Transcript Requirements for the Quality of API from FDA

Requirements for the Quality of
API from FDA Perspective
Brenda Uratani, Ph.D.
FDA Assistant Country Director, China
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Today’s agenda
• Introducing the FDA China Office
• FDA’s requirements for API manufacturing
• Selected Topics and Issues of Most
Concern
• FDA Initiatives on API manufacturing and
drug safety
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Challenges
• Significant demand in resources for inspections
• Consequences of globalization, including more
foreign manufacturing and clinical trials sites
• Greater complexity associated with
manufacturing
• FDA concern about the state of industry
compliance and insufficient investment in
manufacturing and quality systems
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FDA International Efforts
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Beyond Our Borders Initiative
• FDA in-country offices
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Awareness
Capacity building
Standards/inspections
Collaboration
Leveraging opportunities
Locations:
• China, India, EU, Latin America, Middle East
• Leveraging projects
– Pilots/Info sharing
• EMEA pilot
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FDA China Office
In-Country Staff
Beijing
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Chris Hickey, Office Director
Mike Kravchuk, Deputy (device)
Brenda Uratani (drug)
Irene Chan (food)
Shanghai
– Charles Ahn (drug inspection)
– BJ Marciante (device inspection)
Guangzhou
– Dennis Doupnik (food inspection)
– Dennis Hudson (food inspection)
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Agreements Between HHS and SFDA: Key Provisions
Signed December 2007
– Key Provisions:
• All Chinese Producers of Designated Drugs and Devices
Required to Register with SFDA
• Goal: Certify Products Exported to the United States Meet
FDA Standards
• Joint Training/Capacity Building
• Greater/More Rapid Information Sharing
• Greater Access to Facilities
• Product Integrity: Tracking System of Products Likely to Be
Counterfeited
• Strengthened FDA, SFDA Collaboration Under WHO
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• Implementation Focus on Specific Set of Drugs, Devices
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FDA China Office
What Are We Doing?
◦ Continuing to Strengthen Working Relations with
SFDA
◦ Engage in Strategic Capacity Building of,
Confidence Building with SFDA, Provincial and
Municipal Authorities
◦ Work with Regulated Industry re: Exports to U.S.,
FDA Standards and Processes
◦ Monitor and Report on Conditions and Events that
Might Affect the Safety and Quality of FDARegulated Products
◦ Regulatory Reform/Legal Assistance
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◦ Increasing inspections
at
facilities
that
Beijing
CGMP
Requirements & Principles
for API Manufacturing
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CGMP
• C” = current
dynamic and evolve over time
• “GMP” = Good Manufacturing Practices
–Minimal standards
–Not “best” practices unless “best” is, in
fact, current minimal.
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FDA Requirements for API
Historical Perspectives
• 21 CFR 211: Current good manufacturing
practice for finished pharmaceuticals
• FD &C Act Sec 501 (a)(2)(B): drug
• ICH Q7A: Good Manufacturing Practice
Guide for Active Pharmaceutical
Ingredients (November 2000)
• FDA has been inspecting API for decades
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ICH Q7A
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Quality Management
Personnel
Buildings and Facilities
Process Equipment
Documentation and Records
Material Management
Production & In-Process
Controls
• Packaging & Identification
Labeling of APIs &
Intermediates
• Storage & Distribution
• Laboratory Controls
• Validation
• Change Control
• Rejection & Re-Use of
Materials
• Complaints and Recalls
• Contract manufacturers
(including Laboratories)
• Agents, Brokers, Traders,
Distributors, Repackers, and
Relabellers
• API Manufactured by Cell
Culture-Fermentation
• API for Use in Clinical Trials
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Potential Problems from
Non-Compliance with CGMP
• Super-potency or Subpotency
• Impurities
• Contamination
• Safety and Efficacy effects
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Some Issues of most concern
• Day-to-day implementation of CGMP
• Quality system management
• Understanding the product and the process
– Can’t “test” quality into the product
• Material management
• Equipment qualification and use
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Day-to-day
Implementation of CGMP
–Eliminate variability
–Achieving Process Consistency
is of utmost importance to ensure
quality of each batch
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Quality management
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Fundamental
Quality Management Principles
• Strong commitment to drug quality and
patient safety
• Strong “believer” in the value of CGMP
• Understand the importance and impact of
quality management, control, and
implementation
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Quality System
ICH Q10 Concepts
3.1.3 Commercial Manufacturing
“The pharmaceutical quality system should
assure that the desired product quality is
routinely met, suitable process
performance is achieved, the set of controls
are appropriate, improvement opportunities
are identified and evaluated, and the body
of knowledge is continually expanded”
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Pharmaceutical Quality
System
• The Quality System
is the foundation
for the drug
manufacturing
systems
• Quality system
model integrates
manufacturing
systems
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Quality System
– Deviations & investigations
– Change control
– Training
– Audit/ review
– Annual product review
– Contract agreement
– Document control
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Quality System
Critical Commitment from
Top Management
• Understand & recognize the value of quality system
• Strong commitment on producing safe and effective
product- decision to release or reject of batch
justified by data and science (responsibility of QA)
• Clear communication and promotion from top
management on importance of quality to all
employees and units of operation
• Implementation and enforcement on quality system
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Pharmaceutical Quality System
Lifecycle Approach
• Process performance and product quality
monitoring system;
• Corrective action and preventive action
(CAPA) system;
• Change management system;
• Management review of process
performance and product quality.
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Lifecycle Approach
Validation, maintenance, and
continuous improvement of
product quality
• 5% pre-approval
• 95% Post-approval
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Product Life Cycle
Comparability
Protocol
CGMP
Adherence
Evaluation
Propose
Monitor
CAPA
Post-Approval (Continuous
Risk
Assessment/
Mitigation
Improvement
Innovation)
Identify
(Critical/ Key
Attributes/
Parameters)
Formal
Experimental
Design
(DOE)
Confirm
(Control/ Predict)
PAT
Risk
Assessment/
Mitigation
Conformance/
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Validation
Studies
PAT
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Investigation & Deviations
Add Value & Impact Quality
• Learn from mistakes
• Prevent recurrences: corrective action &
preventive action (CAPA)
• Build knowledge: variability reduction,
continuous improvement in product quality
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What is Change Control?
Changes are managed by the firm:
•Evaluates everyday changes to the manufacturing facility,
equipment, personnel, improvements, and minor
adjustments to the process.
•All changes must always be done with a written protocol
under the change control system including approval by QA
•Have procedures in place for the execution of the change
in an orderly manner
•Evaluate the impact of the change
•Document the change and results
Adequacy of changes are evaluated by FDA during
inspection
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Change Control
• Process
– Process improvement /adjustment
– Personnel practice
– Operational procedures
• Equipment/ Facility/ Utilities
• Document, examples
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Revision/ updating of:
SOP
Analytical worksheet
Batch record
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Training
• Qualified employee to perform the
assigned task
• Strict implementation of the established
procedures
• Supervision
• Periodic re-evaluation
• Continuing education in training
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Audit/ Review
Annual Product Review
• Regular trending reviews and evaluation of
process and product
• Evaluation of stability, recalls, OOS, product
complaints, returns
• Risk assessment, mitigation before occurrence
of serious consequences
• Ensure operation is maintained in an ongoing
state of control
• Knowledge gained for continuous improvement
in product life cycle
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Contract Agreement
• Clear contractual agreements on:
– Responsibilities of each party
– Effective communication on all issues that potentially
impact drug quality
• Adequate qualification, auditing and regular
periodic evaluations of contractors
• Notification to FDA for changes in contractors
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Document Controls
A most critical element to support acceptability
of a production batch and GMP compliance
Not just a bureaucratic exercise to satisfy FDA
REQUIRE ORIGINAL RECORDS as the task
(operation) is being performed, not a re-copying
of the original. Data must not be altered
– Production: batch records
– QC: testing records
Violations: Serious Consequences
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Documentation
• All SOP (especially production batch
record) should be in sufficient detail for the
operator to carry out the task in a
consistent manner
• Changes in SOP must be reviewed and
approved by QA
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Material Management
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ICH Q7A: Materials Management
• Manufacturers of intermediates and/or API should have
a system for evaluating the suppliers of critical material
• Materials should be purchased against an agreed
specification, from a suppliers, approved by the quality
unit(s)
• If the supplier of a critical material is not the
manufacturer of that material, the name and address of
that manufacturer should be known by the intermediate
and/or API manufacturer.
• Changing the source of supply of critical raw materials
should be treated according to Section 13, Change
Control.
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Material Controls
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Raw materials
Intermediates
Components
API
Manufacturing materials
– e.g., sterilizing filters
• Facility materials
– e.g., HEPA filters
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Equipment Management
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Qualification of Equipment
Issues especially pertain to:
• Adequate IQ, OQ, PQ
– Old equipment??
• Instruction and training of operation for use of
equipment
• Establish regular maintenance, calibration and
maintain documentation of these activities
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Supply Chain Management
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Supply Chain Management
• Identify critical control points (areas) and
implement adequate controls to ensure
integrity of the supply of raw materials,
component, excipients, API, drug product
through procurement, manufacturing and
distribution.
– Tamper resistant
– Serialization
– testing
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Regulatory Actions for
non-GMP compliant firms
• Warning Letters
• Withholding Approval
• Import Detentions and Alerts
• Seizures
• Injunctions
• Prosecutions
IMPACT: Product NOT suitable for use.
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Thank You
Brenda Uratani
[email protected]
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