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: DICE@fda.hhs.gov 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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