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The FDA Regulatory & Compliance Symposium

Managing Risks – From Pipeline to Patient

August 24-26, 2005



cGMP Good for Business But Who is Enforcing Who?

Presented By: Anthony C. Celeste

Senior Vice President

Kendle/AAC

August 25, 2005



Why GMPs?

• Historical Perspective

– Early concepts

– Development of GMP concept(s)

• Legislative Mandate 1962

– Regulation development

– June 1963

– 1968 “Intensified Drug Inspection Program”

– January 1971 Federal Register (Final Regulations)

– September 1978 umbrella cGMP Regulations



Industry View of GMPs

– FDA Inconsistency

– Investigator expertise

– “Level the playing field”



GMP Benefits to Industry

– Good business practices

– Build in quality

• Enhance reputation

• Cut compliance costs

• Overall savings

• Avoidance of problems and bad publicity



FDA Enforcement Statistics

• Summary of FDA Actions/Activities

– 1999 - 2003



Source of Data: Recall Operations Staff, Division of Compliance

Management and Operations, Office of Enforcement, HFC-210

Recalls = Products Recalled [Center Classification Determined by Product Type]Description

Description



Description

Source of Data: Program Evaluation Branch, DPEM, Office of Resource Management, HFC-42Note: Does not include Office of Criminal Investigations data.

Description



Source of Data: Program Evaluation Branch, DPEM, Office of Resource Management, HFC-42 Note: Does not include Office of Criminal Investigations data.

Description



Source of Data: Division of Compliance Management and Operations, Office of Enforcement, HFC-210

Source of Data: Recall Operations Staff, Division of Compliance Management and Operations, Office of Enforcement, HFC-210

Description



Source of Data: Recall Operations Staff, Division of Compliance Management and Operations, Office of Enforcement, HFC-210

Description



FDA Actions

– Significance of numbers?

– Risk Management

– Changing role of GMPs

– cGMPs for the 21st century



Risk

• Probability of occurrence of harm and the severity of that harm

– Includes concepts of “hazard” and “exposure”

• What is the relevant “harm”?

– Unsafe or ineffective drugs

– Reduction in safety/effectiveness

• Clinically significant

– Reduction in drug quality



Risk Management

• “Systematic application of management policies, procedures and practices to the tasks of analyzing, evaluating and controlling risk”

ISO 14971, Sections 2.13 and 2.18



Risk Management

• Risk Assessment

– Relationship between process knowledge and process risk



Risk Management

• Risk Control

– Option analysis

• Corrective and preventive actions

– Prioritize

– Implementation

– Residual risk evaluation

– Overall risk evaluation



Risk Management

• Post-Production Information

– Post-production experience

– Review of risk management experience



Risk Assessment

• An assessment of the product to determine:

– The probability of occurrence of harm from someone using your product

– The consequences of that harm and how severe it may be



Risk Management

• Major Themes

– Focus cGMP requirements on public health risks

– Ensure FDA’s essential work does not impede innovation by industry

– Enhance the consistency and predictability of FDA’s approach

– Relevance of risk management to compliance activities



Elements Impacting FDA Inspections

• cGMP Inspections

– Work planning (address risks)

– Investigator qualifications

• Communication of Findings

– Evaluate Warning Letters and FDA-483s

– Dispute Resolution

• Rollback of 21 CFR Part 11

• Encourage Best Practices

– Process Analytical Technology (PAT)



CDER Compliance Public Health Mission

• CDER has stated that its primary mission is ensuring that safe and effective drugs are available to the American public.

• CDER’s Office of Compliance advances CDER’s mission primarily by protecting Americans from unsafe or ineffective drugs.



Pharmaceutical GMPs for the 21st Century

• February 20, 2003, FDA provided a progress report on various aspects of its GMP initiative, Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach.

– Integrating a risk-based approach applies to all aspects of the initiative, including various aspects of the GMP inspection programs.



What They Look At: Focus of FDA’s Inspection

• Revise compliance programs to implement risk-based targeting

– Focus inspection on areas most likely to uncover GMP deviations with greatest public health significance

– Statistically-based auditing for areas not known to be high risk



What They Look At: Focus of FDA’s Inspection

• Use risk assessment tools in evaluating significance of GMP deviations for further regulatory action

• Account for potential failures in a process – “Quality by Design”



CAPA

• “Corrective and Preventive Actions”

• One very effective way of managing risk



Industry’s Role

• Participation with FDA

• Innovation and technical advances

• Quality management



Participation with FDA

• Provide review, comment on guidelines and proposals

– Critical Path Initiative

– PAT

• Participate in committee deliberations (PDA, ISPE, Pharma, etc.)

• Training FDA Investigators/Reviewers



Innovation and Technical Advances

• Share research and development initiatives in manufacturing

• Work with FDA on technical improvements

• Process Analytical Technology



Quality Management

• Who is management?

• Results of poor management

• Proactive system(s)



Who is Management

• Level in organization that is responsible for:

– Hiring and firing, especially in quality area

– Organize and respond to audit and inspection findings

– Control availability of resources dollars and personnel.



Management Responsibilities

• Assure employee training and understanding

• Implement and document corrective actions

• Assure proper communications and decision making



Results of Poor Management

• Lack of adequately qualified and well trained employees

• Poor quality systems in place

• Non-conforming manufactured products (GMPs)



Penalties for Non-Compliance• FDA action

• Company’s reputation

• Effect on business



Lessons Learned

• Those who cannot remember the past are doomed to repeat it.

• But the real challenge is quantifying the past for commitment to memory.

• If some is GOOD – more is BETTER.

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