Pharmaceutical Quality - The Office of

Pharmaceutical Quality:The Office ofAjaz S. Hussain, Ph.D.

Executive Director

The National Institute for Pharmaceutical Technology & Education

Duquesne UniversityIllinois Institute of Technology

Purdue UniversityRutgers University

Universidad de Puerto RicoUniversity of Connecticut

University of IowaUniversity of Kansas

University of KentuckyUniversity of MarylandUniversity of Michigan

University of MinnesotaUniversity of Wisconsin

10/27/2014 [email protected] 1

CDER Creates "Super-Office" to Keep Closer Eye on Drug Quality

“The restructuring will improve the way we deal with global challenges and increasing product complexity, and assure that quality medicines are available to the American public,” Dr. Woodcock added.

Genetic Engineering & Biotechnology News, Oct 16, 2014.http://www.genengnews.com/gen-news-highlights/cder-creates-super-office-to-keep-closer-eye-on-drug-quality/81250478/


http://www.genengnews.com/gen-news-highlights/cder-creates-super-office-to-keep-closer-eye-on-drug-quality/81250478/

Assurance of pharmaceutical quality poses a challenge

Pharmaceuticals exhibit market failures that can have devastating consequences

Devastating consequence → intention to change behavior and improve approaches for assuring pharmaceutical quality

Lacking effective means to objectively assess & mitigate risks, we accumulate layers of procedures

Which increases complexity – it , in and of itself, poses challenges & leads to inefficiencies


If you change the way you look at things, the things you look at change.Wayne Dyer

Attitude towards the

behavior

Subjective norm

Perceived behavioral

control

IntentionFuture

Behavior

usually found to predict behavioral intentions with a high degree of accuracy

intentions, in combination with perceived behavioral control, can account for a considerable proportion of variance in behavior.

PastBehavior

Ajen, I. The theory of planned behavior. ORGANIZATIONAL BEHAVIOR AND HUMAN DECISION PROCESSES 50, 179-211 (1991)

http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality



it only provides unnecessary complexity, since a manufacturing facility’s performance is only as good as the last inspector’s opinion of the GMPs

http://www.pharmaceuticalonline.com/doc/cder-s-janet-woodcock-nobody-can-really-tell-me-if-fda-inspections-are-effective-0001


http://www.pharmaceuticalonline.com/doc/cder-s-janet-woodcock-nobody-can-really-tell-me-if-fda-inspections-are-effective-0001

Presentation Outline: Questions

• Assurance of pharmaceutical quality poses a challenge?Why

• Complexities?

• Global challenges?

• Structure of OPQ?What

• Improve assurance of quality?

• CPPR, NIPTE and other similar collaborative efforts can help?

How


Preconditions to malice or disregard




Human behavior is predictably irrational

In trying to understand how best to regulate “market failure” –

Behavioral economics or morality based policies?

We ship! When no one is looking!

http://www.dilbert.com/


http://www.dilbert.com/

Root-cause may be upstream!

Satisfy reviewer requirements

Throw-over the wall

Then just do it …


Development & Application

Commercial Operations

PharmacovigilanceInspections – 483,

WL,…Marketing,….

Manufacturing

Marketing Authorization

Pre-Approval Inspection

ReviewApplication

Development

Prone to ‘process entropy’ without FDA Inspections!

http://www.nike.com/us/en_us/c/justdoit

“Throw-over the wall”

“Satisfy Reviewer Requirements”




Chemometrics

Eco

no

met

rics

Review & Approval

Business Decisions:Commercial operations,

profitability & availability.Periodic Regulatory Inspections

Three Econometric Papers on Quality

Decay, Shock, and Renewal: Operational Routines and Process Entropy in the Pharmaceutical Industry. Gopesh Anand, John Gray, and Enno Siemsen. Organization Science. 23:1700-1716 (2012)

Regulator Heterogeneity and Endogenous Efforts to Close the Information Asymmetry Gap: Evidence from FDA regulation. Jeffrey T. Macher, John W. Mayo and Jack A. Nickerson. Journal of Law and Economics. 54: 25 – 54 (2011)

Quality Risk in Offshore Manufacturing: Evidence from the Pharmaceutical Industry. John Gray, Aleda Roth, and Michael Leiblein. Journal of Operations Management. 29: 737–752 (2011)

How do people really make decisions?

Prospect Theory: An Analysis of Decision under Risk. Daniel Kahneman and Amos Tversky Econometrica. 47: 263-291 (1979)

The Framing of Decisions and the Psychology of Choice. Amos Tversky and Daniel KahnemanScience. 211, pp. 453-458 (1981)

The End of Rational Economics. Dan Ariely. Harvard Business Review, July 2009.

Chemometric, Pharmacometrics & Econometrics: Three Dimensions of QbD. Ajaz S. Hussain. Swiss Pharma (2012).



Complexities & Global Challenges

Devastating Consequences

Heparin Disaster 2007-2008

Compounding Contamination …2011 and

Current Issues

Drug Shortages 2007-2012… Currently.

Therapeutic In-equivalence

Current Issues

Data Integrity and Quality Assurance – India, China,..

Current Issue

Prophylactic medicine: Poor Adherence or Quality

2003

Six illustrative examples


See slide 32 for references.

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm

Recap


• Complexities?





How


Drivers for OPQ:

Past Success (?) & Current Challenges

FDA’s Pharmaceutical Quality for 21st Century Initiative: Successes ‘Enabling’ of modern technology

(e.g., PAT)

Updates to GMP regulations; revised GMP guidance

Multiple ICH documents:

Pharmaceutical Development and Quality by Design

Quality Risk Management;

Quality Systems

Question-based review

Formation of Pharmaceutical Inspectorate

Risk-based selection of facilities for inspection

Current Challenges (Not All-Inclusive or In Order of Priority)

Drug Shortages

State of Quality?

GDUFA Backlog

Internal Process Improvements Needed

Multiple Systems / Databases

Risk Based Quality Assessment Not Fully Realized

Knowledge & Lifecycle Management

Communication / Silos

Innovation is Not Increasing

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf



OPQ StructureOPQ

Immediate Office

Office of Programs & Regulatory Operations

Office of Policy

Office of New Drug Products

Office of Lifecycle Drug Products

Office of Process and Facilities

Office of Surveillance

Office of Testing & Research

Office of Biotechnology Products




Highlights

Quality intelligence, risk analysis & modeling

Organizational excellence, training and development

Process & facility (quality & risk)

Dosage forms & life-cycle




Integrative thinking, actions, and tools




Centralize quality drug review —creating one quality voice by integrating quality review, quality evaluation, and inspection across the product lifecycle

Consistent quality standards and risk -based approaches

OPQ will establish consistent quality standards and clear expectations for industry

Product standards should be captured in clinical quality attributes and clinically -relevant specifications

Identifying quality problems, requiring corrective actions where standards are not met, and making enforcement decisions will require close interaction between OC, OPQ, and ORA

OPQ will anticipate quality problems before they develop and help prevent drug shortages

With better knowledge of product and facility quality, we can help assure better quality drugs that are consistently available




Recap & Summary


• Complexities?




• CPPR, NIPTE and other similar collaborative efforts help?

How


Past successes??

Why the slow progress?

http://www.slideshare.net/a2zpharmsci/us-fdas-pat-guidance-10-years-and-now-final



Some reasons for the slow progress per McKinsey Report (2011)

How will OPQ overcome this?




Reflecting back 10+ years:

Integrated , systems, thinking essential – it is like learning to dance together!

What efforts are planned to ensure OPQ will learn to build effective teams..




Blind-spots (cognitive biases)

Data Integrity and Quality Assurance – India, China,.. Current

Issue

Prophylactic medicine: Poor Adherence or Quality 2003

More that than a decade ago to the current situation…..


More U.S. Marines contract MalariaWednesday, September 10, 2003 Posted: 9:25 AM EDT (1325 GMT)

WASHINGTON (CNN) -- Ten more U.S. military personnel serving as part of the peacekeeping mission in Liberia are showing signs of having contracted malaria.

We faced significant challenges in our analysis: Unexpected inter-laboratory differences that highlighted limitation of the current calibration procedure

“We are at a loss to explain the difference between DPA’s and PHI-DO’s initial results. ………………..

We further contend that the Helium sparging does not remove dissolved air as well as the vacuum procedures and therefore could account for the additional 5 or 6% increase in the dissolution results. And finally, for this formulation basket wobble can significantly increase the dissolution values.”

DPA/CDER/FDA Memo B. J. Westenberger, 17 October 2003

More than a decade ago…….


http://www.cnn.com/

http://www.cnn.com/

Today a better understanding;

Testing into compliance – why?

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”

In general – low empowerment is

a significant challenge (low

perceived behavioral

control); plus reasons to

rationalize….

“Throw-over the wall

What I am learning via surveys and interviews…




Process Validation (2011), Statistical Confidence, Continued Process Verification… Quality Metrics,….

Will need us to confront our ‘blind spots’!

http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004



If we are to anticipate quality problems before they develop – it is essential to learn how not to create problems in the first place!




Recap & Summary


• Complexities?





How


Environment that facilitates individuals to guide their behavior to work consciously in the interest of patients and to continually improve this ability.

Culture of Quality




Consciously

Scientific methodology

Engineering Design

Plan-Do-Check-Act

Habits (work to get rid of bad

ones)

Habits (work to cultivate good

one)

Keystone habits (Safety @

Alcoa; A.L.C.O.A. of data integrity)

Subconsciously

Consciously ask the right questions in the interest of the patients, describe the accepted assumptions and set the level of precision needed for the answers to the questions posed. Be a good scientist –in the interest of the patients.

The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg

(2012)




A useful tool


http://www-2.rotman.utoronto.ca/integrativethinking/definition.htm

http://www-2.rotman.utoronto.ca/integrativethinking/definition.htm

A major step taken by FDA –we all must work together to help.

We all are regulators!


Six illustrative examples –references (additional reading)


HOUSE HEARING, 110th CONGRESS - THE HEPARIN DISASTER: CHINESE COUNTERFEITS AND AMERICAN FAILURES. http://www.gpo.gov/fdsys/pkg/CHRG-110hhrg53183/content-detail.html

Fungal Meningitis Outbreak. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm323946.htm

Seeking solutions to “incredibly complex issue” of drug shortages - See more at: http://www.wdde.org/22573-rx-shortages-update#sthash.1Htx532R.dpuf

Drug Shortages. http://www.fda.gov/drugs/drugsafety/drugshortages/

Update: Bupropion Hydrochloride Extended-Release 300 mg Bioequivalence Studies. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm

In quality crackdown, US drug regulator finds Indian companies critically ill. US FDA turning stricter to ensure compliance levels and quality of medicines. Sushmi Dey. Business Standard. New Delhi , September 24, 2013. http://www.business-standard.com/article/companies/in-quality-crackdown-us-drug-regulator-finds-indian-companies-critically-ill-113092300890_1.html

More Malaria For Liberia Marines, CBS News September 8, 2003. http://www.cbsnews.com/news/more-malaria-for-liberia-marines/

FDA’s ACPS Meeting October 2005. Achieving and demonstrating “Quality by Design” with respect to drug release/dissolution performance for conventional or immediate release solid oral dosage forms . http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4187B1_01_03-Achieve-Demo-QbD.pdf

http://www.gpo.gov/fdsys/pkg/CHRG-110hhrg53183/content-detail.html

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm323946.htm

http://www.wdde.org/22573-rx-shortages-update#sthash.1Htx532R.dpuf

http://www.fda.gov/drugs/drugsafety/drugshortages/

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm

http://www.business-standard.com/article/companies/in-quality-crackdown-us-drug-regulator-finds-indian-companies-critically-ill-113092300890_1.html

http://www.cbsnews.com/news/more-malaria-for-liberia-marines/

http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4187B1_01_03-Achieve-Demo-QbD.pdf

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