ACI’s 27th FDA Boot Camp

Current Good Manufacturing Practices

Kirsten V. Mayer

Ropes & Gray LLP

Kirsten.Mayer@ropesgray.com

March 11, 2016

What are cGMPs?

• The processes by which a medical product is manufactured

•Applies to the entire lifecycle of the medical product

• Design Production Oversight

• Premarket Postmarket

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General cGMP Processes

• Management Oversight

• Design

• Production

• Change Control

• Labeling/Packaging

• Storage/Handling

• Nonconforming Product

• Complaint Handling 3

Premarket to Postmarket CompliancecGMP deficiencies regularly lead to FDA regulatory action

• Premarket: • Clinical Investigation: FDA disapproval, hold, or termination of

an investigation of a medical product

• Premarket Submission: FDA disapproval of a premarket submission

• Postmarket:• Violation Letter (Untitled Letter, Warning Letter)

• Seizure

• Injunction

• Criminal Prosecution4

FDA’s cGMP Philosophy

• Quality, safety, and effectiveness must be designed and built into a product

• Potential product defects cannot be determined solely upon finished product inspection

• Each cGMP process and step must be controlled to maximize the chances that the finished product will meet product specifications

• The purpose of cGMP is to prevent product defects by controlling the manner of production

• Most FDA inspections focus on GMP compliance

• Many voluntary product recalls and market withdrawals result from issues with cGMPs

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Demonstrating cGMP Compliance• Establish standard operating

procedures (SOPs) governing each step of the manufacturing process

• Implement SOPs

•Document compliance with and deviation from SOPs

•Retain documentation/records6

Legal Authority

• Under the Federal Food, Drug, and Cosmetic Act (FDCA) and implementing regulations, drugs, biologics, devices, and combination products are required to be manufactured in accordance with cGMPs

• Methods used in, and the facilities and controls used for, the manufacture, processing, packing, or holding conform to current good manufacturing practice to assure that the medical product will be safe and effective

• Noncompliant product is “adulterated” under 21 U.S.C. §501

• Applicable regulations:• Drugs: 21 CFR Parts 210, 211

• Devices: 21 CFR Part 820

• Biologic Products: 21 CFR Parts 600-680

• HCT/Ps: 21 CFR Part 1271

• Combination Products: 21 CFR Part 4

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General Principles of cGMPs

• Apply to “manufacturers”• Any party that designs, manufactures, fabricates, assembles, or

processes finished device

• Contract sterilizer

• Installer

• Relabeler

• Remanufacturer

• Repackager

• Specification developer

• Holder

• Initial distributor of foreign entities

• Allows a manufacturer only engaged in certain operations to comply with only those regulations applicable to the specific operations

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General Principles of cGMPs

• Can use “contract manufacturing organizations”

• Bears ultimate responsibility

• If company serves as the specification developer, still a “manufacturer” - subject to certain QSR, such as design controls

• Generally applies to finished devices

• Control ingredients/materials through: • Receiving activities

• Purchasing controls

• Vendor/supplier evaluation

• Validation/verification processes 9

General Principles of cGMPs

• Flexible, not prescriptive

• SOPs and processes must be adequate, robust, and satisfy the cGMP objective (e.g., internal audit, labeling) to ensure safety and effectiveness

• Relatively broad standards address and apply equally to wide range of regulated products

• For example, one set of cGMP rules applies to dental fillings and to heart valves

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Common cGMPs

Management

Production/

Process Control

Buildings/

Equipment

Addressing Deficiencies

Packaging/

Labeling

Records/

Reports

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cGMPs

Organization/

PersonnelEquipment

Buildings/

Facilities

Control of Components

Control of Drug Product Containers

and Closures

Corrective and Preventive Action

Purchasing Controls

Production/Process Controls

Packaging/

Labeling Control

Holding/

Distribution

Laboratory

Controls

Design Controls

Records/Reports

Returned/

Salvaged Products

Common

Drug

Device

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Unique Drug cGMPs

• Testing and approval or rejection of components, drug product containers, and closures (21 CFR 211.84)

• Calculation of yield (21 CFR 211.103)

• Tamper-evident packaging requirements for over-the-counter (OTC) human drug products (21 CFR 211.132)

• Expiration dating (21 CFR 211.137)

• Testing and release for distribution (21 CFR 211.165)

• Stability testing (21 CFR 211.166)

• Special testing requirements (21 CFR 211.167)

• Reserve samples (21 CFR 211.170)13

Common Drug cGMP Problems

• Investigating and correcting discrepancies or defects (21 CFR 211.192)

• Micro-controls for sterile & non-sterile (21 CFR 211.113)

• Stability program (21 CFR 211.166(a))

• Process design & qualification (validation) (21 CFR

211.100(a))

• Establishing and following sound tests and sampling plans (21 CFR 211.160)

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From July 2015 presentation Carmelo Rosa, FDLI, Understanding cGMPs – What Attorneys Need to Know (Current Regulatory/Inspection Issues Related to Supply Chain)

Unique Device cGMPs (QSR)

•Management responsibility (21 CFR 820.20)

•Design controls (21 CFR 820.30)

•Purchasing controls (21 CFR 820.50)

•Corrective and preventive action (21 CFR 820.100)

• Installation (21 CFR 820.170)

• Servicing (21 CFR 820.200) 15

Device Verification v. Validation

• Verification - confirmation by examination and provision of objective evidence that specified requirements have been fulfilled

• Validation - confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled

• Process validation - establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications

• Design validation - establishing by objective evidence that device specifications conform with user needs and intended use(s) 16

Common Device cGMP Problems•Design validation (21 CFR 820.30(g))

•Design verification (21 CFR 820.30(f))

•Corrective and preventive action (21 CFR

820.100)

•Recordkeeping (21 CFR 820.180)

•Complaint files (21 CFR 820.198)

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cGMP FDA Oversight• Inspection by District Office

• Domestic• New York (NY)• New England (CT, MA, ME, NH,

RI, VT)• Baltimore (MD, VA, WV,

Washington DC)• Chicago (IL)• Philadelphia (DE, PA)• Minneapolis (MN, ND, SD, WI)• Cincinnati (OH, KY)• Detroit (IN, MI)

New Jersey (NJ)

• International• China (Beijing)• India (New Delhi)• Europe (Brussels)• Latin America (Costa Rica)

• Submitted data reviewed by Center

• Atlanta (GA, NC, SC)• Florida (FL)• New Orleans (AL, LA, MS, TN)• San Juan (Puerto Rico)• Seattle (AK, ID, MT, OR, WA)• Los Angeles (Southern CA, AZ)• San Francisco (Northern CA, HI,

NV)• Denver (CO, NM, WY, UT)• Dallas (AR, TX, OK)• Kansas City (KS, IA, MO, NE)

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FDA cGMP Inspections

• Global • Domestic (can partner with states) • International (can partner with foreign authorities)

• Premarket • Inspect clinical investigation site• Site inspection as part of premarket review process

• Postmarket• Routine cGMP inspection• "For cause" inspection

• Follow-up of previous violative inspection • Recall• Consumer complaints • Competitor complaints

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FDA’s Inspectional Procedures

• Enter at reasonable times

• Inspect within reasonable limits and in a reasonable manner, "upon presenting appropriate credentials and a written notice to the owner"

• Access and copy any FDA-required records or documentation

• May request certain documentation in advance of physical inspection

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Typical cGMP Inspection Activities•Document review, employee

interviews, observations of operations

• Efforts to resolve potential cGMP observations

•Presentation of FDA Form 483 and "discussion with management"

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Post-Inspection Activities• Issuance of 483• FDA classification of inspection as NAI, VAI, OAI• District office reviews evidence and any firm 483

response• Direct issue: regulatory meeting, UL, WL• Center concurrence:• Certain cGMP ULs, WLs

• CDER: API deficiencies; dosage forms• CBER: therapeutic biologic products• CDRH: pre-approval inspections

• Stronger enforcement actions • Could also involve ORA, OCI, OCC

See Regulatory Procedures Manual Chapter 4, “Advisory Actions”

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Potential Consequences of cGMP Violations• Failure to approve/authorize

investigational application

• Terminate/clinical hold

clinical investigation

• Disapprove marketing

authorization

• FDA Form 483

• Regulatory meetings

• Recall

• Untitled or Warning Letter

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• Voluntary shutdown

• Import refusal

• Administrative detention

• Consent decree of permanent injunction

• Product seizure

• Withholds for pending applications

• Withdraw approved applications

• Criminal prosecution

• False Claims Act

Timing of Warning Letters

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Globalization: Shift to Foreign Suppliers• Massive supply shift for FDA-regulated products

• 650% increase between 1990-2005

• More than 150 exporting countries

• More than 300 U.S. ports of entry

• ~80% of drug ingredients are of foreign origin

• Increased sourcing from developing countries

• China and India are largest sources of drug ingredients

• Pharmaceutical imports from China more than doubled from 2002-2007, to $698 million

• Pharmaceutical imports from India increased 2,400% from 1996-2006

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Globalization: Growth in Foreign Establishment Warning Letters

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FCA–driven enforcement of cGMP

• Historically, not many False Claims Act cases in this area – where they were brought, they were typically pursued on a “worthless” goods theory

• GSK (Cidra 2010) settlement was significant in terms of dollars ($750 million), but FCA theory was within then-existing framework

• Recent civil cases sought – largely unsuccessfully -- to expand the use of the FCA to police CGMP or QSR compliance more broadly

• US ex rel Ruhe et al v. Masimo Corp. (9th Cir)

• Diagnostic device; not intervened

• Motion for Summary Judgment granted; 9th Cir. Affirmed 2016

• US ex rel Rostholder v. Omnicare Inc. et al (4th Cir)

• Pharmacy repackaging; not intervened

• Motion to dismiss granted; 4th Cir. Affirmed 2014; SCOTUS denied cert.27

FCA–driven enforcement of cGMP

• However, recently DOJ has pitched a different analytic framework for evaluating potential cGMP liability under the FCA • US ex rel Campie v. Gilead (9th Cir)

• Not intervened but US filed amicus in pending 9th Cir appeal

• The Supreme Court has also weighed in on FCA liability for the first time in many years – the implications of this case for cGMP have yet to be explored• Universal Health Services v. US ex rel Escobar (2016)

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Sources of Additional cGMP Information• Proposed and Final Rules

• Preambles

• Guidance Documents• FDA draft and final guidances

• ICH, ISO or other international guidelines or standards recognized, referenced, or adopted by FDA

• Other FDA Pronouncements• 483s, Establishment Inspection Reports, Warning Letters, Injunctions

• Recall information

• FDA statements at meetings/seminars/workshops, including published proceedings

• FDA's Compliance Program Guidance Manual

• FDA's Compliance Policy Guides Manual

• FDA’s Regulatory Procedures Manual

• FDA’s Investigations Operations Manual29

Questions?

Kirsten MayerRopes & Gray LLP

617-951-7753kirsten.mayer@ropesgray.com

Abram BarthRopes & Gray LLP

202-508-4895abram.barth@ropesgray.com

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