pharmaceutical quality by design travel options keynote @ patheon qbd 2016

Pharmaceutical Quality by Design:Travel Itineraries

Ajaz S. Hussain, Ph.D.

9/11/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1

Quality by DesignMoving to Next Generations

September 7th - 8th 2016 Patheon-Greenville

Keynote Address

Travel ItinerariesEmergency• “No-pain No-gain”

Standard• “Plan Do Check & Act”

Pathfinders• B1: “Don’t Use & Don’t

Tell”; no more!• B2: Every vertex can be

a Tipping Point• G1: Same and Similar• G2: Synthesis & Analysis


Culture of Pharmaceutical Quality


QbD Travel itineraries: 2015 –

20

06

-20

15…

?

History: FDA Packages: 2002-2005

Ajaz S. Hussain. FDA ACPS Meeting, 8 May 2002

Pharmaceutical Quality by Design: Review of Progress and Challenges (2012)

QbR to QbD to CPV 16 February 2015

Reorganization at FDA; Office of Pharmaceutical Quality

CDER/FDA; Emphasis on One Quality Voice . CGMP Alarm bells

– ringing again!

FDA Draft Guidance: Advancement of Emerging Technology

Applications to Modernize the Pharmaceutical Manufacturing

Base Guidance for Industry (December 2015)

http://www.slideshare.net/a2zpharmsci/pharmaceutical-quality-by-design-review-of-progress-and-challenges

http://www.slideshare.net/a2zpharmsci/qb-r-to-qbd-to-cpv-16-february-2015


QbD Travel Itineraries

Emergency Travel Itinerary

Continued Process Verification for all

commercial products with statistical confidence,

effective QMS and CAPA

Prevent a Warning Letter

Standard Travel Itinerary

Confident adoption of PAT, ICH Q8-11 and PV 2011.

Emphasis on patient-related failure modes and justification for scale-up

and manufacturability (in submissions). Optional comparably protocol for anticipated PAS changes.

Pathfinder Option

Rapid and/or more confident development with continuous and/or real-time

release & (optional) comparability protocol for

anticipated changes.

First Traditional and Complex Generic with new

technology1

2

3

G1

G2

B1

B2


Pathfinders

“Don’t Use & Don’t Tell” no more!

B1

Ray Scherzer ‘s challenge to Pharma: Quality By Design!


Pathfinders

Every vertex can be a Tipping Point!

B1

Remembering Einstein’s challenge that we will never solve the problems tomorrow with the same order of consciousness we are using to create the problems of today!

G2: A Destination Reached in 2016

Synthesis

&

Analysis

Disputing a 8 year ANDA review!Totality of Evidence

The clinical endpoint BE unacceptable - API particle size/shape and manufacturing process control the root cause!

FDA accepted the in vitro particle size data from MDRS in lieu of the clinical endpoint BE study


“.. a first in OGD history”

To create a Win-Win-Win!

“.. a first in OGD history”

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM502012.pdf

Alarm Bells are Ringing, Again!

Generic Drug Scandal

Office of Pharmaceutical Science

20th Century to 21st

Century Desired State

SUPAC to Design Space

Rapid Globalization and FDASIA

Breaches in Data Integrity

Office Pharmaceutical Quality

One Quality Voice


..a lot going on underneath..

“we can be blind to the obvious, and we are also blind to our blindness.” ― Daniel Kahneman, Thinking, Fast and Slow


Unaccounted Cognitive Biases & Many reasons to rationalize away dissonance

https://axispraxis.wordpress.com/2016/03/24/the-streetlight-effect-a-metaphor-for-knowledge-and-ignorance/

http://www.nbc.com/blindspot

http://dilbert.com/strips/comic/2000-02-03/

What is Culture of Pharmaceutical Quality?

We make two products –medicinal product and linked evidence of its quality, safety and efficacy

Both, required by law, to be better than Placebo!

FD&C Act & CGMP regulations – quality cannot be tested into products; it has to be built-in by design! (1987 PV Guidance)

Intention determines the punishment under the law

By Design is by intention to established a Plan-Do-Check-Act Practice


Integrating Big Ideas

Fisher, Shewhart, Deming, Kegan, Kahneman,..

Practicing: Looking Good, Being Good, Doing Good?


Epistemology essential in human development (Orders of Consciousness) and for overcoming Immunity to Change (Professor Kegan)

Our procrustean behavior driven by our cognitive biases and blind spots! [Behavioral Economics, Kahneman & others]

Testing to Document Quality Vs QbD

Order of Consciousness and approach to SOP’s, education, training experience, supervisory oversight, etc.


Need to reduce variance & skewness in the distributed understanding of pharmaceutical quality & risk to patients


Elephant in the dark or men with blindfolds on?

Ex

pre

ssP

ha

rma

16

Ma

y 2

016

A 21st Century Fable about Pharmaceutical Quality and Preventing a Clash of Cultures

https://www.linkedin.com/pulse/21st-century-fable-pharmaceutical-quality-preventing-hussain-ph-d-

CPQ: Founded on Quality by Design

We do our best to develop medicines and the evidence needed to satisfy the needs of patients – we develop these products consciously, recognizing that quality cannot be tested into our products .

We know that nothing is perfect and there will be some errors in our design, systems and procedures, or we may make mistakes in following set procedures.

It is normal, easy and rewarding to work within our quality management system, without fear, to detect, correct and to learn from our mistakes.

In doing so we act consciously in the interest of patients –especially when no one else is looking, and we continually improve our quality by design and aim for right first time.



Framework: Culture of Pharmaceutical Quality (CPQ)

Culture –Pharma Quality

Quality is Normal

Quality is Easy

Quality is Rewarding

System-

QMS

Appreciate System

Theory of Knowledge

Knowledge of Variation

Psychology of Change

Practices-GXPs

Fear Removed

Mastery

Awareness

Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment

Connect to CultureConnect to Practice Quality by Design

..a lot going on underneath..

FDASIA

New Office of Product Quality @ CDER/FDA

“One Quality Voice”

Will these changes get to the root-cause?


Latent factors and a globalized supply chain…

Variance and skewness of latent factors


Mental models ….

Thinking about “Not of One Mind” to “One Quality Voice” (OPQ/CDER/FDA 2016)

I believe this is a good model for Confident Quality Assurance.

While I was at FDA.After FDA Inspection

(e.g.,, Breach in Data Integrity) Current model.

Risk of

toppling?

Risk of

toppling?

6 Observations (Form 483)

Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit

Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed

Control procedures are not established which monitor the output and 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

The accuracy, specificity, and reproducibility of test methods have not been established . . .

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures . . .

Laboratory records do not include complete data . . .


Will the pyramid topple?What will prevent a Warning Letter? December 2013; US Facility


How to respond to these Observation? 483 Observation # 3 relates to process which delivers products to patients.

Control procedures are not established which monitor the output and 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.

A. Process Validation Protocols for My Head Aches Capsules, 1 mg lack acceptance criteria. For example: In MyPV420 – Process Validation Protocol for My Head Aches Intermediate Delayed-Release Pellets (0.X%) lack acceptance criteria for Blend Uniformity from drums, particle size and Dissolution.

B. There is no data to support the critical process parameter ranges of the My Favorite Fluid Bed Dryer in the current/proposed commercial batch production record A1234 for My Head Aches Intermediate Delayed-Release Pellets for the following:

• Inlet Air Temperature: XX-YY C

• Inlet Air Volume: XXX- YYYY m³/h

• Microclimate Pressure: XX- YYY mbar

• Dynamic Filter Pres. Max.: X-Y bar

• Dynamic filter Pres. Min.: X -Y bar

• Dynamic filter Time: X-YY seconds

• Spray Air Pressure: X-Y bar

To be Commercialized & Commercial Products

Development or validation reports contain no data supporting identification of critical process parameters and their ranges. Key focus: Process Validation Guidance 2011.

Each observation should be addressed specifically & comprehensively

Process capability roadmap a central theme (for all products at the facility)

Plus – how are CQA’s linked to PPs; what are CPPs’ and range for controlling?

How other observation impact/interact informs the methodology and sequence of work products

Process Capability Roadmap

Measurement system capable for all QA’s & PPs?

Is the process stable for all CQA’s?

What can we do to address special causes we will observe?

Are the processes capable?

Plus +++

483 Observations

Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit

Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed

Control procedures are not established which monitor the output and 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

The accuracy, specificity, and reproducibility of test methods have not been established . . .

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures . . .

Laboratory records do not include complete data . . .


© Light Pharma

Process Capability: If you can’t measure it, you can’t improve it

Process Capability Roadmap:

1

Has Measurement

System capability

been verified?

STOP!

Do not compute

Proc. Cap. statistics.

Improve the Meas. System.

No

2

Is the process stable

or unstable via SPC?

Yes

STOP!

Do not compute

Proc. Cap. statistics.

Investigate special causes.

Improve process stability.

3

Is the data normal

“enough” via the

Normality Test?

STOP!

Transform data.

No4

Compute

Cpk

Yes

Unstable

Stable

0

Challenge

Specs!

p-value < 0.05

p-value > 0.05

Gage R&R

& Calibration

SPC Charts

Scott Tarpley, UK Arden House 2004

Roadmap to process capability?

Challenge specs

Measurement system capability for all CQA’s (including dissolution test)?

Is the process stable for all CQA’s?

What can we do to address special causes we will observe?

Are the processes capable?

Plus – what is the link between CQA’s & PPs; what are CPPs’ and range for controlling?


Scott conducted a training program (2004) at FDA for the PAT Team. This slide is from my talk at a USP Annual Scientific Meeting "The Science of

Quality“. September 26–30, 2004.


Assess impact on CQAs for all process stages and

parameters(Science, Product History,

Investigations, Complaints)

Conduct statistical analyses on all process parameters comparing PV batches and

current batches

Difference between PV and Current

Batches?

Identify potential impact of process parameter on CQA

Low/HighOr

Not Applicable

Calculate Process Capability for CQA(s)

that may be impacted

Ppk > 1.3 ?

Identify Set-point, Set-point range and Operating

Range using existing supporting data

Prepare and Approve Process Parameter Summary Report

Update Master Batch Record with new ranges

YES

YES

Further evaluation required

N/A

Low/High

NO

NO

2

1

3

4

Should we take this path?

Initial decision tree: Validation batches Vs Current?

To be commercialized vs. products in commerce?Current PPs, set-points, ranges – supporting data? Equipment Qualification Ranges Vs. Process set-points and ranges?Analytical method validation & capability? Data in PD Reports, Validation Reports, SOP’s, BMRs,……?Deviations, Complaints, CAPA?

What are the most important questions?What assumptions can we accept/justify?How precise do our answers need to be?


BMRSOPsValidation

Reports

CQAs, PPs & CMA’s30-60 consecutive batches

ComplaintsCAPA

Database ready for statistical analysis

METHADOLOGY[ASTM E2709 & E2281]

Manual input

Manual input

Questions

AssumptionsPrecision

STATISTICAL METHADOLOGY2

Scientific Impact Assessment(Structured/protocol based FMEA)

3

System wide CAPA

Although the other 5 observations posed significant challenge –interconnections; it is a system!

An integrated Statistical Assessment & Scientific Impact Analysis provided a way forward

System wide implementation - an integrated adoption of PAT, ICH Q8-11 and PV 2011!



“No Pain No Gain” the name is justified!

1

2

3

What will you choose (or have already chosen)?

“Travel with Family”

“No-pain No-gain”

FDA current thinking: Question Based Review, Ppk & CPK

Adapted from: “Using process capability to achieve product quality.” March/April 2015. Pharmaceutical Engineering.


Process Capability Roadmap

Patient Related Failure Modes

Patient Related Failure Modes & Totality of Evidence

How is “clinically relevant evaluation of pharmaceutical equivalence” demonstrated?

How will you demonstrate that “fewer risks are managed by BE study alone”?

What additional steps are necessary to design a bioequivalence trial to complement equivalence in design and performance?


Future is upon us!

“No-pain No-gain” : 1 to 2 and then to 3

or

“Travel with Family”: 2 & 3

What will you choose (or have already chosen)?

Vertex or Tipping Point?

Quality & Assurance

Our knowledge pyramid topples easily because it is an upside down pyramid for several reasons

Need to keep regulatory decisions close to observation or review to maintain objectivity (& thwart corruption)

Market failure and information asymmetry

Prevailing ontological and epistemological gaps

Improving the system: One Quality Voice


US FDA is a large complex organization. How to turn a large ship? How to keep the knowledge pyramid from toppling so frequently? How to improve assurance the system delivers?


“Tipping point”

Summary Review of Regulatory Action for

Vertex’s NDA 206038: “Quality-by-Design (QBD)

process for the development of the product,

manufacturing process, and control strategy. A

fully continuous drug product manufacturing

process was applied to the manufacture of the

product, which is a unique and a new process”

“The pharmaceutical industry has been so slow to adopt .., but I think the time is now,” FDA Commissioner Margaret Hamburg said during a tour of Vertex’s new continuous manufacturing line in South Boston. WSJ 9/2/2015

What impact can FDA Commissioners’ comments, made in New England, have in FDA District Offices based in other regions?

A unique and new process was utilized in an NDA submission! It also provided for a rapid Quality-by-Design development of

product, manufacturing process and control strategy! These two aspects justify

the label – Tipping point.

Headquarters andReview Centers.

Independence of District Offices from Review Centers is an important concept.


Martin VanTrieste, R. Ph. SVP Quality Amgen PIA Meeting –June 21, 2012

From an FDA Presentation: “FDA’s Evolving Approach toPharmaceutical Quality” October 21, 2015

One of several ways C” in GGMP Emerges?


The outcome from conducting a single USP test

cannot be assumed for all the untested units in the batch

Implementation of Process Validation 2011 progresses.

Summary

Additional roadmap considerations

Target Product Profile (patient related failure modes)

QTPP – RLD CQA Characterization driven (statistical confidence)

ICH Q8 outlines a QbD methodology; don’t forget QbD is also the paradigm

Culture of Pharmaceutical Quality is founded on QbD Paradigm

QbD @ Patheon

Quality assured for patients

Synthesis of knowledge by integrating analyses

Effective communication of Why with the clients and regulators

Patheon an important Integrator ; Pathfinder opportunity!


Thank you!


Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom. Viktor E. Frankl

Between regulatory query and response there is Design Space. In that space is our comparability protocol…

will be to arrive where we started and know the place for the first time.

T. S. Eliot

We shall not cease from exploration, and the end of all our exploring …….

pharmaceutical quality by design travel options keynote @ patheon qbd 2016

Presentations & Public Speaking