qbr to qbd to cpv 16 february 2015

Question Based Development to Quality by Design to Continued Process

Verification

Ajaz S. Hussain, Ph.D.

Insight Advice & Solutions LLCNational Institute for Pharmaceutical

Technology & Education

4/13/2015 © Ajaz S. Hussain | Insight Advice & Solutions LLC 1


Does your QbD program delivery confidence in CQA’s?

Does it reduce the risk of development failure?

Does it provide a process which is stable and ‘in control’?

Does it reduce risk of GMP noncompliance?


Continuous Process Verification: An alternative approach to process

validation in which manufacturing process performance is continuously

monitored and evaluated. (ICH Q8)

Continuous Quality Verification (CQV) is described as an approach to

process validation where manufacturing process (or supporting utility

system) performance is continuously monitored, evaluated and adjusted

as necessary”. (ASTM E2537-08)

Continued Process Verification - a stage (Stage 3) of the Process

Lifecycle, after Performance Qualification (FDA Process Validation 2011)


Stage 3 ― Continued Process Verification (FDA)

..continual assurance that the process remains

in a state of control (the validated state) during

commercial manufacture…PV Guidance 2011

An ongoing program to collect and analyze product and process data that relate to product quality must be established (§ 211.180(e)). The data collected should include relevant process trends and quality of incoming materials or components, in-process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process.


21 CFR 211.180

“Firm must review, at least annually,

the quality standards of each drug

product to determine the need for

changes in drug product

specifications or manufacturing or

control procedures”


21 CFR 211.110a

“Control procedures shall be

established to monitor the output and

to validate the performance of those

manufacturing processes that may be

responsible for causing variability in

the characteristics of in-process

material and the drug product”


21 CFR 211.110a & 21 CFR 211.180

Expected trend in (2015?): 2016-18?


High risk at foreign facilities;

Quality Unit ineffective

Breaches in assurance of data

integrity; “Data too good to be

true“

Effectiveness of CAPA and

Complaint Resolution

Sporadic & heterogeneous

enforcement of CPV & Statistical

Confidence

[Pharmaceutical Equivalence

challenges and high profile

generic recalls ]

Current Concerns 2015 CPV & Statistical Confidence – the

“C“ in GMP

Ppk & Cpk linked to CAPA; Facility risk

classification

Question based Review improved and

integrated with Process Validation &

CPV

“In Control“ the Engineering

Perspective

Starting to realize the ‘Vision

2020’- “I can see clearly now”

Continual Improvement a reality;

CAPA is not continual

improvement

“And so gradually over the next

couple of years or so I think

purchasers will become aware

that they need to pay for reliability

– just like we would do with a car."

Dr. Janet Woodcock, Director

Center for Drug Evaluation and

Research, FDA (June 2013)

2016-18

2018-2020

OP

Q

Su

cce

ssfu

l

Pre

ssu

re o

f

Sh

ort

age

s

Me

tric

s &

Ris

k

Ba

se

d

GADUFA Challenges @ OGD OPQ Maturing

Culture of Quality

QbD QbR CPV Quality Metrics

http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt


Culture of Quality


Are we asking the right question and at the right time?

Culture of Quality



Are we asking the right question and at the right time?

Effective Date: 11/18/2014


CDER OPS MAPP 5015.10 (Selected Questions 14-17)

• 14. What is the rationale for selecting this manufacturing process for the drug product?

• 15. What is the potential risk of each process step to impact the drug product CQAs and how is the risk level justified?

• 16. For each of the potentially high risk manufacturing unit operations:

• a) What input material attributes and process parameters were selected for study and what are the justifications for the selection?

• b) What process development studies were conducted? Provide a summary table listing batch size, process parameter ranges, equipment type and estimated use of capacity.

• c) What process parameters and material attributes were identified as critical and how do they impact the drug product CQAs?

• d) How were the process parameters adjusted across lab, pilot/registration and commercial scale? What are the justifications for any changes?

• 17. If applicable, what online/at-line/in-line monitoring technologies are proposed for routine commercial production that allows for real-time process monitoring and control? Provide a summary of how each technology was developed.


http://www.raps.org/Regulatory-Focus/News/2015/01/13/21061/FDA-Launches-New-Drug-Quality-Office-With-Goal-of-Improving-the-Pharmaceutical-Industry/

http://www.raps.org/Regulatory-Focus/News/2015/01/13/21061/FDA-Launches-New-Drug-Quality-Office-With-Goal-of-Improving-the-Pharmaceutical-Industry/


Using Process Capability To Ensure Pharmaceutical Product Qualityby Lawrence X. Yu, Daniel Y. Peng, Robert Lionberger, Alex Viehmann and Karthik IyerThis article introduces the definition and calculation of process capability, illustrates their use in the pharmaceutical industry, and describes the relationship of process capability with production batch failure rate. The use of process capability in product development, process scale up and qualification, and commercial production is also described.


Product & Process Design

Process scale-up & Qualification

Commercial Manufacturing

Get the CQA’s right

Ensure your process is

well understood!

Control (CMAs + CPPs) →

CQA in Control

Common & Special

Causes, Control Strategy.

Initial Ppk reasonable.

Sable process on scale-up

and in Operations. Why?

Process Qualification

Protocol with Confidence.

What?

Process Qualified with

Confidence. How?

Process “in control”;

Cpk/Ppk monitoring &

trending; reduced

(traditional) testing.

Process “not in control”;

statistically meaningful

testing; effective CAPA –

identify and eliminate

‘special causes’; improve

control strategy


This journey began decades ago…..Useful information on http://www.slideshare.net/a2zpharmsci

http://www.slideshare.net/a2zpharmsci

“And like the heroes of the

French Revolution, we look to a future that will bring us

everything or nothing, depending

on the public trust”

The Nation Needs a Comprehensive Pharmaceutical Engineering Education and Research System

“A recent re-examination by the US Food and Drug Administration of the current pharmaceutical quality decision-making system raised fundamental questions about its efficiency and its continuing effectiveness to address the increasing complexity of pharmaceutical systems.”

“….low success rate for identifying the root cause of deviations and out-of-specification observations as well as the predominant focus on end-product testing—often based on an inadequate statistical consideration of inherent variability and static process conditions— which, some argue, evolved to facilitate regulatory document expectations for “process validation.”

VIEWPOINT 2005

Pharmaceutical Technology SEPTEMBER 2005


http://images.alfresco.advanstar.com/alfresco_images/pharma/2014/08/22/fcb413f5-f60b-4316-a400-c5e2f02cb9e8/article-178644.pdf

“Generics is all about file first and figure out later” State

of QbD Implementation Report to FDA June 2010, Ted Fuhr, Mckinsey& Company

“It would also mean the FDA had no power to deny tentative

approval to an application that clearly could never win final approval -

an applicant could state in its ANDA that it planned to manufacture a generic drug in an outhouse behind the applicant's house using a child's chemistry set.“ U.S. District Judge Beryl Howell (March 11, 2015)


Generics need to be defended

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM263468.pdf

http://www.courthousenews.com/2015/03/11/disgraced-drugmakers-lawsuit-infuriates-judge.htm

Rationalization & Attitude

Pressure & Incentive

Opportunity –‘holes in the QMS”

“The key to good decision‐making is not knowledge, it is understanding. We are swimming in the former. We are desperately lacking in the latter” ‐ Malcolm Gladwell


Do these questions continue to linger in Company X?

What is pharmaceutical quality?

Compendial testing sufficient?

Process validation – representative of commercial manufacturing?

Any deviation from cGMP means the product is ‘adulterated’?


Practice, Control, Process: Maturity

Initial

• Unpredictable

Managed

• Characterized, but reactive

Defined

• Characterized; proactive

Measured & Controlled

• In control

Optimizing

• Focus on improvement


Capability Maturity Model Integration; Carnegie Mellon University

A validated process?

Maturity Level & Assurance of Quality

Managed Characterized, but reactive

High risk of ‘Cheating by

Design’

“Trial Injections”

“Testing in to Compliance”

Defined Characterized; proactive

Lower level of assurance

Stopping & Correcting

Batch Rejection

Measured & Controlled

In controlQuality by

DesignQuality Assured

Improvement Opportunities


Risk of unintended or intended normative support for ‘testing into compliance’?

attitude toward

performing the

behavior

Process validation is

done so quality is

good;

test prone to error

“Batch failure means I made

a mistake”

subjective norm

Documents not critical;

Compendial testing

sufficient

Local regulators

collect & test samples – no issue there!


“Testing into compliance”

Systems thinking: System is the product of interacting parts; improving the parts

taken separately will not improve the system

CEO &

Sr. Management

Culture

of Quality

Managers &

Leaders

Effective

QMS

GXP

Compliance

All

Employees

Quality is Easy



What will it take to ensure that your QbD program delivers

(a) confidence in the CQA’s?

(b) provides a ‘stable’ and ‘in control’ process?

(c) reduces the risk of development failure?

(d) reduce risk of GMP noncompliance?

To remain true to ‘first do no harm’ we, the legitimate pharmaceutical community, have inherited, and accepted, a culture of quality that demands that our intention, our awareness and our skills deliver ‘quality by design’ with continued vigilance to detect, correct and to prevent errors that have caused, or have the potential to cause, harm to the patients we serve. We also recognize the limitations of our pharmacovigilance.

We must more clearly recognize that CAPA is not ‘continual improvement’ and that we must strengthen our culture of quality to deliver continual improvement in our ability to assure quality, reduce costs and enhance confidence in what we do. Ajaz S. Hussain, Ph.D., Mumbai, 24 March 2015

VIEWPOINT 2015


9. Into a blind darkness they enter who follow after the Ignorance, they as if into a greater darkness who devote themselves to the Knowledge alone.

10. Other, verily, it is said, is that which comes by the Knowledge, other that which comes by the Ignorance; this is the lore we have received from the wise who revealed That to our understanding.

11. He who knows That as both in one, the Knowledge and the Ignorance, by the Ignorance crosses beyond death and by the Knowledge enjoys Immortality

Isha Upanishad: Knowledge and Ignorance, Verses 9 – 11

VIDYA AND AVIDYA

VOLUME 17 THE COMPLETE WORKS OF SRI AUROBINDO (2003)

The problem of reductionism: - it works for small, not for big steps - it misses the whole - it misses the meaning - in the end, it undercuts itself.Systems approach……

Note. I have take a different point of view from that of Dharm P. S. Bhawuk, Science of Culture and Culture of Science: Worldview and Choice of Conceptual Models & Methodology. The Social Engineer. Vol. 11, No. 2, July, 2008.

Practicing to improve (awareness of) our intentions is our wisdom tradition, and is reflected in our laws, in US, India and around the globe…


qbr to qbd to cpv 16 february 2015

Health & Medicine

process data

process performance

process material

process lifecycle

process verificationajaz

process validation cpv

relevant process trends

product quality