cpv slides sk11aug16 - part 1 only

Stephan O. Krause, PhDBioProcessing Summit, Boston MA

Strictly Confidential18-19 August 2016

CPV Acceptance Criteria and Conditions

Outline

CPV/Commercial acceptance criteria - non-microbiological CQAs

– Control strategy development

– CPV conditions/rules

– “QA process”

CPV/Commercial acceptance criteria - microbiological CQAs– Not presented here but available via ShareSlide

The content and views expressed by the author/presenter are not necessarily the views of the organization he represents.

3

Typical CQA Development, CMC Changes, and Specifications

From: Krause, S., WCBP, 30Jan13, Washington, DC.

FTIH POC BLA

Tox Studies Phase 1Phase 2

Phase 3

Clinical ResupplyMfg/Formulation Change(s)

Specifications Revision(s)

Negotiations, Final Commercial Specifications

QTPP

Final CQAs & Control Strategy Approval

Potential CQAsProduct & Process Design

Life-CycleManagement

POST-APPROVALCHANGES

PHASE 3PHASE 1/2Pre-IND

CQ

A D

evel

opm

ent

(QbD

Pro

cess

)Sp

ecs

Life

Cyc

le

Mgm

tC

MC

and

Tec

h Tr

ansf

er P

roce

ss Analytical

Manufacturing

Strategic or Tactical Changes

Method qualification

Dose change

Delivery Device

PQ lots

Setting of Initial Specifications


Mfg Transfer

Method validation

Method transfer

Formulation Change Process Verification

Method Maintenance

Global Supply

Commercial Specifications

Accelerated CQA Development, CMC Changes, and Specifications

4

FTIH POC BLA




Commercial Specifications Negotiations, Final

Commercial Specifications and/or Post-BLA

commitmens

QTPP




POST-APPROVALCHANGESPIVOTAL PHASE (3)PHASE 1 Pre-IND

CQ

A D

evel

opm

ent

(QbD

Pro

cess

)Sp

ecs

Life

Cyc

le

Mgm

tC

MC

and

Tec

h Tr

ansf

er P

roce

ss Analytical

Manufacturing



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer


Method Maintenance

Global Supply

Method Change

Accelerated Development

From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.

Accelerated CQA Development, CMC Changes, and Specifications

5 From: Krause, S., CaSSS CMC Strategy Forum, 27Jan14, Washington, DC.

FTIH POC BLA





QTPP




POST-APPROVALCHANGESPIVOTAL PHASE (3)PHASE 1 Pre-IND

CQ

A D

evel

opm

ent

(QbD

Pro

cess

)Sp

ecs

Life

Cyc

le

Mgm

tC

MC

and

Tec

h Tr

ansf

er P

roce

ss Analytical

Manufacturing



Dose change

Delivery Device

PQ lots


Mfg Transfer

Method validation

Method transfer


Method Maintenance

Global Supply

Method Change

Accelerated Development

CompLots

PQ lots CompLots =

6

Typical CQA Development, CMC Changes, and Specifications

From: Krause, S., WCBP, 30Jan13, Washington, DC.

FTIH POC BLA


Phase 3



Negotiations, Final Commercial Specifications

QTPP




POST-APPROVALCHANGES

PHASE 3PHASE 1/2Pre-IND

CQ

A D

evel

opm

ent

(QbD

Pro

cess

)Sp

ecs

Life

Cyc

le

Mgm

tC

MC

and

Tec

h Tr

ansf

er P

roce

ss Analytical

Manufacturing



Dose change

Delivery Device

PQ lots



Mfg Transfer

Method validation

Method transfer


Method Maintenance

Global Supply


Formal CPV

S. Krause, PDA Annual Meeting - Las Vegas 17March15

CPV

QA Process

Risk Assessment Process During Product Development

Overall Risk Assessment (ex., FMEA) Scoring

Severity Score

Probability Score

Detectability ScoreControl

Strategy

(p)CQA (Prior to PV

Stage 2)

X

CQA (at/after PV

Stage 2)

X

S. Krause, PDA Annual Meeting - Las Vegas 17March15

Assessing Product Quality and/or Process Consistency Impact

Critical Process Parameter (CPP): A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality (ICH Q8 (R2))8.

Non-Critical Process Parameters are process parameters whose variability has no practically significant impact on critical quality attributes. Non-critical process parameters fall into two categories, Key Process Parameters and Non-Key Process Parameters.

Key Process Parameter (KPP): A non-critical process parameter whose variability has a practically significant impact on process performance or process consistency.

Non-Key Process Parameter (NKPP): A non-key process parameter is a non-critical process (control) parameter that has no practically significant impact on process performance or process consistency.

Courtesy of Gisela Ferreira, MedImmune

Output Measurement Impact Type of Criterion / Limit

In-Process Control (IPC)

Determinant of product quality

Acceptance Criteria:“Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures which the drug substance or drug

product or materials at other stages of their manufacture

should meet.” (ICH Q6B9)

Performance Attribute (PA)

Used to indicate that the process

performed as expected; may include quality

measurements that do not directly determine final product quality

Action Limit:“An internal (in-house) value

used to assess the consistency of the process at

less critical steps.” (ICH Q6B9)

Assessing Product Quality and/or Process Consistency Impact

Courtesy of Gisela Ferreira, MedImmune

15

Considerations for CPV (Limits)Data Transformation of Non-Normal Distributions

Original-scaled data

Log-scaled data

Data are not symmetric around center: mean and standard deviation not appropriate metrics.

Courtesy of Steven Novick, MedImmune


16From: Mark DiMartino et al. on behalf of BioPhorum Operations Group, Responses to Signals from a Continued Process Verification System in the Biopharmaceutical Industry (to be submitted to an Autumn 2016 edition of theISPE Journal of Pharmaceutical Engineering).


17

How many lots before we move the center of CLs ?

From: Mark DiMartino et al. on behalf of BioPhorum Operations Group, Responses to Signals from a Continued Process Verification System in the Biopharmaceutical Industry (to be submitted to an Autumn 2016 edition of theISPE Journal of Pharmaceutical Engineering).

Understanding Campaign Differences and Batch Differences Within a Campaign

A 95% upper confidence limit for a standard deviation is K * s, where K is given in the table and s = sample standard deviation.

There is high uncertainty in the estimate of campaign-to-campaign variability when the data set contains only two campaigns; the true standard deviation might be 15.9x greater than the existing data.

Courtesy of Steven Novick, MedImmune

# of campaigns K2 15.9

3 4.4

4 2.9

5 2.4

6 2.1

10 1.6

25 1.3

30 1.3

100 1.1

Example: Drug Substance Specifications and CPV Limit(s)

SK 22Feb16

Time (years)

HPSEC(%Monomer)

1 2 3 4

100.0%

98.5%

DS Release NLT 98.0%

Historical DS Release (n=25)

DS EOSL NLT 97.0% (= DP Release)

99.5%

99.0%

98.0%

97.0%

Example: Drug Substance Specifications and CPV Limit(s)Statistical Release Conditions

SK 22Feb16

HPSEC(%Monomer)

100.0%

98.5%


OOC Limit 99.2% (Stat: One-Sided 99.85% based on 3 SDs)

Future DS Release Result (n=1)


99.5%

99.0%

98.0%

97.0%

Example: Drug Substance Specifications and CPV Limit(s)“Practical” Alert/Action Conditions (based on non-stats DS

release specs)

SK 22Feb16

HPSEC(%Monomer)

100.0%

98.5%


Alert/Action Limit NMT 98.8%

Future DS Release Result (n=1)


99.5%

99.0%

98.0%

97.0%

Example: Drug Substance Specifications and CPV Limit(s)OOT Release Conditions for Sequential Batches

SK 22Feb16

HPSEC(%Monomer)

100.0%

98.5%


OOC Limit 99.2% (Stat: One-Sided 99.85% based on 3 SDs)

Future DS Release Result (lot 31-32)


99.5%

99.0%

98.0%

97.0%

Alert/Action Limit NMT 98.8%

Future DS Release Result (lot 31-37)

Example: Drug Substance Specifications and CPV Limit(s)OOT Stability Conditions (OOT at 18M for 20-25ºC)

HPSEC(%Monomer)

1 2 3 4

100.0%

98.5%



99.5%

99.0%

98.0%

97.0%

OOT

?

Example: Drug Substance Specifications and CPV Limit(s)OOT Stability Conditions (OOT for 2-8C at 18M)

Time (years)

HPSEC(%Monomer)

1 2 3 4

100.0%

98.5%

DS EOSL NLT 97.0%

99.5%

99.0%

98.0%

97.0%

OOT(R)

OOT(S)

OOS

Assay Variation + Slope Uncertainty

(n=5 DS)

PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions

Comparability CQA Result

“OOA”

CPP Result “OOR”

KPP Result “OOR”

NKPP Result “OOR”

(Potential) Failed Comparability

Study

Product Impact

No Product Impact but

Process Impact

No Product and/or Process Impact

CSD Approved

Discoverant CPV Tool Available for

Real-Time Monitoring

NC and CAPA

NC and CAPA

Event and Possible CAPA

Event only (Trended)

PPQ Specification

“OOS”

(Potential) Unacceptable

Product Quality and Failed PPQ

Study

(Potential) Batch Rejection/Recall

N=2 Sets of CQA Acceptance Criteria(PPQ Specifications = PPQ Protocol Acceptance Criteria;

Comparability Protocol Acceptance Criteria)

N=3 Sets of Out-of-Range (OOR) Conditions

Incr

easi

ng S

ever

ity

of P

roce

ss/P

rodu

ct/Q

ualit

y Im

pact

Biostats report and JOS

final

PPQ Specifications, CPV Acceptance Criteria, and Non-Conformance Conditions

Reference

CPV/Commercial acceptance criteria –

microbiological CQAs

– Risk assessment process

– Alert and action level examples

(Krause, S., “Alert, Action, and Specification Limits for Bioburden and Endotoxin”, PDA

Annual Meeting, 2015)

31

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cpv slides sk11aug16 - part 1 only

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