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PharmaceuticalBiotechnology

Biotechnology & GMP

Raw material, Process & Process

Validation and its Regulatory

Aspects

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References:

GMP for pharmaceutical products: main principles;

WHO TRS No. 908,2003 GMP for biological products; WHO TRS No.822,1992

A WHO guide to GMP requirements, part 2:validation;WHO,1997

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GMP

The good practices outlined are to be considered

general guides and they may be adapted to meet

individual needs.

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GMP-are aimed primarily at diminishing the risks

inherent in any pharmaceutical production

Cross contamination; unexpected contaminants

Mix-ups; confusion (false labels)

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Good practices in production Principle: production operations must follow

clearly defined procedures in accordance with

manufacturing and marketing authorizations, withthe objective of obtaining products of the requisitequality.

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Production of Vaccine

Master seed Working seed

Inoculum

Single harvest

Pool/Concentrated material

Purified/Bulk material

Final bulkFinal lot

Media/Cell culture

Excipients

Validation

- process

- method

Stability studies

GMP

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Good practices in

production:General All handling of materials and products;

receipt

cleaning

quarantine sampling

storage

labelling

dispensing

processing

packaging

distribution should be done in accordance with written procedures and recorded.

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Good practices in

production:General Any deviation from instructions or procedures

should be avoid as far as possible.

If deviations occur: should be done in accordance withan approved procedure

approved in writing by a designated person

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Good practices in

production:General Checks on yields and reconciliation of quantities

to ensure that there are no discrepancies outside

acceptable limits.

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Good practices in

production:General Operation on different products should not be

carried out simultaneously or consecutively in the

same room or area unless there is no risk of mix-

up or cross-contamination.

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Good practices in

production:General At all time during processing

all materials

bulk containers major items of equipment

rooms

packaging lines

being used should be labeled or identified

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Good practices in

production:General Access to production premises should be

restricted to authorized personnel.

Non-medicinal products should not be producedin areas or with equipment destined for the

production of pharmaceutical products.

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Good practices in

production:General In-process controls are usually performed within

the production area.

The performance should not have any negative effecton the quality of the product or another product.

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Good practices in production: Prevention of cross-

contamination during production

When dry materials and products are used inproduction, special precautionshould be taken toprevent the generation and dissemination of dust. proper air control e.g. supply and extraction of air of

suitable quality

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Good practices in production: Prevention of

cross-contamination during production

Contamination of a starting material or of a product by

another material or product must be avoid.

accidental cross-contamination arises from

uncontrolled release of dust, gases, particles, vapours. sprays or organismsfrom materials and products in process

residues on equipment

intruding insects

operators clothing, skin, etc.

most hazardous, highly sensitizing materials

living organisms, hormones, cytotoxic substances, and others

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Good practices in production: Prevention of

cross-contamination during production

Avoided by taking appropriate technical e.g.

carrying out production in dedicated and self-contained

areas

conducting campaign production followed by

appropriate cleaning in accordance with a validated

cleaning procedure

providing appropriately designed airlocks, pressure

differentials and air supply and extraction systems

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Good practices in production: Prevention of

cross-contamination during production

minimizing the risk of contamination caused by recirculationor re-entry of untreated or insufficiently treated air

wearing protective clothing

using cleaning and decontamination procedures of knowneffectiveness

using a closed system in production

testing for residues

using cleanliness status labels on equipment

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Good practices in production: Prevention of

cross-contamination during production

Measures to prevent cross-contamination and

their effectiveness should be checked periodically

according to SOP

Production areas periodic

environmental monitoring

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Good practices in production:

Processing operations

Before any processing operation

work area and equipment

clean and free from any starting materials, products,product residues, labels or documents not required for thecurrent operation

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Good practices in production:

Processing operations

Any necessary in-process controls and environmental

controls should be carried out and recorded

Indicate the failures of equipment or services (e.g. water,gas) to equipment

defective EQ withdrawn

after use, production EQ

cleanedwithout delay, stored underclean and dry conditions in separate area

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Good practices in production:

Processing operations Time limits for storage of EQ after cleaning and

before use

Containers for filling should be cleaned beforefilling

Any significant deviation from the expected yield

recorded and investigated

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Good practices in production:

Processing operations Checks

pipelines and other pieces of EQ used fortransportation of products

Pipe used for conveying distilled or deionizedwater sanitized and stored according to written procedures

(action limits for microbiological contamination and

measures

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Good practices in production:

Processing operations EQ and instruments

serviced and calibrated at prespecified interval

records maintained

checked daily or prior to use clearly indicated the date of calibration and servicing,

recalibration (label attached to instrument)

Repair and maintenance operations not present any hazard to the quality of the products

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GMP for biological products

:Production SOP for manufacturing operations: available, up

date

Starting material: source, origin, method ofmanufacture, QC

Media and culture shall be added to fermenter

and other vessels under carefully controlled

conditions, avoid contamination

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GMP for biological products

:Production Media should be sterilized in situ. Inline sterilizing

filters for routine addition of gases, media, acids,

alkalis, deforming agents, etc. to fermenter should be

used where possible.

Validation of sterilization.

Inactivation process: measures should be taken to

avoid risk of cross-contamination between treatedand untreated products.

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GMP for biological products

:Production A wide equipment used for chromatography

should be dedicated to purification of one product

should besterilized or sanitized between batches

define the life span of columns and the sterilization

method

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In-process controls play a specially important rolein ensuring the consistent quality of biologicalproducts because certain deficiencies may not be

revealed by testing the finished product. Tests that are crucial for quality control but that cannot

be carried out on the finished product shall beperformed at an appropriate stage of production.

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Samples of intermediate and final products shall be

retained in sufficient amount and under appropriate

storage conditions to allow the repetition or

confirmation of a batch control.

Certain operations require the continuous monitoring

of data during a production process e.g.monitoring

and recording of physical parameters during

fermentation.

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V

alidation: Definition Validation is the documented act of proving that

any procedure, process, equipment,

material,activity or system actually leads to theexpected result.

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V

alidation studies

analytical test

equipment

facility systems (air, water, steam, process;manufacturing processes, cleaning,sterilization, sterile filling, lyophilization)

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Separate validation for

lyophilizer/ lyophilization process cleaning of

glassware/ cleaning of facility sterilizationprocess/sterility test

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V

alidation studies verify the system under test under the extremes

expected during the process to prove that the

system remains in control.

Critical equipment and processes are routinely

revalidated at appropriate intervals todemonstrate that the process remains in control.

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T

ype of validation Prospective

pre-planned protocol

Concurrent

base on data collected during actual performance of a process alreadyimplemented in a manufacturing facility

suit manufacturers of long standing, have well-controlled manufacturingprocess

Retrospective

for production for a long time, but has not been validated according to aprospective protocol and concurrent validation is not realistic option

is not generally accepted

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Type of validation

Laboratory-and pilot-scale validations

some production processes cannot be carried out

in production facility

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removal of impurities by individual purification steps in process

- not acceptable to bring unacceptable impurities (endotoxin,

unwanted protein, contaminating bacteria and virus) spike intoprocess

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Facility systems and equipment:Stage of validation

Design qualification (DQ)

Installation Qualification (IQ)

Operational Qualification(OQ)

Performance Qualification (PQ)

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Systems and EQ; PQ=validation

Depending on the function and operation of some EQ

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Facility systems and equipment

Design qualification (DQ)

necessary when planning and choosing EQ or

systems to ensure that components selected will have

adequate capacity to function for the intended

purpose, and will adequately serve the operations orfunctions of another piece of EQ or operation.

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Facility systems and equipment

Installation Qualification (IQ)

written for critical processing EQ and systems

list all the identification information, location, utilityrequirements, and any safety features of EQ

verify that the item matches the purchasespecifications

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Facility systems and equipment

Operational Qualification(OQ) outlines the information required to provide evidence that all

component of a system or of a piece of EQ operate as specified.

should provide a listing of SOPs for operation, maintenance andcalibration

define the specification and acceptance criteria

include information on EQ or system calibration, pre-operationalactivities, routine operations and their acceptance criteria

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Facility systems and equipment

Performance Qualification (PQ) performed after both IQ and OQ have been completed, reviewed

and approved

describes the procedures for demonstrating that a system or

piece of EQ can consistently perform and meet requiredspecification under routine operation and, where appropriate,under worst case situations

include description of preliminary procedures required, detailedperformance tests to be done, acceptance criteria

other supporting EQ used during qualification have been

validated.

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Facility systems and equipment

pH meter, incubator, centrifuge, freezer; IQ,OQ

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system: air (HVAC), compressed air, pure steam,

raw steam, purified water, WFI, central vacuum; IQ,OQ, PQ

EQ: autoclave, oven, lyophilizer,continuous flowcentrifuge; IQ, OQ, PQ

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Process validation

A process is a series of interrelated functions and

activities using a variety of specified actions andEQ which is designed to produce a defined result.

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Process validationstudies examine a process under normal operating

conditions to prove that the process is in control

re-validation

modification to the process

problems occur

EQ or systems are changed

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Process validation

To validate the reproducibility and consistency of aprocess

full defined process is carried out using validated EQ

at least 3 times, under established procedure

process must successfully and consistently meet all acceptance

criteria at all steps throughout the procedure at least 3 timesconsecutively

Validated process

Worst case: to ensure that process isacceptable in the extreme case

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Process validation

Example

cleaning

sanitization

fumigation

depyrogenation sterilization

sterile filling

fermentation

bulk production

purification

inactivation

filling, capping, sealing

lyophilization

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Process validation

specific process clearly described in Master

formula or in SOP

all EQ; identity, code number, construction, operation

capacity, actual operating range

processing parameter; sufficiently detailed to permit

complete reproducibility (time period, pH, volume,

temp.etc.)

specification at each step

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Process validation

Very important

specifications for a process undergoing validation be

pre-determined

all critical processing parameters for which

specifications have been set, there must be equipment

to measure all of those parameters during thevalidation study

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Typical content requirements forprocess validations

Cleaning, Fumigation,Sanitization Process collecting liquid and swab

samples for testing of residualproduct

residual protein

endotoxin tests

microbial tests (bioburden)

chemical tests (chlorine and

phosphoric acid) residual cleaning agents

conductivity tests

pH

As relevant to thecleaning process

All analytical tests mustbe validated before

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Typical content requirements forprocess validations

Sterilization

sterilization filtration of solutions

microbial challenge

filter integrity tests

performance tests

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Typical content requirements forprocess validations

Depyrogenation process (dry heat, column

chromatography, other)

endotoxin content reduction of 3 logs

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Typical content requirements forprocess validations

Sterile filling test filling process

perform filling process with nutrient media

run at full scale for at least one fill size worst case; large volume and number of vials

filled vials incubated, observed and test for contamination byvalidated sterility test

must be sterile for 3 consecutive runs

media fill performed twice a year

size of run must be large enough to detect low levels ofcontamination e.g. contamination rate of 1/1000, 3000 units areneeded to provide 95% confidence

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Typical content requirements forprocess validations

Mock fermentation

full scale fermentation of a representative fermentation

process

to validate the parts of process involving connections,

sampling, and additions of nutrients etc.

fermentor prepared and operated in simulated process with

uninoculated nutrient media

process follow the full fermentation process 3 consecutive runs at each stage

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Typical content requirements forprocess validations

Production processes(fermentation, bulkproduction, purification, filling, lyophilization)

run according to approved Master formula including all

raw material, personnel, equipment, and facilitypreparations, in-process tests, processing, through tofinal testing of the batch lot.

all facility systems must be monitored

3 consecutive lots must be produced and all facility,EQ, support systems, product spec, and process beingvalidated must pass at all steps

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Validation: Type ofDocumentation

Validation master plan (VMP)

Validation protocol (VP)

Validation reports (VR) Standard operating procedures(SOPs)

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Master validation plan (MVP)

is a document pertaining to the whole facility thatdescribes which EQ, systems, methods andprocesses will be validated and when they will be

validated. provide the format required for each particular

validation document (IQ, OQ, PQ for EQ andsystems; process validation, analytical assay

validation)

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Master validation plan (MVP)

indicate what information is to be contained withineach document

indicate why and when revalidations will be

performed

who will decide what validations will be performed

order in which each part of the facility is validated

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Master validation plan (MVP)

indicate how to deal with any deviations

state the time interval permitted between eachvalidation

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Validation: In summary, VMPshould containat least Validation policy

Organizational structure

Summary of facilities, systems, equipment, processes

to be validated Documentation format for protocols and reports

Planning and scheduling

Change control

Training requirements

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Validation: Protocol

Objectives of the validation and qualification study

Site of the study

Responsible personnel Description of the equipment

SOPs

Standards

Criteria for the relevant products and processes

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Validation: Report

Title

objective of the study

Refer to the protocol Details of material

Equipment

Programmes and cycles use

Details of procedures and test methods

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Validation: changes that requirerevalidation

Software changes; controllers

Site changes; operational changes

Change of source of material Change in the process

Significant equipment changes

Production area changes

Support system changes

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