CPV Acceptance Criteria and Conditions SK09Aug16

Stephan KrauseDirector, QA TechnologyAstraZeneca Biologics

BioProcessing Summit 17-18 August 2016Boston, MA

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- Risk assessment process- Alert and action level examples

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

5From: 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

CPV

CPV

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

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: Responses to Signals from a Continued Process Verification System in the Biopharmaceutical Industry


17

How many lots before we move the center of CLs ?

From: Responses to Signals from a Continued Process Verification System in the Biopharmaceutical Industry

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)

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





Product Impact


Process Impact


Control Strategy Document => CPV Protocol

NC and CAPA



N=3 Sets of Out-of-Range (OOR) Conditions KPIs in Quality Matrics

Manage Individual Events

Manage Repeat Events

Trend Repeat Events





Product Impact


Process Impact



NC and CAPA






Trend Repeat Events





Product Impact


Process Impact



NC and CAPA






Trend Repeat Events





Product Impact


Process Impact



NC and CAPA






Trend Repeat Events

Outline

CPV/Commercial acceptance criteria - non-microbiological CQAs- Control strategy development

- CPV conditions/rules

- “QA process”

CPV/Commercial acceptance criteria – microbiological CQAs- Risk assessment process- Alert and action level examples

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

Examples for Clinical and Process Qualification (PV Stage 2) Drug Substance Specifications for Bioburden and Endotoxin

Test / Specificat

ionIMP Phase 1-2 IMP Pivotal

or Phase 3PQ Lots

(PV Stage 2)

Reported Results Example

Bioburden NMT 10 CFU per 100 mL

NMT 1 CFU per 10 mL

NMT 1 CFU per 10 mL

0 CFU per 10 mL (1)

Endotoxin (LAL)

NMT 1.75 EU/mg protein



0.01 EU/mg protein

Bioburden: Specification for this critical safety quality attribute is compendia-based and an industry standard. Specification can remain unchanged as it is already tightly controlled for early-stage clinical studies. The use of a 10 mL sample volume was validated and justified with spiked DS samples.

(1) The 100 mL sample volume may be required, if a volume smaller than 100 mL cannot be validated (equivalent) or upon request of a regulatory agency.

Endotoxin (LAL): A specification suggested in USP <85> for the Bacterial Endotoxins Test (by LAL; NMT 5.0 EU/kg body weight) can be used for early and late-stage clinical studies. Calculation: 5.0 EU/kg x 35 kg/100 mg = 1.75 EU/mg (not changed as 1.7549 EU/mg = 5.014 (5.0 EU/kg)). For PQ lots, the DS specification is tightened, based on plant-specific manufacturing experience.


Possible IPC Alert/Action levels of Upstream/Downstream and DS Specification Lifecycle Strategy - Endotoxin

DS Endotoxin Specification:

• For PQ and/or when extensive plant-specific experience exists, tighten DS specifications.

• Use statistically calculated limits and/or use justified limits (ex., clinical experience, maximum patient exposure).

IPC Alert/Action Levels:

• For clinical and/or limited plant-specific historical experience, use QRM tools (ex., modified FMEA) to establish risk-based IPC alert/action limits.

• Use three levels (high, medium, low) for each IPC sample based the QRM risk priority numbers.

• For commercial and/or when extensive plant-specific experience exists,

• Use calculated worse-case limits based on microbial proliferation opportunity. The primary factors that affect the risk of microbial proliferation during hold times are the growth-promoting properties of the in-process materials, initial bioburden level, and storage conditions.

• Or, set statistically calculated limits (ex., based on plant-specific process capability.)

• Or, use a combination between the two as data may not be continuous (most results reported as: < Alert Level (DL/QL) and/or therefore not normally distributed.


Possible IPC Alert/Action levels of Upstream/Downstream and DS Specification Lifecycle Strategy - Bioburden

DS Bioburden Specification:

• Specification for this critical safety quality attribute is compendia-based and an industry standard.

• Specification can remain unchanged as it is already tightly controlled for early-stage clinical studies.

• The use of less than 100 mL sample volume (ex., 10 mL) should be validated and justified with spiked DS samples. Some regulatory agencies may require a 100 mL sample volume.

IPC Alert/Action Levels:

• For clinical and/or limited plant-specific historical experience, use QRM tools (ex., modified FMEA) to establish risk-based IPC alert/action limits.

• Use three levels (high, medium, low) for each IPC sample based the QRM risk priority numbers.

• For commercial and/or when extensive plant-specific experience exists,

• Use calculated worse-case limits based on microbial proliferation opportunity. The primary factors that affect the risk of microbial proliferation during hold times are the growth-promoting properties of the in-process materials, initial bioburden level, and storage conditions.

• Or, set statistically calculated limits (ex., based on plant-specific process capability.)

• Or, use a combination between the two as data may not be continuous and/or normally distributed.


General Considerations for Bioburden and Endotoxin IPC for Downstream


• IPC action and alert limits for bioburden and endotoxin are narrower towards the end of the downstream process.

• Bioburden and endotoxin IPC limits are narrower at/after Virus Filtration.

• The alert limit is further tightened to ≤ 0 CFU/10 mL at the final step(s) so that any presence of bioburden is investigated.

• Proliferation Opportunity (time, temperature, replicability – link to endotoxin)

• Endotoxin limits for in-process intermediates are determined based on the following factors:

• Quantitation Limit of 0.005 EU/mL• Maximum valid dilution (MVD) – Dilution Factor used• Expected clearance through the purification unit operations• Proliferation Opportunity (time, temperature, replicability – link to

bioburden)

Score Rating Overall Risk Rating (for Alert/Action Levels, exluding Occurrence)

1-27 Low The potential impact is minimal or has been minimized through effective controls

36-108 MediumThe potential impact is somewhat significant. Effective controls are in the process of being implemented or the existing controls are not comprehensive enough to fully mitigate the risk.

162-729 HighThe impact is significant. The existing controls are not effective in mitigating the risk or no controls are in place at all.

List of Mfg Process Steps

(Examples)

(Potential) Failure Mode Description

Unwanted Event Result

S (Severity -

Patient and/or Firm)

O (Previous) Occurance

D (Detection

Probability)

P (Proliferation Opportunity)

C (Control in Place or Risk Mitigated)

RPN (Risk Priority Number)

Downstream

(1, 3, 9) 1=low 9=high (patient impact)

(1-3) 1=low

2=medium 3=high

(1-3) 1=high

2=medium 3=low

Hold Time x Temp. x

Replicability (1,3,9)

1=low 9=high

1=yes 2=not complete

3=no

Up to 27 = green 36-108 = yellow

162-729 = red

Modified QRM FMEA for Bioburden and Endotoxin IPC Alert/Action Levels


Modified FMEA Example for Downstream Alert/Action Levels


List of Mfg Process

Steps (Examples)



S (Severity -


O (Previous) Occurance

D (Detection

Probability)

P (Proliferatio

n Opportunity)

C (Control in

Place or Risk Mitigated)


Downstream


(1-3) 1=low

2=medium 3=high

(1-3) 1=high

2=medium 3=low

Hold Time x Temp. x

Replicability (1,3,9) 1=low

9=high


3=no


162-729 = red

Formulation Buffer

Contaminated (bioburden) buffer can further contaminate the filtered, formulated drug substance/bulk.

Bioburden contamination in DS (above Action Level). Unacceptable endotoxin levels post-filtration.

9 [1] 2 3 3 162

Modified FMEA Example for Downstream Alert/Action LevelsIs Previous Occurrence a Factor Here ?


List of Mfg Process

Steps (Examples)



S (Severity -


O (Previous

Occurrence)

D (Detection

Probability)


C (Control in



Downstream


(1-3) 1=low

2=medium 3=high

(1-3) 1=high

2=medium 3=low

Hold Time x Temp. x


9=high


3=no


162-729 = red

Formulation Buffer



9 [1] 2 3 3 162

Modified FMEA Example for Downstream Alert/Action LevelsCan Uncertainty be a Factor ?


List of Mfg Process

Steps (Examples)



S (Severity -


U (Uncertainty)

D (Detection

Probability)


C (Control in



Downstream


(1-3) 1=low

2=medium 3=high

(1-3) 1=high

2=medium 3=low

Hold Time x Temp. x


9=high


3=no


162-729 = red

Formulation Buffer



9 [1] 2 3 3 162

Modified FMEA Example for Downstream Alert/Action Levels


Up to 27 = wide limits 36-108 = medium limits 162-729 = narrow limits

Scoring Description/JustificationCurrent Control(s)

and/or Possible Risk Mitigation

Recommended Action(s)

Sampling/Testing

Bioburden RPN-based Action(s) Alert/Action Level(s)

Endotoxin RPN-based Action(s)

Alert/Action Level(s) (Potential) high bioburden and/or endotoxin levelscould impact product safety. Product released with high Endotoxin levels, causing adverse events in patients. Higher S patient

multiplier (9) used in RPN calculation. Endotoxin levels in Formulation buffer have been below

Alert Level (1). Detectability is limited (2) due to sampling (sample may not be representative and

real-time testing not possible). Limited proliferation possible (3) as processing

temerature and time in manufacturign is RT and up to 10 hours. Replicability (doubling) in

formulation buffer is not prevented. Control is limited to bioburden filtration and not endotoxin. High levels of bioburden would also render the

formulation buffer unacceptable. (RPN = S (patient) [x O] x D x P x C = 9 x 1 x 2

x 3 x 3 = 162

Formulation buffer is to be tested and rejected prior to use if at/above Action Level(s).

Sample formulation buffer no later than xx hours prior to use. Store formulation buffer at 2-8 C and no longer tha xx hours at RT.

Narrow Limit(s): Alert = 1 CFU/10mL; Action = 10 CFU/10mL

Narrow Limit(s): Alert = 0.25 EU/mL; Action = 1.00 EU/mL

Examples of PQ (PV Stage 2) Downstream In-Process Control Alert and Action Limits for Bioburden and Endotoxin

Test / Alert/Action Level

Mfg Process Step/Material

Risk Priority Number Alert/Action Levels

Bioburden Formulation Buffer HighAlert: 1 CFU/10mL

Action: 10 CFU/10mL

Endotoxin (LAL) Formulation Buffer HighAlert: 0.25 EU/mL

Action: 1.00 EU/mL

BioburdenProtein A Column Wash

BufferMedium

Alert: 3 CFU/10mL

Action: 30 CFU/10mL

Endotoxin (LAL)Protein A Column Wash

BufferMedium

Alert: 0.25 EU/mL Action: 2.0 EU/mL

BioburdenCombined Protein A

Column Product PoolLow

Alert: 10 CFU/10mL

Action: 100 CFU/10mL

Endotoxin (LAL)Combined Protein A

Column Product PoolLow



Examples of PQ (PV Stage 2) Upstream In-Process Control Alert and Action Limits for Bioburden and Endotoxin

Test / Alert/Action Level

Mfg Process Step/Material

Risk Priority Number Alert/Action Levels

BioburdenBioreactor Pre-Transfer

Seed SampleHigh Alert/Action: 1 CFU/10mL

Endotoxin (LAL)Bioreactor Pre-Transfer

Seed SampleHigh


BioburdenEquilibration Buffer from

Harvest TankMedium

Alert: 1 CFU/10mL

Action: 10 CFU/10mL

Endotoxin (LAL)Equilibration Buffer from

Harvest TankMedium


BioburdenPost-Harvest Conditioned

MediumLow

Alert: 10 CFU/10mL

Action: 100 CFU/10mL

Endotoxin (LAL)Post-Harvest Conditioned

MediumLow



Documents

CPV Acceptance Criteria and Conditions SK09Aug16