scigmoid publications
Post on 16-May-2015
108 Views
Preview:
DESCRIPTION
TRANSCRIPT
Document SystemsValidation
Scigmoid Publications Incwww.scigmoid.com
cGMP
Biotech companies coming to GMP like large pharma difficult transition
Problems due to: tight budgets limited (trained) personnel R & D scientists only
Scigmoid Publications Incwww.scigmoid.com
Documentation for cGMP
Provides project planning
Record of what and how was done- plus any changes implemented
IT IS REQUIRED THE cGMP
Biotech and Documentation
Overlooked in early stagesViewed as cumbersome and time
consumingFrom this, delays in early
development occurNeed top down commitment to
documentation
Types of Documentation
Early on, scope and project goals timeline or Gantt chart http://www.netmba.com/operations/
project/gantt
http://searchcio.techtarget.com/sDefinition/0,,sid19_gci331397,00.html
Gantt chart
Planning tooltimelines showing duration stages of
the project in chronological orderinterrelationship between various
stages of the projectresponsible parties for each phase of
the projectFigure 3.1, Page 29
Areas of Documentation
Process overview explain major process steps detail sufficient so personnel at each
step knows how the product is made and what their role is
blueprint of project process targets
Areas of Documentation cont’d
Parts of the process overview: 1. Purpose, including cell type and purification
steps 2. Required resources - raw materials,
facilities, equipment, personnel requirements, test methods
3. Process outline- step-by-step outline 4. Product characterization- tests to assure
quality 5. Change authority - how and who
Areas of Documentation cont’d
Research notebooks what you have kept in my courses great support for process validation detailed experimental results anyone picking up notebook can repeat
your steps lots of info about the preclinical
material and its properties
Areas of Documentation cont’d
5 parts to a research notebook: 1. Introduction 2. Experimental plan (include alternate
plans) 3. Observations and data (raw data) 4. Discussion and results 5. Conclusion
Areas of Documentation cont’d
SOPs preclinically after stabilization of
process REPRODUCIBILITY (again, anyone who
knows the techniques can produce the product)
however, not too rigidly written differ from lab notebooks - HOW?
Areas of Documentation cont’d
SOPs cont’d - Value while being written, forced to think of
problems- may avert costly errors this way standardize technician training minimize misunderstandings about the
process if changes are made to the process, SOP
history will be available by end user for review
tells the user what to record
Areas of Documentation cont’d
Testing Documents SOPs standardize test methods - include
equipment, methods and reagents minimize variation from operator to
operator (“pilot error”) include use of positive and negative
controls outline data and test values that need
recording
Areas of Documentation cont’d
Batch Production Records (BPRs) provide lot information- critical in
production (recalls often by lot number) develop lot-specific forms for each
appropriate step in the SOP Pages 33-34- CFR-required batch
record sections go over batch records given in class
GLP documentation
Preclinical operationsuser-friendly document numbering
system (needs to accommodate many doc types)
index should contain 3 parts: functional group (testing vs. processing) stage of process (scale-up, purification) type (general item, specific procedure, etc.)
GLP docs cont’d
Each doc reviewed by a person in each functional unit (process dev., QA, production)
use document review record (Page 35)format of document standardizedBPRs- data and text together or
separate- find consensus (see page 36 Figure 3.3)
GLP docs cont’d
Raw material documents catalogue materials used list all required raw materials assign identity numbers to each reagent inspection of raw materials; visually,
chemically and microbiologically- WHAT are you looking for?
USP or ACS
GLP docs cont’d
Sampling documents create early in process also purity, integrity, yields types of tests:
endotoxinmicrobiologicalELISAPAGEHPLC
GLP docs cont’d
Laboratory documents raw material and in-process testing detailed info, such as time when and
amount of sample to be taken, lot number, date, etc.
how precise and accurate from original test data (accepted standard deviation)
location of original test data
GLP docs cont’d
Laboratory documents cont’d necessary calculations to arrive at data logbooks for instruments and reagents calibration records lab personnel training docs Page 39 Figure 3.4- document of a
simple lab procedure
GMP documentation
Extension of docs begun in preclinical labincludes prompts were information needs
to be enteredneed QA tested raw materials (remember,
the product is now going into a person!)record expiration date- cannot use 1 day
past that date (not so in a research lab)
GMP documents
Contain process limits (maintains control of process)
limits include process parameters pH temperature volume concentration WHAT are some other limits?
GMP documents
Steps after a process is complete: technician verifies and signs that process is
complete supervisor reviews and signs documents independent reviewer QA’s the documents (and
the process) Therefore, each document is reviewed 3 times have review document for this process (GETTING
the picture about how much writing goes on!) FILE docs when done for safe keeping
Misc. GMP Documents
Records for preventative maintenance, calibration and usage of equipment used in production
Make sure equipment functions same from run to run
Validation
Chapter 4
Validation
Document that a manufacturing process is under control
Capable of consistent production of a biopharmaceutical
Begins with product specifications
Validation
Can’t test for quality, so validate
Therefore, each step of manufacturing process validated so you have assurance of quality product
Important Validation Definitions
Calibration measuring device produces results
within predetermined limits (compared to a reference standard)
Cell Seed aliquot of cells derived from single tissue
Certification review and approval process (final step)
Important Definitions, cont’d
Concurrent Validation written evidence that process is working
(by gathering data during the process)Drug Product
a finished dosage that contains active ingredient (s)
HVAC Heating, ventilation, and air conditioning
Important Definitions, cont’d
Intermediate substance produced in one stage of
production and used at another (produced by chemical, biological or physical action)
Installation Qualification (IQ) written proof of installation according to specs
Master Working Cell Bank (MWCB) derived from one or more ampoules of the cell
seed- shown to be uniform composition (WCB)
Important Definitions, cont’d
Operational Qualification (OQ) written proof that system performs as
designedPerformance Qualification (PQ)
approved plan to validate a system or process
Population Doubling Time (PDL) number of doublings that culture has
undergone- Why is this important?
Important Definitions, cont’d
Process Validation documented evidence that a process will
consistently produce a productProspective Validation
written evidence, prior to carrying out a process, that the process will do as suggested
Qualification separate validation- shows system is suitable
to carry out designated process
Regulatory requirements
FDA - safety and efficacy of drug supplySee quote page 48 under section
4.1.3Parts 210 and 211 of GMPs - if FDA
thinks drug is tampered they may take action against the producer
highly trained FDA personnel to carry out inspections of drug makers
Process Development
IF process development weak or absent, inconsistent results will appear during manufacturing runs
Involves personnel from validation, QA, QC, manufacturing and engineering
Section under change control (page 49)
Parameters of Process Validation
Validation of utilities proper installation manufacturer’s specs moisture and airborne product
contamination purity take samples from both inlet and outlet
of unit (when testing water, steam, etc.)
Parameters of Validation, cont’dEnvironmental control
design of facility and environmental controls keep operation within specified limits
conditions differ based process performed in that area (cold, moist, etc.)- e.g. protein purification in a 4ºC room
microbiological testing of surfaces, air, etc (do you need clean room facilities?)
facility sanitization
Parameters of Validation, cont’d
Cleaning methods and changeover not only clean surfaces, but document residual
detergent levels on washed equipment & surfaces
endotoxin testing (what are endotoxins?) - can use LAL test
perform assays on final rinse water- determine levels of residual products
what should be the acceptable level of residual material?
Parameters of Validation, cont’d
Bioinactivation of bacterial or cell culture waste different level of requirements based on
Biosafety level some procedures include:
inactivation of organisms prior to removal from a closed system
inactivate wastes before disposal in normal trash
Parameters of Validation, cont’d
Sterilization validate process so sterility assurance
level is achieved Methods include:
filtrationautoclavingsteam-in-place (SIP - some bioreactors)vessel heated with a solution
Parameters of Validation, cont’d
Sterilization, cont’d Autoclaves - use empty chamber heat
distribution studies (to determine temperature uniformity)
Biological indicators (BIs) to determine when organism is eradicated (called D-value or BI death rate)
vendor specific D-value so keep that in mind
Parameters of Validation, cont’d
Media hold challenge length of time a vessel hold a liquid and
remain sterile push the procedure to see when it fails how does manipulations (adding or
removing items) affect the sterility important if you need to make media in
advance and hold a while (how about the LB we use in class?)
Parameters of Validation, cont’d
Depyrogenation sterilization of heat stable materials use an endotoxin challenge (since
endotoxins are heat stable) empty chamber and loaded chamber
heat studies performed
Parameters of Validation, cont’d
Filtration need to evaluate product, steps and filter
media early process uses: sterilization of media,
removal of cellular debris and removal of intermediate
late stage process uses: microbial retention (with altering final product
evaluate filters themselves
Parameters of Validation, cont’d
Programmable logic controllers (PLCs) computers that automate the processes
- must be validated also hardware software operating system What are some problems here?
Bulk drug manufacturing
Making large batch of drug at once
MWCB important - do the cells and DNA remain intact during production
perform validation tests for acceptability of starting material
MWCB
History and morphology of cell line, plasmid, and transfection into host cell
storage, maintenance and propagation of cell line
cell markerstumorigenicity studiesexpression of endogenous retrovirusestest for presence of virus, fungi, bacteria
or mycoplasma
MWCB cont’d
Bacterial production systems check for: carbohydrate use antibiotic resistance contamination sequence and restriction map of plasmid growth rate of host SDS-PAGE of product profile
Recovery and purification
Remove impurities from the drug substance
eliminate inadvertent contamination (Flu vaccine)
therefore, validate recovery process!
Pharmaceutical Manufacturing Validation
Similar to biotech manufacturing, but has special issues such as aseptic processing, lyophilization and packaging
Aseptic processing aspects of filling of a drug product so
that contamination is not introduced fill with cell growth media as a control
Pharmaceutical Manufacturing Validation, cont’d
Lyophilization freeze drying- extends shelf life and
reduces moisture content freeze-dry placebo as control; test
several cycle to assure process uniformity
filling operation important to duplicate volumes in every vial
Pharmaceutical Manufacturing Validation, cont’d
Container/closure integrity components and methods for forming a
seal SOPs with as much detail as possible to
describe system to produce container seal integrity of container seal under expected
storage conditions 2 tests used- USP bacterial challenge test
and dye leak challenge test
Pharmaceutical Manufacturing Validation, cont’d
Packaging and labeling FDA- up to 30% of product recalls due to
mislabeling (label mix-ups) SOPs for quarantine, inspection, release
and handling don’t make all labels identical (use
varying color and size for different products or strengths
Validation
Good business sense, not just the law!
Scigmoid Publications Incwww.scigmoid.com
top related