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good manufacturing practice for pharmaceutical products

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good manufacturing practice for pharmaceutical products

Good Manufacturing Practice for Pharmaceutical Products

INTRODUCTION

What is GMP?

    Good manufacturing practice (GMP) comprises that part of quality-assurance aimed at ensuring that a product is consistently manufactured to a quality appropriated to its intended use. GMP requires that the manufacturing process is fully defined before it is initiated and that all necessary facilities are provided. In practice, this means that personnel must be adequately trained, suitable premises and equipment used, correct materials used, approved procedures adopted, suitable and transport facilities available and appropriate records made.

    The quality of pharmaceutical products depends on the degree of care taken in its preparation. Final checks carried out on the finished products are useful in confirming that the correct ingredients have been used and that that materials have been correctly processed. It is however

    essential that proper in process control is exercised and that it is adequately documented to provide reliable evidence that the correct procedures have been followed. The need for GMP is recognized throughout the world. More than 20countries have issued their own GMP guidelines. (The essential components of GMP are summarized in figure 1.)

Why it is required?

    The Good Manufacturing Practices are prescribed to ensure that:

    (i) Rawmaterials used in the manufacture of pharmaceuticals are authentic,

    ofprescribed quality and are free from contamination.

    (ii)The manufacturing process is as has been prescribed to maintain the standards.

    (iii)Adequate quality control measures are adopted and

    (iv)The manufactured drug which is released for sale has the prescribed quality.

    (v) To achieve the objectives listed above, each licencee shall evolve methodology

    and procedures for following the prescribed process of manufacture of drugs which

    should be documented as a manual and kept for reference and inspection. However,

    teaching institutions and registered qualified Vaidyas, Siddhas and Hakeems who

    prepare medicines on their own to dispense to their patients and not selling such

    drugs in the market are exempted from the purview of G.M.P.

World Health Organization (WHO) GMP

    WHO defines good manufacturing practice has "that part of quality assurance which assures that

    products are consistently produced and controlled to the quality standards appropriate to their indented use and as required by the marketing authorization"

    GMP covers all aspects of the manufacturing process: defined manufacturing processes; critical manufacturing steps; suitable premises, storage, transport; qualified and trained production and

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    quality control personnel; adequate laboratory facilities; approved written procedures and instructions; records to show all steps of defined procedures have been taken; full traceability of a product through batch rewards and distribution records and systems for recall and investigation of complaints.

GMP REQUIREMENTS FOR PREMISES AND MATERIALS FOR PHARMACEUTICALPRODUCTS

    1. GENERAL REQUIREMENTS

    1.1. Location and surroundings.- The factory building(s) for manufacture of drugs shall be so

    situated and shall have such measures as to avoid risk of contamination from external environment including open sewage, drain, public lavatory or any factory which producesdisagreeable or obnoxious, odour, fumes, excessive soot, dust, smoke, chemicalor biological emissions.

    1.2. Buildings and premises. Thebuilding(s) used for the factory shall be designed, constructed, adapted andmaintained to suit the manufacturing operations so as to permit production ofdrugs under hygienic conditions. They shall conform to the conditions laid downin the Factories Act, 1948 (63 of 1948).

    The premises used for manufacturing, processing, warehousing,packaging, labeling and testing

    purposes shall be -

    1. compatiblewith other drug manufacturing operations that may be carried out in the

    same oradjacent area / section;

    2. adequatelyprovided with working space to allow orderly and logical placement

    ofequipment, materials and movement of personnel so as to :

    3. avoidthe risk of mix-up between different categories of drugs or with raw

    materials,intermediates and in-process material;

    4. avoidthe possibilities of contamination and cross-contamination by providingsuitable

    mechanism;

    (iii) designed / constructed / maintained to prevent entry ofinsects, pests, birds, vermins, and rodents. Interior surface (walls, floors,and ceilings) shall be smooth and free from cracks, and permit easy cleaning,painting and disinfection;

    (iv)air conditioned, where prescribed for the operations and dosage forms

    underproduction. The production and dispensing areas shall be well lighted,effectively

    ventilated, with air control facilities and may have proper AirHandling Units (wherever

    applicable) to maintain conditions includingtemperature and,wherever necessary,

    humidity

    as defined for the relevant product. These conditions shall be appropriateto the category

    of drugs and nature of the operation. These shall also besuitable to the comforts of the

    personnel working with protective clothing,products handled, operations undertaken

    within them in relation to the externalenvironment. These areas shall be regularly

    monitored for compliance withrequired specifications;

    (v)provided with drainage system, as specified for the various categories ofproducts,

    which shall be of adequate size and so designed as to prevent back-flow and/or to

    prevent insects and rodents entering the premises. Open channelsshall be avoided in

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    manufacturing areas and, where provided, these shall beshallow to facilitate cleaning

    and disinfection;

    (vi)The walls and floors of the areas where manufacture of drugs is carried outshall be

    free from cracks and open joints to avoid accumulation of dust. Theseshall be smooth,

    washable, coved and shall permit easy and effective cleaningand disinfection. The

    interior surfaces shall not shed particles. A periodicalrecord of cleaning and painting of

    the premises shall be maintained.

    1.3 Water system

    There shall be validated system for treatment of water drawnfrom own or any other source to render it potable in accordance with standardsspecified by the Bureau of Indian Standards or Local Municipality, as the casemay be, so as to produce Purified Water conforming to Pharmacopoeialspecification. Purified Water so produced shall only be used for all theoperations except washing and cleaning operations where potable water may beused. Water shall be stored in tanks, which do not adversely affect quality ofwater and ensure freedom from microbiological growth. The tank shall be cleanedperiodically and records maintained by the licensee in this behalf.

1.4 Disposal of waste

    (i) The disposal of sewage and effluents (solid, liquid and gas)from the manufactory shall be in conformity with the requirements of EnvironmentPollution Control Board.

    (ii) All bio-medical waste shall be destroyed as per theprovisions of the Bio-Medical Waste (Management and Handling) Rules, 1996.

    (iii) Additional precautions shall be taken for the storage anddisposal of rejected drugs. Records shall be maintained for all disposal ofwaste.

    (iv) Provisions shall be made for the proper and safe storage ofwaste materials awaiting disposal. Hazardous, toxic substances and flammablematerials shall be stored in suitably designed and segregated enclosed areas inconformity with Central and State Legislations.

    2. WAREHOUSING AREA

    1. Adequate areas shall be designed to allow sufficient and orderly warehousing of various

    categories of materials and products like starting and packaging materials, intermediates,

    bulk and finished products, products in quarantine, released, rejected, returned or

    recalled, machine and equipment spare parts and change items.

    2. Warehousing areas shall be designed and adapted to ensure good storage conditions.

    They shall be clean, dry and maintained within acceptable temperature limits. Where

    special storage conditions are required (e.g., temperature, humidity), these shall be

    provided, monitored and recorded. Storage areas shall have appropriate house-keeping

    and rodent, pests and vermin control procedures and records maintained. Proper racks,

    bins and platforms shall be provided for the storage of materials.

    3. Receiving and dispatch bays shall protect materials and products from adverse weather

    conditions.

    4. Where quarantine status is ensured by warehousing in separate earmarked areas in the

    same warehouse or store, these areas shall be clearly demarcated. Any system replacing

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    the physical quarantine, shall give equivalent assurance of segregation. Access to these

    areas shall be restricted to authorized persons.

    5. There shall be a separate sampling area in the warehousing area for active raw materials

    and excipients. If sampling is performed in any other area, it shall be conducted in such a

    way as to prevent contamination, cross- contamination and mix- up.

    6. Segregation shall be provided for the storage of rejected, recalled or returned materials

    or products. Such areas, materials or products shall be suitably marked and secured.

    Access to these areas and materials shall be restricted.

    7. Highly hazardous, poisonous and explosive materials such as narcotics, psychotropic

    drugs and substances presenting potential risks of abuse, fire or explosion shall be stored

    in safe and secure areas. Adequate fire protection measures shall be provided in

    conformity with the rules of the concerned civic authority.

    8. Printed packaging materials shall be stored in safe, separate and secure areas. 9. Separate dispensing areas for (Beta)

    lactum, Sex Hormones and Cyto-toxic substances or any such special categories of

    products shall be provided with proper supply of filtered air and suitable measures for

    dust control to avoid contamination. Such areas shall be under differential pressure. 10. Sampling and dispensing of sterile materials shall be conducted under aseptic conditions

    conforming to Grade A, which can also be performed in a dedicated area within the

    manufacturing facility.

    11. Regular checks shall be made to ensure adequate steps are taken against spillage,

    breakage and leakage of containers.

    12. Rodent treatments (pest control) should be done regularly and at least once in a year

    and record maintained.

    3. PRODUCTION AREA

    1.Theproduction area shall be designed to allow the production preferably inuni-flow

    and with logical sequence of operations.

    2.In orderto avoid the risk of cross-contamination, separate dedicated and self-

    containedfacilities shall be made available for the production of sensitivepharmaceutical

    products like penicillin or biological preparations with livemicro-organisms. Separate

    dedicated facilities shall be provided for themanufacture of contamination causing and

    potent products such as Beta lactum,Sex Hormones and Cyto-toxic substances.

    3.Workingand in-process space shall be adequate to permit orderly and

    logicalpositioning of equipment and materials and movement of personnel to

    avoidcross-contamination and to minimize risk of omission or wrong application ofany of

    manufacturing and control measures.

    4.Pipe-work,electrical fittings, ventilation openings and similar service lines shall

    bedesigned, fixed and constructed to avoid creation of recesses. Service linesshall

    preferably be identified by colours and the

    nature of the

    supply and direction of the flow

    shall be marked/indicated.

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    4. ANCILLARY AREAS

    1. Rest and refreshment rooms shall be separate from other areas. These areas shall not

    lead directly to the manufacturing and storage areas.

    2. Facilities for changing, storing clothes and for washing and toilet purposes shall be easily

    accessible and adequate for the number of users. Toilets, separate for males and

    females, shall not be directly connected with production or storage areas. There shall be

    written instructions for cleaning and disinfection for such areas.

    3. Maintenance workshops shall be separate and away from production areas. Whenever

    spares, changed parts and tools are stored in the production area, these shall be kept in

    dedicated rooms or lockers. Tools and spare parts for use in sterile areas shall be

    disinfected before these are carried inside the production areas.

    4. Areas housing animals shall be isolated from other areas. The other requirements

    regarding animal houses shall be those as prescribed in rule 150-C(3) of the Drugs and

    Cosmetics Rules, 1945 which shall be adopted for production purposes.

    5. QUALITY CONTROL AREA

    1.QualityControl Laboratories shall be independent of the production areas.

    Separateareas shall be provided each for physico-chemical, biological, microbiologicalor

    radio-isotope analysis. Separate instrument room with adequate area shall beprovided

    for sensitive and sophisticated instruments employed for analysis.

    2.QualityControl Laboratories shall be designed appropriately for the operations to

    becarried out in them. Adequate space shall be provided to avoid mix-ups andcross-

    contamination. Sufficient and suitable storage space shall be providedfor test samples,

    retained samples, reference standards, reagents and records.

    3.Thedesign of the laboratory shall take into account the suitability ofconstruction

    materials and ventilation. Separate air handling units and otherrequirements shall be

    provided for biological, microbiological andradioisotopes testing areas. The laboratory

    shall be provided with regularsupply of water of appropriate quality for cleaning and

    testing purposes.

    .4.QualityControl Laboratory shall be divided into separate sections i.e. for

    chemical,microbiological and wherever required, biological Testing. These shall

    haveadequate area for basic installation and for ancillary purposes. Themicrobiology

    section shall have arrangements such as airlocks and laminar airflow work station,

    wherever considered necessary.

    6. PERSONNEL

    1.Themanufacture shall be conducted under the direct supervision of

    competenttechnical staff with prescribed qualifications and practical experience in

    therelevant dosage form and / or active pharmaceutical products.

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    2.Thehead of the Quality Control Laboratory shall be independent of themanufacturing

    unit. The testing shall be conducted under the direct supervisionof competent technical

    staff who shall be whole time employees of the licensee.

    3.Personnelfor Quality Assurance and Quality Control operations shall be

    suitablyqualified and experienced.

    4.Writtenduties of technical and Quality Control personnel shall be laid and

    followedstrictly.

    5.Numberof personnel employed shall be adequate and in direct proportion to

    theworkload.

    6.Thelicensee shall ensure in accordance with a written instruction that allpersonnel in

    production area or into Quality Control Laboratories shall receivetraining appropriate to

    the duties and responsibility assigned to them. Theyshall be provided with

    regular in-service training.

    7. HEALTH, CLOTHING AND SANITATION OF WORKERS

    7.1.The personnel handling Beta-lactum antibiotics shall betested for Penicillin sensitivity before employment and those handling sexhormones, cytotoxic substances and other potent drugs shall be periodicallyexamined for adverse effects. These personnel should be moved out of thesesections

    (except in dedicated facilities), by rotation, as a health safeguard.

    7.2. Prior to employment, all personnel, shall undergo medicalexamination including eye examination, and shall be free from Tuberculosis,skin and other communicable or contagious diseases. Thereafter, they should bemedically examined periodically, at least once a year. Records shall bemaintained thereof. The licensee shall provide the services of a qualifiedphysician for assessing the health status of personnel involved in differentactivities.

    7.3 All persons, prior to and during employment, shall betrained in practices which ensure personnel hygiene. A high level of personalhygiene shall be observed by all those engaged in the manufacturing processes.Instructions to this effect shall be displayed in change-rooms and otherstrategic locations.

    7.4 No person showing, at any time, apparentillness or open lesions which may adversely affect

    the quality of products,shall be allowed to handle starting materials, packaging materials, In-processmaterials, and drug products until his condition is no longer judged to be arisk. 7.5 All employees shall be instructed to report about theirillness or abnormal health condition to their immediate supervisor so thatappropriate action can be taken.

    7.6 Direct contact shall be avoided between the unprotectedhands of personnel and raw materials, intermediate or finished, unpackedproducts.

    7.7 All personnel shall wear clean body coverings appropriate totheir duties. Before entry into the manufacturing area, there shall be changerooms separate for each sex with adequate facilities for personal cleanlinesssuch as wash basin with running water,

    clean towels, hand dryers, soaps, disinfectants etc. The change rooms shallbe provided with cabinets for the storage of personal belongings of thepersonnel.

    7.8 Smoking, eating, drinking, chewing or keeping plants, food,drink and personal medicines shall not be permitted in production, laboratory,storage and other areas where they might adversely influence the productquality.

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8. MANUFACTURING OPERATIONS AND CONTROLS

    8.1. All manufacturing operations shall be carried out under thesupervision of technical staff approved by the Licensing Authority. Eachcritical step in the process relating to the selection, weighing and measuringof raw material addition during various stages shall be performed by trainedpersonnel under the direct personal supervision of approved technical staff. The contents of all vessels and containers used in manufactureand storage during the various manufacturing stages shall be conspicuouslylabeled with the name of the product, batch no., batch size and stage ofmanufacture. Each label should be initialed and dated by the authorized

    technical staff.

    Products not prepared under aseptic conditions are required tobe free from pathogens like Salmonella, Escherichia coli, Pyocyanea etc.

    8. 2. Precautions against mixup and cross-contamination

    8. 2.1. The licensee shall prevent mix-up and cross- contamination of drug materialand

    drug product (from environmental dust) by proper air-handling system,pressure

    differential, segregation, status labeling and cleaning. Properrecords and Standard

    Operating Procedures thereof shall be maintained.

    8. 2.2. The licensee shall ensure processing of sensitive drugs like Beta-Lactumantibiotics,

    sex hormones and cycotoxic substances in segregated areas orisolated production areas

    within the building with independent air-handlingunit and proper pressure differentials.

    The effective segregation of theseareas shall be demonstrated with adequate records of

    maintenance and services.

    8. 2.3. To prevent mix-ups during production stages, material under- process shallbe

    conspicuously labeled to demonstrate their status. All equipment used forproduction

    shall be labeled with their current status.

    8. 2.4. Packaging lines shall be independent and adequately segregated. It shall

    beensured that all left-overs of the previous packaging operations, includinglabels,

    cartons and caps are cleared before the

    closing hour.

    8. 2.5. Before packaging operations are begun, steps shall be taken to ensure thatthe

    work area, packaging lines, printing machines, and other equipment areclean and free

    from any products, materials and spillages. The line clearanceshall be performed

    according to an appropriate checklist and recorded.

    8. 2.6. The correct details of any printing (for example of batch numbers or expirydates)

    done separately or in the course of the packaging shall be re-checked atregular intervals.

    All printing and over-printing shall be authorised inwriting.

    8. 2.7. The manufacturing environment shall be maintained at the required levels

    oftemperature, humidity and cleanliness.

    8. 2.8. Authorised persons shall ensure change-over into specific uniforms

    beforeundertaking any manufacturing operations including packaging.

    8. 2.9. There shall be segregated enclosed areas, secured for recalled or rejectedmaterial

    and for such material which are to be re-processed or recovered.

9. SANITATION IN THE MANUFACTURING PREMISES

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    9. 1. The manufacturing premises shall be cleaned and maintainedin an orderly manner, so that it is free from accumulated waste, dust, debrisand other similar material. A validated cleaning procedure

    shall be maintained.

    9. 2. The manufacturing areas shall not be used for storage ofmaterials, except for the

    material being processed. It shall not be used as a general thoroughfare.

    9. 3. A routine sanitation program shall be drawn up andobserved, which shall be properly recorded and which shall indicate

    1. specificareas to be cleaned and cleaning intervals;

    2. cleaningprocedure to be followed, including equipment and materials to be

    used forcleaning; and

    3. personnelassigned to and responsible for the cleaning operation.

    9. 4. The adequacy of the working and in-process storage spaceshall permit the orderly and logical positioning of equipment and materials soas to minimise the risk of mix-up between different pharmaceutical products ortheir components to avoid cross-contamination, and to minimise the risk ofomission or wrong application of any of the manufacturing or control steps. 9. 5. Production areas shall be well lit, particularly wherevisual on-line controls are carried out. 10. RAW MATERIALS

    10. 1. The licensee shall keep an inventory of all raw-materialsto be used at any stage of manufacture of drugs and maintain records as perSchedule U.

    10. 2. All incoming materials shall be quarantined immediatelyafter receipt or processing. All materials shall be stored under appropriateconditions and in an orderly fashion to permit batch segregation and stockrotation by a 'first in/first expiry' - 'first-out' principle. All incomingmaterials shall be checked to ensure that the consignment corresponds to theorder placed. 10. 3. All incoming materials shall be purchased from approvedsources under valid purchase vouchers. Wherever possible, raw materials shouldbe purchased directly from the producers. 10. 4. Authorised staff appointed by the

    licensee in this behalf, which may include personnel from the quality controldepartment, shall examine each consignment on receipt and shall check eachcontainer for integrity of package and seal. Damaged containers shall beidentified, recorded and segregated.

    10. 5. If a single delivery of material is made up of differentbatches, each batch shall be considered as a separate batch for sampling,testing and release.

    10. 6. Raw materials in the storage area shall be appropriatelylabeled. Labels shall be clearly marked with the following information :

    1. designatedname of the product and the internal code reference, where

    applicable, andanalytical reference number;

    2. manufacturer'sname, address and batch number;

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    3. thestatus of the contents (e.g. quarantine, under test, released,

    approved,rejected);

    4. themanufacturing date, expiry date and re-test date.

    10. 7. There shall be adequate separate areas for materials"under test", "approved ", and "rejected" witharrangements and equipment to allow dry, clean and orderly placement of storedmaterials and products, wherever necessary, under controlled temperature andhumidity. 10. 8. Containers from which samples have been drawn shall beidentified.

    10. 9. Only raw materials which have been released by theQuality Control Department and which are within their shelf-life shall be used.It shall be ensured that shelf-life of formulation product shall not exceedwith that of active raw materials used.

    10. 10. It shall be ensured that all the containers of rawmaterials are placed on the raised platforms/racks and not placed directly onthe floor.

    11. EQUIPMENT

    11. 1. Equipment shall be located, designed, constructed,adapted and maintained to suit the operations to be carried out. The layout anddesign of the equipment shall aim to minimise the risk of errors and permiteffective cleaning and maintenance in order to avoid cross-contamination,build-up of dust or dirt and, in general, any adverse effect on the quality ofproducts. Each equipment shall be provided with a log book, wherevernecessary.

    11. 2. Balances and other measuring equipment of an appropriaterange, accuracy and precision shall be available in the raw-material stores,production and in-process control operations and these shall be calibrated andchecked on a scheduled basis in accordance with Standard Operating Procedures andrecords maintained.

    11. 3. The parts of the production equipment that come intocontact with the product shall not be reactive, additive or adsorptive to anextent that would affect the quality of the product. 11. 4. To avoid accidental contamination, wherever possible,non-toxic/edible grade lubricants shall be used and the equipment shall bemaintained in a way that lubricants do not contaminate the products beingproduced.

    11. 5. Defective equipment shall be removed from production andQuality Control areas or appropriately labeled.

    12. DOCUMENTATION AND RECORDS

    Documentation is an essential part of the Quality assurancesystem and, as such, shall be related to all aspects of Good ManufacturingPractices (GMP). Its aim is to define the specifications for all materials,method of manufacture and control, to ensure that all personnel concerned withmanufacture know the information necessary to decide whether or not to releasea batch of a drug for sale and to provide an audit trail that shall permit investigationof the history of any suspected defective batch.

    12.1. Documents designed, prepared, reviewed and controlled,wherever applicable, shall comply with these rules.

    12. 2. Documents shall be approved, signed and dated byappropriate and authorized persons. 12. 3. Documents shall specify the title, nature and purpose.They shall be laid out in an orderly fashion and be easy to check. Reproduceddocuments shall be clear and legible. Documents shall

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    be regularly reviewed andkept up to date. Any alteration made in the entry of a document shall be signedand dated.

    12. 4. The records shall be made or completed at the time ofeach operation in such a way that all significant activities concerning themanufacture of pharmaceutical products are traceable. Records and associatedStandard Operating Procedures (SOP) shall be retained for at least one yearafter the expiry date of the finished product.

    12. 5. Data may be recorded by electronic data processingsystems or other reliable means, but master formulae and detailed operatingprocedures relating to the system in use shall also

    be available in a hard copy to facilitate checking of the accuracy of therecords. Wherever documentation is handled by electronic data processingmethods, authorized persons shall enter or modify data in the computer. Thereshall be record of changes and deletions. Access shall be restricted by'passwords' or other means and the result of entry of critical data shall beindependently checked. Batch records electronically stored shall be protectedby a suitable back-up. During the period of retention, all relevant data shallbe readily available. 13. LABELS AND OTHER PRINTED MATERIALS

    Labels are absolutely necessary for identification of the drugsand their use. The printing shall be done in bright colours and in a legiblemanner. The label shall carry all the prescribed details about the product.

    13. 1. All containers and equipment shall bear appropriatelabels. Different colour coded labels shall be used to indicate the status of aproduct (for example: under test, approved, passed, rejected).

    13. 2. To avoid chance of mix-up in printed packaging materials,product leaflets, relating to different products, shall be stored separately.

    13. 3. Prior to release, all labels for containers, cartons andboxes and all circulars, inserts and leaflets shall be examined by the QualityControl Department of the licensee. 13. 4. Prior to packaging and labeling of a given batch of adrug, it shall be ensured by the licensee that samples are drawn from the bulkand duly tested, approved and released by the quality control personnel.

    13. 5. Records of receipt of all labelling and packagingmaterials shall be maintained for each shipment received indicating receipt,control reference numbers and whether accepted or rejected. Unused coded anddamaged labels and packaging materials shall be destroyed and recorded. 13.6. The label or accompanying document of reference standardsand reference culture shall indicate concentration, lot number, potency, dateon which container was first opened and storage conditions, where appropriate.

    14. QUALITY ASSURANCE

    This

    is a wide ranging concept concerning all matters that individually orcollectively influence the quality of a product. It is the totality of the arrangementsmade with the object of ensuring that products are of the quality required fortheir intended use.

    14. 1. The system of quality assurance appropriate to themanufacture of pharmaceutical products shall ensure that:

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