Using Risk Assessment Tools to Lead Development into · PDF fileUsing Risk Assessment Tools to Lead Development into the Right Direction ... Pharmaceutical Development, Lek Pharmaceuticals

Using Risk Assessment Tools to Lead Development into the Right Direction A Case Study

Petra Brožič, PhD, Senior Scientist, Pharmaceutical

Development, Lek Pharmaceuticals d.d., a Sandoz company

Arlington, Virginia (Washington DC) USA, 27 January 2015

The views expressed herein are not necessarily the views of Novartis, Sandoz International, GmbH or any of its affiliated companies.

Focusing the development in the right

direction from the very beginning

Transparent technological transfers,

efficient scale ups*, mitigate risks to

launch

Maintain right focus throughout lifecycle of

product, enhance root cause analysis

Sound Science and

Quality Risk

Management

Product & Process

Understanding &

Control

Key message – QbD mindset needs to be maintained throughout the lifecycle of the product

| IFPAC Annual meeting | Petra Brozic | 27 January 2015

* Lab scale → pilot scale → commercial scale

2

Risk Assessment Link material attributes and process

parameters to CQAs and define CMAs, CPPs

Quality Target Product Profile (QTPP)

Critical Quality Attributes (CQAs)

Developing a product Setting the right focus in order to obtain thorough product & process understanding

Set the

right focus

Risk

• Identification

• Analysis

• Evaluation

3 | IFPAC Annual meeting | Petra Brozic | 27 January 2015

Risk reduction/

communication Control Strategy

Development Production

Risk reduction

Product and Process

Understanding

Process Capabilities

Continous Improvement


direction from the early beginning


efficient scale ups, mitigate risks to

launch



Sound Science and

Quality Risk

Management

Product & Process

Understanding &

Control




4






Set the

right focus


Control Strategy


Product and Process

Understanding



Formulation and process information Case study

- extended release (ER) matrix tablet for oral

administration – film coated tablet


ER tablet core

Film coating

6

Quality Target Product Profile (QTPP) Case study

QTPP ELEMENT TARGET JUSTIFICATION

Dosage Form Tablet Pharmaceutical equivalence requirement:

same dosage form.

Dosage Design Film coated prolonged release tablet Needed to match label claims

Route Of Administration Oral Pharmaceutical equivalence requirement:

same route of administration.

Dosage Strength 10 mg

Pharmaceutical equivalence requirement:

same strength.

Pharmacokinetics Fasting and fed study 90% confidence

interval of the AUCi, AUC0-t and Cmax to

fall within bioequivalence limits.

Bioequivalnece requirement.

Stability Shelf life 24 months Market requirements. Equivalent to RLD.

Container Closure system Suitable container closure system to

achieve the target shelf-life and to ensure

tablet integrity during shipping.

Similar to RLD. Protection from moisture

(drug substance unstable in presence of

water)

Administration/concurrence with labeling Taken without regard to food. Information is provided in the RLD labeling

Alternative methods of administration None. None are listed in the RLD labeling.

Drug Product Quality Attributes Identity Pharmaceutical equivalence requirement:

Meeting the same compendial or other

applicable (quality) standards (i.e., identity,

assay, purity, and quality).

Assay

Content Uniformity

Drug Release

Physical attributes

Microbiology

Residual Solvents

Impurities

| IFPAC Annual meeting | Petra Brozic | 27 January 2015 7

Critical quality attribute(s) – CQA(s) Case study

Drug Product

quality attributes

Target Is this

critical?

Justification

Assay 100% w/w of label claim

Yes Variability can influence safety and efficacy.

Process and formulation variables can influence the assay.

(low dose preparation, unstable substance)

Impurities Any unknown impurity:

ICH identification

threshold

Total impurities:

RLD analysis

Yes Amount of impurities can influence safety and efficacy.

Process and formulation variables can influence the

amount of impurities.

(Active is unstable in humid conditions, needs to be

produced and stored under lowered

humidity/stabilized/protected. Influence of formulation,

process and packaging on impurities should be evaluated.)

Drug Release

Comparable to RLD Yes Drug release is important for bioavailability. Safety and

efficacy are influenced. Process and formulation variables

can influence drug release (controlled release product).


*Note: This represents an example of some of the CQAs, not all are listed on this slide

8






Risk

• Identification

• Analysis

• Evaluation


Control Strategy


Product and Process

Understanding



Quality Risk Assessment At the begining of the development

Purpose

Preliminary identification of risks from formulation, process, excipients, API

Rough outline of risks to be tackled during development

General and prior knowledge available

Substance info available

Factors

CQAs

API Excipients Process Packaging

Assay High High High Low

Impurities High High High High

Drug Release Med High High Low


Quality Risk Assessment

Factors

CQAs

API Excipients Process Packaging

Assay High High High Low

Impurities High High High High

Drug Release Med High High Low

Low

Broadly acceptable risk.

Follow-up action not mandatory.

Med

Acceptable risk.

Follow-up action may be needed to reduce the risk.

High

Unacceptable risk.

Follow-up action mandatory to reduce the risk.


At the begining of the development

11





launch



Sound Science and

Quality Risk

Management

Product & Process

Understanding &

Control




12

Process Design

Development TechTransfer to TechOps

Process validation

Commercial production

Site transfers / major

changes


Process Qualification

Continued process Verification Process Design

Definition of CQA, CPP,

CMA, Control strategy

Challenges • Process design must lead to a robust and reproducible

manufacturing process (benefit from prior knowledge)

• Transition from lab scale over pilot scale to full scale

• Verification of product/process criticalities during scale up

• Understand opportunities and limitations of full scale equipment

• Successful technology transfer by early interaction between

Development and TechOps


QRM QRM QRM

Quality Risk Assessment Initial

Purpose Knowledge

To link CQAs with possible CPPs and CMAs

Set the focus for further experimentation



Experimentation results

Factors

CQAs

API Excipients core Excipients

coating

Process

step1

Process

step2

Process

step3

Process

step4

Assay High Low Low High Low Low Low

Impurities High High High Med High High High

Drug release Med Med High Low Low Med Low


Define scale/equipment dependent/independent parameters

{CQAs}

= function (CMAs, CPPs)

Experimentation/DoE Building product and process understanding

( e.g. determine dependent vs. independent parameters – coating layer mass, pan diameter, number of spray nozzles, inlet air flow/temeperature,

relative humidity at product, pan fill fraction, etc...)

Chose experimental design (DoE)

Conduct randomized experimental trials

Analyze data

1

2

4

3

Select relevant output variables

( e.g.: water content, impurities)


CQA - Impurities

Process parameters Active/excipients attributes

Enviromental parameters

relative humidity

Packaging material attributes

material permeability

{CQAs} = function (CMAs, CPPs) Building product and process understanding in a transparent way

inlet air humidity,

inlet air temperature,

dispersion spray rate

active substance crystalline form

excipients water content


Factors

CQAs

API

Assay High

Factors

CQAs

API

Assay Low

No CMA

Factors

CQAs

API

Impurities High

Factors

CQAs

API

Impurities Med

Risk response changes from High to Low

Risk response changes from High to Med (ALARP) CMA1

Factors

CQAs

Process step3

Impurities High

Risk response changes from High to Med (ALARP)

Factors

CQAs

Process step3

Impurities Med

CPP1-3

Factors

CQAs

Process step3

Drug release Med

Risk response changes from Med to Low

Factors

CQAs

Process step3

Drug release Low

No CPP


{CQAs} = function (CMAs, CPPs) Mitigation of risks

17

Quality Risk Assessment Final

Purpose Knowledge

Clear relationship CMAs, CPPs, CQAs

Basis for defining the Control Strategy

Basis for further RA



Experimentation results – development and scale – up activities

Factors

CQAs

API Excipients

core

Excipients

coating

Process

step1

Process

step2

Process

step3

Process

step4

Assay Low Low Low Low Low Low Low

Impurities Med Low Low Low Med Low Med

Drug release Low Low Low Low Low Low Low








Risk reduction/

communication Control Strategy


Product and Process

Understanding



Control Strategy Final

Purpose

Focus on critical aspects of the formulation and process

To set controls for all identified CMAs, CPPs, CQAs

To set In-process testing and controls

Basis for further RA

Basis for PPQ protocol and CPV plan

Product and process understanding gathered through development and scale-up activities

Factor

Attributes or

Parameters

Affected

CQA

Ranged Studied

(Indicate Scale)

Proposed Range

for Commercial

Scale Purpose of Control Control Strategy

Active Crystalline

form Impurities

crystalline form I

amorphous API form I

To ensure impurities inside acceptance criteria

throughout the shelf life.

API

specification

Process step 3

inlet air

humidity,

inlet air

temperature,

dispersion

spray rate

Impurities

inlet air humidity

1–5 g/kg,

inlet air

temperature: 35–

90ºC,

dispersion spray

rate: 60–

110 g/min

inlet air humidity

2–4 g/kg,

inlet air

temperature: 55–

90ºC,

dispersion spray

rate: 50–

100 g/min,

To ensure impurities inside acceptance criteria

throughout the shelf life.

Fixed in BR

| IFPAC Annual meeting | Petra Brozic | 27 January 2015 *Note: This represents only a portion of the

control strategy

20





launch



Sound Science and

Quality Risk

Management

Product & Process

Understanding &

Control




21

Process Qualification (PPQ)


PPQ Commercial production


changes



CMA, Control strategy PPQ report

Update risk assessment

PPQ protocol

PPQ execution

Process Design Process

Qualification Continued process Verification

QRM QRM QRM QRM

QRM


Continued process verification


PPQ Commercial production


changes



CMA, Control strategy PPQ report

Update risk assessment,

redefine CPPs/CMAs

PPQ protocol

PPQ execution

Process Design Process

Qualification Continued process Verification

Continuous Process

Verification (CPV) plan

CPV execution

CPV report/ PQR/APR

Update risk assessment

QRM QRM QRM QRM

QRM


Each challenge leads to a benefit

Improved product and process understanding

• Consistent product quality, reduced failures and recalls

• Increased robustness of processes leverages process transfers

• Potential quality issues are identified and avoided from early stage development on to commercial production

• Helps to evaluate impact of process deviations

Improved knowledge management

• Subjectivity reduced, science and data driven

• Knowledge transfer at interfaces leveraged, e.g. at Tech Transfer due to aligned wording / definitions

• Improved communication with the regulators


Conclusion

The systematic, science and risk-based QbD approach

helps setting the right focus at the right time, leading to

improved product and process understanding, and high

quality products.


References


1. Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms

(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandA

pproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf)

2. Quality by Design for ANDAs: An Example for Modified Release Dosage Forms

(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandA

pproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM286595.pdf)

3. ICH quality guidelines: ICHQ8 Pharmaceutical Development, ICHQ9 Quality Risk

Management, ICHQ10 Pharmaceutical Quality System

4. Markus Kiefer (Head Manufacturing Science & Technology), Sandoz, 9/10-October-2013:

„Challenges in Implementing the Lifecycle Approach to PV for Generic Manufacturing“, ISPE

Process Validation Conference

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf




Acknowledgements


Apiromraj (Pito) Roslansky

Gregor Schuetz

Matej Horvat

Karin Klokkers

Sandoz Global QbD Team

Petra Perhavec

Veronika Debevec

Vicky Pirzas

Sara Cesar

Tatjana Joksimovic

27

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Using Risk Assessment Tools to Lead Development into · PDF fileUsing Risk Assessment Tools to Lead Development into the Right Direction ... Pharmaceutical Development, Lek Pharmaceuticals