Overview of FDA Drug Manufacturing Requirements

Solving FDA Legal Challenges for the Life of a Life Sciences Company 1 www.fdacounsel.com
LAW OFFICES OF MICHAEL A. SWIT
Overview of Drug Manufacturing
Requirements
Michael A. Swit, Esq.
Vice President, Life Sciences
Presentation to the Food & Drug Law Institute
Introduction to Drug Law Course
July 25, 2018
South San Francisco, California

Standard Disclaimers
• Views expressed here are solely mine and do not reflect those of my
firm or any of its clients.
• This presentation supports an oral briefing and should not be relied
upon solely on its own to support any conclusion of law or fact.
• These slides are intended to provide general educational information
and are not intended to convey legal advice.

Agenda
• Establishment Registration and Drug Listing
• Current Good Manufacturing Practices (cGMPs)
• Inspections
– Types
– Conducting
– Responding
– Refusal to permit inspection
• Violations
– Adulteration
– Misbranding

Establishment Registration
and Drug Listing

Why Registration & Listing?
• Legal source -- Section 510 of the Federal Food, Drug, and Cosmetic Act (“the
Act”):
– firms that manufacture, repack, relabel, or salvage drugs (colloquially: “make”) in the U.S. or that are
offered for import into the U.S. must
• register their drug establishment; and
• list all drugs that they make
– foreign firms also must identify a U.S. agent and their importers at time of registration
– private label distributors – exempt, but can submit on behalf of those who make for them
• Recent regulation revisions –
– August 31, 2016 Final Rule on Registration and Listing [“Hot Link”]
– 21 CFR Part 207 -- Registration and Listing (as amended) [“Hot Link”]
• Why registration & listing are needed – helps FDA with key programs such as:
– post-marketing surveillance -- User fee assessments
– monitoring drug shortage -- Identifying unapproved drugs in
– inspections market

Registration
• Timing
– within 5 days of introducing first product into commerce
– annually thereafter between Oct. 1 and Dec. 31
• Must be done electronically, unless waived
– 2009 Guidance on electronic filing – “Providing Regulatory Submissions in
Electronic Format – Drug Establishment Registration and Drug Listing”
• Registration information includes (not exhaustive)
– Unique Facility Identifier (UFI) – DUNS # is preferred;
• Guidance: Specification of the Unique Facility Identifier (UFI) System for Drug
Establishment Registration
– Point-of-contact e-mail address

Registration – Key Definitions – 21 CFR 207.1
• Manufacture means each step in the manufacture, preparation, propagation, compounding, or processing of a drug or an animal
feed bearing or containing a new animal drug. Manufacture includes the making by chemical, physical, biological, or other procedures
or manipulations of a drug, or an animal feed bearing or containing a new animal drug, including control procedures applied to the
final product or to any part of the process. Manufacture includes manipulation, sampling, testing, or control procedures applied to
the final product or to any part of the process, including, for example, analytical testing of drugs for another registered
establishment's drug. For purposes of this part, and in order to clarify the responsibilities of the entities engaged in different operations, the term
manufacture is defined and used separately from the terms relabel, repackage, and salvage, although the term “manufacture, preparation, propagation,
compounding, or processing,” as used in section 510 of the Federal Food, Drug, and Cosmetic Act, includes relabeling, repackaging, and salvaging
activities. [Italics added]
• Relabel means to change the existing label or labels on a drug or drug package, or change or alter the existing labeling for a drug or
drug package, without repacking the drug or drug package. This term does not include the addition or modification of information
affixed solely for purposes of delivery to a customer, customer identification, and/or inventory management.
• Repack or repackage means the act of taking a finished drug product or unfinished drug from the container in which it was placed
in commercial distribution and placing it into a different container without manipulating, changing, or affecting the composition or
formulation of the drug.
• Salvage means the act of segregating out those finished drug products that may have been subjected to improper storage conditions
(such as extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation) for the purpose of returning the products to
the marketplace and includes applying manufacturing controls such as those required by current good manufacturing practice in
parts 210 and 211 of this chapter.

Registration …
• Exempt from Registration
– Pharmacies that:
• Operate in conformance with all applicable local laws regulating the practice of pharmacy and medicine;
• Regularly engage in dispensing prescription drugs upon a valid prescription; and
• Do not manufacture, repack, relabel, or salvage drugs other than in the regular course of their business of dispensing or
selling drugs at retail.
– Hospitals, clinics, other health care entities, and public health agencies that:
• Operate establishments in conformance with all applicable local laws regulating the practice of pharmacy and medicine;
• Regularly engage in dispensing prescription drugs upon a valid order or prescription;
• Do not manufacture, repack, relabel, or salvage drugs other than in the regular course of their practice of pharmacy,
including dispensing;
– Practitioners who are licensed by law to prescribe or administer drugs and who manufacture, repack,
relabel, or salvage drugs solely for use in their professional practice;
– Manufacturers, repackers, relabelers, or salvagers who manufacture, repack, relabel, or salvage drugs solely for
use in research, teaching, or chemical analysis and not for sale;
– Manufacturers, repackers, and relabelers of harmless inactive ingredients such as excipients, colorings,
flavorings, emulsifiers, lubricants, preservatives, or solvents that become components of drugs;
– Carriers, in their receipt, carriage, holding, or delivery of drugs in the usual course of business as carriers; and
– Storage facilities which do not perform any manufacturing function.

Generic Drug Facility Fees
• Generic Drug User Fee Act (GDUFA) -- if drug referenced in at least one approved
ANDA
• Key to abbreviations:
– API = Active Pharmaceutical Ingredient manufacturer – if named in one approved ANDA
– FDF = Finished Dosage Form mfr.
– CMO = Contract Manufacturing Organization – if named in one approved ANDA, but that company does not own the ANDA
– Due -- annually on first business day after October 1 (federal fiscal year starts on 10/1)
– “Manufacturer” – includes packagers that package drug into containers described in “How Supplied” part of labeling
• Fail to pay – no ANDA involving the facility will be “received” (thus, not reviewed)
• Brand name establishments – no fee; did exist under prior User Fee laws; eliminated with 2017 FDARA
Facility Domestic API $45,367
Foreign API $60,367 (+$15,000 over domestic)
Domestic FDF $211,087
Foreign FDF $226,087 (+$15,000 over domestic)
Domestic CMO $70,362
Foreign CMO $85,362 (+$15,000 over domestic)

Listing
• Timing
– within 3 days of initial registration of facility
– updates every June and December, although FDA recommends they be done immediately
– If no changes to one or more of your listings during calendar year, must submit a Product
Listing Certification – between Oct. 1 and Dec. 31 – that no changes made for those drugs
• required under 2016 Regulation revisions
• Product Listing Certification Guide
• If fail to certify or update a listing during calendar year, the drug listing will be considered expired
as of January 1 of the next calendar year.
• NDC Number – unique number assigned by listing party to each drug
subject to listing. Consists of:
– Labeler code – unique to listing party and assigned by FDA
– Product code – unique to drug in question and assigned by listing party
– Package code – unique to listing party and assigned by them

Listing …
• Information required for listing:
– Full 10-digit NDC
– Proprietary and non-proprietary name (generic drugs may use the non-proprietary name for
both)
– Dosage form and route of administration
– The name (with unique ingredient identifier or UNII code) and amount/strength (with
appropriate unit of measure e.g. grams, milliliters, etc.) of each active ingredient
– Each inactive ingredient (name and UNII) only
– A copy of the most up-to-date labeling, including a JPG file of the outer packaging and
principal display panel – submitted in “Structured Product Labeling” or “SPL” format
• Guidance to industry: Providing Regulatory Submissions in Electronic Format - Content of
Labeling (Final)
• Guidance for Industry: SPL Standard for Content of Labeling Technical Questions and Answers
• More info at:
https://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
– The name and DUNS number for each establishment involved in manufacturing drug

current
Good Manufacturing Practices
(cGMPs)

GMPs -- Statutory and Regulatory Sources
• Statute --
– Section 501(a)(1)(B) of the Act provides:
A drug or device shall be deemed to be adulterated—
(a)POISONOUS, INSANITARY, ETC., INGREDIENTS; ADEQUATE CONTROLS IN MANUFACTURE
(1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it has been
prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or
whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the
facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are
not operated or administered in conformity with current good manufacturing practice to assure that such
drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the
quality and purity characteristics, which it purports or is represented to possess; or
• Regulations
– Promulgated on September 29, 1978 – at 43 Fed. Reg. 45077
– 21 CFR Part 210
– 21 CFR Part 211
• Note – is adulterated even if the drug meets its release specs – basic
concept -- you won’t be able to replicate quality if don’t meet GMPs

GMPs -- Main Subparts
• Subpart A—General Provisions
• Subpart B—Organization and Personnel
• Subpart C—Buildings and Facilities
• Subpart D—Equipment
• Subpart E—Control of Components and Drug Product Containers and
Closures
• Subpart F—Production and Process Controls
• Subpart G—Packaging and Labeling Control
• Subpart H—Holding and Distribution
• Subpart I—Laboratory Controls
• Subpart J—Records and Reports
• Subpart K—Returned and Salvaged Drug Products

Selected Key “Drug-Specific” Provisions
• §211.103 Calculation of yield.
• §211.132 Tamper-evident packaging requirements for over-the-counter
(OTC) human drug products.
• §211.137 Expiration dating.
• §211.166 Stability testing.

The Barr Case
• 1993 -- seminal case construing drug GMP provisions
https://law.justia.com/cases/federal/district-courts/FSupp/812/458/1762275/
• The Decision – key points
– 3 types of out-of-specifications results seen (Finding 19 or “F-19)):
• laboratory error
• non-process related – operator error
• process-related – manufacturing error
– Goal of GMP failure investigation – to determine what type of error occurred;
“degree of inquiry may vary with object under investigation” (F-24)

The Barr Case
• Contents of a failure investigation (F-30) …
– reason for investigation
– summarize the process steps that may have caused the problem
– outline corrective actions needed to save the batch (if possible) and prevent recurrence
– list other batches and products possibly affected and results of their investigations
– preserve comments and signatures of all production and quality personnel involved
– Timing: court -- should be done within 30 business days of occurrence (F-32)
• Outlier testing – most appropriate for biologics and antibiotics; rarely for
chemical drugs (F-35)
– should not be used to invalidate content uniformity testing (O-4)

The Barr Case
• Retesting
– only appropriate after an investigation begins (F-38)
– necessary if investigation indicates lab analyst error caused initial OOS results or
review of analyst’s work is inconclusive (F-38)
– inappropriate if the error is viewed as “non-process” (i.e., production operator) or
“process” (i.e., the manufacturing instructions themselves) related
– how much retesting can be done is a matter of scientific judgment (F-40), but cannot
continue ad infinitum (F-41).
• Rather, testing SOP should contain a (justified) point where retesting is cut off and batch
is rejected (F-41)
• Resampling – appropriate if allowed by USP or if investigation suggests
original sample was not representative (F-44)

The Barr Case
• Remixing – ok at blending stage (F-46) if done on occasion (F-47), but not
to replace a bad process
• Averaging – allowed in certain situations (F48-51)
• Release testing – can involve some exercise of appropriate scientific
judgment, but court “cannot articulate” specific procedures (F52-57)
• Blend testing – important because finished product testing is more limited
in nature (F-58)
– sample size –
• content uniformity – 3x dosage size (F-65)
• blend potency – can be larger (F-67)
– sample site – either mixer or drum – but choice must be representative of the whole
blend (F-70)

The Barr Case
• Retrospective validation
– must include all batches, failed and passing, in the review unless can show the batch is
not representative of the process – e.g., an older process (F-93)
• Barr – tried to argue that it could do a retrospective validation with fewer batches. Court
declined to adopt that specifically, but also declined to set a minimum number (F-103)

Barr …
• Key Lessons:
– Can’t test your way into compliance – a theme that continues to today (e.g,. Akorn
allegations)
– Record keeping – must be in lab notebooks or other official records; not on “scrap”
paper or Post-its
– Not a defense that defective procedures were approved in a new drug application
– Recall order – can be a part of equitable relief in a quality-related injunction
proceeding

FDA Policies on GMPs
• CPG Sec. 400.200 Consistent Application of CGMP Determinations
– POLICY:
• CGMP deficiencies supporting a regulatory action also support decisions regarding non-
approval of drug marketing applications, government purchasing contracts, candidates for
MAC, etc. Therefore, the issuance of a *warning* letter or initiation of other
regulatory action based upon CGMP deficiencies must be accompanied by
disapproval of any pending drug marketing application, or government contract
for a product produced under the same deficiencies.
• Similarly, disapproval of any drug marketing application, government contract, etc.,
based upon CGMP deficiencies must be accompanied by regulatory and/or
administrative action against any other product produced under the same
conditions.
[Emphasis added]

The Future
• 1978 – “current” GMPs
• 21st Century – the Quality System
– September 2004 – FDA Final Report on “Pharmaceutical CGMPs for the 21st
Century – A Risk-Based Approach
• Final Guidances
– Process analytical technology (PAT) — A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance (9/2004)
– Sterile Drug Products Produced by Aseptic Processing — Current GMP (9/2004)
– “Quality Systems Approach to Pharmaceutical CGMP Regulations” (9/2006)
• But, regulations still are from 1978 – will they ever be changed?

Inspections

Authority -- § 704(a)(1) of the Act
• “ … officers or employees duly designated by the Secretary, upon presenting appropriate credentials and a
written notice to the owner, operator, or agent in charge, are authorized (A) to enter, at reasonable times, any
factory, warehouse, or establishment in which food, drugs, devices, tobacco products, or cosmetics are
manufactured, processed, packed, or held, for introduction into interstate commerce or after such
introduction, or to enter any vehicle being used to transport or hold such food, drugs, devices, tobacco products,
or cosmetics in interstate commerce; and (B) to inspect, at reasonable times and within reasonable limits
and in a reasonable manner, such factory, warehouse, establishment, or vehicle and all pertinent equipment,
finished and unfinished materials, containers, and labeling therein. ….
• … In the case of any factory, warehouse, establishment, or consulting laboratory in which
prescription drugs, nonprescription drugs intended for human use, restricted devices, or
tobacco products are manufactured, processed, packed, or held, the inspection shall extend to
all things therein (including records, files, papers, processes, controls, and facilities)
bearing on whether prescription drugs, nonprescription drugs intended for human use,
restricted devices, or tobacco products which are adulterated or misbranded within the meaning
of this chapter, or which may not be manufactured, introduced into interstate commerce, …

Authority -- § 704(a)(1) of the Act …
• “ …No inspection authorized by the preceding sentence or by
paragraph (3) shall extend to financial data, sales data other than
shipment data, pricing data, personnel data (other than data as to
qualification of technical and professional personnel performing
functions subject to this chapter), and research data (other than data
relating to new drugs, antibiotic drugs, devices, and tobacco products and
subject to reporting and inspection under regulations lawfully issued
pursuant to section 355(i) or (k) of this title, section 360i of this title, section
360j(g) of this title, or subchapter IX and data relating to other drugs,
devices, or tobacco products which in the case of a new drug would be
subject to reporting or inspection under lawful regulations issued pursuant
to section 355(j) of this title).”

FDASIA Changes to § 704(a)
• Added Subsection (4) – advanced copies of drug records
(4)(A) Any records or other information that the Secretary may inspect under this
section from a person that owns or operates an establishment that is engaged in the
manufacture, preparation, propagation, compounding, or processing of a drug
shall, upon the request of the Secretary, be provided to the Secretary by such person, in
advance of or in lieu of an inspection, within a reasonable timeframe, within
reasonable limits, and in a reasonable manner, and in either electronic or physical
form, at the expense of such person. The Secretary’s request shall include a sufficient
description of the records requested.
(B) Upon receipt of the records requested under subparagraph (A), the Secretary shall
provide to the person confirmation of receipt.
(C) Nothing in this paragraph supplants the authority of the Secretary to conduct
inspections otherwise permitted under this chapter in order to ensure compliance with
this chapter

Types
• “Surveillance” -- planned and conducted pursuant to FDA annual plan or
center compliance program
• Pre-approval or PAI
• Post-Approval
• “For cause” (e.g., public health crisis due to defective or contaminated
FDA-regulated product; follow up to 483 response)
• Government-wide Quality Assurance Program
– FDA may inspect at the request of the DoD or VA to determine, for example,
whether a company bidding on a government contract is in compliance with GMPs
and otherwise in compliance with the FDCA

Access
• FDA Form 482 – Notice of Inspection – usual route
• Inspection Warrants – aka “Administrative Inspection Warrant”
– court-issued; often used when a company has history of refusals
• Search Warrant
– may be used when criminal conduct suspected
– handled by FDA’s Office of Criminal Investigation (OCI)
For more info on inspection warrants and search warrants, see FDA Regulatory Procedures Manual,
Chapters 6-3 and 6-4
• Drug Samples
– Authority – indirect; Section 704 refers to providing receipts for samples and 21 CFR 2.10 also
discusses procedures for handling of samples
– Receipt – FDA Form 484
– Process –
• sample also to be provided to manufacturer – so you can test as well
• technically, FDA has to pay for sample, but most companies don’t charge

How to Prepare for an Inspection
• Know the training and tactics of FDA Investigators
– Investigations Operations Manual (IOM)
http://www.fda.gov/ICECI/Inspections/IOM/default.htm
• See how FDA approaches inspections
– Drug Compliance Program Guidance Manuals
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm252671.htm
– Other Guidance Documents – numerous others of specialized, substantive nature,
such as:
• Pre-Approval Inspections/Investigations (PDF - 406KB) FDA Archive
• Post-Approval Audit Inspections (PDF - 152KB)
• Drug Manufacturing Inspections (PDF - 160KB)
• Sterile Drug Process Inspections (PDF - 292KB)
• 7345.848: Inspection of Biological Drug Products (PDF - 448KB)

Preparing for an Inspection
• Have a written corporate policy for FDA inspections
• Conduct independent audits and internal audits, before FDA shows
up
• Establish attitude of the company – must come from the top
• Designate an inspection coordinator

Train Personnel for Inspections
• Every employee must know his/her job function and regulatory
obligations
• Document employee credentials, training and knowledge
– QA/QC, GCP documentation
– Study, manufacturing and other protocols
– FDA program and inspection guidance documents

Corporate Inspection Policy & Procedures
• Address GCP, GMP, GLP and other types of inspections/inquiries
• Designate who will interact with FDA Investigator
– Inspection Coordinator and Inspection Group
– Production Employees
– Subject Matter Experts (e.g., stability, validation, labeling, etc.)
– Receptionist/Secretary

SOP on Inspection of Records
• What records will be made available
• Have specific policies on:
– photographs
• FDA – contends it has authority, but nowhere does that appear overtly in the Act
– cites a 1986 Supreme Court case involving photos taken from a plane flying over a chemical factory
-- Dow Chemical Co. v. United States, 476 U.S. 227 (1986)
• 501(j) Guidance – FDA cites refusing to allow photographs as unreasonable (more on Slide 47)
• Industry – judgment call as to whether to allow
– if don’t, I recommend you have a policy that bars ALL third parties from photographing in your
facility
– if do, take pictures at same time
– tape recorders – not typically used
– copying records (shipping, financial and business records)
• Questioning of personnel, sampling, affidavits
• FDASIA – as of 2012, FDA can ask for documents in advance

Personnel Interacting With Inspector(s)
• Receptionist/Secretary -- confirm FDA is at correct name and
institution (e.g., Par v. Parmed; Par v. Barr); record inspector’s badge
number
• Receptionist should have list of inspection coordinator and alternate
persons:
– Production V.P. / Quality Control Manager
– Executive V.P. / President
– Legal Counsel
• Never leave investigator unattended

Duties of Inspection Coordinator
• Examine Credentials and 482 Form
• Ask What Type of Inspection
• Write down all pertinent information
– contact core group
– work out inspection agenda
– inform investigator of corporate policies
• Affidavits
– Never sign or read them, and don’t even listen to a reading – don’t let anyone else sign,
read, or listen to
– If they push, ask them to send to your attorney for review

General Tactics During Inspection
• Designate a Conference Room
– Use a computerized system, if possible, for coordinating inspection logistics
• Never Speculate on an Answer
• Don’t Allow Access to Areas Beyond Scope of Inspection under § 704
– You get the items if needed
• Never Mislead the Investigator
• Don’t Panic (e.g., missing documents, questions for which you don’t know
answer)
• Draw the investigator into a conversation when a problem is identified:
– more details (so that I may investigate);
– how/why is what we are doing (apparently) inadequate (so I may explain to management)
• Debrief internally after each day of inspection

Home Interviews …
• Prepare employees to contact company legal counsel before speaking
with an investigator (this assures no waiver or corporate privilege or
disclosure of confidential information)
• Company SOP should reflect desire to cooperate with FDA to the
extent that company understands the purpose of the investigation and
will not waive or jeopardize its or its employees legal rights

The Exit Interview -- end of Inspection
• Make notes of your requested comments and include them in your 483
response
• Never “argue” with inspector
• Never make verbal promises, only written responses – be careful with
correction timelines
• Ask For:
– Explanation and Details
– Examples
• Write Down Exactly What Investigator Says
– some firms are videotaping (OK by FDA per IOM)

Defensive Strategies After Inspection to Avoid
Enforcement …
• Written response to 483:
– Show the likelihood of recurrence of the problem/violation is low
– Show the company is doing all it can reasonably to remedy the situation: specific
steps, timetable, monitoring
– Problems attributable to a specific cause have/will be fixed with permanent remedies
– Show that senior management understands

Written Response to the 483
• Address each observation separately
• Never agree that an observation is valid:
– instead, state changes you intend to make
• Disagreements:
• Present your argument – remember – Science wins!!
• Be responsive, not argumentative
• Attach copies of changed documents

More Defensive Strategies
• Provide specific evidence to minimize public health risk
– number/scope of product’s distribution
– ability to do stock recall
– technical assessment
• If inspection follows product recall, note company was “on the ball”
and caught the problem, as it was supposed to; foreclosing greater risk
• If did not catch, say what changes are being made to catch sentinel
events/data in the future

FDA Expectation on Your Response
• Wants to Hear Your D.R.U.M. – expects your response to have these
qualities:
– Direct – i.e., address the items directly raised in the 483 or warning letter
– Related – go beyond those to potentially related problems
– Universal – expand to review those issues company-wide
– Monitoring and Management –
• show that you will stay on top of the issues
• show that senior management is involved
Source: “Compliance and Enforcement.” Presentation by David K. Elder, Director, FDA Office of Enforcement, at the Orange County
Regulatory Affairs (OCRA)/FDA Joint Educational Conference. June 15, 2005. Irvine, California.

FDA Timely 483 Responses Policy
• Aug. 11, 2009 -- Federal Register notice – Post-inspection 483 responses
timing policy published – 15 business days
• Timely Responses
– FDA will conduct “detailed review” in deciding any enforcement action
– If FDA issues a warning letter, letter will address sufficiency of response
• Late responses
– Response will not be considered by FDA in deciding to take enforcement action such as a
warning letter
– If warning letter issues after a late 483 response, FDA will consider the 483 response in
assessing firm’s later reply to warning letter
• Purpose of Warning Letter:
– “ensure … seriousness and scope of the violations are understood by top management …
and that the appropriate resources are allocated to fully correct the violations and prevent
their recurrence”

483/EIR: Inspection Results
• NAI – “No action indicated” -- no objectionable conditions or practices
were found during the inspection (or the objectionable conditions found do
not justify further regulatory action)
• VAI - “Voluntary action indicated” -- objectionable conditions or
practices were found, but the District is not prepared to take or recommend
any administrative or regulatory action
• OAI – “Official action indicated” -- regulatory and/or administrative
actions will be recommended

Refusal to Permit Inspection – the fruit of FDASIA
• Section 501(j) -- If it is a drug and it has been manufactured, processed, packed,
or held in any factory, warehouse, or establishment and the owner, operator, or
agent of such factory, warehouse, or establishment delays, denies, or limits an
inspection, or refuses to permit entry or inspection.’’
• Guidance -- Circumstances that Constitute Delaying, Denying, Limiting, or
Refusing a Drug Inspection (Oct. 2014) –
– Delay in scheduling a pre-announced inspection without reasonable explanation
– Delay during inspection – e.g., won’t allow access to certain area even though ops are ongoing there
– Delay producing records without reasonable explanation
– Denials
• rejects FDA attempt to schedule a pre-announced inspection
• inspector not allowed to begin inspection upon arrival
• falsely stating the facility does not manufacture drugs (also a violation of 18 USC § 1001)

Refusal to Permit Inspection – the fruit of FDASIA …
• Guidance ….
– Limiting an inspection
• ordering ops to discontinue during inspection without reasonable explanation
• limits on amount of time inspector can observe ops
– Limiting photography
• Guidance: “Photographs are an integral part of an FDA inspection because they present an objective and
contemporaneous representation of facility conditions. Examples of conditions or practices effectively
documented by photographs include, but are not limited to: evidence of rodents or insect infestation; faulty
construction or maintenance of equipment or facilities; product storage conditions; product labels and
labeling; and, visible contamination of raw materials or finished products. Impeding or resisting photography
by an FDA investigator may be considered a limitation if such photographs are determined by the investigator
to be necessary to effectively conduct that particular inspection.”
• reasonable explanation – chemical properties of products are such that taking photos might impact product
quality
– Limiting access to or copying of records
– Limiting or preventing sample collection – as allowed by § 702(a) of the Act
– Refusal – can be active or passive (e.g., fail to respond to FDA attempt to schedule an inspection)

Violations

Statutory Drug Manufacturing Violations
• Adulteration violations -- § 501 of the Act
– (a)(1) -- “consists in whole or in part of any filthy, putrid, or decomposed
substance”
– (a)(2)(A) -- “been prepared, packed, or held under insanitary conditions whereby it
may have been contaminated with filth, or whereby it may have been rendered
injurious to health”
– (a)(2)(B) -- GMP violation …
– (b) – does not conform to an official compendium as far as strength, quality, or
purity
– (j) If it is a drug and it has been manufactured, processed, packed, or held in any
factory, warehouse, or establishment and the owner, operator, or agent of such factory,
warehouse, or establishment delays, denies, or limits an inspection, or refuses to
permit entry or inspection.’’

• Misbranding violations -- § 502 of the Act
– (o) DRUGS OR DEVICES FROM NONREGISTERED ESTABLISHMENTS
If it was manufactured, prepared, propagated, compounded, or processed in an
establishment not duly registered under section 360 of this title, if it is a drug and was
imported or offered for import by a commercial importer of drugs not duly registered
under section 381(s) of this title, if it was not included in a list required by section 360(j)
of this title, …
– (aa) UNPAID FEES; FAILURE TO SUBMIT IDENTIFYING INFORMATION
If it is a drug, or an active pharmaceutical ingredient, and it was manufactured,
prepared, propagated, compounded, or processed in a facility for which fees have not
been paid as required by section 379j–42(a)(4) [i.e., a generic drug facility fee] of this
title or for which identifying information required by section 379j–42(f) of this title has not
been submitted, or it contains an active pharmaceutical ingredient that was manufactured,
prepared, propagated, compounded, or processed in such a facility.

• Prohibited Acts under § 301 of the Act
(a) introduction or delivery into interstate commerce (“IC”)of adulterated or
misbranded drug
(b) adulterating a drug in IC
(c) receipt in IC of an adulterated or misbranded drug and “the delivery or proffered
delivery thereof for pay or otherwise”
(e) refusal to permit access to or copying of any record as required by section … 704(a)
(f) refusal to permit entry or inspection [under] Section 704
(g) manufacturing … any … drug … that is adulterated or misbranded
(p) failure to register … or provide any information (i.e. list) under § 510

Remedies for Violations

Overview
• Statutory Remedies
– Seizure
– Injunctions and Consent Decrees
– Criminal Prosecution
• Administrative Remedies
– Warning Letter
– Import Alert
– Publicity
– Application Integrity Program (if applicable)

GMP Violations –FDA Remedies in Action
• Consent Decrees
– Genzyme
– KV & Caraco
– Ranbaxy
• Import Alerts
– Ranbaxy
– Apotex
• Application Integrity -- Ranbaxy

Genzyme Consent Decree
• GMP issues at its Allston facility
• $175 million disgorgement
• 5-years of audits after corrections made
• Batch reviews – by outside expert and then reviewed by Genzyme Sr.
VP for Global Quality
• Periodic inspections by an auditor
• Penalties for not meeting deadlines in correction plan
– $15,000 per day per drug
– 18.5% of revenue for each drug sold after failing to meet deadline
• Penalties for decree violations -- $15,000 per day
• KV and Caraco Consent Decrees – 2009 – similar to Genzyme

➢ Ranbaxy –
– GMP issues at two facilities in India that produce drugs under
approved ANDAs
– At least 30 different drugs impacted
– Consent decree – January 2012 – unprecedented audit process
– May 2013 -- $500 million criminal and civil fines
➢ Apotex –
– GMP issues at two facilities in Canada that produce drugs under
approved ANDAs
– At least 60 different drugs impacted
– Lifted by July 2011
Import Alerts – Apotex & Ranbaxy

Publicity as an Enforcement Tool

➢ The AIP – Application Integrity Program – barred from
getting submissions reviewed at FDA
– Suspected fraud or rampant sloppiness as to
➢ To get off the list
– Audits – focusing on roots of fraud allegations
– Full cooperation with FDA and other investigatory bodies (e.g., DOJ)
– Re-inspections
➢ Ranbaxy – still on it; but now covered by consent decree
Application Integrity -- Ranbaxy

Questions?
➢ Call, e-mail or write:
Michael A. Swit, Esq.
San Diego, California 92130
m: 760-815-4762
e: mswit@fdacounsel.com
web: www.fdacounsel.com
➢ Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel

About Your Speaker
Michael A. Swit, Esq., has been addressing critical FDA legal and regulatory issues for over 30 years. Before returning to his
private law practice in late 2017, he served for 3 years as the chief regulatory counsel at Illumina, Inc., the world’s leading
developer of gene sequencing technologies. Prior to that, Swit was a special counsel in the FDA Law Practice at the global
law firm of Duane Morris LLP, in its San Diego office. Before joining Duane Morris in March 2012, Swit served for seven
years as a vice president at The Weinberg Group Inc., a preeminent scientific and regulatory consulting firm in the Life
Sciences.
His expertise includes product development, compliance and enforcement, recalls and crisis management, submissions and
related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts for all types of life sciences
companies, with a particular emphasis on drugs, biologics, therapeutic biotech products, medical devices, and IVDs.
His FDA legal and regulatory work also has included tenures in private practice with McKenna & Cuneo and Heller Ehrman,
and as vice president, general counsel and secretary of Par Pharmaceutical, a top public generic and specialty drug firm,
where he helped spearhead the company’s emergence from the Generic Drug Scandal. He also was, from 1994 to 1998, CEO
of FDANews.com, a premier publisher of regulatory newsletters and other specialty information products for FDA-regulated
firms.
He has taught and written on many topics relating to FDA regulation and associated commercial activities and is a past
member of the Food & Drug Law Journal Editorial Board. He earned his A.B., magna cum laude, with high honors in
history, at Bowdoin College, and his law degree at Emory University. A member of the California Bar, Mr. Swit also has been
admitted in Virginia and the District of Columbia, but is not currently active in those jurisdictions.

Overview of FDA Drug Manufacturing Requirements

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