us fda's pat guidance – 10 years and now

US FDA’s PAT Guidance –10 years ago and now

Ajaz S. Hussain, Ph.D.

Insight, Advice & Solutions LLC

11/28/[email protected]

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28. und 29. November 2013

in Ludwigshafen am Rhein / Deutschland

Insight

At FDA the PAT Initiative was a ‘door opener’ to a cultural transformation to prepare for globalization in the 21st Century

Cultural transformation takes time and discipline, needs collaborative vocabulary, constancy of purpose, and link to the heart and bottom-line

The transformation process has progressed to create common regulatory guidelines (ICH Q8 – 11), it is currently struggling to get to a common understanding of the new vocabulary and integrated systems thinking and actions


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Quality of pharmaceutical products

Tablet, capsule, injection, etc.

Information, marketing messages, etc.

Scientific evidence supporting societal license to market


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Pharmaceutical processes

Process for

• Developing a product (safety, efficacy, quality)

• Manufacturing a product (quality - reproducible and repeatable safety and efficacy profile)

• Developing the scientific evidence (safety, efficacy, quality)

• Communicating about the product (ensure reproducible and repeatable safety and efficacy profile)


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License to Manufacture and Market

R&D

Manufacturing

Marketing

Market share Revenues

Pre-market review & inspection Post-market review & inspection

Regulatory Authority


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FDA’s Process Validation Guidance 1987

Quality can not be tested into products, it has to be built-in by design → Quality by Design

Scientific evidence that process is capable of consistently delivering quality products

Scientific evidence that product is of acceptable quality


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Quality by Design Vs. Cheating by Design

Right first time, on-time review & approval

Compliance with cGMP, GLP, GCP,…… GXP

Customer satisfaction with trust & credibility

Deliberate -adulterated drugs

Counterfeit and falsified medicines

Deliberate false claims


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Companies trying to be on the QbD side… facing challenges

• 28 November 2013

• “AAA’s BBB unit gets US FDA import alert”

• 4 November 2013

• “XXX promotion of YYY for unapproved uses threatened the most vulnerable populations of our society - children, the elderly and those with developmental disabilities," said Zane Memeger, U.S. Attorney for the Eastern District of Pennsylvania

• In 2010 a British drugs giant paid £475million to settle allegations it knowingly made and sold adulterated drugs; agreed to Corporate Integrity Agreement (CIA)

• In 2007 a company in New Jersey pleaded guilty to the charge –“Conspiracy to commit an offense against the United States” & “duping the FDA for six years.”


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Quality of the FDA Review & Inspections?

• The PAT Initiative was an attempt to “open the door” significant improvement in multiple functions

• PAT Initiative (2001)

• CGMP for the 21st Century (2002); Pharmaceutical Quality for the 21st

Century (US, EU and Japan via ICH)

• Critical Path Initiative (2003)

US FDA is regarded as the

toughest regulatory

authority; it takes steps to improve

its processes


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Challenges

Before the launch of the PAT Initiative

• Drug shortages due to manufacturing difficulties

• Process deviations coupled with frequent inconclusive investigations

• Batch failures and rejections

• In-process test debates (e.g., blend uniformity)

• Slow and protracted cGMP remediation

• Warning Letters, permanent injunctions and consent decree

• Multiple review cycles for certain products (e.g., inhalation drugs)

• CMC review (and cGMP) harmonization efforts between US, EU and Japan at a impasse on Common Technical Document, Section P2 - ‘Pharmaceutical Development’


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Internal challenge to FDA staff

Questions posed by Dr. Woodcock

• “Will this $ x00 million “consent decree” improve quality of the real product?

• How effective is “process validation”? Is it not just a “well rehearsed demonstration…. 3 times”?

• Is our system truly a “modern quality system”?

• Are our “specifications” based on sound science and risk principles?

• How is “c” in cGMP established?

• Do current regulations support “continuous improvement”?

• How efficient is pharmaceutical manufacturing?


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Process understanding is a key to effective control


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Powder Blend Uniformity

Refers to active ingredient (or preservative) distribution or homogeneity in the “final” blend or mix.

• Adequacy of Mixing - satisfactory blending step to assure uniformity and homogeneity [21 Code of Federal Regulation 211.110 (a)(3),1978]


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GMP lessons from a Federal Judge

• Judge Wolines’ opinion [also] provides scientific and legal guidance to generic and pioneer drug manufacturers about their compliance obligations under the FD&C Act.

• Validation studies … and blend uniformity

• Test averaging

• Retesting

• Investigation of batches of failed products

• Equipment cleaning and

• Record-keeping.

United States of

America v. Barr Labs,

Inc.

812 F. Supp 458,

3/30/93

• “C” in cGMPs

• The sample thief is the state-of-the-art powder sampling technology used by the pharmaceutical industry today for purposes of BUA …. It is prone to sampling error.

The appropriate sample size for Blend

Uniformity Analysis

(BUA) is, at most, three times the weight of the final

dosage unit. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm2

12214.htmPDA J Pharm Sci Technol. 1997;51 Suppl 3:i-iii, S1-99


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http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm212214.htm

http://www.ncbi.nlm.nih.gov/pubmed/9448437

Struggling with sampling…

Stop & go sampling A thief Engineering practice


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The acronym PAT

Putting analyzers on-line without process

understanding would be like “putting ear-rings on a pig”

• Process [P]

• Analyzer, Analytical…? [A]

• Chemistry, System,… Technologies, or Technology? [C, S, or T]

Analytical

• “….. the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner”

Technology (from Greek τέχνη, techne, "art, skill"; and -

λογία, -logia[1])

•the making, modification, usage, and knowledge of tools, machines, techniques, crafts, systems, and methods of organization, in order to solve a problem, improve a pre-existing solution to a problem, achieve a goal, handle an applied input/output relation or perform a specific function

Process Analytical Technology (PAT)


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http://en.wikipedia.org/wiki/Ancient_Greek

http://en.wiktionary.org/wiki/-logia

http://en.wikipedia.org/wiki/Technology

http://en.wikipedia.org/wiki/Tool

http://en.wikipedia.org/wiki/Machine

http://en.wikipedia.org/wiki/Craft

http://en.wikipedia.org/wiki/System

PAT definition

• “The Agency considers PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality”


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PAT: Validation

A focus on process understanding can reduce the burden for validating systems by providing more options for justifying and qualifying systems intended to monitor and control biological, physical, and/or chemical

attributes of materials and processes.

• In the absence of process knowledge, when proposing a new process analyzer, the test-to-test comparison between an online process analyzer and a conventional test method on collected samples may be the only available validation option. In some cases, this approach may be too burdensome and may discourage the use of some new technologies (FDA PAT Guidance 2004)


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Value of ‘Process Understanding”

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).

• 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 (FDA PAT Guidance 2004)


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Integrated systems thinking

The fast pace of innovation in today's information age necessitates integrated systems thinking for evaluating and timely application

of efficient tools and systems that satisfy the needs of patients and the industry.

• Many of the advances that have occurred, and are anticipated to occur, are bringing the development, manufacturing, quality assurance, and information/knowledge management functions so closely together that these four areas should be coordinated in an integrated manner (FDA PAT Guidance 2004)


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Integrated systems thinking at FDA

• “Turf” battles to PAT Team Approach

• Vocabulary: Negative to Collaborative (“process validation to process understanding”)

• “Pharmaceutical Development” information kept at site to shared with CMC reviewers (Quality by Design -ICHQ8)

• Risk-based decisions (ICH Q9)

• Minimize Prior-Approval Supplements to Change Control within company Quality System (“ICH Q10”)

• Reduce regulatory fear to promote continues learning


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PAT Review – Inspection -OPS Team (PATRIOT)

Investigators

• Robert Coleman (ORA/ATL-DO), Rebeca Rodriguez (ORA/SJN-DO), Erin McCaffery (ORA/NWJ-DO), George Pyramides (PHI-DO), Dennis Guilfoyle (ORA/NERL),

Compliance Officers

• Albinus D’Sa (CDER), Mike Gavini (CDER), William Bargo (CVM), Brenda Uratani (CDER)

Reviewers

• Norman Schmuff (CDER), Lorenzo Rocca (CDER) Vibhakar Shah (CDER), Rosario D’Costa (CDER), Raafat Fahmy (CVM), Brian Riley (CDER)


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Preparing the regulatory system for globalization

PAT ICH Q 8-11Process

ValidationFDASIA


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Process Validation keeps the focus on PAT

• Stage 1: Process Design

• Stage 2: Process Qualification

• Stage 3: Continued Process Verification

Process validation

• ASTM E2474-06 Standard Practice for Pharmaceutical Process Design Utilizing Process Analytical Technology.

• ASTM E2476-09 Standard Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture.

• ASTM E2281-03 Standard Practice for Process and Measurement Capability Indices.

• ASTM E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment.

• ASTM E2709-10 Standard Practice for Demonstrating Capability to Comply with a Lot Acceptance Procedure.

ASTM


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FDASIA & “adulterated”: What did the Congress intend?


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Current state of QbD

New Drugs

Novice: 22% Pilot: 33% Roll-out: 22%Full

implementation: 23%

Generics Novice: 40% Pilot: 20% Roll-out: 40%Full

implementation: 0%

Biologics Novice: 17% Pilot: 67% Roll-out: 17%Full

implementation: 0%

Data from: Ted Fuhr, McKinsey & Company. 17 July 2011: FDA Advisory Committee Presentation


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QbD Comments & Challenges

Comments

“Generics are all about file first and figure out later”

“R&D is incentivized on shots on goal not QbD”

“We really don’t understand what effects what”

“Huge amount of reviewer inconsistency”

Challenges

(fully implemented)

Alignment with 3rd parties

Regulators not prepared

Current interaction (FDA) not conducive to QbD

Data from: Ted Fuhr, McKinsey & Company. 17 July 2011: FDA Advisory Committee Presentation


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A 10-year research collaboration aimed at transforming pharmaceutical production

November 18, 2011 FDA WL to Sandoz/Novartis:

•"Corporate management has the responsibility to ensure the quality, safety, and integrity of its products. Neither upper management at Novartis nor at Sandoz ... ensured global, adequate, or timely resolution of the issues.“

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”

Novartis – MIT Continuous

Manufacturing (started in 2009)

http://www.technologyreview.com/view/427895/the-future-of-pharma-is-incredibly-fast/

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11/28/2013

http://www.technologyreview.com/view/427895/the-future-of-pharma-is-incredibly-fast/

On-going organization changes at CDER, FDA

At FDA, focused attention on changes to ensure a more rational approach to CMC review and cGMP inspections

Understand and control sources of variances

relevant to quality during

development and review

process

Improved understanding to make risk-based inspections

Rational question

based review to ensure

QbD; science based process validation,…

Improve ability to detect “too good to be true data and claims” (protracted detection and correction time)

Focus on prevention and reduce reliance on “whistle-blowers” and need for DOJ intervention? Additional

‘quality metrics’.


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Advice

FDA

Focus on prevention and reduce reliance on

“whistle-blowers” and need for DOJ

intervention. Utilize ‘quality metrics 'to gauge performance

Rational question based review to ensure QbD; science based process

validation,…

Integrative systems approach to decisions by understanding sources of

variances relevant to quality

Industry

Pay specific attention to the vocabulary; it can be perceived as a window

to your intentions

Take proactive steps to prevent catastrophic

risks, improve predictability and create competitive advantage

by utilizing the principles outlined in

the PAT and ICH guidelines

Emphasize integrative systems approach to

decisions …. Start now, it is a long journey


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A useful document to read

• The FDA’s PAT Team and Manufacturing Science Working Group Report• A Summary of Learning, Contributions and Proposed Next Steps for Moving

towards the "Desired State" of Pharmaceutical Manufacturing in the 21st Century (2004)

• Innovation and Continuous Improvement in Pharmaceutical Manufacturing Pharmaceutical CGMPs for the 21st Century• http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-

4080b1_01_manufSciWP.pdf


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http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4080b1_01_manufSciWP.pdf

By design; conveys your intention

• “The notion ‘by design,’ in the phrase ‘Quality by Design,’ conveys the intention to deliver a product or service with a pre-defined ‘quality’ so as to satisfy intended customers.” • Ajaz S. Hussain. SWISS PHARMA 34 (2012) Nr. 6.


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us fda's pat guidance – 10 years and now

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