FDA Validation

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FDA Validation

• A Primer

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Topics Presented

• Acronym Soup
• FDA Scope of Inspection
• FDA Actual Inspection
• Laws and Guidelines Governing FDA
• Life Cycle Validation

3
Some New Terms

• FDA - Food and Drug Administration
• ORA - Office of Regulatory Affairs
• CFR - Code of Federal Regulations
• CPG - Compliance Policy Guides
• CDER- Center for Drug Evaluation and Research
• CGMP - Current Good Manufacturing Practice
  Regulations

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Industries Inspected by FDA

• Food
• Human Drugs
• Bioligics
• Animal Drugs
• Medical Devices
• Cosmetics

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An FDA Inspection

• FDA may conduct an inspection of an operation for
  a variety of reasons
• routinely scheduled investigation
• a survey
• response to a reported problem
• Usually, he/she will examine your production
  process, look at certain records and collect
  samples.
• At the conclusion of the inspection, the
  investigator will discuss with the firm's
  management his/her findings and concerns
  however, he/she will not usually recommend
  specific corrective measures.
• He/she will leave with management a written
  report of any conditions or practices which, in
  his/her judgment, indicate objectionable
  conditions or practices. This list of
  "Inspectional Observations," (FDA-483), can be
  used by a firm's management as a guide for
  corrective action.

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Governed byCode of Federal Regulations

• Title 21--Food and Drugs (parts 200 to 299)
• CHAPTER I--FOOD AND DRUG ADMINISTRATION,
  DEPARTMENT OF HEALTH AND HUMAN SERVICES
• Part
• 200 General
• 201 Labeling
• 202 Prescription drug advertising
• 205 Guidelines for State licensing of wholesale
  prescription drug distributors
• 206 Imprinting of solid oral dosage form drug
  products for human use
• 207 Registration of producers of drugs and
  listing of drugs in commercial distribution
• 210 Current good manufacturing practice in
  manufacturing, processing, packing, or holding
  of drugs general
• 211 Current good manufacturing practice for
  finished pharmaceuticals
• 225 Current good manufacturing practice for
  medicated feeds
• 226 Current good manufacturing practice for Type
  A medicated articles
• 250 Special requirements for specific human
  drugs
• 290 Controlled drugs
• 291 Drugs used for treatment of narcotic addicts
  
• 299 Drugs official names and established names
  

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Inspectors are Guided byCPG References

• INVESTIGATIONS OPERATIONS MANUAL Primary
  procedure manual for FDA personnel performing
  inspections and special investigations.
• GUIDES TO INSPECTIONS OF... Guidance documents
  written to assist FDA personnel in applying FDA's
  regulations, policies and procedures during
  specific types of inspection or for specific
  manufacturing processes
• INSPECTION TECHNICAL GUIDES Guidance documents
  that provide FDA personnel with technical
  background in a specific piece of equipment, or a
  specific manufacturing or laboratory procedure,
  or a specific inspectional technique, etc.
• MEDICAL DEVICE GMP REFERENCE INFORMATION
  (maintained by CDRH)
• QS REGULATION/DESIGN CONTROLS ORA and CDRH's
  Design Control Report and Guidance and associated
  documents.
• FIELD MANAGEMENT DIRECTIVES

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Excerpt fromGUIDE TO INSPECTION OFCOMPUTERIZED
SYSTEMS IN DRUG PROCESSING

• For each drug process under computer control
  determine the general system loop (sensors,
  central processor, activator). For example, the
  general system loop for a steam autoclave under
  computer control could consist of
  temperature/pressure sensors connected to a
  microprocessor which transmits commands to
  steam/vacuum control valves. The overview should
  enable the investigator to identify those
  computer controlled processes which are most
  critical to drug product quality. These are the
  systems which, of course, merit closer
  inspection.

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Sample (circa 1983)
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Terms used in CPG

• TITLE A clear concise statement of the subject
  of the CPG.
• BACKGROUND Information concerning the problem or
  situation addressed by the CPG. Whenever
  possible, the original source of the policy
  statement or change will be cited.
• POLICY A clear and concise statement of the
  current FDA policy. Whenever any limitations on,
  or exceptions to the stated policy are necessary,
  those limitations and exceptions will be stated.
• REGULATORY ACTION GUIDANCE Whenever possible,
  each CPG will contain regulatory action guidance.
  This section will include the necessary guidance
  for making regulatory decisions and should
  include, but is not limited to, the following
  information a) the limits at which the field is
  authorized to take direct regulatory action
  without referral to the appropriate center b)
  information for use in making decisions as to
  admissibility of imports c) information on
  products, processes, or conditions for which
  there is insufficient experience or data to
  warrant delegation of authority for direct
  regulatory action by the field and d)
  recommended charges (specimen charges) for direct
  regulatory actions.
• CPG NUMBERING SYSTEM The CPG Manual utilizes
  both a "Section" and a "CPG" number for
  individual Guides. The CPG numbers are preceded
  by CPG and have numbers in the range of
  7100-7199. The CPG numbers were based on the
  previous organization of the CPG. The Guides have
  been reorganized into new chapters and Section
  numbers now indicate the chapter and location
  within the chapter. The Section numbers precede
  the title of each Guide while the CPG numbers
  follow the title in parentheses.

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Sample ofCompliance Policy Guide

• Sec. 425.500 Computerized Drug Processing
  Identification of "Persons" on Batch Production
  and Control Records (CPG 7132a.08)
• BACKGROUND
• Section 211.188(b)(11) of the Current Good
  Manufacturing Practice Regulations requires that
  batch production and control records include
  documentation that each significant step in the
  manufacture, processing, packing, or holding of a
  batch was accomplished, including identification
  of the persons performing, directly supervising
  or checking each significant step in the
  operation.
• POLICY
• When the significant steps in the manufacturing,
  processing, packing or holding of a batch are
  performed, supervised or checked by a
  computerized system an acceptable means of
  complying with the identification requirements of
  21 CFR 211.188(b)(11) would consist of
  conformance to all of the following
• 1. Documentation that the computer program
  controlling step execution contains adequate
  checks, and documentation of the performance of
  the program itself.
• 2. Validation of the performance of the computer
  program controlling the execution of the steps.
• 3. Recording specific checks in batch production
  and control records of the initial step, any
  branching steps and the final step.
• NOTE In assessing how well a computer system
  checks a process step it is necessary to
  demonstrate that the computer system examines the
  same conditions that a human being would look
  for, and that the degree of accuracy in the
  examination is at least equivalent.
• Issued 11/2/82 Reissued 9/4/87

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Life Cycle Validation

• Definition and Design
• Testing
• Operation and Maintenance

The Objective of the Validation is to Demonstrate
that the System, Equipment, or Process does what
it is Intended to do.
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Validation Time Line

• The schedule of events for validation following
  the life-cycle concepts is closely linked to the
  overall project schedule
• This involves review and comment on engineering
  drawings and specifications, field inspections,
  organization of field test reports, and setup of
  the validation files.

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Definition and Design

• The Design phase begins with a Definition of the
  Problem
• In biotechnology, the production, isolation, and
  purification of a recombinant protein may be the
  simple problem. If this is to be used as a drug
  product, the problem becomes more complex.
• The drug must be produced according to CGMP, the
  process must be validated, and the plant must
  pass an FDA inspection.

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The Design Phase continues as details are
developed

• These begin in the form of schematic
  representations of ideas, such as Process Flow
  Diagrams (PFDs) and Piping and Instrumentation
  Diagrams (PIDs).
• They evolve into more complex forms, such as
  piping drawings, equipment specifications, and
  computer programs.
• Design documentation becomes the standard against
  which the installed system is measured during
  Installation and Operational Qualification.

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Testing

• The testing phase is required to determine that
  the system conforms to design and that it does
  what it is supposed to do.
• Testing is usually carried out according to a
  plan or protocol results are compiled into a
  report.
• By itself, testing is not adequate to prove
  system acceptability.

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Testing phase is generally divided into three
major areas of concern

• Installation Qualification (IQ), in which the
  installed system is compared to design
  documentation
• Operational Qualification (OQ), in which the
  operational characteristics of the system are
  documented and, where appropriate, compared to
  design specifications
• Process or Performance Qualification (PQ), in
  which the system is put to its intended use and
  challenged to perform as expected

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Maintenance and Operation

• Standard operating procedures, based on the
  validated operating conditions, are needed
• Data should be reviewed periodically, with an eye
  out for trends
• Changes should be documented and communicated.
• Hardware should be maintained and calibrated
  regularly.
• Routine retesting may be considered.
• The team involved in system design and testing
  should participate in maintaining validation.

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Validation Structure

• Master Plan
• Protocols
• Calibration
• Installation Qualification
• Operational Qualification
• Process Qualification
• Change Control
• Summary Reports

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Example - CIP

• Cleaning-in-place (CIP) processes are in
  widespread use throughout biotechnology
  facilities.
• Residues from the production of proteins and
  other biopharmaceutical processes are difficult
  to clean.
• Vessel interiors are the major objects of CIP,
  but product and medium transfer lines are also
  cleaned in this manner

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ValidatingAutomated Systems

• The first task in validation of an automated
  system is one of definition.
• The system definition may take the form of a
  Functional Requirement document.
• This describes the entire process and the control
  philosophy to employed. It should emphasize what
  needs to be done, not how it should be done.
• Process equipment design proceeds through the
  PID (Piping and Instrumentation Diagram) stage,
  where field instrumentation requirements are
  defined, and through instrumentation design,
  where field inputs and outputs are further
  defined.
• A System Specification (or Engineering
  Specification or Purchase Specification) should
  be prepared

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Programming Software

• It is not usually necessary to pay a great deal
  of attention to operating systems or to the
  development of configurable software.
• This statement also applies to higher level shop
  floor and supervisory programs. The vendors must
  show, either by demonstrated experience or
  through audits, that they practice acceptable
  software quality assurance. The structural
  testing required in the development of a computer
  program may be left to the vendor in these cases.

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Application Software

• The validation team may wish to examine the code
  for correct syntax, structure, adequate
  annotation, and the absence of dead code.
• The programmer must provide evidence of
  structural testing.

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Hardware

• Each computer module is subjected to functional
  testing.
• The module is run to determine that it performs
  as intended.
• This testing, usually done off-line from any
  process hardware, often uses a simulator, a
  device that provides inputs and outputs similar
  to that of field hardware
• These tests should be performed and documented
  under observation from the validation team.

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Installation Qualification

• Component audit against the approved Bill of
  Materials - check models, serial numbers, and
  firmware designations
• Wiring checks from field devices to computer
  input terminals
• Checks for proper system grounding, shielding,
  and noise isolation
• Checks of communications network hookup and
  continuity
• Configuration check for proper setup of DIP
  switches and jumpers according to manufacturers'
  requirements
• Checks for proper power connections, including
  required fusing and disconnects
• Power loss and power backup tests
• Controller redundancy checks to see if bumpless
  transfer to backup units occurs when a control
  element fails and
• Similar checks when redundant communications
  networks are involved.

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Integrated System Qualification

• Verification that the software programs installed
  are identical to those verified in modular
  functional testing
• Verification that the application source code
  exists and is available for inspection if
  requested
• Online input/output testing (loop checks), where
  each I/Q module is exercised to prove that each
  point in the system is addressed correctly and
  that the corresponding data are stored in the
  proper memory locations and appear properly on
  display screens
• Repeat of power loss testing to check system
  recovery, startup procedure, data status, and
  documentation
• Alarm point check

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Next Steps

• The integrated system may then be subjected to
  functional testing online and in real time with
  placebo
• The next necessary step is to use the
  computerized system to perform its intended
  function with real product

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Validation Maintenance

• Utilization of validated SOPs
• Continuing calibration and maintenance and change
  control
• Applies to changes in process, in process
  equipment, and to both control hardware and
  software.

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Summary

• The concepts and techniques presented are meant
  to introduce and familiarize the reader with the
  necessity to validate and to chart an initial
  course
• Along with the design and operational ideas
  presented elsewhere, they should establish the
  foundation for a sound validation program.

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