Transcript Insuring the Production of a Quality Product

Incorporating Validation
Concepts into the Biotechnology
Curriculum
(or minding your P’s and Q’s)
Thomas Burkett, Ph.D.
The Community College of Baltimore County
[email protected]
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
Validation in Biomanufacturing
• Biomanufacturing is a complex process
involving multiple unit operations many of
which are critical to insuring patient safety
and product efficacy
Block Flow Diagram of a typical Production Process
Innoculum
Seed
Fermentati
on
Production
Fermentati
on
Harvest
UPSTREAM
DOWNSTREAM
Ultrafiltrati
on
1
Chrom. 1
1
Ultrafiltrati
on
2
Chrom.
2
Viral
Filtration
VIRAL
NON-VIRAL
Chrom.
3
Ultrafiltrati
on
3
Sterile Fill
Final
Formulation/
Sterile Filtration
Mammalian Antibody Production –
Cell Culture
Media
Prep
HEAT
COOL
Media
Pasteurizer
Vial Thaw /
Inoculum
Expansion
50-Liter
500-Liter
5000-Liter
20,000-Liter
Mammalian Process Flow- Upstream
Diagram
Transfer to
Purification
Suite
Virus
Inactivation
rProtein A
Dia: 1 meter
CV: 236 L
Bed: 30cm
Depth Filter
75m2
Disc-Stack
Centrifuge
Mammalian Antibody Production Downstream Processing
Cation Exchange
Dia: 1.6m
CV: 600L
Bed: 30cm
I.B.I
CryoPreservation
System
Intermediate
Storage
Bulk
Filtration
(BDS)
3m2
Anion Exchange
Dia: 1.6m
CV: 600L
Bed:30cm
UF/DF Step
80m2
Intermediate
Storage
Intermediate
Storage
Viral
Filtration
20m2
Hydrophobic
Interaction
Dia: 1.6m
CV: 600L
Bed: 30cm
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.
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.
Validation in Biomanufacturing
• Validation does not replace testing, but it
does reduce the testing burden for raw
materials, in-process materials, and final
product
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.
Validation in Biomanufacturing
• A fully validated process is “locked in”
• Any change outside of the validated space
invalidates process
Validated Production Process
Δ
• Change must be evaluated for effect on patient
safety and product efficacy
Process Flow Diagram
Vent
CIPS
516A,B
SC
INC-xxx
Incubator
M
208
Released Mobil
Dew ar
LN2 Freezer
209
PU-xxx
Media Pump
6 x 1 L Spinner
From Media
Prep
D-C-1101
210
15 x 1 L Spinner
Air
202
CO2
203
N2
204
O2
205
From Bags
201
206
R-12000
100L Seed
Bioreactor Package
Temperature
Control
Module
1 ml Ampules
Gas
Manifold
207
Glycol Return
Option A - 1:5 Split
Plant Steam
125 ml Flask
3x500 ml Flask
To 400 liter
M
211A
Glycol Supply
D-C-1201
Option B - 1:10 Split
CIPR
BSC-xxx
Biosafety Cabinet
211B
SCC
Inoculation/Seed Lab
Process Step
>>>
201
Media
(Bolus)
Liters
202
Air
SLPM
203
CO2
SLPM
204
N2
SLPM
D-C-1202
PD
205
206
207
O2
SLPM
Bottom
Aeration
SLPM
Top
Aeration
SLPM
10.0
100.0
208
Inoculum
Liters
209
Nutrients
Liters
210
Base
Liters
211A
Harvest
211B
Liters
211C
420
Waste
Flask &
Roller bottle
Media
Com ponent
Basal Media
(L)
Air
SLPM
CO2
SLPM
N2
SLPM
O2
SLPM
Nutrients
(L)
1N NaOH
(L)
Media with Cells
(L)
Mab
Grams
To 2000 liter
BioReactor
211C
Fermentation
Stream Number >>>
BioReactor
75.0
110.0
10.0
10.0
110.0
10.0
10.0
100.0
10.0
5.0
5.0
15.0
75.0
75.0
25.0
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
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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
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.
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).
•
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.”
Regulatory guidance on validation
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Guideline on General Principals of Process Validation
http://www.fda.gov/cder/guidance/pv.htm
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.
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).
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.
Learning Objectives
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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.
Concepts of Quality
Biomanufacturing
Quality Attributes
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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
– The ability of the product and/or process to reliably possess specified quality attributes on an ongoing basis.
3 consecutive batches of product meeting predetermined specifications is accepted as proof that a process
is consistent. However, in NDA data from up to twenty batches may be submitted.
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 GMP’s
•
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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
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Raw material specifications
In-process material specifications
Final Product Specifications
Predetermined specifications
• Identity:
– Size, amino acid sequence, presence of post
translational modifications, 3-D structure.
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.
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)?
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)
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
Testing
• Usually done by the Quality Control
Laboratory
– CFR requires that quality unit be under
independent supervision and report directly to
senior management
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
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
Insuring the Production of a
Quality Product - II
Validation & its role in quality
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 ?
Validation
• The FDA’s 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.”
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
– The ability of the product and/or process to reliably possess specified quality attributes on an ongoing basis.
3 consecutive batches of product meeting predetermined specifications is accepted as proof that a process
is consistent. However, in NDA data from up to twenty batches may be submitted.
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!
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
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).
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
Validation Protocol
• Specific protocols (SOP’s) 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.
Example of a protocol for the
IQ component of validating a
pH meter
As with all other SOP’s this
document will contain an
Objective, scope, and responsibility
Section.
Validation Protocol
• Validation Protocols may consist of
multiple SOP’s each describing specific
steps in the validation process
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
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!
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.
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?
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.
Example of a protocol for the
IQ component of validating a
pH meter
As with all other SOP’s this
document will contain an
Objective, scope, and responsibility
Section.
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.
OQ Protocol
Example of a protocol for the
OQ component of validating a
pH meter
As with all other SOP’s this
document will contain an
Objective, scope, and responsibility
Section.
OQ Protocol
Example of a protocol for the
OQ component of validating an
autoclave
As with all other SOP’s this
document will contain an
Objective, scope, and responsibility
Section.
Typical OQ Protocol Components
• Objective
• Responsibility
• Equipment required (Calibration
verification & Traceability)
• SOP(s) used
• Equipment Identification
• Parameters measured (Specifications)
• Documentation
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
A prospective validation study
IQ
Calibration
OQ
PQ protocol
approval
PQ protocol
execution
Data
Analysis
Validation
Report
Approve
Conclusions
A concurent / retrospective
validation study
Data
Analysis
Calibrations
Correct ?
No
Calibrate
system
No
Are
systems
qualified?
Qualify system
Yes
Yes
Approval
The V-Model
User
Requirements
Specification
(URS)
Performance
Qualification
Related to
Related to
Operational
Qualification
Re
la
te
d
to
Functional
Specification
Detail Design
Related to
Installation
Qualification
Implement/Build
57
Planning for Validation
Project Plan
Agreed by team members
Details phases, activities, and milestones
Gantt Chart most commonly used
Jan 2003
Task Name
ID
Start
Finish
1/12 1/19 1/26 2/2
1
Design
1/13/03
1/31/03
15d
2
Prepare Quality Plan
2/3/03
2/14/03
10d
3
Prepare URS
2/17/03
2/21/03
5d
4
Prepare Project Justification
Document
2/24/03
3/21/03
20d
5
Obtain Funding
3/24/03
3/28/03
5d
6
Construct
3/31/03
4/18/03
15d
7
Commission
4/21/03
5/2/03
10d
8
Validate
5/23/03
6/5/03
10d
9
Turnover
6/6/03
6/6/03
1d
- Project Complete
Feb 2003
Mar 2003
Apr 2003
May 2003
Duration
2/9 2/16 2/23 3/2
3/9 3/16 3/23 3/30 4/6 4/13 4/20 4/27 5/4 5/11
Putting it
all together
Val
ida
tion
Qu
alif
ica
tion
Com
mis
sio
nin
g
Des
ign
Pha
se
PQrnover e
c
u
tan
al T
Fin Accep
and
The
Compliance
Pyramid
IQ
OQ
n
atio
ific tion
l
a
Qu
fica
tion Quali
a
l
l
ta
al
Ins ration
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p
O
ts
Tes s
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abi Accep anua
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e
Op tory tion M
Fac Opera
Good
Engineering
Practice
n
atio lan
c
i
f
i
pec tion P
S
s
a
ent Valid
m
e
t
c
ir
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R
r
io
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c
Use ty Pla Proje GMP R cificat s
/
i
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Qu
lian sign S cifica
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Comnal De n Spe
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ctio l Desi
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u
F
ai
Det
59
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
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).
An example of a facility / process validation
• Remicade® (infliximab) is a chimeric mAb*
directed against TNF-α.
• Approved in 1998 (US) and 1999 (EU) to
treat Crohn’s disease, and RA.
• Produced by Centocor, Inc. in Malvern, PA
* Contains mouse variable domains and human constant domains
(IgG1)
Antibodies
• Proteins
– 2 heavy Chains
– 2 Light Chains
– Disulfide Bonds
• Variable region
– Recognizes
antigen
• Constant region
– Effecter function
– Classes &
subclasses
Ig G class
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
Changes in Production Process in
Malvern, PA
Example of a 1000 L Bioreactor with an external spin filter used in the production of Remicade®
in Malvern, PA
Remicade Production
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?
Some Questions
•
A valve used to transfer material from a holding tank to the purification
suite jam’s 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?
•
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?
References
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Pharmaceutical Manufacturers Association’s (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. 142:109-40.
Laboratory Activities
• Students develop and carry out a
simplified validation plan / protocol
– Autoclave validation
– Bioreactor sterilization
– Bioreactor cleaning
– Spectroscopy
– Chromatography
– Plasmid construct
Items in orange are completed by Production. Items in turquoise are
completed by Quality Control
Day 1
Day 2
Retrieve B. subtillus culture from -80o Freezer.
Inoculate liquid culture & grow overnight at
37o.
Dilute overnight culture into fresh media.
Monitor OD as described in SOP P008
When OD is between 0.5-0.75 pool
cultures and mix.
Determine the number of
viable B. subtillus cells as
per SOP Q001
Prepare Fermentation Vessel
as described in SOP P002
Prepare media as
described in SOP P006
Add media to fermentation
vessel as described in SOP
P003
Add 50 mls of culture material to
fermentation vessel. Mix for 10
minutes. Collect sample as per
SOP
P005
Autoclave fermentation vessel
as per SOP P004
Allow fermentation vessel to cool to
room temperature. Collect sample
as per SOP P005
Day 3
Determine the number of
viable B. subtillus cells as
per SOP Q001
Determine the number of viable cells present pre
and post autoclave as per SOP Q001. Record
results and forward to Validation.