Validation

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Validation Biomanufacturing
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What is Validation

• Validation An Essential Part of GMPs!
• Validation is the scientific study of a system
• To prove that the facility/system/equipment/method
  is consistently doing what it is supposed to do
  (i.e., that the process is under control).
• We want to make decisions based on good science
  and not hunches and assumptions!
• To determine the process variables and acceptable
  limits for these variables, and to set-up
  appropriate in-process controls.
• Is it ok if the wash from a chromatography column
  is pH 6.8 vs. 7.0 ?

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FDA definition of validation

• Validation is a process of demonstrating,
  through documented evidence, that a process,
  procedure, method, piece of equipment, or
  facility will consistently produce a product or
  result that meets predetermined specifications
  and quality attributes.

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Quality Attributes Remember these?

• Identity
• 21 CFR 211.84 (d) at least one test shall be
  conducted to verify the identity of each
  component of a drug product.
• Chemical, biological, Immunological
• Raw materials, In-process intermediates, final
  products.
• Safety
• 21 CFR 600.3 (p) safety as the relative freedom
  from harmful effect to persons affected, directly
  or indirectly, by a product when prudently
  administered, taking into consideration the
  character of the product in relationship to the
  condition of the recipient at the time.
• Activity of active ingredients
• Activity of the excipients or additives
• Activity of process related impurities
• Efficacy
• Effectiveness of the product in achieving its
  medicinal purpose (therapeutic, prophylactic,
  diagnostic). Gathered at phase II and Phase III
  trials.
• Potency
• 21 CFR 600.3 (s) specific ability or capacity of
  the product, as indicated by its appropriate
  laboratory tests or by adequately controlled
  clinical data obtained through the administration
  of the product in the manner indicated to effect
  the given result.
• Purity
• 21 CFR 600.3 (r) relative freedom from extraneous
  matters in the finished product, whether or not
  harmful to the recipient or deleterious to the
  product.
• Cleaning Procedures
• Stability
• 21 CFR 211.137 (a) to assure that a drug product
  meets applicable standards of identity, quality,
  and purity at the time of use it shall bear an
  expiration date determined by stability testing.
  Drugs may use accelerated time studies, biologics
  must use real time studies.
• Consistency

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Biomanufacturing

• Biomanufacturing is a complex process involving
  multiple unit operations many of which are
  critical to insuring patient safety and product
  efficacy

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Block Flow Diagram of a typical Production Process
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Historical Basis for Validation

• Assumptions concerning virus inactivation
  resulted in ten deaths and 200 children becoming
  paralyzed, from a supposedly inactivated polio
  vaccine.
• Assumptions about sterilization caused severe
  infections among burn victims given supposedly
  sterile solutions.
• Validation eliminates assumptions and relies on
  experimental proof!

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Quality by Design

• A central concept in quality is that quality can
  not be tested for. Quality must be designed and
  built into the production process.
• Requires careful attention to raw material
  specifications, in process material
  specifications, and final product specifications.

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Validation and Quality

• Validating the performance of unit operations,
  analytical methods, and critical process points
  (sterilization, viral inactivation, cleaning
  procedures) is essential in insuring that the
  process generates a quality product.

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Validation in Biomanufacturing

• Validation does not replace testing, but it does
  reduce the testing burden for raw materials,
  in-process materials, and final product

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Validation in Biomanufacturing

• Validation itself is a process that evolves with
  the product.
• Validation requirements for production of
  pre-clinical material less stringent then for
  phase III clinical material.
• Critical operations must be validated For
  example raw materials, analytical methods, viral
  clearance, sterilization, cleaning.

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Validation in Biomanufacturing

• A fully validated process is locked in
• Any change outside of the validated space
  invalidates process
• Change must be evaluated for effect on patient
  safety and product efficacy-Change control !

Validated Production Process
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Regulatory requirement for validation

• 21 CFR 211 Subpart H- Holding and Distribution
• 211.165 Testing and release for distribution
• Requires that the accuracy, sensitivity,
  specificity, and reproducibility of test methods
  employed by the firm shall be established and
  documented. Such validation and documentation may
  be accomplished in accordance with 21 CFR 211.194
  (a)(2)

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Regulatory requirement for validation

• Sec. 211.113 Control of microbiological
  contamination.
• (a) Appropriate written procedures, designed to
  prevent objectionable microorganisms in drug
  products not required to be sterile, shall be
  established and followed.
• (b) Appropriate written procedures, designed to
  prevent microbiological contamination of drug
  products purporting to be sterile, shall be
  established and followed. Such procedures shall
  include validation of any sterilization process.

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What does validation of anysterilization
process mean ?

• What parameters are critical to sterilization?
• Temperatures, pressures, time, pore size
  (filtration), radiation dosage, chemical
  concentration.
• Must demonstrate that your autoclave reaches the
  temperatures, pressures, and times necessary for
  sterilization.
• Must demonstrate that items representing real
  world samples achieve those conditions ( 20 ft of
  1 ½ hose a 20 L carboy a 500 ml bottle).
• Must challenge with worse case scenario (may take
  place in pilot plant if scalability
  demonstrated).

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Regulatory guidance on validation

• Guideline on General Principals of Process
  Validation http//www.fda.gov/cder/guidance/pv.ht
  m
• Guidance for Industry For the Submission
  Documentation for Sterilization Process
  Validation in Applications for Human and
  Veterinary Drug Products. CDER CVM November 1994.
  www.fda.gov/CDER/GUIDANCE/cmc2.pdf
• Working Party on Control of Medicines and
  Inspections
• Final Version of Annex 15 to the EU Guide to Good
  Manufacturing Practice
• Title Qualification and validation
• http//pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-
  en/v4an15.pdf
• ICH Q7a Section 12 on validation
• http//www.fda.gov/cder/meeting/ICH_Q7A/index.htm
• A WHO guide to good manufacturing practice (GMP)
  requirements. Part 2 Validation
• Chaloner-Larsson, G., Anderson, R., and Egan, A.
  1997. World Health Organization, Geneva.

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Critical Operations in Biomanufacturing

• Some operations are more critical than others.
• Viral filtration, sterilization, cleaning,
  analytical methods.
• These operations will require greater validation
  efforts then less critical operations (media
  blending).

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Testing

• Usually done by the Quality Control Laboratory
• CFR requires that quality unit be under
  independent supervision and report directly to
  senior management

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Quality Assurance

• Reviews records from quality control and
  production departments
• Verifies that all specifications and production
  operations met / performed
• Investigations necessary for any deviations
• Root cause
• Affect on quality
• Corrective action (CAPA)
• Approves final release of product

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Designing Quality into the Product

• Design of production process and specifications
  all contribute to a quality product
• Absence of contamination
• Clean rooms, closed systems, use of BSC for
  critical operations.
• Purity
• Separation process (chromatography) designed to
  remove potential contaminants
• Viral purification / inactivation

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Validation Plan

• Organizations must define an approach towards
  validation
• What is to be validated
• How is it to be validated
• Who is to validate it
• Who is to approve the validation
• When it must be revalidated

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Validation

• Examples of individual systems subject to
  validation
• HVAC systems
• Autoclaves
• pH meters
• Depyrogenation Ovens
• Lyopholyzers
• Centrifuges
• Steam generators
• Water systems
• Compressed air systems
• Vacuum systems

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Validation Plan

• Regulatory agencies (FDA, EMEA, WHO, etc)
  identify minimum components of validation.
• Industry standards (the c in cGMP) can increase
  validation requirements.
• New Novel processes / equipment require greater
  scrutiny then established processes / equipment.
• Validation requirements increase as a product
  moves through development (phase I, phase II,
  phase III).

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Validation Plans

• The Validation Master Plan
• A high level document that outlines the
  organizations philosophical approach to
  validation and revalidation. The master
  validation plan becomes a guideline by which
  individual validation protocol are developed and
  implemented.
• May contain a flow chart or other diagram of the
  validation process

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A prospective validation study
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Developmental studies

• Experiments designed to explore and define the
  limits of the system to be validated
• Sterilization developmental studies may focus on
  worst case or hard to sterilize items
• Cleaning developmental studies may focus on
  worst case or hard to clean items
• Analytical methods may focus on defining the
  limits of the procedure (range, recovery, etc)
• Developmental studies then used to develop
  validation protocols and refine SOPs

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Validation Protocol

• Specific protocols (SOPs) that provide detailed
  information on what is to be validated.
• Validation Protocols consist of
• A description of the process, equipment, or
  method to be validated.
• A description of the validation method.
• A description of the sampling procedure including
  the kind and number of samples.
• Acceptance criteria for test results.
• Schedule or criteria for revalidation.

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Example of a protocol for the IQ component of
validating a pH meter

As with all other SOPs this document will
contain an Objective, scope, and
responsibility Section.
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Validation Protocol

• Validation Protocols may consist of multiple
  SOPs each describing specific steps in the
  validation process

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Critical Systems

• How critical is the system being validated to
  final product quality?
• Media blending systems for cell growth vs. final
  fill finish operations
• Demonstrating that the device which fills,
  labels, and caps the final product will require
  more extensive validation then the blenders used
  to prepare media for bioreactors.
• Validation of complex devices may take years!

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Validation

• Proceeds in stages with new facilities /
  equipment.
• Planning for validation should start with the
  design process.
• Leaving validation to the last minute is asking
  for trouble.

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Stages of Validation

• Starts with Design Receipt
• Does the equipment meet the needs (is the
  autoclave big enough?)
• Do you have the manuals, spare parts, can you
  plug it in?
• Is it installed properly (drain lines, vents,
  etc)
• Does it work?
• Does the autoclave reach the necessary temp. and
  pressure?
• Can the autoclave sterilize your equipment (worse
  case situation)?
• How does it work in the manufacturing process?
• Can it handle production quantities?
• Will failure compromise product quality?

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IQ, OQ, PQ ?

• Installation Qualification (IQ)
• A process used to document that the piece of
  equipment was supplied and installed properly and
  that appropriate utilities, i.e., electrical,
  steam, gas, etc. are available to operate the
  equipment according to the manufacturers
  specifications.
• Operational Qualification (OQ)
• A process designed to supply the documented
  evidence that a piece of equipment operates as it
  is intended through all anticipated operational
  ranges.
• Performance (Process) Qualification (PQ)
• Verifies that a process / piece of equipment
  performs as it is intended to in the
  manufacturing process and produces product (in
  process or final) meeting predetermined
  specifications.

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Typical information in an IQ protocol

• Name and description of equipment, including
  model numbers
• Identification, including model and serial
  numbers
• Location of the equipment
• Any utility requirements, i.e. electrical
  voltage, steam or water pressure, etc.
• Any safety features of the equipment, including
  alarms, interlocks, or relief valves.
• That all documentation, including manufacturers
  contact information, spare parts inventory,
  operational manual, and installation drawings are
  available on site.

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Typical OQ Protocol Components

• Objective
• Responsibility
• Equipment required (Calibration verification
  Traceability)
• SOP(s) used
• Equipment Identification
• Parameters measured (Specifications)
• Documentation

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Validation

• Ideally validation takes place prior to actual
  production runs, however in some cases validation
  may take place as product is produced, or past
  production runs may be used to provide validation
  data.
• Prospective Validation
• Concurrent Validation
• Retrospective Validation

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Revalidation

• Is the initial validation of a piece of equipment
  the end?
• No!
• Periodic revalidation may be necessary depending
  on the criticality of the equipment
• Changes need to be evaluated for their impact on
  validation
• Deviations from specifications may require
  revalidation
• Revalidation spelled out in Master Validation Plan

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Change Control

• Must assess impact of changes on FDA compliance
  and validation state.
• Change control is a formal process defined in
  company SOP on how process/equipment changes are
  evaluated.
• Any change that takes place outside the change
  control process can jeopardize product quality
  (patient safety).

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References

• Pharmaceutical Manufacturers Associations
  (Pharmaceutical Research and Manufacturers of
  America) Validation Advisory Committee Process
  Validation Concepts for Drug Products
  Pharmaceutical Technology, September 1985 p 82.
• Bismuth, G. Cleaning Validation A Practical
  Approach. CRC Press, 2000. ISBN 1574911082.
• Pharmaceutical Process Validation, 3rd Ed. Edited
  by Robert Nash and Alfred Wachter, Marcel Decker,
  2003. ISBN 082470838-5
• Validation of Pharmaceutical Processes Sterile
  Products. 1998. 2nd Edition. Edited by Frederick
  J. Carlton and James Agalloco. Marcel Decker,
  1998. ISBN 0824793846.
• Validation Standard Operating Procedures A step
  by Step Guide for Achieving Compliance in the
  Pharmaceutical, Medical Device, and Biotech
  Industries, Syed Imtiaz Haider, St. Lucie Press,
  2002. ISBN 1574443313.
• Good Manufacturing Practices for Pharmaceuticals
  A Plan for Total Quality Control From
  Manufacturer to Consumer, Sidney J. Willig.
  Marcel Decker, 2000. ISBN 0824704258.
• Voss, J. Cleaning and Cleaning Validation A
  Biotechnology Perspective. CRC Press, 1995. ISBN
  0939459507.
• LeBlanc, D.A. 2000. Validated Cleaning
  Technologies for Pharmaceutical Manufacturing.
  CRC Press. ISBN 1574911163.
• Cloud, P. 1998. Pharmaceutical Equipment
  Validation The Ultimate Qualification Guidebook.
  CRC Press. ISBN 1574910795.
• Juran, Quality Control Handbook, 4th Edition.,
  McGraw-Hill, 1988.
• DeSain C, Sutton C. (1995). Process development
  that supports process validation. Pharmaceutical
  Technology 19 (Oct.) 130-136, 1995.
• Garcia T, Wilkinson S, Scott J. The development
  of a blend-sampling technique to assess the
  uniformity of a powder mixture. Drug Development
  and Industrial Pharmacy 27(4) 297-307, 2001. 
• Chaloner-Larsson, G., Anderson, R., Egan, A.
  1997. A WHO guide to good manufacturing practice
  (GMP) requirements Part 2 Validation . World
  Health Organization, Geneva. www.who.int/vaccines-
  documents/DocsPDF/www9666.pdf Accessed on October
  2nd, 2006.
• Brown, F. 1993. Review of accidents caused by
  incomplete inactivation of viruses. Dev. Biol.
  Stand. 81 103-7
• Nathanson, N. and Langmuir, A.D. 1995. The
  Cutter incident. Poliomyelitis following
  formaldehyde-inactivated poliovirus vaccination
  in the United States during the Spring of 1955.
  II. Relationship of poliomyelitis to Cutter
  vaccine. 1963. Am. J. Epidemiol. 142109-40.

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Autoclave Validation

• IQ-
• Design specifications meet users needs
• Proper installation, utilities, manuals, spare
  parts

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The DQ, IQ, OQ process insures that this
autoclave will meet the needs of the
manufacturing group.
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Sample Format for Installation Qualification of
an autoclave. Courtesy of WHO. Chaloner-Larsson,
G., Anderson, R., Egan, A. 1997. A WHO guide to
good manufacturing practice (GMP) requirements
Part 2 Validation . World Health Organization,
Geneva . www.who.int/vaccines-documents/DocsPDF/ww
w9666.pdf Accessed on October 2nd, 2006.
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Autoclave Validation

• OQ
• Does it operate properly
• Does it reach the specified temperature and
  pressure
• Do timers work
• Does the operator interface panel work
• Are safety interlocks functional

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Sample Format for Operational Qualification of an
autoclave. Courtesy of WHO. Chaloner-Larsson,
G., Anderson, R., Egan, A. 1997. A WHO guide to
good manufacturing practice (GMP) requirements
Part 2 Validation . World Health Organization,
Geneva . www.who.int/vaccines-documents/DocsPDF/ww
w9666.pdf A ccessed on October 2nd, 2006.
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Calibration
Figure 1 Operational qualification of an
autoclave requires the calibration of instruments
against traceable standards. This figure shows
the calibration of a validator (out of view)
against the IRTD probe.
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Monitoring Temperature
Figure 2 A validator, used in the operational
qualification of an autoclave. The validator is
attached to individual thermocouples by wires
coming from the rear of the instrument (arrow).
Tha validator has been previously calibrated and
the data gathered from the thermocouples will be
logged on the laptop computer. The software on
the computer is also subject to validation
requirements.
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Figure 4. The validator is attached to individual
thermocouples (TC) by thin wires that pass
through the wall of the autoclave through a
specially designed port (arrow). This picture
shows the back side of the autoclave. The
validator is out of view at the lower left.
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Figure 5. The inside of the autoclave showing the
maze of wiring connecting the individual TCs to
the validator. The port through which the wires
pass is visible in the middle left of the
picture. The individual TCs will be placed in
various areas of the autoclave or equipment being
autoclaved to generate a thermal map of the
interior of the autoclave.
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Figure 3. Output from the validator. The
temperature at each connected thermocouple is
displayed. Accumulated lethality (F 0 ) may also
be displayed. Notice how some TC have failed and
will not record a temperature. Accounting for TC
failure is necessary to keep from having to
repeat a study.
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Figure 6. Proving that sufficient lethality (F0)
is achieved within the nooks and crannies of
biomanufacturing equipment requires the placement
of TCs in hard to reach areas, in this case deep
within a piece of tubing. Special gaskets with
openings for the TC are used to insert the TC
within pieces of equipment.
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Developmental studies

• Experiments designed to explore and define the
  limits of the system to be validated
• Sterilization developmental studies may focus on
  worst case or hard to sterilize items
• Cleaning developmental studies may focus on
  worst case or hard to clean items
• Analytical methods may focus on defining the
  limits of the procedure (range, recovery, etc)
• Developmental studies then used to develop
  validation protocols and refine SOPs

53
Developmental Studies
Developmental studies are used to identify hard
to autoclave items and to test if item
preparation has an effect on ability to be
sterilized
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Developmental Studies
Every little nook and cranny Needs to be
assessed ! We have to prove that the inside of
the pipe reaches sufficient temperature, for a
long enough time to insure sterility!
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Developmental Studies
Does bagging make a difference?
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Cleaning Validation
Validating the cleaning cycle on a loaded
dishwasher. Notice the various pipes and parts
with narrow openings. Identification of hard to
clean and easy to clean areas starts with
developmental studies
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How do we validate a dishwasher ?

• How do we identify hard to clean easy to clean
  items?
• How do we test to see if they are cleaned?

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Going over the documentation
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Cleaning Validation
Sampling, documenting, and verifying is a labor
intensive process
Why is cleaning considered a critical process?
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Sampling
Figure 8. Swabbing is commonly used to sample the
surface of cleaned materials. The swab is then
placed in a sample vial and sent to the Quality
Control lab for analysis. Proper technique is
essential in order to evaluate the effectiveness
of cleaning techniques. Even so, swabbing results
are typically corrected for known deficiencies in
recovery.
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Cleaning Validation
Figure 9. Analysis of rinse water for residual
cleaning agents or process materials is an
essential component of cleaning validation.
Insuring that the sample is not contaminated
requires vigilance and properly following the
relevant SOPs.
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Analytical methods validation

• Considered a critical step in the manufacturing
  process
• Requirements for validated analytical methods
  explicitly written into the CFRs
• 211.165 Testing and release for distribution
• Requires that the accuracy, sensitivity,
  specificity, and reproducibility of test methods
  employed by the firm shall be established and
  documented. Such validation and documentation may
  be accomplished in accordance with 21 CFR 211.194
  (a)(2)

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Testing For Identity

• Requires the development of validated analytical
  methods that can determine identity.
• Chemical Tests
• Is the molecule chemically what it is supposed to
  be?
• Biological Activity Tests
• Does the molecules have the biologic activity
  that it is supposed to have?
• Immunogenic Tests
• Is the molecule immunogenic (allergic)?

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Identity

• 21 CFR requires testing of raw materials
• Raw materials quarantined until identity verified
• Raw materials must meet predetermined
  specifications
• Vendors (and alternates) specified in BLA (NDA)

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Identity

• 21 CFR requires testing of in-process materials
• Product from bioreactor / fermentor
• Product from purification steps
• Waste products from above
• Must meet specifications, if not - stop the
• process to investigate take corrective action

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Regulatory guidance on validation

• Guideline on General Principals of Process
  Validation http//www.fda.gov/cder/guidance/pv.ht
  m
• Guidance for Industry For the Submission
  Documentation for Sterilization Process
  Validation in Applications for Human and
  Veterinary Drug Products. CDER CVM November 1994.
  www.fda.gov/CDER/GUIDANCE/cmc2.pdf
• Working Party on Control of Medicines and
  Inspections
• Final Version of Annex 15 to the EU Guide to Good
  Manufacturing Practice
• Title Qualification and validation
• http//pharmacos.eudra.org/F2/eudralex/vol-4/pdfs-
  en/v4an15.pdf
• ICH Q7a Section 12 on validation
• http//www.fda.gov/cder/meeting/ICH_Q7A/index.htm
• A WHO guide to good manufacturing practice (GMP)
  requirements. Part 2 Validation
• Chaloner-Larsson, G., Anderson, R., and Egan, A.
  1997. World Health Organization, Geneva.

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Validation Protocol

• Specific protocol based on developmental studies
• Protocol is written, reviewed and approved
• Protocol is executed
• Report written and approved
• System is validated

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Analytical Methods Validation

• Being a critical component of production process
  analytical methods must be validated
• Raw material testing
• In process materials
• Final product specifications

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What must be demonstrated

• Selectivity (specificity)
• Accuracy
• Precision
• Linear Range
• Limit of detection (LOD)
• Limit of quantification (LOQ or LLOQ)
• Robustness

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Validated methods

• USP NF (United States Pharmacopeia National
  Formulary) contains validated analytical
  methods
• Use of a USP method does not eliminate the
  organizations obligation to demonstrate that the
  method performs adequetly

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Selectivity (specificity)

• Does the analytical method detect the component
  it is supposed to detect?
• Cross reactivity in antibody based methods
• Demonstrate specificity by conducting analytical
  method on materials that may mimic analyte of
  interest
• Looking for false positives

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Accuracy

• Ability of analytical method to accurately
  determine the presence and amount of the analyte
  of interest
• Typically done by analyzing a traceable standard

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Recovery

• Can we recover all of the analyte from a complex
  matrix
• May reflect sample preparation problems
• Typical recovery studies done using spiked
  samples
• Final results may be corrected by the recovery
• Swab samples typically corrected to reflect
  recovery

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Linear Range

• Must define the linear range of a method
• Assay may have multiple linear ranges

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Precision

• How much variability does the assay exhibit when
  analyzing the same sample
• Typically demonstrated by analyzing multiple
  aliquots of a homogenous sample
• Acceptance criteria will depend on the assay and
  the material being assayed (2-20 RSD)
• Typically expressed as RSD (relative standard
  deviation)

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Limit of Detection (LOD)

• Lowest level at which method can detect analyte
• Results reported as less than LOD
• Based on signal to noise specification (101,
  201)

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Robustness studies

• How sensitive is the method to minor variations
  in method
• Pipetting variation
• Temperature fluctuation
• Reagent stability
• Etc.
• Detailed robustness studies will be reflected in
  final SOPs

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Limit of Quantification (LOQ)

• Lowest level at which method can accurately
  quantify analyte
• Based on signal-to-noise ratio specification
  (101, 201) and precision specification
• Precision and LOQ related
• Lower LOQ will typically result in lower precision

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Bradford Assayfor total protein

• Well known colorimetric assay that relies on the
  binding of Commassie G-250 dye to the proteins in
  an acidic solution
• Dye binding proportional to number of positive
  charges in protein
• Proteins gt3000 dal not detected
• Simple, quick, wide range, few interfering agents

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Bradford Assay
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Disadvantages

• Incompatability with surfactants
• Staining of glass and quartz cuvettes
• Use disposable polystyrene cuvettes
• Or wash with strong detergents and methanol

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Validating the Bradford

• Selectivity (specificity)
• Accuracy
• Recovery
• Precision
• Linear Range
• Limit of detection (LOD)
• Limit of quantification (LOQ or LLOQ)
• Robustness

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Some Questions

• A valve used to transfer material from a holding
  tank to the purification suite jams closed. You
  have a spare valve that is an identical model.
  Can you change this valve with the spare and
  continue operations? What if the valve is from a
  different manufacturer?
• You notice that your autoclave loading plan
  leaves room for additional material. Realizing
  that increasing that amount of material in the
  autoclave will shorten the turn around time for
  the production line you contemplate increasing
  the amount of material loaded into the autoclave
  then specified by the loading plan. What should
  you do? What will be required to implement this
  change?
• An SOP for calibration of a pH meter calls for a
  two point calibration at pH 4 and pH 7. You
  notice that a single point calibration at pH 7
  produces the same result from pH measurements of
  your buffer solutions and allows you to take a
  longer break. Is it Ok to do the one point
  calibration when the SOP calls for a two point
  calibration? How would you go about changing the
  SOP to allow for a one point calibration?

84

• What documents would provide information
  concerning the make and model of a particular
  valve used to regulate the transfer of material
  from a holding tank to the purification suite?
• Your supervisor is concerned that the
  fermentation vessel is not providing sufficient
  aeration of the culture to get optimal growth and
  suggests installing a different kind of baffle in
  the vessel. How would you demonstrate that this
  change has no effect on product quality?