Quality systems for continuous manufacturing

Engineering Conferences InternationalECI Digital Archives

Integrated Continuous Biomanufacturing II Proceedings

Fall 11-4-2015

Quality systems for continuous manufacturingRon BranningRBC LLC, [email protected]

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This Conference Proceeding is brought to you for free and open access by the Proceedings at ECI Digital Archives. It has been accepted for inclusion inIntegrated Continuous Biomanufacturing II by an authorized administrator of ECI Digital Archives. For more information, please [email protected].

Recommended CitationRon Branning, "Quality systems for continuous manufacturing" in "Integrated Continuous Biomanufacturing II", Chetan Goudar,Amgen Inc. Suzanne Farid, University College London Christopher Hwang, Genzyme-Sanofi Karol Lacki, Novo Nordisk Eds, ECISymposium Series, (2015). http://dc.engconfintl.org/biomanufact_ii/91

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Con$nuous Manufacturing A Quality System Approach To Process Monitoring and Control

ICB II Ron Branning November 2015 President, RBC LLC

Implemen$ng World-‐Class Produc$on Quality Systems The Focus of My Career

•  J&J – 1968 – Beginning of Modern GMPs

•  45 years of prac$cal, world wide, science and compliance solu$on implementa$on : J&J, Searle, Boehringer Ingelheim, Serono, Gene$cs Ins$tute, Aven$s Behring, Somatogen, Genentech, Gilead, Genzyme

•  VP, SVP Quality and Compliance Issues Experience: – Quality Organiza$on and Opera$onal Performance –  FDA 483s and WW Regulatory Inspec$on Observa$ons –  FDA CRLs, WLs, CDs and DOJ Inves$ga$ons – MHRA, IMB, TGA, ANVISA, JMOH, SFDA, PICS Commitments –  CHMP Oral Presenta$on:Commitments and Implementa$on

FDA’s (World Regulator’s) Expecta$ons : Produc$on Quality Systems

“We rely upon the manufacturing controls and standards to ensure that $me and $me again, lot aaer lot, year aaer year the same clinical profile will be delivered because the product will be the same in its quality…We have to think of the primary customers as people consuming that medicine and we have to think of the statute and what we are guaranteeing in there, that the drug will con$nue to be safe and effec$ve and perform as described in the label”

Janet Woodcock, M.D.

Presenta$on Outline

•  Con$nuous Manufacturing •  Quality System •  Process Development •  Technology Transfer •  Manufacturing •  Process Monitoring and Control •  Quality Control •  Quality Assurance

Con$nuous Manufacturing

•  Glass, Plas$c Manufacturing •  Radia$on Steriliza$on •  McNeil Tylenol Response •  Serono – Perfusion Disks •  GI – Batch Harvest / Re-‐Feed •  Con$nuus -‐ MIT / Novar$s Collabora$on •  DARPA – Tractor / Trailer Sized BioManufacturing •  Genzyme – Integrated Con$nuous BioMFG Plajorm

Product & Process Improvement

Supply Chain Management

Management of Documentation

Personnel Qualification & Training

Control and Release

Qualification and Validation

Quality Audit

Manufacturing and Packaging

Environmental and Critical Utilities Monitoring

Cleaning Validation

Process Validation

Document and Records Control and Retention

Facilities Utilities and Equipment

Quality Risk Management

Design and Development

Management of Suppliers & Subcontractors

Counterfeiting, Product Diversion, and Tampering

VisioDocument

Quality Process

XXXXXX

LEGEND

Terminal Sterilization

Aseptic Process Validation

Laboratory Equipment Qualification

Quality Technical Agreements

Rework, Reprocessing, And Re-inspection

Sampling

Supplier Qualification & Lifecycle Management

Stability Monitoring

Document Architecture, Format, and Content

Standards

Laboratory Investigations

Pharmaceutical Quality System

Technology Transfer

Investigational Products

Master & Batch Production Records

Governance Structure, Notification, and Escalation

Production Labeling Controls

Sterilization & Depyrogenation Control

External GMP Inspections

Management of Computerized Systems

Material Management

Certificates of Analysis

Purchasing Control

Lot DispositionRecall Management

Facility and Engineering Documents, Content & Format

Hygiene & Gowning

Design Control

XXX

Drug Development

Quality Management Review

Product Event Management

Change Control

Training

Personnel Qualification

Risk Management

Deviations & Investigations

Calibration

Maintenance of Facilities & Equipment

Environmental Control

Production Control

Validation Program

Materials Control

Laboratory Controls

Trending & Statistical Analysis

Corrective and Preventive Action (CAPA)

Design & Construction of Facilities,Utilities, and Equipment

Periodic Product Review

Lifecycle Management of Computer Systems

Product Event Reporting to Regulatory/Competent Authorities for Drugs and Biologics

Specification Development

XXX

Product Lifecycle Processes Organizational Processes

Quality Systems Management

Transversal Processes

Method Development and Validation

Aseptic And Controlled Area Processing

Requalification

Viral Risk Mitigation & Contamination Response

Sterilization & Depyrogenation Validation

Labeling Development and Labeling Change Management

Technology Transfer

Audits & Walk-Through Inspections

Quality and Supplier Audits

Warehousing and Distribution

Storage & Distribution

Collection, Communication and Review of Safety Information

Validation of the Transportation of Temperature-Sensitive Material

Product Discontinuation

See: Drug Development Standard Quality Organization,

Management, Planning, and Objectives

Quality Management Of Subcontractors

Integrated Product / Process Quality System Organiza$on Chart – SME’s, Risk Assessment, Culture Building

Quality System – Process Map

Knowledge Management

Change Management Deviation Management/CAPAAudit ManagementPersonnel Management

Supplier ManagementValidation

Quality Control

Production Management

Facility & Equipment Management

Risk Management

Product/Process Development

ComplaintManagement

VisioDocument

Printed Thursday, June 28, 2012

QSE

LEGEND


Management Control

Regulatory Materials ManagementQuality Assurance

Follow-up and complete CAPA for Outcomes

Schedule Periodic Quality Management Review Meetings

Conduct Quality Management Review Meetings

Determine Outcomes

Report Outcomes

CAPA

Governance & Management Notification

CAPA


Quality Planning & Objectives


CAPA

Evaluate Data For Abnormal Trends

Establish And Maintain Quality Organization, Quality Manual,

GQS, QSEs & Standards

Communicate Quality Program To All Employees

Develop Dashboard, KPIs, KQIs (as Applicable)

Report Periodically KPIs, KQIs & QSE Gaps, Integration And Effectiveness Of The GQS

CAPA

Training

Risk Management

Deviation & Investigations

CAPA

Escalate Issues To Appropriate Senior Management Risk Management

Sampling

Test Preparation

Preparation Of Reagents And

Standards

Test Performance

Results Review

Report Results

Maintain Reserve Samples

Training

Lot Disposition Laboratory Investigations

Sampling

Sampling

Personnel Qualifications

Method ValidationCalibration


Supplier QualificationPurchasing Controls

Establish Procedures For Sampling Of Materials And Product

Store Samples As Required By Procedure

Destroy Or Retain Samples As Required By Procedure

Maintain Sample Chain Of Custody Records

Test Samples As Required By Procedure

Training

Document Control

Perform & Label Samples As Required By Procedure

Train Sampling Personnel

Laboratory Controls

Laboratory Controls

Design Environmental Monitoring Program

Identify Monitoring Locations & Frequencies

Validate Environmental

Monitoring Program

Establish Alert & Action Limits

Collect Samples

Change Control

Laboratory Controls


Risk Mangement

Determine Environmental Control

Requirements

Lot Disposition


Method Validation

Test Samples

Report Results

Data/Trend Analysis Reports

Sampling


Qualification & Validation

Commissioning

Planning & Feasibility

Requirements Or Conceptual Design

Preliminary & Detail Design

Construction

Decommission

Purchase

Establish Operational Procedures &

Maintenance & Calibration Schedules

Operate & Maintain Records

Repair Or Improve

Purchasing Controls

Validation Program

Change Control


Preventive & Routine Maintenance


Calibration

Qualification

Identification Of Product & Process

Environmental Control Requirements And Critical Elements

Identification Of Environmental

Controls

Implementation Of Environmental Control

System

Control System Maintenance By

Review Of Environmental

Monitoring Data

Identification Of Monitoring Plan

Changes Made As Required To Ensure

System Requirements Are Continually Met

Change Control

Facility & Utility Design, Architecture & Construction

Environmental Monitoring

Change Control



Facility & Utility Design Architecture & Construction


Laboratory Controls

Sampling


Laboratory Investigation

Generate Stability Protocol

Perform Time Zero Test

Perform Scheduled Testing

Obtain Interval Results

Store Samples

Evaluate & Report Results

Incomplete Stability Study

Laboratory Controls


Laboratory Investigation

Regulatory Reporting

Complete Stability Study

Regulatory Affairs

Laboratory Controls

Perform SamplingSampling


Materials Control

Laboratory Controls

Environmental MonitoringProduction Control Records

Change Control

Perform Lot And Data Record Review

Disposition Lot

Communicate Lot Disposition

Approve Lot Record Submit To QA

QA Account For All Records And Data

Perform Lot Record Review

Ensure All Changes & Deviations Closed &

Regulatory Filings Approved

Resolve DeviationsDeviation & Investigations


Regulatory Affairs



Lot Disposition

Establish GQS Standards & Practices

Inform & Train Genzyme Employees

Measure Performance Against Quality

Objectives

Establish GQS Quality Manual & Quality

Objectives

Management ReviewGovernance & Management Notification

Design & Maintain GQS QSEs

Document Control

Document Control

Training

Recommend Improvements To

GQSManagement Review

Quality Planning & Objectives

Establish Procedures & Collect KQI & KPI

Data

Report Adverse Trends Or Issues

Issue Routine Reports

Analyze Data For Adverse Trends Or

Issues


Management ReviewGovernance &

Management Notification

Management ReviewGovernance & Management Notification



Generate Or Change Controlled Documents

Review, Approve Controlled Documents

Implement Controlled Documents

Retire Obsolete Versions

Conduct Training As Applicable Training

Records Control

Initiate New Document Or

Document Change

CAPA

Review Periodically Controlled Documents

Change Control

Establish Procedures And Genzyme

Engineering Practices For Documents

Project Plan

Change Control

Project Management

Facility & Engineering Documents, Content & Format

Construction & Configuration

Development

Planning, Feasibility & System Specification

Risk Assessment

User Requirements Specification

Decommission

Supplier Review, Approval & Purchase

Design

Qualification & Validation

Operation & Improvement

Document Control

Purchasing

Routine & Preventive Maintenance

Calibration

Deviation Investigation

Change Control

Change Control

Risk Management

Supplier Qualification

Computer Validation

QualificationRisk Management

Routine & Preventive Maintenance

Calibration

Qualification

Design & implementation of Computer Systems/Automation Systems

Commission

Qualify & Establish Maintenance Schedules & Procedures

Perform Preventive Maintenance

Repair Or Improve

Decommission

Change Control

Qualification



Change Control

Supplier Control


Commission

Qualify & Establish Calibration

Schedules, Master List & Instructions

Perform Calibration

Repair Or Adjust

Decommission

Change Control

Qualification



Change Control

Supplier Control

Yes

Within Calibration Limits

No

Continue To Use

Perform Final Calibration


Supplier Control

YesWithin Calibration

Limits NoEnd Deviation & Investigation

Calibration

Validation Risk Assessment & Planning

Protocol Development & Execution

Data Analysis & Reporting

Installation Qualification

Operational Qualification

Design Qualification

Process Validation

Performance Qualification

Method Validation

Cleaning Validation

Re-Qualification Re-Validation

Change Control

Change Control

Training

Production Control

Aseptic Production Control


Laboratory Control

Calibration

Facility & Utility Design, Architecture, & Construction

Design & Construction of Equipment

Maintenance of Facility & Equipment



Process Control Strategy

Establish User Requirements

Perform Commissioning

Perform Operational Qualification

Perform Design Qualification

Perform Installation Qualification

Perform Performance Qualification

Laboratory Controls

Deviation Investigations

TrainingChange Control

Develop Functional Requirements And Design

SpecificationsRisk Management

Laboratory Controls

Perform Periodic Qualification Assessment

Requalify As Required

Change Control


Facility & Utility Design, Architecture & Construction

TrainingCalibration


Requalification

Document Control

Design & Implementation of Computer Systems

Validation Program

Facility, Utility & Equipment Qualification







Obtain Functional Requirements And Design

Specifications



Change Control Training

Laboratory Controls

Laboratory ControlsLaboratory Investigations


Change Control

Laboratory Equipment Qualification Identify Product Contact Equipment

Develop or identify cleaning requirements including cleaning & disinfection agents, procedures,

critical soils, sampling & analytical methods

Conduct Pre-Validation Engineering trials if needed

Generate a Qualification & Cleaning Validation Protocols

Complete Equipment/System Qualifications

Execute Cleaning Validation

Generate Qualification & Validation Protocol Reports

Validate Sampling & Test Methods

Develop & Establish Quantitative Acceptance Criteria

Design ControlDrug Development

Method Validation

Lot Disposition

Material Control

Facility, Utility, & Equipment Qualification


Validation Program

Change Control


Cleaning Validation

Establish Product Development File & Approved Development Report

Including Control Strategy

Train Personnel And Approve Procedures Including Batch Records

Execute Process Validation Protocol

Qualify Process Facility, Utilities, Equipment

Approve Process Validation Protocol

Approve Protocol Report

Perform Risk Assessment Based On ISs, IPCs, CPPs, PARs, kPPs & ARs

Traning

Risk Management

Drug Development Change Control

Change Control

Deviation Investigations Laboratory Controls

Change Control

Production Control Records


Process Validation

Receive New Or Revised Method

Perform Instrument Qualification By Generating IQ, OQ, PQ Protocols As Needed. Qualify Facilities & Systems

Generate, Review & Approve Validation Protocol

Generate, Review & Approve Protocol Report

Assess Requirements For Validation

Execute Protocol


Change Control

Document Control

Laboratory InvestigationsTraining

Record Control

Laboratory Controls

Change Control


Revalidate As Appropriate Change Control

Method Validation

Determine Method Of Sterilization For Material Or Product

Perform DQ, IQ, OQ, PQ Of Sterilization Process

Execute Process Validation Protocol

Design Terminal Sterilization

Approve Process Validation Protocol


Yes

Terminal Sterilization ?

No




Laboratory Control

Sampling


Deviation & Investigation

Validation ProgramFacility, Equipment & Utility Qualification

Terminal Sterilization Validation

Determine Method Of Sterilization For Component Or Equipment

Perform DQ, IQ, OQ, PQ Of Sterilization Process

Execute Validation Protocols

Design Sterilization Or Depyrogenation Process


Yes Aseptic Process?

No




Laboratory Control

Sampling



Validation ProgramFacility, Equipment & Utility Qualification

Change Control


Minimize Bacterial Load on Materials &

Equipment

Maintain & Control Clean Manufacturing

Conditions

Maintain Time Limits On Processing

Control Product Sterilization

Sterilize Components And Equipment

Maintain & Control Product Integrity

Hygiene & Gowning

Validation

Facility, Equipment & Utility Qualification

Laboratory Controls


Certify Personnel for Clean Room Operations








TrainingChange Control

Develop Functional Requirements And Design

SpecificationsRisk Management



Qualification

Change Control




Qualification

Validation Program

Validation Program

Change Control

Computer System Validation

Periodic Review Of Equipment, Facilities, Or Utilities

Perform Requalification

Report Requalification

Develop And Approve Requalification Protocol

Risk ManagementDocument Control

Change To Equipment, Facility, Or Utility Change Control

Other Quality System Element Reviews





Calibration


Change Control

Dev

iatio

ns &

Inve

stig

atio

ns

Per

iodi

c P

rodu

ct R

evie

w

Qua

lity

Man

agem

ent R

evie

w

Gov

erna

nce

&

Man

agem

ent N

otifi

catio

n

Calibration


Requalification

Prepare detailed site Schedule and Communicate within the site (Site

Quality)

Assemble Site Management Team for Review of draft SIte PPR Report

and recommendations (Site Quality)

Distribute Site PPR Report

No

PPR Schedule

Compilation of PPR Elements

Site Management Review and Approval

Compilation of Final PPR Report

Create Master Schedule and Communicate to Sites

(CQO QA)

Assemble Multi-Site Management Team for Review of draft PPR Report and recommendations

(Lead Site Quality)

Is PPR Report Approved?

No

Issue PPR and make available

Compile data into PPR template, evaluate, and provide conclusions/

recommendations

Compile PPR Templates into site PPR Report and draft Executive

Summary(Site Quality)

Is Site PPR Report

approved?

Yes

Compile Site PPR reports into Final PPR Report and draft Executive

Summary(Lead Site Quality)

Yes

Multi-Site Management Review and Approval

Issuance of PPR

Is this a Multi-Site

PPR?

No

Yes


CAPA

CAPA

Initiate QC testing

Retain study materials

Knownlaboratory erroror atypical event

duringtesting?

Identifying and Documenting Events

Phase I Investigation

Interpretation of Phase II investigation results

Investigation closure

Discontinue testing. Document

and invalidate results. Reinitiate testing

Notify QA

Lab assignable cause?

No

Reinitiate testing

Phase II Investigation

Close Phase I Investigation (QA)

Laboratory assignable

cause confirmed?

Yes

Document and invalidate results.

Reinitiate testing

Invalidate results Close Phase I

Investigation (QA)Yes

Close Phase II investigation (QA)

Accept original result?Yes

Execute approved retesting plan

No

Is original test result confirmed?

Yes

Prepare and execute approved Phase II Plan

Review of production-related

activities

Additional Laboratory

Testing

No

Yes

Initiate Laboratory Management review

No

Atypicalor failingtest result

Report results as per

procedureNo

Yes

Phase I checklist and confirmatory testing

Review dataReview data

Assignablecause identified/

confirmed?

Yes

NoNo



Laboratory Controls

Determine deviation

classification(QA)

Investigation Initiation: Initial impact assessment and

Immediate actions (containment, initial data gathering)

Root Cause Determination

Minor

Is CAPA required?

QA review and approval

Enter CAPA plan into CAPA

system

No

Yes

Deviation closed

Impact Assessment

(product, other lots and systems)

Formal Root Cause Analysis

Determine appropriate CAPA plan

Final review and approval

Deviation closed

Deviationpotentially impact

distributed product?

Assign cross-functional team

with leader

Develop investigation plan

Escalation and post-marketing

assessment

Yes

Management Notification

Deviation classification appropriate?

Yes

Yes

Escalation and post-marketing

assessment

Impact Assessment

(product, other lots and systems)

Deviationimpact distributed

product?

Enter CAPA plan into CAPA

system

No

Event is Deviation?

Follow alternate system such as good

documentation practices or change control practifces

Yes

No

Deviation identification and QA notification

Deviation classification appropriate?

No

No

No

Critical/Major

Assign a cross-

functional team with

leader

Approve the CAPA Plan

(QA)

Perform Effectiveness

Review

Generate a site CAPA

plan

Implement and manage the CAPA Plan

CAPA Approved and Closed

(QA)

Verify CAPA completion

(QA)

CAPAMulti-Site?

(QA)

Prepare Multi-Site Master

Plan

Assign a Corporate

CAPA Team and Corporate CAPA Team

Leader

Multi-Site CAPA required?

(Corp. QA)

Approve Multi-Site Master

Plan (Corporate QA)

Multi-Site CAPA Approved and Closed

(Corp. QA)

CAPAEffective?

(QA)

Corporate ManagementNotification (Corp. QA)

No

Multi-Site CAPA

Team needed?(Corp. QA)

No

Risk Assessment

(QA)

Implement CAPA

Verify CAPA Completion

(QA)

Minor Impact

Major/Critical Impact

Yes

No

Yes

Yes

Classification and Establishment of a CAPA Team

CAPA Plan Implementation and Management

Development of a CAPA plan

CAPA Approval and Closure (In Control)

Effectiveness Review (In Use)

Verification of CAPA Completion (In Place)

Change Control

If Applicable

No

Yes

Reg

ulat

ory

Rep

ortin

g


CAPA


Change Multi-Site?

Assign SMEs for assessment

Prepare change plan with prerequisite, post-execution, post-implementation, and effectiveness

review activities

Perform Prerequisite Activities

Execute change and perform Post-Execution Activities

Yes

No

Change Closed

Perform Effectiveness Review activities required by plan

Effectiveness Review complete and approved

System Owner Approve?

Change rejected

Modify change?No Noyes

Yes

Plan approved?

No

Authorize execution

Review of Change Approved?

Perform Post-Implementation Activities

Approve implementation of change for production

Submit Change Request with detailed description

Proposed change identified

Return system to original state

according to plan

Yes

Initiation

Change Assessment

Change Authorization

Change Execution

Change Closure

Change Effectiveness

Identify Change Owner

Evaluate business and compliance strategies and commitments to

identify change

Quality review

CAPAs and proposed

improvements

Confirm Plan

Change Implementation

yes

Initiate a new Change

Request to describe required activities

No

Rejected change closed.Product impact evaluation per

plan

Permanent

Temporary

Review of Change

Product impact evaluation per plan

Change Plan Development and Approval

Initiate investigation to review impact

on product produced

under change

Submit Multi-Site Change Request

Assign SME’s for assessment

Prepare Multi-Site Change Plan including Prerequisite Activities

Multi-Site Plan Approval?

Close new Change

Request and associated

investigation

No

Change Control

Risk Management

Initiate Project

Construction and Verification

Initiate Engineering Change Management

Establish Requirements

Specification, Design, and Approval

Generate detailed project plan

Approve project plan

Create and approve User Requirements Specification

(URS)

Assign a Project Manager and assemble Project Team

Create and approve

Technical Specifications

Perform technical and commercial bid analyses

Perform Risk Assessments

Design Development

Select vendor and award contract

Approve Design?

Create and approve basis

of design

Initiate Engineering Change Management

Commence Construction

FAT Acceptable?

Commissioning and Verification

Installation

Close Engineering Change Management

Acceptance and ReleaseRelease equipment for validation

or use

Prepare Request for Quote (RFQ)

Create and approve project charter

Submit Capital Approval Form (CAF)

ReviseDocument Project

Closeout No

Yes

Verification SAT Acceptable?

Document Control

Purchasing Control


Document Control

No

Calibration


Validation Program

Document Control

No

Yes

Yes

No

Yes

No


Generate Data

Review & Approve Data Or Record

Archive Record For Retention Period

Retrieve Record As Needed

Destroy Records At End Of Retention


Regulatory Inspections

Document Control

Generate Or Change Controlled Documents

Review, Approve Controlled Documents

Implement Controlled Documents

Retire Obsolete Versions

Conduct Training Training

Records Control

Initiate Change Request For Non-

Substantive Changes

Close Document Change Request As

Applicable

Change Control

Review Periodically Controlled Documents


Change Control

Change Control

Document Control

Record Control

Select Qualified Personnel For GMP

Activities

Identify Training Requirements And

Plan Training

Design Training Curriculum Materials

Execute Training

Monitor Training Effectiveness

Retrain As Appropriate

Audit & Walk Through Inspections



Document Control

Management Review

CAPA

CAPA

Develop & Identify Organizational

Structure Necessary To Support GQS

Define Organizational Relationships &

Numbers Of Personnel

Create Job Descriptions &

Organization Charts

Assess Personnel Qualifications

Acquire Or Assign Personnel According

To Qualifications

Train Qualified Personnel



Training


CAPA

Business & QMS Requirements

Document Control

Design Gowning Program

Train & Implement Gowning Procedures

Determine Gowning Control Requirements

Change Control

Risk Mangement

Train & Certify Personnel For Aseptic

AreasTraining


Training

Hygiene & Gowning

Prepare and Communicate Audit Plan

Draft Audit Report

Generate/Submit Response

Approve Response?

(QA)

No

Execute post-audit activities

All post-audit activities

complete?

Close Audit

No

Yes

Communicate Audit Schedule

Assign Lead Auditor and Audit Team

Execute Audit

Prepare Annual Audit Schedule

Approve Schedule?

(Site Quality Head)

Yes

No

Yes

Notify Lead Auditor

Audit Schedule

Audit Preparation

Approve Audit Report?

(QA)

Issue Audit Report

Yes

No

Audit Response

Post-Audit Activities

Audit Closure

Audit Execution

Inspection/Audit Preparation

Receive Inspector/Auditor

Conduct Inspection/Audit

Inspection/Audit Wrap-up

Develop Response And Commitment/

CAPA

Submit Responses For Commitment/

CAPA

Complete Commitment/CAPA & Close Inspection/Audit

CAPA


CAPA



Regulatory Inspections & Customer Audits

Consider Possible RecallDeviation Investigations

Develop Strategy And Planning

Determine Health Hazard & Class As

AppropriateNotify Regulatory

Agency Or Competent Authority As Required

Reg

ulat

ory

Rep

ortin

g

Implement Plan Storage & Distribution

Periodic Reports As Required

Complete & Close Regulatory ReportingDeviation Investigations

Report Event To Regulatory Agency

Report Followup To Regulatory Agency

Yes

Receive Product Event Information




Complaint Management

Counterfeiting, Product Diversion, & Tampering

Event Reportable? No Trend

Deviations & InvestigationsLaboratory Investigations

Evaluate Labeling Change Risk Assessment

Initiate Labeling Change Request For Review & Approval

Implement Labeling Change

Validation


Facility &Equipment Management

Materials Control

Close Labeling Change

Materials Controls

ValidationRegulatory Authority

Submission

Labeling Change Planning

Qualification

Regulatory Authority Submission

Train & Certify Licensed

Representative

Perform Duties in Accordance with

Licensed Requirements

Maintain Certification As Required

Regulatory Affairs

Management Review

Lot Disposition

Training

Designate Sufficient Number of Licensed

Representatives

Training

Other GQS Standards

Labeling Development & Change Management

Recall


Licensed Representatives

Form a Technology Transfer Team

Assess Sending & Receiving Unit readiness

Define project scope and requirements

Process/method ready for transfer?

Generate a detailed Transfer Plan

Technology Transfer Initiation

Perform technical gap analysis and Risk Assessment

Technology Transfer Plan

Item has been identified for transfer to an identified Receiving Unit

Transfer Plan approved?

Execution of Plan Execute

Transfer Plan

Transfer meet acceptance

criteria?

Compile transfer final report

Post-Transfer monitoring

Post-Transfer Monitoring

Identify a Technical Leader/project manager

Project approved to proceed?

Technology Transfer Proposal

Document and File

Document and File

No

Yes

No

Complete Technology Transfer and lessons learned

Completion of Technology Transfer

Drug DevelopmentDesign Control

Risk Assessment

More information

Cancel

More information

Cancel

Change Control

Change Control


Quality Management ReviewPeriodic Product Review

Technology Transfer

Develop Design Plan

Conduct Review

Design Product & Develop Design Outputs

Develop & Execute Verification Protocol

Develop & Document Design Inputs

Design Validation (Clinical Trial, Animal

Studies, IDE) Activities

Conduct Review

Select Product to Market & Determine Product

Regulatory ClassificationResearch Report

Manufacture Commercial Product, Improve Design,

Update DHF

Lab Investigations


Research


Change Control

Risk Management

Risk Management

Transfer Activities

Conduct Transfer Review





Change Control

Production Controls

Risk Management

Technology Transfer

Regulatory Affairs

Design Control

Develop Test Method

Develop Stability (Shelf Life)

Specification Specifications

Develop Finished Product Specifications

Develop In-Process Specifications

Validate Test Method

Transfer Method

Identify CQA Or CPP Drug Development

Use & Improve Specifications

Lab Investigations


Research

Complaint ManagementEnvironmental Monitoring




Change Control

Technology Transfer

Design Control

Method Validation

Determine Instrumentation And

Sampling

Laboratory Instrument QualificationSampling



Develop, Characterize API, Develop PCS

With QTPP

Develop DP Formulation Process

& PCS

Develop & Validate Cleaning Process &

Methods

Develop & Transfer Manufacturing

Process & MBR, Update PCS

Transfer & Qualify API Manufacturer Based

Upon PCS

Validate Process, Update PCS

Manufacture Clinical Supplies

Validation

Identify Molecule Research Report

Manufacture Commercial Product

& Improve PCS

Lab Investigations


Research

Complaint ManagementEnvironmental Monitoring




Change Control

Technology Transfer

Drug Development

Receive & Document Complaint

Complaint Investigation

Complaint Report

Acknowledge Complaint

Pharmacovigiliance

Communication To Complainant




Counterfeit, Product Diversion, & Tampering

Receive Complaint Where Counterfeiting, Diversion

Or Tampering Is Suspected

Request & Receive Sample

Notify Senior Management &

Regulatory Authorities

Perform Assessment And Testing

Continue In Accordance With Complaint Policy

Laboratory Controls

Counterfeit, Diverted, Tampered

Product?Yes

No

Pharmacovigiliance


Recall


Pharmacovigiliance



Verify & Move to Distribution Inventory

Receive Customer Order

Material Picked, Verified, & Staged

Material Shipped

Store Product

Product destroyed

Product Returned?

Yes

End No

Is product to be returned to

Distribution?Yes No

Release Lot for Distribution

Verify Product Storage & Integrity


Deviation & InvestigationsEnvironmental Monitoring

Lot Disposition


Dev

iatio

n &

Inve

stig

atio

ns

Com

plai

nt

Cou

nter

feiti

ng, P

rodu

ct

Div

ersi

on, a

nd T

ampe

ring

Rew

ork,

Rep

roce

ssin

g,

Rei

nspe

ctio

n, R

ecov

ery

Receipt

Material Quarantine & Disposition

Warehousing

Product Quarantine & Disposition

Shipping/Distribution


Production Controls


Purchasing

Lot Disposition

Supplier Control

Sampling

Lot Disposition




Labeling Development & Change Management

Completed Product Batch Record And

Testing

Generate Certificate Of Analysis (CofA)

Verify That CofA Is Consistent With Raw

Data

Verify That CofA Meets Requirements

Final Approval

Send To Customer And Archive Copy

Laboratory ControlsReceive Certificate Of Analysis (CofA) From

Supplier

Review For Completeness

Verify CofA Results Meet Specifications

Resolve Discrepancies Or

Issues

File With Material Lot Record

Purchasing Controls

Lot Disposition


Purchasing Controls


Material Control


Material Control

Certificate of Analysis

Risk Assessment Categorize Supplier

Initial Assessment & Questionnaire

Qualify Supplier

Re-Qualify Or Disqualify Supplier

Prepare For Audit

Execute Audit

Response And CAPAClose Audit

Schedule Supplier Audit

Laboratory Controls

Supplier Control

Supplier Control



Monitor SupplierCAPA

Complaints Regulatory Inspection

Supplier Control


Qualify Supplier that will be subject to a Quality Agreement (QAG)

Determine Risk Mitigation

Generate QAG

Review QAG & Corresponding Supply

Agreement (SAG)

Submit QAG for review and approval of Stakeholders

Submit approved Quality Agreement to Customer

Obtain signed approval from Customer

Monitor, Review, & Modify Quality Agreements


Risk Management

Document Control

Quality Agreements

Receive Purchase Request

Supplier Qualified?

Initiate Supplier Qualification

Process

No

Yes

Maintain Purchasing Records

Place Order with Supplier

Corrective Action

Required?

No

Yes

Initiate Supplier Corrective Action

Process

Receive Sourced Product or Services


Material Control

CAPA

Develop/Revise Specifications/Quality

Agreement

Qualify Supplier

Purchase Material, Product Or Service

Monitor, Re-qualify, Disqualify Supplier

Approve Supplier



Quality Agreement

Identify Supplier (s)

Issue Batch Record

Complete Batch Record

Monitor Production

Generate Records

Manufacture Product

Master Batch Record

Sample & Inspect

Completed Batch Record

Materials Control

Training

Lot Disposition



Laboratory Controls

Change Control

Document Control

Complaint ManagementProduction Control

Purchasing Control

Counterfeiting, Product Diversion, Tampering

Produce Non-Conforming Material

or Product


Perform Remediation As Rework,

Reprocessing, Reinspection,

Recovery

Evaluate & Report Results


Covered by Procedure?

Yes

No


Lot DispositionSampling

Laboratory Controls

Material Control

Production Controls


Develop & Approve Protocol

Issue Batch Record


Monitor Production

Generate Records

Manufacture Product

Master Batch Record

Sample & Inspect


Materials Control

Training

Lot Disposition



Laboratory Controls

Change Control

Document Control


Rework, Reprocessing, Reinspection, Recovery

Minimize Bacterial Load on Materials &

Equipment


Conditions


Control Product Sterilization


Maintain & Control Product Integrity

Hygiene & Gowning

Validation


Laboratory Controls


Certify Personnel for Clean Room Operations


Issue Batch Record


Monitor Production

Generate Records

Manufacture Product

Master Batch Record

Sample & Inspect


Materials Control


Laboratory Controls

Sampling

Change Control


Training

Lot Disposition

Document Control

Production Control




Minimize Bacterial Load on Components

& Equipment


Conditions


Control Equipment & Component

Sterilization Or Depyrogenation


Validation




Aseptic Processing Controls


Issue Approved Packaging And

Labeling

Sample & Inspect Product Labeling &

Packaging

Reconcile Labeling & Packaging Materials

Perform Line Clearance

Label & Package Product

Receipt Of First Supply

Issue Approved Printed Labels

Laboratory ControlsDeviations & Investigations

Return Or Destroy Packaging & Labeling

Sampling


Materials Control

Materials Control


InitiateQuality Risk Management Process

Risk Identification

Review Events

Risk Acceptance

Risk Reduction

Risk Evaluation

Risk Analysis

Risk M

anagement ToolsR

isk

Com

mun

icat

ion

Output/Result Of TheQuality Risk Management Process

Risk Assessment

Risk Review

Unacceptable

Risk Control

.

Current Standard

KPC

Cri$cality Assessment : Quality System Map Annual Product Review

Change Control

Regulatory Agency Submissions

Validation

Testing Lot Release Training

Discrepancy Management

Complaint/Adverse Event

Audits Facility & Equipment Maintenance Facility & Equipment Engineering

Production Packaging & Labeling


Materials Management

Record Management PROP Systems Program

Interfaces

Design Environmental

Controls Design

Environmental Monitoring Procedures

Analyze Data for Trends

Implement Environmental

Monitoring Program

F & E Engineering Validation Change Control

Testing Validation F & E Engineering F & E Maintenance

Lot Release Discrepancy

Change Control Testing

Discrepancy Change Control

Validation Study Planning

Protocol Development and

Execution Data analysis and

Reporting

Production (I) Facilities & Equipment

Engineering (I) Document Control (I)

Testing (I) Facilities &

Equipment Engineering

(I) Change Control Discrepancy

Testing Production

Training Materials

Management Change Control

Identify Facility or Equipment

Equipment and Facility

Maintenance Facilities & Equipment Preventative Maintenance

Facilities & Equipment Calibration

Facilities & Equipment

Cleaning and Sanitization Pest Control

Change Control (I) F & E Engineering (I)

Production (I) Discrepancy

Discrepancy Discrepancy Discrepancy Discrepancy

Change Control Change Control

Training

Collection of Data Evaluation &

Analysis of Data Reporting of Findings &

Implementation of CAPA

Lot Release (I) Change Control (I)

Discrepancy Management (I)

Product Complaints (I) Testing (I) Audit (I)


Change Control (I) Regulatory Assessment

Strategy Development

Implement Strategy Change Control

Lot Release Receiving/

Warehouse Quarantine Warehousing

Shipping/ Distribution

Change Control (I)

Audit Lot Release

Testing Discrepancy

Lot Release Testing

Production Packaging &

Labeling

Issuance & Inspection Perform,

Reconcile, Review Production Materials

Record

Discovery and Initial Assessment

Validation (I) Regulatory Agency Submissions (I)

Testing (I) Audits (I)

Materials Management (I) Complaints/Adverse Events (I)

Annual Product Review (I) Lot Release (I)

F & E Maintenance (I) Production (I)

Labeling & Packaging (I) Environmental Control (I)

Immediate Corrective Action Investigation, root Cause Analysis, and Preventative

Action Follow through and Closure

Document/Report/ Analyze

Change Control Change Control Regulatory Agency

Submission Lot Release

Annual Product Review (I) Lot Release (I)

Validation (I) Training (I)

Deviation Management (I) Change Control (I)

Complaint/Adverse Event (I) Audit (I)

F & E Maintenance (I) F & E equipment (I)

Production (I) Labeling & Packaging (I)

Environmental Monitoring (I) Materials Management (I)

Testing (I) Regulatory Agency

Submissions (I) Record Management (I)

Audit Preparation Audit Execution

Creation & Issuance of Audit

Report Follow-up and

Closure

Responding to Audit/Inspection

Observations Audit/Inspection Closure

Inte

rnal

/Ext

erna

l Aud

it H

ostin

g A

udit Audit/Inspection

Execution Audit/Inspection Audit/Inspection Preparation



Change Control (I) Production (I)

Packaging and Labeling (I)

Material Management (I) F & E Maintenance (I)

Regulatory Agency Submissions (I)

Environmental Control (I) Planning or Feasibility

Requirements or Conceptual

Design Preliminary and Detail Design Construction,

Commissioning and Qualification

Change Control Change Control

F & E Maintenance Validation

Operation & Maintenance F & E Maintenance Decommission Change Control

Batch Planning Raw Material/ Component

Allocation Process

Preparation Bulk Production Final Production

Materials Management (I)

Records Environmental

Change Control (I)

Training (I) Validation (I)

Change Control (I) F & E Maintenance (I)

Materials Management (I)

Materials Training

Change Control Records

Environmental Materials Training

Records Testing

Lot Release Environmental Materials

Training Records

Testing Lot Release

Discrepancy

Discrepancy

Record Design Record

Generation Record Review Record Archive and Destruction

Production (I) Maintenance-

Facilities&Equipment (I) Engineering-

Facilities&Equipment (I) Testing (I)

Materials Management (I) Lot Release (I)

Change Control (I) Validation (I)

Environmental Monitoring (I) Annual Product Review (I) Packaging and Labeling (I)

Discrepancies Management (I) Complaints/Adverse Events (I)

Audits (I) Training (I)

Change Control

Discrepancy

Initiate & Evaluate Change

Change Review & Approval

Implement Change Close Change &

Monitor Effectiveness

Validation (I) Regulatory Agency

Submissions (I) Lot Disposition (I)

Testing (I) Training (I)

F&E Maintenance (I) F&E Engineering (I)

Packaging & Labeling (I) Production (I)

Environmental Control (I)

Lot Release Training

F & E Engineering F & E Maintenance Validation Environmental Control Regulatory Agency

Submissions Lot Release

Audit (I) Annual Product Review (I)

Production Support Testing Support Training Support

Validation Support Discrepancy Management Action

Regulatory Agency Submissions Support Materials Management Support Change Control Support

Lot Release (I) Environmental Control (I) Materials Management (I)

Validation (I) Complaint/Adverse Event (I)

Production (I) Packaging & Labeling (I) Annual Product Review (I)

Scheduling & Planning Testing

Preparation Sample Receipt

Test Performance & Reporting

Test Evaluation Laboratory

Investigation Discrepancy

Validation Training Records Records Records

Record Management Support Change Control (I)

Discrepancy Management (I) Testing (I)

Environmental Control (I) Production (I)

Packaging and Labeling (I) Regulatory Submissions (I)

Collection of Records and Data

QA Review of Records and Data

Approval and Disposition Materials

Records Discrepancy

Production Discrepancy

Material Management Support Complaint Receipt

Adverse Event Notification/

Sample Retrival Product

Nonconformance Investigation

Report, Corrective Action & Close Out

Testing Regulatory Agency

Submission Change Control

Trend Analysis Regulatory Submissions (I)

Production (I) Testing (QC) (I)

Production (I)

Discrepancy Discrepancy

Identify Training Events

Determine Training Needs

Implement Training

Monitor Training Effectiveness

Production (I) F&E Maintenance (I) F&E Engineering (I)

Testing (I) Materials Management(I)

Lot Release (I) Change Control (I)

Validation (I) Environmental Control (I) Annual Product Review (I) Packaging and Labeling (I)

Discrepancy Management (I) Compliant/Adverse Events (I)

Audits (I) Regulatory Agency Submissions (I)

Audit Record

Testing Production

Production

Materials Management

Materials Management Packaging &

Labeling

Packaging & Labeling

Discrepancy

Discrepancy Action

Training Support

Record Management Action Record Management Support

Rec

ord

Man

agem

ent A

ctio

n R

ecor

d M

anag

emen

t Sup

port

Discrepancy Action Change Control Action Lot Release Action

Change Control Action

Audit Support A

udit Support

Production Support

Blue Lines Are Good; Red Lines … Not So Much

Core Quality System Elements TM





Control and Release


Quality Audit



Cleaning Validation

Process Validation







VisioDocument

Quality Process

XXXXXX

LEGEND






Sampling




Standards



Technology Transfer








Material Management


Purchasing Control



Hygiene & Gowning

Design Control

XXX

Drug Development



Change Control

Training


Risk Management


Calibration



Production Control

Validation Program

Materials Control

Laboratory Controls








XXX






Requalification




Technology Transfer











Development Engineering & Maintenance Manufacturing Q C Q A

ICH Q10 Quality System – Organiza$on Chart

QC QA Development Manufacturing Engineering

Core Quality System Elements

Quality System -‐ Development

•  PD Experiments Define Process CQAs, CPPs •  CQA Test Method Development •  Produc$on Opera$ons Risk Assessment (RA) •  Process Development Report (PDR) •  Verify CQAs & CPPs – Valida$on Protocols •  Verify CQAs & CPPs – Batch Records, •  Ongoing Test Method Support •  Monitor Process Data •  Monitor QC Test Data •  APQR Assessment

KNOWLEDGE SPACE

DESIGN

SPACE

CO

NTR

OL STR

ATEGY

CRITICALITY

Development of Product A:ributes, Process Parameters, Design Space & Control Strategy

Quality System – Engineering Basis : Process Development Report

•  Design Facili$es, Equipment, Instruments, U$li$es

•  Develop Engineering, Cal/ Maintenance Program

•  Install Control System •  Qualifica$on •  Rou$ne Manufacturing Support •  Engineering, Cal/ Maintenance data to QA

Quality System – Manufacturing Basis : Process Development Report

•  Drive Process Valida$on •  Finalize Process Monitoring and Control •  Complete Produc$on Batch Record •  Devia$ons •  Inves$ga$ons •  Correc$ve and Preven$ve Ac$on (CAPA)

•  Manufacturing •  Data to QA

Quality System -‐ Quality Control Basis : Process Development Report

•  Define Environmental Monitoring Requirements •  Test Method Transfer Valida$on

•  Rou$ne IP, QC Sampling and Tes$ng •  IP and QC data to QA

Quality System -‐ Quality Assurance Oversight Basis : Process Development Report

•  Engineering Design •  Training Materials •  Calibra$on and Maintenance Program, •  Manufacturing BR & SOPs •  In-‐Process and QC Test Methods •  Process Valida$on •  CPPs and Cri$cal Unit Opera$ons •  Review IP and QC Test Results •  QA Produc$on Data Review – Product Disposi$on

Core Quality System Elements TM





Control and Release


Quality Audit



Cleaning Validation

Process Validation







VisioDocument

Quality Process

XXXXXX

LEGEND






Sampling




Standards



Technology Transfer








Material Management


Purchasing Control



Hygiene & Gowning

Design Control

XXX

Drug Development



Change Control

Training


Risk Management


Calibration



Production Control

Validation Program

Materials Control

Laboratory Controls








XXX






Requalification




Technology Transfer











Development Engineering & Maintenance Manufacturing Q C Q A

ICH Q10 Quality System – Organiza$on Chart

11/19/15 17

QC QA Development Manufacturing Engineering

FDA Quality Metrics -‐ Repor$ng •  Lots Anempted •  Rejected Lots •  Anempted Batches •  OOS (Including Stability) •  Lot Release Tests •  Stability Tests •  Invalid OOS (Including Stability) •  Product Quality Complaints •  Lots Anempted •  APR (QPR) On Time Comple$on •  AQRs (PQRs) Required

Management Governance •  Corporate Product Quality & Compliance Goals •  Rou$ne Produc$on Monitoring and Control •  Devia$ons, Inves$ga$ons •  Rejected Materials / Products •  Product Complaints •  Adverse Events •  Recalls •  Annual/Periodic Product Quality Reviews •  Correc$ve and Preven$ve Ac$ons •  Con$nuous Improvement •  Periodic Management Reviews – Goals / Progress

Final Thoughts

•  Put in Place an ICH Q 10 Based QS •  Understand the Product (CQAs) •  Understand the Process and its Impact on the Product (CPPs, QbD and Control Strategy)

•  Validate QC Test Methods •  Validate, Monitor and Control the Process •  Inves$gate and CAPA all Devia$ons •  Con$nuously Improve all Opera$ons

Thank You

Ques$ons ?

Comments?

Quality systems for continuous manufacturing

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