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Validation of Virus Removal

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Title: Validation of Virus Removal Author: FDA / CBER Last modified by: CBER Created Date: 6/24/1999 12:50:08 AM Document presentation format: On-screen Show – PowerPoint PPT presentation

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Title: Validation of Virus Removal


1
Validation of Virus Removal
  • Keith O.Webber, Ph.D.

Deputy Director, Div. of Monoclonal
Antibodies OTRR/CBER/FDA PDA/FDA
Meeting September 26, 2000
2
SCOPE - Products
  • Specified Biologics
  • Monoclonal Antibodies
  • rDNA-derived products
  • Traditional Biologics
  • Some Blood-products
  • Some Vaccines

3
SCOPE - Methods
  • Column Chromatography
  • Nano-Filtration (Viral Filtration)
  • Other Methods
  • Precipitation
  • Centrifugation

4
Example
Production Fermentor
Protein A affinity chromatography
Anion Exchange Chromatography
Virus filtration
Gel Filtration
Formulation and Fill
5
GENERALITIES
  • Validation conditions must be representative of
    the actual manufacturing process.
  • Validation should use virus-spiking studies.
  • Viral clearance studies should not be done in the
    production facility.
  • Validations should be done in duplicate.

6
SCALE-DOWN
  • Scale Down
  • Allows validation to be performed in testing labs
  • Maintains high titers of the spiking virus
  • Must be done appropriately

7
CHROMATOGRAPHY
  • Parameters that should be representative of
    commercial-scale manufacturing
  • CHROMATOGRAPHY MEDIUM
  • COLUMN BED HEIGHT
  • LINEAR FLOW RATE
  • BUFFER COMPONENTS AND CONCENTRATIONS
  • pH
  • TEMPERATURE
  • PRODUCT LOAD

8
CHROMATOGRAPHY
  • and
  • the chromatographic profile and product
    recovery of the scale-down process should be
    comparable to that of the manufacturing process.

9
FILTRATION
  • Parameters that should be representative of
    commercial-scale manufacturing
  • VISCOSITY
  • VOLUME PER cm2 OF FILTER AREA
  • IONIC STRENGTH
  • TEMPERATURE
  • pH
  • PROTEIN COMPOSITION CONCENTRATION

10
FILTRATION
  • and
  • the product recovery of the scale-down process
    should be comparable to that of the manufacturing
    process.

11
CHOOSING VIRUSES
  • The aims of viral validation studies are
  • to provide evidence that the production process
    will effectively remove viruses which are either
    known to contaminate the starting materials, or
    which could conceivably do so, and
  • to provide indirect evidence that the production
    process might remove novel or unpredictable virus
    contamination.

12
CHOOSING VIRUSES
  • The clearance validation should include
  • relevant viruses that may be anticipated to occur
    in the system
  • specific model viruses that are physically and
    chemically similar to relevant viruses
  • non-specific model viruses that represent the
    extremes of virus properties

13
CHOOSING VIRUSES
  • Examples of model viruses
  • Retrovirus X-MuLV
  • Small non-enveloped virus SV40, parvovirus,
    polio virus 1
  • Medium to large enveloped RNA virus
    Parainfluenza, Sindbis virus
  • Medium to large DNA virus HSV-1, pseudorabies
    virus

14
PRECAUTIONS
  • Avoid aggregation of spiking virus
  • Use small volumes of spiking virus in order to
    retain the sample composition.
  • Assess the potential for assay interference by
    the product or buffers.
  • Use control assays in parallel to assess the loss
    of infectivity due to dilution, concentration,
    filtration, or storage.
  • Include controls to demonstrate the effect of
    procedures used solely to prepare the sample for
    assay.

15
General Procedure
  • Titer Sample Load
  • Take Hold Control sample

Add high Titer Spike to Sample Load
  • Titer Hold Control
  • Titer Column Flowthrough
  • Titer Eluate Sample

16
Virus Assay Methodology
  • Infectivity is the standard method for clearance
    studies.
  • PCR assays and Polymerase Enhanced Reverse
    Transcriptase assays are being developed.

17
Evaluation of Results
  • Clearance factors from sequential orthogonal
    processes may be combined to give a Cumulative
    Clearance Factor
  • Orthogonal processes are those that clear virus
    by independent modes of action (e.g., Anion
    Exchange chromatography and Cation-Exchange
    chromatography)

18
Evaluation of Results
  • Beware of including both
  • a low-pH treatment step and
  • a chromatography step that uses elution at a low
    pH
  • in the Cumulative Clearance Factor.

19
Evaluation of Results
  • The Cumulative Clearance Factor must be
    substantially greater than the estimated number
    of virus particles in a volume of the starting
    material required to produce a human dose of the
    drug.

20
Evaluation of Results
  • The number of virions per mL of starting material
    should generally be estimated by Transmission
    Electron Microscopy.
  • One dose of product is generally considered to
    be the total regimen of drug.
  • e.g., 1 mg/week x 4 weeks 4 mg dose

21
Example
Product
Homologous Product
Protein A affinity chromatography
Anion Exchange Chromatography
Virus filtration
Gel Filtration
Formulation and Fill
22
Generic and Modular Validation
  • A generic validation study demonstrates virus
    removal or inactivation by a process using a
    model product and allows the use of that process
    with an homologous product without the need to
    revalidate.

23
Generic and Modular Validation
  • Generic viral clearance validation is applicable
    to situations when the purification process of a
    product is the same as a process that has already
    been validated for an homologous product.

24
Chromatography
  • The two processes must have the same
  • -chromatography medium,
  • -column geometry,
  • -equilibration buffers,
  • -load composition concentration,
  • -elution buffers,
  • -elution parameters,
  • -wash procedure.

25
Virus Filtration
  • The two processes must have the same
  • type of virus filter
  • solution characteristics
  • VOLUME PER cm2 OF FILTER AREA
  • IONIC STRENGTH
  • TEMPERATURE
  • pH
  • PROTEIN COMPOSITION CONCENTRATION

26
Generic and Modular Validation
  • Example of Homologous Products
  • Monoclonal Antibodies of the same species, class,
    and subclass and derived from the same source
    (e.g., ascites, tissue culture, etc.) and cell
    substrate.

27
Generic and Modular Validation
  • NOTE
  • GENERIC VALIDATIONS ARE NOT APPLICABLE TO
    HUMAN-DERIVED PRODUCTS OR PRODUCTS THAT MAY BE
    CONTAMINATED WITH HUMAN PATHOGENS.

28
Post-Approval Changes
  • Whenever a change is made in the production or
    purification process, the effect of that change
    on the viral clearance should be considered and
    the system re-validated as needed.

29
Additional Reading
  • ICH Guidance on Viral Safety Evaluation of
    Biotechnology Products Derived from Cell Lines of
    Human or Animal Origin,1998 (www.fda.gov/cber/guid
    ance/)
  • Points to Consider in the Manufacture and Testing
    of Monoclonal Antibody Products for Human Use,
    1997 (www.fda.gov/cber/guidance/)
  • Guideline on General Principles of Process
    Validation, 1987 (www.fda.gov/cder/guidance/pv.htm
    )
  • Reviewer Guidance Validation of Chromatographic
    Methods, 1994 (www.fda.gov/cder/guidance/)
  • Validation of the Purification Process for Viral
    Clearance Evaluation, 1997, A.J. Darling, in
    Biopharmaceutical Process Validation, G. Sofer
    and D.W. Zabriskie, editors. Marcel Dekker, Inc
    (New York)

30
Guidance
  • CBER Office of Therapeutics 301-827-5101
  • CBER Office of Vaccines 301-827-3070
  • CBER Office of Blood 301-827-3524

31
Obtaining Documents
  • Fax (888) CBER-FAX
  • Internet http//www.fda.gov/cber/guidelines.htm
  • E-mail OCTMA_at_CBER.FDA.GOV
  • Mail Training and Manufacturer Assistance
  • (HFM-40) CBER/FDA
  • 1401 Rockville Pike
  • Rockville, MD 20852-1448
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