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Implementation of QbD
for Existing Products
An Example from GSK

Jonathan Parks
B.Sc (Hons) from Monash University in 1990
Started at Glaxo (as it was called then) in 1991 as a Development Chemist in Pharmaceutical Development
Worked on the development of Blow-Fill-Seal (BFS) products for nebulisation and Dry Powder Inhalation (DPI) products Moved into Manufacturing/Quality Assurance for GSK in 2001
Led the QC Technical and Laboratory Operations and Steriles and Inhaled Product Groups Moved to Technical as a Technical Project Leader in 2009
Work on the interface with R&D and GMS called NPI – New Product Introduction Sterile and Inhaled New Products for Current and Emerging Markets Collaboration with Monash University Institute of Pharmaceutical Science (MIPS) Manage the implementation of Product Lifecycle Management (PLM) (or QbD) at site – "Product Owner" for all DPI products

• QbD = Key Quality requirements for the development, manufacture and control of drug products – Drug Product Pharmaceutical Development – Quality by Design (QbD) Approaches – Product Control Strategy – Product Lifecycle Management (PLM) Approach to ensure ongoing Product Robustness • How these feed into the final registered details – Drug Product Pharmaceutical Development – Control of Critical Steps (In Process Controls – IPC) – Drug Product Specifications • Example of Ventolin Nebules – Virtual product tour where we will follow the product through the manufacturing and how the Product Control Strategy supports the Quality and Robustness of the Product Manufacture process

Drug Product Pharmaceutical Development
• The aim of Pharmaceutical Development is to design a quality
– Manufacturing Process • to consistently deliver the intended performance of the product
• Provides scientific understanding to support the establishment of – Design Space
Manufacturing Controls
Design Space:
The multidimensional combination and interaction of
input variables (e.g. material attributes) and process
parameters that have been demonstrated to provide
assurance of final drug product quality
"Quality cannot be tested into
products; Quality should be built
Working within the design space is NOT considered a change
Movement outside the design space is considered to be a change
(Likely to initiate a regulatory post approval change process)

Minimal Approaches
"Oliver" Top Gear Africa Challenge
Gets the job done but the journey can be rough, interrupted, require frequent changes and always the potential for catastrophic failure • Components of the Drug Product
– Drug Substance/s All aspects that are Critical to Product
Drug Product
Quality should be determined and
– Formulation Development control strategies justified – Physicochemical and Biological Properties Critical formulation attributes and process parameters are generally • Manufacturing Process Development
identified through an assessment of the • Container Closure System
extent to which their variation can have
impact on the quality of the drug
Microbiological Attributes
Enhanced Quality by Design (QbD) Approaches
Toyota Hilux (Top Gear North Pole Special)
More ROBUST Approach to the Challenge
• Choose to conduct Pharmaceutical Development studies that can lead to an enhanced knowledge of product
performance over a wider range of material attributes, processing options and process parameters.
• Demonstrate a higher degree of understanding • Facilitates an expanded design space • Opportunity to develop flexible regulatory approaches: – risk-based regulatory decisions (reviews and inspections) – manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review – reduction of post-approval submissions – real-time quality control, leading to a reduction of end-product release testing Thinking
Enhanced, Quality by Design Approaches (Combination of
ICH Q8, Q9 and Q10)

• Defining the Quality Target Product Profile
Quality Target Product Profile (QTPP):
• Identifying potential Critical Quality Attributes
A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account – Drug Substance safety and efficacy of the drug product. – Drug Product • Conduct a Risk Assessment (ICH Q9) to link Material
Critical Quality Attribute (CQA):
A physical, chemical, biological or microbiological property or characteristic
Attributes and Process Parameters to Drug Product CQA and that should be within an appropriate limit, range, or distribution to ensure build a Design Space
the desired product quality.
Critical Process Parameter (CPP):
• Use the enhanced product and process understanding in A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the combination with quality risk management to establish an process produces the desired quality. appropriate Control Strategy
Implement Product Lifecycle Management by continuous
evaluation of innovative approaches to improve product GSK has implemented a phased introduction to enable a clear quality (ICH Q10) end-to-end understanding of our products and processes which ensures: Process robustness
Batch uniformity (within/between)
Ongoing improvements to current performance
Regulatory Compliance with emerging expectations

Validation Lifecycle Approaches (ICH Q10)
Stage 1 Process Design documents are developed (Development History, Technology Transfer, Risk Assessment, Draft Product Control Strategy). (Stage 1)
Change Control
Master Plan
For Existing Products - Pragmatic Start with Stage 3 (Data Trending) Assessment
& Product
Stage 3 is used to capture changes, Monitoring
trend and demonstrate that the process Continued
is still operating in a state of control. (Stage 2)
(Stage 3)
Stage 2 the Product Control Strategy is demonstrated to be fit Validation
Risk Assessment
Product & Process Risk Management
• Risks are associated with the quality, safety and efficacy of the product itself – How the product behaves during processing – How it interacts with equipment, devices, packaging and its environment. • Single team, structured approach focussed on product and process understanding • Supports development of good control strategies and standard work AIM: To predict risks based on knowledge and
• The RA is maintained through the product lifecycle, regularly reviewed process understanding and implement mitigation
and updated in response to change plans to prevent issues from occurring
– Process Definition Diagrams BUILD UP OF
RA's if correctly executed (leading to an effective MATERIAL ON
– Mechanism Maps control strategy) will reduce the likelihood of problems – Failure Mode and Effects Analysis (FMEA). RESULTS IN
Product Control Strategy
A control strategy is designed to ensure that a product of required quality will be produced consistently.
– Derived from the Risk Assessment (plus any pharmaceutical development studies which have identified sources of variability that can impact product quality and should be controlled) • A control strategy can include the following: – Control of input material attributes based on an understanding of their impact on manufacture process or product quality – Product specifications – Controls for unit operations that have an impact on downstream processing or product quality – In-process or real-time release testing in lieu of end-product testing – A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models. • A control strategy can include different elements. For example, one element of the control strategy could rely on end-product testing, whereas another could depend on in process testing. • Used to define the batch manufacturing record, testing regime, validation approach and registered product specification Process Performance and Product Quality Monitoring
• Data trending provides us feedback on what the process is doing – Verification of a statistically stable process • A Regulatory expectation of ‘Continued Process Verification' – Expected to be predictive and anticipatory of failure
– Batch by batch, week by week, or similar Regulators
expect that we
can do this for

all our products
• Continual Improvement • Output of process performance and product quality monitoring • CAPA (Corrective and Preventative Action) • All changes MUST be evaluated properly using an effective change management system that – Is Timely and Effective – Provides a high degree of assurance there are no unintended consequences of the change. – Utilises quality risk management to evaluate ALL proposed changes against • The Marketing Authorisation • Design Space (where established) • Current Product and Process Understanding. – Involved expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., Technical, Manufacturing, Quality, Regulatory Affairs and Medical), to ensure the change is technically justified – Monitors the effectiveness of the change after implementation • The cumulative effect of change should also be undertaken at regular intervals (usually through Process Performance and Product Quality Monitoring) to confirm product quality VENTOLIN NEBULES (VNS)
SALBUTAMOL is a selective β2 adrenoceptor At therapeutic doses it acts on the β2 adrenoceptors of bronchial muscle, with little or no action on the heart. With its fast onset of action, it is particularly suitable for the management and prevention of asthma attack – Available in many respiratory dose formats (DPI, MDI, Oral Syrups, Respirator Solutions) • VENTOLIN NEBULES (VNS) – Solution Dose form administered to the lungs with the use of a portable nebuliser system Available as both 2.5mg/2.5mL and 5mg/2.5mL strengths – Marketed in Australia and many markets across Europe, Middle East, Asia, Africa, North and South America. VNS DRUG PRODUCT CQA's
Derived from
Regulatory Guidance on Inhalation Products
• Based on Dose Form/Intended use of the product • Ventolin Nebules is Single Dose Nebulised Product • Standard aqueous drug product
specification tests. Refer to ICH Q3B
(Impurities) and ICH Q6A (Specifications)

• e.g. ID, degradation products, pH, • Specification values based on • Observed range of variation in batches evaluated in-vivo • Process Capability data • Stability data • Note different tests and limits may apply at release versus shelf life . Shelf life acceptance criteria should be derived from stability data and the changes observed on storage Presentation title in footer VNS MANUFACTURING PROCESS

• CQAs / CPPs (and their defined ranges) define the Design Space Assurance of Final Control Strategy Product Quality • What's needed is to translate this Control
Strategy effectively into STANDARD WORK
across all product and process operations
• Consider 4 Areas: Compliance with
Ongoing operation
Control Strategy
•The capability of the •The processes for •The way the equipment •What is measured / people maintaining, is setup to ensure the trended and what setting-up, running and validated state of the CPPs / CQAs are under actions are taken to managing the process equipment over the long control at the start of the ensure the CQAs / term (Reliability)
batch (Batch
CPPs remain under Document / SOP)
control (IPC Checks /
Product Quality

Ideas for how to Integrate Product Control Strategy into Production
Product Robustness Boards and Single Best Ways Product Robustness Boards are being developed
Single Best Ways (SBW's) in place for steps that are critical to
• Situated in Production the process/considered higher risk of going wrong • Reviewed regularly by Production/Technical/Quality/Validation • Summary PCS information • Ongoing Process Performance Information as it related to Product Quality/Robustness • GEMBA sheets to enable PCS understanding across the value stream to be assessed • Intended to enable a focus on the Product and share and improve people capability and understanding Ideas for how to Integrate Product Control Strategy into Production
Critical Process Parameters (CPP) Control Chart
As part of the PPA process the CPP's (as identified in the Control Strategy) are also trended at the point of use by Process Performance and Product Quality Monitoring
(Product Performance Assessment - PPA)

Formal Review by Wider PPA Team
Review each Product Dashboard and escalation items. Review and approve all decisions taken. Ensure appropriate actions are in place to mitigate all risks and confirm product robustness and capability. Issue Product Dashboard and PPA Log with all actions and decisions tracked. Escalate serious risks to SQC. Routine Review by Core PPA Team
Detailed statistical review of each product. Major rule breakages identified and escalated to Wider Team. Initiate PSG's. Implement JDI's. Prepare Product Dashboard and PPA Log for Wider PPA Team Review. First Line Review Data Entry and Review by Data Owners
Known changes are recorded in data entry sheet. Issues identified to escalate to Core Team. Signal to Stop – An Example of the Value of Real Time Product Quality
Monitoring and knowing your Product and when something "feels wrong"

Dry Powder Inhaler Product – Uniformity of Delivered Dose (Highest Individual Dose) Trend Trend shows typical variation given the nature of the test (sample prep, individual dose test) Sudden change with high (OOS) result Campaign had already made further batches – another high result (Atypical) noted Considered sufficiently unusual to trigger a "signal to stop"
RCA determined to be due to inappropriate storage of the current lot of API Manufacture commenced with new lot of API – trend returned to normal. Control Strategy Updated Highest Delivered Dose Provisional Ppk 1.14
5 per. Mov. Avg. (Highest Delivered Dose) Benefits of QbD to Existing Products
• Benefit to PRODUCT QUALITY – Captures the key Quality requirements for a drug • Benefit to MANUFACTURING PROCESS PERFORMANCE – Improves Operational Efficiency – Less Down time – Better Yields • More Robust Manufacturing Processes = a More Robust Product • Benefit to the Patient at the end of the Supply QUESTIONS ?
Control Chart Rules
• Documented Data Trending Plan states what parameters are trended for each product – Typically trend all drug product and input material CQA's (Critical Quality Attributes) and Critical Process Parameters (CPP's) as determined in the RA – Trend against historical data (typically a minimum of 30 batches) Control Chart Rules
– Look for PPA Rule Breakages using three Control Chart Rules Run Rule 1: Single point outside 3 std deviations
Run Rule 2: 8 consecutive points on one side of
center line
Run Rule 3: 7 consecutive points increasing or
Product Performance Assessment – Boronia Approach Capability (Ppk) Interpretation
Process Status
2>P > 1.33 1.33>P > 1 Marginally capable (Risk of OOS) Incapable (Significant risk of OOS) *PPM=Parts Per Million • Process Off Target and Low Variability (Ppk<Pp) • Process On Target and High Variability (Ppk≈Pp) • Ppk interpretation in PPM is based on the assumption of data distribution is Normal • Non-normal data distribution needs different approach of capability assessment

Source: https://www.pda.org/docs/default-source/website-document-library/chapters/presentations/australia/implementation-of-qbd-for-existing-products---an-example-from-gsk-australia.pdf?sfvrsn=6

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