QbD @ Continous Improvment

QbD in virtue of continuous

improvement

Glenmark Pharmaceuticals Ltd.,

Presented By: Santanu Roy


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.


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


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


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.



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)


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.


Two ways of optimization


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.


Relationship between CQAs and CPPs/CMAs


QbD Eagle view


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)


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


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


Current vs. QbD Approach to Pharmaceutical Development


Overview of QbD


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


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


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


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


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.


QTPP and CQAs


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


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


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.


Risk assessment

Risk assessment for formulation components


Risk assessment

Risk assessment of DP manufacturing process


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)


Critical Material Attributes (CMAs)


Risk Assessment of the drug substance attributes

Solid state form and particle size of DS are CMAs

CPPs


• Risk assessment of manufacturing process

• Identify high risk steps (unit operation) that affect the CQAs of DP.

CPPs


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.


Control Strategy


Control Strategy


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


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.


DOE Methodology


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.


DOE & Design Space


Identify Risk Factors


Factor & Responses


Interpret Model Graph


Develop Design Space


Verify Design Space

After completion of all experiments according to DOE verification was require to confirm Design Space


What is Continuous Improvement


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


QbD is Implemented in Stages


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


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


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


QbD


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).


http://www.6sigma-consecpt.com/


Thank you

QbD @ Continous Improvment

Documents

Transcript of QbD @ Continous Improvment