Report and Manage Post Marketing Changes of Specifications/Methods · PDF file ·...

Report and Manage Post Marketing Changes of Specifications/Methods to an Approved NDA

Xiande (Andy) Wang, Ph.D.

Analytical Development

Janssen Pharmaceutical Companies of Johnson & Johnson

IVT Analytical Procedures and Validation, December 2015, Philadelphia

Outline

I. FDA guidance and references

II. Specification and life cycle of analytical procedures

III. Category of post-marketing changes• Annual report• PAS • CB-30 or CB-0

VI. Change control• Basics• Templates • Process

VII. Summary

Specification

Specification (Spec) is a list of tests, references to analytical procedures and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests described.

Spec establishes the set of criteria to be met in order to be considered “acceptable for intended use”.

“Conformance to specification” means that the API/product will meet the acceptance criteria WHEN tested.

Specs are proposed/justified by applicant and approved by regulatory authorities as conditions of approval.

Specification

Specs are one part of a total control strategy for the API/product. Other parts or this strategy include thorough product characterization during development and adherence to GMP.

Specs are chosen to confirm the quality rather than to establish full characterization, should focus on those characteristics useful in ensuring the safety and efficacy of the product.

Specifications (i.e., tests, analytical procedures, and acceptance criteria) are the quality standards provided in an approved application to confirm the quality of drug substances, drug products, intermediates, raw materials, reagents, components, in-process materials, container closure systems, and other materials used in the production of a drug substance or drug product.

Examples of a test, an analytical procedure, and an acceptance criterion are, respectively, an assay, a specific, fully described high pressure liquid chromatography (HPLC) procedure, and a range of 95.0–105.0 percent.

Analytical Procedures and Methods Validation for Drugs and Biologics: FDA Guidance Feb 2014

Analytical Procedures and Methods Validation: FDA Guidance Aug 2000

What is New in FDA Guidance February 2014:Life Cycle Management of Analytical Procedures

Method Development Life Cycle

Planning

Development and Validation Policy

Objectives/Requirements of Method

Information Gathering

Resource Gathering

Method developmentInitital Method Development

Pre-Validation Evaluation

Method Optimization

Robustness

System Suitability

Development

Plan –

Project

Customer Evaluation

Testing Validation

Method Transfer Filed Method in Use

Periodically

Monitoring/Review

of Methods

in Testing Labs

• Is the method inadequate by today’s scientific standard or regulatory requirement?

• Is sufficient data available to permit simplification of the method?

• Does monitoring of laboratory deviation suggest a need for method improvement ?

• Do newer method for similar products significantly outperform?

• Is the volume of testing justify further method optimization or automation?

Periodically Monitoring/Review of Methods in Testing Labs

Reporting Categories of Post Marketing Changes Major “Substantial”

Prior Approval Supplement (PAS)

Applicant must submit and receive FDA approval before the drug product made with the change is distributed

Regulatory pathway that provides FDA the ability to perform a scientific assessment that the proposed change will not have an adverse effect on drug safety and efficacy

Moderate

Change Being Effected –30 Days (CBE-30)

Applicant must submit a supplement at least 30 days before the drug product is distributed (a CBE-30 supplement) ; Submit a supplement at the time of distribution (a CBE-0 )

FDA reviews each of these submissions after the sponsor has implemented the changeSponsor may be requested to perform additional studies or provide additional data to support the changeApplicability of the filing category may be clarified prior to submission

Change Being Effected (CBE-0)

Minor“Minimal”

Annual Report (AR)

Include the change in the annual report“Do and tell”

Review AR

Old Guideline: Changes Included in Annual Report

The following are examples of changes in specs considered to have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.

– Any change in a specification made to comply with an official compendium, except the changes described in section VIII.C.1.e, that is consistent with FDA statutory and regulatory requirements (§ 314.70(d)(2)(i)).

– For drug substance and drug product, the addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application or deletion of an alternative analytical procedure.

– Tightening of acceptance criteria.

– A change in an analytical procedure used for testing raw materials used in drug substance synthesis, starting materials introduced prior to the final drug substance intermediate, in-process materials prior to the final intermediate, or drug substance intermediates (excluding final intermediate) that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application.

Highlight of the Guidelines of Annual Report March 2014

• The number of CMC manufacturing supplements for NDAs and ANDAs has continued to increase over the last several years. In connection with FDA’s Pharmaceutical Product Quality Initiative and our risk-based approach to CMC review, we have evaluated the types of changes that have been submitted in CMC post-approval manufacturing supplements and determined that many of the changes being reported present low risk to the quality of the product and do not need to be submitted in supplements.

• Based on our risk-based evaluation, we developed a list (see Appendix A) to provide additional current recommendations to companies regarding some post-approval manufacturing changes for NDAs and ANDAs that may be considered to have a minimal potential to have an adverse effect on product quality, and, therefore, may be classified as a change to be documented in the next annual report (i.e., notification of a change after implementation) rather than in a supplement.

Example of Changes That Can Be Included in Annual Report: Components and Composition (1)

• Change in coating formulation for immediate-release solid dosage forms if the coating material and quantity have been approved for another similar product and the change does not alter release of the drug, specification (i.e., tests, analytical procedures, and acceptance criteria for test results), or stability.

• In instances where the supplier of an inactive ingredient was specified in an approved application, change to a new supplier of that inactive ingredient (e.g., change from one drug master file (DMF) holder to other DMF holder or change to a new qualified supplier). This is applicable only if the inactive ingredient’s specification remains unchanged.

• Any change made to comply with the official compendium, except relaxation of an acceptance criterion or deletion of a test (see 21 CFR 314.70(c)(2)(iii)).

Example of Changes That Can Be Included in Annual Report: Components and Composition (2)

• Complete or partial deletion of an ingredient intended to affect only the color, flavor, or fragrance of the drug product without change in other approved specification.

• Change in the supplier of an excipient, where the technical grade and specification for the excipient remain the same.

• Changes in release controlling excipients less than or equal to 5% expressed as a percentage (w/w) of total release controlling excipients approved in the original application of a modified-release solid oral dosage form. After the change, the total weight of the dosage form and its specification would remain the same as originally approved.

Example of Changes That Can Be Included in Annual Report: Manufacturing Site, Process, Batch Size, and Equipment

• Minor structural modifications made in the sterile product manufacturing facility approved in an application that do not affect a product manufacturing area or sterility assurance and do not change product quality or specification.

• Addition of identical processing lines that operate parallel to each other in the drug substance and drug product manufacturing process with no change in in-process control limits or product specification.

Example of Changes That Can Be Included in Annual Report: Specifications (1)

• Revision of an analytical procedure be reported to allow for the use of a

company (i.e., secondary) standard in addition to the U. S. Pharmacopeia

(USP) standard.

• Addition of a new test to the specification for an excipient

• Change to the specification for a drug substance, drug product, or pharmacopial excipient that is made to comply with the official compendia if it is a change that does not relax an acceptance criterion or delete a test.– Addition of HPLC retention time as secondary ID

– Tighten the system suitability criteria

• Change in the approved analytical procedure if the revised method maintains the original test methodology and provides equivalent or increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it claims to have or is represented to possess and the acceptance criteria remain unchanged – change in the flow rate for an HPLC method


• Replacement of a nonspecific identity test with a discriminating identity test that includes a change in acceptance criteria (e.g., replacing SDS-PAGE11 with peptide map).

• Addition of an in-process test.

• Replacement of blend uniformity and in-process homogeneity tests with other appropriate testing that ensures adequacy of mix.

• Revision of tablet hardness (e.g., acceptance criterion for test result or change to a different analytical procedure and its associated acceptance criterion for test result) if there is no change in the approved dissolution analytical procedure, criteria, or associated dissolution profile.

• Addition of a test for packaging material to provide increased assurance of quality.


• Tightening of an approved acceptance criterion for a drug substance, a drug product, drug product formulation components, and in-process material.

• For drug substance and drug product, the addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application or deletion of an alternative analytical procedure.

• A change in an analytical procedure used for testing raw materials used in drug substance synthesis, starting materials introduced prior to the final drug substance intermediate, in-process materials prior to the final intermediate, or drug substance intermediates (excluding final intermediate) that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application.

Example of Changes That Should NOT Be Included in Annual Report: Specifications

• Specification changes not suitable for documentation in an annual report include

– changes to an assay

– tests for impurities

– degradation products

– product-related substances

– biological activities


• All major changes in specifications from those in the approved application must be submitted in a prior approval supplement unless otherwise exempted by regulation or guidance.

• Prior Approval Supplements (PAS) – 21 CFR 314.70 (b)

Examples of Major Changes -PAS

• Relaxing an acceptance criteria

• A change in the fill volume of a drug product involves a change to the specification and must be submitted in a prior approval supplement unless exempted by regulation or guidance (506A(c)(2)(A) of the Act). There is no exemption for this type of specification change; therefore, a prior approval supplement should be submitted.

• If the microbiological assay will also be deleted, the deletion of a test should be reported in a prior approval supplement.

• Establishing a new regulatory analytical procedure

– UPLC to replace HPLC

Examples of Major Changes -PAS

• Deleting any part of a specification

• A change in a regulatory analytical procedure that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the regulatory analytical procedure described in the approved application.

• A change in an analytical procedure used for testing components, packaging components, the final intermediate, in-process materials after the final intermediate, or starting materials introduced after the final intermediate that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application except as otherwise noted. – For example, a change from an HPLC procedure that distinguishes impurities to (1) an HPLC

procedure that does not, (2) another type of analytical procedure (e.g., titrimetric) that does not, or (3) an HPLC procedure that distinguishes impurities but the limit of detection and/or limit of quantitation is higher.

• Relating to testing of raw materials for viruses or adventitious agents.– relaxing an acceptance criterion,

– deleting a test, or

– a change in the analytical procedure that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application.

Examples of Moderate Changes – CBE-30

• Change in a regulatory analytical procedure other than those identified as major changes or editorial changes

– Minor change of gradient

• A change in an analytical procedure used for testing of raw materials used in drug substance manufacturing.

• Any change in a regulatory analytical procedure other than those identified as major changes or editorial changes.

• Relaxing an acceptance criterion or deleting a test for raw materials used in drug substance manufacturing, in-process materials prior to the final intermediate, starting materials introduced prior to the final drug substance intermediate, or drug substance intermediates (excluding final intermediate).


• A change in an analytical procedure used for testing raw materials used in drug substance manufacturing, in-process materials prior to the intermediate, starting materials introduced prior to the final drug substance intermediate, or drug substance intermediates (excluding final intermediate) that does not provide the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application.

• Relaxing an in-process acceptance criterion associated with microbiological monitoring of the production environment, materials, and components that are included in NDA and ANDA submissions.

– For example, increasing the microbiological alert or action limits for critical processing environments in an aseptic fill facility or increasing the acceptance limit for bio-burden in bulk solution intended for filtration and aseptic filling.

• Relaxing an acceptance criterion or deleting a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements .


• An addition to a specification that provides increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it purports or is represented to possess.

– For example, adding a new test and associated analytical procedure and acceptance criterion.

How to Implement the Post-marketing Changes?

Change Control

Basics of Change Control

• Each change to previously approved requirements requires a review and authorization to keep the system in its original state of “proven suitability”

• Formal change control guarantees that all changes are evaluated for their effect on product quality or validation status

• Change control minimizes the risk that changes can have on the quality or process characteristics

• Change control programs have become recognized as essential element of the pharmaceutical quality assurance system

• Change control is not department-specific, rather the task of the whole company

Change Control System Requirement

• Inadequate change control procedures end up creating a huge risk of non-compliance.

• The process of change is the end result of initiatives aimed at improving quality, increasing yield, reducing costs, cutting waste, streamlining processes etc.

• It would be very difficult to carefully manage change control in a large company or a fast growing organization without an enterprise-wide change control system.

• One of the most important aspects of change control is to maintain a history of changes for audit trail purposes – a capability better facilitated by such systems.

• The system must manage the end-to-end change control process including initiating, reviewing, approving, distributing and storing change history.


• Such a system can provide evidence of compliance to FDA. In addition, the system should also help capture relevant information about the objective, nature and scope of change.

• The scope of the change control program must also cover a broad set of possibilities including changes to test methods and specifications.

• Change control allows manufacturers to enable certain changes (those that alter specifications, a critical product attribute or bioavailability) as requiring regulatory filings and prior regulatory approval.

• In addition, a change control system maintains a history of the lifecycle of all change requests - requester name; reviewer(s) name, date reviewed, approval date and name, implementation date etc.

• Such information is used by FDA during audits to ensure change control procedures are working well.


• The system should be flexible enough to allow change control while responding to emergencies or temporary changes by documenting appropriate change justifications.

• A change control system provides checks and balances in the quality system by tracking, reviewing and approving changes to materials (e.g., specification, supplier, or materials handling).

• The implementation also extends change control to suppliers, so that necessary adjustments to the process can be undertaken before processing components impacted by the changes.

• Following these critical steps allows for a robust change control system for the enterprise that can help manufacturers manage change and implement continuous improvement in manufacturing.

Key Benefits in Using a Change Control System

• It facilitates a regulatory environment while supporting change for continuous improvement.

• Change control ensures that the company continues to comply with cGXP.

• Structured and consistent approach towards managing change

• Documenting the details of change

• Routing of change requests to appropriate individuals/team for approvals

• Documentation of change approvals and implementation

• Maintenance of change history and easy retrieval of information

• Tracking changes effectively and providing an audit trail

• Demonstrate compliance to FDA regulations

General Procedures in Managing Change Controls

• Identify stakeholders– Impacted sites

– Site specific contact person(s)

– Quality

– Regulatory

– Team leader

– Documentation managers

• Initiate pre-CC meeting

• Create change control

• Child record assessment

• Change control approval

• Execution

• Closure

Change Control Process Flow

Pre-CoCmeeting

Open CoC

Site/functional approval

QA/Board approval

Authority approval

Site/functional Implementation

Site/funtional assessment

Close change control

Change Control

• Request for change

• Change control No.

• Date

• Type/category of change

• Change related to product/document/system/facility

• Concerned documents with number

• Description of change

• Reason for change

• Impact of change

• Assessment of Impacted sites/functions

• Proposed methodology for Implementation

• Closure

Why Is Change Control Critical?

• Compliance risks due to no/ineffective change control

o Method not aligned with Local regulatory filing

o Local regulatory filing not consistent with global regulatory filing

o Global regulatory filing not consistent with latest version of methods

o Translation to local language is not accurate

o Wrong version of test method is used at different sites

o Methods not validated

o Method not validated according to today’s standard

o Missing information

o Calculation error

o Inappropriate system suitability

o Compendial changes in each country

• Effective change control system provides evidence of compliance to FDA.

• It is invaluable to maintain a history of the lifecycle of all change requests.

Managing Change Control

• The level of detail in the Current State , Proposed State & Justification Details should be concise, clear and allow to fully understand the quality, compliance, business and regulatory risks of the change (e.g. by person with no prior knowledge, auditor, …).

• Current state: • What to change: Method/spec #, Version#, actual section

(content), acceptance criteria to be changed• Who: which sites the method/specs are being used.

Specifications information: Specifications references.

• Proposed state: • What is changed: Method/spec #, version #, actual section of

changes, acceptance criteria. if new method/spec is created, list the new method/spec number.

• Who: If new sites added or removed, list the sites.


.

Justification details: Provide concise description to provide people with all information needed to understand changea. Why the change is neededb. Who or what is driving request for changec. Criticality impact statement Technical justification: provide appropriate supporting documentation for the change (e.g. scientific reports, validation, qualification, justification of specifications, etc.)

Source of change: - CAPA- Health Authority Request - Health Authority Commitment- Health Authority Notifications- Quality Compliance- Regulation requirement- Process Improvement- Event & Deviation- Life Cycle Management- Technology Transfer


•.

Implementation Strategy DefinitionsImmediate Implementation change without regulatory impact or change with

regulatory impact that does not require response prior to implementation and that can be implemented when all actions are completed (e.g. Do and Tell)

Awaiting Notification change that requires notification to health authorities only

Wait For Appoval change that requires official approval of all involved health authorities before it may be implemented

Country by Country implementation

change that can be implemented country per country upon local approval (e.g. shelf life change, label changes, ...)

FID implementation Fixed implementation date selected when approvals of all countries are involved.


The regulatory assessment will be key to determine if the CC level is High or Low.

“Low” if there is no regulatory impact or regulatory notification that does not require response prior to implementation. (Annual report, CB-0)

“High” if there is a regulatory “Wait for Approval” or significant impact to quality (e.g. sterility assurance) or continuity of supply (stock out during implementation, decreased product yield or throughput).

Note: a high impact change can be downgraded to ‘low impact’ to align with an already approved submission, align with pharmacopeia updates, regulatory actions will be managed from parent/umbrella change.

FID field is mandatory. This field should be populated by Regulatory Affairs or Change Owner (in agreement with Regulatory Affairs).

For a wait for approval, define fixed implementation date

FID timeframe: Standard 18 months

.


Expected closing date of the CC (including all child records)

Note: assign realistic timeframe to include completion of all activities and Health Authority approvals. The target closing date is based on the completion dates entered in the implementation grids, FID time and date supporting info available.

Typical closing date timelines: Closing Date = Date documents available + x months (to prepare file) + approx. y months (FID) + z months (for closure) In Practice, last action completed + z months

Summary

I. FDA’s new guidance emphasizes life cycle management of specifications and analytical methods

II. The new guidelines expand the category of post-marketing changes that can be included in annul report.

III. Examples were given on the three categories of post-marketing changes• Annual report• PAS • CBE-30 or CBE-0

VI. Change control is an essential tool to implement the changes and ensure quality and compliance

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