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Overview of FDA Drug Manufacturing Requirements

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Presentation on FDA Regulation of Drug Manufacturing to the Introduction to Drug Law Course sponsored by the Food & Drug Law Institute (FDLI) on July 25, 2018 in San Francisco.

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Overview of FDA Drug Manufacturing Requirements

  1. 1. 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
  2. 2. Solving FDA Legal Challenges for the Life of a Life Sciences Company 2 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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.
  3. 3. Solving FDA Legal Challenges for the Life of a Life Sciences Company 3 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Agenda • Establishment Registration and Drug Listing • Current Good Manufacturing Practices (cGMPs) • Inspections – Types – Conducting – Responding – Refusal to permit inspection • Violations – Adulteration – Misbranding
  4. 4. Solving FDA Legal Challenges for the Life of a Life Sciences Company 4 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Establishment Registration and Drug Listing
  5. 5. Solving FDA Legal Challenges for the Life of a Life Sciences Company 5 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  6. 6. Solving FDA Legal Challenges for the Life of a Life Sciences Company 6 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  7. 7. Solving FDA Legal Challenges for the Life of a Life Sciences Company 7 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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.
  8. 8. Solving FDA Legal Challenges for the Life of a Life Sciences Company 8 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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.
  9. 9. Solving FDA Legal Challenges for the Life of a Life Sciences Company 9 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  10. 10. Solving FDA Legal Challenges for the Life of a Life Sciences Company 10 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  11. 11. Solving FDA Legal Challenges for the Life of a Life Sciences Company 11 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  12. 12. Solving FDA Legal Challenges for the Life of a Life Sciences Company 12 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT current Good Manufacturing Practices (cGMPs)
  13. 13. Solving FDA Legal Challenges for the Life of a Life Sciences Company 13 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  14. 14. Solving FDA Legal Challenges for the Life of a Life Sciences Company 14 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  15. 15. Solving FDA Legal Challenges for the Life of a Life Sciences Company 15 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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.
  16. 16. Solving FDA Legal Challenges for the Life of a Life Sciences Company 16 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  17. 17. Solving FDA Legal Challenges for the Life of a Life Sciences Company 17 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  18. 18. Solving FDA Legal Challenges for the Life of a Life Sciences Company 18 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  19. 19. Solving FDA Legal Challenges for the Life of a Life Sciences Company 19 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  20. 20. Solving FDA Legal Challenges for the Life of a Life Sciences Company 20 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  21. 21. Solving FDA Legal Challenges for the Life of a Life Sciences Company 21 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  22. 22. Solving FDA Legal Challenges for the Life of a Life Sciences Company 22 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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]
  23. 23. Solving FDA Legal Challenges for the Life of a Life Sciences Company 23 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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?
  24. 24. Solving FDA Legal Challenges for the Life of a Life Sciences Company 24 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Inspections
  25. 25. Solving FDA Legal Challenges for the Life of a Life Sciences Company 25 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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, …
  26. 26. Solving FDA Legal Challenges for the Life of a Life Sciences Company 26 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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).”
  27. 27. Solving FDA Legal Challenges for the Life of a Life Sciences Company 27 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  28. 28. Solving FDA Legal Challenges for the Life of a Life Sciences Company 28 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  29. 29. Solving FDA Legal Challenges for the Life of a Life Sciences Company 29 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  30. 30. Solving FDA Legal Challenges for the Life of a Life Sciences Company 30 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  31. 31. Solving FDA Legal Challenges for the Life of a Life Sciences Company 31 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  32. 32. Solving FDA Legal Challenges for the Life of a Life Sciences Company 32 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  33. 33. Solving FDA Legal Challenges for the Life of a Life Sciences Company 33 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  34. 34. Solving FDA Legal Challenges for the Life of a Life Sciences Company 34 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  35. 35. Solving FDA Legal Challenges for the Life of a Life Sciences Company 35 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  36. 36. Solving FDA Legal Challenges for the Life of a Life Sciences Company 36 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  37. 37. Solving FDA Legal Challenges for the Life of a Life Sciences Company 37 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  38. 38. Solving FDA Legal Challenges for the Life of a Life Sciences Company 38 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  39. 39. Solving FDA Legal Challenges for the Life of a Life Sciences Company 39 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  40. 40. Solving FDA Legal Challenges for the Life of a Life Sciences Company 40 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  41. 41. Solving FDA Legal Challenges for the Life of a Life Sciences Company 41 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  42. 42. Solving FDA Legal Challenges for the Life of a Life Sciences Company 42 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  43. 43. Solving FDA Legal Challenges for the Life of a Life Sciences Company 43 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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.
  44. 44. Solving FDA Legal Challenges for the Life of a Life Sciences Company 44 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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”
  45. 45. Solving FDA Legal Challenges for the Life of a Life Sciences Company 45 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  46. 46. Solving FDA Legal Challenges for the Life of a Life Sciences Company 46 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  47. 47. Solving FDA Legal Challenges for the Life of a Life Sciences Company 47 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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)
  48. 48. Solving FDA Legal Challenges for the Life of a Life Sciences Company 48 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Violations
  49. 49. Solving FDA Legal Challenges for the Life of a Life Sciences Company 49 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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.’’
  50. 50. Solving FDA Legal Challenges for the Life of a Life Sciences Company 50 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Statutory Drug Manufacturing Violations • 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.
  51. 51. Solving FDA Legal Challenges for the Life of a Life Sciences Company 51 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Statutory Drug Manufacturing Violations • 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
  52. 52. Solving FDA Legal Challenges for the Life of a Life Sciences Company 52 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Remedies for Violations
  53. 53. Solving FDA Legal Challenges for the Life of a Life Sciences Company 53 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Overview • Statutory Remedies – Seizure – Injunctions and Consent Decrees – Criminal Prosecution • Administrative Remedies – Warning Letter – Import Alert – Publicity – Application Integrity Program (if applicable)
  54. 54. Solving FDA Legal Challenges for the Life of a Life Sciences Company 54 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT GMP Violations –FDA Remedies in Action • Consent Decrees – Genzyme – KV & Caraco – Ranbaxy • Import Alerts – Ranbaxy – Apotex • Application Integrity -- Ranbaxy
  55. 55. Solving FDA Legal Challenges for the Life of a Life Sciences Company 55 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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
  56. 56. Solving FDA Legal Challenges for the Life of a Life Sciences Company 56 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT ➢ 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
  57. 57. Solving FDA Legal Challenges for the Life of a Life Sciences Company 57 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Publicity as an Enforcement Tool
  58. 58. Solving FDA Legal Challenges for the Life of a Life Sciences Company 58 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT ➢ 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
  59. 59. Solving FDA Legal Challenges for the Life of a Life Sciences Company 59 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT Questions? ➢ Call, e-mail or write: Michael A. Swit, Esq. LAW OFFICES OF MICHAEL A. SWIT 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
  60. 60. Solving FDA Legal Challenges for the Life of a Life Sciences Company 60 www.fdacounsel.com LAW OFFICES OF MICHAEL A. SWIT 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.

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