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

[email protected]

mailto:[email protected]


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



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

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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

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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.

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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.

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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

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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


http://www.gartner.com/technology/research/methodologies/hype-cycle.jsp


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?







http://unm2020.unm.edu/knowledgebase/healthcare-reform/31-the-future-of-pharma-is-incredibly-fast-technology-review-12-05-10.pdf


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

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http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=210.3


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).

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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).

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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)

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http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/2013-07-09_general_notices_usp37-nf32_final.pdf


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/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/


http://www.fiercepharmamanufacturing.com/story/favorably-minded-fda-holds-continuous-processing-symposium-staff/2010-04-14

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM341197.pdf

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

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http://www.forbes.com/sites/scottgottlieb/2013/09/08/did-fda-just-announce-a-major-reorganization/


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.

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Ajaz S. Hussain. Express Pharma. Saturday, 02 November 2013


http://pharma.financialexpress.com/sections/management/2907-strategies-for-making-high-pharma-quality-affordable

http://pharma.financialexpress.com/sections/management/2907-strategies-for-making-high-pharma-quality-affordable