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Requirements for the Quality of API from FDA Perspective. Brenda Uratani, Ph.D. FDA Assistant Country Director, China. Today’s agenda. Introducing the FDA China Office FDA’s requirements for API manufacturing Selected Topics and Issues of Most Concern

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requirements for the quality of api from fda perspective

Requirements for the Quality of API from FDA Perspective

Brenda Uratani, Ph.D.

FDA Assistant Country Director, China

API Conference- March 2010- Beijing

today s agenda
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

API Conference- March 2010- Beijing

challenges
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

API Conference- March 2010- Beijing

fda international efforts
FDA International Efforts

API Conference- March 2010- Beijing

beyond our borders initiative
Beyond Our Borders Initiative
  • FDA in-country offices
    • Awareness
    • Capacity building
    • Standards/inspections
    • Collaboration
    • Leveraging opportunities
    • Locations:
      • China, India, EU, Latin America, Middle East
  • Leveraging projects
    • Pilots/Info sharing
      • EMEA pilot

API Conference- March 2010- Beijing

fda china office in country staff
FDA China OfficeIn-Country Staff

Beijing

  • 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)

API Conference- March 2010- Beijing

agreements between hhs and sfda key provisions
Agreements Between HHS and SFDA: Key Provisions

API Conference- March 2010- Beijing

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 Auspices
    • Implementation Focus on Specific Set of Drugs, Devices
fda china office what are we doing
FDA China Office What Are We Doing?

API Conference- March 2010- Beijing

  • 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 FDA-Regulated Products
  • Regulatory Reform/Legal Assistance
  • Increasing inspections at facilities that manufacture FDA-regulated goods; and
cgmp requirements principles for api manufacturing
CGMPRequirements & Principlesfor API Manufacturing

API Conference- March 2010- Beijing

slide10
CGMP
  • C” = currentdynamic and evolve over time
  • “GMP” = Good Manufacturing Practices
    • Minimal standards
    • Not “best” practices unless “best” is, in fact, current minimal.

API Conference- March 2010- Beijing

fda requirements for api historical perspectives
FDA Requirements for APIHistorical 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

API Conference- March 2010- Beijing

ich q7a
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

ICH Q7A

API Conference- March 2010- Beijing

potential problems from non compliance with cgmp
Potential Problems from Non-Compliance with CGMP

Super-potency or Subpotency

Impurities

Contamination

Safety and Efficacy effects

API Conference- March 2010- Beijing

some issues of most concern
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

API Conference- March 2010- Beijing

day to day implementation of cgmp

Day-to-day Implementation of CGMP

Eliminate variability

Achieving Process Consistency is of utmost importance to ensure quality of each batch

API Conference- March 2010- Beijing

quality management
Quality management

API Conference- March 2010- Beijing

fundamental quality management principles
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

API Conference- March 2010- Beijing

quality system ich q10 concepts
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”

API Conference- March 2010- Beijing

pharmaceutical quality system
PharmaceuticalQuality System
  • The Quality System is the foundation for the drug manufacturing systems
  • Quality system model integrates manufacturing systems

API Conference- March 2010- Beijing

quality system
Quality System
  • Deviations & investigations
  • Change control
  • Training
  • Audit/ review
  • Annual product review
  • Contract agreement
  • Document control

API Conference- March 2010- Beijing

quality system critical commitment from top management
Quality SystemCritical 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 promotionfrom top management on importance of quality to all employees and units of operation
  • Implementation and enforcement on quality system

API Conference- March 2010- Beijing

pharmaceutical quality system lifecycle approach
Pharmaceutical Quality SystemLifecycle 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.

API Conference- March 2010- Beijing

lifecycle approach
Lifecycle Approach

Validation, maintenance, and continuous improvement of product quality

  • 5% pre-approval
  • 95% Post-approval

API Conference- March 2010- Beijing

slide24

Product Life Cycle

Comparability

Protocol

Evaluation

Risk

Assessment/

Mitigation

Propose

CGMP

Adherence

Formal

Experimental

Design (DOE)

Monitor

(CAPA

Continuous

Improvement

Innovation)

Identify

(Critical/ Key

Attributes/

Parameters)

Post-Approval

Risk

Assessment/

Mitigation

Confirm

(Control/ Predict)

PAT

PAT

Conformance/

Validation Studies

API Conference- March 2010- Beijing

investigation deviations add value impact quality
Investigation & DeviationsAdd Value & Impact Quality
  • Learn from mistakes
  • Prevent recurrences: corrective action & preventive action (CAPA)
  • Build knowledge: variability reduction, continuous improvement in product quality

API Conference- March 2010- Beijing

what is change control
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

API Conference- March 2010- Beijing

change control
Change Control
  • Process
    • Process improvement /adjustment
    • Personnel practice
    • Operational procedures
  • Equipment/ Facility/ Utilities
  • Document, examples
    • Revision/ updating of:
    • SOP
    • Analytical worksheet
    • Batch record

API Conference- March 2010- Beijing

training
Training
  • Qualified employee to perform the assigned task
  • Strict implementation of the established procedures
  • Supervision
  • Periodic re-evaluation
  • Continuing education in training

API Conference- March 2010- Beijing

audit review annual product review
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

API Conference- March 2010- Beijing

contract agreement
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

API Conference- March 2010- Beijing

document controls
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

API Conference- March 2010- Beijing

documentation
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

API Conference- March 2010- Beijing

material management
Material Management

API Conference- March 2010- Beijing

ich q7a materials management
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.

API Conference- March 2010- Beijing

material controls
Material Controls
  • Raw materials
  • Intermediates
  • Components
  • API
  • Manufacturing materials
    • e.g., sterilizing filters
  • Facility materials
    • e.g., HEPA filters

API Conference- March 2010- Beijing

equipment management
Equipment Management

API Conference- March 2010- Beijing

qualification of equipment
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

API Conference- March 2010- Beijing

supply chain management
Supply Chain Management

API Conference- March 2010- Beijing

supply chain management39
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

API Conference- March 2010- Beijing

regulatory actions for non gmp compliant firms
Regulatory Actions for non-GMP compliant firms
  • Warning Letters
  • Withholding Approval
  • Import Detentions and Alerts
  • Seizures
  • Injunctions
  • Prosecutions

IMPACT: Product NOT suitable for use.

API Conference- March 2010- Beijing

thank you
Thank You

Brenda Uratani

Brenda.uratani@fda.hhs.gov

API Conference- March 2010- Beijing