Role of Internal Auditing in GMP Management

1
Role of Internal Auditing in GMP Management

• Nancy Rolli, Pre-Approval Manager
• New Jersey District

2
Internal Audits

• Within all FDA regulated industries firms may
  establish Quality Assurance Units (QAU) to
  perform functions independently from the
  manufacturing of quality control organization.
  
• The Quality Assurance Unit should periodically
  audit and critically review processes and
  procedures to determine whether the established
  protocols and procedures have been followed.

3
Internal Audits

• During routine inspections FDA policy is not to
  review or copy a firms records and reports that
  result from audits of a quality assurance
  program when such audits are conducted according
  to a firms written quality assurance program
• The intent of the policy is to encourage firms to
  conduct quality assurance program audits and
  inspections that are candid and meaningful.

4
Internal Audits

• FDA may seek written certification that such
  audits and inspections have been implemented ,
  performed, and documented and that any required
  corrective action has been taken.

5
Internal Audits

• FDA will review and copy of internal audits
• In directed or for cause inspection and
  investigations of a sponsor or monitor of a
  clinical investigation
• In litigation (for example, and not limited to
  grand jury subpoenas, discovery, or other agency
  or Department of Justice activity
• During inspections made by inspection warrant
  where access is authorized
• When executing any judicial search warrant.

6
Internal Audits

• There should be a system for internal audits to
  assess compliance with the requirements of the
  quality system.
• Audit reports and associated corrective actions
  should be included in the management review
  process

7
Product Risk Analysis

• Common Elements
• Hazard identification
• Severity ranking
• Probability ranking (with cause identification)
• Assessment of risk level for each identified
  hazard (risk matrix)

8
Defining Risk in the Context of Drug Quality

• Risk to pharmaceutical quality is related to the
  probability and severity of factors that have an
  adverse effect on a drugs critical performance
  characteristics, e.g.
• Identity
• Strength
• Bioavailability
• Purity
• Clear/accurate labeling

9
Purpose of Internal Audits

• To ensure that adequate quality systems are
  maintained.
• To assess compliance with the cGMPs and firms
  standard operating procedures.
• To achieve consistency between manufacturing and
  testing facilities.
• To identify problems internally and correct
  problems prior to an FDA inspection.

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Internal Audits

• Should follow documented procedures and should be
  conducted with a frequency to ensure compliance
  with internal procedures and procedures
  established by regulatory agencies.
• Should be conducted by personnel with
  appropriate qualifications, training and
  expertise to determine compliance with current
  good manufacturing practices.

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Internal Audit Procedures

• List systems to be audited
• Frequency of audit
• Responsibility for audit
• Reporting arrangements
• Implementing and verifying corrective action and
  record keeping

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Internal Audits

• Corrective and Preventative Action
• There should be 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.

13
Internal Audits

• Corrective and Preventative Action
• The need for preventative action should be
  identified by a review of trends associated with
  internal audits , corrective actions taken and
  complaints received.

14
Internal Audits

• Should include a review of electronic audit
  trails
• Should not be just a paper review
• Speak with personnel and observe practices
• Verify that written procedures are followed
• Verify that SOPs accurately describe tasks that
  are performed.

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Internal Audits

• Identification of critical control points and
  adequacy of manufacturing processes.
• Ensure that personnel are adequately trained.
• Should include an evaluation as to the adequacy
  of laboratory and manufacturing deviations
• Verify that corrective actions have been
  implemented

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FDA-483 Observation

• Employees are not given training in the
  particular operations they perform as part of
  their job function.
• The manufacturer of ____strongly recommended a
  training session for the operators. Operators
  were observed by the vendor to be operating the
  equipment incorrectly.
• GMP training consists of reading the SOPs,
  employees are not required to demonstrate an
  understanding of the procedures

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FDA-483 Observation

• There is no assurance that operators performing
  and verifying critical manufacturing steps are
  actually performing the checks.
• The addition of the incorrect drums of material
  was not detected by production operators who
  signed and verified that the correct blend was
  added to the batch.
• Line clearances were signed as completed prior to
  the completion of the line clearances.

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FDA-483 Observation

• Deviations from written production and control
  procedures are not recorded at the time of the
  occurrence.
• Drug product XXX was rejected when the blend
  spilled on the floor. The batch record does not
  document any problems during the discharge of the
  blend.

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FDA-483 Observation

• The Quality Unit and Senior Management failed to
  assure all drug products distributed have the
  safety, identity, quality and purity that they
  represented to possess. The Quality Unit failed
  to review electronic data as part of batch
  release, review computer audit trails and provide
  adequate training to analytical chemists.

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FDA-483 cont

• These practices led to the submission of
  erroneous data in Annual Reports and Prior
  Approval Supplements. The lack of quality
  oversight resulted in the ceasing of
  manufacturing on 5/13/05, the ceasing of
  distribution of all drug products on 5/23/05 and
  the recall of all batches of drug products and
  the withdrawal of five ANDAs.

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Process Change

• Change control program should evaluate changes in
  raw materials, manufacturing sites, scale of
  manufacturing, manufacturing equipment and
  production processes. Any changes shall be
  drafted, reviewed and approved by the appropriate
  organizational units and reviewed by the quality
  control unit.

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When to implement Change Control Procedures

• Change Control Procedures should be followed
  throughout the manufacturing process, starting
  with the bio-batch.

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Process Change System

• Rationale
• Justification
• Review by regulatory for possible filing issues
• Test results
• Equivalency Evaluation
• Determine need for Validation/Stability
• Approval

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Managing Change

• Conduct Training
• Implement Change
• Monitor impact of change
• Follow-up
• Document Everything

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Investigation Documentation

• Description of problem/event
• Cause of problem/event (if known)
• Scope of problem (other lots/products)
• Recommendation Corrective Action
• Conclusion Follow-up
• Management Review Approval of Investigation
  Documentation
• Implementation and Assessment of Corrective
  Action Plan

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Reduce Risk by Conducting Internal Audits

• Ensure that adequate quality systems are
  maintained.
• Assess compliance with the GMPs and firms
  standard operating procedures
• Achieve consistency between manufacturing and
  testing facilities.
• Identify problems internally and correct problems
  prior to an FDA inspection.

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Desired State in Pharmaceutical Manufacturing

• Use of techniques and technology to better
  understand what is critical to product and
  process performance (Quality by Design)
• Manage risk through a focus on controlling
  critical process parameters
• Continuous improvements based on effective
  feedback mechanisms
• Regulatory oversight equal with risk

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Top 10 FDA-483 Drug Citations

• 607 - CFR 211.22(d) The responsibilities and
  procedures applicable to the quality control unit
  are not fully followed
• 568 CFR 211.100(b) Written production and
  process control procedures are not documented at
  the time of performance
• 457 CFR 211.110(a) Control procedures are not
  established with validate the performance of
  those manufacturing processes that may be
  responsible for causing variability in the
  characteristics of the drug product.

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Top 10 FDA-483 Drug Citations

• 400 21CFR 211.100(a) There are no written
  procedures for production and process controls
  designed to assure that the drug products have
  the identity, strength, quality, and purity they
  purport or are represented to possess.
• 386 21CFR.160(d) Laboratory controls do not
  include the establishment of scientifically sound
  and appropriate specifications designed to assure
  that drug products conform to the appropriate
  standards of identity, strength, quality and
  purity.

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Top 10 FDA-483 Drug Citations

• 368 211 CFR 211.165(a) Testing and release of
  drug product for distribution do not include
  appropriate laboratory determination of
  satisfactory conformance to the final
  specifications prior to release.
• 361 211 CFR 211.192 There is a failure to
  thoroughly review any unexplained discrepancy
  whether or not the batch has already been
  distributed.

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Top 10 FDA-483 Drug Citations

• 360 211 CFR 211.188 Batch production and
  control records do not include complete
  information relating to the production and
  control of each batch.
• 353 211 CFR 211.25(e) Employees are not given
  training in the particular operations they
  perform as part of their job function.
• 301 211 CFR 211.167 (b) Written procedures are
  not established for the cleaning and maintenance
  of equipment, including utensils, used in the
  manufacture, processing, packing or holding of a
  drug product.

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Conclusion

• Internal Audits should be conducted at
  established timeframes to assess the firms
  compliance with current good manufacturing
  practices and internal standard operating
  procedures.
• A system should be in place to ensure problems
  identified during internal audits are corrected
  and preventative actions are implemented when
  warranted.