must be monitored or

controlled to achieve

other product attributes &

business requirements

Analytical, Engineering & Other Control Methods

Analytical methods (off line, at-line, in-line, or on-line)

Equipment and facility engineering controls

PAT (including process models and control models)

Automation and manual controls

Procedures

Analytical, Engineering & Other Control Methods

Analytical methods (off line, at-line, in-line, or on-line)

Equipment and facility engineering controls

PAT (including process models and control models)

Automation and manual controls

Procedures

Control

Strategy

Level 2

Control

Strategy

Level 3

PATIENT BUSINESS

Control

Strategy

Level 1

Systems

to

facilitate

other

business

controls

PQLI Control Strategy Model

PQS (ICH

Q10) and

GMPs


Lifecycle View of Control Strategy

Understand CQAs and CPPs to

enable a Control Strategy to be

developed

Provide sufficient details of

Controls to enable technology

transfer

Pharmaceutical Development Technology Transfer Manufacturing

Execute in a State of

Control with Efficient

Operations & Continuous

Improvement

Pro

du

ct

an

d P

rocess K

no

wle

dg

e

Patient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3

Create Knowledge Prepare to Execute Execute

Initial Focus:

Safety, Efficacy, and

Product Quality

Later Focus:

Maintain Safety, Efficacy & Quality

within the PQS and

Increase Efficiency

Pharmaceutical Quality System



developed



transfer



developed



transfer



developed



transfer

Pharmaceutical Development Technology TransferPharmaceutical Development Technology Transfer Manufacturing

Execute in a State of

Control with Efficient

Operations & Continuous

Improvement

Pro

du

ct

an

d P

rocess K

no

wle

dg

e

Patient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3

Patient BusinessPatient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3


1

2

3

Patient Business

1

2

3

Patient Business

1

2

3


1

2

3

Patient Business

1

2

3

Patient Business

1

2

3


1

2

3

Patient Business

1

2

3

Patient Business

1

2

3

Patient Business

1

2

3


1

2

3

Create Knowledge Prepare to Execute Execute

Initial Focus:

Safety, Efficacy, and

Product Quality

Later Focus:

Maintain Safety, Efficacy & Quality

within the PQS and

Increase Efficiency

Pharmaceutical Quality System


Summary

• Science and risk based principles

• From API to final product

• PAT tools and conventional controls applied

• Evolving Control Strategy based on process understanding


Overall Summary

•The QbD process is a mindset vs a set of tools or a check list to ensure product quality.

•The process can improve business efficiency within development and when the product is launched.

•The process is a great communication tool to obtain alignment across an organization.


Date post:	31-May-2020
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TOPIC: IMPLEMENTING A QUALITY BY DESIGN PROGRAM FOR DRUG PRODUCT...

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