history of validation

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Validation History

(with some current issues)

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History

Prior to 1978, drug product quality and sterility was based solely on finished product testing.

Sterile products – USP Sterility Testing

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History

USP Sterility Test

Defect Rate Detection Probability

1% 18%

5% 64%

15% 95%

30% 99%

Batch Size 60,000 units

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History

Serious Incidents

Thalidomide – 1962

Septicimia – 1970’s

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History

Septicemia outbreaks greatest impact Sterility problems with large volume parenterals

(LVP) 54 deaths and 410 serious injuries FDA inspections, product recalls and plant closure

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History

LVP and SVP facilities problems

Inadequate process specs, SOPs and test data No EM specs, SOPs, and test data

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History

1976: FDA proposed changes to the GMP’s Focused on Sterilization Procedures, Steam and

Dry Heat Sterilization, ETO, Depyrogenation, SIP, and filtration.

Terms such as Validation, Protocol, and Qualification began to be used.

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History

“Validation is a documented program which provides a high degree of assurance that a specific process will consistently and repeatedly produce a product meeting its predetermined specification and quality attributes.”

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History

FDA expanded the need for validation Aseptic processing Filtration Environmental Controls Sanitation Water Systems Etc.

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History

FDA stepped things up.

Companies started defensively. FDA’s strength moved things along.

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History

FDA recognized potential improvements

In 1978, revised GMP’s introduced.

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What Must Be Validated

The CGMPs (1978) state that any facilities or systems used in the manufacturing, processing, packing or holding of a drug or device shall conform with Current Good Manufacturing Practice Guidelines, to assure the product meets its predetermined quality characteristics.

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What Must Be Validated

Processes: Sterilization Systems Aseptic Filling Operations Solution Preparation Systems WFI (Water For Injection) Systems Environmental Systems

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What Must Be Validated

Processes (continued): Utilities Sanitation Processes Filtration Processes Labeling Systems Packaging Systems

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History

Pharmaceutical manufacturers realize benefits.

Reduction of down time and defective product Improved Quality Reduced risk of Product recalls, Fatalities,

Lawsuits, etc.

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Current Issues

For first 20 years of Validation, many problems “Over validation” More documents vs. scientific basis Validation for all processes was treated the same Rising cost Stifled Innovation

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Current Issues

Improvements in the last 10 years

FDA improved training and consistency FDA incorporated Pre Approval Inspections FDA offered Parametric Release

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Current Issues – Part 11

21 CFR part 11 Acceptance of the following in place of paper

records Electronic records Electronic signatures Handwritten signatures executed to electronic

records Effective on August 20, 1997

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Current Issues – Part 11

1991: Industry met with FDA about paperless record systems

A proposed rule was issued in 1994 Final Rule 21 CFR part 11 became effective on

August 20, 1997 Compliance Policy Guide and several Guidance

Documents were issued in 1999-2002

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Current Issues – Part 11

Objectives Behind FDA 21 CFR Part 11

Permit introduction of new technology Allow FDA to operate on same technological level as industry Preserve & protect electronic GxP records Prevent fraudulent changes to electronic records Protect product quality

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Current Issues – Part 11

Interpretations Created Great Confusion

Scope unclear, broad interpretations Unnecessary controls and cost without adding to public safety Restricted use of technology and discourage innovation March, 2003: FDA will exercise “enforcement discretion” and

withdrew all guidance documents August, 2003: FDA issued the Scope and Application Guidance

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Current Issues – Part 11

Part 11 Scope and Application Guidance Summary

FDA is re-examining part 11 FDA anticipates changes to part 11 Enforcement Discretion

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Current Issues –CGMPs for the 21st Century Health and Human Services efforts to improve and streamline the

regulatory process

State-of-the-art pharmaceutical science to be used regulatory review and inspection

Encouraging the adoption of new technology Assessing the applicable CGMP requirements Use risk-based approach to strengthen public health protection Enhancing the consistency and coordination of FDA’s drug quality oversight

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Current Issues –CGMPs for the 21st Century

Pharmaceutical CGMPs for the 21st Century

Science Based Risk Assessment Target Inspections on areas of greatest risk Uses FDA resources more effectively and

efficiently Will place more emphasis on sterile products