fda’s draft guidance – request for quality metrics...current quality concepts •ich q10:...

FDA’s Draft Guidance –Request for Quality Metrics:

What All Drug and Biologics Manufacturers Need to KnowJune 2017

2017 © Regulatory Compliance Associates Inc.

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W E L L N E S S F O R B U S I N E S S®

Discussion Topics

• Quality Concepts

• The Journey

• The Guidance Details

• Industry Responses

• Summary


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Quality Metrics Concepts

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Understanding Quality Performance

• FDA Vision:

“A maximally efficient, agile, flexible pharmaceuticalmanufacturing sector that reliably produces high quality drugproducts without extensive regulatory oversight.”

Janet Woodcock, October 2005


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Definition of QualityFrom ICH Q10: Pharmaceutical Quality System

The degree to which a set of inherent properties of a product, system orprocess fulfills requirements

From ICH Q9: Quality Risk Management

Definition of Quality: The degree to which a set of inherent properties of aproduct, system or process fulfills requirements

From ICH Q6: Specifications

Definition of Quality: The suitability of either a drug substance or drugproduct for its intended use. This term includes such attributes as theidentify, strength, and purity.”


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Current Quality Concepts

• ICH Q10: Pharmaceutical Quality System

–Senior management has the ultimate responsibility toensure an effective pharmaceutical quality system is inplace to achieve the quality objectives, and that roles,responsibilities, and authorities are defined,communicated and implemented throughout thecompany.


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ICH Q10 Management Principles

• Participate in the design, implementation, monitoring and maintenance of aneffective pharmaceutical quality system

• Demonstrate strong and visible support for the pharmaceutical quality systemand ensure its implementation throughout their organization

• Ensure a timely and effective communication and escalation process exists toraise quality issues to the appropriate levels of management

• Define individual and collective roles, responsibilities, authorities and inter-relationships of all organizational units related to the pharmaceutical qualitysystem. Ensure these interactions are communicated and understood at all levelsof the organization.

• Conduct management reviews of process performance and product quality andof the pharmaceutical quality system

• Advocate continual improvement

• Commit appropriate resources


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Quality Metrics as a Tool

• Demonstrated Quality Performance = Privileges

–Less frequent inspection

–Preferred handling of Post Approval Changes


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Quality Metrics as a Tool (cont’)

• Metrics Create a Dialog Within a Company to:

–Drive continuous improvement

–Provide early detection of control drifts

–Focus resources on a particular area

–Ensure a stable supply of drug product.


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Linking Drug Shortages and Quality Metrics

•Food and Drug Administration Safety andInnovation Act (FDASIA)

–Signed into Law on July 9, 2012

•Pertinent Sections of the Act

–Title VII Section 705 and 706

–Title X Section 506C

•Federal Register Notice


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Title VII Section 705:Risk-based Inspectional Frequency

• Risk Factors

–The compliance history of the establishment.

–The record, history, and nature of recalls linked to theestablishment.

–The inherent risk of the drug manufactured, prepared,propagated, compounded, or processed at theestablishment.


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Title VII Section 705 (cont’)

• Risk-based Inspectional Frequency: Risk Factors (cont’)

–The inspection frequency and history of the establishment,including whether the establishment has been inspectedpursuant to section 704 within the last 4 years.

–Whether the establishment has been inspected by a foreigngovernment or an agency of a foreign government recognizedunder section 809.

–Any other criteria deemed necessary and appropriate by theSecretary for purposes of allocating inspection resources.


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Title VII Section 706: Records for Inspection

• Any records or other information that theSecretary may inspect under this section from aperson that owns or operates an establishmentthat is engaged in the manufacture, preparation,propagation, compounding, or processing of adrug shall, upon the request of the Secretary, beprovided to the Secretary by such person, inadvance of or in lieu of an inspection, within areasonable timeframe, within reasonable limits, andin a reasonable manner, and in either electronic orphysical form, at the expense of such person.


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Title X: Drug Shortages

• Section 506C: Discontinuation or Interruption inthe Production of Life-Saving Drugs

–Discontinuation or Shortage Notification

• 6 Months Prior or as Soon as Practical for:

–Life Supporting Medicines

–Life Sustaining Medicines

–Medicines Used in Prevention or Treatment ofDebilitating Disease


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Title X: Drug Shortages (cont’)• Section 506C-1: Annual Reporting on Drug Shortages

–Requires Annual Reports to Congress starting in 2013

• Specifying the Number of Manufacturers Submitting DrugShortage Notifications

• Describing Communication Between the FDA FieldInvestigators and the Center for Drug Evaluation andResearch’s Office of Compliance and Drug ShortageProgram

• Lists the Major Actions Taken to Prevent or Mitigate theDrug Shortages


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Federal Register Notice 12 Feb 13• Summary: To assist the FDA or Agency in drafting a

strategic plan on drug shortages as required by the FDASIASEC. 506D. COORDINATION; TASK FORCE AND STRATEGIC PLAN

• FDA formed an internal Drug Shortages Task Force (TaskForce) to develop and implement the drug shortagesstrategic plan

• To assist in the evaluation of product manufacturing quality,FDA is exploring the broader use of manufacturing qualitymetrics


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Federal Register Notice (cont’)• Questions Asked of Industry:

– What metrics do manufacturers currently use to monitor productionquality?

– To what extent do purchasers and prescribers use information aboutmanufacturing quality when deciding how to purchase or utilizeproducts?

– What kinds of manufacturing quality metrics might be valuable forpurchasers and prescribers when determining which manufacturers topurchase from or which manufacturers' products to prescribe?

– What kinds of manufacturing quality metrics might be valuable formanufacturers when choosing a contract manufacturer?

– How frequently would such metrics need to be updated to bemeaningful?


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The Guidance


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Nov

PDA CultureMetrics Survey

ISPE PilotAnnounced

ISPE PilotResultsWave 1

PDA MetricConf #2

FDA DraftGuidance(rev 1)

“Metrics ofPotentialInterest”

Feb2013 May Aug Nov

Feb2014 May Aug

Feb2015

BrookingsStakeholder

Meeting

InitialIndustry

Responses

FR NoticeRequestingMetrics to

Prevent DrugShortages

Metrics Journey 2013- 2017

May Aug Nov

PDA MetricConf #3

PDA MetricConf #1

Industry WhitePapersPublished

NovFeb2016 May Aug Nov

Feb2017

FDA DraftGuidance(rev 2)

PDA MetricConf #4

FDATechnicalConformanceGuidance

May

ISPE PilotResultsWave 2

PDA Q CultureAssessment Pilot


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Original Proposed Metrics - 2015

Guidance Details

• Lot Acceptance Rate

• Product Quality Complaint Rate

• Invalidates OOS Rate

• Annual Product Review or ProductQuality Review on Time Rate


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• Measuring Quality Culture

• Measuring Senior Management Engagement

–CAPA Effectiveness

–Process Capability/Performance

Guidance Details (continued)

Optional Proposed Metrics - 2015


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Optional Proposed Metrics - 2015• A “yes” or “no” value of whether the establishment’s

management calculated a process capability or performanceindex for each critical quality attribute (CQA) as part of thatproduct’s APR or PQR.

• A “yes” or “no” value of whether the establishment’smanagement has a policy of requiring a corrective action orpreventive action (CAPA) at some lower process capability orperformance index.

• If “yes” to the above question – what is the process capability orperformance index that triggers a CAPA? If “no” to the abovequestion – please do not respond.



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Current Proposed Metric

•Lot Acceptance Rate

•Product Quality Complaint Rate

•Invalidated OOS Rate



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• Owners and operators of each establishment that is engaged inthe manufacture, preparation, propagation, compounding, orprocessing of a covered drug product, or an API used in themanufacture of a covered drug product, may submit qualitymetrics data.


Who Reports


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Reporting Metrics• Time Span Definition:

–Data segmented on a quarterly basis throughout asingle calendar year.

• Voluntary Reporting

–Participation in this voluntary reporting phase ofthe program also demonstrates a commitment toincreasing transparency between industry andFDA and a contribution to improving qualitymonitoring throughout the industry.



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FDA Use of Metrics• establish a signal detection program as one factor in

identifying establishments and products that may posesignificant risk to consumers;identify situations in which there may be a risk fordrug supply disruption;

• improve the effectiveness of establishment inspections;and

• improve FDA’s evaluation of drug manufacturing andcontrol operations



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Lessons Learned


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PDA’s Quality Metric: Look Back• Organized four conferences focused on Metrics

• Published Metric White Paper

• Provided three sets of Comments

–Original Draft Guidance

–Technical Guidance

–Revised Guidance

• Presented at FDA Public Metric Meeting (‘15)

• Spun off a Quality Culture Task Force

PDA Activities


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PDA Quality Metric Task Force: Future• Remain Nimble and Flexible

• Provide comments / feedback on draft Metric documents

• Continue to support Metric implementation across the industry

–Explore future conference opportunities

–Dialog with FDA on their program

Moving Forward


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Docket Comments


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Comments to Revised Draft GuidanceMarch 2017

• 25 Docket Submissions

–83 to first version of guidance

• 12 Associations

• 10 Individual Firms

• 1 Hospital Group

• 1 Academic Institution

• 1 Individual


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Industry Groups haveIndividual Interests

• Medical Gases, Plasma Products, Excipients, andOTCs, want their products excluded.

• CMOs want to report data to License Holders whowould then submit to FDA.

• BIO

• AAM (formerly GpHA) and PhRMA asking forentire program to pause


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Key Points in PDA Response

• Define success criteria for voluntary phase

• Q&A Document developed to clarify definitions

• Focus on metric/data trends rather than comparisonof absolute values

• Ask FDA to advocate for harmonization efforts

• Recognition list of all voluntary participants


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Common Themes in Docket Responses

• Support for FDA objectives

• Acknowledgement that FDA listened and actedupon industry concerns in second draft

• Revised Draft doesn’t resolve all the issues

• Metrics commonly used by individual firms butchallenges with standardized program

• Many questions on calculations, definitions,datasets


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Reporting by Site or Product

• Site Metrics align with FDA Inspectional Readiness goals

• Product Metrics align with ability to predict and reduce drugshortages

• “The product-related metrics necessary to predict and alleviatedrug shortage situations might be at odds with the site-relatedones that could assess quality at a facility level.”

• “It is unclear how the metrics identified in this Guideline willlead to insights that will help predict, and possibly mitigate, drugshortages.”

• PDA supports reporting by both product and site and thelicense holder be responsible for submission.


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CMO Reporting• Don’t see benefit to their firms

–Don’t file PACs

–Majority of site audits are by clients not FDA

• Some metrics don’t apply to API only sites

• Option of site or product reporting may double theirwork

• Don’t have visibility to metrics in other steps ofsupply chain – i.e. complaints

• Current Quality Agreements will likely need to berenegotiated.


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External Interest in Metrics

• Hospital Organization Docket comment

–“Reviewing a manufacturers’ quality records thatare available is a key component when selectingcontracted vendors for our health systems.”

• Software Vendors with Big Data Systems

–The “JD Powers” for pharmaceuticals


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Internal Use vs. Submission

• Agility: Local metrics defined based on local needs andchange and adapt to process improvement and situations.

• Verification: The requirement for 100% verifiable data withprecision needed for a government submission that isrequired through this initiative would increase human andsystem resources to support it without necessarily addingsignificant additional value.

• Ownership: Quality Unit use of metrics vs. Reg Affairs usein submissions


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Information Disclosure and Security

• Need clarity on whether metrics is considered a“voluntary submission” and therefore protectedfrom FOIA.

• Data reveals production volumes consideredproprietary information

• Concern over electronic security of data withinFDA systems

• Will metrics data be shared with other HealthAuthorities – what are security precautions there?


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• Metrics is a very complex topic, fraught withunintended consequences.

• Trending is most important

• Optimizing a metric program takes time to evolve

• Metrics has to be combined with a strong QualityCulture to be meaningful

• Focusing on a metric can compromise its utility

• Finding forward looking metrics is very difficult

Lessons Learned


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