Fda gmp compliance for the Life Science Industry

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Regulatory Issues for Drugs, Devices, and Combination Products

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  • Here we see what FDA considers the important additional considerations for drugs in a device GMP environment
    Testing and approval of components, containers, closures makes sense overall- and can probably be part of Acceptance Activities
    Calculation of yield in Production and Process Control makes sense for everything
    Special packaging may be required
    Expiration dating will always be part of a drug containing product
    Testing and release for distribution can also be part of Acceptance Activities
    Stability Testing goes hand in hand with expiration dating
    Special testing requirements can also be part of the Device Master record and Acceptance Activities
    And finally, reserve sample to allow retesting of released lots makes good sense for most products that have expiration dates.
  • The resulting quality system manual would then contain these headings- or you could combine the testing-approval with Acceptance, and similar actions
  • We know that FDA wants to see evidence of the State of Control
    We know the requirements in the GMPs to establish the robust quality system
    Once we’ve accomplished most of the compliance tasks,
    we need to think about the best way to demonstrate this to a third party- the FDA
  • To show that our quality system is robust, we have to present it properly.
    Using the FDA Compliance Program Guidance Manual, we can see the instructions to the inspector.
    Once we know what the inspector is seeking, we can quickly and efficiently provide it- a mini demonstration of our “State of Control”
    Whether you have an internal quality audit system in place or not, you need to walk through your facility and the quality system the way FDA will.
  • Unlike many audit approaches, a checklist of many items is not typical of an FDA inspection.
    In both drug inspections and device inspections, the elements of the GMP are grouped into systems,
    not unlike the process approach for ISO 9001 and ISO 13485. The two primary reasons for a systems approach are
    Efficiency- and focus on the most important items first
    The ability to conclude that the various products are in conformance by using the system assessment of one product.
    NOTE: That means all of your products and processes must be of similar quality-
    you wouldn’t want your facility judged wanting because FDA picked a product that you hadn’t brought into full compliance.
  • The systems for Drug GMP are Quality, Facilities and Equipment, Materials, Production, Packaging and Labeling, and Laboratory control.
    The various GMP subparts are included in one or more systems- in fact Organization-Personnel and Records-Reports are important to every system.
  • In an abbreviated inspection, two or three of the systems are examined, however one must be the quality system.
    First, the Quality Unit is evaluated for fulfilling its responsibilities.
    The data collected is then assessed to identify links to other systems that may be included
  • In device inspections, there are seven subsystems, four Major and three Less than major.
    The focus on Management is consistent with what we saw earlier in GMPs for Combination Products,
    the drug GMPs get Management Responsibility added for a combination product.

  • In the Quality Systems Inspection Technique guide, the focus is on starting and ending with management.
    First- all problems with the other major systems can be tied to management
    Second- Can the inspector conclude that an adequate and effective Quality System has been established
  • Similar to drug inspections, there are different levels of device inspections
    The abbreviated inspection requires CAPA plus either Production and Process Controls or Design Controls
    The comprehensive involves all four Major subsystems
    FDA will generally tell you what type of inspection they are planning to execute.
  • Fda gmp compliance for the Life Science Industry

    1. 1. David A. Manalan, FASQ INQC Consulting, Inc.
    2. 2. SCOPE  FDA, a government agency that regulates drugs, biologics, and medical devices (including IVDs) in the US.  GMP, Good Manufacturing Practices required by FDA that differ for drugs, biologics, medical devices, and combinations.  Life Sciences, companies that make one or more of these product categories. 3/19/2014 2INQC Consulting, Inc.
    3. 3. Is GMP Compliance Important? Lilly’s diabetes drug rejected by FDA By Drew Armstrong | BLOOMBERG NEWS MARCH 06, 2014 NEW YORK — A diabetes pill developed by Eli Lilly and Co. and Boehringer Ingelheim Pharmaceuticals Inc. was rejected by US regulators because of previously disclosed manufacturing deficiencies that had not been resolved at a German plant. The FDA won’t approve the drug until the problems are fixed. The FDA reinspection of Boehringer’s plant is continuing, said Emily Baier, a spokeswoman for the company. It could take up to six months after the inspection for the FDA to decide whether the problems have been fixed. 3/19/2014 3INQC Consulting, Inc.
    4. 4. Missing the Point  A top executive at Ranbaxy —  which has pleaded guilty to felony charges,  paid a $500 million fine last year, and  found to have conditions such as- flies “too numerous to count” in critical plant areas —  pleaded with Dr. Hamburg, FDA Commissioner, to allow his products into the United States so that the company could more easily pay for fixes.  She politely declined. 3/19/2014 4INQC Consulting, Inc.
    5. 5. Compliance with GMP-3 items  FDA focus on "State of control" as a key compliance objective and indicator.  Contrast the GMPs for Finished Pharmaceuticals, Medical Devices, and combination products.  Review the FDA's Office of Regulatory Affairs system based inspection techniques for assessing compliance. 3/19/2014 5INQC Consulting, Inc.
    6. 6. Life Science companies  Life Science companies: those whose products are significant to human health and well being.  Examples in Massachusetts:  Genzyme, a Sanofi company, makes drugs for rare inherited disorders and multiple sclerosis  Philips Healthcare, makes imaging systems, home health solutions, patient care, and clinical informatics  Biogen Idec Inc., provides therapies for neurodegenerative diseases, hemophilia, and autoimmune disorders  Covidien, makes medical devices and supplies  and others, such as Pfizer, Novartis, Fresenius, ThermoFisher, and Boston Scientific, are all part of the Life Science family. 3/19/2014 6INQC Consulting, Inc.
    7. 7. FDA and Regulation  Life Science products are generally regulated by the U.S. Food and Drug Administration (FDA)  FDA is a large part of the Department of Health and Human Services.  FDA regulations are legally enforceable requirements that are authorized by law.  FDA regulations provide specifics on complying with the law(s) and its intent. 3/19/2014 7INQC Consulting, Inc.
    8. 8. FDA and Regulation  The Food, Drug, and Cosmetics Act, as amended, authorizes the FDA to issue various regulations.  One authorized regulation is good manufacturing practices (GMP) for life science products.  There are also FDA regulations related to registration, clinical investigations, product approval, adverse event reporting, recalls, labeling, corrections and removals, etc.  Compliance with those additional regulations are not included in this presentation on GMP- Good Manufacturing Practices. 3/19/2014 8INQC Consulting, Inc.
    9. 9. FDA Organization  FDA has science and technology offices that regulate food, drugs, devices, biologics, tobacco products, and veterinary medicine.  FDA also has an Office of Regulatory Affairs (ORA)  ORA focuses on inspections, compliance, enforcement, and criminal investigations.  ORA staffs most of the regional offices of the FDA.  The ORA Vision is assuring that all food is safe; all medical products are safe and effective; and the public health is advanced and protected.  The ORA Mission is to protect consumers and enhance public health by maximizing the compliance of FDA regulated products and minimizing risk associated with those products.  When FDA comes to your facility, it's probably employees of ORA with these goals in mind. 3/19/2014 9INQC Consulting, Inc.
    10. 10. Compliance with GMP-item 1  FDA focus on "State of control" as a key compliance objective and indicator.  Contrast the GMPs for Finished Pharmaceuticals, Medical Devices, and combination products.  Review the FDA's Office of Regulatory Affairs system based inspection techniques for assessing compliance. 3/19/2014 10INQC Consulting, Inc.
    11. 11. State of Control  Where does the concept of "State of Control" originate?  It’s a basic concept in evaluating companies during an inspection.  It's a basic FDA expectation of responsible management.  It’s found in the FDA Inspection Programs 3/19/2014 11INQC Consulting, Inc.
    12. 12. State of Control  State of Control: A drug firm is considered to be operating in a state of control when it employs conditions and practices that assure compliance with the intent of the Act and portions of the GMP regulations that pertain to their systems.  A firm in a state of control produces finished drug products for which there is an adequate level of assurance of quality, strength, identity and purity. 3/19/2014 12INQC Consulting, Inc.
    13. 13. State of Control  Devices Compliance Program 7382.845, Inspections should generally start with a walk through of the facility to become familiar with the firm’s operations and general state of control.  Drug Manufacturing Inspections Program 7356.002, Coverage of a system should be sufficiently detailed so that the inspection outcome reflects the state of control in that system for every profile class. 3/19/2014 13INQC Consulting, Inc.
    14. 14. FDA Expectations* Assure a State of Control  Companies are accountable for the quality of the products they produce.  FDA evaluates the state of control using its quality systems inspection approach.  A robust quality system will assure a state of control *Regulatory Expectations of Executive Management, 2012, Steven Lynn, Office of Compliance, CDER/US FDA 3/19/2014 14INQC Consulting, Inc.
    15. 15. Compliance with GMP-item 2  FDA focus on "State of control" as a key compliance objective and indicator.  Contrast the GMPs for Finished Pharmaceuticals, Medical Devices, and combination products.  Review the FDA's Office of Regulatory Affairs system based inspection techniques for assessing compliance. 3/19/2014 15INQC Consulting, Inc.
    16. 16. Robust Quality System  We know that a robust quality system will assure a state of control.  Let's look at what the GMP (or QS regulation) require for a Robust Quality System.  First, drugs and devices are different.  Combination products are different. 3/19/2014 16INQC Consulting, Inc.
    17. 17. Drug/Pharmaceutical GMP  21 CFR 210 & 211, GMP for Finished Pharmaceuticals  GMP relates to drug products, the finished dosage form, ready for administration.  Drug products contain drug substances, the therapeutic ingredient.  Drug substances are regulated by FDA using the ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.  Compliance with ICH Q7 is not part of this presentation 3/19/2014 17INQC Consulting, Inc.
    18. 18. Medical Device QS regulations  21 CFR 820, Quality System regulation, is also known as the Good Manufacturing Practice for Medical Devices.  The law defines components and accessories of medical devices as medical devices.  21 CFR 820 compliance is required for finished devices intended for human use. 3/19/2014 18INQC Consulting, Inc.
    19. 19. Robust Quality System  The Drug GMP and Device GMP regulations provide a framework to build the Robust Quality System.  The Robust Quality System will enable operating in a State of Control.  We'll look at the Drug and Device GMPs on a side-by- side basis, and also at FDA's recent GMPs for combination products. 3/19/2014 19INQC Consulting, Inc.
    20. 20. Device and Drug GMP Medical Devices Finished Pharmaceuticals  General Provisions  Quality System Requirements  Design Controls  Document Controls  Purchasing Controls  Identification and Traceability  Production and Process Controls  Acceptance Activities  Nonconforming Product  Corrective and Preventive Action  Labeling and Packaging Control  Handling, Storage, Distribution, and Installation  Records  Servicing  Statistical Techniques  General Provisions  Organization and Personnel  Buildings and Facilities  Equipment  Control of Components and Drug Product Containers and Closures  Production and Process Controls  Packaging and Labeling Control  Holding and Distribution  Laboratory Controls  Records and Reports  Returned and Salvaged Drug Products 3/19/2014 20INQC Consulting, Inc.
    21. 21. Lot of differences- true?  Generally, the differences are in terms of details and additional requirements  Overall systems are pretty similar.  The FDA's approach to Combination Products provides more details.  Well, I see Statistical Techniques in the Device QSR, where is that in the Drug GMP?  The next slide shows some of the Drug GMP Subparts where Statistical Techniques are mandated. 3/19/2014 21INQC Consulting, Inc.
    22. 22. Statistical Techniques- Drug GMP  Sec. 211.84 Testing and approval or rejection of components, drug product containers  The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired.  Sec. 211.110 Sampling and testing of in-process materials and drug products.  Valid in-process specifications …determined by the application of suitable statistical procedures 3/19/2014 22INQC Consulting, Inc.
    23. 23. Combination Products  Combination Products are combinations of 2 or more DIFFERENT products:  Drug + Device  Device + Biologic  Drug + Biologic  Drug + Device + Biologic  The Device and Drug GMPs for a compliant quality system are consolidated in the GMPs for Combination Products. 3/19/2014 23INQC Consulting, Inc.
    24. 24. Combination Products  Regulated based upon how they are combined.  Co-packaged / Kit  Bandage with antimicrobial coating  Bandage packaged with tube of antibiotic ointment  Pre-filled delivery device, e.g., syringe or inhaler that contains drug or biologic (EpiPen, Advair)  Drug-eluting stent (Taxus, Xience)  Sold separately and labeled for use together  Light source and photo-activated drug (Photofrin)  IVD’s for monitoring drugs-biologics  Nebulizer and nebulizer solutions 3/19/2014 24INQC Consulting, Inc.
    25. 25. GMP for Combination Products  Uses the new regulation format-  Four sections 4.1 What is the scope of this subpart? 4.2 How does FDA define key terms and phrases in this subpart? 4.3 What current good manufacturing practice requirements apply to my combination product? 4.4 How can I comply with these current good manufacturing practice requirements for a co-packaged or single-entity combination product?  Not quite that simple! 3/19/2014 25INQC Consulting, Inc.
    26. 26. Complying with GMP regulations  Cross-labeled combination products:  Constituent parts are subject to the GMP requirements applicable to that type of article (e.g., drug GMPs if article is a drug).  Co-packaged and single-entity combination products:  Rule provides streamlined approach to comply with GMP requirements. 3/19/2014 26INQC Consulting, Inc.
    27. 27. Streamlined Approach  Co-packaged and single-entity combination products: Manufacturers subject to both the drug GMPs and device QS regulation may:  Implement both drug GMP and device QSR, or  Implement either the drug GMPs (at 21 CFR 210 and 211) or device Quality System regulation (at 21 CFR 820), if they also implement specified provisions of the other of these two sets of GMP requirements. 3/19/2014 27INQC Consulting, Inc.
    28. 28. Part 210/211 drug approach  You must also comply with these from device QSr  21 CFR 820.20 - Management responsibility  21 CFR 820.30 - Design controls  21 CFR 820.50 - Purchasing Controls  21CFR820.100 - Corrective and preventive action  21CFR820.170 - Installation  21CFR820.200 - Servicing 3/19/2014 28INQC Consulting, Inc.
    29. 29. Your Quality System-Drug +  General Provisions  Management responsibility  Organization and Personnel  Design controls  Buildings and Facilities  Equipment  Purchasing Controls  Control of Components and Drug Product Containers and Closures  Production and Process Controls  Packaging and Labeling Control  Corrective and preventive action  Holding and Distribution  Installation  Laboratory Controls  Records and Reports  Returned and Salvaged Drug Products  Servicing 3/19/2014 29INQC Consulting, Inc.
    30. 30. Part 820 device approach  You must also comply with these from drug GMP  21 CFR 211.84 - Testing and approval or rejection of components, drug product containers, and closures.  21 CFR 211.103 - Calculation of yield  21 CFR 211.132 - Tamper-evident packaging for over-the- counter (OTC) human drug products  21 CFR 211.137 - Expiration dating  21 CFR 211.165 - Testing and release for distribution  21 CFR 211.166 - Stability testing  21 CFR 211.167 - Special testing requirements  21 CFR 211.170 - Reserve samples 3/19/2014 30INQC Consulting, Inc.
    31. 31. Your Quality System-Device +  General Provisions  Quality System Requirements  Design Controls  Document Controls  Purchasing Controls  Identification and Traceability  Production and Process Controls  Acceptance Activities  Testing and approval or rejection of components, drug product containers, and closures  Testing and release for distribution  Stability testing  Special testing requirements  Reserve samples  Nonconforming Product  Calculation of yield  Corrective and Preventive Action  Labeling and Packaging Control  Tamper-evident packaging for over-the-counter (OTC) human drug products  Expiration dating  Handling, Storage, Distribution, and Installation  Records  Servicing  Statistical Techniques 3/19/2014 31INQC Consulting, Inc.
    32. 32. Compliance with GMP-item 3  FDA focus on "State of control" as a key compliance objective and indicator.  Contrast the GMPs for Finished Pharmaceuticals, Medical Devices, and combination products.  Review the FDA's Office of Regulatory Affairs system based inspection techniques for assessing compliance. 3/19/2014 32INQC Consulting, Inc.
    33. 33. Preparing for inspection  A robust quality system must be presented as such.  FDA publishes a Compliance Program Guidance Manual, with Drug Inspection Programs, Device Inspection Programs, and instructions to inspectors.  Know what the inspector is looking for, and be prepared to provide it.  Walk through your facility looking for evidence of problems.  If you have a robust quality system, be prepared and proud to show it. 3/19/2014 33INQC Consulting, Inc.
    34. 34. Inspection- Systems Approach  A GMP regulation checklist is not the FDA’s inspection method.  FDA has created a systems approach to inspections.  Related areas of the GMP become system elements.  Focusing on systems increases efficiency in conducting inspections.  Systems are often applicable to multiple profile classes. 3/19/2014 34INQC Consulting, Inc.
    35. 35. Systems for Drug GMP Inspections  QUALITY SYSTEM, Subparts B, E, F, G, I, J, and K.  FACILITIES AND EQUIPMENT SYSTEM, Subparts B, C, D, and J.  MATERIALS SYSTEM, Subparts B, E, H, and J.  PRODUCTION SYSTEM, Subparts B, F, and J.  PACKAGING AND LABELING SYSTEM, Subparts B, G, and J.  LABORATORY CONTROL SYSTEM, Subparts B, I, J, and K. -Subpart B Organization and Personnel -Subpart J Records and Reports 3/19/2014 35INQC Consulting, Inc.
    36. 36. Abbreviated Inspection  Surveillance or compliance inspection.  At least two systems but not more than three systems.  One must be the Quality System.  Assessment of the Quality System has two phases  Evaluate whether the Quality Unit has fulfilled the responsibility to review and approve all procedures related to production, quality control, and quality assurance and assure the procedures are adequate.  Assess the data collected to identify quality problems, may link to other system(s) 3/19/2014 36INQC Consulting, Inc.
    37. 37. Device’s Quality System Inspection Technique: “QSIT”  Incorporates the seven subsystems concept with these four considered Major subsystems :  Management  Design Controls  Corrective & Preventive Actions  Production & Process Controls  Remaining three subsystems evaluated as part of the four Major subsystems  Material Controls  Records, Documents, & Change Controls  Equipment & Facility Controls  Provides specific guidance on auditing each Major subsystem 3/19/2014 37INQC Consulting, Inc.
    38. 38. Management Focus  Management is responsible for implementing the Quality System  Inspection begins and ends with Management  All product, process, design, and CAPA problems can be tied to Management  Inspection Conclusion  “Did management ensure that an adequate and effective Quality System has been established?” 3/19/2014 38INQC Consulting, Inc.
    39. 39. Device Quality System Inspections Inspection Level Type of Inspection Guide to Inspections 1 Abbreviated QSIT – Two major subsystems; Corrective and Preventive Actions (CAPA) plus Production and Process Controls (P&PC) or Design Controls 2 Comprehensive QSIT – All four major subsystems; Management Controls, Design Controls, CAPA and P&PC 3 Compliance Follow-up* As directed by inspectional guidance and elements of QSIT Special For Cause* As directed by inspectional guidance and elements of QSIT Special Risk Based Work Plan As directed by CDRH inspection assignment and elements of QSIT 3/19/2014 39INQC Consulting, Inc.
    40. 40. Inspection Systems Compared Medical Devices Pharmaceuticals MANAGEMENT QUALITY SYSTEM DESIGN CONTROLS CAPA PRODUCTION & PROCESS CONTROLS PRODUCTION SYSTEM, PACKAGING AND LABELING SYSTEM Equipment & Facility Controls FACILITIES AND EQUIPMENT SYSTEM Records, Documents, & Change Controls QUALITY SYSTEM Material Controls MATERIALS SYSTEM LABORATORY CONTROL SYSTEM 3/19/2014 40INQC Consulting, Inc.
    41. 41. Take aways  GMP Compliance is not just important, but critical.  FDA expects a “State of Control” as the result of a robust quality system.  There are differences between Drug and Device GMPs.  Combination product GMPs show how to combine the different GMPs.  There are differences between system inspections done for drugs and those done for devices.  Prepare for FDA by using the inspection systems approach for internal audits. 3/19/2014 41INQC Consulting, Inc.
    42. 42. Thank you More information:  QSIT Guide http://www.fda.gov/downloads/ICECI/Inspections/UCM142981.pdf  Inspection Operations Manual http://www.fda.gov/ICECI/Inspections/IOM/default.htm  Office of Manufacturing and Product Quality http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProdu ctsandTobacco/CDER/ucm095412.htm  David Manalan, dmanalan@alum.MIT.edu 3/19/2014 42INQC Consulting, Inc.

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