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1. CONCEPT

WHO adopted at 22nd Health assembly in July 1969 the Importance of GMP -

Maintenance of Quality of Pharmaceutical Products

Well accepted worldwide and most developed Countries have strengthened this with

statutes

Violations are severely dealt with

India- standards vary from State to State

GMP has become a part of Companys Philosophy and has its tacit acceptance

Consumer has the right to get best quality products for the price he pays

Manufacturer is responsible for the Product Quality and Performance

Product performance and bioavailability is paramount for cure of ailments

In India this concept is yet to find place

Having accepted this Philosophy, Company has to cater to

Continuous training & education of both present and new recruits

Continuously update the methods and incorporate the latest techniques

GMP is dynamic hence cGMP

Cost of failure is very high, hence adopt Prevention is better than cure proactive

Doing it right for the first time is most cost effective

Thinking starts from designing stage to prevent committing errors

Lay down right manufacturing procedures to be followed at the shop floor level

Conduct regular in-Company Self GMP Audit and implement course correction

GMP is more a Management Practice and an approach to Quality Assurance System

Merely complying to Statutes or GMP guide lines is not enough

Real success will come only if Concept of GMP is deeply ingrained in the minds of

people associated with the business, to make it a way of daily working life in the

Organization

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2. NOMENCLATURE

Analytical Method

A detailed description of the procedures to be followed in performing tests for conformity with

a Specification

Batch

A defined quantity of material or of bulk, intermediate or finished product that is uniform in

character and quality, and which has been produced during a defined cycle of manufacture.

To complete certain stages of manufacture it may be necessary to divide a batch into a

number of sub-batches, which are later brought together to form a final uniform batch. A

batch is sometimes described as a lot.

Batch Number (or Lot Number)

The designation of a batch by means of a distinctive combination of numbers and/or letters,

which identifies it and permits its history to be traced

Batch Manufacturing Record

A document stating the materials used and the operations carried out during the processing

of a given batch, including details of in-process controls, but normally excluding packaging

information. It should be based on the Master Formula and Method and be compiled as the

manufacturing operation proceeds.

Batch Packaging Record

A document stating the bulk product and packaging materials used, and the processes

carried out, during the packaging of a given batch, with details of in-process controls. It

should be based on the Master Packaging Instruction and be complied during the packaging

operation.

Bulk Product

Any product that has completed all processing stages up to, but not including, packaging

Contract Manufacture and/or Analysis

Manufacture and/ or Analysis ordered by one person or organization (the Contract giver) and

carried out by an independent person or organization (the Contract Acceptor).

Documentation

All the written production procedures, instructions and records, quality control procedures,

and recorded test results involved in the manufacture of medicinal product.

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Finished Product

A medicinal product, which has undergone all stages of manufacture, including packaging

Good Manufacturing Practice

Is that part of Quality Assurance aimed at ensuring that products are consistently

manufactured to a quality appropriate to their intended use? It is thus concerned with both

manufacturing and Quality Control Procedures.

In-Process Control

Tests made during the course of manufacture (including packaging) to ensure that the

resultant product will comply with its specification. Tests applied to the environment or to

equipment, as well as to products in process, may be regarded as a part of in-process

control.

Intermediate Product

A partly processed material which must undergo further processing before it becomes a Bulk

or Finished Product

Manufacture

The complete cycle of production of a medicinal product from the acquisition of all materials

through all processing and subsequent packaging to the dispatch of the finished product

(Unless the context otherwise requires, manufacture includes packaging).

Master Formula and Method

A document stating the starting materials, with their quantities, to be used in the manufacture

of a medicinal product, together with the manufacturing operations, including details of

specific in-process controls, but normally excluding packaging information.

Master Packaging Instruction

A document listing the components to be used for a stated container or package

together with a description of the method of packaging and with details of specific

in-process controls

The instructions should include the method of assembling the component parts, if

the package is complex.

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Packaging Material

Any material used in the packaging of a product. The term is not normally extended to cover

the outer packing or delivery cases used for transportation or shipment of orders. The

categories of packaging materials used are:

Packaging materials which come in contact with the product (often called Primary

Packaging Materials)

Printed packaging materials

Other packaging materials

Quality Control

Is that part of good Manufacturing Practice which is concerned with sampling, specification

and testing, and with the organization, documentation and release procedures which ensure

that the necessary and relevant tests are, in fact, carried out, and that materials are not

released for use, nor products released for sale or supply, until their quality has been judged

to be satisfactory. Quality Control is also used in the sense of the organizational entity,

which has the responsibility for these functions.

Quality Assurance

Is the sum total of the organized arrangements made with the object of ensuring that

products will be of the quality required by their intended use? It is Good Manufacturing

Practice plus original design and development. (Which may not strictly fall within the scope

of norms of GMP)

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3. HYGIENE

Objective

To avoid any sort of contamination, pharmaceutical products have to be produced with clean

materials, machines, and personnel. Personal hygiene therefore attains an important role in

GMP of Pharma Production.

Requirements of health, personal cleanliness, hygienic operation, protective clothing

applicable to all production people, maintenance staff and all other visitors have to be strictly

adhered to.

SSccooppee:: The scope covers

Personal Hygiene

Personal Hygiene - Sterile Products

PPeerrssoonnaall HHyyggiieennee

1. General Requirements & Responsibilities

Drugs are intended for treatment of disease & protection of health.

Drug manufacturers, have a special responsibility to ensure products are free from

contamination.

A major contributory factor - human body - carries organisms and particulate matter.

Every drug producer- complies with minimum requirement of health, personal cleanliness

and clothing to protect him and product.

Requirements apply to all persons entering production areas. Includes, visitors, maintenance

staff, senior management staff governmental & other inspecting authorities

Responsibility of Management to implement these requirements

2. Health

Written down requirements on minimum health requirements of all personnel working in

factory

Pre-employment medical exam, including eye, to be insisted upon, including temporary staff

Yearly Health checks up of all personnel including tests for communicable diseases.

Employees suffering from infectious disease like conjunctivitis, severe cold, should not report

for work

Employees reporting after absence from an illness involving communicable disease, should

not commence work, till assessed by Doctor

Staff should be encouraged to report infectious diseases, viz. Enteric and respiratory and

also any infectious diseases at home, so that temporary transfer to other departments can

be made.

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Staff trained to report boils, carbuncles, open wounds, or rashes on exposed parts of body.

Such persons must be excluded from operations involving direct contact with materials

Supervisory staff should be trained to look for such signs or symptoms of unhealthy

conditions of their staff.

3. Personal Cleanliness

Strict attention should be given to personal hygiene

Staff encouraged to have regular baths and change underclothes frequently

Hands to be cleaned regularly certainly after visiting toilet

Nails to be clipped regularly

Carbolic soap to be used

Hair should be kept clean. Males encouraged to be clean shaven, beards if kept, should be

covered

Wearing of jewelry viz. Bracelets, pendants rings, earrings etc. to be discouraged

Women operators should wear a minimum make-up.

False eye lashes, false nails, hairpieces, wigs or any other beauty aids, likely to fall into

product, not to be permitted.

Staff to be advised on use of suitable jewelry at work

4. Hygienic Operations

Food and drinks not to be consumed in production/operational/storage areas

This includes chewing of paan, betel nuts etc.

Smoking must not be permitted in any of the operational areas. No Smoking areas to be

displayed prominently at points of entry to such areas.

Food, drink and smoking material should not be stored in operational areas, which could

adversely affect product quality. Personal medication should not permit in such areas.

Protective clothing pockets should not be used for storing food.

Staff to be trained to keep working areas clean and uncluttered, and clean and clear away all

items before starting another

Staff trained to keep their lockers cleans and tidies. Unclean lockers source-contamination

5. Protective Clothing

Protective clothing is not only for individual but also for protection of product from the

individual.

No person should enter the production area wearing street clothes.

Clean working garments and protective apparels viz. head, face, hand, shoe and arm

coverings must be worn.

While handling dangerous or volatile materials, suitable additional devices such as head

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covering, anti-dust masks safety goggles etc must be worn.

Protective garments should not be worn outside factory premises. Practice of going into

street and back to work, in factory garments must be prohibited.

Protective clothing must be clean and laundered regularly (twice a week). The Laundering

contractor should have good facilities for washing and drying. Source of water used is

important.

Clothing must be worn properly, with buttons if present, should be fastened. Damages to the

clothing should be mended.

Headgear provided should cover the hair completely. Beards should be properly covered.

Protective garment should have no pockets above the waist level, to prevent any article

falling from the pocket into the product, during the course of work.

SStteerriillee PPrroodduuccttss

1. General

Manufacture of sterile products especially Injectables require special procedures to prevent

contamination. Operators working and their clothes could become a source of

contamination.

2. Health

Staff with opens wounds, rashes, boils, or any other skin ailment must not be permitted to

work in and aseptic areas.

Staff suffering from upper respiratory tract infection, cold, coughs, hay fever etc. must not be

allowed to work in clean and aseptic areas.

Periodic checks for these conditions must be done.

All operators working in aseptic areas should be monitored microbiologically. Weakly swaps

of persons working in sterile areas viz. Nose, ear, skin, and throat may be taken. Weekly

finger dabs of the operators should be taken preferably at the end of days work.

3. Personal Cleanliness

Nails of operators working in aseptic areas should be regularly trimmed

Staff to be encouraged to keep hair short and clean shaven to minimize contamination from

hair,

Use of jewelry, cosmetics, rings and watches should not be allowed in sterile areas.

Attitude of cleanliness to be instilled in staff through training in basic elements of

microbiology

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4. Hygienic Operations

Number of persons working in sterile areas to be kept to a minimum

Inspection and control procedures to be done from outside, if possible

Restrict unnecessary movement of staff in sterile areas, to minimize contamination.

Maintenance staff working in sterile areas should observe same precautions on hygiene

5. Protective Clothing

Staff working in aseptic areas, should change into special garments provided viz. Head and

footgear. Such garments should be comfortable with loose fitting

Edges of garments should be sealed and seams should be enveloping. Garments should

have no external pockets and unnecessary tucks

Sterile garments should shed virtually no fibers or particulate matter and retain particles

shed by body.

Operators should wear sterilized single or two-piece trouser suits, gathered at wrists and

ankles and with high necks. Hair must be completely covered by suitable head gear and also

totally enclose, beard/mustache.

Footwear (Booties) should totally enclose the feet, and bottom edge of trousers should be

tucked inside booties.

Garments should be restricted for use only in relevant clean and aseptic areas.

Sterile garments should be properly stored and handled, to minimize contamination

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4. SANITATION

OBJECTIVE AND SCOPE

Operations in Pharmaceutical Production have to be carried out in clean areas to avoid

contamination. Cleaning of areas, equipment, and microbial monitoring are very important. Hence

aspects covered are Selection and use of cleaning agents

Facilities and equipment for cleaning

Cleaning/disinfecting of manufacturing areas

Cleaning schedule

INTRODUCTION

Manufacturing areas require regular and frequent cleaning and disinfecting, and these are done: 1. Create and maintain a safe working environment

2. Remove dust and dirt, which are hazardous to product and operator

3. Minimize the risks of cross contamination, occurring between different products, made in the

same area

4. Reduce levels of contaminating microorganisms.

5. Water alone is not sufficient for cleaning and disinfecting.

6. Hence cleaning and disinfecting agents are necessary DEFINITIONS

Cleaning agents

Materials which help to remove extraneous matter from surfaces

Disinfectants

Potent substances which destroy pathogenic micro-organisms but not necessarily resistant spores

Antiseptics

Reasonably non-toxic substances and can be applied to live tissues for killing microorganisms.

GENERAL PRECAUTIONS

1. Cleaning agents and disinfectants should be handled with care.

Potent and often hazardous

Manufacturers instruction- Use of protective gears viz. Gloves, eye-shield, aprons, safety

footwear etc.

2. Cleaning agents and disinfectants should not be mixed

Certain mixtures are known to be reactive and dangerous.

3. Disinfectants containing alcohol or other inflammable solvents should be stored and handled

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in a safe manner.

4. Do not substitute Cleaning agents or a disinfectant- by another

Ensure- the alternative is as effective as the original one.

5. Disinfectant - If to be diluted prior to use, a document should specify the procedure to be

adopted while diluting.

6. Shelf life of the diluted disinfectant should be specified in the standard operating procedure.

CLEANING AGENTS

Cleaning ability of any commercial preparation to be ascertained from the manufacturer

before selection

Its preferable to use- liquid cleaning agents. Cleaning preparations in powder form may

cause particulate contamination.

DISINFECTANTS

Disinfectants with varying levels of activity are available in the market. Suitable one should

be selected only on the basis of a test for potency done by a qualified microbiologist. Ascertain whether disinfectant is compatible with the surfaces & appliances to be disinfected Take care to ensure that disinfectant does not corrode or discolor the metal surface,

paintwork or flooring. Obtain information on any possible health hazards Use two or more alternative disinfectants at regular intervals to obviate proliferation of any

resistant strains of microorganisms. Alternative should be of two different chemical types and not a different brand of the same.

USING CLEANING AGENTS/ DISINFECTANTS

1. Disinfectants- normally diluted before use as recommended by manufacturers. Dilutions

should be proper and procedure documented.

2. Dilutions made with freshly collected potable water. Avoid hard water- reduces effectiveness

of cleaning and efficacy.

3. Do not mix disinfectants of different chemical type and also with cleaning agents- Reduces

microbial activity

4. Use freshly diluted disinfected or cleaning solutions and use during the shift. Do not store

overnights pathogenic organisms can grow on storage.

5. Store diluted disinfectants as per SOPs.

6. Unused solutions must be drained and containers washed at the end of each day.

7. Destroy or deface original empty containers of manufactures, to prevent misuse, before

throwing away.

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CLEANING EQUIPMENT FOR MANUFACTURING AREAS

Depend on the nature of manufacture and surface of the facilities.

Routine for cleaning of non-aseptic manufacturing areas:

Equipment

1. Floor Mops

Made of sponge- squeeze type

Cotton mops do not shed fibers- cleaned daily after use with soap water, and stored dry.

2. Cloths and Sponges

Useful for cleaning walls, ceiling and equipment

Absorbent and non- shedding

But a limited life and discard regularly

Wash & dry in clean area

Nylon cloths - advantage -can be sterilized

3. Vacuum Cleaners

Preferred to brooms and brushes- dust free and free from fiber and bristles.

Portable vacuum cleaners or built in ones

Sterile areas need dedicated cleaners

Dust collecting bags cleaned after every use in case of portable

Central unit -cleaned at predetermined frequency

Provide cleaning port lines to prevent cross contamination of main vacuum lines

4. Mechanical Floor cleaners

Suitable for large manufacturing areas- but splash lot of water in surrounding areas, walls

Useful for cleaning sticky surface

Mop area and drain and clean mopped up water. Never store.

5. Jet cleaners

Devices spray hot water or detergent solutions

Fitted with different nozzles

Suitable for dislodging materials adhering to surface

6. Brooms

Not recommended as produces dust, which gets dislodged from one place to other.

Suitable for non -production areas

Swabbing should follow sweeping.

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CLEANING AND DISINFECTION PROCEDURE

Good housekeeping an important part of GMP

Sanitation assumes equal importance as other critical factors in pharmaceutical production

Operators to be made aware of importance

Cleaning/sanitation log book should be maintained

General Requirements

1. All procedures should be documented in simple language- understood by operators.

2. Procedure should include

Areas & surfaces e.g. Floors, walls, windows, doors etc to be cleaned

Cleaning agents to be used

Cleaning equipment

Frequency

3. Persons responsible for each activity

4. Frequent wet areas require regular treatment

5. Written procedure- cant be changed without approval from QC or Production Manager

6. Cleaning by contractors - same procedures apply- needs better supervision

7. Records to maintained- processing areas cleaned, name of person and date cleaned.

8. Display in each manufacturing area- Written sanitation program and schedule so that is person

are made familiar.

Cleaning procedure

General 1. Frequency should be laid down

2. Long production campaign -frequency less and shorter ones more

3. Interval between two cleaning not more than 3 days

4. Through cleaning after every product change over

5. Clean walls etc. regularly, vacuum cleaned 3 monthly

6. Validated cleaning program - yearly

Liquid and Ointment areas

1. Spillage mopped up immediately- not at the end of each shift

2. Floor is cleaned with hot water at end of each shift. Attend to walls and floor joints.

3. Weekly - entire-manufacturing areas including walls, platforms, pallets, and drains should be

cleaned with hot water/cleaning aids, flexible hose. Scrubbing machines may be used

4. Cleaning to be followed by disinfecting- by agents effective on moulds/water borne bacteria

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5. Ointment base traps, drains, equipment, washing areas require special attention.

6. Broken glass pieces must be removed from filling lines immediately- nylon brushes/dust pans

7. Clean all drains at regular intervals.

8. Pass steam and disinfectant solutions in drain openings in manufacturing areas at least 3

times a day.

Tablet and Capsule Manufacturing Area

1. Spillage to be cleaned up immediately

2. Remove powders by suction followed by wet mopping

3. Tracking of powder from footwear from one department to another by operators- avoided by

using mats

4. Wash mats daily and dry.

5. End of each shift- floor, wall ledges, and machine cubicles - cleaned with vacuum cleaner.

6. Use of brooms to be discouraged- Corridors washed with hot water and detergent dried.

7. Advisable to disinfect floor, walls and ceiling to prevent moulds especially when Vitamins and

other growth promoting products are used.

8. Special attention during monsoon- cleans and disinfects more frequently to prevent mould and

fungus growth.

CLEANING SCHEDULE

General

1. Code of GMP- written procedures must exist for sanitation, with details of procedures,

schedule, materials, safety precautions, and responsibility etc. to be stated.

2. Methods and materials to use must be described.

3. Cleaning schedule for each area- summarized - methods, stating, daily, weekly, monthly, and

yearly.

4. Procedures would depend on scale of operation, size, complexity of facilities, nature of floors,

walls, ceilings, product mix etc.

Typical schedule

Liquid Oral Manufacturing Area

Daily

Damp mop all accessible area-twice a day with cotton mops and 0.5% teepol (neutral

detergent) solution.

Wash sink and brackets with cleaning powder and water.

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Monday and Wednesday

Clean all vertical and horizontal surfaces- glass view panels, structural support of

equipment, work tables, telephones etc. with wet mop followed by drying.

Tuesday and Thursday

Clean platforms and all surfaces, using scrubbers. Hose down the platforms and walls-

Clean floors and flush out drainage channels.

Friday

Vacuum clean- dust from doors, windows, ledges, and louvers.

Clean walls, platforms, floors using mechanical scrubber, hose down all surfaces with water.

Use suction floor drier to remove water. Wipe with 0.1% Sodium hypochlorite sol, allow

drying.

Wipe down hand rails with detergent solution

Scrub equipment, washing area with powder, hose down and dry.

Fortnightly

De-dust all ledges, windows; exhaust fans, light fixtures, and insceticutors, with vacuum

cleaner.

Wash window glasses with cleaner, wipe and dry.

Damp-wipe all fixtures with sponge using 0.1% Tee pol solution.

Monthly

Clean with 0.1% detergent in hot water all surfaces including ceiling.

Dislodge all deposits of syrup.

Hose down with detergent solution.

Remove manhole covers and catch-pit baskets.

Remove debris and hose down with water.

Replace basket and sprinkle detergent.

Dust all shelves, floors, and walls, weighing scale with vacuum cleaner.

Damp wipe with detergent solution all surfaces.

Quarterly

Clean all areas and mezzanine floor using a vacuum cleaner

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5. TRAINING SCOPE

Policy applies to all employees, including contract and temporary staff, production, testing,

distribution, (related activities) and marketing of products produced by the Company. POLICY

Company must identify positions in Organization- performance may affect product quality.

Management responsible to ensure he has right Education - Training - Experience Training must cover

Specific operations that employee performs

Relevant aspects of GMP and Companys Business Policy

Training to be carried by appropriately qualified individuals

SCOPE

1. Content of training program must include

GPM, personal hygiene, safety awareness and procedures

Personnel from Production, quality assessment, engineering and housekeeping staff

permanent + temporary)

Clear understanding of basic principles and their role and expectations in maintaining

good quality of Companys products

Training records for individual employees must be maintained

2. Special emphasis on training of staff working in aseptic areas, including housekeeping and

engineering staff

3. Special training for operators handling highly toxic or potent materials

4. Program should monitor effectiveness of training periodically

5. Emphasize on retention of production records for a definite period of time

6. Enable to

Review draft, approve, monitor the adequacy of standard Operating Procedures from

time to time

Issue instructions on production and quality assurance to persons concerned.

7. Monitor and ensure that validation of production process and equipment are adequate

8. Ensure that all significant changes to validated process, facilities, equipment, materials,

manufacturing steps, computer control systems, utilities are subject to comprehensive review

and approval by designated authorities including quality control personnel.

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REQUIREMENTS

All personnel involved in processing a drug product must have

1. Appropriate level of education, training and experience to enable them to perform the job

adequately

2. Training must be in areas specific to their responsibilities

3. Trained in GMP before they perform the job and subject to periodic re-training

4. Trained in safety procedures before they perform the jobs, and receive periodic re-training

5. Special training for personnel working in hazardous areas or controlled environments e.g.

Clean rooms, sterile areas, handling toxic materials, on how to minimize risk to personnel

and drug products.

FREQUENCY

After induction a follow-up training at sufficient frequency to ensure that employees are

familiar with latest GMP requirements.

The frequency will also be decided based on the results of self-GMP audit conducted by the

Company. EFFECTIVENESS

Should be evaluated to ensure that the requirements are fully met with

DOCUMENTATION

Training program must be documented and records maintained to demonstrate that

1. All personnel - capable of performing their assigned tasks

2. All processes are carried out by appropriately qualified and trained personnel

3. Maintain records- contents of training program both in-house and external- received by the

individual employees

4. Maintain records- for a definite period of time depending on the Companys Policy.

MANUAL OF INSTRUCTION

1. Training manual - updated from time to time incorporating additional requirements of the

Company

2. An appropriate person- designated to oversee needs of Company - updating and issuing

instructions to participating departments

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6. CALIBRATION Preamble

Instruments - critical part of Pharmaceutical Manufacture

Used to measure and record conditions and control various processes set to preset

parameters

Conditions are very critical for the product quality and inaccuracies - can mare the effect of

product

Continuous monitoring is paramount- Calibration

Objective

Determine difference in error between known and unknown reading

Adjust the output of equipment measured to bring it desired value

Proper calibration helps to produce materials within the specification

Prevent errors, reduce costs, reduce failure and re-work expenses

Procedures

The normal activities are

1. Documentation Program

2. Identification systems

3. Calibration Control Mechanism

4. SOPs for Calibration

5. Calibration Data Sheet

6. Handling and maintenance of Test Standards

7. Calibration Certification requirement

8. Pre-purchase Review of new Instrumentation

9. Review of Calibration Program

10. Training of Technicians

1. Documentation Program

i) Documentation structure should include

Specifications

Standard Operating Procedures (SOP)

Forms, Data sheet and Check list

ii) Guide Lines for Documentation Forms

Specifications or SOP describing how to complete the Form

Forms should be designed for specific tasks

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A Typical Form will state

Item used

Identification No

Instrument Standard Sheet

Date and Time of calibration

Calibration site

Environmental condition

Calibration Completion Date

Calibration Status

Calibration Frequency

Calibration Due Date

iii) Calibration Program Documentation

Calibration dates-Instruments tagged with ID No. Date and review due date

Calibration date review- immediately against standard. Results within limits or not should

be reported

Calibration Documentation- within a week of calibration, data must be approved, signed

and taken in documents

iv) Documentation: This should include standard specification, raw data sheets, and the

calibration certificate

2. Identification Systems

Identification required both for documentation and systems.

Give each unit a unique identification number

XX-YY-I23 contains three fields

XX - consists of group of letters- location of plant

YY- indicate the equipment on which instrument fitted

I23- alpha numeric indicate type of equipment and inventory number

PR-RT2- TI6

PR- Location of Plant

RT2 - Reaction tank No.2

TI6- Temp indicator No.6

3. General Calibration Control Mechanism

Frequency - depend on amount of use, accuracy required and sensitivity of process or

system and past experience.

Also on manufacturers recommendation

Instrument affected by environment- calibrate at site

Each instrument must have unique No.

Records stored in record file

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3.1. Hierarchy of Calibration Standards

Primary Standard-

Reference calibrating equipment available with approved National Laboratories- normally 4 times

more accurate than transfer standard

Transfer Standard or Secondary Standard-

Equipment used to calibrate measuring standard equipment- 4 times more accurate than

measuring Standard

Measuring Standard

Instrument used to measure process parameters

3.2. Classification of Instruments

Classified as Critical, Major, Reference depending on process importance

Critical- Performance affects process and product

Major Instruments- affects process or product

Reference Standard- Convenience - do not affect process or product

3.3. Calibration intervals

Aseptic core instruments- minimum twice a year

Critical Equipment- 6 monthly intervals

Major Equipment- 12 monthly intervals

Reference Instruments- at time of installation

3.4. Calibration Control Mechanism

Ascertain- list of instruments to be calibrated in a month from data sheet.

Issue status report to Production department

3.5. Calibration Due date

First date of the month after actual due date

Instruments exceeding calibration due date must be documented

Calibration tags should be fixed after calibration

3.6. Damaged Instruments

Should be removed till they are repaired

3.7. Documentation

Instrument standard specification and raw calibration are used to support Calibration

Control Mechanism.

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3.8. Calibrating equipment

Primary reference Standard, Transfer Standard that is calibrated using primary reference

standard

Some of the commonly used equipment:

Universal Calibrator

Digital Equipment

Stable Thermo bath

Temperature Gauge

Dead Weight Tester

Pressure/Vac. Gauge

Multipoint Temp Scan

Autoclaves/Sterilize

Stand Sol Kit

pH meter

4. Standard Operating Procedure

Guide line for approval of calibration specification, procedure and forms.

SOP should outline detailed step-by-step action to be taken of calibrating equipment

employed.

A typical SOP

Section Engineering: Instrumentation

Subject: Procedure for Calibration of Temperature Indicators, Controllers and Recorders

Objective- to establish a procedure for Calibration

Responsibility: Instrumentation Engineer/Electronic Technician

Equipment Used: Universal Calibrator

Procedure

1. Connect the output terminals of the temperature calibrator to the inputs terminals of instrument

2. Apply appropriate millivolt (taking cold junction compensation i.e. CJC into account) or

resistance corresponding to the ambient temperature.

3. Observe reading on the display and compare it with ambient temperature.

4. Adjust potentiometer marked AMBIENT if required and bring the reading and display, to the

ambient temperature.

5. Apply mille volts (taking CJC into account) or resistance corresponding to the full span in

operating range of the instrument.

6. Observe reading on display

7. If the reading differs from actual span, adjust potentiometer marked span till display shows

exact span reading

8. Apply requisite millivolt (taking CJC into account) or resistance corresponding to 0%, 25%,

50%, 75% and 100% of the range of the instrument and note the readings observed on

display.

Page | 21

9. Apply proper millivolt (taking CJC into account) or resistance corresponding to 100%, 75%, 50

25%, and 0% of the range and note readings

10. Observe deviation of the actual readings from set values

11. If relationship is nonlinear, adjust the potentiometer marked LINEAR if any.

12. Repeat steps (2 to 11) till proper ambient span adjustments and linearity are observed.

13. For controllers, adjust the set point to 25% of the operating range.

14. Apply proper millivolt (taking CJC into account) or resistance corresponding to a value which is

more than 25% of the range

15. Confirm that output relay is operating

16. Change set point to 50% of the range and repeat step 14 and 15

5. Calibration Data Sheet

Type of Instrument:

a) Instrument Identification Number:

Description

Model No.

Serial No

Range /Scale

b) Instrument Standard Used:

Description Model No Serial No Precision/Accuracy

c) SOP Procedure Number to be followed

d) Calibration Date and Time

e) Calibration site

f) Environmental Conditions

Temperature Humidity Pressure

g) Calibration Completion Date

h) Calibration Status: Accepted/ Rejected

i) Calibration Frequency

j) Next calibration Due Date

k) Name & Signature of Calibrating Technician

Page | 22

6. Handling and Maintaining Test Standards

Procedure

1. Before using or handling a system, determine the problems involved in using the instruments.

Some requires balancing and some instruments zeroed before use.

2. Use Primary Standard against Transfer Standard.

3. Check instrument working properly before switching off.

4. Store instruments in proper place. Improper storage can affect performance

5. Improper temperature can affect performance.

6. Avoid mishandling- might affect performance.

Documentation

1. Calibration sites temperature and humidity must be documented

2. Calibration supervisor must document

Improper instrument performance

Improper handling and consequent damage to instruments

Improper environmental conditions

If a Vendor performs calibration, the following should be done.

1. Vendors name address

2. Calibration Site

3. Calibration completion date

4. SOP or specification and its issue date

5. Instrument standard

Description Model No Serial No Precision/Accuracy

6. Instrument being calibrated

Description Model No Serial No Range/Scale

7. Summary of data at various data collection intervals and the correction value for both

instrument and standard

8. Environmental conditions

9. Calibration frequency, next due date and exceptional conditions

10. Name and signature of calibrating technicians

11. Summary of report and audit findings 8. Pre-Purchase Review of New or modified Instruments

8.1. Instrumentation Review

a. Determine what instrument is expected to do, capacity?

b. Determine how functions, what control mechanisms.

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c. Design not self limiting- Restrict use and future use.

d. What Process and Instrument? Should not over ride.

e. New instrument not affect other monitoring instruments no need to recalibrate

f. If so, what should be calibrated?

g. Check whether Calibration department has adequate standards

h. Determine when initial calibration done and schedule

8.2 New calibration equipment

a. New calibration equipment should comply with specification regarding hierarchy of

calibration standards and precision ratio.

b. New calibration equipment - buy along with new equipment

c. New and modified instruments must have an instrument master record - stating

calibration criteria.

9. Review of Calibration Program

Must be reviewed yearly and altered as necessary. Review concerns

Frequency of calibration and performance of instrument

Operating procedure calibration

Consistent performing instrument - consider for reduction in calibration frequency

Frequency can be reduced one level in a year.

Calibration done at entire range of instrument from 25% to 100% accuracy

Amendment in new SOP will succeed the old one, and recorded.

10. Training of Technicians

Training includes persons performing field calibrations

Operations Training

a. Instructor should give proper demonstrations on safety aspects, correction measures,

documentation, efficiency, instrument care, calibrations limits, approval time limits and

deviation reporting

b. Trainee to carry out procedure under observation of instructor

c. Instructor should list out all documents reviewed, date and trainees check list, to make

him a qualified technician for an operation

Ongoing training

a. Each technicians training check list should be reviewed continuously

b. Trainee check list - maintained by department instructor

c. When new procedures is incorporated- all technicians, approvers, reviewers must receive

formal training and documented.

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7. CONTAMINATION CONTROL FEATURES

Contamination- unwanted presence of material, component or product in another raw

material

Source unknown and not easy to test

Prevention is very important

Objective- Identify some causes and outline some measures to prevent it PROCEDURES

1. Receiving

Pre-entry Cleaning

Clean containers thoroughly before taking inside

SOP to followed

Vacuum cleaning preferred

Avoid wooden cases- harbor pests. Open outside

Report any contamination from vehicle

Check container Integrity- segregate damaged ones- subject to detailed examination

2. Sampling

SOP evolved to prevent contamination

Sample only one material at a time

Sample in segregated cubicle-minimize risks

Dedicated tools for sampling

Prescribe and follow procedure for cleaning tools

Do not return residues to original container

Validate all procedures regularly, ensure compliance

3. Dispensing

Lay down detailed procedures- ensure followed

Equip dispensing cubicles -dust extraction system

Dispense only one material at a time

Use clean scoops for each material- and product

Ensure containers are clean before use

Clean weighing equipment and bench each time

Use disposable gloves

Do not use ceiling fans in dispensing cubicles

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4. Production

Segregate each production activity

Provide adequate dust extraction equipment

Evolve suitable cleaning procedure operation wise

Ensure effective of procedures- validate

Identify parts not assessable- each equipment

Train personnel- special care for cleaning

Check integrity of oil seals- tend to leak

Use dedicated accessories- filter bags, dust covers, sleeves

5. In-process Control

Do not return samples drawn for tests to original container

Common facilities used in in-process control- a source of major contamination.

Extra vigilance required - product with same color and similar appearance

6. Work in process

Material segregated and properly labeled

7. Packaging

Primary packaging components - bottles, caps -handle for one product at a time.

If more than one product- segregate and handle

Common Component- Surplus quantities issued for one product- cannot be used for

another product

Dust or color from product can contaminate another

Clean packing equipment before using for another

Institute a line clearance system before starting

8. General Precautions

Follow unidirectional flow of materials

Personnel made aware of hazards of contamination

Operators to wear clean and suitable garments

Regular training of operators to avoid risks of contamination

Air supply should be suitably filtered

Water major source of contamination- Ensure regular monitoring- microbial organisms

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8. VALIDATION

MEANING

Validation to prove that a process works using scientific and statistical principle to produce

acceptable product.

OBJECTIVE

Validation determines process variables and set acceptable limits -in process controls-

specifies

Alert levels - set to indicate deviation from accepted level.

Action levels- range for corrective action.

BENEFITS

Reduced testing-raw, bulk and finished products

Improves QA, reduces cost- optimization

Enables effective and rapid trouble shooting

Enables better system and maintenance

Shortens lead time- low inventories

Empowers employees-control process & improve

Assurance that specific process will consistently produce a predetermined quality of

product

1. GUIDELINES

Protocols established through effort- Production, Quality operations, Engineering.

All protocols documented

Changes/deviation critical- understood & revalidated

i. Prospective Validation- establish documented evidence that a system works- prior to

implementation

ii. Concurrent Validation- establish documented evidence data generated during actual

process

iii. Retrospective Validation- establish documented evidence based on review and

analysis of historical data

2. APPLICABILITY

Process validation expects qualification

2.1. Analytical quality test procedures

2.2. Instruments

2.3. Personnel

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2.4. Raw and packing materials

2.5 Equipment design, installation and operation

2.6 Facility design, installation and operation

2.7 Critical support systems

Water (DM, Distilled, Water for Injection)

Steam

Compressed air

Nitrogen and other gases if any used

Drainage system

HVAC (Heating, Ventilation, and Air Conditioning)

2.8. Manufacturing process

2.9. Product design (formulation and Product Development)

2.1. Analytical and quality Test procedures

Qualification requires that test procedure demonstrates suitable accuracy, precision,

specificity, sensitivity and ruggedness of method

Precision or repeatability is variability within a given laboratory, affected by analyst,

environmental conditions, laboratory equipment; none of is constant from time to time

2.2. Instruments

Many processing instruments used- Calibration is essential- thermometer, pressure

gauges, relative humidity meters, conductivity meters, timers, and alarms.

Laboratory instruments- balances, spectrophotometers, chromatographs, calculators,

computers, pH meters

2.3. Personnel Qualification

Qualification by training and experience is essential

Untrained persons can negate work done in qualifying process and other components of

process

Qualified person trained in all aspects of job, technical, supervisory

Training should emphasize necessity of not making changes in a validating process

without sufficient data

2.4. Raw and Packaging Materials

Set specification based on process used and end product

Additional tests, particle size for suspensions

Vendors need to be qualified as manufacturers

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2.5. Equipment design, installation and operation

Selection followed by installation- verify equipment performs well- Establish fail safe

devices- no-fill detection in tablets

Written procedures available for each operation of equipment and process step

Training of operators to use equipment and follow process

Cleaning procedures- product change over- clearance

Computer controlled equipment challenged to ensure that system will work under variety

of conditions

Vendors requested to supply software to validate system

2.6. Facility design, installation and operation

Facility qualification, include design, installation, construction and maintenance and

monitoring

Flow of material

Area and equipment lay out available

Room surfaces, to facilitate ease of cleaning

Drawing and written specification for all equipment

Adequate supervision during construction to ensure design parameters are met

On-going preventive maintenance schedule should be established

2.7. Water Qualification

Schematic drawing of water source must be available

Water quality, specifications, testing methods should be documented

Frequency of inspection of filters, DM units, traps, storage tanks, distribution pipe lines,

valves etc should be established and documented

Water treatment efficacy qualified and calibrated with conductivity meter

Cleaning sanitizing procedures documented

Trouble shooting, corrective steps after failure, qualify

Use seamless pipes for DM, water for Injection, & sloped

Storage of Water for Injection to prevent stagnation water and microbial growth

Sterilization of water for Injection by steam or hydrogen peroxide

2.8. Manufacturing Process

Every formulation must have a Master Formulation Order, specifying raw materials,

quality, quantity per lot, approved by responsible persons

Documented and validated step by step procedure

Each step qualified to validate the complete process

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2.9. Guidelines for Sterile Products

Dispensing

Balances calibrated

Formulation is current

Ingredients dispensed and countersigned

Component preparation

pH meters, balances, conductivity meter calibrated

Materials issued are countersigned

Identify and dedicate containers with proper labels

Compounding

Equipment clearance before use

Environment controls as per GMP

Compounding parameters within limits

Blend uniformity

Sterile filtration

Manufacturers Quality Assurance Certificate for filter

Check Integrity of filters before use

Ensure filter sanitation frequency

Check UV lamp intensity testing and replacement frequency

Filling

Filling under aseptic conditions

Filling heads deliver predetermined volumes

Sealing

Sealed containers are leak tested

Particulate inspection

Examine units under black and white background

Packaging

Line clearance obtained before starting

Verify stereos used for overprinting- current product lot

2.10. Product design

Manufacturing procedure validated for Product Development- at least three pilot lots

produced

Fix tentative limits for critical variables- modified after stability studies

Methodology to monitor critical variables

Monitor three production lots- before confirmation

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9. WATER FOR PHARMACEUTICAL USE

OBJECTIVE

Guide line for production of water for Pharmaceutical use and high critical areas

Purified Water for oral dosage forms

Water for injection (WFI) for parenteral

Water for drinking purposes to meet health standards

Untreated water - non-potable for non-critical use e.g. fire fighting, cooling water

1. Responsibilities

a. Head of manufacturing unit to ensure water systems are designed and operate under

standard conditions

b. Plant Engineer -written instructions- inspection of water systems, pumps, treatment

plants, traps, tanks, line

c. Cleaning and sanitizing systems, frequency

d. Corrective actions, if quality fails

e. Water system should indicate, source, treatment, storage, distribution, outlets,

drainage and sampling

f. QC Manager responsible for- monitoring performance

g. Taking corrective actions- failures

h. Written procedures for sampling, testing, for records

2. Types of Water

a. Source water- Varies- Periodically monitored- WHO guide lines available

b. Potable Water- Meet drinking standards, not production, but used for bulk chemical

manufacture

c. Purified Water- Meet standard Specifications of Pharmacopoeia

d. Prepared from potable water

e. Distillation, ion- exchanges or reverses osmosis. Used in non- parenteral preparations

f. Water for Injection- Meet standards- prepared by distillation of potable water- prevent

entertainment

g. Water for final Rinse- same chemical/microbial quality as WFI - not necessarily

prepared by distillation

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3. Water treatment systems

Several systems available- depend on the requirement of Organization or Country.

Storage conditions are critical

1. Coarse Filtration

2. Carbon Beds

3. Chemical additives

4. Water Softeners

5. Deionization (DI) and Continuous

Deionization (CDI)

6. Reverse Osmosis

7. Ultra Filtration

8. Distillation

9. Micro retentive Filters/ Ultraviolet Lights

1. Coarse Filtration- Remove coarse particulate > 10 microns prevent damage to system. Cause microbial growth, blocking. Back washing important

2. Carbon Beds- Remove organic and oxidizing chemicals- absorption, Control includes, - steam sanitation, stagnant conditions leading to biofilm- monitoring

3. Chemical additives- oxidizing agents for microbial control, sod hypochlorite, chlorine, flocculating, and sodium bisulfate, Control levels to prevent excess of additives

4. Water Softeners- Resins to remove cat ions and anions (cal and Ma) -protect downstream units i.e. RO membranes, deionization resins and stills

5. Deionization (DI) and Continuous Deionization (CDI): Improve chemical characteristics by replacing cat ions and anions- Normally mixed bed exchangers are used

6. Reverse Osmosis (RO) - Uses high-pressure differential to force water through semi-permeable to remove chemical, microbial and colloidal endotoxin. Failure of membrane to

be detected

7. Ultra Filtration-(UF) - Mechanical separation against osmosis in RO system- Pressure differential is lower than RO. Used to remove bacteria, colloids, suspended solids. UF

membranes can be used as final filters

8. Distillation- Reliable method for WFI, Main concern is entrainment, flooding, and variations during start-up operation and contamination of steam. Eliminated through continuous

conductivity sensing and monitoring

9. Micro retentive filters- separate material of 0.05 to 10-micron range- prevents microorganism but not endotoxin. Sensitized regularly, since formation of biofilm is

common

10. Ultraviolet light- Low microbial maintained by using wavelengths of 254 nanometers with a residence time of 15 seconds, Good for maintaining low levels but not well for major bio

burden. Replace bulb regularly.

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4. Storage/Distribution and Piping

Crucial to prevent microbial invasion, Heated, recirculating system is most reliable.

Approaches:

Storage and recirculating systems at 75 to 80 C

Storage at 75 to 80 C

Recirculating between ambient and 60 C

Total system at 55 to 60 superheated periodically to 75 C

Avoid dead legs of any type, including fittings

Material of construction important- polished surfaces

Distribution piping configured as recirculating loop

Protect vents by micro retentive filters

5. Microbiological purity

Limits for microbial contamination are set for

Drinking Water

Purified Water

WFI

Fix limits for endotoxin

Maintain Conductivity instruments and calibrate regularly

Validate all systems that treat water for pharmaceutical use

Establish Test frequency- potable and purified water weekly. WFI - twice a week

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10. ASEPTIC PROCESS CONTROL

OBJECTIVE

Sterile Products are free from microorganisms, pyrogen, with high standards of quality

and purity

Greater significance- maintaining high standards for sterility- than on End product testing

Ensure design parameters and setting up practices and precautions and following them

consistently meet conditions.

GOWNING AREA- RREQUIREMENT

Must be adjacent to sterile area

Maintain air pressure differentials to prevent flow of air between gowning areas to other

areas.

Easy to disinfect- flushed with filtered air

Mechanism to open only one door at a time

Restricted to only operating personnel

Adequate facilities for washing, disinfecting, drying hands, storage of clean sterile

garments and disposal of used garments

GOWNING PROCEDURE- STERILE ROOM ENTRY

Access to clean and aseptic areas only through change room, the general procedure

Change over from street clothes to factory uniform and footwear

Wash hands and feet with soap and water before putting factory uniform

Air pressure differentials should sweep air from aseptic area to change rooms and

non-sterile corridor

Doors of change room not to be opened simultaneously before entry/exit to sterile

area

Stagger entry- pre-determines no. of persons using room minimum

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ENTRY PROCEDURES First Change Room

Enter after ensuring room is under positive pressure

Remove factory clothing and footwear. Keep at the designated proper place

Disinfect arms up to elbows and swab feet with disinfectant solution. Renew disinfectant

solution.

Before entering second change room, stand on a mat soaked with antiseptic, kept at the

entrance

Push door open with elbow, without contaminating wet hands, and ensure first entrance

door is shut.

Second Change Room

Dry washed hands and arm with foot-operated hot air drier. Pick up sterilized garments

and put on as follows

Sterilized head gear (hood, stored under UV lamp) should be put on first, covering hair,

nose and mouth

Put on sterile suit or tunic, so that the lower end of hood is tucked to neck of suit, with

arms gathered at wrist.

Put on sterile trousers so that they cover lower portion of suit. Trousers should not

sweep the floor, but gathered at the ankle.

Third Change Room

Pick up sterilized booties and put them while crossing over a step-over bench provided in

the room. Tuck in the trouser bottom inside bootie, which is then laced up.

Insert the booted feet into footwear reserved for use in sterile area and previously

washed. Put on visor goggles

Put on sterilized gloves with suit tucked inside gloves

Swap gloves with alcohol or antiseptic, enter aseptic room, by pushing doors open with

elbow

End of work, remove gloves and deposit for washing. Change garments in reverse order

and deposit for washing. Gowns may be kept under UV and during short breaks

Garments can be re-used only after cleaning and sterilization

Mandatory to display gowning procedure in change in the form of display and sequence

of changing

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Operators working in clean and aseptic areas should open and shut doors gently. Do not

rush or run in the rooms and avoid talking

FUMIGATION OF ASEPTIC AREA

Control of environment essential to keep bio-burden low

Formaldehyde is normally used

Formaldehyde is irritating to eyes and skin. Rubber gloves and goggles must be worn

37% formaldehyde solution is placed on stainless steel container with perforated lid.

Place container on hot plate. Put off blower during fumigation

Potassium permanganate can be used as alternate to heating,

Seal off entrance to areas and leave it undisturbed for some time to ensure proper

sterilization

Prior to fumigation entire area must be cleaned and sanitized. Put off air supply and UV

lights

Formaldehyde vapors are effective at a relative humidity of not less than 50% at 25c.

Monitoring humidity and temperature during fumigation is essential.

After exposure for adequate time interval, put on exhaust fan. Room is flushed with clean

filtered air.

Clean surfaces with suitable disinfectant

Switch on UV lamps

Expose nutrient agar at various locations, to ensure that microbial load is within limits.

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11. CLEANING & MONITORING - MANUFACTURING EQUIPMENT

CONCEPTS

All manufacturing equipment must be cleaned and sanitized regularly. SOP should be written

down and must be available at the shop floor level. The document should state:

Date of Issue

Revision No

Due date of next revision

Signature of writer, authorizing and issuing authority

Brief statement of purpose of SOP and intended use

Person responsible for cleaning and maintenance

Schedule of cleaning, sanitation and maintenance

Detailed description of method of cleaning to be employed

Methods of dismantling and assembling equipment

Removal of identity of the previous batch/product

Protection of clean equipment from contamination

Inspection procedures before use

Record keeping of cleaning, maintenance, sanitation and final inspection

Procedures to ensure achievement of appropriate level of cleanliness by sampling,

testing, inspection or validation

Sensitive analytical methods to check residue levels

CLEANING SYSTEM

Cleaning system must be automatic with the following:

Equipment to be cleaned

Equipment used for cleaning process

Selection and qualification of cleaning materials

Method of dismantling and assembling

SOP should state

Cleaning methods

Sampling methods

Testing methods

Inspection procedures

Product contact surfaces must be smooth, non- reactive and easily accessible and non-

Page | 37

absorbent

SELECTION OF CLEANING AGENTS

Cleaning agents must fulfill:

Non- corrosive

Not stain the equipment

Compatible with the equipment surface to be cleaned

Solubilize the drug product residue within a short time

Anti-microbial in nature

Safe both to user and cleaning equipment

VALIDATION OF CLEANING PROCESS

Validation of cleaning process is of utmost importance

Ensure that desired level of cleanliness is achieved every time

Effectiveness of cleaning must be validated

Critical areas where residue can accumulate Red spot identified

Baffle plate-to prevent contamination from mixing rotor - is a major source where

particles can accumulate

Sampling Methods

Swab Technique- Potential areas swabbed with cotton swab wetted in solvent and

extracted in same solvent and tested. Useful in determining microbial residues

Solvent Rinse Method- Rinse with solvent of known volumes given to the cleaned

equipment and aliquot analyzed for residues

Placebo Rinse Method- Residues which are difficult to flush out are removed by

duplicating process with a placebo and analyzing the residues

HPLC - employed for determining residues

CLEANING GUIDE LINES

GENERAL

Cleaning done in specially designed areas

Operators must wear protective clothing, shoes, gloves, head gear

Cleaned parts to be covered and stored in dust free area and properly labeled

Cleanliness and suitability to be checked before use

SOP should be written down. A model:

Disconnect machine from the mains

Close hazardous utilities being fed to the machine

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Dismantle machine parts coming in direct contact with product

Wash all SS parts with 0.5% Tee pol. Use live steam

Wash all rubber gaskets with 0.5% Tee pol or suitable agent

Dust painted MS body parts of machine. Clean with 0.5% Tee pol solution.

Wipe all clean dismantled parts with lint free cloth

Certify effectiveness of cleaning system, sample residues

Take a trial run, to check machine is running properly

Cover machine with lint free synthetic fiber so prevent re-contamination with dust

Complete all related documentation records

Complete and through cleaning necessary at product change over

For dedicated products, clean at end of each shift

All dedicated manufacturing lines, end of last shift or weekends- through cleaning

Carry out swab test on all cleaned equipment for residues of previous product

Swab/rinse tests revalidated for product change over on non-dedicated lines every three

months or earlier

Swab tests validated every six months for dedicated ones

For products containing steroids or biologically active materials, swab tests done after

every change over

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12. PACKAGING & LABELING Packaging and labeling controls are very essential and attention must be given:

Minimize the risk of cross-contamination

Prevent mix-ups or substitutions

Physical segregation of packaging of different products

Requirements

Examination and usage

Labels or packaging material to be released on specification

Maintain records of each shipment of labels/packaging material

Separately store labels and packaging material of diff. Prod.

Destroy obsolete packaging materials

Monitor printing devise to ensure proper imprint

Issuing and control of Labels

Strict control while issuing

Mislabeling is a common hazard and exercise adequate control.

Store Printed packaging materials separately and transport in sealed containers

Responsibility rests with Factory Manager

Labels to be properly coded, identity of material, & current

Detailed written procedure for issuance and storage

On-line rejection should be accounted, destroyed, recorded

Check correctness of labels, before use

Reconcile labels issued, used, returned, destroyed

Returned labels stored properly to prevent mix-up

Different products must have distinct appearance for labels and packaging materials.

Educate the supplier to take adequate steps to prevent mix-up at stage of printing.

Not to print different products at the same time.

Labels to be kept under quarantine till cleared by QC

All printed material Checked for size, appearance, details etc.

Pre-printed labels not to overprinted with different name

Over printed Batch coding must be authorized

Issue a known quantity of labels under proper security

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Packaging and labeling operations

Important to ensure use of correct labels for each product, Written procedure should be detail:

Procedures for prevention of mix-up and cross contamination

Steps taken to ensure work area clean, clear and free. A line clearance to be performed

Drug product identified with a proper lot or control number

Display Name and Lot No being packed

Packaging department-check correctness of packaging material

Printing by hand to be checked at regular intervals

Check containers are clean before use

Filling and sealing followed by labeling, if stopped, adequate care taken to prevent mix-

up

Check electronic readers are working properly

Embossed information should be distinct, and not fade away

On-line checks for - appearance, completeness and correctness of packaging materials

used, overprinting is correct, line controls are functioning

Samples taken not to be returned to packing line

All discrepancies should be investigated and recorded

On completion of operation, all un-used batch-coded material should destroyed and

recorded

Packaging Specification

Use of right packaging materials is very important for quality of the final product. Guide lines are:

Master Packaging Instructions should be created. Listing all components with their

specifications to be used

For every product, all components to be listed in detail along with coding and over

printing instructions

Specimen should be attached for easy identification

Special Instructions- packing moisture sensitive products

LINE CLEARANCE

Important to inspect packaging and labeling facilities and clear all materials before starting

Filing/Packaging line and areas close to it should be cleared of materials from previous

product

Rejects, inadequately filled bottles, broken or damaged packs, strips, empty pouches,

Page | 41

should be removed

Spillage on lines should be cleaned

Left over labels, cartons to be removed

Equipment, certified clean and tagged, by supervisor

Equipment used, re-inspected for cleanliness, before use

Details of cleaning, recorded in Equipment Cleaning and Use Log sheets

After satisfactory line clearance, relevant details filled in and initialed by supervisor, in

order format

Filling or packing should not commence before satisfactory checking and line clearance

If filling/packaging is interrupted for some time, a new line clearance is necessary

PACKAGING INSTRUCTIONS

At times variations are required depending on market needs for each product. Such variations

should be clearly stated. Normal details:

Name of Product

Description, pharmacopoeia form, strength

Pack size - number, weight, volume

List of materials required for standard batch size, code reference number for each

specification

Specimen sample, Batch no, shelf life etc

Special precaution required if any, including inspection details if any

Brief description of packaging operation, including any subsidiary operations or

equipment to be used

Overprinting details, batch no. date of manufacture, expiry date, retail price, physicians

sample- not for sale

Any specific labeling requirement

DRUG PRODUCT INSPECTION

Examine correctness of label, right containers used

Representative sample collected and visually examined

Record results in batch control records

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13. PRODUCT CODING Objective

Easy Identification or tagging of Product, so that History can be traced easily

Coding of Inputs

1. Supplier

All raw materials are coded;

exceptions are sugar, starch, produced in bulk

2. Packaging materials

Not mandatory and end-user can assign lot No.

Coding by Receiver

Not mandatory, But system of Numeric or Alpha numeric used

Control No Lot No.

On receipt of material

Original I.D. No;

Is not of much significance.

User assigns a specific or unique identification number

E.g. Number of certification of Analysis.

System should provide complete history of Lot till consumption and disposal

Printed Packaging Material: Art Work- May carry a unique code number

0931. 2. 93 Finished Product code/ Second Version/ Year

Help to check on packing lines to monitor packaging materials in use

Bar Code:

Single code Bar- Printed at the edge of materials viz. Labels or carton. Bars provide

check and prevent mix-up and easy to inspect

Multicolor Bars- Help to quickly check all colors of a multicolor are printed or not

Spacing and location of Bars- Distinct shift in position of code bars, size, and spacing

between consecutive bars are helpful in establishing conformance to standard.

Cyclic codes- Help in establishing period (a month) when component was printed.

Used normally in paperboard cartons clock in inner flap indicate month of printing.

Supplier code- Asked to incorporate a logo

Page | 43

Batch coding:

Provisions of Drugs and Cosmetics Rules 1945 are applicable. How the conditions are left to

the manufacturer.

CODE- could be alpha numeric.

The system should be simple and practical.

Ease of documentation during manufacture.

Operational convenience

Space should be available for batch coding

Subsequent documentations at stages viz., excise, invoicing, to stockiest/ trade must not be

over looked

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14. REWORK AND RE PROCESSING

Objective

Residues of drug product re worked using authorized method, validated to demonstrate

suitability, of meeting specifications without altering the product quality

General Guidelines:

1. A minimum value of material below which re processing not to be considered to be set

2. Investigate reasons for out of specifications to minimize recurrence.

3. Maintain register giving quantities and reasons

4. Re processing or re labeling should be rare

5. Normal manufacturing process applicable unless evidence to prove alteration of quality,

shelf life and stability

6. Re processing method to be authorized and documented, after potential risks evaluated and

found negligible

7. Need for additional testing of reprocessed product to be considered viz. Re grinding and re

granulation of tablets affect tablet dissolution

8. At times original release specifications of product may not be applicable. Revise

specifications. Review constantly quality of re processed products.

9. Residues and reworked or recovered material may adversely affect product quality. Must not

be used in subsequently batches.

10. Deciding factor for use or not is the stability of batches containing known amount of

residues.

11. Collect stability incorporating varying amounts of residues of varying ages.

12. Stability profile should not be different from standard batches without any residues

13. If stability is different, ascertain period for which product will meet end of life specifications.

Life period of such batches to be suitably amended.

14. If sufficient quantities can be re processed into are processed batch, discard residues from

re processed batches

15. Residues from inspection stage containing foreign matter viz. Metal particles should not be

re used.

16. Batches containing residues are not released by QC, until batches from residues came are

fully tested and certified for use.

Page | 45

Specific Requirements:

Method of handling residues, additions to fresh batch are documented and approved by the

Quality Control Manager

Batches containing residues are subjected to additional tests before release

Batch Manufacturing records should indicate that the batch contains residues, with the

details of origin of residues, and quantities used

Any reduction of normal shelf life recommended by quality control should be recorded, in

batch packaging Order and labeling order instructions

Page | 46

15. WAREHOUSING OBJECTIVE

To provide adequate facilities and systems for storage, handling of raw and packaging

materials required for manufacture and packaging of Pharmaceutical Products

SCOPE

Good Warehousing practice include Guide lines for receiving, verifying, inspecting, all incoming raw materials

Premises for storage of materials

Handling of raw and packaging materials

Weighing of materials for batch production

Storage and handling of finished goods

General Guidelines:

1. Receive materials against specific supply advice (Purchase Order)

2. Each consignment should accompany written document which should state

Name of material

Name of manufacturer

Batch No., date of manufacture/expiry date as applicable

Quantity of material batch wise

Number of containers, Quantity per container

3. Delivered material received by designated person responsible for the warehouse

4. Materials are checked for cleanliness and pack integrity. Damaged/broken containers are

segregated and reported accordingly

5. All receipts are numbered and taken into stock as per system employed to enable review

and first in first out basis.

6. Each container labeled indicating

7. Serial No. of receipt ***************

Name of material(as followed in Company Register)

Total Quantity, including Number of containers

Date of receipt

Labeled material must state

Under Test

Awaiting Approval or any such legend.

Material must not be used by Production until approved by Quality Control.

Distinct color label may be used

Page | 47

PREMISES

Must have separate areas suitable size, and construction for

Receiving (initial inspection, cleaning, check weighing)

Sampling (adequate facilities to prevent cross contamination during sampling)

Storage (including specified air-conditioned, cold rooms, store for hazardous chemicals)

Dispensing) adequate facilities to prevent cross contamination during dispensing)

Rejected materials (secure storage facilities for goods to be returned to supplier, or to be

destroyed or rendered unusable)

Free of insects, birds, and pests

Facilities for pest control treatment

Storage of Raw Materials

Storage conditions

General storage area or special storage depending on material and required conditions

Must not be stored on ground but off floor on pallets

Segregation

1. To be sampled

2. Under Test

3. Approved

4. Rejected

5. Storage area for hazardous materials with restricted entry

Storage of Packaging Materials:

1. Primary packaging materials

2. Bottles, vials, ampoules, tins, tubes, stored as they are to prevent contamination

3. Printed packaging materials properly identified pack size etc.

4. Printed materials- labels, foils, cartons, stored in secured area with restricted entry

5. Proper identity maintained- check labels before issue

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6. Do not store similar looking labels at same place

7. Special instruction Control of labeling Materials should be including in control documents

8. Air conditioned store for foils, temperature sensitive, moisture sensitive materials

Handling and Issue of Raw Materials:

1. Attention to cross contamination, safety hazards

2. Keep containers always secured

3. Dust extraction facilities are required

4. Use of protective clothing, hand gloves, face masks

5. Handling inflammable materials

6. Safety data sheets must available handy

7. Materials prone to support microbial growth

8. Materials issued only against written work order

9. Issues against Packaging Material Order

10. Adequate check before issuing printed materials

11. Difficult to issue specific quantities, but keep proper count

12. Unused materials returned to warehouse

13. Take care while re-issuing returned materials

Warehousing of Finished Products:

1. Proper storage area, with suitable environment control

2. Only Quality Control approved material released for sale

3. Good housing requirement

General Guidelines:

Suitable racking and storage

Arrangement for temperature and humidity control

Arrangements to prevent flooding, entry of rain water

Suitable firefighting equipment

Separate area for receiving orders/dispatch

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Premises

Safe and orderly receipt of materials

Segregated area-quarantine for rejected materials

No. of exits should be minimum

Arrangements for storage on racks and pallets

Proper lighting and ventilation

Storage for housekeeping, pest control equipment

Warehousing Procedure

Stocks received against proper documents with all details viz. Batch No., quantity, Analytical

reports

Under test to be maintained under quarantine

Stock rotation on First in First out basis

Order require dispatch of variety of products, arrangement for order picking and assembling

Order and assembling area close to minimize distance traveled

Storage of picked stock on shelves for easy checking

Picking and assembling of order done against a standard, dated, serially numbered

documents

Assembled product checked for accuracy before dispatch

Batch details to be recorded

Dispatch of Finished Goods:

Only released products to be dispatched

Adequate precaution to prevent spillage/breakage on transit

Vehicles carrying goods must be clean and well protected

Free from infestation

Do not give strong odors to contaminate the product

Vehicle has ability to withstand weight

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Returned Goods

Goods returned properly accounted with reasons

Isolate returned goods- clearly labeled

Quality control Manager to examine and instruct to re process or destroy

Destruction to be supervised by responsible person

Re processing done according to instructions from Quality control Manager

Weighing of materials

General Guidelines

Skilled operation- to be done by designated person

Observe safety precautions

Moisture sensitive materials- separate cubicle

Choose right type of balance- minimum weight should reflect error. Follow guide lines of

manufacturer

Check balance is clean- no dust- no contaminants

Check zero error before first use

Record tare weight

When two or more lots are used- record amounts from each lots

Label each material:

Name of material

Product used for

Tare/ net weight

Upon receiving at manufacturing area, check

Labels against formulation order

Cross check weight

Sheet signed- becomes part of record

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16. RETURNED GOODS OBJECTIVE

Finished products returned to Company for various reasons for reprocessing/destruction.

Clear guidelines should exist for handling such items

SCOPE

Provide clear guidelines for

1. Classification of returned goods

2. Responsibilities/Authorities for dealing with such situations

AUTHORITY AND RESPONSIBILITY

Head of Quality Control or his nominee responsible to formulate procedures and

implementation

CLASSIFICATION OF RETURNED GOODS

Date expired goods

Damaged/broken primary containers

Leaky/broken seals of closures of containers

Mutilated/smudged labels- unidentifiable

Soiled labels- aesthetically not presentable

Products recalled, voluntarily for reasons/Company

Products recalled under directive of Drug Control

HANDLING PROCEDURE: General Guidelines

All returned goods should be properly

Documented

Inspected

Accounted

Labeled (to identify primary cause for return)

Segregated/quarantined till further action is taken

Ensure that statutory requirements are met

All operation/actions are well documented

Date Expired Goods

Destruction to be authorized by designated person

All destruction to be supervised by responsible person

Contents destroyed so that Product not usable in any manner what so ever

All primary and secondary container with printed matter destroyed to render them unusable

All operations documented to reconcile stock received and stock destroyed

Safety and health of employees to be considered.

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Damaged/Broken Primary Containers

Goods examined by designated person to ascertain for re-use/recovery

Product recovered, carefully evaluated for quality, efficacy and safety.

Mere conformity to specification is not enough, to return such product to stock

Possibility of non-detectable contamination and/or degradation product not overlooked

If felt, that the damage to primary container can make the contents unusable/unsafe,

c