data integrity validation keynote address boston august 2016
TRANSCRIPT
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Compliance Draft Guidance and Other Global Regulations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
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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?
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5
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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
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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
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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.”
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"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
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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?
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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
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.
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http://www.pharmacompass.com/pharma-news/18-reasons-spelt-out-by-peter-j-werth-to-delete-analytical-data
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.
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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)
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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
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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)
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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)
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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.
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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
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Keynote Stance:
Attitude of a person or organization
towards CGMP
Stance
Ex-Regulator
Advisor
Patient
Questions
Why?
How?
What?
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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?
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Stance:
Ex-Regulator
Effective Remediation to Proactive Compliance
Global Regulatory Landscape
FDA Draft Guidance 2016
Top Challenges
Culture of Pharmaceutical Quality (Bonus)
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Why an increase in BDI?
How to ensure effective CAPA?
What will promote confidence?
Outline (contd.)
Why an increase in BDI?
How to ensure effective CAPA?
What will promote confidence?
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
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Stance:
Advisor (Industry)
Effective Remediation to Proactive Compliance
Global Regulatory Landscape
FDA Draft Guidance 2016
Top Challenges
Culture of Pharmaceutical Quality (Bonus)
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Why confidence is a CQA?
How confidence is achieved & sustained?
What confidence (should)contributeto top &
bottom-line?
Outline (contd.)
Why confidence is a CQA?
How confidence is achieved & sustained?
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
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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
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Evaluate the Global Regulatory Landscape
Historical perspectiveCurrent context & trends
Global regulatory expectations
Assess EU statements of non-compliance with GMP and WHO notices of concern
Understand FDA regulations and draft guidance
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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 )
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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)
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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
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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)?
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§ 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
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Company Date Issuer Subject
RL
Posted Closeout
Review selected WLs & NOCsUS FDA, EU (MHRA/EMA) , WHO
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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)).
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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.
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Statement of Non-compliance with GMP
Exchange of information between regulators
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Evidence of data integrity issues within GMP documentations, buildings were also falsified to mislead……
Directive 2003/94/EC GMPC Withdrawn!
Nature of non-compliance
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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
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Notice of Concern
Steps taken by inspectors
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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.
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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
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“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)
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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
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Why an increase in BDI?
How to ensure effective CAPA?
What will promote confidence?
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).
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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?
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Data Integrity & Compliance with CGMPApril 2016 Draft Guidance
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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.
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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.)”
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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.”
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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.
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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.
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US FDA: Remediation expectations(Warning Letter)
Third party auditor with experience in detecting data integrity problems (contd.)
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.
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US FDA: Remediation expectations(Warning Letter)
Third party auditor with experience in detecting data integrity problems (contd.)
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.
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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.
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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.
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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.
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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.
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Outline (contd.)
Why an increase in BDI?
How to ensure effective CAPA?
What will promote confidence?
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
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Outline (contd.)
Why confidence is a CQA?
How confidence is achieved & sustained?
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
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Stance:
Advisor (Industry)
Effective Remediation to Proactive Compliance
Global Regulatory Landscape
FDA Draft Guidance 2016
Top Challenges
Culture of Pharmaceutical Quality (Bonus)
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Why confidence is a CQA?
How confidence is achieved & sustained?
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.
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http://indianexpress.com/article/india/india-others/central-drug-controller-unveils-worlds-biggest-quality-check/
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
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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
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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
Indian pharmaceutical, major strides to becoming proactive
Over one-third of the total data integrity reviews conducted by EY are done proactively
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http://www.ey.com/IN/en/Services/Assurance/Fraud-Investigation---Dispute-Services/ey-data-integrity-compliance-in-the-pharma-industry (June 2015)
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.
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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.
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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
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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
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Attitude & Rationalization
Incentive & Pressure
Governance & Disregard/Neglect
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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)
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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
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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…”
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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.)
Why confidence is a CQA?
How confidence is achieved & sustained?
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
8/24/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 74
Framework developed for Culture of PharmaceuticalQualityBonus Material
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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
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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,…
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At minimum
It is and must be much more… takes a human development stance for sustainable betterment!
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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
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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
X
Y
Z
Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment
Connect to CultureConnect to Practice Quality by Design
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..
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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.
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Specific considerations for Pharmaceuticals: We make two inter-linked products; medicinal product & evidence
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
X
Y
Z
Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment
Connect to CultureConnect to Practice Quality by Design
Important to account for pharmaceutical ‘market failure’, ‘information asymmetry’ & cognitive biases (blind-spots)
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Exp
ress
Ph
arm
a 16
May
20
16
Elephant in the dark or men with blindfolds on?
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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
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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
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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
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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
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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
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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 -
Psychology of Change
A, B, C, D
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• 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
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CPQ: Need for Emphasizing Systems Thinking & Practices; QbD is the foundation (Plan-Do-Check-Act)
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
X
Y
Z
Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment
Connect to CultureConnect to Practice Quality by Design
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
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B
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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.
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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
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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
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.
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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
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8/24/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 101
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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[email protected] +12404577064