Vaccines Drug Product development: how QbD -...

Vaccines Drug Product development: how QbD paradigm is the driving principle for product and process understanding

Francesca Titta GSK, Siena, Italy

Vaccine Products

Antigen(s) Adjuvant Administered Vaccine

• Typically, complex and multiple antigens with different structural features and doses

• Needed for specificity of the immune response

• Aluminum salts or Adjuvant Systems (combination of immunostimulatory molecules).

• Needed for most of the inactivated (whole or subunit) vaccines to enhance and modulate immunogenicity of the vaccine antigen

• All components in an appropriate buffer

• May require reconstitution/ mixing of different component solutions before administration

• Typically filled in vial or syringe, depending on formulation composition and patient needs

This work was sponsored by Novartis Vaccines and Diagnostics srl; in March 2015 the Novartis non-influenza Vaccines business was acquired by the GSK group of companies. The sponsor was involved in all stages of the study conduct and analysis. Francesca Titta was employee of Novartis Vaccines and now employee of the GSK group of companies

MILANO, 8 Maggio 2018 Applicazione del Qualityby Design (QbD) nella produzione dei medicinali

Quality by Design Paradigm

“A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management in order to ensure the quality of the product” (ICH Q8 (R2))

Courtesy of Amin Khan, Global Head of TRD (GSK Vaccines)

3 MILANO, 8 Maggio 2018 Applicazione del Qualityby Design (QbD) nella produzione dei medicinali/ confidentiality text here

Which path for pharmaceutical development? QbD flexible application, scope can vary based on products needs

Target Product Profile summarizes program development strategy based on patient’s needs

Quality Target Product Profile forms the basis of design for development of the product.

Linking Process Parameters and critical material attributes to CQAs.

Determine Critical Quality Attributes and link to clinical safety and efficacy

Define the design space: (multivariate) acceptable ranges for Process Parameters

Design and execute control strategy using Risk Management tool (link CQAs to process capability and analytical detectability)

Manage Lifecycle through continuous process verification and continual improvement

QTPP

CQAs

Process RA

Design Space & Ranges

Control strategy

Life cycle

Anal

ytic

al c

ontr

ol s

trat

egy

TPP

Stat

istic

al a

ppro

ache

s


Quality Target Product Profile (QTPP) What do we want?

QTPP defined by ICH Q8(R2) “A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the product”

QTPP initial setting

• List of QA/CQA/pCQA

• Target development ranges/limits

• Initial ATP

Prior Knowledge Scientific literature

Textbooks Similar products

Platform knowledge

Benefits Guarantee maximum available

knowledge Starting point for preformulation/

formulation/ analytical

development 5 MILANO, 8 Maggio 2018 Applicazione del Qualityby

Design (QbD) nella produzione dei medicinali/ confidentiality text here

Lifecycle for criticality assessmente Quality attributes criticality

6

List of CQAs/pCQAs

and QAs

List of CQAs and QAs

Unconstrained list of Quality

Attributes

New Antigens (discovery) Structural

characterization & composition:

Physicochemical characterization

Preformulation studies Preliminary information of formulation development

Structural- Function relationship:

criticality confirmation studies

Non clinical/clinical studies

Previous knowledge

QTPP Specifications

Control strategy

MILANO, 8 Maggio 2018 Applicazione del Qualityby Design (QbD) nella produzione dei medicinali/ confidentiality text here

Example of first version of CQA assessment Quality attributes criticality

7

Product Quality

Attribute Process step Safety Efficacy Quality Attribute Risk Assessment

USP DS DP RV

Justification of the (potential) impact on Safety

Knowledge regarding the justification of the (potential) impact on Safety

Justification of the (potential) impact on Efficacy

Knowledge regarding the justification of the (potential) impact on Efficacy

Scoring based on Safety and/or Efficacy

Impact 25 - 8 - 2

Uncertainty 1 - 2 - 3 - 4 - 5

Severity (S) = I x U

Truncated forms DP & RV

Not expected impact- not toxic in animal models

Tested in animal models and literature

Potential impact as an important epitope might be missing, and potential impact on structure

Not complete knowledge on the epitope

E 8 5 40

The highest score of Efficacy or Safety is equal to the overall score for the attribute, leading to final criticality assessment for each attribute. In the proposed approach, all attributes with overall score equal to 25 or above are considered equally critical.


Quality Target Product Profile (QTPP) Evolution of Product and Process understanding and Anaytical development


QTPP refinement throughout

development



• Initial ATP



Platform knowledge

Physico-chemical characterization Pre-formulation/

formulation, Process and Analytical

Development Criticality

Confirmation Studies

– Refined list of QA/pCQA/CQA

– Refined target development ranges/limits for all QA/CQA

Final TPP Final ATP to cover method changes

Definition of Process design spce Definition of

formulation space


Formulation development path

Pre-formulation Formulation screening

Formulation space

Profiling of the active vaccine ingredient

Understanding of APIs susceptibility to pharmaceutical relevant stress conditions (determination of degradation pathways).

Anticipation of suitable formulation conditions.

Excipients and primary packaging screening: studies to set up formulation factors with respect to API degradation pathways.

Compatibility studies amongst formulation components and vs primary container.

DoE studies application for optimization of formulation composition by assessing formulation stability properties as a function of formulation factors interactions with CQA.

Understanding of formulation factors interactions.


Preformulation flow

Anal

ytic

al to

ols

deve

lopm

ent

QTPP initial setting Prior knowledge

DS representative material

Liability identification

Effect of formulation variables/stress conditions on molecular degradation

pathways

Preliminary compatibility with adjuvants and other antigens

QA/CQA/pCQA list Input for formulation development & antigen stability profile (for DS and DP)

Stat

ical

sup

port


10

Acidic Basic

Selection of stability

indicating QA

Stability studies at the storage,

accelerated and stress T°C

Statistical evaluation of

results

Output Combination

Identification of the optimal space

where quality attributes are

acceptable

Preformulation case study Focus on pH optimal condition identification

Free Saccharide %

O-acetylation degree

Size changes

Conformational changes

Benefit: Increased product

understanding Strong base for formulation

development and optimization


Formulation screening Risk Assessments for formulation development

Stable Solution Formulation

API bulk composition Forced Degradation

API Bulk Conc.

API Bulk pH

API Bulk Buffer

pH Excipients

Type

Concentration

Temperature

Shear

Light

Oxidation

Trace Metals

Acceptable Range

Buffer

Type

Concentration

Buffer

Type

Concentration

Surfactant/additive

Type

Concentration

Tonicity agent

Type

Concentration

12 (Elaboration from “Application of Quality by Design and Risk Assessment principles for the development of Formulation Design Space” by Kingman Ng and Natarajan Rajagopalan)

Ishikawa diagram example could be used to identify the formulation factors’ impact on DP

Formulation screening case study Excipients screening

Change excipients each formulation Select stability indicating QA

Monitor QA during stability studies

Compare attributes between formulations

Selection based on attributes which

showed a difference

Antio

xida

nt

In orange selected formulation composition:

Surfactant


Process development In support of Drug Product initial development

Process development mainly based on platform feasibility and applicability.

Benefit: - Start with a DP development by

adapting preexisting

process platform - Start Process

Understanding in parallel with

Product


Quality Target Product Profile (QTPP) Consolidation phase


QTPP refinement throughout

development

Consolidation of QTPP



• Initial ATP



Platform knowledge

Physico-chemical characterization Pre-formulation/

formulation, Process and Analytical

Development Criticality

Confirmation Studies

– Refined list of QA/CQA – Refined target

development ranges/limits for all QA/CQA

– Final QA/CQA list – Specifications clinically/

toxicologically confirmed

– Control strategy

Final TPP Final ATP to cover method changes

Definition of Process design spce Definition of

formulation space


Process development TRA and Design Space


Link unit operations to CQA

Identify Critical Process Parameters

(CPP) and Manufacturing

Process Parameters based on impact on

CQAs

FMEA (Failure mode and Effect Analysis) and identification of

Design Space

Optimization- Formulation space

• Formulation space: where product CQAs ranges or limits are deemed acceptable and stable with respect to those relevant degradations identified during preformulation and formulation development studies

• Optimization studies are aimed to: 1. Formulation factors ranges identification 2. Confirmation of formulation factors concentration.

Formulation development

List formulation factors and

relevant process parameters

Evaluate link to product

QAs/CQAs

Define stress conditions

significant for product stability.

Design of Experiment

Analyze results and identify a

space


17

Specification setting

Specifications Definition: “Lists of tests, references to analytical procedures and appropriate acceptance criteria…. that should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product” (ICH Q6B) Specifications content: – Tested attributes CQAs – Analytical method- selection based on ability

to meet ATP requirements – Acceptance Criteria the target for acceptance

criteria setting for product-specific attributes is to be supported/justified by nonclinical/clinical information including stability considerations

Acceptance criteria

clinically justified

Analytical method

based on ATP

Critical Quality

attribute


Analytical strategy for specifications setting

Project:: GBS Attribute: Free sialic acid Version: 01

Section 1. General Information

Sample Intended Purposes of Measurement Scope Category Output

Product 1. Measure free sialic acid as CQA and

stability indicator to be monitored in stability studies

1. Measure a CQA 2. Stability

Quantitative test for a product related impurity

Section 2. Performance Requirements (related to the most challenging purpose)

Specificity Accuracy

(meaning of) Accuracy Requirement Rationale Precision

Requirement Rationale

Able to discriminate analyte from matrix

signals

Concordance with the true value

80-120% Adequate to current knowledge

about effect of sialic acid cleavage for immunogenicity

CV≤10%

Adequate for a stability indicator

method considering current specs limit

19

Extract from Analytical Target Profile: case study Sialic acid for GBS


Specifications lifecycle

List quality attributes included in specifications

Select CQAs to be included in specs based on product

knowledge/ compendial /

control on process

Evaluate method capability vs ATP

Critical quality attributes (CQA) identification by

suitable risk assessment

Set ranges of quality attributes

included in specifications

List analytical methods used to

test quality attributes in specification

Analytical Target Profile (ATP)

Combine all inputs

Nonclinical/ clinical evaluation of CQA

ranges, method performances,

stability, process capability

Inputs Actions Setting/ reviewing specifications

Periodic iteration during product lifecycle


21

Control Strategy


Technical development and lifecycle management

■

Benefit: - Holistic view of product, process and analytical development & life cycle - Document risks/ gaps related to these aspects - Continuously ensure the manufacturing of safe and efficacious products in a consistent manner

For each Critical Quality Attribute/ Quality Attribute / Performance Attribute : • Rationale about criticality (CQAs/QAs)/ relevance (PAs) • Confidence in analytical testing approach • Information on ability to control CQAs/QAs/PAs through process • Rationale for reducing release testing can be defined, as applicable.

Acknowledgments

Cristiana Campa Technical Research and Development, Head of Science and Dev. Practices Daniela Stranges Technical Research and Development, Drug Product Giovanna Campanella Technical Research and Development, Drug Product Malte Meppen Technical Research and Development, Head of Drug Product Development Technical Research and Development, Drug Product Development Team QbD Integration Team

22

Back up

23

Ranking of potential CQAs Quality attributes criticality Risk Assessment scoring (according to a-Vax case-study)

Criticality = Impact on safety and/or efficacy x Uncertainty

Impact Score Attribute impact on Efficacy and/or safety for the patient

Very High 25

Significant impact on efficacy or safety

Moderate 8

Moderate impact on efficacy or safety

Minimal 2 Minor to no change on efficacy and safety

Uncertainty Score Level of uncertainty about impact on the safety and/or efficacy

Very High 5 No information available

High 4 External information available from literature or similar products

Moderate 3 Data supporting from internal laboratory or nonclinical* studies

Low 2 Supportive data from clinical studies with this product

Minimal 1 Published limits widely accepted by regulatory, scientific community & authorities

Critical Process Parameters Manufacturing Process Parameters*

PAT IPC

CPP MPP

Product and Process development + Analytical testing Interactions to reach the final product and process

Process Analytical Technology In Process Control

* Parameters impacting performance 25

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