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

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