data integrity validation keynote address boston august 2016

Data Integrity: ComplianceAjaz S. Hussain, Ph.D.

KEYNOTE OPENING SESSION

Critical Update — Navigate the

2016 FDA Data Integrity

Compliance Draft Guidance and Other Global Regulations

Evaluate the Global RegulatoryLandscape

Expectations of the 2016 FDADraft Guidance

Overcome Top Challenges

Proactive Approach to Assurance of Data Integrity

Bonus Material

8/24/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1

Since 20o8 FDA has been increasing the number of inspections at foreign facilities; parity (per FDASIA) with frequency of domestic inspections by 2017?

What about ‘rigor of inspections’ -unannounced inspections?


5

24

0

5

10

15

20

25

30

2010-2012 2013-2015 2016-2018

Breaches of DI Noted in FDA CGMP Warning Letters

500

1000

1500

2000

2500

3000

3500

2008 2010 2012 2014 2016

FDA CGMP Inspections Overseas Drug Facilities

?

Breach of data integrity

Breach: an act of breaking or failing to observe a law, agreement, or code of conduct.

Failure (or error) Vs Planned (or malicious)

Planned (or by design): Local vs System-wide

Cheating by Design


Breach of dataintegrity

Data: facts and statistics collected together for reference or analysis.

Evidence based decision-making

Assurance: Quality, Safety & Efficacy

Market access, cost of doing business, profitability


Carmelo Rosa: Data Integrity, Essential Part of a Quality System

DIA Multicenter International Data Integrity Workshop. 13-14, Nov. 2014. Bangalore, India.

“Testing into compliance, data manipulation, data deletion/ record destruction, misreporting, disregarding failing and/or questionable results, all leading to possible breaches in the integrity of critical data, has become one of the most important and relevant topics currently discussed by industry and regulators from around the world.”


"Data integrity [issues] really sounds off alarm bells for us ... if you see data integrity [issues] on the surface, there is likely a lot going on underneath.“

Thomas Cosgrove, FDA on Observations related to Breaches of Data Integrity (BDI)I


The FDA issued warnings to 10 drug companies in 2015 for data integrity violations – the most in at least 10 years.

Data integrity related to Quality, Safety & Efficacy?

“All 70 batches were retested and all were found to be in specification. “

FDA is unnecessarily obsessed with data integrity issues?


http://www.pharmacompass.com/pharma-news/data-integrity-has-no-relationship-with-product-quality

ALL OTHERS BRING DATAhttp://www.pharmacompass.com/pharma-news/18-reasons-spelt-out-by-peter-j-werth-to-delete-analytical-data

http://www.pharmacompass.com/pharma-news/data-integrity-has-no-relationship-with-product-quality

http://www.pharmacompass.com/pharma-news/18-reasons-spelt-out-by-peter-j-werth-to-delete-analytical-data

The main reason data is deleted is because

the analyst (often) knows the result is not correct for reasons not related to quality (gross errors/laboratory gross errors).

They do not want to conduct an expensive, time-consuming, and cumbersome OOS (out-of-specification) investigation.



Acceptable reasons for deleting?


Quality = Meeting Specifications

Central drug controller unveils ‘world’s biggest’ quality check

This survey is likely to make or break India’s reputation as one of the leading manufacturers of generic drugs in the world.


http://indianexpress.com/article/india/india-others/central-drug-controller-unveils-worlds-biggest-quality-check/


Reactive System

Errors & failure are our drivers; low tolerance

Few failures sufficient to change laws seeking change in our behavior

Our success is not acknowledged by law makers (public)


Importance of CGMP & Documentation

Past tragedies that occurred with products that “met specifications”

Limitations of pharmacovigilance

Basic duty of care for patients we serve

Not making false claims

Epistemic trust

Even playing field


8/24/2016 Confidential. Designed for Ipca labs by Ajaz S. Hussain, Ph.D. 12

Are you aware?

Six Blind Men & the Elephant or Elephant in the Dark?

Pharmaceutical ‘market failure’, ‘information asymmetry’ & cognitive biases (blind-spots)



Attitude/drivers: Output oriented

Non-compliance

Slow to fill gaps in IT controls & other safeguards

Poor staff training , inability to escalate issues

Inadequate QA & supervisory oversight & planning

Lack of Sr. Mgmt. involvement in quality; not asking the right questions

Human factors that undermine a QMS

Culture of Pharmaceutical Quality (latent factors)

Production pressures;weak leadership skills; silos

Overwork, fear of error, low empowerment

Reliance on previous audits(reactive); not-broken – why fix it?

Ineffective root-causeinvestigations & CAPA

If “a lot going on underneath” – What is the root cause?

Set of Whys

Set of Whys

Set of Whys

Set of Whys

Breach of data integrity

Integrity: the state of being whole and undivided; the quality of being honest and having strong moral principles

Time to approval, manufacturing costs, and profitability are precisely and frequently measured

It is easier to improve what we measure; Attitude documentation is not critical to quality

Pharmacovigilance is a blunt (or highly variable) instrument; review & inspections can be heterogeneous

Can be a reason to rationalize deviant behavior; I am not causing any harm (rationalization)

The end justifies the means

increasingly dominant mindset; humans are predictably irrational (incentive & pressure)


Streetlight effect

A policeman sees a drunk man searching for something under a streetlight and asks the drunk what he’s lost.

The drunk says, “I lost my keys,” and they both look under the streetlight together.

After a few minutes, the policeman asks if he’s sure he lost them here.

The drunk replies, “No, I lost them in the park.”

The policeman asks, “Why are you searching here then?”

The drunk replies, “This is where the light is.


David H. Freedman (August 1, 2010). "The Streetlight Effect". Discover magazine

Why Is The Placebo Effect Exploding In The U.S. But

Nowhere Else?Forbes |Pharma & Healthcare

OCT 7, 2015

We are finally beginning to understand that

irrationality is the real invisible hand that drives human decision making.The End of Rational Economics.

HBR July-August 2009

Outline: Keynote

Effective Remediation,

Proactive Compliance

Global Regulatory Landscape

FDA Draft Guidance 2016

Top Challenges

Culture of Pharmaceutical

Quality


Keynote Stance:

Attitude of a person or organization

towards CGMP

Stance

Ex-Regulator

Advisor

Patient

Questions

Why?

How?

What?


Questions

Ex-Regulator

Why an increase in BDI?

How to ensure effective CAPA?

What will promote

confidence?

Advisor

Why confidence is a CQA?

How confidence is achieved &

sustained?

What confidence contributes to top

& bottom-line?

Patient

Why confidence in quality matters?

How to communicate confidence?

What metrics to track?


Stance:

Ex-Regulator

Effective Remediation to Proactive Compliance



Top Challenges

Culture of Pharmaceutical Quality (Bonus)




What will promote confidence?

Outline (contd.)




Evaluate the Global Regulatory Landscape Historical perspective

Current context & trends (483’s & Warning Letters)

Global regulatory expectations

Assess EU statements of non-compliance with

GMP and WHO notices of concern

Understand FDA regulations and draft guidance

Expectations of the 2016 FDA Draft Guidance What does the draft guidance really tell us?

What to expect for the full implementation of this guidance

How to implement meaningful and effective strategies that align with cGMP


Stance:

Advisor (Industry)




Top Challenges




How confidence is achieved & sustained?

What confidence (should)contributeto top &

bottom-line?

Outline (contd.)



What confidence contributes to top & bottom-line?

Overcome Top Challenges Understand human factors — Cognitive biases and ‘blind spots’

How does these factors contribute to breaches in assurance of data integrity?

Implement appropriate (soft and hardware) controls to ensure an effective quality management system

Simplify the framework for the culture of pharmaceutical quality

Proactive Approach to Assurance of Data Integrity Expected challenges in remediating breaches in data integrity

How to conduct effective investigations

How to make the necessary corrections

How to measure effectiveness and assess confidence to prevent reoccurrence

Effective communication — Credibility and rebuilding trust with FDA


Stance:

Patient

An implicit stance Health-care system- medical errors the third leading cause of death

Evidence of the increasing importance of placebo/nocebo effect

Our (pharmaco-) vigilance is blunt and highly variable

We measure top & bottom-line precisely and frequently

We are predictably irrational; sustained high level of fear/anxiety

We are all patients and we must all be regulators

Confidence (in medicine, regulators and companies) is a Critical Quality Attribute (CQA)

As a patient – have confidence that the medicine will do what it is supposed to do


Evaluate the Global Regulatory Landscape

Historical perspectiveCurrent context & trends


Assess EU statements of non-compliance with GMP and WHO notices of concern



Definition Data integrity refers to the completeness, consistency, and accuracy of data.

Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA)

FDA’s Draft Guidance for Industry: Data Integrity and Compliance With CGMP (April 2016 )


Historical perspective (personal

observations @ FDA)

When breaches in data integrity are reported by insiders and/or observed by regulators

Problem are often way beyond individual errors

Root causes are systemic and system wide

Reasons for rationalization include regulatory approval/validation and “doing no harm”

Business reasons (pass a filing batch or study) for allowing breaches to occur

Expert Witness for the Prosecution

Requests (e.g., Center Director) to facilitate difficult to resolve CGMP issues; prevent drug shortages

Warning Letter (re-design product/process)

Lingering Consent Decrees (re-design product/process)


Historical perspective (US Regulatory snap-shot)

Application Integrity Policy Integrity of data and information in applications submitted for FDA review and

approval. AIP List (CDER): Hill Dermaceuticals, Inc., Ranbaxy Laboratories, Ltd.,

Biopharmaceutics Inc.*, Solopak Pharmaceuticals, Inc., Superpharm Corp* (* to the agency's knowledge, the firm is out of business)

Bioresearch Monitoring FDA Debarment List (Drug Product Applications) Good Laboratory Practice (GLP), Amendment, Final Rule, 9/4/1987 Computerized Systems Used in Clinical Investigations Compliance Policy Guides:

Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities (CPG 7150.09) (July, 1991)

International Memoranda of Understanding (June, 1995) FDA Access to Results of Quality Assurance Program Audits and Inspections

(CPG 7151.02) (January 1996)

Part 11, Electronic Records; Electronic Signatures — Scope and Application March of 1997, FDA issued final part 11 regulations CPG 7153.17: Enforcement Policy: 21 CFR Part 11 Several draft guidance documents Federal Register of February 4, 2003 (68 FR 5645) – withdrawal of draft

guidance,……

Prosecution recommendations, including referrals for criminal investigation

Criminal Prosecution after Section 305 Notice & without Section 305 Notice

Special Procedures and Considerations for Park Doctrine Prosecutions


Historical Perspective: Role of data integrity in CGMP for drugs (USA)

Implicit (past)?

Requirements (e.g., 21 CFR)

§ 211.68

§ 211.180

§ 211.160

§ 211.188

§ 211.194

Other (Part 11, etc.)

Explicit (Draft

Guidance 2016)?


§ 211.68

“backup data are exact and complete,” and “secure from alteration, inadvertent erasures, or loss”

Irvine Stem Cell Treatment Center 12/30/2015 CDERCGMP/Deviations/Biologics License Application

(BLA) No

Chan Yat Hing Medicine Factory 12/15/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Sandoz Private Limited 10/22/2015 CDERCGMP/Active Pharmaceutical Ingredient

(API)/Adulterated No

Mylan Laboratories Limited 08/06/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Hospira Spa 03/31/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Apotex Research Private Limited 01/30/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Micro Labs Limited 01/09/2015 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Allergy Laboratories, Inc. 10/04/2013 ORA CGMP Deviations No

Agila Specialties Private Limited 09/09/2013 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Jabones Pardo S.A. 08/22/2013 CDERCGMP/Finished

Pharmaceuticals/Adulterated/Misbranded No

RPG Life Sciences Limited 05/28/2013 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Puget Sound Blood Center and Program 04/16/2013 Seattle CGMPs for Blood & Blood Products/Finished

Pharmaceuticals/Adulterated No

Performance Products Inc. 11/20/2012 KansasCGMP/Finished Pharmaceuticals/Animal

Drugs/Misbranded No 07/16/2013

Celltex Therapeutics Corporation 09/24/2012 CDER Human Cells, Tissues & Cellular Products Yes

Infupharma, LLC 07/30/2012 Florida CGMP for Finished Pharmaceutical/Adulterated No 06/26/2013

Shamrock Medical Solutions Group LLC 06/15/2012 CincinnatiCGMP for Finished

Pharmaceuticals/Adulterated/Misbranded No

Compania Internacional de Comercio, S.A. de

C.V.06/13/2012 CDER CGMP/Finished Pharmaceuticals/Adulterated No

Gulf Pharmaceutical Industries 02/23/2012 CDER CGMP/Finished Pharmaceuticals/Adulterated, No

Biochem Laboratories Inc. 02/17/2012 New Jersey CGMP Regulations for Finished

Pharmaceuticals/Adulterated No 11/18/2013


Company Date Issuer Subject

RL

Posted Closeout

Review selected WLs & NOCsUS FDA, EU (MHRA/EMA) , WHO


Prior to issuance of DI guidance (drafts)

Our investigator identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211.

Your firm (a CMO) failed to ensure that laboratory records included complete data derived from

all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

to follow written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to document same at the time of performance (21 CFR 211.100(b)).

establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).


These violations cause your drug products to be adulterated within the meaning of Section 501(a)(2)(B)…..

Your laboratory records did not contain all raw data generated during each test for finished drug products manufactured at your firm. Your quality unit relied on incomplete records to make batch release decisions in support of regulatory submissions to the Agency.

A QC analyst deleted original test method validation data and admitted plans to fabricate sample preparation data.

The trial injection was stored in the “trails” [sic] folder located on a personal computer. The release chromatogram identified injection (b)(4)141119009 as the sample. The trial and release chromatograms for (b)(4)141119009 do not match, and they identify different peaks.


Statement of Non-compliance with GMP

Exchange of information between regulators



Evidence of data integrity issues within GMP documentations, buildings were also falsified to mislead……

Directive 2003/94/EC GMPC Withdrawn!

Nature of non-compliance


Major deficiencies

Data falsification in relation to training records

Not routinely recording unplanned deviations

Poor QA oversight

WHO Prequalification Team - Inspection Services

Serious concerns regarding the integrity, reliability and accuracy of the data generated and available at your manufacturing site and on your ability to prevent contamination and cross contamination of your products.

The company failed to adequately perform dissolution tests and may have manipulated

dissolution test results

ensure the integrity of data

adequately conduct stability tests in line with stability protocols and commitments:

maintain adequate records of equipment usage and failed to ensure data integrity in production

provide adequate controls of contamination and cross-contamination of the product

maintain adequate standards of housekeeping and hygiene

adequate and true records for in-process controls in production

package products under adequate conditions on blister packaging lines

ensure cleanliness of the air supply to manufacturing areas where the product may have been exposed

The company may have falsified analytical test data


Notice of Concern

Steps taken by inspectors


The company failed to adequately perform dissolution tests and may have manipulated dissolution test results

The laboratory was requested to perform, under observation, the dissolution tests for X

During the first test, one of the solution vials inside the auto-injector was switched, without notifying inspectors of what was being done

However, after injection, the refrigerated bracketing solution did not fall within system suitability acceptance criteria (x.xx % RSD) and the run was rejected by the company

Dissolution results were … did not comply …

The run was restarted overnight in absence of the inspectors and passing dissolution results …were obtained

The inspectors requested that the dissolution test be repeated, in front of them

Results of…..were obtained, which differed from the results obtained by the laboratory in the absence of inspectors

Notice of Concern

Inadequate responses

The corrective and preventive actions described in your response, consisted of installing and qualifying one new dissolution tester.

This response is inadequate because it does not address the inability of your current quality management system to detect and prevent intentional and biased influencing of dissolution testing results.

The issues of training and personnel qualification, for instance, are still not addressed. Moreover, you have yet to provide a suitable explanation as to why the xx passed

Your explanations that the dissolution test results may have been affected by calibration, ….. is not substantiated by adequate evidence either.

Your statement that the deviation between the results obtained in the absence of inspectors are within the normal acceptable range is debatable and was not supported by any statistical calculations or scientific evidence.


US FDA 8/1/2016 2015 2014 2013 2012

§ 211.68 0 7 0 5 7

§ 212.110(b) 0 0 0 0 0

§ 211.100 4 5 2 2 8

§ 211.160 3 1 1 6 5

§ 211.180 0 1 2 2 3

§ 211.188 0 3 2 1 6

§ 211.194 3 3 0 4 6

§ 212.60(g) 0 0 0 0 0


“backup data are exact and complete,”

and “secure from alteration,

inadvertent erasures, or loss”

“stored to prevent deterioration or loss”

“documented at the time of

performance” and that laboratory

controls be “scientifically sound”

“original records,” “true copies,” or

other “accurate reproductions of the

original records”

“complete information,” “complete

data derived from all tests,” “complete

record of all data,” and “complete

records of all tests performed”

EudraGMDP (Public Site)


GMP Non-Compliance Search Results

Total Records: 104, Wed Aug 03 01:51:46 BST 2016

Global regulatory landscape (CGMP)

Likelihood of protracted remediation: High (USA)

Likelihood of effective CAPA: Low (USA)

Tom is right! When issues related to DI are noted - it should sounds off alarm bells …there is likely a lot going on underneath!

Company responses illustrate the lack of appreciation for QMS and inability to undertake effective investigations and CAPA

IT controls necessary but not sufficient – human factors and management accountability specifically need to be addressed to improve QMS and to ensure effective CAPA

US regulations provide more precise context BDI as these relate to QMS deficiencies (some WHO NOC trending similar to US FDA approach)

Different emphasis and actions related to GLP and GMP (infrequent use of AIP by FDA); QC vs. Production records

Remediation expectations differ with respect to the need to account for past and current deviations, in outlining the role of 3rd

party experts, and effectiveness of CAPA





Growing cluster of BDI due to improved regulatory awareness of the issue (in part to whistleblowers), increased attention to DI during inspections, improved ability to rigorously audit IT systems and gather information from company staff, and increasing frequency and rigor ( e.g., unannounced visits) of inspections

Effective root-cause investigation; system wide. 5 Whys across the system; including upstream to holes in validation, development, regulatory review and approval. Verification of CAPA effectiveness and sustainability based on objective metrics

Efficient effective remediation (WL close-out) and rapidly declining incidences of WLs & Import Alerts in 2017 on-wards (proactive compliance).


Summary: Context

Breaches of data integrity (DI) in CGMP a “hot topic”

DI implicit and integral to QMS

Violations being noted - a new trend or due to improved detectability?

Individual and organizational behaviors; errors or malicious?

What to do when the knowledge pyramid is toppled?


Data Integrity & Compliance with CGMPApril 2016 Draft Guidance


To understand FDA regulations we must take a systems perspective when reviewing

Implicit to Explicit: The role of data integrity

CGMP for drugs, as required in 21 CFR parts 210, 211, and 212

Part 210 CGMP in Manufacturing, Processing, Packing, or Holding of Drugs; General;

Part 211 covers CGMP Finished 19 Pharmaceuticals; and

Part 212 covers CGMP for Positron 20 Emission Tomography Drugs.

Flexible and risk-based strategies to prevent and detect data integrity issues

Strategies to manage data integrity risks based upon their process understanding and knowledge management of technologies and business models.

Electronic signature and record-keeping requirements are laid out in 21 CFR part 11 and apply to certain records subject to records requirements set forth in Agency regulations, including parts 210, 211, and 212.


Making it explicit

CGMP record : Any and all data to fulfill CGMP requirements; cannot be excluded from decision-making process without “valid, documented, scientific justification”

Metadata: “structured information that describes, explains, or otherwise makes it easier to retrieve, use or manage data.” All electronic CGMP records must include metadata

Workflow validation: “appropriate controls to manage risks associated with each element of a computer system”

Access control “restrict the ability to alter specifications, process parameters, or manufacturing or testing methods by technical means (for example, by limiting permissions to change settings or data.)”


Making it explicit

Audit trails : “secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the creation, modification or deletion of an electronic record.” Reviewed and approved by quality personnel

Trail Injections: Standard solution (not sample) for system suitability “requirements for precision are satisfied.” If a sample needs to be used “properly characterized (as) secondary standard”

Tips/escalation of issues: Train staff to detect and report. investigated under the documented CGMP quality system to “determine the effect of the event on patient safety, product quality, and data reliability; determine the root cause; and to ensure the necessary corrective actions are taken.”

Remediation expectations mirror those developed for the Application Integrity Policy; “hiring a third party auditor [to] determine the scope of the problem, implement a corrective action plan (globally), and remove at all levels individuals responsible for problems from CGMP positions.”


US FDA: Remediation expectations (Warning Letter)

Third party auditor with experience in detecting data integrity problems

Identify any historical period(s) during which inaccurate data reporting occurred at your facilities.

Identify and interview your current employees who were employed prior to, during, or immediately after the relevant period(s) to identify activities, systems, procedures, and management behaviors that may have resulted in or contributed to inaccurate data reporting.

Identify former employees who departed prior to, during, or after the relevant periods and make diligent efforts to interview them to determine whether they possess any relevant information regarding any inaccurate data reporting.


US FDA: Remediation expectations(Warning Letter)

Third party auditor with experience in detecting data integrity problems (contd.)

Determine whether other evidence supports the information gathered during the interviews, and determine whether additional facilities were involved in or affected by inaccurate data reporting.

Use organizational charts and SOPs to identify the specific managers in place when the inaccurate data reporting was occurring and determine the extent of top and middle management involvement in, or awareness of, data manipulation.




Determine whether any individual managers identified in item (5) above are still in a position to influence data integrity with respect to CGMP requirements or the submission of applications; and establish procedures to expand your internal review to any other facilities determined to be involved in, or affected by, the inaccurate data reporting.




As part of this comprehensive data integrity audit of your laboratory, your audit report also should include any discrepancies between data or information identified in approved applications (including Drug Master Files), and the actual results, methods, or testing conditions submitted to the Agency. Include an explanation of the impact of all discrepancies. Provide a corrective action operating plan describing the specific procedures, actions and controls that your firm will implement to ensure integrity of the data in each application currently submitted to the Agency and all future applications. This should not only cover methods validation, but any other testing (e.g., stability tests, release tests) or operations you have performed for customers that may have been used to support a drug application-related submission to the agency.


US FDA: Remediation expectations(Progress reports)

Provide an update on the status of your on-going review of data generated from your chromatographic systems that have XXX installed.

Provide a detailed description of the process followed by 3rd Party during their review of batch production and electronic laboratory records and the batch certification process.

Provide your third party assessment and certification of the integrity of data in previously approved drug applications.


US FDA: Remediation expectations(Progress reports –extended to applications)

Provide details on the following items in your response (note these elements requested are the baseline expectations for each application and we may request additional clarification or information to support the review of your applications):

Should you decide to commercialize any of your terminated products that are affected by this data integrity issue, we expect you to provide the analysis consistent with the expectations listed above (Part A) for these applications.

For already approved applications affected by data integrity breaches, we expect you to provide an analysis consistent with the expectations listed above (Part A) for these applications.

You may provide this package for selected priority applications in advance of a follow up inspection to allow FDA to prepare for possible outcomes following the re-inspection.


US FDA: Remediation expectations(Progress reports)

Provide verification that metadata files not identified by the algorithm were correctly rejected.

For the metadata files that the algorithm did not flag, split the data into two groups for data integrity review.

One group should be a random sample of records from analysts previously identified as involved in questionable laboratory practices.

The second group should randomly sample records from analysts not previously identified as involved in questionable practices. Provide the protocol, the sample size, and justification of the proposed sampling plans.


US FDA: Remediation expectations(Reminder)

Note that the FDA will refuse to approve an abbreviated application for a new drug under section 505(j) of the act for any of the following reasons: the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug product are inadequate to ensure and preserve its identity, strength, quality, and purity; i.e. if any pertinent xxx facility is named in the application, the application cannot be approved as long as it has an unacceptable compliance status.


Outline (contd.)




Evaluate the Global Regulatory Landscape Historical perspective

Current context & trends (483’s & Warning Letters)


Assess EU statements of non-compliance with

GMP and WHO notices of concern


Expectations of the 2016 FDA Draft Guidance What does the draft guidance really tell us?

What to expect for the full implementation of this guidance

How to implement meaningful and effective strategies that align with cGMP


Outline (contd.)














Stance:

Advisor (Industry)




Top Challenges





What confidence (should)contributeto top &

bottom-line?

Quality = Meeting Specifications

Central drug controller unveils ‘world’s biggest’ quality check

This survey is likely to make or break India’s reputation as one of the leading manufacturers of generic drugs in the world.




Importance of CGMP & Documentation Past tragedies that occurred with products that “met specifications”

Limitations of pharmacovigilance

Basic duty of care for patients we serve

Not making false claims

Epistemic trust

Even playing field


India has the second-largest number of manufacturing facilities outside of the US registered with the US FDA

Key highlights:

Absence of quality process and procedures

Technology upgrade is the need of the hour

Work pressure and shortage of manpower affect quality compliance

Lapses in data integrity continue to rise

Setting up whistle-blowing frameworks – work in progress


EY Survey: The state of

data integrity

compliance; Indian

Pharma

http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data-integrity-compliance-in-the-pharma-industry (June 2015)

Following CGMPs IS a commitment, it saves

lives. We make medicines – our first promise is

– ‘Do No Harm’. With our skills, awareness,

and commitment to a culture of quality – we

work to provide the ‘healing touch’ –

Confidence and Authenticity.”

Ajaz S. Hussain

http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data-integrity-compliance-in-the-pharma-industry

Indian pharmaceutical, major strides to becoming proactive

Over one-third of the total data integrity reviews conducted by EY are done proactively


http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data-integrity-compliance-in-the-pharma-industry (June 2015)

http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data-integrity-compliance-in-the-pharma-industry

Streetlight effect

A policeman sees a drunk man searching for something under a streetlight and asks the drunk what he’s lost.

The drunk says, “I lost my keys,” and they both look under the streetlight together.

After a few minutes, the policeman asks if he’s sure he lost them here.

The drunk replies, “No, I lost them in the park.”

The policeman asks, “Why are you searching here then?”

The drunk replies, “This is where the light is.


David H. Freedman (August 1, 2010). "The Streetlight Effect". Discover magazine

Why Is The Placebo Effect Exploding In The U.S. But

Nowhere Else?Forbes |Pharma & Healthcare

OCT 7, 2015

We are finally beginning to understand that

irrationality is the real invisible hand that drives human decision making.The End of Rational Economics.

HBR July-August 2009

Humans are predictably irrational; some are capable of deliberately poisoning others to make money

Daniel Kahneman and Amos Tversky. Prospect Theory: An Analysis of Decision under Risk. Econometrica, 47(2), pp. 263-291, March 1979

Losses have a bigger emotional impact than an equivalent amount of gain. People often make decisions to avoid a loss (short-term) at the expense of gains (often long-term)

Company finances are allocated differently – R&D is a “Gain” or “Investment” whereas Operations are “Costs” or “Losses”

Amos Tversky and Daniel Kahneman. The framing of decisions and the psychology of choice. Science. 1981 Jan 30;211(4481):453-8

The psychological principles that govern the perception of decision problems and the evaluation of probabilities and outcomes produce predictable shifts of preference when the same problem is framed in different ways. Reversals of preference are demonstrated in choices regarding monetary outcomes, both hypothetical and real, and in questions pertaining to the loss of human lives.


From “Art” to “Science” of pharmaceutical product and process development

21st Century Desired State: Strengthen scientific foundation to facilitate risk-based orientation

Current State: Majority still at the bottom of the pyramid + regulatory heterogeneity



Attitude/drivers: Output oriented

Non-compliance

Slow to fill gaps in IT controls & other safeguards

Poor staff training , inability to escalate issues

Inadequate QA & supervisory oversight & planning

Lack of Sr. Mgmt. involvement in quality; not asking the right questions

Human factors that undermine a QMS

Culture of Pharmaceutical Quality (latent factors)

Production pressures;weak leadership skills; silos

Overwork, fear of error, low empowerment

Reliance on previous audits(reactive); not-broken – why fix it?

Ineffective root-causeinvestigations & CAPA

If “a lot going on underneath” – What is the root cause?

Set of Whys

Set of Whys

Set of Whys

Set of Whys

Individual & Organizational Behavior


Attitude & Rationalization

Incentive & Pressure

Governance & Disregard/Neglect


Anatomy of Testing into Compliance (dissolution)

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

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….

Anatomy of Testing into Compliance (dissolution)


Pharma patterns suggestive of ‘intentional holes’“….records not

completed contemporaneously”

“…observed analyst back-date logbooks”

“…trial injections…..”

“…results failing specifications are

retested until acceptable results are

obtained….”

“…over-writing electronic raw data…..”

“…OOS not investigates per XYZ SOP”

“…appropriate controls not established….”

Each additional observation

adds reasons to confirm that

this is very likely a system with

intentional ‘holes’ in its

defenses.

A pattern suggestive of ‘intentional disregard’: Cheating by Design

Predictably irrational: Cognitive biases,…..

The cGMP issues with BDI currently being noted “new”? Not likely – rigor and frequency of US FDA inspections is changing;

more “unannounced” inspections at foreign facilities

Improving ability & capacity to conduct a thorough DI & IT system audit; Large “regulator heterogeneity” reducing (slowly)

Incorrect organizational assumptions – “FDA Approved”, “Process Validated”; push for “speed” and uninformed “Lean” programs to improve efficiency – ineffective management focus/support

Additionally, lax local regulatory norms (foreign facilities) providing reasons to rationalize deviations from cGMPs with a preferred narrow interpretation of “adulteration” to analytics

Systemic weakness in QMS – inadequate systems thinking A general disregard for the intrinsic (as opposed to just satisfy FDA)

value of documentation and assurance of data integrity; Quality by Design - much misunderstood & “file first and figure it out later” business model



Epistemic Trust

Toppled Knowledge Pyramid: Preventing a Complete Collapse

Re-building ‘epistemic trust” is difficult; First Principle is Culture

of Quality !

“a lot going on underneath…”


To understand FDA regulations we must take a systems perspective when reviewing the draft guidance – Data Integrity and Compliance with CGMP

Re-organization at FDA: OPQ & One Quality Voice

Quality Metrics & Culture of Quality

Process Validations: General Principles & Practices

CGMPs for the 21st Century & the PAT Initiatives

Outline (contd.)














Framework developed for Culture of PharmaceuticalQualityBonus Material



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


Attribute Rating

Good progress,

continue efforts

already initiated

Blind-spots, current

efforts need additional

considerations

Blind-spot + new

targeted projects

/efforts needed

CPQ Score-card• Leadership emphasis

• Message credibility

• Peer involvement

• Employee empowerment

Re-shaping the Environment

• Quality is normal

• Quality is easy

• Quality is rewarding

Re-setting the Norms

• Commitment to the System

• Knowledge based

• Understanding & controlling variations

• Safe-guards + pride of workmanship

Ensuring effective QMS

• Fear removed

• Mastery

• Awareness

Promoting proactive behaviors

Peer Involvement: It is essential that all functions recognize that “Quality is everyone's responsibility”.Employee Empowerment:However, class discussions suggested that the level of empowerment is variable within functions. This may be a ‘blind-spot’. Perhaps the high attrition rate in certain functions may be suggestive of this variability. High attrition rates (> 35%), in and of itself, is a reason for concern.

Why Culture of Pharmaceutical Quality (CPQ)?

FDA inspections are

Periodic, of limited duration, face information asymmetry, are heterogeneous,..

• Environment facilitates human behavior to do the right thing when no one is looking

• Effective QMS

• Compliance to GXP

CPQ

Safeguard for Pre-conditions to Malice or Disregard

• Attitude & Rationalization

• Pressure & Incentive

• Opportunity – “holes” in QMS, supervision, policies,…


At minimum

It is and must be much more… takes a human development stance for sustainable betterment!


Building the connect the dots framework

Pharmaceutical GXPs – Rational, Proactive, Practices

How proactive compliance is achieved? X, Y, Z

Pharmaceutical Quality Management System

What makes a QMS reliable? A, B, C, D

Culture of Pharmaceutical Quality

Why people change their behavior: 1, 2, 3

Attitude - Behavior

Predictors of Culture of Quality



Quality is Normal

Quality is Easy


System-

QMS

Appreciate System

Theory of Knowledge



Practices-GXPs

X

Y

Z



Creating a Culture of Quality: Financial incentives don’t reduce errors. Employees must be passionate about eliminating mistakes. Ashwin Srinivasan and Bryan Kurey. Harvard Business Review, April 2014.

Going beyond rules pays..



Predictors of Culture of Quality

Only four attributes

actually predict a culture of

quality:

Leadership Emphasis

Message Credibility

Peer Involvement

Employee Empowerment

People will change their

behavior if they see the new behavior as

Normal (1)

Easy (2)

Rewarding (3)

Creating a Culture of Quality: Financial incentives don’t reduce errors. Employees must be passionate about eliminating mistakes. Ashwin Srinivasan and Bryan Kurey. Harvard Business Review, April 2014.


Specific considerations for Pharmaceuticals: We make two inter-linked products; medicinal product & evidence


Quality is Normal

Quality is Easy


System-

QMS

Appreciate System

Theory of Knowledge



Practices-GXPs

X

Y

Z



Important to account for pharmaceutical ‘market failure’, ‘information asymmetry’ & cognitive biases (blind-spots)


Exp

ress

Ph

arm

a 16

May

20

16

Elephant in the dark or men with blindfolds on?


Struggle for effective cGMP remediation

Company 1: Struggling Company 2: Progressing

• Focus on ‘Root Cause’• System wide improvements• Management metrics &

data

• Inadequate Investigations• Inadequate focus on System• Superficial Management

Commitment


US FDA’s emphasis on management responsibility

Richard L. Friedman, M.S. Management Oversight and Lifecycle Quality Assurance. FDLI Workshop, Washington DC, 14-15 July, 2014


US FDA’s evolving thinking on maturity of QMS

Richard L. Friedman, M.S. Management Oversight and Lifecycle Quality Assurance. FDLI Workshop, Washington DC, 14-15 July, 2014

Historically resolution of process problems slow



Multiple causes; getting to “root” is difficult

Specific considerations for ‘Pharmaceuticals’Sector-wide issues

Market failure and information asymmetry

Two products – API or medicinal product and documented evidence of compliance; any non-compliance = adulterated under the US FD&C Act

State of control of manufacturing process often not quantified (e.g., via control charts and statistical process control) and right-first-time (i.e., without SOP deviations and/or out of specification results) for dosage form manufacturing at about 60-70%

Investigation predominantly end in “root cause unknown”; often confusion between common and special cause

Likelihood of incorrect assumption of a simple or complicated process for which “Good” practices such as SOP’s, project management are reliable tools; i.e., given a specified starting conditions adherence to SOP will reliably deliver expected results

Market standards (Pharmacopeia tests) predominantly used as “release test”; posing many challenges with respect to method validation (particularly of test methods for physical attributes) and root-cause investigations

Variable interpretation of US FDA comments in 483 and Warning Letters; work-flow often targeting to achieve minimal regulatory requirements

Lack of verifiable knowledge bases and knowledge sharing between R&D and operations

Common usage of “this is FDA approved” or “the process is validated” or “we have not received any complaints” to justify that all is well



Principles of “Out of the Crisis” by W. Edward DemingMIT Press (2000)

The journey requires leadership with

Profound Knowledge as a guide.

• As leaders responsible for system change, top management is most in need of profound knowledge

• Quality is often determined in the boardroom.

• Problems arise when management reacts to common cause or chance variation as if it were special cause variation

• Prediction based in theory provides a foundation for planning a course of action. Plan – Do – Check – Act

• The leader serves the people with clear vision and guidance to empower them. To be empowered is to share ownership in the identity

• Giving people a certain degree of control over their work fulfills the need for freedom and provides opportunity for taking joy in work


Pharmaceutical Quality for 21st Century had intended to limit the “crisis”; FDA now accelerating One Quality Voice

Paradigm It has to be built consciously – by design

QMSQ7, Quality Systems Approach to cGMPs, ICH Q10

ICH Q 8 and ICH Q11; linking API to FormulationFDA’s Process Validation Guidance (2011)

Revision of European Commission Guidelines on GMP

Risk-based ICH Q9.

Life cycle approach

Continued Process Verification – process performance and capability; statistical confidence

One Quality

Voice

OPQ, ……Culture,……Quality Metrics

Integrated Question Based Review & Inspection

Appreciation for a System

Theory of Knowledge

Knowledge about

Variation

Human Behavior -


A, B, C, D


• Appreciation for System

• Organization viewed as a system; an orchestraA

• Theory of Knowledge

• Without theory – there is no learning; Asking the right questions; Plan-Do-Check-Act

B

• Knowledge of Variation

• Common cause and special cause variability; control chartsC

• Human behavior (pride/satisfaction + conscious/subconscious biases)

• System support and safe guards; system for error management

D


CPQ: Need for Emphasizing Systems Thinking & Practices; QbD is the foundation (Plan-Do-Check-Act)


Quality is Normal

Quality is Easy


System-

QMS

Appreciate System

Theory of Knowledge



Practices-GXPs

X

Y

Z



The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg (2012)

• Scientific methodology

• Engineering Design

• Plan-Do-Check-ActConsciously

• 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


B


Maturity Level & Assurance of Quality

Managed Characterized, but reactive

High risk of ‘Cheating by

Design’

“Trail 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

C &D

Integrated implementation of FDA’s PAT guidance, ICH Q8-11 and FDA’s Process Validation Guidance (2011) essential.


X, Y & Z: Reduce Fear, Awareness & Mastery

Reduce Fear of Errors

Error strain

Covering up

Awareness

Anticipation

Risk taking

Mastery orientation

QbD/RFT

Error detection

Escalating

Analyzing errors

Correction & PreventionHigh turn-over

On-boarding new hires“Re-set” for current staff

Low awareness; passive waiting to be toldAnticipation, visualization, prevention attitudeEmpowerment to fail and take risk

Accurate RFT estimate Correct analysis of knowledgeEffective investigations Effective communicationStatistical know-howEngineering know-how


Framework: Culture of Pharmaceutical Quality (CPQ)


Quality is Normal

Quality is Easy


System-

QMS

Appreciate System

Theory of Knowledge



Practices-GXPs

Fear Removed

Mastery

Awareness



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.


From “Art” to “Science” of pharmaceutical product and process development

21st Century Desired State: Strengthen scientific foundation to facilitate risk-based orientation

Current State: Majority still at the bottom of the pyramid + regulatory heterogeneity



Epistemic Trust

Toppled Knowledge Pyramid: Preventing a Complete Collapse

Re-building ‘epistemic trust” is difficult; First Principle is Culture

of Quality !

We will never solve the problems tomorrow with the same order of consciousness we are using to create the problems of today

Assurance is predominantly in the documented evidence of adherence to cGMPs

Inspectional observations and warnings undermine public’s confidence

Deviations from SOP’s are widespread

A high demand on operators to work consciously, often under fear of not delivering expected results.

Matching order of consciousness with complexity of task and the level of assurance needed is increasingly difficult.


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data integrity validation keynote address boston august 2016

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