ICH Q12 for Marketed/Already Approved Products

Nirdosh Jagota, Ph.D.Vice PresidentGRACS CMC, MSD

Novas Fronteiras Farmaceuticas Symposium Brasilia18 June 2019

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AGENDA

ICH Q12 background ICH Q12 Tools and relationship

to marketed productso Established conditions (ECs)o Post approval change

management protocols (PACMPs)o Post approval changes

for marketed products Regulatory readiness for ICH Q12

ICH Q12 Background

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CurrentRegulatory

Environment

• More markets globally, many with unique requirements

• Divergence of regulatory decisions• Inconsistent review timelines for

post-approval changes• Lack of regulatory pathways to

facilitate continual improvement

Manufacturing Inefficiencies

• Inefficient supply chains with multiple product versions

• Suboptimal manufacturing processes with disincentives for continual improvement

• Outdated equipment and technologies

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Patient Supply at Risk

• Increased potential for drug stockouts and shortages

• Missed opportunities to improve assurance of product quality

Pharmaceutical Manufacturing and Supply Today

RegulatorsManufacturers

Less Reportable Changes

Faster Implementation of Changes

Simplification of Supply Chains

Uninterrupted Supply

Assurance of Product Quality

Confidence in Quality Systems

The Balance

Both manufacturer and regulators want reliable supply of quality product

Quality

Objectives: • Provide a framework to facilitate the management of post-approval CMC changes in a

predictable and efficient manner• Demonstrate how increased product and process knowledge can contribute to a reduction

in the number of regulatory submissions• Enhance industry's ability to manage many CMC changes effectively under the firm's

Pharmaceutical Quality System with less regulatory oversight prior to implementation

Scope:• Pharmaceutical drug substances • Pharmaceutical drug products• Chemically, biotechnological/biological products, and vaccines that require marketing

authorization• Drug-device combination products regulated as drugs • New and already approved / marketed products

ICH Q12 “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management”

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DRAFT ICH Q12 “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management”

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1. Introduction2. Categorisation of Post-Approval CMC Changes3. Established Conditions (ECs)4. Post-Approval Change Management Protocol 5. Product Lifecycle Management 6. Pharmaceutical Quality System and Change

Management 7. Relationship between Regulatory Assessment

and Inspection8. Post-Approval Changes for Marketed Products

Target for finalization: November 2019

Draft released: November 2017

Established Conditions

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Established Conditions• Established conditions (ECs) are legally binding information (or approved matters) considered necessary to

assure product quality. Any change to ECs require a submission to the regulatory authority

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Supportive Information, (non-ECs), e.g.:• Development data• Stability data• Batch records• Validation reports

Established Conditions, e.g.:• Raw material specifications• Product specifications• Critical process parameters• Analytical procedures• Manufacturing sites

Changes require regulatory reporting Changes within PQS only, no reporting

Approved ECs provide clarity of what changes need to be reported, and how to report them

• Parameter based:o Minimal (traditional) development approach - limited understanding leading to a large number of ECs

(e.g., process parameters and material attributes) along with outputs (including in-process controls) o Enhanced (QbD) development approach - increased understanding and more focused ECs

• Performance based: - ECs primarily focused on control of unit operation outputs rather than process inputs (e.g., process parameters and material attributes)

Approaches to Identifying ECs

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Operation Parameter based approach Performance based approach

Blending prior to tableting

• Equipment type• Equipment size/scale• Fill Volume• Rotation Speed• Blend Time

• Equipment type• Homogeneity measurement

(e.g., Blend NIR)

Established Conditions Examples

• Established conditions (ECs) can be in an original dossier or a Prior Approval Variation• ECs can be defined for whole dossier or for only parts (e.g. single step of the

manufacturing process)• ECs can be defined for analytical procedures• Different types of ECs can be used in the same dossier (parameter-based,

performance-based)• An enhanced (QbD) development approach is not required for ECs

How can Established Conditions be used?

• ECs are not mandatory, unless specified by regulators

• Examples of when a manufacturer could benefit by submitting ECs for a marketed product:– Major change of manufacturing process (e.g., synthesis route)– Major change of an analytical procedure (e.g., TLC to HPLC)– For product with high level of knowledge to decrease regulatory

burden for future changes

Established Conditions for Already Approved/Marketed Products

Post Approval Change Management Protocols (PACMPs)

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What is a PACMP?A post approval change management protocol (PACMP) is a regulatory tool that provides predictability and transparency in terms of the requirements and studies needed to implement a change as the approved protocol provides an agreement between the MAH and the regulatory authority.

History of Adoption:• Comparability protocols have been in US regulations for decades • PACMPs have been part of EU regulations since 2010• PACMPs will be included in ICH Q12 (expected final in November 2019) o Japan and Canada have pledged to adopt PACMPso Japan has a pilot ongoing for PACMPs

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(PACMP = Comparability Protocol in US)

How do PACMPs Work?

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Without PACMP With PACMP

EMA Original Submission or Type II Variation Type IA/IAin or IB Variation

US FDA Original Submission or Prior Approval Supplement CBE/30 or Annual Report

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Regulatory Expectations Q12 Draft FDA Draft Guidance

EMA Q&A

Description of change X X XStudies and tests that will be performed to evaluate change

X X X

Acceptance criteria for change X X XProposed reporting category X Recommended XData to be provided upon implementation XRationale/justification for change X X XSupportive information on feasibility of change X X XRisk assessment for change and assessment methodology

X X X

Justification of assessment methodology suitability X X X

Regulatory Expectations for PACMPsPA

CMP

Cont

ent

Supp

ortiv

e In

form

ation

Advantages of PACMPs

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• Reduces regulatory uncertainty

Pre-agreement on data requirements

• Faster implementation of changes

Reduced reporting categories

• Regulatory efficiency

Applicable for multiple changes

• All changes made under a PACMP are still reported

Transparency of changes to regulators

PACMPs facilitate post approval changes and continual improvement

Potential Opportunities for PACMPs

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Site changes for Drug Products

Site changes for Drug Substance

Non-critical process

parameter changes

Container closure changes

Mathematical Model Changes

New Product Introduction for

Biologics or Vaccines

Shelf life extensions

Source: Susan Rosencrance (FDA/CDER/OPQ/OLDP), AAPS Annual Meeting, Nov 2016

Small Molecule – Brand Drugs Small Molecule – Generic Drugs

US FDA Experience with Comparability Protocols

The majority of PACMPs are for changes of manufacturing sites and/or processes

How can PACMPs be used?

• A PAMCP can be included in an original dossier or a Prior Approval Variation• PACMPs are not required• An enhanced (QbD) development approach is not required for PACMPs, however, the

potential risk of the change must be known• PACMPs can be used multiple time for the same/similar change• PACMPS can be used for multiple products for the same change

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PACMPs for Already Approved/Marketed ProductsPACMPs can be beneficial when:• Shorter implementation timeline is desired for a future change • Repetitive changes/variations are needed • Opportunity exits to combine multiple changes across several products

(e.g., container closure changes)• Regulatory pre-agreement is sought for the information needed to support a change• Multiple site changes for same product are anticipated

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Post-Approval Changes for Marketed Products

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Post-Approval Changes for Marketed Products

ICH Q12 Chapter 8 discusses a structured approaches for frequent CMC changes• Similar to “Pre-made” post approval change protocols

Examples include:• Changes in analytical methods that provide the same or better• Approaches for stability studies that support future post approval changes• Other examples may follow in the future

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Streamlining Changes to Marketed Products: Analytical Methods

Change in analytical

method (same method type)

• Prepare a prospective validation protocol, following Q2, with equivalent or better rigor than original method validation and with assessment of equivalency between the methods

• Establish system suitability for the revised method

• Execute the validation protocol and compare results to predetermined acceptance criteria

• Revise regulatory filing if needed (e.g., new or revised impurity content)

• Prepare a written summary report for the validation

• Follow the internal change process to implement the change

• Complete post-change monitoring

• Have information available for verification during inspections

Out of scope: Complex procedures (e.g., peptide map), general comparison tests, changes to test using biological reagent orbiological or immunological principle, changes to predictive multivariate models

Define the change Describe how change willbe assessed

Evaluate success of change

Monitor thechange

• Appropriately notify theregulatoryauthorities

Inform regulators through“notification” category

Regulatory Readiness for Q12

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Current Status toward ICH Q12 Adoption• Established conditions o US has a draft guideline on Established Conditions, and has a pilot ongoingo Concept is similar to Japan Application Form and Canada CPID, but modifications may be

needed

• PACMPso PACMPs already exist in EU and US (as comparability protocols)o PACMPs also are willing to be accepted by other countries including Switzerlando Japan has instituted a pilot to review PACMPs using a meeting format

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Thoughts about ICH Q12 Implementation in Brazil

• ICH Tools can be implemented for new dossiers and already approved/marketed products

• Implementation of ICH Q8/9/10/11 will lead to maximum benefits of ICH Q12, however:o PACMPs and Established Conditions tools can be based on minimal/traditional development approach

(i.e., without Quality by Design, ICH Q8/11)o Some elements of Risk Assessment (ICH Q9) and robust Pharmaceutical Quality System

(ICH Q10) will likely be needed

• PACMPs will likely be easier to implement than Established Conditionso Not a new concept globally, experience in industry and several regulatorso High level of transparency before and after the change

• ANVISA is encourage to explore ICH Q12 concepts through further dialogue o Pilot programs help both industry and regulators learn together

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We need to reform our Post Approval Change approaches!

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• The resources used for post approval changes is staggering!• Backlogs of post approval changes can lead to supply chain

challenges and potential shortages

Conclusions

• ICH Q12 provides a risk and science based framework for post-approval CMC changeso Applicable to both original dossiers and marketed products

• Timely adoption of ICH Q12 across all ICH countries is encouraged

29MSD is willing to work with ANVISA to develop concepts ofestablished conditions and PACMPs

Industry and regulatorsmust work together!

Obrigado

Questions, comments, copies:nirdosh.jagota@merck.com