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Pharmaceutical Biotechnology

Biotechnology & GMP Raw material, Process & Process Validation and its Regulatory Aspects



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


The good practices outlined are to be considered general guides and they may be adapted to meet individual needs.

-are aimed primarily at diminishing the risks inherent in any pharmaceutical production

Cross contamination; unexpected contaminants Mix-ups; confusion (false labels)

Good practices in production

Principle: production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality.

Production of Vaccine Master seed


Working seed Inoculum

Media/Cell culture
Excipients Validation - process - method Stability studies

Single harvest Pool/Concentrated material Purified/Bulk material

Final lot

Final bulk

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.

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 with an approved procedure approved in writing by a designated person

Good practices in production:General

Checks on yields and reconciliation of quantities to ensure that there are no discrepancies outside acceptable limits.

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 mixup or cross-contamination.


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


Good practices in production:General

Access to production premises should be restricted to authorized personnel. Non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.


Good practices in production:General

In-process controls are usually performed within the production area.

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


Good practices in production: Prevention of crosscontamination during production

When dry materials and products are used in production, special precaution should be taken to prevent the generation and dissemination of dust.

proper air control e.g. supply and extraction of air of suitable quality


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 organisms from materials and products in process residues on equipment intruding insects operators clothing, skin, etc. living organisms, hormones, cytotoxic substances, and others


most hazardous, highly sensitizing materials


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


Good practices in production: Prevention of cross-contamination during production


minimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air wearing protective clothing using cleaning and decontamination procedures of known effectiveness using a closed system in production testing for residues using cleanliness status labels on equipment


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


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 the current operation


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


cleaned without delay, stored under clean and dry conditions in separate area


Good practices in production: Processing operations

Time limits for storage of EQ after cleaning and before use Containers for filling should be cleaned before filling Any significant deviation from the expected yield

recorded and investigated


Good practices in production: Processing operations


pipelines and other pieces of EQ used for transportation of products

Pipe used for conveying distilled or deionized water

sanitized and stored according to written procedures (action limits for microbiological contamination and measures


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) not present any hazard to the quality of the products

Repair and maintenance operations


GMP for biological products :Production

SOP for manufacturing operations: available, up date Starting material: source, origin, method of manufacture, QC Media and culture shall be added to fermenter and other vessels under carefully controlled conditions, avoid contamination


GMP for biological products :Production


Media should be sterilized in situ. In line 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 treated and untreated products.


GMP for biological products :Production

A wide equipment used for chromatography


should be dedicated to purification of one product should be sterilized or sanitized between batches define the life span of columns and the sterilization method


In-process controls play a specially important role in ensuring the consistent quality of biological products 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 be performed at an appropriate stage of production.


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.


Validation: Definition

Validation is the documented act of proving that any procedure, process, equipment, material,activity or system actually leads to the expected result.


Validation studies

analytical test equipment facility systems (air, water, steam, process; manufacturing processes, cleaning, sterilization, sterile filling, lyophilization)
Separate validation for

lyophilizer/ lyophilization process cleaning of glassware/ cleaning of facility sterilization process/ sterility test


Validation 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 to demonstrate that the process remains in control.


Type of validation


pre-planned protocol base on data collected during actual performance of a process already implemented in a manufacturing facility suit manufacturers of long standing, have well-controlled manufacturing process for production for a long time, but has not been validated according to a prospective protocol and concurrent validation is not realistic option is not generally accepted




Type of validation

Laboratory-and pilot-scale validations

some production processes cannot be carried out in production facility

removal of impurities by individual purification steps in process - not acceptable to bring unacceptable impurities (endotoxin, unwanted protein, contaminating bacteria and virus) spike into process


Facility systems and equipment: Stage of validation


Design qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ)

Systems and EQ; PQ=validation

Depending on the function and operation of some EQ

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 or functions of another piece of EQ or operation.


Facility systems and equipment

Installation Qualification (IQ)


written for critical processing EQ and systems list all the identification information, location, utility requirements, and any safety features of EQ verify that the item matches the purchase specifications


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 and calibration define the specification and acceptance criteria include information on EQ or system calibration, pre-operational activities, routine operations and their acceptance criteria


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 required specification under routine operation and, where appropriate, under worst case situations include description of preliminary procedures required, detailed performance tests to be done, acceptance criteria other supporting EQ used during qualification have been validated.


Facility systems and equipment

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

system: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQ EQ: autoclave, oven, lyophilizer, continuous flow centrifuge; IQ, OQ, PQ

Process validation

A process is a series of interrelated functions and activities using a variety of specified actions and EQ which is designed to produce a defined result.


Process validation studies

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


Process validation

To validate the reproducibility and consistency of a process


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 times consecutively

Validated process Worst case: to ensure that process is acceptable in the extreme case


Process validation

Example  cleaning  sanitization  fumigation  depyrogenation  sterilization  sterile filling  fermentation  bulk production  purification  inactivation  filling, capping, sealing  lyophilization

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


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 the validation study


Typical content requirements for process validations

Cleaning, Fumigation, Sanitization Process

collecting liquid and swab samples for testing of residual product  residual protein  endotoxin tests  microbial tests (bioburden)  chemical tests (chlorine and phosphoric acid)  residual cleaning agents  conductivity tests  pH

As relevant to the cleaning process

All analytical tests must be validated before


Typical content requirements for process validations


sterilization filtration of solutions

microbial challenge

filter integrity tests performance tests


Typical content requirements for process validations

Depyrogenation process (dry heat, column chromatography, other)

endotoxin content reduction of 3 logs


Typical content requirements for process 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 by validated 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 of contamination e.g. contamination rate of 1/1000, 3000 units are needed to provide 95% confidence

Typical content requirements for process 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


Typical content requirements for process validations

Production processes(fermentation, bulk production, purification, filling, lyophilization)


run according to approved Master formula including all raw material, personnel, equipment, and facility preparations, in-process tests, processing, through to final 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 being validated must pass at all steps

Validation: Type of Documentation


Validation master plan (VMP) Validation protocol (VP) Validation reports (VR) Standard operating procedures (SOPs)


Master validation plan (MVP)

is a document pertaining to the whole facility that describes which EQ, systems, methods and processes will be validated and when they will be validated. provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation)


Master validation plan (MVP)


indicate what information is to be contained within each 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


Master validation plan (MVP)


indicate how to deal with any deviations state the time interval permitted between each validation


Validation: VMP

Enables overview of entire validation project List items to be validated with planning schedule as its heart like a map


Validation: In summary, VMP should contain at 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


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


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

Validation: changes that require revalidation


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