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TRANSCRIPT
Regulations & Warning Letters Related
to Device Validation and
Manufacturing
Medical Device Validation Week
San Diego, CA
March 29, 2016
Dr. Raymond W. Brullo, DPMDoctor of Podiatric Medicine
Compliance Officer
Office of Regulatory Affairs/Los Angeles District Office
U.S. Food and Drug Administration
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Learning Objectives
• Understand Background and Definitions
• Know Process Validation Regulations
• Be aware of Regulatory Actions Related to
Device Validation and Quality System
Regulations
• Be Equipped with WL Data and
Resources
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Background• The Quality System Regulation [e.g. P&PC]
• Preamble to QS Regulation [search: 61 FR 52602]
• GHTF [IMDRF] Guidance: Quality Management System Medical Devices – Process Validation Guidance; SG3; 2004
• FDA Guidance Process Validation: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf
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Background
Production and Process Control linkages to other sections of the Quality System
• Design Control
• Purchasing Controls
• Personnel
Quality System Regulation
Definitions 21 CFR 820.3 (aa)
Verification means confirmation by
examination and provision of objective
evidence that specified requirements have
been fulfilled.
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Quality System Regulation
Definitions 21 CFR 820.3 (z)
Validation means confirmation by
examination and provision of objective
evidence that the particular requirements
for a specific intended use can be
consistently fulfilled.
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Quality System Regulation
Definitions 21 CFR 820.3 (z)(1)
Process Validation means establishing
by objective evidence that a process
consistently produces a result or product
meeting its predetermined specifications.
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Food Drug Cosmetic Act – 501(h)
• This inspection revealed that your devices are
adulterated within the meaning of section 501(h)
of the Act, 21 U.S.C. § 351(h), in that the
methods used in, or the facilities or controls
used for, their manufacture, packing, storage, or
installation are not in conformance with the
current Good Manufacturing Practice (cGMP)
requirements for medical devices which are set
forth in …, as specified in Title 21, Code of
Federal Regulations (CFR), Part 820. 8
Regulatory Requirements
Where the results of a process cannot
be fully verified by subsequent
inspection and test, the process shall be
validated with a high degree of
assurance and approved according to
established procedures.
21 CFR 820.75(a)
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Regulatory Requirements
The validated activities and results,
including the date and signature of the
individual(s) approving the validation
and where appropriate the major
equipment validated, shall be
documented.
21 CFR 820.75 (a)
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Warning Letter - 820.75(a)
• Manufacturer - ceramic dental brackets
• For example, your firm has not validated the following
processes for the manufacture of your ceramic
orthodontic brackets:
• The tumbling of your brackets using tumbling matter,
Alumina Balls 95% and water. The bracket coating
processes “A” and “B”. Both coating processes require a
series of cleaning, heating, and mixing steps.
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Personnel Performing Validation
• Each manufacturer shall ensure that validated
processes are performed by qualified
individual(s). 21 CFR 820.75(b)(1). WL = 0
• Related: make personnel who perform
verification & validation activities aware of
defects and errors that could be encountered as
part of their job. 21 CFR 820.25
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Warning Letter - 820.25
• Manufacturer – wound dressings
• Employees of your firm who are responsible for
the development, manufacture, storage and
distribution of medical devices are not trained
with respect to established quality objectives
related to the performance of their jobs. Further,
written operating procedures that coincide with
the requirements of the current Good
Manufacturing Procedures have not been
established 13
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Regulatory Requirements
Equipment. Each manufacturer shall ensure
that all equipment used in the manufacturing
process meets specified requirements and is
appropriately designed, constructed, placed,
and installed to facilitate maintenance,
adjustment, cleaning and use.
21 CFR 820.70(g)
Warning Letter - 820.70(g)
• Manufacturer – electrical stimulation devices promoted
for uses other than Therapeutic Massager
• For example, you stated your firm had no calibration
records for its Fluke digital multimeter; Simpson Analog
VOM; Owon Oscilloscope; and Sorenson Digital Power
Supply.
• Also misbranded per: 501(f)(1)(b); 520(g); 502(o). Lack
of: Premarket Approval; Investigational Device
Exemption; 510(k) – due to violative claims
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Regulatory Requirements
Each manufacturer shall establish and
maintain procedures for monitoring and
control of process parameters for
validated processes to ensure that the
specified requirements continue to be
met.
21 CFR 820.75(b)
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Warning Letter – 820.75(b)
• Manufacturer – vascular implants and catheters
• Your firm performs process monitoring on forty-
four validated processes that are considered
critical; however, this monitoring is required to
be performed once every 5 years and
evaluations for revalidation have not occurred
since the initial validations of these processes.
This frequency does not provide for sufficient
detection and mitigation of process drifts.
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Production and Process Changes
Establish and maintain procedures for changes
to a specification, method, process or
procedure. Such changes shall be verified or
where appropriate validated according to 21
CFR 820.75 before implementation…Changes
shall be approved in accordance with 21 CFR
820.40
21 CFR 820.70(b)
Warning Letter - 820.70(b)
• Manufacturer – synthetic bone grafts
• Specifically, your firm made changes to product or
process specifications without verifying or validating that
the changes would have no adverse effect on the final
product.
• For example, you made a change to raw material
specifications for porosity, bulk density, and pH on
6/21/12. Your firm lacks objective evidence of verification
and/or validation activities for all of these changes
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Revalidation
When changes or process deviations
occur, the manufacturer shall review
and evaluate the process and perform
revalidation where appropriate. These
activities shall be documented.
21 CFR 820.75(c)
Warning Letter - 820.75(c)
• Manufacturer – foldable implantable eye lenses
• Specifically, your firm has not established a real-time
stability protocol or conducted a stability study
supporting the two year shelf-life. In addition, there are
no documents and control methods and data, the date
performed and the individual performing the process
• Your firm management reported that they do not have a
procedure and do not monitor production samples for
lenses for shelf-life and stated they do not retain
production lenses that could be used to monitor shelf-life
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Software and Testing MethodsWhen computers or automated data processing
systems are used as part of production or the
quality system, the manufacturer shall validate
computer software for its intended use according to
an established protocol. 21CFR 820.70(i)
Each manufacturer shall ensure that all inspection,
measuring, and test equipment…is suitable for its
intended use and is capable of producing valid
results. 21 CFR 820.72(a)22
Warning Letter – 820.70(i)
• Manufacturer – dermal micro-channeling system
• For example, your firm uses the software Access,
developed by Microsoft, to document, maintain, and
track customer complaints electronically. However, as
stated by your firm’s Director of Quality Assurance (QA)
& Regulatory Affairs (RA) during the inspection, the
software does not generate time-stamped audit trails to
independently record the date and time of operator
entries and actions that create, edit, or modify electronic
records
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Warning Letter – 820.72(a)
• Manufacturer – infusion pumps
• Specifically, your procedure containing calibration
instructions for the cell load tester, that was used to test
infusion pumps, does not contain sufficient instructions
to ensure routine calibration and maintenance, adequate
instructions for completing calibration, adequate
documentation of calibration results, and provisions for
remedial action to correct the fixture if not operating
within precision or accuracy limits
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CY2014 FDA Form 483 (483)
Observations Data
• Source of data - FDA’s Turbo Establishment Inspection Reporting (EIR) Database
• Timeframe January 1 – December 31, 2014
• 2201 Inspections performed, 1741 domestic
• 3,740 FDA Form 483 observations cited for 21 CFR 820 (Quality System regulation) deficiencies
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CY2014 483 Observations Data
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QS Subsystem# of
ObservationsPercentage
P&PC 1,197 32%
CAPA 1,148 31%
DES 515 14%
MGMT 497 13%
DOC 383 10%
3,740
CY2014 Top 5 P&PC Observations
Observation (QS Regulation) # of ObservationsPercentage of Total
P&PC
21 CFR 820.75(a) 175 15%
21 CFR 820.50 143 12%
21 CFR 820.70(a) 95 8%
21 CFR 820.72(a) 74 6%
21 CFR 820.80(b) 56 5%
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FDA Warning Letter (WL)
Citations
• Source of data - FDA’s warning letters and FDA’s Compliance Management System (CMS)
• Timeframe January 1 – December 31, 2014
• 121 warning letters with 21 CFR 820 (Quality System regulation*) deficiencies
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Most Frequent CY2014 QS Warning Letter
Cites
WL Citation QS Subsystem # of WL Cites
21 CFR 820.100(a) CAPA 77
21 CFR 820.198(a) CAPA 55
21 CFR 820.75(a) P&PC 35
21 CFR 820.30(g) DES 31
21 CFR 820.90(a) CAPA 27
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Summary
• Guidances exist to understand validation
activities, particularly process validation
• The completion of appropriate process validation
can help reduce waste, cost and time it takes to
get your medical devices to the marketplace
• You are legally obligated to meet the regulatory
requirements in 21 CFR 820
• Significant deficiencies [CFR] and violations [the
FDCA] may result in regulatory actions
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Providing Industry EducationFDA Internet Resources
1. CDRH Learn – Multi-Media Industry Education over 80 modules videos, audio recordings, power point presentations, software-based “how to” modules mobile-friendly: access CDRH Learn on your portable deviceshttp://www.fda.gov/Training/CDRHLearn
2. Device Advice – Text-Based Education comprehensive regulatory information on premarket and postmarket topicshttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance
3. Division of Industry and Consumer Education (DICE) Contact DICE if you have a question Email: [email protected] Phone: 1(800) 638-2014 or (301) 796-7100 (Hours: 9 am-12:30 pm; 1 pm-4:30pm EST) Web: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ContactUs--
DivisionofIndustryandConsumerEducation/default.htm
Thank you
• Dr. Raymond W. Brullo
• 19701 Fairchild, Irvine, CA 92612
• Office [direct]: 949.608.2918
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