Continuous Manufacturing Regulatory Update

© 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

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

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
Ajaz S. Hussain | Insight, Advice & Solutions LLC

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

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

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

Are we moving towards the ‘tipping point’ or a ‘peak
of inflated (regulatory) expectations’?
Technical
feasibility?
Business
case?
Societal
need?

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

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

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?

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?

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

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

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

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

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/

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/

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

Closing thoughts
A few question on my mind…. unintended consequences?
Strategy for making high quality affordable?

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

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

Continuous Manufacturing Regulatory Update

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Andere mochten auch

Andere mochten auch (20)

Ähnlich wie Continuous Manufacturing Regulatory Update

Ähnlich wie Continuous Manufacturing Regulatory Update (20)

Mehr von Ajaz Hussain

Mehr von Ajaz Hussain (20)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

Continuous Manufacturing Regulatory Update