GMP Regulation and the FSMA: Lessons for Understanding

GMP Regulation and the FSMA: Lessons for Understanding Future Tobacco GMPs Dra$, Patricia Kovacevic Lorillard/blu Conﬁden8al -‐ not reviewed -‐ for discussion purposes only Agenda • 
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Deﬁni8on of GMPs Brief History of GMPs GMP Key Features / Comparisons Food Safety Moderniza8on Act (FSMA) Implica8ons for Tobacco GMPs Adultera8on and Misbranding What are GMPs / cGMPs? •  Good Manufacturing Prac0ces (GMPs) or Current Good Manufacturing Prac0ces (cGMPs) are: •  Minimum manufacturing and control prac8ces/systems •  Focused on procedure, process, and documenta8on •  GMPs are intended to ensure the manufacture of quality products •  Failure to comply with GMPs results in adultera8on •  Regardless of actual product quality •  Adulterated products are subject to regulatory ac8on by FDA Historical Development of GMPs •  1941: Sulfathiazole Tragedy •  Winthrop Chemical markets sulfathiazole tablets contaminated with phenobarbital •  Hundreds of deaths and injuries resulted •  FDA’s inves8ga8on revealed control deﬁciencies and irregulari8es in both produc8on and recall processes •  Result: FDA dras8cally revises rules on manufacturing and quality controls •  Considered by many as “the birth” of GMPs even though GMP regula8ons were not issued un8l 23 years later Historical Development of GMPs Thalidomide Tragedy •  1953: Thalidomide synthesized by Chemie Grünenthal •  No side eﬀects, high animal dose tolerances •  Employees given product and asked to help determine what it could do •  1956: FDA denies applica8on to sell product in U.S. •  Drug approved and sold in 40+ other countries to treat morning sickness and aid sleep •  1956 – 1962: Approximately 10,000 European babies born with severe birth defects •  Result: Kefauver-‐Harris Amendment (1962 Drug Amendments) •  2-‐year inspec8on mandate •  Authorized FDA to issue GMP regula8ons for the “manufacturing, packaging, or holding of ﬁnished pharmaceu8cals” Selected GMP Timeline Year 21 CFR Part 1963 210 Manufacturing, Processing, Packing, or Holding of Drugs 211 Finished Pharmaceu8cals 226 Type A Medicated Ar8cles 606 Blood & Blood Components 820 Medical Devices 1975 1978 210 & 211 GMPs For Manufacturing, Processing, Packing, or Holding of Drugs; Finished Pharmaceu8cals -‐-‐ signiﬁcant expansion of 1963 GMPs (from 3 to 76 pages in the Fed. Reg.) 1986 110 Manufacturing, Packing, or Holding Human Food 1996 820 Quality System Regula8on (QSR) for Medical Devices -‐-‐
updated 1978 GMPs 2001 1271.145-‐320 Current Good Tissue Prac8ces 2007 111 Manufacturing, Packaging, Labeling, or Holding Opera8ons for Dietary Supplements 2009 212 Positron Emission Tomography (PET) Drugs GMP Regulations for Food •  21 CFR Part 110: Current Good Manufacturing Prac0ce in Manufacturing, Packing, or Holding Human Food •  Subpart A -‐ General Provisions •  110.3 Deﬁni8ons •  110.5 Current good manufacturing prac8ce •  110.10 Personnel •  110.19 Exclusions •  Subpart B -‐ Buildings and Facili8es •  110.20 Plants and grounds •  110.35 Sanitary opera8ons •  110.37 Sanitary facili8es and controls •  Subpart C -‐ Equipment •  110.40 Equipment and utensils •  Subpart E -‐ Produc8on and Process Controls •  Processes and controls •  Warehousing and distribu8on •  Subpart G -‐ Defect Ac8on Levels •  Natural or unavoidable defects in food for human use that present no health hazard GMP Regulations for Dietary Supplements •  21 CFR Part 111: Current Good Manufacturing Prac0ce in Manufacturing, Packaging, Labeling, or Holding Opera0ons for Dietary Supplements • 
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Subpart A -‐ General Provisions Subpart B -‐ Personnel Subpart C -‐ Physical Plant and Grounds Subpart D -‐ Equipment and Utensils Subparts E through L -‐ Process and Control System •  Requirements to: Establish a Produc8on and Process Control System; Quality Control; Components, Packaging, and Labels for Product that you Receive for Packaging or Labeling as a Dietary Supplement; Master Manufacturing Record; Batch Produc8on Record; Laboratory Opera8ons; Manufacturing Opera8ons; Packaging and Labeling Opera8ons • 
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Subpart M -‐ Holding and Distribu8ng Subpart N -‐ Returned Dietary Supplements Subpart O -‐ Product Complaints Subpart P -‐ Records and Recordkeeping GMP (QSR) Regulations for Medical Devices 21 CFR Part 820: Quality System Regula0on [Medical Devices] • 
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Subpart A -‐ General Provisions Subpart B -‐ Quality System Requirements Subpart C -‐ Design Controls Subpart D -‐ Document Controls Subpart E -‐ Purchasing Controls Subpart F -‐ Iden8ﬁca8on and Traceability Subpart G -‐ Produc8on and Process Controls Subpart H -‐ Acceptance Ac8vi8es Subpart I -‐ Nonconforming Product Subpart J -‐ Correc8ve and Preventa8ve Ac8on Subpart K -‐ Labeling and Packaging Control Subpart L -‐ Handling, Storage, Distribu8on, and Installa8on Subpart M -‐ Records Subpart N -‐ Servicing Subpart O -‐ Sta8s8cal Techniques General GMP Principles • 
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Qualified Personnel
Quality Control / Quality Assurance function
Appropriate Facilities and Equipment
Recordkeeping
Validated Processes - “under control”
Failure Investigations - “closed loop”
Comparison of GMP Areas: Key Provisions FOOD GMPs Personnel -‐ Disease control -‐ Cleanliness -‐ Educa8on and training, supervision Plants and Grounds -‐ Grounds -‐ Plant design and construc8on Sanitary Opera0ons -‐ General maintenance -‐ Substances used for cleaning -‐ Pest control -‐ Sanita8on of food-‐contact surfaces -‐ Storage and handling Sanitary Facili0es and Controls -‐ Water supply -‐ Plumbing -‐ Sewage disposal -‐ Toilet facili8es -‐ Hand-‐washing facili8es -‐ Rubbish and oﬀal disposal Equipment and Utensils Processes and Controls -‐ Raw materials -‐ Manufacturing opera8ons Warehousing and Distribu0on MEDICAL DEVICE GMPs QS Requirements -‐ Management responsibility -‐ Quality audit -‐ Personnel Design Control Document Controls Purchasing Controls Iden0ﬁca0on and Traceability Produc0on and Process Controls Acceptance Ac0vi0es Nonconforming Product Correc0ve and Preventa0ve Ac0on Labeling and Packaging Handling, Storage, Distribu0on, and Installa0on Records Servicing Sta0s0cal Techniques Comparison of GMP Areas: Training FOOD GMPs MEDICAL DEVICE GMPs •  Appropriate training for food handlers •  Management responsibility to deﬁne and supervisors in proper food training needs for personnel handling techniques and food protec8on principles •  Training in current GMP regula8on and how individual job func8ons relate to •  Training should ensure awareness of the overall quality system the dangers of poor personal hygiene •  Training for temporary work under and insanitary prac8ces special environmental condi8ons Comparison of GMP Areas: Audits and Documentation FOOD GMPs Audits •  Audits are not explicitly speciﬁed MEDICAL DEVICE GMPs Audits •  Management needs to establish procedures for quality audits of its documented quality system and ensure that they are performed • 
Documenta0on •  No documenta8on requirements explicitly speciﬁed, except for supplier cer8ﬁca8on for cleaning compounds and raw materials Only those records that demonstrate the quality audi8ng system are to be made available to an FDA inspector. FDA does not have access to the actual audit reports Documenta0on •  Explicitly requires that all of the following records be readily available to FDA inspectors: •  Device master record: device, produc8on process, quality assurance, packaging and labeling, and installa8on speciﬁca8ons. •  Device history record: date of manufacture, quan8ty manufactured, quan8ty distributed, acceptance records (of DMR), iden8ﬁca8on label and control numbers. •  Quality system record: procedures and documenta8on of ac8vi8es •  Complaint ﬁles: compliant ﬁles to determine if inves8ga8on needed. If so, record of inves8ga8on Comparison of GMP Areas: Evaluation/Validation FOOD GMPs • 
There are no evalua8on/valida8on requirements to determine whether a performed ac8vity is achieving its goal. Only for raw materials, the facility is to "verify" compliance using supplier cer8ﬁca8on or some other method. MEDICAL DEVICE GMPs • 
Veriﬁca8on of product design, i.e., tes8ng to determine whether the design output meets the func8onal and opera8onal requirements of design inputs • 
Design valida8on with lab tes8ng of prototypes • 
Process valida8on and revalida8on in case of changes or process devia8ons • 
Valida8on of computer so$ware when it is used as part of produc8on or the quality system • 
Evalua8on of the need for an inves8ga8on of a nonconforming product • 
Retes8ng and reevalua8on of the nonconforming product a$er it has been reworked Differences Within Industry •  Medical Devices: Flexible approach so GMP requirements vary depending on device classiﬁca8on (classiﬁca8on is based on the intended use and indica8ons of use for the device) •  More stringent requirements for life-‐sustaining devices (e.g., pacemakers, stents) •  Some devices are exempt from GMPs except for general requirements related to recordkeeping and complaint ﬁles (e.g., tongue depressors, manual toothbrushes) •  Food: Compliance requirements vary depending on category of food •  Diﬀerent requirements exist for diﬀerent categories of food such as seafood, frozen foods, etc. •  Drugs: Movement toward a more risk-‐based approach Dietary Supplement GMPs: Lessons Learned •  The Dietary Supplement Health and Educa8on Act of 1994 (DSHEA) authorized FDA to promulgate GMP regula8ons for dietary supplements, modeled a+er the food GMP regula2ons •  In 2003, FDA ﬁnally proposed GMP regula8ons which the industry cri8cized as being modeled on drug GMPs •  Final Regula8ons published in 2007 •  Despite revising and reorganizing the regula8ons in the ﬁnal rule, many s8ll feel the regula0ons modeled a_er drug GMPs •  Most consider the Dietary Supplement GMPs (including 16 subparts) to represent a comprehensive approach FSMA •  In January 2011, President Obama signed the Food Safety Moderniza8on Act into law •  Amended key provisions of the FDCA •  Signiﬁcantly revised food safety laws •  Key Provisions of FSMA address: • 
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Preventa8ve Process Controls and Hazard Evalua8on Traceability Imports Recordkeeping and Access Inspec8ons Enforcement Provisions Recalls FSMA: Hazard Evaluations & Preventative Controls •  FSMA requires facili8es to conduct a hazard evalua0on to iden8fy hazards that are reasonably likely to occur, including “biological, chemical, physical, and radiological hazards, natural toxins, pes8cides, drug residues, decomposi8on, parasites, and unapproved food or color addi8ves,” and iden0fy and implement preventa0ve controls to provide assurances that the iden8ﬁed hazards would be signiﬁcantly minimized and that food would not be adulterated. •  Preventa8ve Controls must include: •  Sanita8on, Training, Environmental Controls, Allergen Controls, Recall Con8ngency Plan, GMPs, Supplier Veriﬁca8on Ac8vi8es •  Facili8es must: •  Monitor the controls; Establish correc8ve ac8ons; Maintain records of monitoring, instance of conformance, and correc8ve ac8ons taken; Verify the plan is working including through use of tes8ng programs FSMA Lessons for Tobacco GMPs •  FSMA may provide insight into how FDA will regulate tobacco (e.g., preventa8ve process and hazard controls, imports, inspec8ons) because: •  FSMA is rela8vely recent (passed by Congress in 2010), so it may provide clues regarding Congress’ current approach •  FSPTCA speciﬁcally references “hazard analysis and cri8cal control point methodology” in sec8on on tobacco GMPs •  Some of these same concepts (e.g., imports, recordkeeping) for food safety could apply to tobacco safety •  FSMA passed despite concerns over economic costs •  Costs for food industry to become compliant are signiﬁcant •  Congressional Budget Oﬃce es8mated it would cost $1.4B over 2011-‐2015 to implement and enforce Tobacco GMPs: FSPTCA Requirements •  Diﬃcult to predict exact approach to GMPs un8l rulemaking begins •  Sec8on 906(e) of the FSPTCA provides, in part, the following about tobacco GMPs: •  “In applying manufacturing restric8ons to tobacco, the Secretary shall, in accordance with subparagraph (B), prescribe regula8ons (which may diﬀer based on the type of tobacco product involved) requiring that the methods used in, and the facili8es and controls used for, the manufacture, preproduc8on design valida8on (including a process to assess the performance of a tobacco product), packing, and storage of a tobacco product conform to current good manufacturing prac8ce, or hazard analysis and cri8cal control point methodology, as prescribed in such regula8ons to assure that the public health is protected and that the tobacco product is in compliance with this chapter. Such regula8ons may provide for the tes8ng of raw tobacco for pes8cide chemical residues regardless of whether a tolerance for such chemical residues has been established.” Tobacco GMPs: What Will They Address? •  Remember, GMPs focus on process •  We an8cipate tobacco GMPs will address the following areas: • 
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Facility Standards Equipment Sanita8on Audits Labeling and Packaging Training Qualiﬁca8on Process Controls for Raw Materials and Manufacturing Warehousing and Distribu8on Documenta8on •  Part 11 “Electronic Records, Electronic Signatures” would apply to electronic records Adulteration and Misbranding are Currently Actionable •  The Federal Food, Drug & Cosme8c Act already provides it is a prohibited act to: •  introduce into interstate commerce any tobacco product that is adulterated or misbranded •  adulterate or misbrand any tobacco product in interstate commerce •  receive an adulterated or misbranded tobacco product in interstate commerce •  Sec8on 902 deﬁnes adulterated tobacco products •  In part, it provides a tobacco product is adulterated if: •  (1) it consists in whole or in part of any ﬁlthy, putrid, or decomposed substance, or is otherwise contaminated by any added poisonous or added deleterious substance that may render the product injurious to health •  (2) it has been prepared, packed, or held under insanitary condi8ons whereby it may have been contaminated with ﬁlth, or whereby it may have been rendered injurious to health •  (3) its package is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health •  Sec8on 903 deﬁnes misbranded tobacco products •  Tobacco product is misbranded if (among other things) its labeling is false or misleading or fails to bear required informa8on Adulteration and Misbranding are Currently Actionable •  A lack of appropriate manufacturing prac8ces could result in adultera8on (e.g., contamina8on) or misbranding (e.g., a product that is inconsistent with the labeled contents) •  Thus, despite the fact tobacco GMPs have not been issued, and there is no guidance on tobacco contaminant ac8on levels etc., best eﬀorts should be made to ensure exis2ng manufacturing prac8ces do not result in adultera8on or misbranding. •  FDA may exercise enforcement over tobacco products through a variety of mechanisms including: •  Un8tled and Warning Leuers, Civil Money Penal8es, No-‐tobacco-‐sale Orders, Criminal Prosecu8on, Seizure, and Injunc8on Tobacco GMPs: Modeled After Which Approach? •  We believe the tobacco GMPs will likely be modeled a$er the Medical Device and Food GMPs •  Drug GMPs should be an unlikely model because many concepts would not apply (e.g., eﬃcacy and strength) •  GMPs may ul8mately diﬀer based on tobacco product type •  BUT FDA webinars indicate FDA looks for stricter controls than for food •  Device GMPs may be used as a model for, e.g.: • 
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Documenta8on Requirements Audits Iden8ﬁca8on and Traceability Correc8ve and Preventa8ve Ac8on Labeling and Packaging Food GMPs may be used as a model for, e.g.: • 
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Concept of Chemical Residues and Contaminants (Defect Ac8on Levels) Sanitary Opera8ons Sanitary Facili8es and Controls Equipment and Utensils Process Controls for Raw Materials and Manufacturing Warehousing and Distribu8on Thank you for your attention QUESTIONS?

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