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Document Systems Validation. BIT 230 Chapters 3 and 4 (Huxsoll). cGMP. Biotech companies coming to GMP like large pharma difficult transition Problems due to: tight budgets limited (trained) personnel R & D scientists only. Documentation for cGMP. Provides project planning

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document systems validation

Document SystemsValidation

BIT 230

Chapters 3 and 4 (Huxsoll)

slide2
cGMP
  • Biotech companies coming to GMP like large pharma difficult transition
  • Problems due to:
    • tight budgets
    • limited (trained) personnel
    • R & D scientists only
documentation for cgmp
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
Biotech and Documentation
  • Overlooked in early stages
  • Viewed as cumbersome and time consuming
  • From this, delays in early development occur
  • Need top down commitment to documentation
types of 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
Gantt chart
  • Planning tool
  • timelines showing duration stages of the project in chronological order
  • interrelationship between various stages of the project
  • responsible parties for each phase of the project
  • Figure 3.1, Page 29
areas of documentation
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
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 d9
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 d10
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 d11
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 d12
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 d13
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 d14
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
GLP documentation
  • Preclinical operations
  • user-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
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 standardized
  • BPRs- data and text together or separate- find consensus (see page 36 Figure 3.3)
glp docs cont d17
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 d18
GLP docs cont’d
  • Sampling documents
    • create early in process also
    • purity, integrity, yields
    • types of tests:
      • endotoxin
      • microbiological
      • ELISA
      • PAGE
      • HPLC
glp docs cont d19
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 d20
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
GMP documentation
  • Extension of docs begun in preclinical lab
  • includes prompts were information needs to be entered
  • need 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
GMP documents
  • Contain process limits (maintains control of process)
  • limits include process parameters
    • pH
    • temperature
    • volume
    • concentration
    • WHAT are some other limits?
gmp documents23
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
Misc. GMP Documents
  • Records for preventative maintenance, calibration and usage of equipment used in production
  • Make sure equipment functions same from run to run
slide25

Validation

Chapter 4

validation
Validation
  • Document that a manufacturing process is under control
  • Capable of consistent production of a biopharmaceutical
  • Begins with product specifications
validation27
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
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
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 d30
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 d31
Important Definitions, cont’d
  • Operational Qualification (OQ)
    • written proof that system performs as designed
  • Performance 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 d32
Important Definitions, cont’d
  • Process Validation
    • documented evidence that a process will consistently produce a product
  • Prospective 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
Regulatory requirements
  • FDA - safety and efficacy of drug supply
  • See quote page 48 under section 4.1.3
  • Parts 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
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
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 d
Parameters of Validation, cont’d
  • Environmental 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 d37
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 d38
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 d39
Parameters of Validation, cont’d
  • Sterilization
    • validate process so sterility assurance level is achieved
    • Methods include:
      • filtration
      • autoclaving
      • steam-in-place (SIP - some bioreactors)
      • vessel heated with a solution
parameters of validation cont d40
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 d41
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 d42
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 d43
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 d44
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
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
slide46
MWCB
  • History and morphology of cell line, plasmid, and transfection into host cell
  • storage, maintenance and propagation of cell line
  • cell markers
  • tumorigenicity studies
  • expression of endogenous retroviruses
  • test for presence of virus, fungi, bacteria or mycoplasma
mwcb cont d
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
Recovery and purification
  • Remove impurities from the drug substance
  • eliminate inadvertent contamination (Flu vaccine)
  • therefore, validate recovery process!
pharmaceutical manufacturing validation
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
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 d51
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 d52
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
validation53
Validation
  • Good business sense, not just the law!