The ACPSs Process Analytical Technology Subcommittee Ajaz S. Hussain, Ph.D. Deputy Director Office...

The ACPS’s Process Analytical Technology Subcommittee

Ajaz S. Hussain, Ph.D.

Deputy Director

Office of Pharmaceutical Science

CDER, FDA

ACPS Meeting November 28, 2001

Objectives of PAT Discussion

• To delineate the goals and objectives of the ACPS’s Subcommittee on PAT

• Enumerate expectations of the ACPS – reporting and timeline

Outline

• Overview (Ajaz Hussain)– Background Information

• July 19, 2001 ACPS Discussion

• November 16, 2001 FDA Science Board Discussion

– A Vision for PAT in Pharmaceutical Manufacturing

– Proposed responsibilities and timelines• October 25, 2001 FR Notice on PAT Subcommittee

• ACPS discussion and recommendations

July 19, 2001 ACPS Discussion on Optimal Applications of PAT

• Initiate public discussion on application of process analytical chemistry tools in pharmaceutical manufacturing– Strong ACPS support to move forward– Recommendation to form a PAT Subcommittee

• Related discussion on “Rapid Microbial Testing”– No further development to report at this time

FDA Science Board Discussion Nov. 16, 2001

• Speakers– Janet Woodcock

• CDER, FDA

– Doug Dean and Frances Bruttin• PricewaterhouseCoopers

– G. K. Raju• MIT

– Norman Winskills and Steve Hammond• Pfizer

– Ajaz Hussain• OPS, CDER, FDA

Science Board’s Response

• Strong unanimous endorsement of the proposal

• Would like to support this initiative– talks, seminars,…

• Would like to receive updates on progress

Questions from ACPS?

Current Status

• US Drug products are of high quality, BUT– Increasing trend toward manufacturing-related

problems– Low manufacturing and QA process efficiency--cost

implications– Innovation, modernization and adoption of new

technologies slowed • Introduction of new technologies in facilities not for US

market

– High burden on FDA resources

Dr. Woodcock’s presentation summary

How Did We Get Here?

• System evolved beginning 30-40 years ago--when sectors of industry lacked rigorous SOPs

• Science/technology base did not evolve as quickly as in other sectors

• Empirical GMP standards necessitates stringent scrutiny

• International conference on Harmonization--consensus based standards (1990’s)

• Industry--regulatory risk averse


Challenges for FDA

• How to encourage innovation while ensuring high quality– Successful adoption of new technologies will IMPROVE

overall quality

• How to successfully shift from empirical to science based standards for manufacturing process quality

• How to decrease reliance on pre-approval review and physical evaluation

• How to recruit and train a scientific workforce proficient in application of new technologies


Questions for the Science Board

• Are you able to support the approach?

• What resources do you suggest FDA draw on?

• Are there additional aspects to regulation of pharmaceutic quality that we should focus on?


Measurement Shows Potential for Improvement

0%

100%

35 daysBest Practice: VA Ratio 50%3days

Cost reduction

Time Compression

Benefits - Increased Effectiveness of Compliance Infrastructure

0% 100%Level of Compliance

Cos

t

55

22

Compliance Gain

Direct Cost Recovery

PROCESS D WITH QC TESTS:Cycle Times including BULK ACTIVE

QC1

BLEND 2: PRE-BLEND

CHEMICAL WEIGHING

GRANULATIONSTEP

BLEND 1:FINALBLEND

COMPRESS

FILMCOATING

BOTTLEPACKAGING

QC2QC3

15 DAYS10 DAYS

20 DAYS 15 DAYS

60 DAYS 21-90 DAYS

PROCESSING

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES

STEPS IN THE PROCESS/PLANT IN QC/QA

Process/Unit operation

Interruption of the process

Securing of sample from process

Holding of sample in plant

Documentation and verification of sampling

Transferring of samples to QC lab

Batching of samples in QC

Preparation of test samples

Actual test - separation

Actual test - measurement

Test data collection and processing

Documentation and verification of testing

Transferring of results for review

Decision regarding impact on process

Process/Process Step Primarily Manual OperationInventory Hold Actual test

On-line LIF, NIR, Data Analysis, etc.


LOOKING BEYOND THE “AVERAGE”

0 100 200 300 400 500 600 700 800

LOT NUMBER

OV

ER

AL

L C

YC

LE

TIM

ES

Lots without Exceptions

Lots with Exceptions

NEED FOR FUNDAMENTAL TECHNOLOGY


• Average Cycle time 95 days• Std dev(Cycle time) > 100 days• Exceptions increase cycle time by > 50 %• Exceptions increase variability by > 100%• Capacity Utilization of “System” LOW

PERFORMANCE MEASURE VALUE

Impact of Exceptions

(Detailed Analysis of 2 Products)

NEED FOR FUNDAMENTAL TECHNOLOGY


PAT Applications at DP Sites

• RM Testing (warehouse based)

• Packaging Components

• Blending (at-line or on-line)

• Drying

• Tableting (potency and CU)

• Encapsulation (potency and CU)

• Tablet Coating (coating thickness)

• Packaged product

• Equipment cleaning (on line monitoring of CIP)

• Equipment cleaning (surface monitoring)

Note - Less than 15% of applications at US sites

The “Don’t Use” Scenario• What:

– Modern PAT methods not used/developed during product development so not used for routine process control

• Why:– Fear of regulatory delays– Wasteful of resources to duplicate method development -“current

methods work OK”– Concern of “raising the bar” unnecessarily: information generated

for one process may be expected from all

• Issues:– Loss of benefit of PAT - improved process information and

control

The “Don’t Tell” Scenario• What:

– PAT methods not registered but used in parallel with registered (conventional) methods to gain greater process insight and control

• Why:– Concern over delays in regulatory approval– Concern that data may be interpreted inappropriately by

regulators. More data will lead to more deviations from “norms” - need to be able to determine which are relevant and which are not

• Issues:– Duplication, inefficiency, environment of “mistrust”

The “Win - Win” Scenario• What:

– Modern PAT methods used to gain greater understanding of processes during development, are registered and used as in-process control (and release?) methods

– PAT methods accepted as alternatives to traditional lab based methods - but not required

• Why:– Methodology understood and accepted by regulators and

industry alike

• Issues:– This is where we should all want to get to. Making progress,

but we are not there yet……….

How can we create a “Win-Win” Environment?

• Sponsor joint forums to promote discussion and enhance understanding of the issues and opportunities offered by PAT

• Develop an effective process for the evaluation of new PATs

• Develop appropriate guidelines for the development, validation and implementation of new PATs– lab based extraction/chromatography rules don’t apply

– participate in “dummy run” submissions

• Ensure consistent approach to PAT by Review and Inspection

Dealing with the real or perceived regulatory hurdles:

Shift the Manufacturing Paradigm

Issue: Need for FDA to Facilitate Introduction of PAT

• Industry is hesitant to introduce PAT in US– Regulatory uncertainty/risk leads to “Don’t Tell” or

“Don’t Use” practice• New Technology = New Questions

– Method suitability, chemometrics and validation

• Old products + New technology = New Regulatory Concerns

– Problems not visible under the current system

– Mindset: Why change?• PAT application will add to current regulatory requirements

Ajaz Hussain’s presentation summary

“Win-Win” Opportunities

• Optimal application of modern process analytical technologies can– Improve quality and manufacturing efficiency – Reduce the likelihood of scrap/recalls– Improve the scientific and engineering basis of

many current FDA-Industry debates


What Should FDA Do to Facilitate Introduction of PAT?

• Eliminate regulatory uncertainty– Official position - FDA will accept new

technology that is based on “good” science– Develop standards for PAT

• Method suitability and validation

• Multivariate statistical/computer pattern recognition

• Critical process control points and specifications

• Changes

• OOS….


What Should FDA do to Facilitate Introduction of PAT?

– Define a clear science based regulatory process• Current system “adequate for intended use”• Introduction of PAT not a requirement• Define conditions under which PAT may replace

current “regulatory release testing”• Process for addressing existing “invisible” problems in

marketed products• Review and inspection practices • International harmonization


How Should FDA Facilitate PAT?

• Limited institutional knowledge and experience at FDA

• Seek input and collaboration– Advisory Committee for Pharmaceutical Science -

Subcommittee on PAT– Industry (individual companies?)– Academic Pharmaceutical Engineering and Process

Analytical Chemistry programs– PQRI


A Perspective on PAT: One piece of the puzzle

• “Vision 2020 - I can see clearly now”– Quality & performance by design +

Continuous “real time” monitoring of quality

– Specifications based on mechanistic understanding of how formulation and process factors impact product performance

– High efficiency and capacity utilization

– “Real time” review and inspection from

Rockville, White Oak, NJDO,...

Key Elements of the Emerging Program on PAT (Draft)

• A “general principles” guidance on PAT– Articulate an FDA position on PAT

• Definitions and terminology

– Outline a regulatory process for introducing PAT • Pre- and post approval phases • Addressing existing but invisible problems• “Team” approach for review and inspection

– Types of experimental evidence and justification• “Alternate” and “Primary” control/test • “Direct” and “Correlation-based” control/test• Appropriate level of redundancy or backup systems• On/In/At-line release testing (parametric release)

Types of Tests/Controls

• “Alternate” control/test– A PAT tool validated by comparison to a traditional in-

process test using development data and/or data from routine production for a period of time. Traditional in-process test discontinued after sufficient data collected to support validation.

• On-line blend uniformity using NIR validated by comparison to data obtained on blend samples collected using a “thief”

• “Primary” control/test– A PAT tool is developed and validated on its own merits

• Accuracy, precision, specificity,…….

Types of Tests/Controls (Contd.)

• Correlation-based controls/tests– Use of chemometrics or pattern recognition

methods to identify and develop a correlation between a measurement and product attribute

• E.g., Prediction of tablet hardness, dissolution rate from NIR spectral fingerprints

– Validation based on predictive performance only– Validation based on predictive performance plus

mechanistic justification (causal links)

Cumulative Dissolution and Disintegration Data: Critical Formulation Variables

Time in Minutes

0 5 10 15 20 25 30 35

% D

ru

g D

issolv

ed

0

20

40

60

80

100

120

Corresponding Disintegration Time

Data

MCC(-)SSG(+)MgS(-)

MCC(-)SSG(+)[MgS(-)]

),,.(% SSGMCCSMgDissolved

Parametric Release & Release Tests

• What is “parametric release” – When "data derived from the manufacturing process

sterility assurance validation studies and from in-process controls are judged to provide greater assurance that the lot meets the required low probability of containing a contaminated unit (compared to sterility testing results from finished units drawn from the lot), any sterility test procedure adopted may be minimal, or dispensed with on a routine basis.” (USP)

– Need to redefine this term

EMEA's Note for Guidance on Parametric Release (effective since 9/01)

• Defines Parametric Release as: – " a system of release that gives assurance that the

product is of the intended quality based on the information collected during the manufacturing process and on the compliance with specific GMP requirements related to parametric release."

– In addition, this note extends the Parametric Release concept to other dosage forms.

Parametric Release: Dissolution?• Provide a greater assurance (compared to the current

dissolution test method)– Lot will meet established specification

– Lot will meet established BA/BE

• Data derived from – Process that utilizes in-process controls that can measure and

control all critical variables that effect dissolution

– Appropriately designed manufacturing process validation studies• Validation based on predictive performance plus mechanistic

justification (causal links)

Non-homogeneous distribution of magnesium stearate

0 2 4 6 80

25

50

75

100

60 65 70 75 80 85Box Number

%D

isso

luti

on

aaps Annual Meeting 37

ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION

What specific test conditions and acceptance criteria are appropriate? [IR]

dissolution significantlyaffect BA?

Develop test conditions and acceptance distinguish batches with unacceptable BA

YES

NO

YES

NOYES

NO

Do changes informulation or

manufacturing variables affect dissolution?

Are these changes controlledby another procedure

and acceptancecriterion?

Adopt appropriate test conditionsand acceptance criteria without

regard to discriminating power, topass clinically acceptable batches.

Adopt test conditions and acceptance criteria which can distinguish

these changes. Generally, single point acceptance criteria are acceptable.

PAT FR Notice Oct. 25, 2001

• Request names of qualified individuals– Process analytical chemistry, pharmaceutics, industrial pharmacy,

chemical engineering, pharmaceutical analysis, chemometrics, pattern recognition, expert systems, IT, and statistics

• Report on scientific issues related to application and validation of on-line process technologies (e.g., NIR).– Both drug substance and drug product manufacture– Feasibility of “parametric” release concept– Potential benefits and risks

• Applications should be received by 11/30/01

Subcommittee should report on (?)• Current status and future trends: PAT in pharmaceutical

development and manufacturing– Available technologies, capabilities,... – Application in US Vs. Non-US plants– Perceived and/or real regulatory hurdles

• General principles for regulatory application – Principles of method validation, specifications, OOS– Appropriate use and validation of chemometric tools– Feasibility of “parametric release” concept (also, redefine)– Case study: vibrational spectroscopy (NIR)?

• Research and training needs (FDA and industry)

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