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Considerations for Implementation ofContinuous Manufacturing (CM) in a Legacy Product

Quality Systems Management, General Regulatory Aspects, and Relevant Terminology

FDA/PQRI ConferenceMarch 22, 2017

Gilfredo Navarro – RPh, MSAssociate Director - CMC Regulatory Affairs

Janssen Research and DevelopmentGuaynabo, Puerto Rico

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Presentation Topics

•Quality Systems•QA Organization•Training

Quality Systems Management

•Communications with Regulatory Agencies•Initial/Preliminary Meetings (Agency Facilities)•Courtesy/Pre-Operational Visits (Company Facilities)•Pre-Approval Inspections (PAI)

General Regulatory Aspects

Relevant Terminology

•Definitions & Clarifications

3

Quality Systems Management Quality Systems

•Quality Agreements•Complaints•Change Control (CC)•Annual Product Review (APR)•CAPA

NOT-IMPACTED Quality Systems

•It can be impacted based on batch definition.

Product Disposition / Batch Release

Release Data Strategy

•Data input from CM line to LIMS

•Data Review and Approval (QC)

Batch Record Review

•Batch Record review on a daily basis for GMP Compliance. A concept of Real Time Batch Record Review might be established .

•Expedites the process at the end of the batch since only last day manufacturing is pending for review

Investigation

•More investigational elements to consider (PAT , CM, RTRt, etc.)

Stability Strategy

•Make sure data is obtained with the same methods

•Re-assess methods, if there is a formulation change

Product Specification

•RTR testing (Assay, UDU, ID) + Conventional Testing (Dissolution, Appearance, etc.)

•Conventional Testing (Stability, Investigations, Complaints, Chemometric Models Maintenance)

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•Material attributes were suitable for CM process without limits modifications

•Raw Materials did not require changes in specifications

NOT-IMPACTED Material Specifications

4

Quality Systems Management Quality Systems

Product Specification Strategy

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Test Batch Process CM Process/PAT

Assay 1 Analytical Test for the Batch 1 NIR/Chemometric Test per QH/Drum (RTRt)

UDU 1 Analytical Test for the Batch: Weight Variation

1 NIR/Chemometric Test per QH/Drum: Content Uniformity (RTRt)

ID 1 Analytical Test for the Batch 1 NIR/Chemometric Test per QH/Drum (RTRt)

Dissolution 1 Analytical Test for the Batch 3 Analytical Tests for the Run: Beginning/Middle/End

Appearance 1 Analytical Test for the Batch 1 Analytical Test for the Batch

CM Process/PAT enables more tests to be performed real-time leading to higher Quality Assurance

RTRt & Conventional Testing Strategy

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Quality Systems Management Quality Systems

Product Specification Strategy

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Moving to Complete RTRt Strategy

Test Batch Process(No RTRt)

CM Process(RTRt)

Identity Lab: HPLC Line: RTRt (PAT/NIR)

CU Lab: HPLC Line: RTRt (PAT/NIR)

Assay Lab: HPLC Line: RTRt (PAT/NIR)

Dissolution Lab: HPLC Line: RTRt (Surrogate Method)

Appearance Lab: Visual Line: RTRt (Visual)

6

Quality Systems Management QA Organization

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Main Resources

Don’t under estimate QA resources required for CM Implementation

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Quality Systems Management Training

Training Strategy: Training Matrix

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Audience Content Duration

Technical Operations & QA Auditors

- Project Overview-Detailed PAT, RTRt, CM Concepts

(CBT & Room Training) 3 hrs

Management- Project Overview

-General PAT, RTRt, CM Concepts(CBT & Room Training)

2 hr

Operations(Production)

- Project Overview-Intro PAT, RTRt, CM Concepts

(Room Training, On-the-Job Training)3 hr

Exempt Colleagues (Non Technical Personnel)

- Project Overview-General PAT, RTRt, CM Concepts

(CBT)2 hr

QC - Project Overview

-General PAT, RTRt, CM Concepts(Room Training)

1.5 hr

CM / PAT / RTRt

• SOPs• Forms• Job Aids• Protocols• Batch Records

Operations (Production)

• SOPs• Forms• Protocols• Batch Records

Technical Operations

• SOPs• Forms• Protocols• Batch Records

Quality Assurance

• SOPs• Forms• Protocols• Batch Records

Automation

Functional Areas

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without specific permission of Janssen is strictly prohibited.”

Presentation Topics

•Quality Systems•QA Organization•Training

Quality Systems Management

•Communications with Regulatory Agencies•Initial/Preliminary Meetings (Agency Facilities)•Courtesy/Pre-Operational Visits (Company Facilities)•Pre-Approval Inspections (PAI)

General Regulatory Aspects

Relevant Terminology

•Definitions & Clarifications

9

General Regulatory Aspects Communications

Regulatory Agency

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Communications with Regulatory Agencies are essential to establish a Partnering Relationship

Courtesy Meetings/POV

Submission

PAI

ApprovalPost Approval Feedback Meetings

Initial/Preliminary Meetings

MEETINGS WITH REGULATORY AGENCIES

Key Activities

10

General Regulatory Aspects Meetings/Inspections

Key Points

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Initial-Preliminary / Type C Meetings

• Project Overview• Biowaiver Agreements• Sampling Strategy (Sample Size and Frequency)• Control Strategies

• Provide the Regulatory Agency the opportunity to visit the facilities and see the equipment

• Further expand on control strategy, sampling strategy, and other relevant topics

• Offer the setting for the Regulatory Agency to preliminarily preview the available documentation

Courtesy Meetings/Pre-Operational Visit

11

General Regulatory Aspects Meetings/Inspections

Key Points

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Pre-Approval Inspection

• Demonstrate company competencies on: –Systems/Equipment Qualifications–Process Understanding, Robustness, and Efficiency–Documentation Completeness–People Qualifications–Quality Systems Readiness

• Prove to the Regulatory Agency the suitability of the control strategy, sampling strategy, and other relevant topics

• Provide the Regulatory Agency the opportunity to see the equipment running and processing of a batch

Post Approval Meeting

• Results/Key Points from previous meetings

• Learnings to be applied for the next CM product

• What areas would FDA have liked to spend more time

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Presentation Topics

•Quality Systems•QA Organization•Training

Quality Systems Management

•Communications with Regulatory Agencies•Initial/Preliminary Meetings (Agency Facilities)•Courtesy/Pre-Operational Visits (Company Facilities)•Pre-Approval Inspections (PAI)

General Regulatory Aspects

Relevant Terminology

•Definitions & Clarifications

13

Relevant Terminology

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is strictly prohibited.”

Acronyms

RTRt Real Time Release testing

RTBR Real Time Batch Release

RTRR Real Time Record Review

RTNC Real Time Non Conformance

Material is continuously transferred from one operation to the other

Does not mean the batch is run without planned and/or unplanned interruptions

CMProcessing time of the continuous material feeding operation allowing for more accurate material reconciliation (includes startup and state of control)

Does not include equipment pauses when CM line is not processing material

Runtime

RTRt

RTRRRTNC

rTBR can be OK when translating

to OTBR

OTBR On Time Batch Release

rTBR reduced Time Batch Release

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Q & A

16

Continuous Manufacturing Line Process Overview

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Continuous Manufacturing A Transformation in Manufacturing Capability

Extremely consistent Product Quality Results

Control Strategy: Real Time Release testing – reduces

testing cycle time

More flexible operation: production can be adjusted

based on orders

Cycle Time Reduced from Batch Process Reduction in Footprint

Reduced Development Requirements (no scale-up/scale-down needed)

Continuous Manufacturing Realized Benefits

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