Pharmaceutical Industry: Global Regulatory Environment Regulation_July2013FINAL.pdfhave an adverse effect on the … A oderate change m is a change that has a moderate potential to

©2013 Waters Corporation 1

Pharmaceutical Industry: Global Regulatory Environment

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Pharmaceutical Market Method Transfer and Modernization

Method Transfer

– Improvement or adjustment of method

– Change of instrumentation

– Site to Site transfers

Pharmaceutical business landscape - elevates importance of instrument and methods transfer

– Greater focus on collaborative R&D, development

– Need to operate efficiently – manage costs and maximize profit

– Work globally and with different partners

– Regulatory bodies looking more stringently at quality of drugs, particularly generics, and spearheading modernization and innovation

Regulatory landscape of method transfer and modernization

– What are the regulatory bodies allowing?

– What is the status of USP Chapter <621>? And what does this mean?

– What can customers do regarding method transfer?

– What is modernization?

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Regulation is a Global Affair

Who are the official regulatory bodies: – US: Food and Drug Administration (FDA) – Canada: Health Canada – Europe: European Medicines Agencies (EMA) – Brazil: National Health Surveillance Agency (Anvisa) – Japan: Ministry of Health, Labor & Welfare (MHLW) – Argentina: National Administration of Drugs, Foods and Medical Devices – India: Drug Controller General of India (DCGI) – Chile: National Agency of Medicines (ANAMED) which is part of the Public Health

Institute (ISP)

Who publishes the local pharmacopoeia: – USP: U.S. Pharmacopoeial Convention – UK: British Pharmacopeia – EP: European Directorate for the Qualities of Medicine and

Health Care (EDQM) – Brazil: Brazilian and MERCOSUR Pharmacopoeia – Chile: Chilean Pharmacopoeia Foundation (CPF) – JP: Pharmaceutical and Medical Device Agency (PMDA) – India: India Pharmacopoeia Commission (IPC)

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US FDA Current 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

– Pre-approval of changes before refilling may be needed

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

o Minor changes

o Moderate changes

o Major changes

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

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

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



US FDA Definition of changes

A minor change is a change that has minimal potential to have an adverse effect on the …

A moderate change is a change that has a moderate potential to have an adverse effect on the …

A major change is a change that has a substantial 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.

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US FDA What’s required for minor change?

For qualified minor changes (defined in Appendix A) – …may be classified as a change reportable in an annual report (e.g., notification

of a change after implementation) rather than in a supplement.

Appendix A, 4.3: Recommendation for minor changes: − …if the revised method maintains basic 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

(e.g., change in the flow rate or sample preparation for

a high performance liquid chromatography (HPLC) method)


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What’s changed?

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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

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


FDA’s 21st Century Quality Vision

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Application of novel science and technologies

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Europe EMA Current Status

For existing applications: – Adopted change strategy for API and drug product

– Developed clear categorization of changes, strictly documented

For new applications – Look for strategies/guidelines for potential change in future (EU only)

At the forefront in promoting international harmonization – Within Europe: with the countries (40) under their scope

– Globally: with USFDA, SFDA, KFDA etc

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EMA

Use new Post Approval Change Management Protocol (but 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

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EMA Made ajustements

Use new Post Approval Change Management Protocol (EU only) – first step: describe the strategy (in PAC management protocol),

either in the Initial Application, or in a type II variation o for any existing classical LC method, describe the possibility of switching to

UHPLC, with type of supporting data to be provided to justify this switch

– second step: provide the new UHPLC test methods in a type IA variation, with supporting data

o full description of UHPLC method(s)

o analytical validation data

o comparison of methods, e.g. via tables and chromatograms

o batch data

o etc...

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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

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Europe EMA Variation for drug substances

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Europe EMA Variation for finished product

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Europe EMA Conditions for Variation

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The document provides FDA’s “current thinking on defining, establishing, and documenting the responsibilities of each party (or all parties) involved in the contract manufacturing of drugs.” – The Guidance outlines the statutory and regulatory basis

for concept of the Quality Agreement and establishes the link between current final Guidance (e.g., ICH Q7, ICH Q9 and ICH Q10) and the FDA expectation that well-defined Quality Agreements are necessary to assure that the requirements for complying with cGMPs are clearly spelled out by the parties involved.

– For the purposes of this guidance, the term

“manufacturing” includes processing, packing, holding, labeling operations, testing, and operations of the Quality Unit.”

The issuance of this document is expected to result in

an increase in enforcement activity relative to the area of contracted facilities and start a series of Warning Letters and 483 observations for virtual companies, owners, as well as contracted facilities

FDA reiterates that regardless of the type of operation that the contracted facility performs, the Quality Agreement DOES NOT exempt contracted facilities from cGMP requirements related to the operations they perform.

New Draft Guidance – May 24, 2013


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The Office of Generic Drugs (OGD) indicated that its January 1, 2014 implementation date is firm

Guidance is an attempt to harmonize with the ICH stability requirements so that everything is the same for new drugs as for generics – In the document, the FDA goes on to say

"Currently, the only published direction from OGD is contained in a1995 letter to industry which states that OGD will accept ICH recommended long-term room temperature conditions for stability studies (i.e., 25±2°C, 60±5% RH),"

– And, the FDA continues, "Although adequate in the context of other guidance existing at that time, this recommendation is no longer sufficient to serve as a basis for stability testing for ANDAs."

Supposedly, a Q&A document is going to be issued to address some of these issues.

New Final Guidance – June 18, 2013


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g y g g p p p p g g

New in July 2013

Wednesday, July 3, 2013, the FDA signaled its intention to permit generic drug makers to make changes to their safety labels.

Could open the door to lawsuits against generic drug companies for the first time since a Supreme Court decision barred such suits two years ago in the Mensing decision and again in June 2013 in the Mutual Pharmaceutical Co v. Bartlett decision.

The Office of Management and Budget (“OMB”) website was recently updated to show plans for FDA to issue a Notice of Proposed Rulemaking titled “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products.”

The projected time for publication of the Notice of Proposed Rule Making (NPRM) was cited as September 2013.

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USP-NF Effort on modernization and harmonization

Modernize general chapters and monographs – FDA priority around high volume products – Over 2000 monographs identified and prioritized to be updated – Trade groups, FDA and others involved

Harmonization – Elimination of redundant testing – Multi-compendia compliance – Stronger monographs with a global set of experts setting and

reviewing standards – Specifications (test methods) are representative of the global supply

chain – Harmonized: A pharmacopeial general chapter or other pharmacopeial document is harmonized when a

pharmaceutical substance or product tested by the document’s harmonized procedure as published in EP, JP and USP yields the same results, and the same accept/reject decision is reached.

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Monograph Modernization

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

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http://ipecamericas.org/sites/default/files/ef12april25-hall.a





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














USP Monograph Modernization Initiative - 2011

General announcement made in Feb. 8th, 2011 – To update and improve its monographs for drug substances, drug

products and excipients in the USP and USP-NF

– Focusing on monographs identified as a priority by FDA

– A letter to USP from FDA listed o acetaminophen and diphenhydramine and several related dosage forms,

most of which are over-the-counter (OTC) medications, as high priority monographs for updating

Complete listing of the affected monographs posted on Monograph Modernization Hot Topics Page

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http://www.usp.org/usp-nf/key-issues/monograph-modernization


FDA pushing USP to modernize monographs

Source: FDA and USP websites

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MMTG

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

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USP and method transfer

USP - Reviewing and updating general chapters and monographs – USP <1224>, <1225>, <1226>

o <1224>Transfer of Analytical Procedures

o <1225> Elements Recommended for the Transfer of Analytical Procedures

o <1226> Verification of Compendial Procedures

– USP <621> & EP <2.2.46>changes under review o Focus first on isocratic methods, gradient methods are not included at this time

o USP <621> modernization is currently stalled due to differing opinions inside the USP

o USP 621 allowed limits

• The specific allowed deviations include column length, particle size, and flow rate.

• Within these allowed limits, the change of method is only regarded as an adjustment of the method, so there is no need for method revalidation after modification.

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

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Chapter <621> and European Pharmacopeia

Will EurP follow USP? – USP and EurP are harmonizing both chapter <621> and 2.2.46 to

the extent possible

What about the EurP Chapter 2.2.46? – Draft 2.2.46 chapter has already been written

When will this be released? – EurP expect to release the new 2.2.46 chapter at the same time as

the USP <621> or with a short delay

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In 2009, Dr. Uwe Neue et. al. wrote a ‘Stimuli Article’ (PF 35) describing the scientific rationale behind proper LC method transfer – Dr. Neue’s calculations are the basis of the ACQUITY UPLC Columns Calculator

– No distinction is made between HPLC and UPLC

Modernize General Chapter <621> The stimuli article

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Stimuli Article

Change the length to particle size ratio (L/dp) simultaneously

Different lengths, diameters and particle sizes can be used

Length to particle size (L/dp) must be ± 25% of original column

Flow rate scaled to particle size and column diameter

Stationary phase characteristics must not change

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Modernize General Chapter <621> What does the stimuli article propose?

Analysts Will Have More Flexibility to Utilize Modern Chromatographic Techniques Such as UPLC Technology

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USP-NF Development Workflow What’s the status for the stimuli article?

Waters submitted PF 35 (6) Nov 2009

Amended chromatography <621>

Posted in PF 37(3) May 2nd, 2011

Comment period end Expert Committee discussion began

July 31st, 2011

Chromatography <621> System Suitability Deferred

Dec 29th, 2011

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USP-NF Development Workflow What’s the status for the stimuli article?

Waters submitted PF 35 (6) Nov 2009

Amended chromatography <621>

Posted in PF 37(3) May 2nd, 2011

Comment period end Expert Committee discussion began

July 31st, 2011

Chromatography <621> System Suitability Deferred

Dec 29th, 2011

Revised Proposal Posted in PF 38 (2) March 1st, 2012

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Modernize General Chapter <621> What would be the benefits?

Chromatographic Benefits – More flexibility to change the column dimensions and/or particle

size as long as an equivalent (or better) separation is achieved

– Provides a rational, science-based approach to change a column or method that requires an equivalent separation (performance) be obtained

Organizational Benefits – Analyses can continue even if the prescribed column is no longer

available

– A faster, greener and more sustainable separation can be obtained using a more modern separation technique

– Ease or remove the revalidations step when moving to UPLC technologies (assuming system suitability requirements are met)

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Recent Compendial UPLC Methods

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Three Options

Use existing monograph to letter

Adjust method within USP <621> – Verification require - system suitability

– If at 5 µm, can go to 2.5

Step beyond USP <621>, working with FDA, report as minor change in annual report – Validation required

– Possibly submit monograph

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Summary of Method Transfer Environment Today

Industry and regulators looking for compromise – Allowing implementation of new techniques while maintaining standards – FDA looking to allow for changes in methods but not methodology – EMA bringing the gap with European procedures to allow for adjustments

USP and EP reviewing and updating general chapters and

monographs – USP <621> & EP <2.2.46>changes under review

o Focus first on isocratic methods – Prioritized list of monographs to be updated – Harmonization effort world wide

Companies making decisions in parallel to regulatory changes

All parties realize that barriers to technology changes need to be reduced and technology will continue to advance

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Documents

Pharmaceutical Industry: Global Regulatory Environment Regulation_July2013FINAL.pdfhave an adverse effect on the … A oderate change m is a change that has a moderate potential to