USFDA Foreign Priorities, Inspections and Compliance

by

USFDA Foreign Priorities, Inspections and Compliance

  • Priorities
  • Challenges of globalization
  • cGMP deficiencies
  • Comparison
  • Post inspection regulatory actionsAdvance Regulatory Science:  the science of developing new tools, standards and approaches to assess the safety and effectiveness, quality and performance of FDA-regulated productsStrengthen the safety and integrity of the global supply chain
    • A paradigm shift is required to meet this challenge: focus on prevention of threats
    • Innovative analytical tools
    • International capacity building

Advancing Regulatory Science at USFDA

  1. Modernize Toxicology
  2. Stimulate Innovation in Clinical Evaluations
  3. Support New Approaches to Improve Product Manufacturing and Quality
  4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies
  5. Harness Diverse Data through Information Sciences
  6. Implement a New Prevention-Focused Food Safety System to Protect Public Health
  7. Facilitate Development of Medical Countermeasures
  8. Strengthen Social and Behavioral Science – Make Informed Decisions about Regulated Products

Pathway to Global Product Safety and Quality

  • Global economic forces are having a dramatic effect on food and drug supply chains.
  • Cross border flows of goods, information and capital are increasing much faster than global GDP.

Four Pillars of the Strategy

1.Create global coalitions of regulators

2.Build global data-information systems and networks and proactively share data with peers

3.Expand intelligence-gathering, with an increased focus on risk analytics

4.Effectively allocate agency resources based on risk, and leveraging government, industry and public and private third parties

Globalization Challenges

  • Explosion of production of FDA-regulated goods
  • Distinction between domestic and imported products is obsolete
  • Supply chain more complex, oversight much more difficult
  • FDA-regulated products originate from more than 150 countries and pass through 300 ports of entry
  1. 130,000 importers
  2. 300,000 foreign facilities
  • Increase in variety and complexity of imported medical products
  • Growing demand, yet constrained supply

Understanding FDA’s Approach and Expectations

  • Communicate
  • Leverage Resources
  • Establish and use new “tools”
  • Secure supply chain
  • Become a global agency
  1. Stop distinguishing between foreign and domestic procedures, policies, and expectations

Objectives of FDA’s Foreign Offices

  • Gain improved knowledge about product manufacturing and transport to the United States.
  • Leverage knowledge and resources and strengthen capacity to better assure product safety.
  • Work with regulated industry so they will better understand FDA regulations, standards and guidance.
  • Coordinate with USG colleagues in-country (e.g., USDA/FAS, DOC/CBP, USAID, USTR,) on approaches to enhance product safety  and
  • Increase capacity to perform more timely FDA overseas inspections, especially of high risk products.

FDA’s Enforcement Priorities

  • Drug quality in OTCs
  • Assure investigations (complaints, rejects) are prompt and root causes corrected
  • Data integrity and quality systems
  • ØSupply chain security
  1. Contract manufacturers
  2. Raw material/excipient vendor qualification programs
  • Combating economically motivated adulterated products/ingredients
  • Field alert reporting (defect reports)
  • Contaminated, sub- or super-potent, high-risk compounded drugs
  • Post-market adverse event reporting

Major Inspection Types

1.Pre-approval

2.“For-cause” or directed

3.Post-marketing adverse drug event

4.CGMP surveillance (routine)

Foreign establishments routinely inspected

Manufacturers of drugs, including

  • API and dosage form
  • human and animal
  • biotech, vaccine, etc. (biologicals)

Re-packagers/re-labelers

Independent sterilizers

Independent laboratories

FDA’s Inspectorate

1,700 investigators in our field offices conducting domestic inspections

About 400 investigators and 150 analysts qualified  to conduct  foreign inspections (all commodities)

Dedicated Foreign Cadres

–Drugs

–Foods

–Medical devices

FDA Foreign Inspections types

Factors which result in inspections

  • Pre-Approval Submissions (PEPFAR)
  • Routine surveillance
  • Follow – up
  • Food assessments
  • MOUs/international agreements
  • Import issues
  • Emergencies

FDA inspection process

FDA -

 

  • Are fact finding
  • Require evidence
  • Require organization and time management
  • Are regulatory

Purpose of GMP Audits

  • To ensure that adequate quality systems are maintained.
  • To assess compliance with the cGMP’s and firm’s standard operating procedures.
  • To identify problems that can impact product quality.
  • To assure there is  a procedure for investigating non-compliance with the quality system and for prescribing and verifying corrective action.  The procedures should include a description of how records of corrective actions are maintained.

System Based Inspections

GMP Inspections will follow a system based inspectional approach.  The Quality System will always be covered while coverage of the other 5 systems will be rotated.

  • Quality System
  • Facilities and Equipment System
  • Materials System
  • Production System
  • Laboratory System
  • Packaging and Labeling System

Product Risk Analysis

Common Elements

  • Difficulty associated with manufacturing process, products with most critical manufacturing steps (sterile/non-sterile, wet granulation/dry blends, suspensions/solutions Hazard identification
  • Severity ranking
  • Probability ranking (with cause identification)
  • Assessment of risk level for each identified hazard (risk matrix)

Inspection objectives

  • Conduct inspection in accordance with FDA law and regulations
    Current Good Manufacturing Practice
  • Accomplish what is necessary per established inspection procedures
    (“Compliance Programs”)
  • Follow-up on additional questions/ concerns in inspection assignment

CGMP Inspection Programs (Compliance Program Guidance Manuals)

Pre-approval:

  • 7346.832/7352.832, Pre-Approval Inspections/Investigations

Post-Approval/Surveillance:

  • 7356.002, Drug Process Inspections
  • Sterile Drug Process Inspections
  • Drug Repackers and relabelers
  • Radioactive Drugs
  • Compressed Medical Gases
  • Active Pharmaceutical Ingredients Process Inspections
  • Inspections of Licensed Biological Therapeutic Drug Products

Refer to: http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm

Inspection Participation

  • Investigators (inspectors)
  • Analysts (lab experts)
  • GMP Assessors/Evaluators
  • Product Reviewers/Assessors
  • Other Specialists

Systems-Based Approach

  • Quality Systems
  • Materials Management
  • Production
  • Facilities & Equipment
  • Packaging & Labeling
  • Laboratory Control

FDA 1 -

Conduct of an inspection

Quality

  • Annual Product Reviews
  • List of non-conformance reports
  • Out-of-specification results
  • Complaints
  • Rejected/Aborted/Destroyed batches
  • Field Alerts (defect reports)
  • Corrective actions since previous inspection

Materials Management (ingredients & packaging)

  • Separation and control of materials
  • Identification of materials
  • Labeling practices
  • Sampling of incoming materials
  • Inventory control systems

Production

  • Personnel practices
  • Contemporaneous completion of documents
  • Written procedures
  • Calibration stickers for critical equipment
  • Condition of equipment

Facilities & Equipment

  • Equipment design
  • Heating/Ventilation/Cooling systems
  • Water systems

Packaging and Labeling

  • Appropriate controls
  • Line clearance procedures
  • Visual inspection procedures (sterile products)
  • Label issuance and reconciliation documents

Laboratory control

  • Raw data practices
  • Sample flow
  • Sample/standard identification
  • Status of the instruments
  • Stability
  • Methods in use

Conclusion of an inspection

Formal close out

May include:

  • Sample collections
  • Issuance of FDA 483,
  • Inspectional Observations

Top 10 deficiencies cited  in international inspections

  • Inadequate Quality Systems
  • Lack of investigations of batches that fail to meet specifications
  • Lack of written procedures or inadequate SOPs
  • Inadequate laboratory controls
  • Un-validated test methods
  • Inadequate stability program
  • Inadequate process validation or no process validation
  • Lack of process controls that validate the performance of manufacturing process
  • Inadequate validation of equipment cleaning and maintenance cleaning.
  • Inadequate controls of components, intermediates, and raw materials

Top 10 common deficiencies cited in India

  • Inadequate Quality Systems
  • Lack of investigations of batches that fail to meet specifications
  • Deficient records and reports
  • Inadequate process validation or no process validation
  • Lack of process controls that validate the performance of manufacturing process.
  • Inadequate laboratory controls
  • Inadequate stability program
  • Lack of written procedures or inadequate SOPs
  • Inadequate controls of components, intermediates, and raw materials
  • Inadequate validation of equipment cleaning and   maintenance cleaning

After the inspection

Write the Establishment Inspection Report (EIR)

  • Must be done in a timely manner–

Submit recommendation

EIR reviewed by GMP product experts

Final classification of inspection (acceptable, unacceptable: Warning Letter, Untitled Letter, Import Alert etc.)

Global marketplace

Ensuring safe, effective and quality foods and drugs for the citizens of India, the United States and the world

Key Initiatives

1.Set post-inspection deadlines

2.Take responsible steps to speed the warning letter process

3.Work more closely with FDA’s regulatory partners.

4.Swift, appropriate enforcement action with prioritizing on follow-up.

5.Be prepared to take immediate action in response to public health risks

6.Develop and implement a formal warning letter “close-out” process

 

Referances:PPT on FDA Foreign Priorities, Inspections and Compliance by Bruce Ross, M.A. M.P.H.Director, India Office

 

 

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