Current issues and challenges in demonstrating QbD Korea 1 December 2014

Current Issues and Challenges in Demonstrating QbD: Solutions to Consider
Ajaz S. Hussain, Ph.D.
Insight Advice & Solutions LLC
2014 Ministry of Food and Drug Safety (MFDS) International Workshop: Quality by Design (QbD) Implementation and Regulatory Challenges in theNew Pharmaceutical Quality ParadigmDecember 1 -2, 2014, Grand Hilton Hotel, Seoul, Korea
12/1/2014 ajaz@ajazhussain.com 1

Outline
•A Perspective on Demonstrating QbD
•Current Issues and Challenges
•Solutions to Consider

Legitimate efficiency –is a key business driver, good for the patients, and the society overall
A Perspective on Demonstrating QbD

QbD
•Quality
•By Design
•“….quality cannot be tested into products, it has to be built in by design”
•a phrase broadly used and it has been the foundation of process validationfor many decades
•For example, the1987 FDA Guidance on Process Validation.

Demonstration of QbD is multifaceted
•Effective Quality Management System
•Continued Process Verification, Reliability, Capability (Process Validation 2011)
•Effective resolution (i.e., system wide, not repeating) of complaints, deviations, CAPA, ..
•Level of understanding and control of critical quality material attributes and process parameters relevant to the patients (safety and efficacy)
•Right attributes, analytics and acceptance range
•Structured development methodology (not just trial-n-error); asking the right questions, making assumptions transparent, and pre-defining the level of precision needed in the answers needed
•Legitimate pharmaceutical community has practiced QbD for decades; however in ways that vary undesirably
•ICH Q8, 9, 10 are intended to improve the common understanding so as to reduce variability and facilitate continual improvement

…in ways that can vary undesirably…
•CMC Review approach in US, EU, Japan,…. (e.g., prior to CTD-P2)
•Historically, very different attitude towards the utility of ‘Development Report’ in the review process
•Regulatory specifications
•Same product and manufacturing process often with different specifications in US & EU (often resulting in a higher rate of batch rejections, landfill/incinerator costs in the US)
•Different inspectional approaches
•Audit, System-based, Risk-based; Very different risk-assessment

…in ways that can vary undesirably…
•Batch that do not conform to set specifications
•Have to be investigated and often rejected –significant cost/efficiency implications
•In affluent societies/companies, rejection maybe ‘affordable’
•In less affluent companies and/or emerging economies (now an integral part of global supply chain) batch rejection may be unaffordable or may not be the norm; and may occur relatively less frequently than anticipated;
•This suspicion is currently raising a concern (in the US) that perhaps some of these ‘data are too good to be true’

92% of GMP Warning Letters in 2014 (until 7/14/14) related to lapses in data integrity (Alicia M. Mozzachio, July 15, 2014; FDLI, Washington, DC.)
•Not recording activities contemporaneously
•Backdating
•Fabricating data
•Copying existing data as new data
•Re-running samples
•Discarding data
Challenges in the assurance of Data IntegrityWL in 2013
•+ 31% WL in 2014 (7/14/14)
•+ 92%

This situation, in my opinion, is an embracement for all of us
•These observations, being noted today, I suggest, have always been there; and we can expect more of these observation to be noted in other regions with a reduction in regulator heterogeneity
•Currently, a high level of regulator heterogeneity regarding ability to detect lapses in data integrity
•For example in India –it is widely known that if a particular FDA inspector comes to a facility –there is a high likelihood of a disastrous inspection; if he does not -it is time to celebrate!

Consequences of …in ways that can vary undesirably…
•For example, bad press –often uninformed; contributing to an erosion of confidence which patients need in their medicines
•Meds banned in US pose no risk to consumers: TGA
•''Feeble’ Health Canada can't block dodgy drug imports

Legitimate efficiency –is a key business driver, good for the patients, and for the society overall
•In part, this was recognized by the FDA’s Science Board (2001- 2004); however, it is not widely understood or appreciated in the regulatory community
•Additionally, the pressure of low efficiency on maintaining an adequate assurance of data integrity, I hope, will soon be more widely recognized

Report to the FDA’s Science Board (2004)

Compendial standards and manufacturing

10%
> 1 year

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
documentation not critical
Compendial testing sufficient
Indian regulators collect & test samples –no issue there! “Testing into compliance” “Throw-over the wall”
Why ‘testing into compliance’ behavior can occur? Why it may be easy to rationalize?
Based on interviews conducted in India.

Beyond the legitimate pharmaceutical community
•We are reminded, that there are those who will substitute a rat poison for an API
•The consequence of “Cheating by Design” are almost always catastrophic

Quality By Design’ is a foundational element of
•Pharmaceutical Culture of Quality
•QbD applications can provide a measure for ‘Culture of Quality’
•Perhaps we need to view QbD applications/submissions as an additional layer of protection;
•Ameans to weed out suspicion of ‘cheating by design’?
•This can only occur when there is optimal integration
•Of all stakeholder perspectives, know-how and talent in decision making

Summary: My Perspective on QbD
•Demonstration of QbD is multifaceted
•There are serious consequences …in ways that can vary undesirably…
•Perhaps we need to view QbD applications/submissions as an additional layer of protection; to gauge the Culture of Quality
•Legitimate efficiency –is a key business driver, good for the patients, and the society overall

To QbD or not? That is the question today; unfortunately
Current Issues and Challenges?

The Pharmaceutical Development Section (P2) provides an opportunity
•To present the knowledge gainedthrough the application of scientific approaches and quality risk management …..
•Provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors.
•The [ICH Q8] guideline also indicates areas where the demonstration of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.

Integrative or Systems Approach to Pharmaceutical Quality Decisions
•Pharmaceutical exhibit market failure in that the patients or their health care provider are often unable to judge quality
•Societies empower regulators to be informed on how to judge quality on their behalf and then to ensure patients have the confidence in medicines
•Assurance of pharmaceutical quality is best approached by incorporating all stakeholder perspectives, know-how and talent in decision making
•ICH Q8, 9 and 10, among others, are tools for the various decision makers to be informed on how to evaluate quality and to utilize methodologies (by design) that can reliably delivery quality (QbD)

Common framework, vocabulary & understanding to guide decisions in the interest of patients
•For multiple functions and disciples responsible and accountable for QbD
•Review, Compliance, Inspection
•Development, QC, QA, Manufacturing
•ICH Q8, Q9, and Q10, among others, are intended to provide a basis to facilitate the establishment of a common
•Framework
•Vocabulary
•Understanding

Intended outcome
•Good decisions -in the interest of the Patients
•Higher efficiency
•Facilitate continual improvement

Current Issues and Challenges?
Before (ICH Q8-10)
Good decisions
Higher efficiency
Continual improvement
Expected After (ICH Q8-10)
Good decisions
Higher efficiency
Continual improvement
Integrated:
Framework?
Vocabulary?
Understanding?
Divisive:
Framework
Vocabulary
Understanding?

What are the current challenges?
•Where companies stand on QbD (2010)?
•Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee
•Little regulatory incentive for industry to pursue continuous improvement
•To QbD or not to QbD? That is the question…..(July 2013)
•“Industry’s view on the regulatory challenges when implementing QbD” –Roger Nosal, Pfizer, ISPE, December 2013
•EMA-FDA pilot program for parallel assessment ofQuality-by-Design applications
•Final Concept Paper Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management dated 28 July 2014

Where companies stand on QbD (2010)?
None / Novice
NCE: 22%
Generic: 40%
Biologic: 17%
Pilot
NCE: 33%
Generic: 20%
Biologic: 67%
Rollout
NCE: 22%
Generic: 40%
Biologic: 17%
Full Implemented
NCE: 22%
Generic: 0 %
Biologic; 0%
Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee

Top 10 Challenges (2010)
1
Internal misalignment
2
Lacking a business case
3
Lacking technology
4
Alignment with 3rdparties (fully implemented companies)
5
Lack of guidance for industry
6
Inconsistent treatment of QbD across FDA
7
Regulators not prepared to handle QbD (fully implemented companies)
8
Regulatory communication not inspiring confidence
9
Misalignment of international regulatory bodies
10
Interaction with FDA not conducive to QbD (fully implemented companies
Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee 12/1/2014 ajaz@ajazhussain.com 29

Key challenges by industry segments
New
Regulators are not prepared to handle QbD applications
New
Misalignment of international regulatory authorities
New and Generics
R&D incentivized for ‘shots on the goal’; not QbD
Generics
Lack of belief in business case –‘Generics are all about file first; figure out later’
Biologics
Lack of technology to execute
Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee 12/1/2014 ajaz@ajazhussain.com 30

To QbD or not to QbD? That is the question…(July 2013)
•Context: Biologics; Observations of a Senior Quality Assessor, MHRA; BioPharma-Reporter.Com
•QbD elements in most [MAA’s] come across as “flights of fancy into an imaginary parallel world”
•Some companies incorrectly see QbD as a route to accelerate approval; QbD is not a short-cut.
To QbD or not to QbD? That is the question…..(July 2013)

Very different perspectives!
•QbD elements in ~4 MAA’s for biologics submitted “flights of fancy into an imaginary parallel world”
•A viewpoint of a Senior EU regulator
•The other point –“QbD is not a short-cut”
•It is just the opposite –“over 400 small scale runs using DOE” in the most promising MAA
To QbD or not to QbD? That is the question…..(July 2013)

Some companies incorrectly see QbD as a route to accelerate approval?
•The foundational premise (ICH ‘Desired State’) has always been to make better and more efficient decisions in the interest of patients!
•We should not rule-out QbD as a route to accelerate approvals
•The divergent perspective simply means we have more work to do
•Improve integration of various perspectives (assuming all stakeholder viewpoints add value and, thefore, are worthy of integration)

Illustrative case example: Enoxaparin, Biosimilar or Generic?
Europe: Biosimilar
•Sandoz-Momenta proposed MAA presented and discussed
•With MPA & BfArM
•EMEA Workshop on Process Analytical Technologies for Biologicals (15th March 2007, Room 3A, EMEA)
•A related presentation is at 5thEGA Symposium on Biosimilars, London
USA: Generic
•Sandoz-Momenta ANDA approved July 23, 2010 (first to be approved)
•“This [enoxaparin] approval represents a major development in US regulatory science and policy that will likely affect several other complex drug products...the extensive analytical characterization, as carried out for enoxaparin, will be important in the evaluation of protein products and may help to reduce the scope and extent of animal and clinical studies for biosimilars.”
•Sau Lee, et. al., Scientific Considerations in the Review and Approval of Generic Enoxaparin in the United States. Nature Biotechnology. Volume 3, 220- 226 (2013)

Illustrative case example: Accelerated Approval –Breakthrough Therapy Designation
Peter Mueller, PhD CSO & Executive Vice President, Global R&D Vertex Pharmaceuticals, Inc. IFPAC Conference, January 2013, Baltimore, MD

IFPAC Conference, January 2013, Baltimore, MD

Lets’ be clear
•Continuous manufacturing is not the only way to demonstrate QbD!
•It does, however, provide the means to a paradigm shift needed to look at the problem at hand, from a different perspective; I am aware of several similar example which are rapidly progressing

EMA-FDA pilot program for parallel assessment ofQuality-by-Design applications
•Consistent implementation between EU and US of ICH Q8, 9, 10, 11 guidelines in the assessment
•What are the Agencies’ expectations in a regulatory submission for Quality Target Product Profile (QTPP)?
•What are the Agencies’ expectations in a regulatory submission for Critical Quality Attributes (CQAs)?
•Would the Agencies accept a three-tier classification of criticality for process parameters?
•What are the Agencies’ expectations in a regulatory submission for manufacturing process descriptions?
•What are the Agencies’ views with respect to the use of analytical target profile (ATP) for analytical methods?
•What are the Agencies’ expectations in regulatory submissions for Method Operational Design Ranges (MODR)?
•Questions and Answers on Design Space Verification
•EMA and FDA extend pilot programme for parallel assessment of quality-by-design applications
•Applications can be accepted till March 2016

Both Agencies met all their timelines and milestones
•Over 50% of FDA’s IR questions common with EMA LoQs
•Close agreement on:
•QTPP and CQAs
•Criticality
•Design Space verification
•Level of detail in manufacturing process descriptions
•QbD for Analytical Methods
Limited time to reach agreement for controversial issues
•Differences in regional requirement leading to different submission requirements
•More work needed –NIR, Design Space development, & Risk assessment detail in dossier
•A company (1st) reported: 35 questions by FDA and 100 by EMA; only 19 were common!
What worked and what didn't
http://www.pqri.org/workshops/EVP2014/Chatterjee.pdfhttp://www.in-pharmatechnologist.com/Regulatory-Safety/Manufacturing-Must-be-Described-Whether-QbD-or-Not-say-EMA-and-FDA

Proposed ICH Q12
•“…lack of alignment has led to confusion on the necessary information and level of detail in the dossier and its impact on change management and regulatory reporting.”
•“Intended to work with ICH Q8 to Q11 Guidelines”
•“Provide a framework to facilitate the management of post-approval changes in a more predictable and efficient manner across the product lifecycle”
•“Adoption of this guideline will promote innovation and continual improvement, and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustment”
•“It will allow regulators (assessors and inspectors) to better understand, and have more confidence and trust in a firm’s Pharmaceutical Quality System (PQS) for management of post-approval CMC changes”
Final Concept Paper. Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. 28 July 2014

Summary -Current Issues and Challenges
•Lack of integrated implementation (QMS, GMP not effectively included)
•Inadequate consensus on the ICH framework, vocabulary, understanding –Why
•Review focus on data and not on knowledge; increasing burden on those who were willing to share additional information
•Leading to the question: To QbD or Not?

Beyond what has already been proposed
Solutions to Consider

ICH Q12: Issues to be Resolved
•Regulatory Dossier -“regulatory commitments”
•Pharmaceutical Quality System aspects (ICH Q10) –risk and knowledge management system
•Post-Approval Change Management Plans and Protocols
Final Concept Paper. Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. 28 July 2014

What has already been proposed
•ICH Q12
•“…allow regulators (assessors and inspectors) to better understand, and have more confidence and trust in a firm’s Pharmaceutical Quality System (PQS) for management of post-approval CMC change.”

Human aspects
•Team approach to review and inspection
•Different but equally important functions
•Team-building and training is essential
•Culture of Quality
•Regulatory bodies
•Companies
•Recognize that QbD applications/submissions serve as an additional layer of protection; to gauge the Culture of Quality

Culture of Quality
•Environment that facilitates individuals to guide their behavior to work consciously in the interest of patients and to continually improve this ability
•Through our disciplined training and experience –it should be our habit to work consciously in the interest of patients
•It is a measure of safeguards against pre-conditions to malice or disregard
•Attitude & Rationalization
•Pressure & Incentive
•Opportunity –“holes” in QMS, supervision, policies,…

A framework for Culture of Qualityhttp://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality

Summary
•Demonstration of QbD is multifaceted
•There are serious consequences …in ways that can vary undesirably…
•Perhaps we need to view QbD Applications/submissions as an additional layer of protection; to gauge the Culture of Quality
•Legitimate efficiency –is a key business driver, good for the patients, and the society overall

Summary
•Lack of integrated implementation (QMS, GMP not effectively included)
•Inadequate consensus on the ICH framework, vocabulary, understanding –Why
•Review focus on data and not on knowledge; increasing burden on those who were willing to share additional information
•Leading to the question: To QbD or Not?

Summary
•Proposed
•ICH Q12 Regulatory Dossier -“regulatory commitments”
•Pharmaceutical Quality System aspects (ICH Q10) –risk and knowledge management system
•Post-Approval Change Management Plans and Protocols
•A reminder of the approach utilized for FDA’s PAT Guidance, Comparability Protocol and Team Approach
•Must focus on integrated implementation
•Team-building and training for Review, Compliance & Inspection functions
•Recognize that QbD Applications/submissions serve as an additional layer of protection; to gauge the Culture of Quality

Acknowledging the contributions of the FDA’s PAT Team…..

Current issues and challenges in demonstrating QbD Korea 1 December 2014

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