fda trend: new validation strategies

Ajaz S Hussain | Insight, Advice & Solutions LLC

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FDA Trends: New Validation Strategies2ND INTERNATIONAL CONFERENCE ON CONTINUED AND ON-GOING PROCESS VERIFICATION 20TH MARCH 2017, NOVOTEL HAMBURG, GERMANY

3/19/2017

Ajaz Insights [email protected]

mailto:[email protected]


2Outline• Part 1: FDA Trends

• Background: The little secret – swept under the rug? No more!• Challenge or opportunity: Unprecedented juxtaposition – at the Tipping Point!• Questions: What consideration are needed for building your validation roadmap?

Three options: Pathfinder, Standard or Emergency; what will you choose?

• Part II: A higher level of confidence in quality assurance : State of Control (stability, capability with statistical confidence) • Case example: Challenges of implementing a roadmap to process capability for

some currently commercialized products.

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3 A story about manufacturing two products, medicinal product and documented data, and a “little secret”

• Little Secret? Perhaps some of you may remember and recall the front page article in the Wall Street Journal dated 3 September 2003

• “The Pharmaceutical Industry Has a Little Secret”

• “Even as it invents futuristic new drugs, its manufacturing techniques lag far behind those of potato-chip and laundry soap makers.”

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[Pharmaceutical] Industrial Revolutions: 1.0, 2.0, 3.0, and 4.0?

•Background: How did the journey begin in 2000 and progress until 2005? If you are interested please click on the video message from the past

• Pharmaceutical cGMPs for the 21st Century — A Risk-Based Approach

•Today we have an unprecedented juxtaposition of the main forces necessary for the US pharmaceutical manufacturing renaissance – we are at the Tipping Point3/19/2017


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https://youtu.be/II0_nE6hr9c

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UCM071836

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodManufacturingPracticescGMPforDrugs/UCM071836


5 Hello, I am Dr. Ajaz S. Hussain.

I am passionate about making high pharmaceutical quality affordable to all.

• President, the National Institute for Pharmaceutical Technology & Education http://nipte.org/

• Ajaz S Hussain Insight, Advice & Solutions LLC http://www.ajazhussain.com/

• Professional practice related to development of complex generics, biosimilars, QbD, Real-Time-Release, Continuous Manufacturing & strengthening culture of pharmaceutical quality • Not-for-profit

• Advocacy of NIPTE Education & Research Programs• Advisor (pro bono) to the USP & C-SOPS; Programing for

Continuous Manufacturing• Commercial

• Advisor to several pharmaceutical, biopharmaceutical, software and consulting firms

• Advisor & shareholder, CONTINUUS Pharmaceuticals

Academia: Currently Adjunct Professor @ Long Island University; previously tenured faculty @ University of Cincinnati (1989-1994)

US FDA: CDER /OPS Deputy Director (2000-2005) and other positons (1995-2000); Lead PAT & Pharmaceutical Quality for the 21st Century Initiatives & related ICH efforts

Industry: Formerly President & CSO @ Wockhardt (USA, 6/2012 to 6/2013), CSO & VP @ Philip Morris International (Switzerland, 2009-2012), Global Head & VP @ Sandoz (USA & Germany, 2005-2009)

3/19/2017

http://nipte.org/

http://www.ajazhussain.com/


6 Unprecedented juxtaposition – at the Tipping Point• In the 21st Century, Quality

entangled with Security• With rapid globalization, societies

are experiencing increasing level of fear/apprehension

• Quality – Clinical entanglement remains elusive while placebo/nocebo effects are increasing

• The progress in pharmaceutical technologies such as real-time controls and continuous manufacturing,

• legislative recognition of the need for efficient pharmaceutical manufacturing as in the 21st Century Cures Act, and

• President Trump’s focus on manufacturing in the USA.

3/19/2017

Increasing societal demand for higher assurance of pharmaceutical quality and lower prices, historical regulatory opposition and uncertainty is turning to regulatory preference for PAT based real-time-controls, continuous manufacturing and digital manufacturing enablers – the Tipping Point!


7

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8 The consequence of the little secret is now being understood more broadly

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http://www.fda.gov/ohrms/dockets/ac/02/briefing/3841B1_05_PFIZER.PDF ; FDA Science Board 16 November 2001

http://www.fda.gov/ohrms/dockets/ac/02/briefing/3841B1_05_PFIZER.PDF

The “little secret” in (solid dosage) manufacturing•Certificate of Analysis : Uncertainty in solid-state material attributes•Research laboratory measurement systems such as dissolution : Life-cycle stability and reproducibility in QC?•Fixed equipment and process parameters: Committed in submissions, difficult to change post approval; why bother finding the real cause? •Uncertainty in the stability and capability of measurements and manufacturing process: Raises questions on adequacy of sampling and obstructs risk-based decisions•Globalization – variable empowerment/oversight: “FDA Approved” and “Validated”; frames the mindset and ease of rationalization - cheating by design & breaches in data integrity

3/19/2017Ajaz S Hussain | Insight, Advice & Solutions LLC

9

If you keep your head in the sand, you don't know where the kick's coming from. Herbie Mann

http://www.searchquotes.com/quotes/author/Herbie_Mann/


10 Where there is a will there is a way!3/19/2017


11 NDA 26038; Orkambi®, Vertex Pharmaceuticals 25 June 2015

3/19/2017

From: Martin Warman, Kelly Swinney and Justin Pritchard. PAT for In Process Control (IPC) and Real Time Release Testing (RTRT) in Continuous Manufacturing. 7th Pharmaceutical Technology Conference on Continuous Manufacturing, Japan (December 2015)

Angle of Repose Tipping Point


12 Two illustrative examples (small molecules)

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• FDA Awards $4.9 Million to Rutgers-Led C-SOPS• FDA invitation to prepare and

submit a proposal for an "FDA guidance in Continuous Manufacturing“

• FDA Awards $4.4 Million to CONTINUUS Pharmaceuticals, Inc.• “Advancement of Integrated

Continuous Manufacturing (ICM) Unit Operations”; to develop a science and risk-approach on how drug quality can be monitored and improved through integrated continuous manufacturing (ICM).

C-SOPS GEA

MIT-Novartis: Continuus

http://csops.rutgers.edu/regulatory-working-group-continous-manufacturing-guidance

http://www.gea.com/en/binaries/Continuous-Tablet-Manufacturing_tcm11-23357_w570.jpg

https://engineering.mit.edu/labs/novartis

The Manufacturing USA Strategy is rapidly evolving!

•Manufacturing USA consists of multiple linked Manufacturing Innovation Institutes• The National Institute for

Innovation in Manufacturing Biopharmaceuticals NIIMBL

•USP and C-SOPS Collaboration PCM

3/19/2017


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https://energycommerce.house.gov/

Credit: Ron Sachs/SIPA/Newscom

http://www.niimbl.us/

http://qualitymatters.usp.org/exploring-continuous-manufacturing-technology-and-applications-pharmaceutical-industry


14 Serious consideration needed for building your roadmap….

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


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How?

• Pathfinder Option• You have the “PAT spirit”; you are not waiting for “guidance”

from regulators • You move now; engaging the regulators and taking them with

you on your visionary journey ; then you offer to train the regulators!

• Standard Option• You will wait for regulators to issue guidance • You get ready to move in about 3 years; you complete

implementation of Process Validation 2011 and QbD (Q8-11) –with a vigorous check for risk of breaches in the assurance of data integrity (and prevent suspicion of “are these data too good to be true?”)

• Emergency Option• Oh no! A bad inspection with the “dreaded” observations!• CAPA, process improvement & smart HPLC that says STOP to

“trial injections”

Leadership-drive and options

Industry 1.0

Industry 2.0

Industry 3.0

Industry 4.0

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What?

• Technology platforms• Manufacturing with controls [PAT-RTRT partial or full]

• API only, DF only, Integrated API & DF

• Rapid development, manufacturing with controls • PAT-RTRT with continuous manufacturing

• Other – human behavior motivation & monitoring , Big Data, pattern recognitions, etc.

• New (generic or brand) development Vs. Post Approval • OSD IR: BCS Class I, Direct Compression,….• OSD IR: BCS Class IV, Wet Granulation….• OSD MR: Extended Release• …….

• People & Organization Development , Partnerships & Collaboration

• Internal mindset shift and collaborations• Regulator communication and collaboration• Partnership & collaboration with Suppliers & Technical Experts• Collaboration with Academia (e.g., NIPTE)

You need to consider

3/19/2017


17 FDA TrendsTrend: a general direction in which something is developing or changing

2000-2016

• FDA Initiatives; PAT, CGMPs for 21st Century, Critical Path…

• ICH Desired State: Pharmaceutical Quality for the 21st Century

• Guidelines PAT, ICH Q8, 9, 10, Process Validation (2011), ICH Q11 and (Q 12)

• Guideline effectively practiced?

• 2007 – Heparin Tragedy, drug shortages, Warning Letters,. Breeches in Data Integrity…..

• FDA reorganization: OPQ, One Quality Voice,.. Real-Time-Controls & Continuous Mfg.

2017-

• 21st Century Cures Act (13 Dec 2016)

• President Trump’s Focus (2017-)• We have got to get our drug industry back

and bring drug prices “way down,” and promised to curb regulations and lower tax rates to boost their competitiveness

• New Business, Process and Analytical Method Validation Strategies

3/19/2017

https://www.nytimes.com/2017/01/11/us/politics/trump-press-conference-transcript.html

https://www.wsj.com/articles/trump-tells-pharmaceutical-ceos-he-wants-prices-down-1485875553



Summary: Part I

•The little secret – swept under the rug? No more!

•Unprecedented juxtaposition – at the Tipping Point!

•Serious consideration needed for building your roadmap!

•Three options: Pathfinder, Standard or Emergency; what will you choose?

3/19/2017


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What

• PAT based Real-Time Release Testing (RTRT) provides by design a higher assurance of quality• Statistically valid sampling and testing of starting and in-

process materials and finished dosage forms utilizing non-destructive and non-compendial methods

• Simultaneous (real-time) recording of data with traceability• Necessitates up-front design and development efforts while

considering product life-cycle; this yields a robust control strategy based on knowledge and understanding of sources of variability

• Technological advancement now allow rapid development (even in the context of Breakthrough Therapies) with more realistic definition of Design Space

• Availability of technological platforms to address concerns associated with irrational human behaviors, reduce time and cost of development and justification & motivation to encourage manufacturing in the USA

FDA is encouraging real-time-controls (and

continuous manufacturing):

A higher level of confidence in quality assurance : State of Control (stability, capability with statistical confidence)

3/19/2017


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How?

• Pathfinder Option• You have the “PAT spirit”; you are not waiting for “guidance”

from regulators • You move now; engaging the regulators and taking them with

you on your visionary journey ; then you offer to train the regulators!

• Standard Option• You will wait for regulators to issue guidance • You get ready to move in about 3 years; you complete

implementation of Process Validation 2011 and QbD (Q8-11) –with a vigorous check for risk of breaches in the assurance of data integrity (and prevent suspicion of “are these data too good to be true?”)

• Emergency Option• Oh no! A bad inspection with the “dreaded” observations!• CAPA, process improvement & smart HPLC that says STOP to

“trial injections”

Leadership-drive and options

Industry 1.0

Industry 2.0

Industry 3.0

Industry 4.0

3/19/2017


21 How to respond to these Observation?

483 Observation # 3 relates to process which delivers products to patients

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

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

• Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product

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

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

• Laboratory records do not include complete data . . .

Following an FDA inspection at a Generic Facility in the USA a Form 483 was issued with 6 observations

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483 Observation # 3

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

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

• • Inlet Air Temperature: XX-YY C

• • Inlet Air Volume: XXX- YYYY m³/h

• • Microclimate Pressure: XX- YYY mbar

• • Dynamic Filter Pres. Max.: X-Y bar

• • Dynamic filter Pres. Min.: X -Y bar

• • Dynamic filter Time: X-YY seconds

• • Spray Air Pressure: X-Y bar

Control procedures are not established which monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

To be Commercialized & Commercial Products

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

3/19/2017


23How to address the 483 Observations• Each observation should be addressed

specifically & comprehensively

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

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

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

• Measurement system capable for all QA’s & PPs?

• Is the process stable for all CQA’s?

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

• Are the processes capable?

• Plus +++

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24Roadmap to process capability?

Challenge specs

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

Is the process stable for all CQA’s?

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

Are the processes capable?

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

Scott conducted a training program (2004) at FDA for the PAT Team.

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

STATISTICAL METHODOLOGY


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3/19/2017

The “little secret” in (solid dosage) manufacturing•Certificate of Analysis : Uncertainty in solid-state material attributes•Research laboratory measurement systems such as dissolution : Life-cycle stability and reproducibility in QC?•Fixed equipment and process parameters: Committed in submissions, difficult to change post approval; why bother finding the real cause? •Uncertainty in the stability and capability of measurements and manufacturing process: Raises questions on adequacy of sampling and obstructs risk-based decisions•Globalization – variable empowerment/oversight: “FDA Approved” and “Validated”; frames the mindset and ease of rationalization - cheating by design & breaches in data integrity

3/19/2017Ajaz S Hussain | Insight, Advice & Solutions LLC

29

If you keep your head in the sand, you don't know where the kick's coming from. Herbie Mann

http://www.searchquotes.com/quotes/author/Herbie_Mann/


30Summary: More confident assurance of pharmaceutical quality

• Effective CAPA to continual improvement

• Process capability roadmap for legacy products

• Stability & capability in Continued Process Verification with clearer understanding of Common Cause Vs Special Cause Variations

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

• Removing blind-spots and changing mindsets• Compendial test: Release Test Vs. Market Standards• Measurement system capability for all CQA’s

(including dissolution test)?• Life-cycle validation for analytical methods ;

specifically these for physical attributes

Effective CAPA and achievement and communication on the State of Control – stability and capability (and statistical confidence)

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FDA Trends: New Validation Strategies

• Why: • Need for more confident assurance of pharmaceutical

quality has increased? • FDA is encouraging PAT based real-time-controls (and

continuous manufacturing) as a preferred means to achieve higher confidence?

• How:• A higher level of confidence in quality assurance can be

achieved and demonstrated; • Without real-time-controls (and continuous

manufacturing)?• With real-time-controls (and continuous manufacturing)?

• What:• Benefits can be expected for a company• Benefits can be expected for patients and society

Summary

3/19/2017