Lifecycle Management considerations

as it includes changes throughout the

lifecycle of the product
Hasmukh B. Patel,, Ph.D.
Division Director
Division of Product Quality Assessment III
Office of Pharmaceutical Assessment I
OPQ/CDER

IPAC-RS Sustainability Roundtable

March 14, 2024
 Outline

• Lifecycle management of drug products

• Type of post-approval changes
• Enablers of post-approval changes
• Conclusion

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 OPQ Focus on Lifecycle Management
Ensures medicines
of consistent quality
are available to the
American public
Emphasizes a
lifecycle approach to Proactively
OPQ product quality prevents drug
using knowledge shortage situations
management
Monitor the state of
Enhances parity
quality for all regulated
between brand and
manuf. Sites and drug generic products
product
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 OPQ Focus on Lifecycle Management
OPQ’s Holistic Approach
The product lifecycle can be divided into 4 phases
based on the natural progress of drug product
development.
Focus is given to the entire drug product line with an
emphasis on knowledge sharing

Post- Post-
IND NDA Marketing ANDA Marketing
NDA ANDA

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 Why Post-Approval CMC Changes?
• Continuous improvement
₋ Product optimization
₋ Incorporating a new technologies
₋ Process improvement
• Regulatory Requirements/Commitments
• Product quality issues
• Business reasons
• Supply and demand

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 Typical Post-Approval CMC Changes
Drug substance
• New manufacturing site
• New supplier for regulatory starting materials
• Route/method of synthesis
• Manufacturing process
• In-process controls and/or drug substance specifications
• Retest period

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 Typical Post-Approval CMC Changes
Drug product
• New manufacturing site
• Manufacturing process and/equipment
• Formulation
• Container/closure system
• Device/ device material change in drug-device combination products
• Specifications
• Shelf-life
• Introduction of new strengths

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 Regulatory basis for Post-approval
Changes
21 CFR 314.70
• § 314.70 Supplements and other changes to an approved
application.
• The applicant must notify FDA about each change in each condition
established in an approved application

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 Classification of CMC Changes
• Major changes (Prior Approval Supplements)
₋ Cannot be implemented until approved
• Moderate changes (Changes Being Effected in
30 Days Supplements)
₋ Can be implemented 30 days after submission at the
applicants own risk
• Minor changes (changes being effected in 0
days supplement or Annual report
₋ Can be implemented immediately upon receipt by FDA

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 Type of Supplements
• Efficacy supplement
– New indication
– Changes in the dosing regimen
– Safety Changes (precautionary statements/Blackbox warning/new
contraindications)
– Addition of dosing information for special population
• Labeling supplements
– Changes in the approved labeling, including prescribing information, immediate
container and carton labels, medication guide, etc.
• CMC supplements
– Changes in the drug substance and/or drug product manufacturing, analytical
changes, site changes etc..

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 Enablers of Lifecycle Management

• Comparability protocols
• Post-approval change management protocol (PACMP)
(ICH Q12)
• Emerging technology

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 Comparability Protocols

• A Comparability Protocol is a comprehensive, prospectively

written plan for assessing the effect of a proposed CMC post-
approval change(s) on the identity, strength, quality, purity, and
potency of a drug product or a biological product (i.e., product),
as these factors may relate to the safety or effectiveness of the
product (i.e., product quality).

Agency definition in draft guidance published April 2016

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 Comparability Protocols

• An optional way to manage post-approval changes [21CFR314.70© and 21

CFR 601.12(e)
• Can be used to implement a CMC post-approval change
• Facilitates post-approval changes and drug product lifecycle management
• Useful for drug products with accelerated manufacturing development
• Reporting category for implementation of CP may be downgraded depending
on the product and process knowledge, risk assessment, and the controls
strategy.

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 Comparability Protocols
• Can be submitted in the original applications (NDA, ANDA, and BLA)
and in supplements
• Submitted post-approval, submission of a PAS is required.
• Can be submitted for one or more changes
• Can be submitted to cover an identical change(s) that affects multiple
applications
• Can be for one-time change(s) or be used repeatedly for a specified
change over the life cycle of a product

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 Comparability Protocols

When submitting a comparability protocol, consider:

• Effective use of knowledge and understanding of the product and manufacturing
process
• A robust control strategy
• Risk management
• An effective pharmaceutical quality system

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 ICH-Q12 – Technical and Regulatory
Considerations for Pharmaceutical Product
Lifecycle Management
• Scope:
• Applies to pharmaceutical products, including marketed chemical, biological
and biotechnological products
• Objectives:
• Best practices for management of post-approval CMC changes
• Emphasis on risk-based approaches (compliments ICH Q8-Q11)
• Facilitates regulatory flexibility

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 ICH-Q12 – Technical and Regulatory
Considerations for Pharmaceutical Product
Lifecycle Management
ICHQ12 contains the following fundamental tools and
enablers to support a harmonized lifecycle management:
• Established Conditions (EC)
• Product Lifecycle Management (PLCM)
• Post-Approval Change Management Protocols (PACMP)
• Pharmaceutical Quality Systems (PQS)
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 Established Conditions (ICH Q12)
• Elements in an application considered necessary to assure product quality
• Legally binding when submitted and approved in the application
• Can be submitted in the original application or post-approval
• If submitted post-approval, submission of a PAS is required.
• Established conditions should be justified.
• PLCM should list proposed established conditions and filing categories for making
changes.
• Filing categories could be other than that required by existing regulations and/or
guidances
• Any change to ECs necessitates a submission to the regulatory authority

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 Post-approval Change Management
Protocol (PACMP)
• Also known as “comparability protocols”
• Post Approval Change Management Protocols (PACMPs): A
regulatory tool that provides predictability and
transparency in terms of the requirements and studies
needed to implement a change
• An approved PACMP provides an agreement between the
firm and the regulatory authority

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 Post-approval Change Management
Protocol (PACMP)

• Outline future change(s) to be made

• Tests, studies, etc. to be conducted to verify
acceptability of change
• Proposed reporting category; often reduced
compared to existing guidance and regulation.

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 Emerging Technology
What is Emerging Technology?
• Technology with the potential to modernize the body of
knowledge associated with pharmaceutical development to
support more robust, predictable, and/or cost-effective
processes or novel products and with which the FDA has limited
review or inspection experiences, due to its relative novelty

• Innovative or novel product, manufacturing process, or analytical

technology subject to quality assessment (including review and
inspection)
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 Emerging Technology
• Emerging technologies for small molecules
₋ Continuous manufacturing of drug substance
₋ Continuous manufacturing of drug product
₋ Model-based control strategy for continuous manufacturing
₋ Continuous aseptic spray drying
₋ 3D printing manufacturing
₋ Ultra long-acting oral formulation
• Emerging technologies for biological molecules
₋ Controlled ice nucleation for lyophilization processes
₋ Advanced process control: predictive modeling for process monitoring; close
loop bioreactor control; feed forward impurity control

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 Changes to Container Closure Systems
Inhalation Drug Products
• Inhalation drug products
₋ Metered dose inhalers (MDIs)
₋ Dry powder inhalers (DPIs)
₋ Nasal spray
₋ Inhalation solutions and suspensions

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 Container Closure System for
Drug Device Combination Products

• Inhalation drug products

• Propellant-based inhalation and nasal aerosols
₋ Metered dose inhalers (MDIs)
₋ Dry Powder inhalers (DPIs)
• Non-propellant-based inhalation products
₋ Nasal spray
₋ Inhalation solutions and suspensions

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 Suitability of Container Closure System

• Compatibility with the drug product formulation (leachables)

• Performance (dose delivered)

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 Changes Over the Lifecycle of Drug Product

• Change in the components of drug product container closure

system
• Changes in the device components

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Factors Affecting Safety and Efficacy of Drug
Products

• Materials used for fabrication of device and container closure

systems
• Leachables (safety and effectiveness)
• Aerodynamic performance (delivered dose and aerodynamic particle size
distribution (APSD) by surface properties of device part
• Drug particle surface interactions (adhesion) affecting delivered dose and
APSD
• Biocompatibility

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 Meetings with FDA
• Types of meeting
• Type A
• Granted within 30 days
• Type B
• Granted within 60 days
• Type C
• Granted within 75 days

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 Relevant FDA Guidances
• Guidance for Industry: Changes to an Approved NDA or ANDA, 4/8/2004
• Guidance for Industry: Changes to an approved NDA or ANDA, Questions and Answers,
1/1/2001
• Guidance for Industry - Advancement of Emerging Technology Applications for
Pharmaceutical Innovation and Modernization Guidance for Industry, September 2017
• Guidance for Industry - Q12 Technical and Regulatory Considerations for Pharmaceutical
Product Lifecycle Management Guidance for Industry, MAY 2021
• Guidance for Industry – Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
Products – Chemistry, Manufacturing and Controls Documentation, July 2002

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 Conclusion/Summary
• Application of ICH Q12 and emerging technologies enable
enhancement of product quality and continual improvement of
product manufacturing process and controls throughout the
product lifecycle.
• Effective use of knowledge management and product and process
understanding along with a robust control strategy, risk assessment,
and pharmaceutical quality system are essential for regulatory
flexibility throughout the drug product lifecycle management.

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Thank You!