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Incorporating Validation Concepts into the Biotechnology Curriculum (or minding your P’s and Q’s)

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Title: Incorporating Validation Concepts into the Biotechnology Curriculum (or minding your P’s and Q’s)


1
Incorporating Validation Concepts into the
Biotechnology Curriculum (or minding your Ps
and Qs)
  • Thomas Burkett, Ph.D.
  • The Community College of Baltimore County
  • tburkett_at_ccbcmd.edu

2
Aims
  • Introduce the role of validation in
    biomanufacturing
  • Explain basic validation concepts and terminology
  • Provide an example of how validation is
    incorporated into the biotech. curriculum at CCBC
  • Provide examples of validation exercises
  • Provide examples of validation resources

3
Validation in Biomanufacturing
  • Biomanufacturing is a complex process involving
    multiple unit operations many of which are
    critical to insuring patient safety and product
    efficacy

4
Block Flow Diagram of a typical Production Process
5
Mammalian Antibody Production Cell Culture
6
Mammalian Process Flow - Upstream Diagram
Transfer to Purification Suite
rProtein A Dia 1 meter CV 236 L Bed 30cm
Virus Inactivation
7
Mammalian Antibody Production - Downstream
Processing
8
Validation in Biomanufacturing
  • 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.

9
Validation in Biomanufacturing
  • 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.

10
Validation in Biomanufacturing
  • Validation does not replace testing, but it does
    reduce the testing burden for raw materials,
    in-process materials, and final product

11
Validation in Biomanufacturing
  • Validation itself is a process that evolves with
    the product.
  • Validation requirements for production of
    pre-clinical material much less stringent then
    for phase III clinical material.
  • Critical operations raw materials, analytical
    methods, viral clearance, sterilization,
    cleaning.

12
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

Validated Production Process
?
13
Process Flow Diagram
14
Regulatory requirement for validation
  • 21 CFR 211 Subpart F Production and Process
    Controls
  • 211.100 Written procedures deviations
  • (a) Requires written procedures for production
    and process control designed to assure that
    products possess the quality attributes that they
    purport or are represented to possess.
  • (b) Requires that any deviations from written
    production and process control procedures be
    recorded and justified.
  • 211.101 Change in of components
  • 211.103 Calculation of yield
  • 211.105 Equipment identification
  • 211.110 Sampling and testing of in-process
    materials and drug products
  • Requires that control procedures be established
    to monitor the output and validate the
    performance of those manufacturing processes that
    may be responsible for causing variability of in
    process material and drug product.
  • 211.111 Time limit on production
  • 211.113 Control of microbiological
    contamination
  • Requires that sterilization processes be
    validated
  • 211.115 Reprocessing
  • 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)
  • 21 CFR 211 Subpart I- Laboratory Controls
  • 21 CFR 211 Subpart J Record and Reports
  • 21 CFR 820 Quality Systems Regulations

15
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.

16
What does validation of any sterilization
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).

17
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.

18
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.

19
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).

20
Validation in the biotech. curriculum at CCBC
  • Validation introduced as part of quality
    systems section in intro. Course
  • First lecture is on concepts of quality and
    quality attributes
  • Second lecture introduces validation as part of
    the production process
  • Lab exercises varies. Past examples include
    validation protocol for an autoclave validation
    of bioreactor sterilization.

21
Learning Objectives
  • Upon completion of this module students should
  • Be familiar with the various government and third
    party literature pertaining to validation.
  • Understand how component, process, and methods
    validation fits into the overall quality system.
  • Be aware of pertinent regulations that apply to
    validation strategies.
  • Understand concept of criticality and be able to
    identify points in the production process that
    are critical to product quality.
  • Be able to distinguish between installation
    qualification, operation qualification, and
    performance qualification (IQ, OQ, PQ).
  • Given the function of a piece of equipment used
    in biomanufacturing, discuss valtidation issues
    related to that specific piece of equipment.
  • Be aware of the vendor, installation, and
    maintenance documentation required for initiating
    the validation process.
  • Follow a validation SOP
  • Be able to design a validation protocol for an
    individual piece of equipment.

22
Concepts of Quality
  • Biomanufacturing

23
Quality Attributes
  • 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

24
Designing Quality into the product
  • A central concept is that quality can not be
    tested for!
  • Testing programs are based on testing a
    statistically significant number of samples
  • However to be absolutely sure that all of your
    product meets specifications you would have to
    test everything.
  • Testing by itself will not insure quality and is
    inefficient
  • Testing is required under the GMPs
  • Raw materials
  • In-process samples
  • Final Product
  • Quality (identity, safety, efficacy, potency,
    purity, stability, consistency) must be designed
    into the production process
  • Begins with predetermined specifications
  • Raw material specifications
  • In-process material specifications
  • Final Product Specifications

25
Predetermined specifications
  • Identity
  • Size, amino acid sequence, presence of post
    translational modifications, 3-D structure.

26
Predetermined specifications
Identity
21 CFR 211.84 (d) at least one test shall be
conducted to verify the identity of each
component of a drug product. Tests consist of
Chemical, biological, and Immunological
methods. Requires testing of Raw materials,
In-process intermediates, final products.
27
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)?

28
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)

29
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

30
Testing
  • Usually done by the Quality Control Laboratory
  • CFR requires that quality unit be under
    independent supervision and report directly to
    senior management

31
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

32
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

33
Insuring the Production of a Quality Product - II
  • Validation its role in quality

34
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 ?

35
Validation
  • The FDAs 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.

36
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.

37
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!

38
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

39
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).

40
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

41
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.

42
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.
43
Validation Protocol
  • Validation Protocols may consist of multiple
    SOPs each describing specific steps in the
    validation process

44
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

45
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 can take years!

46
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.

47
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?

48
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.

49
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.
50
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.

51
OQ Protocol
Example of a protocol for the OQ component of
validating a pH meter
As with all other SOPs this document will
contain an Objective, scope, and
responsibility Section.
52
OQ Protocol
Example of a protocol for the OQ component of
validating an autoclave
As with all other SOPs this document will
contain an Objective, scope, and
responsibility Section.
53
Typical OQ Protocol Components
  • Objective
  • Responsibility
  • Equipment required (Calibration verification
    Traceability)
  • SOP(s) used
  • Equipment Identification
  • Parameters measured (Specifications)
  • Documentation

54
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

55
A prospective validation study
56
A concurent / retrospective validation study
No
Qualify system
Calibrate system
Yes
Yes
Approval
57
The V-Model
58
Planning for Validation
  • Project Plan
  • Agreed by team members
  • Details phases, activities, and milestones
  • Gantt Chart most commonly used

59
  • Putting it
  • all together

60
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

61
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).

62
An example of a facility / process validation
  • Remicade (infliximab) is a chimeric mAb
    directed against TNF-a.
  • Approved in 1998 (US) and 1999 (EU) to treat
    Crohns disease, and RA.
  • Produced by Centocor, Inc. in Malvern, PA
  • Contains mouse variable domains and human
    constant domains (IgG1)

63
Antibodies
  • Proteins
  • 2 heavy Chains
  • 2 Light Chains
  • Disulfide Bonds
  • Variable region
  • Recognizes antigen
  • Constant region
  • Effecter function
  • Classes subclasses

Ig G class
64
Production of Remicade
  • BLA approved in August 1998 (FDA), 1999 (EMEA).
  • First site for bulk manufacture was Leiden, The
    Netherlands.
  • Process was transferred to Malvern, PA in April
    2002.
  • Process changes, including larger bioreactors,
    external spin filters, and a change in media
    components were introduced to meet increased
    demand.
  • Not only did a new facility have to be validated,
    but also the changes to the manufacturing process
    had to be validated.
  • Necessary to demonstrate that product produced
    under these new conditions had same quality
    attributes as product produced in Leiden.
  • An unanticipated consequence of increased product
    yield was a change in chromatography conditions
    due to product breakthrough under old conditions.
  • Minor changes can have unanticipated consequences
    on product quality!
  • A new facility for production of remicade is
    being constructed in the Republic of Ireland and
    should be on line in 2007

65
Changes in Production Process in Malvern, PA
66
Example of a 1000 L Bioreactor with an external
spin filter used in the production of Remicade
in Malvern, PA
67
Remicade Production
68
These tanks are used for the holding of material
from the bioreactors prior to product capture
and initial chromatography. What performance
aspects of these tanks do you think need to be
validated? How does cleaning of these tanks
between use affect validation?
69
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?

70
Some More Questions
  • 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?

71
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.

72
Laboratory Activities
  • Students develop and carry out a simplified
    validation plan / protocol
  • Autoclave validation
  • Bioreactor sterilization
  • Bioreactor cleaning
  • Spectroscopy
  • Chromatography
  • Plasmid construct

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