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Drug and Medical Devices: GMPs
Cathy Burgess, Partner, Alston & Bird LLP
Sarah Spurgeon, Assistant General Counsel, PhRMA
Litigation and
December 910, 2015
Gregory Levine, Partner, Ropes & Gray LLP
Moderated by Jack Garvey, Principal/Chief Executive Officer,
Compliance Architects LLC
Pharmaceutical &
Medical Device GMPs
Traditional Risks • Current Issues • New Initiatives
FDLI Enforcement, Litigation & Compliance Conference
December 9 & 10, 2015
Breakout Session: Wednesday, December 9, 3PM – 4PM
Expert Panelists
Cathy Burgess
Alston & Bird LLP
Sarah Spurgeon
Assistant General Counsel
Greg Levine
Ropes & Gray LLP
Jack Garvey
CEO / Principal
Compliance Architects LLC
Panel Discussion Structure
Part 1: Topical Presentations
• cGMPs – A New Paradigm for Drug Inspection? – Cathy Burgess
• Quality Metrics Draft Guidance – Sarah Spurgeon
• Developments in FDA Regulation of Medical Device Quality –
Greg Levine
Part 2: Structured Panel Questions
Audience Q & A
Part 1:
Current Good Manufacturing Practices
A New Paradigm for Drug
FDLI Enforcement , Litigation
and Compliance Conference
December 9, 2015
Cathy L. Burgess
Legal Background for cGMPS
 Federal Food, Drug, and Cosmetic Act (“FDCA”)
 A drug is deemed to be adulterated if:
 Methods, facilities or controls used
 For the manufacture, processing, packing, or holding of drugs
 Do not conform to or are not operated or administered in conformity with
current good manufacturing practice
 To assure that the drug meets FDA requirements
 For safety, identity, strength, quality and purity
Legal Background for cGMPS
 FDA regulations enforce drug quality through cGMP
regulations (21 CFR parts 210 and 211)
 cGMP regulations mandate proper design, monitoring,
and control of manufacturing processes and facilities
 Regulations first published in 1963
 Significant revisions in 1978. Preamble stated cGMP
regulations were intended to be general enough to apply to a
wide variety of drug products but flexible enough to permit
 Described “what” not “how.” Major changes proposed in 1996
were withdrawn when “Pharmaceutical cGMPs for the 21st
Century” initiative as well underway
 Guidance documents are also used to address application
of cGMPs in specific context, e.g., sterile/aseptic drug
 Guidances are important resources for determining FDA
expectations for cGMPs
New cGMP Authorities – FDA’s “Wake Up
Supply Chain Issues
Despite existing cGMP regulations there have been recurring
issues with the quality of the supplies, components, raw materials
being used in drug manufacturing as well as contract
E.g., heparin contamination –
 Distribution of unsafe products
 Over-sulfated chondroitin sulfate contamination
 Unacceptable risk to patients
 Reports of 149 confirmed deaths and hundreds of injuries
Drug supply chain is global, long, and complex
More than 80% of APIs are manufactured outside the United States
FDA requested new authorities to explicitly address supplier
quality issues
New cGMP Authorities –FDASIA
Title VII
– Sections 701 and 702: “unique facility identifier”
– Section 705: risk-based schedule for inspections
– Section 706: authority to request records before, or
instead of, an inspection
– Section 707: inspection refusal = adulteration
– Section 710: exchanges with foreign regulators
– Section 711: requires oversight and control
– Section 712: foreign government inspection recognition
– Section 713: Shifts burden for imported drugs. FDA no longer
required to meet Section 801 appearance standard.
Information regarding regulatory compliance of product
required before admission
Title X – new authorities to combat drug shortages
Quality Metrics Draft Guidance - Details
 Issued July 2015
 Mandatory Program
 Failure to comply would constitute a prohibited act
 Data collected by product on quarterly basis
 Reporting establishments collect from covered
 Reporting Establishments submit reports annually
 FDA unsure how it will use metrics
 Data: product complaint rate, lot acceptance
rate, invalidated OOS rate, APRs completed w/i
30 days
Quality Metrics Draft Guidance - Concerns
 Statutory Authority under Section 704?
 Requires generation of new records
 Requires submission of data from third party
 Guidance or Substantive Rule?
 Mandatory program
 Enforcement action
 Burden underestimated
 Product v. Site
 Lack of Agreement on Definitions
Quality Metrics Draft Guidance –
Broader Questions
 Data to be collected by product – how will FDA
evaluate site risk?
 Data collected annually – how will this help
mitigate drug shortages?
 Will FDA have adequate resources to evaluate
 How will FDA establish inspection frequency for
establishments with drugs and devices or with
combination products?
 Will Investigators focus on manufacturing
records or on verification of data submissions?
FDA’s Quality Metrics Draft Guidance
Practical Implications
Sarah A. Spurgeon
PhRMA – Assistant General Counsel
Proposed “Required” Quality Metrics
Lot Acceptance Rate = 1 – x (x = the number of specification-related rejected lots in a timeframe
divided by the number of lots attempted by the same establishment in the same timeframe).
Product Quality Complaint Rate = the number of product quality complaints received for the
product divided by the total number of lots of the product released in the same timeframe.
Invalidated Out-of-Specification (OOS) Rate = the number of OOS test results for the finished
product invalidated by the establishment divided by the total number of OOS test results divided
by the total number of tests performed by the establishment in the same timeframe.
Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate = the number
of APRs or PQRs completed within 30 days of annual due date at the establishment divided by
the number of products produced at the establishment
Proposed “Optional” Quality Metrics
Proposed as “Evidence of Manufacturing Robustness and a Commitment to Quality”
•Senior Management Engagement
Was each APR or PQR reviewed and approved by the following:
1) the head of the quality unit; (2) the head of the operations unit; (3) both; or (4) neither?
•CAPA Effectiveness
What percentage of your corrective actions involved re-training of personnel (i.e., a root cause of the deviation is lack of
adequate training)?
•Process Capability/Performance
A “yes” or “no” value of whether the establishment’s management calculated a process capability or performance index
for each critical quality attribute (CQA) as part of that product’s APR or PQR.
A “yes” or “no” value of whether the establishment’s management has a policy of requiring a corrective action or
preventive action (CAPA) at some lower process capability or performance index.
If “yes” to the above question – what is the process capability or performance index that triggers a CAPA? If “no” to the
above question – please do not respond.
Quality Data To Be Reported
The number of lots attempted of the product.
The number of specification-related rejected lots of the product, rejected during or after
3. The number of attempted lots pending disposition for more than 30 days.
4. The number of OOS results for the product, including stability testing.
5. The number of lot release and stability tests conducted for the product.
6. The number of OOS results for lot release and stability tests for the product which are invalidated
due to lab error.
7. The number of product quality complaints received for the product.
8. The number of lots attempted which are released for distribution or for the next stage of
manufacturing the product.
9. If the associated APRs or PQRs were completed within 30 days of annual due date for the
10. The number of APRs or PQRs required for the product.
PhRMA Comments: Key Themes
• PhRMA supports the development of a quality metrics program that
will permit the Agency to
Optimize its approach to risk-based inspection frequency
Create timely pathways for managing post-approval mfg. changes without extensive
regulatory oversight
• Supports an initially voluntary, phased approach to implementation
Industry/Agency Burden Underestimated
Need to Further Refine Definitions and Understand FDA’s Plans for Data Analysis
Any “mandatory” scheme legally requires formal rulemaking
Data should be considered “confidential commercial information”
No support for public ranking system
Industry & Agency Burden
Estimated Burden
• Using information from “experts,” FDA estimates an average industry burden per
response of 10.6 hours for compiling information that is “currently developed and
maintained” and for populating spreadsheet(s) necessary for reporting
• FDA expects to receive 63,000 product reports containing the 15 quality metrics data
outlined in this document and described in the draft guidance
Weaknesses and Problems with Estimate:
– Individual firms may not track the information in requested format
– Especially more burdensome if require reporting on a “by product” basis
– Need more information on how QM data would reduce inspection frequency—
potentially offsets burden
– FDA provides no information on tools it will use to process this volume of data
Industry Burden
Example #1:
Invalidated Out-of-Specification (OOS) Rate = #OOS test results for the product invalidated by the
establishment divided by the total number of OOS test results divided by the total number of tests performed
by the establishment in the same timeframe
Possible Firm Practice: A MAH may have a centralized release and stability facility. In this case, OOS data
may not be collected separately for each manufacturing site. Reporting this aggregated data could skew
FDA’s risk conclusions for each manufacturing site that feeds into this centralized data collection facility.
Example #2:
Lot Acceptance Rate = 1 – x (x = the number of specification-related rejected lots in a timeframe divided by
the number of lots attempted by the same establishment in the same timeframe).
Possible Firm Practice: A manufacturer’s enterprise resource planning (ERP) data structure may not allow
for identification of lots specifically manufactured for the U.S. market as required. Costs to restructure ERP
systems to accommodate such segmentation of QM data will be significant.
Feedback on Metrics
Supports With Refinements
Invalidated Out-of-Specification (OOS) Rate
Lot Acceptance Rate
Product Quality Complaint Rate
Certain Optional, Survey Style Metrics Including
A metric relating to Process Capability and Performance
A metric related to Measuring Review of APRs/PQRs by Management
Does Not Support:
Annual Product Review (APR) or Product Quality Review (PQR) on Time
Of limited value, especially during expected implementation challenges during initial phase
Optional metric regarding CAPA effectiveness
Developments in FDA Regulation of
Medical Device Quality
Greg Levine
Partner & Co-Chair of Life Sciences Practice,
Ropes & Gray LLP
Developments in FDA Regulation of Medical
Device Quality
• Device Quality Challenges
• Recent FDA Initiatives
• What to Expect
Device Quality Challenges
• Increasing device complexity and rapid innovation
• Supply chain globalization and complexity
• Ever-increasing number of regulated firms, devices, adverse event
reports, recalls
• Finite FDA resources
• Cost and time to market pressures within industry
• Limitations on quality metrics/visibility of comparative quality
FDA Report, “Understanding Barriers to Medical Device Quality” (Oct. 2011)
Recent FDA Initiatives and Actions
Voluntary compliance Improvement Program (VCIP) Pilot
International Programs
Critical-to-Quality (CTQ) Initiative
Program Alignment Initiative
Unique Device Identifiers
Consent Decree Actions
Voluntary Compliance Improvement Program (VCIP) Pilot
• Launched in December 2013
• 3-5 manufacturers may participate
– Limited to manufacturers of class II devices that are non-life saving and non-life
• Alternative to surveillance inspections
– Manufacturers self-identify and correct deficiencies
– FDA meets regularly with participants to review their analyses, consider
corrective actions identified, and evaluate efficacy of those actions
– Participants must retain an expert consultant to monitor and certify they have
defined problems, analyzed root causes, and taken effective corrective action
• No public updates on status of program, participation, or results
International Programs
• IMDRF Medical Device Single Audit Program (MDSAP) Pilot
– FDA began participating in January 2014
– Allows a single audit to satisfy requirements of all regulatory authorities
participating in the pilot program
– Participating nations include U.S., Australia, Brazil, Canada, and Japan
– August 2015 status report : August 2015 status report: 10 audits completed
• Other international initiatives
– Permanent offices in China, India, Europe, Latin America (since 2008/2009)
– Participation in International Medical Device Regulators Forum (IMDRF) with
regulators from Australia, Brazil, Canada, China, EU, Japan, and Russia
– Information sharing with international regulatory authorities through trainings,
scientific and policy discussions, confidentiality commitments
Critical-to-Quality (CTQ) Initiative
• FDA launched Case for Quality in 2011 with three core components:
– Critical-to-Quality initiative
– Enhanced data transparency
– Stakeholder engagement
• Battery-powered implantable device CTQ pilot
– Completed inspection pilot involving 4 manufacturers
– Inspections focused on critical-to-quality factors (developed with input from
CDRH/ORA and stakeholders)
• FDA plans to shift strategy to issuing CTQ guidances
– 13 product-specific CTQ information documents developed to date (e.g., implantable
spine devices, semi-constrained knee implants, defibrillator leads, infusion pumps)
– CTQ guidances will be available to public as well as investigators; will serve as a
resource for traditional QSIT audits
Program Alignment Initiative
• Initiative announced in 2013 to reorganize ORA to create teams of
specialized investigators by product type (e.g., device inspectorate)
– Sub-specialties within device inspectorate to be developed over time; will
include sub-specialty in radiological health and Mammography Quality
Standards Act (MQSA)
• Action plans developed by each respective center and ORA
• ORA/CDRH 2015 action plan includes
– Establish baseline of staff involved in device and radiological health activities
– Develop plan for establishing device and MQSA inspectorates
• Work in progress; timing of reorganization not yet announced
Unique Device Identifiers (UDI)
• 2013 regulation established unique device identification system
– Requires UDIs on device labels and packages (and directly on multiple use
devices) with limited exceptions
– Device labelers must submit information to FDA’s Global Unique Device
Identification Database (GUDID)
• Potential quality/safety benefits
– Ability to identify and correct problem devices more quickly
– Standardized identifier to facilitate recalls
– Foundation for a more secure global distribution chain
• System goes into effect in stages over 7 years, from 2014-2018
• 5 UDI guidances/draft guidances issued in 2014/2015
• Case for Quality transparency strategy
– Publish releasable quality data to permit independent analyses by stakeholders
– Conduct and publish analyses of quality-related data
• Launch of in June 2014
– Release of extensive device data in August 2015 including data on device
classifications, registrations, listings, recalls, and adverse events
– Intended to be flexible platform for easier access and searching of data
• Medical Device Metrics
– Joint FDA/Xavier Health initiative to develop, pilot, and publicize defined product
quality metrics for devices
– Metrics developed in 2015 to be piloted in Q4 2015/Q1 2016
Consent Decree Actions
• Maquet consent decree (Feb. 2015)
– Atrium may continue to distribute certain products deemed medically necessary if
customer signs a certificate of medical necessity
• Medtronic consent decree (Apr. 2015)
– Contains exception to prohibition on manufacturing and distribution of Synchromed II
Implantable Infusion Pump Systems where the device is used to treat certain
enumerated conditions and a physician completes a certificate of medical necessity
• Custom Ultrasonics
– Under 2007 consent decree, FDA ordered a recall of all automated endoscope
reprocessors (Nov. 2015)
What Should Manufacturers Expect: One Outside
FDA is challenged by the dynamic forces of innovation, globalization,
industry economic pressures, and limited agency resources
Agency is searching for ways to make the most effective use of its finite
Initiatives to date are preliminary and have limited scope and applicability
For the immediately foreseeable future, most firms should expect business
as usual
Despite challenges facing FDA and pressures affecting industry,
manufacturers that emphasize quality are more likely to reduce the risks of
regulatory enforcement, recalls, adverse publicity, and litigation
Part 2:
Pharmaceutical Metrics
• What is missing in the current regulatory oversight framework that
this new initiative is necessary?
• Do the FDASIA metrics authority provisions pertain only to
pharmaceutical manufacturers?
– Are CDER and CDRH collaborating at all on their respective initiatives?? If
not, why not?
– Do the benefits and possible concerns about metrics differ between devices
and drugs?
• Is FDA’s Guidance “binding” on Industry?
– When FDA requests the information, does the company, by law, have to
provide it?
– If so, what could the penalties be for non-compliance?
– Could a Notice of Refusal be issued for failure to provide requested
• How might FDA use the provided information?
– Could FDA issue a FDA Form 483 based solely on the information provided?
– What if a company provides incorrect or inaccurate information?
The “Yates Memo”, Individual Accountability &
Current Enforcement Focus
The “Yates Memorandum” (DOJ Deputy Attorney General Sally Yates, 9/9/15) reiterated
and expanded upon DOJ’s long-standing position that individual accountability for acts
of corporate malfeasance will be pursued to incentivize proper corporate behavior, and
hold the proper parties responsible for their actions.
Is the Yates Memorandum substantively different, and impactful, or, is it
much ado about nothing relative to traditional DOJ enforcement approach?
What impact do you expect the Yates memo to have on drug and device
firms more broadly, if any?
Are there any current FDA enforcement areas, i.e., dietary supplement
claims, pharmacy compounding, pharmaceutical data integrity, etc. that
create more risk for individual executives or employees under the Yates
approach and traditional DOJ enforcement approach?
Compounding Response to
Pharmaceutical Price Concerns
In response to Turing Pharmaceutical’s price increase to $750/tablet for Daraprim,
Imprimis Pharmaceuticals “announced a program available throughout the United
States. [sic] which would work with third party insurers, pharmacy benefit managers and
buying groups to provide these compounded drug formulations at lowered prices.”
(Imprimis website, emphasis added)
Is this action legal? Doesn’t this action, by definition, turn Imprimis into a
“manufacturer” of Daraprim, regardless of whether Imprimis claimed orders
were individual requests?
If this action is legal, which manufacturing requirements should apply:
those that currently apply to pharmaceutical “compounders” or traditional
cGMPs under 21 CFR 211 that apply to pharmaceutical “manufacturers”?
How widespread do you expect this practice to become?
FDA Medical Device Single Audit Program
The MDSAP audit process was designed and developed to ensure a single audit will provide
efficient yet thorough coverage of the requirements of medical devices. FDA will accept the
MDSAP audit reports as a substitute for routine Agency inspections. Developed under
International Medical Device Regulators Forum (IMDRF) cooperation. Pilot in process to 31 Dec
Are there limits to how far can international harmonization can go? When it comes to
enforcement, what are the limits?
What is the legal authority for a “Single Audit Program”, specifically to include possible
enforcement actions based on non-US FDA inspectors? FDASIA §610? Presumably the Chief
Counsel has opined in the affirmative on this program – is there any indication legal authority is
not valid?
How would courts possibly view legal challenges to enforcement actions based on non-US
inspectors, and non-QSR citations?
Do you see any other practical issues for FDA’s desire to implement the Single Audit Program?
If this approach does not work, what are the alternatives?
New Pharmaceutical
Inspection Protocol Project
FDA is developing a new model for assessing plant operations based on standardized measures of a
facility’s state of quality and compliance. The project will apply to pre-approval, GMP surveillance, and
for-cause inspections. CDER OPQ is developing the new protocols and planning pilot NIPP
inspections with ORA. Stated objectives:
to obtain quantitative scores that can help compare sites, and reduce variability in observations by
different Investigators;
to provide manufacturers with a clearer idea of what they need to do to maintain quality.
Do you believe this will:
• Make pharmaceutical inspections more efficient and improve outcomes for
• Generally extend pharmaceutical inspections, requiring deeper analysis of technical
and compliance decision making and data, and resulting in tougher inspections and
worse outcomes? or
• A little of both – more balanced and efficient, with better outcomes for prepared
manufacturers and worse outcomes for unprepared manufacturers?

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