Product Quality Management

Product Quality Management 

Deborah Baly, Ph.D

Sr. Director, Commercial Product 

Quality Management, GNE/ROCHE

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Presentation Outline:

• Product Quality Management – Regulatory landscape and need for integrated product quality management

• Role of the Product Quality Steward – Product quality oversight by linking systems, data, and people

• Product Lifecycle Management - Commercial Product Lifecycle approach

Regulatory Landscape

Growing Expectations for Modern Manufacturing  • Quality is built in • Lifecycle approach from Development to Product  Discontinuation • Understand complex supply chain CMO networks • Robust process measurement & analytical tools  • Real‐time assessment of product & process capability • Maintaining “state of control” throughout commercial lifecycle

Product Quality Management: 

Fundamental Elements

Slide 4 Product Complaints

• Identifying early warning signals of product quality issues in the field

Product Assessment & Trending

• Proactive assessment of product quality attributes across the manufacturing process

Product Quality Stewards

• Single point of Contact for Quality to key stakeholders • Routine assessment of product control plans to address trends • 8 Qtr Plan provides foresight and proactive approach

QC testing network support

• Harmonized approach to test method execution & support • Raw Materials & Stability Program Management

• Critical Reagent & Reference Material Program Management

Analytical methods management

Scientific rigor engrained in analytical method performance

Product control systems based on science

Product Quality Management

Benefits

•Proactively minimize risks to patients, operations, and supply chain through early detection and end‐to‐end product oversight •Meets Regulatory expectations of science‐ and risk‐based product  knowledge management – Risk assessment of product quality attributes linked to  control strategy – Proactive monitoring & trending of product data – Product specific control plans across the global Mfg network – A focus on innovation, lifecycle management and continual  improvement

•Maintain reputation as a trusted source of high quality product among patients, regulators, and industry

Presentation Outline:

• Product Quality Management – Regulatory landscape and need for integrated product quality management

• Role of the Product Quality Steward – product quality oversight by linking systems, data, and people

• Product Lifecycle Management - Commercial Product Lifecycle approach

Supply Chain Teams:

Product Quality Steward Role

External Quality Product Quality Sub-Team Quality Steward Product Complaints Investigations Stability Lot Disposition QC IP/FP

Ad Hoc Quality Sub Team Members

• Change Control

• Methods Mgmt and Technology • Inspection Mgmt • Compliance • External QC • Validation PROP Finance PTTL DS Quality Steward CMC RegA Planning Launch STL _{Dev CMC} STL PMTL PTTL DP PSCT • Own monthly product‐specific Health Assessment Report &  escalation of risks to senior management • Own Product‐specific Risk Assessments & accountable to drive  completion of risk reduction activities • Lead Product Quality Supply Team • Quality SPOC on Product Supply Chain Team; responsible for  ensuring that Quality requirements are met  • SPOC for Quality for Tech Transfer Teams • Review APQR’s and AR’s for accuracy and completeness as well  as for lifecycle management commitments

Product Quality Steward Role Leadership & Accountability

• Knowledge & Lifecycle Management – Manage product commercialization with IMP Quality – Conduit of Information within Quality for Product Knowledge – Own and manage E2E Control Plans and Quality Lifecycle Management  (continual improvement) for product • Decision Making, Investigations & Issues  – Manage team of Quality SMEs for cross‐site investigations/issues   – Influence and drive decisions at Product Quality Supply Chain Teams   – Escalate product‐specific product quality and compliance issues for  review at relevant Quality Review Boards and/or Senior Management    – Decision maker for lifecycle management and product control plans  

Product Quality Steward Role Key Accountabilities

Quality Risk Management

Understanding E2E Supply Chain

Risk Review Risk Assessment Risk Evaluation Risk Control Risk Analysis Risk Reduction Risk Identification Review Events Risk Acceptance Initiate Quality Risk Management Process

Output/Result of the Quality Risk Management Process

Ri

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unication

Scope: End-to-end supply chain for commercial products

Data collection checklist: complaints, investigations, stability, QC, lot disposition, audits, supplier quality, APQR, validation, facilities, warehousing, distribution, PQST input, etc.

Gather data & reconfirm risk is still relevant

Score each risk for severity, occurrence & detectability (S, O and D):

ۛ Up to DP: Quality/Regulatory scoring matrix ۛ For distribution and on: Patient Safety scoring matrix

Cross-product review to identify additional risks “Not acceptable/intolerable” risks need risk reduction

actions identified

When risk reduction activities are completed, a rationale for acceptance of residual risk is documented

Presentation Outline:

• Product Quality Management – Regulatory landscape and need for integrated product quality management

• Role of the Product Quality Steward – Product quality oversight by linking systems, data, and people

• Product Lifecycle Management - Commercial Product Lifecycle approach • Conclusions ─ Pharmaceutical companies should plan and execute a system  for the monitoring of process performance and product  quality to ensure a state of control is maintained.   ─ Use quality risk management to establish the control  strategy.  ─ Provide the tools (e.g., data management and statistical  tools) for measurement and analysis of parameters and  attributes identified in the control strategy ─Identify sources of variation affecting process performance  and product quality for potential continual improvement  activities ─Knowledge management

ICH Q10 Elements

Product Quality Assessment

• ICH Q10 Pharmaceutical Quality System, Process

Assessment & Management of Process Changes

Process Monitoring: Process & Quality

Attributes Management of Analytical Control System Changes Post-Approval Lifecycle Management Plan

Post-Approval Lifecycle Management Plan (PALM)…….Leveraging QbD

• Health Authority expectation that commercial products are monitored and

continuously improved post-approval

• License claims are expected to be updated as sponsor learns more about the

product and process

Management of Analytical Control System Changes Assay Specific Triggers • Recommendation in response to  out‐of‐trend results • Recommendation as a result of  Annual Product Review (APR/PQR)  process • Implementation of “better” assay  for other commercial products • Assess suitability of assay • Determine if options exist to  improve current assay performance • Determine suitability of new assays  Control System Triggers • Recommendation in response to  out‐of‐trend results • Recommendation as a result of  Annual Product Review (APR/PQR)  process • A significant process change or new  device being implemented  • New knowledge from additional  clinical/non‐clinical studies for this  product • Mandated every 5 years if no other  triggers require assessment

Goal of Product Monitoring: Ensuring a Continued State of Control of Process  Performance and Product Quality Delivered! STABLE CAP AB L E NOT CAPAB L E

The Place to be!!

Target not around the center of specification ranges & variation is too large

Not acceptable!

You can’t tell what the quality of the next unit will be.

NOT STABLE

Product & Process Monitoring

Process Capable Chart:  Capable vs. Un‐capable Process •A capable process that delivers on target  for this CQA: •CpK>1 •Process delivers right on target. •Process Capability: …is  a statistical estimate of the outcome of a characteristic  from a process that has been demonstrated to be in a state of statistical control.  •Process Capability Index: a statistical measure of process capability •CpK = Ratio of Spec Range to Total Data Variation •CpM= Measurement of how “centered” around the “target” the process can deliver

Correlation of CpK value with % Defective Product

•Not a capable process, even though it  centers around the target  •CpK<1 Cpk % Defective product 0.8 0.819 1.0 0.135 1.33 0.0033 1.8 0.00033

Analytical method and specification not optimized Excessive OOSs and OOTs observed  31 28 25 22 19 16 13 10 7 4 1 7.0 6.5 6.0 In d iv id u a l V a lu e _ X = 6.346 UC L= 7.033 LC L= 5.658 31 28 25 22 19 16 13 10 7 4 1 0.8 0.4 0.0 Mo v in g R a n g e __ M R = 0.2586 UC L= 0.8448 LC L= 0 30 25 20 15 10 6.50 6.25 6.00 O b se rv a tio n Va lu e s 6.8 6.6 6.4 6.2 6.0 5.8 5.6 LSL U SL LS L 5 .4 7 U S L 6 .8 6 S pe cifica tio n s 7.0 6.5 6.0 5.5 W ithin O v e ra ll S pe cs S tD e v 0 .2 2 9 2 2 5 C p 1 .0 1 C p k 0 .7 5 W ithin S tD e v 0 .2 2 0 1 9 2 P p 1 .0 5 P p k 0 .7 8 C pm * O v e ra ll P r oduct_ A T e s t M e thod_ 1 2 5 B e for e M e thod/ S pe c C ha nge

I C ha r t M ov ing R a nge C ha r t L a st 2 5 O bse r v a tions C a pa bility H istogr a m Nor m a l P r ob P lot A D : 0 .3 9 7 , P : 0 .3 5 0 C a pa bility P lot

Example 1:A Un-Capable Process for Potency Assay (Cpk <1.0, and not centered)

• Both analytical method and specification have been optimized in order to  achieve a capable (CpK=1.29) and centered process for the potency assay. 25 22 19 16 13 10 7 4 1 6.5 6.0 5.5 In di v idu a l V a lu e _ X = 5.933 UC L= 6.413 LC L= 5.453 25 22 19 16 13 10 7 4 1 0.50 0.25 0.00 Mo v ing R a nge __ MR= 0.1805 UC L= 0.5896 LC L= 0 25 20 15 10 5 6.4 6.0 5.6 Obse rv a tion Va lu e s 6.4 6.2 6.0 5.8 5.6 5.4 5.2 LSL U SL LS L 5.16 U S L 6.55 S pecifications 6.25 6.00 5.75 5.50 W ithin O v erall S pecs S tD ev 0.159979 C p 1.45 C pk 1.29 W ithin S tD ev 0.159204 P p 1.46 P pk 1.29 C pm * O v erall 2

Product_A Test Me thod_125 A fte r Me thod/ Spec Change

I C har t

M oving Range C har t

Last 2 5 O bser v ations

C apability H istogr am

Nor mal P r ob P lot A D : 0.417, P : 0.308

C apability P lot

Example 1 continued:

• Integral to the analytical method life cycle management

• Focus is on purity and potency methods

• Ensures method performance across complex 

manufacturing network & testing sites is consistent

– Analysis of reference material, assay & product controls data

• Provides analytical trending support to process/product 

trending 

• A key component of the Annual Product Review (APR

– Regulatory requirement by Health Canada

• Stability investigation support

• Serves as an inspection tool for analytical methods

QC Method Monitoring

Program

Example: 

QC Method Monitoring Results

A Mab product, Ion Exchange Method

Sy stem suitability limits M e thod M oni tor ing li m it s

Top:Reference Material data trend

chart for all valid assays across 6 global testing sites

Bottom:Site Mean trend chart for

the 6 sites showing that the method performance is consistent throughout all sites

PALM & Annual Product Review

• Product Quality Monitoring Information would be documented with APR

Performed and Documented by QA per QSR Excursion data monitored via Discrepancy System per Quality System Requirement

Performed and documented by MSAT

Documented by QC per QS requirement

Performed & Documented by QA per QS Requirement Documented by QA per QS Requirement

Product Quality Management:

• The end‐to‐end quality review and control of 

Roche’s products throughout the supply chain

• Drives continual improvement throughout the 

product and process lifecycle to ensure a reliable 

supply of quality products to our patients

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Conclusion

Raw Materials Drug Substance Drug Product Testing Distribution