an effective and efficient testing strategy utilizes qbd...

An effective and efficient testing strategy utilizes QbD concepts

Characterize

attributes

and perform

risk

assessment

Characterize

process.

Measure the

critical

quality

attribute at

the point

where it is

controlled

Eliminate

redundant

testing

A lean and targeted control strategy eliminates “noise” and puts

focus on what is important to control

Develop

method(s)

specific for

critical

quality

attributes

E.g. MS Based method

(Future State)

A1

A3

A5 Attribute

DS Process

Step

1 2 DS

CQA 1 X X

Control strategy integrates all aspects of process and product controls

Production Process

Procedural controls (facility, equipment and operational parameters)

Input controls (raw materials and components)

In-process testing (validation, IPCs, process monitoring)

What is the right size and scope of end product testing?

(specifications, comparability, stability)

Control elements are well coordinated and integrated in

effective control strategies

3

There are many Elements to the Overall Control Strategy

• Characterize product attributes

• Characterize processes

• Use characterization methods to further define the process capability

• Establish process monitoring

• Raw material controls

• Conduct product formulation studies, understand degradation pathways

• Establish a comparability program

• NC/CAPA system with product characterization and forensics capabilities

Process and product knowledge enable a rational, risk-based specification design

• Critical quality attributes are identified

• Stability and degradation pathway studies enable understanding of process, formulation, device, container, etc on product stability

• Process control points and stability control points for those attributes are identified

• Process characterization studies enable understanding of process capability to robustly clear / control undesired attributes

• A quantifiable and scientific risk-based strategy can be utilized to create a streamlined and focused control strategy

A Holistic Review of the Control Strategy Resulted in Approaches to Revise Existing Specifications

• Removal of tests for impurities with well understood mechanisms for removal and proven process capability

• Removal of redundant tests that are performed at multiple points in the process and move testing to the point at which it is controlled

• Apply Real-Time-Release-Testing (RTRT) where appropriate

• Removal of tests for quality attributes that are well controlled during manufacturing and where adequate detections are in place in manufacturing and quality control to detect issues

• Removal of stability tests for attributes that are not impacted by the known mechanisms of product degradation and do not change over time

Maintain the ability to “bring back” tests, as needed

e.g., for comparability and non-conformance investigations

Application of the Optimised Testing Strategy to mAb X

Removal of tests for process related impurities with well understood mechanisms for removal and proven process capability for clearance

CHOP levels are well controlled through critical operational parameters

• Process characterization studies elucidated operating parameters that influence CHOP level

• Process controls are in place at the Production Bioreactor, Harvest steps and three chromatography steps

• Historical data shows CHOP is consistently reduced to extremely low levels by the first two steps in the purification process (Col. 1 and VI)

• Excess process capacity to clear CHOP has been demonstrated through challenge studies at Column 2 and Column 3

• Of the 3 purification steps that have been routinely monitored for all mAb X commercial batches, there have been no IPC action limit excursions.

Process Consistency and Excess Capacity for Removal of Host Cell Protein has been Demonstrated

CHO Protein in VI Pool

Lot History

CHOP Challenge Study Demonstrates

Excess Clearance Capacity at Column 3

Process Step Normal Process Challenge

Study Results

Column 1 pool 2500 to 3300

ng/mg

2148 ng/mg

VI pool 1 to 2 ng/mg Skip

Column 2 pool 0 to 1 ng/mg Skip

Column 3 pool NT 8.3 ng/mg

(2.4 LRV)

Removal of redundant tests and movement of testing to the most appropriate control point

Attribute Process Step

VI Pool DS DP

CQA 1 X X X

Attribute Process Step

VI Pool DS DP

CQA 1 X

Current Optimized

11

CE- HPLC control point will be moved to VI Pool with

rejection limits

12

Overlay of Historical VI Pool and DP CE-

HPLC % Main Peak

Parameter Name N p-Value

Purification Pool 2 CE-HPLC vs. Drug Product CE-HPLC

246 < 0.0001

Summary of Testing Assessment

• DP release testing is redundant with VI Pool which is predictive of DP results.

Change from VI pool to DP is minor

• Retention of CE-HPLC testing for future comparability exercises to assess

manufacturing changes that may impact CE-HPLC attributes

pH and osmo testing to be moved off of the DS and DP specifications and retained at the Formulation step

13

Formulated Bulk Product and DP pH


• Stringent DS formulation buffer and DP formulation buffer acceptance criteria

• Positive statistical correlation between Formulated Bulk and DP

• IPC testing is redundant with DP release

• Establish reject limit at Form bulk


FBP pH vs. DP pH 142 < 0.0001

Formulated Bulk Product and DP Osmolality


FBP pH vs. DP Osmolality 142 < 0.0001

Product potency testing will be retained on the DS specification and removed from DP specification

14

Overlay Plot of DS and DP Potency

Histogram of DS and DP Potency Paired Differences


• No significant change in product potency between DS and DP under normal

processing conditions

• Characterization studies demonstrate that DP process stresses are not expected to

impact potency, critical operating parameters are well controlled

• Aggregation is the primary degradation product impacting potency. Changes would

be detected by SE-HPLC which will be retained on the DP specification

Aggregation is the primary degradation product with the

potential to impact potency. Changes are more readily

detected by SE-HPLC

15

Impact of Accelerated Condition at 60oC of mAb X

Assessed by SE-HPLC and Bioassays

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8

Days at 60°C

% R

ela

tive P

ote

ncy

0

20

40

60

80

100

120

% M

ain

Peak

HTRF

Reporter Gene

TRAP

SEC

85

90

95

100

105

110

115

120

0 0.5 1 1.5 2 2.5 3 3.5

% R

ela

tive

Po

ten

cy

Time (Months)

HTRF Bioassay A

98.2

98.4

98.6

98.8

99

99.2

99.4

99.6

99.8

0 0.5 1 1.5 2 2.5 3 3.5

% M

ain

Pe

ak

Time (Months)

SE-HPLC Main Peak B

Impact of Accelerated Thermal Storage Condition at 37C of mAb

X Assessed by HTRF Assays (Panel A) and SE-HPLC (Panel B)

Real Time Release Tests

Proposed Real Time Release Tests

• Proposal to move the lot release test point and retain on the specification

• Protein concentration

• Robust manufacturing controls at the UF/DF and DP formulation steps • Positive statistical correlation (p<0.0001) between UF/DF IPC and DS,

then DS to DP and Formulated Bulk and DP • Proposal is to remove redundant DP release test and replace with real

time release at the formulation step

• Deliverable Volume • Fill weight by in-process testing provides a larger, more statistically

relevant sample size taken across the entire batch

17

Removal of stability tests for attributes that are not stability indicating

Stability Testing for Frozen mAb X Drug Substance

Current State:

(Red—assays to remove)

• Appearance, color, clarity

• CE-HPLC

• SE-HPLC

• rCE-SDS

• Bioassay

• pH

• Protein Concentration

Proposed Actions: Retain

methods which historically have shown change over time at the recommended storage condition (ICH Q5C)

• SE-HPLC

19

Use statistical tools to identify attributes that are not stability indicating

• The lack of significant change observed over time when DS is stored at the recommended storage condition (-30°C) was determined through statistical modeling for quantitative methods

Example - Bioassay

% R

ela

tive P

ote

ncy

70

80

90

100

110

120

130

140

Time (months)

0 6 12 18 24 30 36 42 48

AOFdata.BIOds

___ Predicted Mean __ __ 95% Confidence Bound on Mean

Lot Number

0010023946001003145900100556690010067117001006807600100683330010068338001008852800100893110010110845001011488100101183700010129046001014262400101478440010148022001014850400101557720010173317049C048022049C048023049C080952049D106926049D108163

Lower Spec = 80

Upper Spec = 130

Historical mAb X DS Stability Chart

for Bioassay at the -30C

Recommended Storage Condition.

Individual lots identified, Mean

regression line

Stability Testing for Drug Product

Current State:

(Red—assays to remove)

• Appearance, color, clarity, particulate description

• CE-HPLC

• SE-HPLC

• rCE-SDS

• Bioassay

• pH

• Sub-visible particulates

• Protein Concentration

• Sterility/CCI

Proposed Actions: Retain

methods which historically have shown change over time (ICH Q5C) at the recommended storage condition and those that ensure DP safety

• SE-HPLC

• Sub-visible particles

• Sterility/CCI

21

Statistical Rationale for Removing Attributes that are not Stability-indicating

• The lack of significant change observed over time when DP is stored at the recommended storage condition (5°C) was determined through statistical modeling for quantitative methods.

Example - Bioassay

% R

ela

tive P

ote

ncy

70

80

90

100

110

120

130

140

Time (months)

0 6 12 18 24 30 36

AOFdata.BIO70

___ Predicted Mean __ __ 95% Confidence Bound on Mean

Lot Number

001000702100100070220010007023001007370200100765820010076583001007658400101182610010118714001011907400101375450010166543001017308010263641034781

Lower Spec = 80

Upper Spec = 130

Historical mAb X DP Stability Chart

for Bioassay at the 5C

Recommended Storage Condition.

Individual lots identified, Mean

regression line

Conclusions

• Quality by design principles are improving our basis for process, stability and quality control and offer us the opportunity to have an optimized testing strategy that provides control of important attributes at the appropriate point in the process

• An integrated, risk-based strategy including product quality attribute understanding and process knowledge enables selection of the right methods at the right time

• Many tests and test points can be removed without impacting overall assurance of product quality

23

Acknowledgements

• Chantal Cazeault

• Barry Cherney

• Darrin Cowley

• Alex Mercier

• Karen Miller

• Tony Mire-Sluis

• Tom Monica

24

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