continuous manufacturing regulatory update
DESCRIPTION
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,TRANSCRIPT
© 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
© 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 ResearchFood and Drug AdministrationDepartment of Health and Human Services
Before theSubcommittee on Energy Policy, Health Care and EntitlementsCommittee on Oversight and Government ReformU.S. House of Representatives
December 12, 2013
http://www.fda.gov/NewsEvents/Testimony/ucm378343.htm
2Ajaz S. Hussain | Insight, Advice & Solutions LLC
© 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
© 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
© 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
© 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
© 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
© 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
Vis
ibili
ty
ICH Q8-10
Ajaz S. Hussain | Insight, Advice & Solutions LLC
© 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
© 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
© 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
© 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
© 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
© 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
© 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
© 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/OfficeofMedicalProductsandTobacco/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
© 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
© 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
© 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
© 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
© 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