usp modernization initiative in the context of method ... · – cmc postapproval manufacturing...

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USP Modernization Initiative in the Context of Method Transfer and Working Globally


Method Transfer Environment

How operate today – Work Globally – With Partners – Use CMOs and CROs – Elevates importance of instrument and methods transfer

Aged Instrumentation and Standardization – Need to replace older HPLCs – Many of this older units are in QC laboratories – Looking at ability to standardize and reduce variability – Pressures to “Modernize” and utilize newer technology

Need for Efficiency – New regulatory pressures – Require “lean” laboratory operation


HPLC install base, legacy methods, moderization, utilization...


Guidance Documents Important to Technology Transfer

US-FDA Guidance for Industry; – PAC-ATLS: Post Approval Changes – Analytical Testing Laboratory Sites (1998) – Comparability protocols (February 2003) – Changes to an Approved NDA or ANDA (April 2004) – Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for

Compendial Changes (November 2004) – CMC Postapproval Manufacturing Changes Reportable in Annual Reports (March 2014) – Process validation Guideline (2011) – Analytical Procedures and Methods Validation for Drugs and Biologics (February 2014)

European Variation guideline ISPE Technology Transfer Guide World Health Organization - WHO Annex 7 Technology Transfer ICH

– Q1A-E Stability Testing of New Drug Substances and Products – Q2 (R1): Validation of Analytical Procedures: Text and Methodology – Q8 Pharmaceutical Development – Q9 Quality Risk Management – Q10 Pharmaceutical Quality Systems – Q11 Product Life Cycle Management/applies to API

US Pharmacopeia – Chapter <1224>, <1225>, <1226> – Chapter <621> (specific to chromatography)


Method Transfer Approaches

Use existing method and/or monograph

Adjust method within USP Chapter <621> or EP <2.4.46> guidelines

o These modifications of parameters are allowed only when the chromatogram improvement is still within the stated system suitability factors

o Within these allowed limits, the change of method is only regarded as an adjustment of the method

Make changes to an approved method and report as minor change in annual report to FDA or EMA – Validation required; Possibly submit monograph

Re-develop Method(s)


Streamlining Analysis Historical methods to modern method

• Reduced run time 88% • Reduced solvent consumption by 96% • Eliminated the use of an instrument

Two HPLC methods and one GC method for the APIs and related compounds were transferred to one UPLC methods.


US FDA Guidelines for method change

Changes are allowed to registered methods – FDA - Allowing implementation of new techniques while maintaining

standards – FDA looking to allow for changes in methods but not methodology

FDA recognizes that there needs to be balance – Allow for some changes to be more routine

o Minor changes, Moderate changes, Major changes – Minor (annual report – no fees), Moderate (supplement), Major (Prior

approval supplement)

Exercise of Enforcement Discretion – Notification that FDA intends to exercise enforcement discretion and does

not intend to take action to enforce compliance with the compendial changes requirement as stated in 21 CFR 314.70(c)(2)(iii) if manufacturers submit such changes in their annual reports.

– FDA intends to develop further guidance to clarify the requirements of 21 CFR 314.70(c)(2)(iii).

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM077097.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM122871.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070544.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM077097.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM122871.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070544.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070544.pdf


US FDA New Guidance March 2014

The revised 13 page document covers changes to both NDAs and ANDAs Appendix A and Appendix B describe the types of changes that can now be submitted

in the Annual Report. – Appendix A contains those types of changes that can be submitted in the Annual Report if the

change has minimal potential to have an adverse effect on product quality – Appendix B restates the annual reportable changes found in the various Scale-up and Post-

approval Changes (SUPAC) Guidances. FDA reminds the industry to continue to pay attention to the older “Changes to an

Approved NDA and ANDA” Guidance and also notes that data supporting the change should be adequately presented to support the applicant’s determination that the change did not require the submission of a supplement.

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm217043.pdf

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm217043.pdf


FDA’s 21st Century Quality Vision and Advancing Regulatory Science


FDA’s 21st Century Quality Vision

FDA’s Center for Drugs Redoubles Effort to Achieve 21st Century Quality Vision and Foster Continuous Process Improvement Jun 25th, 2013 FDA doubles down on its effort to achieve the vision laid out under its Pharmaceutical Quality for the 21st Century initiative a decade ago of a “maximally efficient, agile, flexible pharmaceutical manufacturing sector that can reliably produce high-quality drugs without extensive regulatory oversight.” Delivering the keynote speech at the generic drug CMC conference cosponsored by the Generic Pharmaceutical Association (GPhA) and FDA in early June 2013, CDER Director Janet Woodcock reviewed:

● The “historical trajectory of FDA quality regulation” ● Where the agency has succeeded and fallen short in realizing its 21st century vision ● What the obstacles are ● What the agency is now doing across the CMC and GMP arenas organizationally and policy-wise to overcome them.

Woodcock stated candidly, “we did not achieve a regulatory system that would enable the vision that we put forth, and we knew that. We knew we had not gotten there. And therefore what we are going to do now is make another attempt to do this.” Source: International Pharmaceutical Quality Pulications

http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RegulatoryScience/UCM268225.pdf




Application of novel science and technologies


Categories of Post Approval Changes

Classification of Post Approval Changes

FDA EMA Major Change Type II Variation Substantial potential to have an adverse effect on the identity, strenth, quality, purity, or potency of a drug product.

Significant impact on the quality, safety or efficacy of a medicineal product.

Prior Approval Supplement (PAS) Prior Approval Procedure

PDUFA V goal date - 4 months Validation +(30, 60, 90) CHMP + 15 days to review and approve

Moderate Change Type IB Variation Moderate potential to have an adverse effect on the identity, strenth, quality, purity, or potency of a drug product.

Minor Variation which is neither a Type IA nor a Type II Variation nor an Extension

CBE 30 - Submission at least 30 days before ditribution of the post change product

Notification Procedure Validation +30 days

CBE-0 Distribution can occcure whe the FDA recieves the supplement

Minor Change Type IA, IAin Variation Minimal potential to have an adverse effect on the identity, strenth, quality, purity, or potency of a drug product.

Minimal impact, or no impact on the quality, safety or efficacy of the medincal product

Annual Report Notification Procedure 30 days


Europe EMA Variation (Change) categories

IA: Minor variations – Do not require prior approval for implementation – Require notification

o IA: require notification within 12 months of implementation o IAIN: require immediate notification

IB: Minor variations that are not IA/IAIN nor II nor extension – Must be notified to the National Competent Authority/European Medicines

Agency (‘the Agency’) by the Marketing Authorization Holder (MAH) before implementation, but do not require a formal approval

II: Major variations – Require formal approval prior to implementation

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500003981.pdf


Europe EMA Variation for drug substances


Europe EMA Variation for finished product


Europe EMA Conditions for Variation


European Medicines Agency (EMA) Current guidelines for method change

Use new Post Approval Change Management Protocol (for EU only) – principale: declare in PAC MP the expected future changes

(strategy), that will then be later considered as minor changes (results)

– introduce in a new Application, or as variation (type II) in an existing file

– easier in a centralized procedure

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/04/WC500125400.pdf






USP and Method Transfer

USP Monographs USP Chapter <621> USP Chapters <1224>, <1225>, <1226>

– <1224>Transfer of Analytical Procedures – <1225> Elements Recommended for the Transfer of Analytical Procedures – <1226> Verification of Compendial Procedures


USP Standards: Monographs

USP – USP creates the official public monographs for prescription and over-the counter medications in the United

States in conjunction with the pharmaceutical industry and others. – Monographs for these products are published in the United States Pharmacopeia and National Formulary

(USP–NF). – The current USP–NF comprises more than 4,500 monographs and are named in the U.S. Federal Food, Drug,

and Cosmetic Act as the official compendia of the nation. – USP–NF standards are also used in more than 130 countries

What is a Monograph? – A written document, or standard, that describes an item (e.g., a finished drug, a drug ingredient, or food

chemical). – A monograph published in any USP compendium provides:

• the name of a substance; its definition; package, storage, and labeling requirements; • and information on tests needed to ensure the substance is of the appropriate strength, quality, and

purity.

Importance of Monographs – Monographs give scientists, governments, manufacturers, and others a public standard by which to judge

an article’s quality. – The existence of a public standard for substances consumed in the global marketplace is a key element of

the safety nets that help maintain and improve public health. What is a public standard?

– Public standards are developed in an open and collaborative process, seeking informed input from independent experts with a wide variety of backgrounds – healthcare, regulatory, industry, academia, and others.

– This is different from private standards, which may be developed by a manufacturer and not made available for outside assessment and commentary.

– The transparency of USP’s open process provides a high level of public assurance that the standard had been developed using a broadly representative body of science.


How are monographs developed? – The process begins with manufacturers, who

submit a draft monograph to USP. – USP scientific staff review the draft monograph

and the data, conduct laboratory tests, and then prepare proposed monograph.

– The proposed monograph is sent to a group of expert scientific volunteers (USP’s Council of Experts [CoE] and its Expert Committees) for their scientific opinion of the relative merits of the proposal.

– If approved by the CoE, the proposed monograph is published in the Pharmacopeial Forum (PF).

• PF is a peer-reviewed journal that provides interested parties, such as pharmaceutical and dietary supplement manufacturers, government agencies and others, the opportunity to review and comment as the CoE develops and/or revises USP–NF standards— and is the working vehicle of the CoE.

• Public comments are received and reviewed by the appropriate USP Expert Committee.

– Once the comments are accepted and incorporated, the new monograph is published in the USP–NF.

USP Standards: Monographs


USP Monograph Modernization Initiative

Driver is to maintain up-to-date standards to support USP’s commitment to public health

Need for modernization – Aging of monographs, decades old in some cases – Content does not reflect current expectation for procedure and

acceptance criteria – Complaints from manufactures – General lack of specificity

Benefits – Strengths the public standards – Moves from non-specific to specific procedures – Considers practical factors (removes unnecessary test, eliminates

safety/environment issues – Increases consistency across monographs


Modernization History in the USP

2004-2005 Initial evaluations of monograph status – Many monographs identified as needing revision

2005 Initial Priority List (~700 articles) 2009 Expanded Priority List (~2700)

– Modernization is a subset of USP’s ongoing revision work – Started using the term “modernization” in 2009

Working with FDA Monograph Modernization Task Group (MMTG, Nov 2010-ongoing)

2011 FDA Modernization request w/ priorities Launched modernization “hot topics” web page (Feb 2011) Continued Collaboration with FDA and Industry

– Prioritization – Timing considerations

22

http://ipecamericas.org/sites/default/files/ef12april25-hall.a%232-catherine.sheehan(usp).pdf http://ipecamericas.org/system/files/EF13May1HallB3CatherineSheehan(USP).pdf http://www.usp.org/sites/default/files/events/stakeholder_forums/2013/meeting-1/5-excipient-modernization-2013-06-07.pdf

http://ipecamericas.org/sites/default/files/ef12april25-hall.a%232-catherine.sheehan(usp).pdf





http://ipecamericas.org/system/files/EF13May1HallB3CatherineSheehan(USP).pdf

http://www.usp.org/sites/default/files/events/stakeholder_forums/2013/meeting-1/5-excipient-modernization-2013-06-07.pdf














Communications regarding modernization of monographs


Communications regarding modernization of monographs

Source: FDA and USP websites


US Pharmacopeia (USP) USP Monograph Modernization Initiative

http://www.usp.org/usp-nf/development-process/monograph-modernization









Lists


Lists comments


USP Monograph Modernization Initiative - 2013


USP Modernization

Monographs needing update: >2600 Approaches

– Donor model • Sponsored monographs • Alternative source monographs

– Internal Development model • Samples procured from market/sponsor • Reference procedure developed in USP labs

– Development under FDA Cooperative Research and Development

Agreement (CRADA), which includes as one of its objectives the development of procedures to support monograph modernization.


Barriers

Sample Procurement – Potential Solutions being identified

Impurity Standards Timing Public Review Timing Reference Standards Pipeline


USP and Method Transfer

USP 621 – This chapter defines the terms and procedures used in chromatography – Adjustments of operating conditions can be made to meet system suitability

requirements and these adjustments are listed. – The specific allowed deviations listed include column length, particle size,

and flow rate, etc. – Within these allowed limits, the change of method is regarded as an

adjustment of the method. Although the suitability of an analytical procedure should be verified under actual conditions of use.

USP <1224>, <1225>, <1226> – <1224>Transfer of Analytical Procedures – <1225> Elements Recommended for the Transfer of Analytical Procedures – <1226> Verification of Compendial Procedures


What System Adjustments Can be Made in Chromatography <621>?

Variable Allowed Adjustments in USP Chromatography <621>

Particle Size -50% Column Length ±70%

Flow Rate F2=F1 (d22/d12) and ±50% Column ID Any allowed if linear velocity is constant

Injection Volume Any reduction consistent with precision and detection

limits; no increase permitted Column Temperature ±10%

Mobile Phase pH ±0.2 unit

USP 36-NF 31 Currently Official


USP 37-NF 32 through First Supplement August 1, 2014

Variable USP 36-NF 31 USP 37-NF 32 Through first supplement

Isocratic Gradient

Particle Size -50% L/dp Ratio Constant or N: -25 to + 50%

No changes allowed

Column Length ±70%

No changes allowed

Flow Rate F2=F1 (d22/d12) and ±50% F2-F1 x[(dc22 x dp1)/dC12 x dp2)] and ±50% Not applicable

Column ID

Any allowed if linear velocity is constant

Any allowed if linear velocity is constant

No changes allowed

Injection Volume

Any reduction consistent with precision and detection limits;

no increase permitted

Can be adjusted as consistent with precision and detection

limits

Can be adjusted as consistent with precision and

detection limits

Column Temperature ±10% ±10%

±10%

Mobile Phase pH ±0.2 unit ±0.2 unit

±0.2 unit

F=Flow rate; d = internal column diameter; dc = column diameter, dp = particle size


USP Stimuli Article PF39 (6)

http://www.usp.org/usp-nf/notices/stimuli-article-lifecycle-management-analytical-procedures-posted-comment



















Lifecycle Management of Analytical Procedures

Published July 2013; Comments close January 2014 The Expert Panel recommends adoption of a lifecycle

approach for the management of analytical procedures. – This approach builds on and enhances the current

information contained in several USP general chapters and ICH guidance documents.

– Adoption of this approach would introduce new concepts to the USP: o The Analytical Target Profile and associated

predefined acceptance criteria o Evaluation of the uncertainty associated with the

analytical procedure o Incorporation of risk analysis strategies o Consideration of the potential effect of changes to an

analytical procedure in the context of the analytical procedure's lifecycle

– The traditional approaches to validation, transfer, and verification would be integrated into the analytical procedure lifecycle process rather than being viewed as separate entities.

– The modern concept of a lifecycle model, which is based on process validation and described in ICH guidelines Q8, Q9, and Q10 (and more recently Q11), and can be applied to analytical procedures

Proposed Chapters: – Concepts addressed in 1224 , 1225, and 1226 would be

revised and compiled into a single new general information chapter, Lifecycle Management of Analytical Procedures 1220

– A new general chapter 220 specifying the basic requirements


FDA and EMA on QbD in 2013


Supersedes the 2000 draft guidance on Analytical Procedures and Methods Validations

Also when finalized it will replace the 1987 FDA guidance Submitting Samples and Analytical Data for Methods Validations

This new document explicitly mentions biologics in its title.

The objective of the Guideline is to inform applicants about what data are expected by the FDA in marketing authorization dossiers.

The provisions of the Guideline apply to – New drug applications (NDAs), – Abbreviated new drug applications (ANDAs) – Biologics license applications (BLAs), – Variation applications regarding these types of

application, as well as to Type II Drug Master Files. – Cannot be directly used for investigational new drug

applications (INDs) New chapters have been added

– Chapter VIII. Life cycle management of analytical procedures"

– Chapter IX: FDA methods verification A chapter on the verification of analytical methods in FDA's own laboratories

Guidance has become shorter due to references – Cross-references to corresponding 21 CFR paragraphs – Extensive list of essential FDA Guidelines which have to

be considered in this context, references to corresponding USP chapters, and technical literature on statistical topics.

New Guidance 2014


Lifecycle Management of an Analytical Procedure

Lifecycle Management involves: – Revalidation – Analytical Method Comparability Studies

o Alternative Analytical Procedures o Analytical Methods Transfer

– Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA Over the Life Cycle of a validated and implemented procedure

– Trend analysis on method performance should be performed at regular intervals to evaluate the need to optimize the analytical procedure or to revalidate all or a part of the analytical procedure. o If an analytical procedure can only meet the established system suitability requirements with

repeated adjustments to the operating conditions stated in the analytical procedure, the analytical procedure should be reevaluated, revalidated, or amended, as appropriate.

– New information (e.g., a better understanding of product CQAs or awareness of a new impurity) may warrant the development and validation of a new or alternative analytical method.

– New technologies may allow for greater understanding and/or confidence when ensuring product quality.

– In anticipation of life cycle changes in analytics, an appropriate number of samples should be archived to allow for comparative studies.

– If a risk-based evaluation or other drivers lead to changes in an analytical procedure or replacement with a new method

– If the procedure is transferred to a new testing site; revalidation, a new validation exercise, an analytical method comparability study, or a combination of these exercises should be considered.

– Changes to the drug substance or drug product manufacturing process may also warrant analytical procedure revalidation.


Method Transfer Approaches

Use existing method and/or monograph

Adjust method within USP Chapter <621> or EP <2.4.46> guidelines

o These modifications of parameters are allowed only when the chromatogram improvement is still within the stated system suitability factors

o Within these allowed limits, the change of method is only regarded as an adjustment of the method

Make changes to an approved method and report as minor change in annual report to FDA or EMA – Validation required; Possibly submit monograph

Re-develop Method(s)


Summary

Method transfer decisions need to consider – Regulatory allowances – Business parameters – Technology and knowledge advances – Continuing Quality

Methods going forward: – High quality and robust – Validated – Equivalency or comparable – Able to use lab to lab around the world – Modernized

o Specific ID tests and related impurities/degradants o Updated technology o Run on either a HPLC or UPLC instrument (desired) o MS compatible, if possible

Life cycle management of analytical procedures