Lyophilization Processes: A ComplianceEnforcement Perspective

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Lyophilization ProcessesA Compliance/Enforcement
Perspective

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

DELAWARE VALLEY CHAPTER MEETING of
the INTERNATIONAL SOCIETY OF LYOPHILIZATION PLYMOU
TH MEETING, PA JANUARY 25, 2005
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OBJECTIVES

• Organizational Structure of FDA Compliance
• FDAs Regulatory Options/Enforcement Posture
• Specific Examples of Deviations
• Written Responses
• Dispute Resolution

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F D A
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OFFICE OF REGULATORY AFFAIRS
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FDA DISTRICT

• ORA DISTRICT INVESTIGATOR
• ORA DISTRICT COMPLIANCE BRANCH
• APPROPRIATE CENTER FOR REVIEW AND CONCURRENCE
  (CDER)
• OFFICE OF CHIEF COUNSEL
• ORA OFFICE OF ENFORCEMENT (HIGHER ACTIONS SUCH AS
  INJUNCTIONS, ETC.)

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FDA DISTRICTS

• LETTER ISSUED OR ACTION EXECUTED BY ORA DISTRICT
  STAFF
• RESPONSES AND COMMUNICATIONS COORDINATED WITH
  DISTRICT STAFF

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TEAM BIOLOGICS - Inspections

• SPECIALIZED GROUP OF ORA INVESTIGATORS THAT
  REPORT TO ORAs OFFICE OF REGIONAL OPERATIONS
• PRODUCTS COVERED
• Vaccines, Allergenic Products, Plasma
  Fractionated Products, In Vitro Diagnostic
  Products, and Therapeutic Products (CBER and
  CDER)
• Domestic and Foreign Establishments

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TEAM BIOLOGICS - Compliance

• SPECIALIZED GROUP OF ORA COMPLIANCE OFFICERS THAT
  REPORT TO ORAS OFFICE OF ENFORCEMENT
• REVIEW AND EVALUATE INSPECTIONS PERFORMED BY TEAM
  BIOLOGICS INVESTIGATORS
• WORK CLOSELY WITH CBER AND CDER COMPLIANCE
• SUBJECT TO OCC REVIEW PROCEDURES

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CENTER COMPLIANCE

• CBER OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY
• CDER OFFICE OF COMPLIANCE

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REGULATORY OPTIONS

• ADVISORY ACTIONS
• UNTITLED LETTERS
• 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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REGULATORY OPTIONS

• ADVISORY ACTIONS (contd)
• 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 FDC 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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REGULATORY OPTIONS

• ADMINISTRATIVE ACTIONS
• CITATIONS
• DETENTIONS OF PRODUCT
• LICENSE SUSPENSION AND REVOCATION
• CIVIL MONEY PENALTIES
• FDA ORDERED RECALLS (LIMITED)

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JUDICIAL ACTIONS

• SEIZURES an action against the product, not a
  person
• INJUNCTIONS to prevent future violations of law
• PROSECUTIONS a punitive action for past
  violations of law

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ENFORCEMENT POSTURE

• CONSUMER ACCESS TO SAFE AND EFFECTIVE PRODUCTS
• VOLUNTARY CORRECTION

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ENFORCEMENT POSTURE

• PRODUCTS SCOPE AND IMPACT
• PRIOR HISTORY VERY IMPORTANT
• PREVIOUS INSPECTIONAL FINDINGS
• RESPONSES
• EFFECTIVENESS OF CORRECTIVE ACTIONS AND
  PREVENTATIVE MEASURES
• ADVISORY AND ENFORCEMENT ACTIONS

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ENFORCEMENT POSTURE

• IMPORT ACTIVITIES
• ALERTS
• DETENTION OF PRODUCT
• REFUSAL OF ENTRY

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VIOLATION EXAMPLES

• a 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 performed

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VIOLATION EXAMPLES

• The lyophilization cycle for the vial
  configuration has not been validated.

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VIOLATION EXAMPLES

• Failure to notify FDAofchanges in equipment
  and the product process for your productin
  thata six shelflyophilizer was installed and
  is being utilized in the freeze drying of your
  product.

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VIOLATION EXAMPLES

• lyophilizerdid not achieve the specified
  pressure during primary dryingPartially
  stoppered product vials were storedfor 62 hours
  inside lyophilizerno documentation that the
  impactwas evaluated

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VIOLATION EXAMPLES

• the lyophilization cycle currently in usehas
  not been validated

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VIOLATION EXAMPLES

• process validation was performed using data
  from eight lyophilization runs. Three lots were
  rejected, and one lot was not released

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VIOLATION EXAMPLES

• Failure to validate processes which can not be
  verified by subsequent inspection in that the
  lyophilization process has not been validated.

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RESPONSES

• Clear understanding of the deviation/violation
• If you dont agree, then say so. Explain your
  reasoning
• How and when???
• - During the inspection,
• - At the closeout,
• - In your written response.

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RESPONSES

• 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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RESPONSES

• - 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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Dispute Resolution

• Policies and procedures that would allow rapid,
  objective resolution of scientific and technical
  questions and issues that may arise either during
  an inspection or as the result of an inspection.

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Dispute Resolution Working Group

• The goal of the working group was to promote
  integrity, neutrality, consistency, transparency,
  fairness and scientific soundness in the dispute
  resolution process.

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WHO MAY DISPUTE?

• The Manufacturer or Establishment that was
  inspected.
• Domestic or International Entity
• Human and Veterinary Drugs
• Human Biological Drugs

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WHY WOULD YOU DISPUTE?

• A SATISFACTORY RESOLUTION COULD NOT BE OBTAINED
  DURING THE INSPECTION(complexity, etc)
• - AND -
• THE FDA-483 HAS BEEN ISSUED

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What May Be Disputed?

• A Scientific or Technical Issue related to Good
  Manufacturing Practices
• Adequacy
• Appropriateness
• Interpretation
• A Scientific or Technical Issue Raised During an
  Inspection
• GMP CBER/CDER/CVM or
• PAI CDER/CVM

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What May Not Be Disputed?

• Precise Requirements of the regulations or in
  an Approved Application
• Issues Not Raised During An Inspection
• Procedural or Administrative Issues
• Writing style/wording differences

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WHEN CAN YOU DISPUTE?

• 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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WHEN?

• TIER-1 WITHIN 10 BUSINESS DAYS OF THE ISSUANCE
  OF THE 483
• TIER-2 WITHIN 60 DAYS OF RECEIPT OF THE TIER-1
  DECISION
• Failure to adhere to these time frames could
  result in a refusal to consider

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TIER-1 Initial Request For Resolution

• Nature of dispute in written format
• Include supporting documentation
• This should not include any information that was
  not presented to the Inspection Team during the
  inspection.

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TIER-1 Process

• ORA Review and Evaluation
• Written response within 30 days
• We agree with you
• We disagree with you
• You request does not qualify or additional
  review time is needed

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TIER-2 APPEAL INITIAL DECISION

• Must be in written format
• Request resolution by D.R. Panel
• Nature of continuing dispute
• Include supporting documents

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TIER-2 Process

• Dispute Resolution Panel
• Panel Membership (integrated and neutral no
  previously involved decision makers)
• Decide to accept, review, and evaluate
• Dispute is reviewed during Panel Meetings

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TIER-2 Process

• D.R. Panel Review and Evaluation
• Written response within 30 days
• We agree with you
• We disagree with you
• You request does not qualify or additional
  review time is needed

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FINAL DECISIONSTIER-1 and TIER-2

• The Program Center is notified and makes decision
  available for public dissemination, to promote
  consistency of application and interpretation.

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Questions?
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References

• Warning Letters are posted at www.fda.gov
• Inspectional Guidances www.fda.gov/ora/inspect_r
  ef
• Title 21 Code of Federal Regulations (CFR)
• Draft Dispute Resolution Procedures
• www.fda.gov/cder/guidance/5804dft.htm