Regulatory Issues for Drugs, Devices, and Combination Products

1. David A. Manalan, FASQ
INQC Consulting, Inc.

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. 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. 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.
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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.
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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.
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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.
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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.
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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. 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.
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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
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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.
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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.
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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
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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.
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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.
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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
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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.
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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.
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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
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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.
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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
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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.
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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
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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!
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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.
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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.
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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
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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
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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
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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
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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. 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.
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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.
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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
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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)
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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
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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?”
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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
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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
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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.
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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
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