Eight ghth h An Annual al F FDA A Inspect spections ons Summi mmit Be Bethesda esda, , MD MD Sept eptember er 23 23-25 25, 2013 2013 INSPEC PECTIONS W S WORKSH SHOP October ber 23, 23, 2013 2013 Presented by: Freder derick H. H. Br Brandin ing R. R. Ph Ph., JD JD Pr Prin incip ipal, , OFW Law Law Washi hingt ngton, on, D D.C.; Chi hicago ago (C) Frederick H. Branding 2013 1
Re Reas asons f for FDA FDA Admi dmini nistrative Inspe pections ns • Routine • For Cause • Warning Letter or Enforcement Action • Complaints - Consumers, Industry, and Current or Former Employees • Recall Effectiveness Check • Pre-Approval Inspection • Special Enforcement Initiative (C) Frederick H. Branding 2013 2
Pre Pre-App pproval I Inspe pections FDA FDA appro approval of of N NDAs s or or ANDAs Only if the methods used in, and the facilities and controls used for, the manufacture, processing, packing, and testing of the drug are found adequate to ensure and preserve its identity, strength, quality and purity. 21 U.S.C. §§ 355(d)(3) and 355(j)(4)(A) (C) Frederick H. Branding 2013 3
Pre Pre-App pproval I Inspe pections (cont.) FDA’s s On S n Site O e Obj bject ective: e: • Readiness for Commercial Manufacturing (Compliance with cGMPs, equipment, etc.) • Conformance to Application • Data Integrity (C) Frederick H. Branding 2013 4
Fo Focus us o of Pre-App pproval I Inspe pection (cont.) Areas C eas Cov overed I ed Inc nclude: ude: • Data Audits to Assess cGMP Compliance • Batch Record Review • Manufacture of Drug Substances • Excipients • Raw Materials (cGMP Controls) (C) Frederick H. Branding 2013 5
Fo Focus us o of Pre-App pproval I Inspe pection cont nt. Areas C eas Cov overed: ed: • Raw Materials (Tests, Methods, and Specifications) • Composition and Formulation of Finished Dosage Form • Container/Closure System(s) • Analytical Methods Validation • Product (cGMP) Controls (C) Frederick H. Branding 2013 6
Fo Focus us o of Pre-App pproval I Inspe pection (cont.) Areas C eas Cov overed: ed: • Product Tests, Methods, and Specifications • Product Stability • Comparison of the Relevant Preapproval, Validation and Proposed Commercial Production Batches (scale-up) (C) Frederick H. Branding 2013 7
Fo Focus us o of Pre-App pproval I Inspe pection (cont.) Areas C eas Cov overed: ed: • Product Tests, Methods, and Specifications • Product Stability • Comparison of the Relevant Preapproval, Validation and Proposed Commercial Production Batches (scale-up) (C) Frederick H. Branding 2013 8
Fo Focus us o of Pre-App pproval I Inspe pection cont nt. Areas C eas Cov overed: ed: • Facilities, Personnel, Equipment Qualifications • Equipment Specification(s) • Packaging and Labeling (cGMP Controls) • Process Validation • Reprocessing • Ancillary Facilities (C) Frederick H. Branding 2013 9
Statutory A Aut uthor ority t to Con Condu duct Estab ablishme ment I Ins nspection ons • Section 704 [21 USC § 374] • Reasonableness of the Inspection • Frequency of Inspections • Consent Unnecessary • Inspection Warrants • Warrant Unnecessary • Miranda Warnings Unnecessary (C) Frederick H. Branding 2013 10
Proced edure f e for Co Cond nducting I Inspections • Investigation Operations Manual (IOM) Ch. 5 • Guidance documents • Present Credentials and Notice of Inspection (Form FDA 482); 21 USC § 374 • Entry may be refused if the investigator fails to show credentials or does not issue a 482 (C) Frederick H. Branding 2013 11
Scope ope o of Inspec pecti tion on • FDA i is Not ot Expr press ssly A y Aut uthor horized t zed to o Obt btai ain, n, But ut May May A Attem empt pt t to o Obt btai ain: n: – Affidavits from individuals – Interviews of employees • FDCA does not expressly authorize investigators to interview a company’s employees – Non-managerial employees – Managerial employees: firm “admissions”. Notice to firm and opportunity to be present. – U.S. v. Bhutani (Criminal) (C) Frederick H. Branding 2013 12
Scope ope o of Inspec pecti tion on • FDA i is Not ot Expr press ssly A y Aut uthor horized t zed to o Obt btai ain, Bu But t May May Attempt pt t to o Obt btai ain: – In-plant photographs • Not specifically authorized – Dow Chemical Co. – Acri Wholesale Grocery Co. – NB: Draft Guidance for Industry: Circumstances that Constitute Delaying, Denying, Limiting or Refusing a Drug Inspection. ( July 12, 2013). (C) Frederick H. Branding 2013 13
Scope ope o of Inspec pecti tion on • FDA’s A s Aut uthor hority t to o Ent nter er and and to o Ins nspect pect Establ ablishm hment ents – Prescription drugs or nonprescription drugs – Medical device records – Biologics establishments – Animal drugs and animal feeds – Food and cosmetic establishments – Radiation emitting electronic products – Internal quality audit reports (CPG Sec. 130.300) – Reasonable time, limits, and manner (C) Frederick H. Branding 2013 14
Scope ope o of Inspec pecti tion on • Li Limi mitation ons s to o the he Scope ope of of Ins nspe pect ction on – Retail pharmacies (regular course, retail) – Licensed practitioners – Research, teaching, or chemical analysis – Exempted by regulation 21 USC § 374(a)(2)(A)-(D) (C) Frederick H. Branding 2013 15
Scope ope o of Inspec pecti tion on • Inspection is authorized to the extent necessary to ensure compliance with the Act and regulations. • FDA may review any Records required to be kept under the Act and regulations to determine compliance – No authority to review financial, sales, pricing, personnel, and research data – No express authority to review location of files – No clear authority to obtain background documents (C) Frederick H. Branding 2013 16
Refus using a ng an Inspec pecti tion on FDA Op Opti tions: • Administrative Inspection Warrant • Prohibited Acts; Refusal to permit: – (e) Access to or copying of Required Records – (f) Entry or Inspection [21 U.S.C. § 331(f); 333(a); CPG 130.100] • Adulterated Drug: Delays, Denies, Limits, Refuses Inspection. [21 USC § 351(j)] • Guidance: “…Delaying, Denying, Limiting or Refusing a Drug Inspection” (July 12, 2013) (C) Frederick H. Branding 2013 17
“…Del Delaying, De Deny nying ng, Limi miting or or Re Refus using a a Dr Drug Inspection” n” FDA S Saf afet ety and y and Innov nnovat ation A on Act ( (“FDASIA”) Amended ended § 704(a)(4): FDA may request required records prior to or in lieu of an inspection, within reasonable time, limits, and manner. [21 USC §374(a)(4)] Added dded § 501(j): deems a drug adulterated where inspection is delayed, denied, limited, or refused. [21 USC § 351(j)] Required FDA to issue Guidance – July 12, 2013. (C) Frederick H. Branding 2013 18
Guidanc idance: D Delay laying, ng, D Deny nying ing, L Limit iting ing or R Refus using ing a a Drug ug Inspe pection ion • Del elay of ay of Ins nspect pection ons – Scheduling Pre-Announced Inspections – During an Inspection – Producing Records (C) Frederick H. Branding 2013 19
Guidanc idance: D Delay laying, ng, D Deny nying ing, L Limit iting ing or R Refus using ing a a Drug ug Inspe pection ion • Deni enial al of of Ins nspect pection on – Rejects attempt to schedule inspection – Does not allow inspection to begin – No inspection due to absence of certain staff – False statement re: non-manufacture of drugs (C) Frederick H. Branding 2013 20
Guidanc idance: D Delay laying, ng, D Deny nying ing, L Limit iting ing or R Refus using ing a a Drug ug Inspe pection ion • Limit iting ing o of I Inspe pection ion – Access to Facilities and/or Manuf. Processes • Limited time to view operations • Restricts entry to certain areas – Limiting Photography Rodent/insect infestation • Construction, Maintenance – equip., facility • Contamination – raw materials, finished • product Labels, Labeling • (C) Frederick H. Branding 2013 21
Guidanc idance: D Delay laying, ng, D Deny nying ing, L Limit iting ing or R Refus using ing a a Drug ug Inspe pection ion • Li Limi miting of ng of Ins nspe pect ction ( n (cont ont.) – Access to or Copying of Required Records • Refuses review of shipping records • Partial record production • Records unreasonably redacted – Limiting/Preventing Collection of Samples • Environmental, raw mtrls., finished products, etc. (C) Frederick H. Branding 2013 22
Guidanc idance: D Delay laying, ng, D Deny nying ing, L Limit iting ing or R Refus using ing a a Drug ug Inspe pection ion • Ref efusal usal t to o Per ermi mit E Ent ntry or y or Ins nspect pection on – Action or Inaction: • Bars Investigator from entering facility/areas • Fails to unlock areas or take other action • Fails to answer calls from FDA (C) Frederick H. Branding 2013 23
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