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QbD in virtue of continuous
improvement
Glenmark Pharmaceuticals Ltd.,
Presented By: Santanu Roy
Glenmark Pharmaceuticals Ltd.,
4A’S
QbD is of paramount importance for the patient safety but there is another side of the coin. QbD is also required for timely and uninterrupted supply of medicines into the market. This timely uninterrupted supply is required to fulfill the 4A’s requirement of any Regulatory body.
Glenmark Pharmaceuticals Ltd.,
Regulators Expectations
A: Acceptable (quality, safety and efficacy)A: Affordable medicinesA: Availability (no shortage) in their country all the timeA: Accessible to patients at their local pharmacies
Glenmark Pharmaceuticals Ltd.,
Regulator’s unsaid expectations
This affected the (4A’s) of the regulatory bodies; hence they were forced to interfere with the supplier’s system. They realized that in order to ensure their 4A’s, there has to be a robust process at manufacturer’s site and if it is done the medicines would automatically be available in their country (no shortages) and will be accessible to all patients at affordable price.
Regulators changed from “high quality and low price” to “quality
medicine at affordable price
In earlier days the main focus of Regulators was on the quality and price
of the medicines
Glenmark Pharmaceuticals Ltd.,
Manufacturer’s point of view
As Regulators were insisting on QbD, manufacturers have their own constraints in plant due to inconsistency of the process and Regulator’s emphasis was on the patient’s safety.
Glenmark Pharmaceuticals Ltd.,
Manufacturer’s point of view
Profit = MP – COGS MP = market PriceCOGS = genuine manufacturing cost + waste cost (COPQ)COPQ = Variation/Batch failure/Reprocessing & rework /product recall = increase in drug product/drug substance cost = loosing customerfaith (intangible cost)
Manufacturer’s point of view
Coming to prevailing market scenario, the manufacturers doesn’t have luxury to define the selling price, now the market is very competitive and the price of goods and services are dictated by the market, hence it is called as market price (MP) instead of selling price (SP).
Change in the perception of quality, now quality was defined as producing goods and services meeting customer’s specification at the right price.
Manufacturers are now forced to sell their goods and services at the market rate.
As a result the profit is now defined as the difference of market rate and cost of goods sold (COGS).
If manufacturing process is not robust enough then COPQ will be high resulting in high COGS and either (patient or manufacturer) of the party has to bear the cost.
Glenmark Pharmaceuticals Ltd.,
Two ways of optimization
Glenmark Pharmaceuticals Ltd.,
Two ways of optimization
Real customer generic manufacturer is not the patients but the Regulators. This is because patients can’t decide and they don’t have capability to test the quality of the medicines, for them all brands are same. Hence, Regulators comes into the pictures.
On the behalf of patients are dealing with manufacturers because they have all means and capability of doing so.
Glenmark Pharmaceuticals Ltd.,
Relationship between CQAs and CPPs/CMAs
Glenmark Pharmaceuticals Ltd.,
QbD Eagle view
Glenmark Pharmaceuticals Ltd.,
Why QbD?
Systematic, holistic and proactive approach to pharmaceutical
development.
Begins with predefined objectives
Emphasizes product and process understanding and process control
Based on sound science and quality risk managementRef.: ICH Q8 (R2)
Glenmark Pharmaceuticals Ltd.,
Why QbD?
Generic industry business model: Regulator’s perspective
File first, learn later
Major amendments during review process
- Exhibit batch stability failure, formulation revision
Longer time for generic product approval
Approved product may not be marketed
Post approval changes – prior approval supplements
Glenmark Pharmaceuticals Ltd.,
How QbD will help improve?
Ensure higher level of assurance of product quality for patient Improved product and process design & understandingMonitoring, tracking & trending of product & process.
More efficient regulatory oversight Efficiency and cost saving for industry
Increase efficiency of manufacturing processMinimize / eliminate potential compliance actions
Glenmark Pharmaceuticals Ltd.,
Current vs. QbD Approach to Pharmaceutical Development
Glenmark Pharmaceuticals Ltd.,
Overview of QbD
Glenmark Pharmaceuticals Ltd.,
Quality Target Product Profile
Product Design and
Understanding
Process Design and
Understanding
Control Strategy
Continuous Improvement
Elements of QbD
Quality Target Product Profile (QTPP)
Define Critical Quality Attributes (CQAs)
Perform risk assessment
Link raw material attributes and process parameters to CQAs
Design and implement a control strategy
Manage product lifecycle, including continuous improvement
Glenmark Pharmaceuticals Ltd.,
Quality Target Product Profile-QTPP
What is QTPP? A set of elements that defines the drug product The target or goal set in advance A guide to Drug Product development
What forms the basis for QTPP? The RLD and its label Applicable regulatory guidelines
When to define QTPP? At the start of development Knowledge gained in development may change some elements
Glenmark Pharmaceuticals Ltd.,
Components of QTPP
Components related to safety, efficacy, identity, purity and potency
Critical and non-critical components, e.g. Critical: Assay, content uniformity Non-critical: Appearance
Fixed and variable components Fixed elements must be present
e.g. Dosage form, strength Variable elements may have a range of acceptable values
e.g. Tablet weight, assay
Glenmark Pharmaceuticals Ltd.,
Specific requirements in QTPP
Scored tablets Weight variation between two halves Dissolution of half tablet
Orally Disintegrating tablets Hardness Disintegration time Container closure
Extended Release products Alcohol induced dose dumping
Glenmark Pharmaceuticals Ltd.,
Critical Quality Attributes – CQAs
CQAs are a subset of the QTPP
Include critical parameters that are likely to change based upon variations
in raw materials and processes-Identity test for dosage form – Not a CQA-Assay, Content uniformity – CQAs
CQAs are monitored throughout the DP development.
CQAs ensure that DP remains within safe and effective levels.
Glenmark Pharmaceuticals Ltd.,
QTPP and CQAs
Glenmark Pharmaceuticals Ltd.,
QTPP and Specifications
QTPP
• Desired target for
developmental work
• Components of QTPP may or
may not be in specification- Not in spec – Dosage form,
strength- In spec – Assay, impurities
• Does not include acceptance criteria
Glenmark Pharmaceuticals Ltd.,
Specifications
Includes all of the CQAs
Specification is a list of - tests, - references to analytical
procedures - acceptance criteria
Establishes the set of criteria to
which DP should conform to
be considered acceptable for
its intended use
Risk Assessment
Risk assessment for Formulation – starting material properties, levels of components Manufacturing process
Steps for risk assessment List out all components / processes Prepare the process flow chart Identify all potential failure modes for each item with risk query (what
might go wrong?) Risk analysis Risk evaluation
Glenmark Pharmaceuticals Ltd.,
Risk Assessment
Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms
Generic product development for Acetriptan Tablets, 20 mg. Acetriptan is a BCS Class II compound displaying poor aqueous
solubility (less than 0.015 mg/mL) across the physiological pH range. It exists in three different polymorphic forms which may affect
dissolution. Polymorph III is the most stable polymorph. Drug product is prepared with roller compaction process.
Glenmark Pharmaceuticals Ltd.,
Risk assessment
Risk assessment for formulation components
Glenmark Pharmaceuticals Ltd.,
Risk assessment
Risk assessment of DP manufacturing process
Glenmark Pharmaceuticals Ltd.,
CMAs, CPPs and CQAs
What factors affect drug product CQAs? Properties of Input Materials- Identify Critical Material Attributes (CMAs) Properties of in-process materials- CQAs of one step become CMAs for a
downstream unit operation Manufacturing process parameters- Identify Critical Process Parameters (CPPs)
Glenmark Pharmaceuticals Ltd.,
Critical Material Attributes (CMAs)
Glenmark Pharmaceuticals Ltd.,
Risk Assessment of the drug substance attributes
Solid state form and particle size of DS are CMAs
CPPs
Glenmark Pharmaceuticals Ltd.,
• Risk assessment of manufacturing process
• Identify high risk steps (unit operation) that affect the CQAs of DP.
CPPs
Glenmark Pharmaceuticals Ltd.,
Process Step: Compression
Control Strategy
“A planned set of controls, derived from current product and process understanding that ensures process performance and product quality…..”
Control Strategy includes following elements (but not limited to): – Input material attributes (e.g. drug substance, excipients, container
closure) – Equipment operating conditions (process parameters) – In-process controls – Finished product specifications – Controls for each unit operations – Methods and frequency of monitoring and control.
Glenmark Pharmaceuticals Ltd.,
Control Strategy
Glenmark Pharmaceuticals Ltd.,
Control Strategy
Glenmark Pharmaceuticals Ltd.,
Control Strategy Implementation Options
Design of Experiments (DOE)
Structured, organized method for determining the relationship between factors affecting a process and the response of that process
Application of DOEs: Scope out initial formulation or process design Optimize product or process Determine design space, including multivariate relationships
Glenmark Pharmaceuticals Ltd.,
QbD Tools – DoE
Design of experiments (DoE)
Useful for screening of variables with significant impact on DP CQAs
Classical approach uses OFAT (One Factor At A Time)
Limited number of experiments gives limited information.
DoE helps study effects of interaction of multiple factors at a time
Used in optimization studies, enables creation of “design space”
“Design space” is proposed by the applicant and subject to regulatory
assessment and approval.
“Design space” developed at lab or pilot scale can be proposed for
commercial scale, but needs to be verified at production scale for scale
dependent parameters.
Glenmark Pharmaceuticals Ltd.,
DOE Methodology
Glenmark Pharmaceuticals Ltd.,
Design Space
Definition: The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process.
Glenmark Pharmaceuticals Ltd.,
DOE & Design Space
Glenmark Pharmaceuticals Ltd.,
Identify Risk Factors
Glenmark Pharmaceuticals Ltd.,
Factor & Responses
Glenmark Pharmaceuticals Ltd.,
Interpret Model Graph
Glenmark Pharmaceuticals Ltd.,
Develop Design Space
Glenmark Pharmaceuticals Ltd.,
Verify Design Space
After completion of all experiments according to DOE verification was require to confirm Design Space
Glenmark Pharmaceuticals Ltd.,
What is Continuous Improvement
Glenmark Pharmaceuticals Ltd.,
Two concepts that describe Continuous Improvement are
KAIZEN (Ky’ zen) a Japanese word is often translated in the west as ongoing, continuous improvement
Evolutionary Operation (EVOP)
It is distinguished from “innovation” and “corrective actions”
Elements necessary for Continuous Improvement
Human resources are the most important company asset
Processes must evolve by gradual improvement rather than radical changes
Improvement must be based on statistical/quantitative evaluation of process performance
Glenmark Pharmaceuticals Ltd.,
QbD is Implemented in Stages
Glenmark Pharmaceuticals Ltd.,
Design Space Regulatory Filing Approach
Implementation at Manufacturing
Sites
Continuous Improvement
Phase 1 Phase 2 Phase 3 Phase 4
Classification of Post-Approval Changes is Consistent with SUPAC
Glenmark Pharmaceuticals Ltd.,
Change to specifications or change likely to impact safety,
quality, or efficacy?
Critical Key
Yes No – Moderate Impact
Non-critical
Yes No
Change Assessment
Substantial impact on safety, quality, or
efficacy?
Risk Management and Continuous Improvement are Achieved Through a Coordinated Trending Process
Glenmark Pharmaceuticals Ltd.,
Product measurements data collection
Deviation measurements data collection
Compliance measurements data collection
Change controlTrending
Existing Systems – nothing new under QbD
All product performance and compliance data
are evaluated together under
QbD
Example: Correlating Drug Product Assay with Input Material
Glenmark Pharmaceuticals Ltd.,
QbD
Glenmark Pharmaceuticals Ltd.,
References for QbD
1. Guidance for Industry: Q8(R2) Pharmaceutical Development
2. Guidance for Industry: Q9 Quality Risk Management
3. Guidance for Industry: Q10 Pharmaceutical Quality System
4. Guidance for Industry PAT: A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance
5. Quality by Design for ANDAs: An Example for Immediate Release Dosage Forms
6. GPhA presentations
7. QbR updated
8. www.6sigma-consecpt.com• Jacky Musters, Leendert van den Bos, Edwin Kellenbach, Org. Process Res. Dev.,
2013, 17, 87. (b) Zadeo Cimarosti, Fernando Bravo,• Damiano Castoldi, Francesco Tinazzi, Stefano Provera, Alcide Perboni, Damiano
Papini, Pieter Westerduin, Org. Process Res. Dev., 2010, 14, 805. (c).
Glenmark Pharmaceuticals Ltd.,
Glenmark Pharmaceuticals Ltd.,
Thank you