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Document Systems Validation

BIT 230 Chapters 3 and 4 (Huxsoll)

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 Record of what and how was done- plus any changes implemented IT IS REQUIRED THE cGMP

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
Early on, scope and project goals
timeline or Gantt chart gantt, ,sid19_gci331397,00.html

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
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 contd

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 contd

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 contd

5 parts to a research notebook:
1. 2. 3. 4. 5. Introduction Experimental plan (include alternate plans) Observations and data (raw data) Discussion and results Conclusion

Areas of Documentation contd

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 contd

SOPs contd - 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 contd

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 contd

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 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 contd

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 separatefind consensus (see page 36 Figure 3.3)

GLP docs contd

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 contd

Sampling documents
create early in process also purity, integrity, yields types of tests:
endotoxin microbiological ELISA PAGE HPLC

GLP docs contd

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 contd

Laboratory documents contd
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 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
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 QAs 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!)

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

Document that a manufacturing process is under control Capable of consistent production of a biopharmaceutical Begins with product specifications

Cant test for quality, so validate Therefore, each step of manufacturing process validated so you have assurance of quality product

Important Validation Definitions

measuring device produces results within predetermined limits (compared to a reference standard)

Cell Seed
aliquot of cells derived from single tissue

review and approval process (final step)

Important Definitions, contd

Concurrent Validation
written evidence that process is working (by gathering data during the process)

Drug Product
a finished dosage that contains active ingredient (s)

Heating, ventilation, and air conditioning

Important Definitions, contd

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

Important Definitions, contd

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, contd

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

separate validation- shows system is suitable to carry out designated process

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
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 manufacturers specs moisture and airborne product contamination purity take samples from both inlet and outlet of unit (when testing water, steam, etc.)

Parameters of Validation, contd

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 4C room microbiological testing of surfaces, air, etc (do you need clean room facilities?) facility sanitization

Parameters of Validation, contd

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, contd

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, contd

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, contd

Sterilization, contd
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, contd

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, contd

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, contd

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, contd

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

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

MWCB contd
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

Manufacturing Validation, contd

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

Manufacturing Validation, contd

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

Manufacturing Validation, contd

Packaging and labeling
FDA- up to 30% of product recalls due to mislabeling (label mix-ups) SOPs for quarantine, inspection, release and handling dont make all labels identical (use varying color and size for different products or strengths


Good business sense, not just the law!