Regulatory Aspects of Continuous Pharmaceutical Manufacturing

05/02/2023Ajaz S Hussain | Insight, Advice & Solutions LLC

1 Regulatory Aspects of Continuous Pharmaceutical ManufacturingDIGITAL PHARMA MANUFACTURING ROUNDTABLEKRONBERG, GERMANY, MARCH 17 2017

Ajaz Insights [email protected]

mailto:[email protected]


2 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.”

[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 Point05/02/2023

Ajaz S Hussain | Insight, Advice & Solutions LLC

3

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




4 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)

http://nipte.org/

http://www.ajazhussain.com/


5 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.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!


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

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


8

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/


9 Where there is a will there is a way!


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

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


11 Two illustrative examples (small molecules)• 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

05/02/2023


12

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


13 Serious consideration needed for building your roadmap….

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

Summary

•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?

05/02/2023


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Regulatory Aspects of Continuous Pharmaceutical Manufacturing

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