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Anne Johnson, Compliance Officer
Office of Regulatory Affairs/Office of Enforcement
Division of Compliance Management and Operations

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½ Organizational Structure of FDA Compliance

½ FDAƞs Regulatory Options/Enforcement Posture

½ Specific Examples of Deviations

½ Written Responses

½ Dispute Resolution
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½ ORA DISTRICT INVESTIGATOR
½ ORA DISTRICT COMPLIANCE BRANCH
½ APPROPRIATE CENTER FOR REVIEW AND
CONCURRENCE (CDER)
½ OFFICE OF CHIEF COUNSEL
½ ORA OFFICE OF ENFORCEMENT (HIGHER
ACTIONS SUCH AS INJUNCTIONS, ETC.)
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½ LETTER ISSUED OR ACTION EXECUTED

BY ORA DISTRICT STAFF

½ RESPONSES AND COMMUNICATIONS

COORDINATED WITH DISTRICT STAFF
 
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½ SPECIALIZED GROUP OF ORA INVESTIGATORS

THAT REPORT TO ORAƞs OFFICE OF REGIONAL
OPERATIONS

½ PRODUCTS COVERED:
½ Vaccines, Allergenic Products, Plasma Fractionated
Products, In Vitro Diagnostic Products, and
Therapeutic Products (CBER and CDER)

½ Domestic and Foreign Establishments

 
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½ SPECIALIZED GROUP OF ORA COMPLIANCE OFFICERS

THAT REPORT TO ORAƞS OFFICE OF ENFORCEMENT

½ REVIEW AND EVALUATE INSPECTIONS PERFORMED BY

TEAM BIOLOGICS INVESTIGATORS

½ WORK CLOSELY WITH CBER AND CDER COMPLIANCE

½ SUBJECT TO OCC REVIEW PROCEDURES

  
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½ CBER OFFICE OF
COMPLIANCE AND
BIOLOGICS QUALITY

½ CDER OFFICE OF
COMPLIANCE
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½ ADVISORY ACTIONS

½ UNTITLED LETTERS ƛ

The agency has a need to communicate with

regulated industry about documented
violations that do not meet the threshold of
regulatory significance
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½ ADVISORY ACTIONS (contƞd):

WARNING LETTERS

A Warning Letter is a written communication from FDA

notifying an individual or firm that the agency considers
one or more products, practices, processes, or other
activities to be in violation of the Federal FD&C Act, or
other acts, and that failure of the responsible party to
take appropriate and prompt action to correct and
prevent any future repeat of the violation, may result in
administrative and/or regulatory enforcement action
without further notice.
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½ ADMINISTRATIVE ACTIONS

½ CITATIONS
½ DETENTIONS OF PRODUCT
½ LICENSE SUSPENSION AND REVOCATION
½ CIVIL MONEY PENALTIES
½ FDA ORDERED RECALLS (LIMITED)
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½ SEIZURES ƛ an action
against the product, not a
person

½ INJUNCTIONS ƛ to
prevent future violations
of law

½ PROSECUTIONS ƛ a
punitive action for past
violations of law
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½ CONSUMER ACCESS TO SAFE AND

EFFECTIVE PRODUCTS

½ VOLUNTARY CORRECTION
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½ PRODUCTS ƛ SCOPE AND IMPACT

½ PRIOR HISTORY ƛ VERY IMPORTANT

½ PREVIOUS INSPECTIONAL FINDINGS
½ RESPONSES
½ EFFECTIVENESS OF CORRECTIVE ACTIONS AND
PREVENTATIVE MEASURES
½ ADVISORY AND ENFORCEMENT ACTIONS
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IMPORT ACTIVITIES

½ ALERTS

½ DETENTION OF PRODUCT

½ REFUSAL OF ENTRY
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ƠƦa temperature distribution study to

assure that all shelves of the lyophilizers
obtain and maintain a temperature of -
40ºC during freeze drying operations has
not been performedƦơ
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ƠThe lyophilization cycle for the vial

configuration has not been validated.ơ
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ƠFailure to notify FDAƦofƦchanges in

equipment and the product process for
your productƦin that:Ʀa six
shelfƦlyophilizer was installed and is being
utilized in the freeze drying of your
product.ơ
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ƠƦlyophilizerƦdid not achieve the specified

pressure during primary dryingƦPartially
stoppered product vials were storedƦfor
62 hours inside lyophilizerƦno
documentation that the impactƦwas
evaluatedƦơ
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ƠƦthe lyophilization cycle currently in

useƦhas not been validatedƦơ
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ƠƦprocess validation was performed using

data from eight lyophilization runs. Three
lots were rejected, and one lot was not
releasedƦơ
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ƠFailure to validate processes which can not

be verified by subsequent inspection Ʀin
that the lyophilization process has not
been validated.ơ
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å. Clear understanding of the deviation/violation

2. If you donƞt agree, then say so. Explain your

reasoningƦ

How and when???

- During the inspection,
- At the closeout,
- In your written response.
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An evaluation of the deviation/violation that
includes:

- the specific incident(s) cited

- impact on product(s) or process(es)

- specific corrective actions for that

incident
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- possibility of other affected lots, products,
processes, manufacturing locations

- affected marketed lots/products

- global corrective actions, employee

training, SOP revisions, etc.
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½ Policies and procedures that would allow

à
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, ecte resolution of
ent
scent
and e    questions and issues that
may arise either during an inspection or as
the result of an inspection.
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½ The goal of the working group was to

promote  egà euà 


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in the dispute
resolution process.
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½ The Manufacturer or Establishment that
was inspected.

½ Domestic or International Entity

½ Human and Veterinary Drugs

½ Human Biological Drugs


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½ A SATISFACTORY RESOLUTION COULD

NOT BE OBTAINED DURING THE
INSPECTIONƦ(complexity, etc)

- AND -

½ THE FDA-
FDA-483 HAS BEEN ISSUED
 

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½ A Scientific or Technical Issue related to
Good Manufacturing Practices
½ Adequacy
½ Appropriateness
½ Interpretation

½ A Scientific or Technical Issue Raised

During an Inspection
GMP [CBER/CDER/CVM] or
PAI [CDER/CVM]
 



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½ ƠPrecise Requirementsơ of the regulations
or in an Approved Application

½ Issues Not Raised During An Inspection

½ Procedural or Administrative Issues

½ Writing style/wording differences



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DURING THE INSPECTION, FDA

STRONGLY ENCOURAGES OPEN
DIALOGUE ON ALL ISSUES BY AND WITH
THE INSPECTION TEAM IN HOPES TO
HAVE ALL ISSUES UNDERSTOOD AND
RESOLVED, IN THE MOST EFFICIENT
MANNER.
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½ TIER-å: WITHIN å0 BUSINESS DAYS OF
TIER-
THE ISSUANCE OF THE 483

½ TIER-2: WITHIN 60 DAYS OF RECEIPT

TIER-
OF THE TIER-
TIER-å DECISION

Failure to adhere to these time frames could

result in a refusal to considerƦ
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å. Nature of dispute in written format

2. Include supporting documentation *

*This should not include any information that was not

presented to the Inspection Team during the
inspection.
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½ ORA Review and Evaluation

½ Written response within 30 days:

½ We agree with you
½ We disagree with you
½ You request does not qualify or
additional review time is needed
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å. Must be in written format

2. Request resolution by D.R. Panel
3. Nature of continuing dispute
4. Include supporting documents
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½ Dispute Resolution Panel

½ Panel Memership (integrated and neutral Ɗ no

previously involved decision makers)

½ Decide to accept, review, and evaluate

½ Dispute is reviewed during Panel Meetings

 --)




½ D.R. Panel Review and Evaluation

½ Written response within 30 days:

½ We agree with you
½ We disagree with you
½ You request does not qualify or
additional review time is needed
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½ The Program Center is notified and makes

decision available for public dissemination,
to promote consistency of application and
interpretation.
  
Warning Letters are posted at: www.fda.gov

Inspectional Guidances:
www.fda.gov/ora/inspect_ref

Title 2å Code of Federal Regulations (CFR)

Draft Dispute Resolution Procedures:

www.fda.gov/cder/guidance/5804dft.htm