api conference- march 2010- beijing 1 requirements for the quality of api from fda perspective...

API Conference- March 2010- Beijing

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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– 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 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)


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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 Auspices• 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 FDA-Regulated Products

◦ Regulatory Reform/Legal Assistance

◦ Increasing inspections at facilities that manufacture FDA-regulated goods; and


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CGMPRequirements & Principles

for API Manufacturing


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CGMP

• C” = currentdynamic 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 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


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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


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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 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 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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Formal Formal ExperimentalExperimental

Design Design (DOE)(DOE)

Conformance/Conformance/ Validation StudiesValidation Studies

Post-ApprovalPost-Approval

ProposePropose

Product Life Cycle

EvaluationEvaluation

IdentifyIdentify(Critical/ Key (Critical/ Key Attributes/Attributes/Parameters)Parameters)

ConfirmConfirm(Control/ Predict)(Control/ Predict)

MonitorMonitor((CAPACAPAContinuousContinuousImprovementImprovementInnovation)Innovation)

RiskRisk Assessment/ Assessment/

MitigationMitigation

ComparabilityComparabilityProtocolProtocol

RiskRisk Assessment/ Assessment/

MitigationMitigation

CGMPCGMPAdherenceAdherence

PATPATPATPAT


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Investigation & DeviationsAdd 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– 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 ControlsA most critical element to support acceptability

of a production batch and GMP complianceNot 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 recordsViolations: 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• 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 [email protected]

mailto:[email protected]

api conference- march 2010- beijing 1 requirements for the quality of api from fda perspective...

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