Product Life Cycle

Management, FDA inspection

and enforcement
Presented by: Gargi Harit
Take away from this PPT
• Overview of ICH
• PLM
• Objective
• Principle
• Tools and Enablers
• Case Studies
• FDA Inspection
• Enforcement
The International Council for Harmonization of Technical
Requirements for Pharmaceuticals for Human Use (ICH)

 Quality (Q1 – Q14)  Safety (S1 – S12)

1 2
 Stability Studies  Non- Clinical Testing Strategy
 Life Cycle Management  Carcinogenicity
 GMP Risk Management  Genotoxicity

 Efficacy (E1-E21) 3 4  Multidisciplinary (M1 – M15)

 Clinical Trials  CTD
 Targeted Medicine  ICH Medical Terminology
 Pharamcogenetics  Regulatory Information System

3
Pharmaceutical Product Lifecycle Management
• Objectives
• Consistency: Ensuring consistency of the product's quality attributes throughout its
lifecycle.

• Facilitate Innovation: Encouraging the adoption of new technologies and

manufacturing processes.

• Continuous Improvement: Supporting continuous improvement in the efficiency

of the manufacturing process.

• Facilitate Post-Approval Changes: Streamlining the regulatory approval process

for post-approval changes.
Scope: Product Lifecycle Management

• Applies to all pharmaceutical products like small molecules, large

molecules (biologics), vaccines, blood derived products

• Cover all changes made after the product has been approved,
including changes to:
• Composition
• Manufacturing process & Equipments
• Testing of DS & DP
• Packaging
• Labelling
• Storage and transport conditions
Principles of Life Cycle Management
• Lifecycle Management Approach

• Product Lifecycle Management Document (PLCM)

• Management of Post-Approval CMC Changes

• Facilitate Innovation and Continuous Improvement

Regulatory Tools and Enablers
• Categorisation of Post-Approval CMC Changes

• Established Conditions (ECs)

• Product Lifecycle Management (PLCM) Document

• Pharmaceutical Quality System (PQS)

• Change Management
Regulatory Tools and Enablers cont..

• Relationship Between Regulatory Assessment and Inspection

• Structured Approaches for Frequent CMC Post-Approval Changes

• Stability Data Approaches to Support the Evaluation of CMC Changes

Categorization of Post-Approval CMC Changes

Approach ICH EU US Japan Risk Level

Prior Approval Partial Change

Prior Approval Prior Approval Type II Supplement Application High
(PAS) (PCA)

Changes being
Tell, Wait and
Type IB effected in 30 N/A
DO
days (CBE-30)
Moderate
Changes being
Type IAIN N/A
Tell and Do Notification effected (CBE-
0)

Minor Change
Do and Tell Type IA Annual Reports Notification Low
(MCN)
Established Conditions (ECs)
• ECs are legally binding information considered necessary to assure
product quality. Consequently, any change to ECs necessitates a
submission to the regulatory authority

• should not be confused with CMC regulatory commitments (e.g.,

stability, post approval CMC commitment and other commitments)
made by a MAH to provide data or information to the regulatory
agency in a MAA

• Identification of ECs (depending on the dosage form)

Product lifecycle management (PLCM)
document
• The PLCM document outlines the specific plan for product lifecycle
management that includes the ECs, reporting categories for changes
to ECs, PACMPs (if used) and any post-approval CMC commitments.

• Maintainence of PLCM Documents

• Format and Location of PLCM Document

Pharmaceutical Quality System (PQS) and
Change Management
Relationship Between Regulatory Assessment and Inspection

• Effective communication between assessors and inspectors can

facilitate regulatory oversight of product lifecycle management

• The conclusions from inspections should be available to assessors to

support ongoing oversight of product lifecycle management and the
most recent PLCM document, when applicable, should be available to
inspectors so they are aware of the currently approved status of the
PLCM element
Structured Approaches for Frequent CMC Post-Approval Changes

• One CC; Multiple product impact (e.g. Warehouse change)

• Consequential Changes
• Name change of Organization
Case Studies
• Addition of new DP manufacturing site
• Categorization based on Country guidance and requirements

Country Risk Category of Change Timelines

USA High PAS 12-18 months

EU High Type II 6-9 months

Japan High PCN 6 months

• Consequential Changes
• Module 3 Regulatory requirements: 3.2.P, depending on changes filed along
• Administrative docs : Cover letter, Application form, regional documents
Case Studies cont..
• Name & address change of manufacturing site
• Categorization based on Country guidance and requirements
Country Risk Category of Change Timelines

USA Low AR Notified annually

EU Low Type IA To be notified within

12 months
Japan Low Notiifcation

• Module 3 Regulatory requirements : 3.2.P.3.1, Chamber of Commerce

• Administrative Documents: Cover letter, Application form, regional documents
FDA Inspection
An inspection is a careful, critical, official onsite examination of a
facility to determine its compliance with federal law
What the FDA inspects
• The FDA inspects manufacturers of FDA-regulated products to verify
that they comply with relevant regulations, including:
• vaccine and drug manufacturers
• blood banks
• food processing facilities
• dairy and produce farms
• animal feed processors
• outsourcing facilities and compounding pharmacies
• tobacco manufacturers
Types of FDA Inspection

• Surveillance inspections are conducted to monitor the manufacturing

process and the quality of FDA regulated products on the market. The
agency uses the inspection to evaluate whether a manufacturer is
complying with quality manufacturing practices.

• For-cause inspections are triggered when the agency has reason to

believe that a facility has quality problems, to follow up on
complaints or to evaluate corrections that have been made to address
previous violations.
Types of FDA Inspection cont..
• Application-based inspections are conducted for about 20% of the
application reviews conducted by the agency. These inspections are
part of the application review process to market a new drug, device or
biologic to determine whether the new product is manufactured in
compliance with FDA regulations and to ensure the facility is capable
of manufacturing the product consistently and that submitted data are
accurate and complete. Additionally, the agency conducts inspections
of tobacco facilities as part of the premarket review of tobacco
applications.
• The agency also conducts inspections to verify the reliability,
integrity and compliance of clinical and non-clinical
research being reviewed in support of pending applications.
Risk Based Approach
• facility type, such as manufacturer, control laboratory, etc.
• the facility’s compliance history, including whether it has been
inspected in the last four years
• hazard signals, including the record of signals, history and nature of
product recalls linked to the facility, etc.
• inherent risks of the product manufactured at a facility, such as
dosage form, route of administration, products intended to be sterile,
concentration of active pharmaceutical ingredient in dosage form,
emergency use, etc.
• whether the facility has been inspected by a foreign regulatory
partner
Classification of Inspection
• No action indicated (NAI), which means no objectionable conditions
or practices were found during the inspection,
• Voluntary action indicated (VAI), which means objectionable
conditions or practices were found, but the agency is not prepared to
take or recommend any administrative or regulatory action or
• Official action indicated (OAI), which means regulatory and/or
administrative actions are recommended.
What actions does the FDA take when violations are observed
during an inspection?

• If a facility does not meet current good manufacturing practice standards (CGMPs) upon inspection, the
FDA has an array of regulatory tools it can use to encourage a company to remediate their
manufacturing processes and achieve compliance. These tools include warning letters, import alerts,
injunctions, seizures and civil money penalties.
• The agency may request (if we have mandatory recall authority under the law) or recommend a
manufacturer recall its products following an inspection. This happens when we observe federal law
violations that may impact the quality of the product manufactured at the facility.
• If the agency observes on a follow-up inspection that a facility still does not meet CGMP standards, it
can escalate the matter as appropriate.
• The FDA often meets with manufacturers to discuss inspection findings to achieve more timely and
effective corrective action. Sometimes we do this prior to taking formal actions to encourage voluntary
compliance with FDA regulations.
• If a facility does not meet current good clinical practice (CGCP) or current good laboratory practice
(CGLP) requirements upon a clinical or non-clinical research inspection, the agency can take action, such
as warning letters, clinical holds, withdrawal of approval, injunctions, disqualifications and civil money
penalties.
Thanks