Document SystemsValidation

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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