© European Compliance Academy (ECA)
Manufacture of Oral Solid Dosage Forms
Continuous Manufacturing: Update on Regulatory ...
© European Compliance Academy (ECA)
Recent testimony to the US Congress
FDA Check Up:
Drug
Development and
Manufacturing
C...
© European Compliance Academy (ECA)
US no longer in the forefront of drug manufacturing
40 percent of the finished drugs t...
© European Compliance Academy (ECA)
Advances in pharmaceutical manufacturing
technology in the last decade
New opportuniti...
© European Compliance Academy (ECA)
There are a multitude of advantages
Product quality can be precisely controlled
Produc...
© European Compliance Academy (ECA)
Dr. Woodcock concluded …
In summary, FDA has been working diligently for over a
decade...
© European Compliance Academy (ECA)
Are we moving towards the ‘tipping point’ or a ‘peak
of inflated (regulatory) expectat...
© European Compliance Academy (ECA)
Five key phases of a technology’s regulatory
change life cycle
8
Adaptation- based on ...
© European Compliance Academy (ECA)
Climbing the slope of enlightenment?
Technical
feasibility?•Novartis – MIT;
CONTINUUS
...
© European Compliance Academy (ECA)
Is this a representative example of ‘climbing the
slope of enlightenment’?
10
The FDA ...
© European Compliance Academy (ECA)
Regulatory uncertainty
Questions – the US context
Do regulations need to be changed?
C...
© European Compliance Academy (ECA)
Any part of the regulation need to be changed? No.
• Sec. 210.3 Definitions
• (2) Batc...
© European Compliance Academy (ECA)
What about Sec. 211.165 Testing and release for
distribution?
(a) For each batch of dr...
© European Compliance Academy (ECA)
Furthermore…
FDA’s
PAT
Guidance
Quality decisions should be based on process understan...
© European Compliance Academy (ECA)
What are the Compendial implications, if any?
 At times, compendial standards take on...
© European Compliance Academy (ECA)
Are the FDA staff open and ready…?
1st CONTINUOUS MANUFACTURING ONE DAY SYMPOSIUM was
...
© European Compliance Academy (ECA)
FDA’s “Program Alignment Group”
 From: Hamburg, Margaret
• Sent: Friday, September 06...
© European Compliance Academy (ECA)
Summary
Sense of urgency, lessons learned, organizational alignment, team approach, tr...
© European Compliance Academy (ECA)
Closing thoughts
A few question on my mind…. unintended consequences?
Strategy for mak...
© European Compliance Academy (ECA)
A few questions on my mind….
• What steps will FDA take to ensure it optimally
support...
© European Compliance Academy (ECA)
Strategy for making high quality affordable?
 Today, with the active encouragement of...
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Continuous Manufacturing Regulatory Update

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Sense of urgency, lessons learned, organizational alignment, team approach, training and an increasing engineering and statistical capability at CDER FDA can be expected to facilitate a move by industry towards continues manufacturing, FDA’s current emphasis on ‘statistical confidence’, Process Validation Guidance 2011, is likely to highlight certain issues (e.g., special causes) within current batch processing; these observation will need to be addressed in an appropriate risk-based manner
Ensuring that pragmatic consideration for specifications & control (intended use) is essential and importance of pragmatic decisions should not be forgotten (e.g., as in case of Design Space Vs. SUPAC), Effective regulatory communication (considering the engineering and statistical emphasis) will be crucial for ensuring regulatory uncertainty is managed in a timely manner,

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Continuous Manufacturing Regulatory Update

  1. 1. © European Compliance Academy (ECA) Manufacture of Oral Solid Dosage Forms Continuous Manufacturing: Update on Regulatory Requirments 26 March 2014, DÜSSELDORF AJAZ S. HUSSAIN, PH.D. INSIGHT, ADVICE & SOLUTIONS LLC AJAZ@AJAZHUSSAIN.COM
  2. 2. © European Compliance Academy (ECA) Recent testimony to the US Congress FDA Check Up: Drug Development and Manufacturing Challenges Statement of Janet Woodcock, M.D. Director, Center for Drug Evaluation and Research Food and Drug Administration Department of Health and Human Services Before the Subcommittee on Energy Policy, Health Care and Entitlements Committee on Oversight and Government Reform U.S. House of Representatives December 12, 2013 http://www.fda.gov/NewsEvents/Testimony/ucm378343.htm 2Ajaz S. Hussain | Insight, Advice & Solutions LLC
  3. 3. © European Compliance Academy (ECA) US no longer in the forefront of drug manufacturing 40 percent of the finished drugs taken by U.S. patients and 80 percent of the active ingredients come from sources overseas …..most traditional drug production processes require a large footprint, often have environmental liabilities, and can utilize a low-cost labor force Use of foreign-sourced materials creates vulnerabilities in the U.S. drug supply 3 http://www.fda.gov/NewsEvents/Testimony/ucm378343.htm Ajaz S. Hussain | Insight, Advice & Solutions LLC
  4. 4. © European Compliance Academy (ECA) Advances in pharmaceutical manufacturing technology in the last decade New opportunities to address this situation and to reinvigorate …manufacturing sector in the United States …….enable “continuous manufacturing” In examples …, production is continuous from chemical synthesis of the active ingredient through production of the tablets or other dosage form This type of manufacturing is on the verge of entering commercial production 4 http://www.fda.gov/NewsEvents/Testimony/ucm378343.htm Ajaz S. Hussain | Insight, Advice & Solutions LLC
  5. 5. © European Compliance Academy (ECA) There are a multitude of advantages Product quality can be precisely controlled Production scale-up issues, which frequently bedevil drug development, will likely be much less of an issue. Increases in capacity can be handled in a straightforward manner. A range of strengths or doses may be prepared more easily, which may be important for personalized medicine. Continuous manufacturing plants require a smaller footprint and can be located closer to markets, thus reducing the need for transcontinental shipping of components. 5 http://www.fda.gov/NewsEvents/Testimony/ucm378343.htm Ajaz S. Hussain | Insight, Advice & Solutions LLC
  6. 6. © European Compliance Academy (ECA) Dr. Woodcock concluded … In summary, FDA has been working diligently for over a decade …. to improve drug manufacturing. … groundbreaking new manufacturing .. within reach. …with the proper strategies, revitalize pharmaceutical manufacturing in the United States. 6 http://www.fda.gov/NewsEvents/Testimony/ucm378343.htm Ajaz S. Hussain | Insight, Advice & Solutions LLC
  7. 7. © European Compliance Academy (ECA) Are we moving towards the ‘tipping point’ or a ‘peak of inflated (regulatory) expectations’? Technical feasibility? Business case? Societal need? 7Ajaz S. Hussain | Insight, Advice & Solutions LLC
  8. 8. © European Compliance Academy (ECA) Five key phases of a technology’s regulatory change life cycle 8 Adaptation- based on Gartner's Hype Cycles http://www.gartner.com/technology/research/methodologies/hype-cycle.jsp Technology Regulatory Trigger (2002) Peak of Inflated Expectations Trough of Disillusionment Slope of Enlightenment Plateau of Productivity Time - Maturity Visibility ICH Q8-10 Ajaz S. Hussain | Insight, Advice & Solutions LLC
  9. 9. © European Compliance Academy (ECA) Climbing the slope of enlightenment? Technical feasibility?•Novartis – MIT; CONTINUUS •GlaxoSmithKline - GEA, Siemens, Sagentia and the Universities of Newcastle, Warwick and Surrey •Others Business case? •Novartis - Commercial implementation planned ~ 2015; CONTINUUS •Several companies (GSK, Pfizer, Vertex,….) moving forward Societal need? • Confidence in reliability of supply • Confidence in quality of FDA approved drugs • Emerging ‘Metrics’ to inform the society 9Ajaz S. Hussain | Insight, Advice & Solutions LLC
  10. 10. © European Compliance Academy (ECA) Is this a representative example of ‘climbing the slope of enlightenment’? 10 The FDA – Novartis CRADA: A Risk-Based and Systems Approach to QbD (2006) Novartis-MIT Center for CM (2009) 11/18/2011 FDA WL GMP Problems Result in 300 Jobs Chopped At Novartis Plant After Manufacturing Gaffes, Worried Novartis CEO Insists 'Quality Matters’ Novartis CEO Joseph Jimenez ..his company plans to build a commercial- scale continuous- manufacturing facility by 2015 “This will change the way medicine is made around the world” https://aiche.confex.com/aiche/2008/techprogram/P132000.HTM http://www.boston.com/business/articles/2007/09/28/novartis_to_give_mit_65m_to_find_new_way_to_produce_drugs/?page=full http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm281843.htm http://www.expertbriefings.com/news/novartis-gmp-problems-results-in-300-jobs-cut-at-nebraska-manufacturing-plant/ http://www.forbes.com/sites/edsilverman/2012/09/05/after-manufacturing-gaffes-worried-novartis-ceo-insists-quality-matters/ http://unm2020.unm.edu/knowledgebase/healthcare-reform/31-the-future-of-pharma-is-incredibly-fast-technology-review-12-05-10.pdf Testable predictions What lessons can we learn to ensure this grand experiment does not fail due to regulatory uncertainty? Ajaz S. Hussain | Insight, Advice & Solutions LLC
  11. 11. © European Compliance Academy (ECA) Regulatory uncertainty Questions – the US context Do regulations need to be changed? Compendial implications, if any? Are the FDA staff open to, and ready for, continuous manufacturing? 11Ajaz S. Hussain | Insight, Advice & Solutions LLC
  12. 12. © European Compliance Academy (ECA) Any part of the regulation need to be changed? No. • Sec. 210.3 Definitions • (2) Batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture. • (10) Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. ‘Batch’ and ‘Lot’ in regulations 12 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=210.3 Ajaz S. Hussain | Insight, Advice & Solutions LLC
  13. 13. © European Compliance Academy (ECA) What about Sec. 211.165 Testing and release for distribution? (a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product….. prior to release. • FDA’s PAT Guidance • Process understanding, control strategies, plus on-, in-, or at- line measurement of critical attributes that relate to product quality provides a scientific risk-based approach to justify how real time quality assurance is at least equivalent to, or better than, laboratory-based testing on collected samples. • Real time release as defined in this guidance meets the requirements of testing and release for distribution (21 CFR 211.165). 13 http://www.fda.gov/downloads/Drugs/Guidances/ucm070305.pdf Ajaz S. Hussain | Insight, Advice & Solutions LLC
  14. 14. © European Compliance Academy (ECA) Furthermore… FDA’s PAT Guidance Quality decisions should be based on process understanding and the prediction and control of relevant process/product attributes. This is one way to be consistent with relevant CGMP requirements, as such control procedures that validate the performance of the manufacturing process (21 CFR 211.110(a)). In a PAT framework, validation can be demonstrated through continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and process end points. Systems that promote greater product and process understanding can provide a high assurance of quality on every batch and provide alternative, effective mechanisms to demonstrate validation (per 21 CFR 211.100(a), i.e., production and process controls are designed to ensure quality). 14 http://www.fda.g ov/downloads/D rugs/Guidances/ ucm070305.pdf Ajaz S. Hussain | Insight, Advice & Solutions LLC
  15. 15. © European Compliance Academy (ECA) What are the Compendial implications, if any?  At times, compendial standards take on the character of statistical procedures, with multiple units involved and perhaps a sequential procedural design to allow the user to determine that the tested article meets or does not meet the standard. The similarity to statistical procedures may seem to suggest an intent to make inference to some larger group of units, but in all cases, statements about whether the compendial standard is met apply only to the units tested. Repeats, replicates, statistical rejection of outliers, or extrapolations of results to larger populations, as well as the necessity and appropriate frequency of batch testing, are neither specified nor proscribed by the compendia. (USP General Notices: 37th Revision) 15 http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/2013-07-09_general_notices_usp37-nf32_final.pdf Ajaz S. Hussain | Insight, Advice & Solutions LLC
  16. 16. © European Compliance Academy (ECA) Are the FDA staff open and ready…? 1st CONTINUOUS MANUFACTURING ONE DAY SYMPOSIUM was held, exclusively for FDA personnel, on March 11 2010 in Bethesda, MD - Pfizer, GSK and equipment-maker GEA Pharma Systems made presentations to more than 100 FDA staffers •http://www.fiercepharmamanufacturing.com/story/favorably-minded-fda-holds-continuous- processing-symposium-staff/2010-04-14 Plus, based on recent presentation at meetings such as IFPAC it appears that some are not just ready but eager to receive submissions based on continuous manufacturing •http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTo bacco/CDER/UCM341197.pdf CMC Review & CGMP Compliance coming together…”Godwin’s GMP perspective on CM design and implementation at the ISPE session complemented Moore’s exploration of the CMC and development implications of continuous processes at AAPS” •http://www.ipqpubs.com/news/quality-system-adjustments-for-continuous- manufacturing-explored-by-fda/ 16Ajaz S. Hussain | Insight, Advice & Solutions LLC
  17. 17. © European Compliance Academy (ECA) FDA’s “Program Alignment Group”  From: Hamburg, Margaret • Sent: Friday, September 06, 2013 10:09 AM  To: Dunham, Bernadette M; Landa, Michael; Midthun, Karen; Plaisier, Melinda K; Shuren, Jeff; Solomon, Steven M; Taylor, John M.; Taylor, Michael R; Woodcock, Janet; Zeller, Mitchell • Cc: Barclay, Lisa; Harris, Walter  Subject: Program Alignment Group • “This group of senior leaders will attain this goal by working together to promote the strategic, operational, and resource management alignment needed for FDA to continue to fulfill its public health mission.”  Specialization across FDA’s inspection and compliance functions based on specialization within FDA’s regulated industries and the demands of new legislation  Training that is developed collaboratively by ORA and the Centers and leads to the development of competency and training requirements to enhance and maintain FDA's workforce  New work planning that improves FDA’s selection of firms, inspection frequency, and compliance efforts that is based on risk factors, public health outcomes, past inspectional history and operational experience  Compliance policy and enforcement strategies that are clear, current, outcome-based and effectively communicated  Laboratory optimization that increases specialization; alignment and collaboration between the Directorates, ORA, and the Centers; and enhances efficiency  Effective alignment to support ORA’s implementation of FDA’s regulatory programs 17 http://www.forbes.com/sites/scottgottlieb/2013/09/08/did-fda-just-announce-a-major-reorganization/ Ajaz S. Hussain | Insight, Advice & Solutions LLC
  18. 18. © European Compliance Academy (ECA) Summary Sense of urgency, lessons learned, organizational alignment, team approach, training and an increasing engineering and statistical capability at CDER FDA can be expected to facilitate a move towards continues manufacturing FDA’s current emphasis on ‘statistical confidence’, Process Validation Guidance 2011, is likely to highlight certain issues (e.g., special causes) within current batch processing; these observation will need to be addressed in an appropriate risk-based manner Ensuring that pragmatic consideration for specifications & control (intended use) is essential and importance of pragmatic decisions should not be forgotten (e.g., as in case of Design Space Vs. SUPAC) Effective regulatory communication (considering the engineering and statistical emphasis) will be crucial for ensuring regulatory uncertainty is managed in a timely manner 18Ajaz S. Hussain | Insight, Advice & Solutions LLC
  19. 19. © European Compliance Academy (ECA) Closing thoughts A few question on my mind…. unintended consequences? Strategy for making high quality affordable? 19Ajaz S. Hussain | Insight, Advice & Solutions LLC
  20. 20. © European Compliance Academy (ECA) A few questions on my mind…. • What steps will FDA take to ensure it optimally supports innovation while ensuring the approach it adapts (e.g., c in GMP) will not un-intentionally drive the system to a particular solution that may have unintended consequences? • What do we need to do to ensure rapid and continual improvement of access and affordability for all patients? • How do we encourage regulators from around the world to be at the policy table? Making high quality accessible and affordable 20Ajaz S. Hussain | Insight, Advice & Solutions LLC
  21. 21. © European Compliance Academy (ECA) Strategy for making high quality affordable?  Today, with the active encouragement of the US FDA, there is visible progress in the area of continuous manufacturing – a ‘paradigm shift’ in the making.  Possibly a different path for making high quality affordable; a different platform to reclaim the title – “Pharmacy to the World.”  Let’s hope the strategy that reliably makes high quality affordable wins!  Increasingly patients across the globe will ask the question “who makes the drug I take”; and trust and credibility will be critical. 21 Ajaz S. Hussain. Express Pharma. Saturday, 02 November 2013 Ajaz S. Hussain | Insight, Advice & Solutions LLC
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