WHO good manufacturing practices for pharmaceutical products: main principles

8/20/2019 WHO good manufacturing practices for pharmaceutical products: main principles

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Annex 2

WHO good manufacturing practices for pharmaceuticalproducts: main principles1

Introduction 79

General considerations 80Glossary 81

Quality management in the medicines industry: philosophy and

essential elements 85

1. Pharmaceutical quality system 85

Quality risk management 88Product quality review 88

2. Good manufacturing practices for pharmaceutical products 90

3. Sanitation and hygiene 91

4. Qualification and validation 91

5. Complaints 92

6. Product recalls 93

7. Contract production, analysis and other activities 94

General 94The contract giver 94

The contract acceptor 95The contract 96

8. Self-inspection, quality audits and suppliers’ audits and approval 97

Items for self-inspection 97Self-inspection team 98Frequency of self-inspection 98Self-inspection report 98Follow-up action 98Quality audit 98

Suppliers’ audits and approval 98

1 The current document is a revision of WHO Good manufacturing practices for pharmaceutical products:main principles, previously published in WHO Technical Report Series, No. 961, 2011, Annex 3.



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WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-eighth report

9. Personnel 99

General 99

Key personnel 99

10. Training 103

11. Personal hygiene 103

12. Premises 104

General 104Ancillary areas 105Storage areas 106Weighing areas 106

Production areas 107Quality control areas 108

13. Equipment 108

14. Materials 109

General 110Starting materials 110Packaging materials 111Intermediate and bulk products 112Finished products 112

Rejected, recovered, reprocessed and reworked materials 112Recalled products 113Returned goods 113Reagents and culture media 113Reference standards 114Waste materials 114Miscellaneous 115

15. Documentation 115

General 115

Documents required 11616. Good practices in production 125

General 125Prevention of cross-contamination and bacterial contamination during production 126Processing operations 127Packaging operations 128

17. Good practices in quality control 129

Control of starting materials and intermediate, bulk and finished products 131Test requirements 132

Batch record review 134Stability studies 134References 135



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Introduction

Te first WHO draf text on good manuacturing practices (GMP) was preparedin 1967 by a group o consultants at the request o the wentieth World HealthAssembly (resolution WHA20.34). It was subsequently submitted to the wenty-first World Health Assembly under the title Draf requirements or goodmanuacturing practice in the manuacture and quality control o medicines and pharmaceutical specialities and was accepted.

Te revised text was discussed by the WHO Expert Committee onSpecifications or Pharmaceutical Preparations in 1968 and published asan annex to its twenty-second report. Te text was then reproduced (withsome revisions) in 1971 in the Supplement to the second edition o TeInternational Pharmacopoeia.

In 1969, when the World Health Assembly recommended the first versiono the WHO Certification Scheme on the quality o pharmaceutical productsmoving in international commerce in resolution WHA22.50, it accepted at thesame time the GMP text as an integral part o the Scheme. Revised versionso both the Certification Scheme and the GMP text were adopted in 1975 byresolution WHA28.65. Since then, the Certification Scheme has been extended

to include the certification o:

– veterinary products administered to ood-producing animals;

– starting materials or use in dosage orms, when they are subject tocontrol by legislation in both the exporting Member State and theimporting Member State;

– inormation on saety and efficacy (resolution WHA41.18, 1988).

In 1992, the revised draf requirements or GMP were presented in three

parts, o which only parts 1 and 2 are reproduced in this document (1). “Qualitymanagement in the medicines industry: philosophy and essential elements”,outlines the general concepts o quality assurance (QA) as well as the principalcomponents or subsystems o GMP, which are joint responsibilities o topmanagement and o production and quality control management. Tese includehygiene, validation, sel-inspection, personnel, premises, equipment, materialsand documentation.

“Good practices in production and quality control”, provides guidanceon actions to be taken separately by production and by quality control personnel

or the implementation o the general principles o QA.Tese two parts were subsequently supplemented by urther guidelines

which are integral parts o these GMP or pharmaceutical products. All thesetexts are available on the Medicines web page (http.www.who.int/medicines/organization/qsm/activities/qualityassurance/gmp/gmpcover. html).



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Considerable developments in GMP have taken place in the interveningyears, and important national and international documents, including new

revisions, have appeared (2–5). Tus there is a necessity to revise the mainprinciples and incorporate the concept o validation.

Among other items o eedback discussed during the consultationon WHO guidelines or medicines quality assurance, quality control (QC)laboratories and transer o technology on 27–31 July 2009, the need wasidentified to incorporate a new section on “Product quality review” underChapter 1: “Quality assurance”.

In addition, several updates were suggested to urther enhance theguidelines. Tese included the concept o risk management, replacing “drugs”

by the term “medicines” and introducing the concept o a “quality unit”.During 2012 the Secretariat was made aware that the current Good

manuacturing practices (GMP) or pharmaceutical products: main principles,published as Annex 3 in the WHO echnical Report Series, No. 961, 2011,would need updating (http://www.who.int/medicines/areas/quality_saety/quality_assurance/production/en/index.html − Quality assurance o pharmaceuticals:a compendium o guidelines and related materials).

Te WHO Expert Committee on Specifications or PharmaceuticalPreparations discussed the need or an update during its orty-seventh meetingand agreed to pursue the matter accordingly.

Te ollowing sections were updated in the newly revised version and,afer the usual consultation process, were presented to the orty-eighth ExpertCommittee or adoption:

Section: Pharmaceutical quality system

Section 2: 2. Good manufacturing practices for pharmaceutical products

Section 7: Contract production, analysis and other activities

Section 17: 17. Good practices in quality control

General considerations

Licensed pharmaceutical products (marketing authorization) should bemanuactured only by licensed manuacturers (holders o a manuacturingauthorization) whose activities are regularly inspected by competent nationalauthorities. Tis guide to GMP shall be used as a standard to justiy GMP status,which constitutes one o the elements o the WHO Certification Scheme on the

quality o pharmaceutical products moving in international commerce, throughthe assessment o applications or manuacturing authorizations and as a basisor the inspection o manuacturing acilities. It may also be used as trainingmaterial or government medicines inspectors, as well as or production, QCand QA personnel in the industry.



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Te guide is applicable to operations or the manuacture o medicinesin their finished dosage orms, including large-scale processes in hospitals and

the preparation o supplies or use in clinical trials.Te good practices outlined below are to be considered general guides,2

and they may be adapted to meet individual needs. Te equivalence o alternativeapproaches to QA, however, should be validated. Te guide as a whole does notcover saety aspects or the personnel engaged in manuacture, or environmentalprotection: these are normally governed by national legislation. A new concepto hazard analysis related to the risks in production and personnel saety has alsobeen recently recommended (WHO echnical Report Series, No. 961, Annex 7).

Te manuacturer should assure the saety o workers and take the necessarymeasures to prevent pollution o the external environment.International Nonproprietary Names (INN) or pharmaceutical substances

designated by WHO should be used when available, together with otherdesignated names.

Glossary

Te definitions given below apply to the terms used in this guide. Tey may have

different meanings in other contexts.active pharmaceutical ingredient (API). Any substance or mixture o

substances intended to be used in the manuacture o a pharmaceutical dosageorm and that, when so used, becomes an active ingredient o that pharmaceuticaldosage orm. Such substances are intended to urnish pharmacological activityor other direct effect in the diagnosis, cure, mitigation, treatment, or preventiono disease or to affect the structure and unction o the body.

airlock. An enclosed space with two or more doors, which is interposed

between two or more rooms, e.g. o differing classes o cleanliness, or the purposeo controlling the airflow between those rooms when they need to be entered.An airlock is designed or use either by people or or goods and/or equipment.

authorized person. Te person recognized by the national regulatoryauthority as having the responsibility or ensuring that each batch o finishedproduct has been manuactured, tested and approved or release in compliancewith the laws and regulations in orce in that country.

batch (or lot). A defined quantity o starting material, packagingmaterial, or product processed in a single process or series o processes so that

it is expected to be homogeneous. It may sometimes be necessary to divide abatch into a number o sub-batches, which are later brought together to orm

2 The word “should” in the text means a strong recommendation.



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a final homogeneous batch. In the case o terminal sterilization, the batch sizeis determined by the capacity o the autoclave. In continuous manuacture, the

batch must correspond to a defined raction o the production, characterized byits intended homogeneity. Te batch size can be defined either as a fixed quantityor as the amount produced in a fixed time interval.

batch number (or lot number). A distinctive combination o numbersand/or letters which uniquely identifies a batch on the labels, its batch recordsand corresponding certificates o analysis, etc.

batch records. All documents associated with the manuacture o a batcho bulk product or finished product. Tey provide a history o each batch oproduct and o all circumstances pertinent to the quality o the final product.

bulk product. Any product that has completed all processing stages upto, but not including, final packaging.

calibration. Te set o operations that establish, under specifiedconditions, the relationship between values indicated by an instrument or systemor measuring (especially weighing), recording, and controlling, or the valuesrepresented by a material measure, and the corresponding known values o areerence standard. Limits or acceptance o the results o measuring shouldbe established.

clean area. An area with defined environmental control o particulateand microbial contamination, constructed and used in such a way as to reducethe introduction, generation, and retention o contaminants within the area.

consignment (or delivery). Te quantity o a pharmaceutical orpharmaceuticals, made by one manuacturer and supplied at one time inresponse to a particular request or order. A consignment may comprise one ormore packages or containers and may include material belonging to more thanone batch.

contamination. Te undesired introduction o impurities o a chemical

or microbiological nature, or o oreign matter, into or on to a starting material orintermediate during production, sampling, packaging or repackaging, storageor transport.

critical operation. An operation in the manuacturing process that maycause variation in the quality o the pharmaceutical product.

cross-contamination. Contamination o a starting material, intermediateproduct or finished product with another starting material or product duringproduction.

finished product. A finished dosage orm that has undergone all stages

o manuacture, including packaging in its final container and labelling.in-process control. Checks perormed during production in order

to monitor and, i necessary, to adjust the process to ensure that the productconorms to its specifications. Te control o the environment or equipmentmay also be regarded as a part o in-process control.



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intermediate product. Partly processed product that must undergourther manuacturing steps beore it becomes a bulk product.

large-volume parenterals. Sterile solutions intended or parenteralapplication with a volume o 100 ml or more in one container o the finisheddosage orm.

manufacture. All operations o purchase o materials and products,production, quality control (QC), release, storage and distribution opharmaceutical products, and the related controls.

manufacturer. A company that carries out operations such as production,packaging, repackaging, labelling and relabelling o pharmaceuticals.

marketing authorization (product licence, registration certificate). Alegal document issued by the competent medicines regulatory authority thatestablishes the detailed composition and ormulation o the product and thepharmacopoeial or other recognized specifications o its ingredients and othe final product itsel, and includes details o packaging, labelling and shel-lie.

master formula. A document or set o documents speciying the startingmaterials with their quantities and the packaging materials, together with adescription o the procedures and precautions required to produce a specifiedquantity o a finished product as well as the processing instructions, including

the in-process controls.master record. A document or set o documents that serve as a basis orthe batch documentation (blank batch record).

packaging. All operations, including filling and labelling, that a bulkproduct has to undergo in order to become a finished product. Filling o asterile product under aseptic conditions or a product intended to be terminallysterilized, would not normally be regarded as part o packaging.

packaging material. Any material, including printed material, employedin the packaging o a pharmaceutical, but excluding any outer packaging used

or transportation or shipment. Packaging materials are reerred to as primary orsecondary according to whether or not they are intended to be in direct contactwith the product.

pharmaceutical product. Any material or product intended or humanor veterinary use presented in its finished dosage orm, or as a starting materialor use in such a dosage orm, that is subject to control by pharmaceuticallegislation in the exporting state and/or the importing state.

production. All operations involved in the preparation o a pharmaceuticalproduct, rom receipt o materials, through processing, packaging and repackaging,

labelling and relabelling, to completion o the finished product.qualification. Action o proving that any premises, systems and items o

equipment work correctly and actually lead to the expected results. Te meaningo the word “validation” is sometimes extended to incorporate the concepto qualification.



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quality assurance. See Part 1 (6 ).quality control. See Part 1 (6 ).

quality unit(s). An organizational unit independent o production whichulfils both quality assurance (QA) and quality control (QC) responsibilities. Tiscan be in the orm o separate QA and QC units or a single individual or group,depending upon the size and structure o the organization.

quarantine. Te status o starting or packaging materials, intermediates,or bulk or finished products isolated physically or by other effective means whilea decision is awaited on their release, rejection or reprocessing.

reconciliation. A comparison between the theoretical quantity and the

actual quantity.recovery. Te introduction o all or part o previous batches (or oredistilled solvents and similar products) o the required quality into anotherbatch at a defined stage o manuacture. It includes the removal o impuritiesrom waste to obtain a pure substance or the recovery o used materials or aseparate use.

reprocessing. Subjecting all or part o a batch or lot o an in-processmedicine, bulk process intermediate (final biological bulk intermediate) or bulkproduct o a single batch or lot to a previous step in the validated manuacturing

process due to ailure to meet predetermined specifications. Reprocessingprocedures are oreseen as occasionally necessary or biological medicines and, insuch cases, are validated and pre-approved as part o the marketing authorization.

reworking. Subjecting an in-process or bulk process intermediate (finalbiological bulk intermediate) or final product o a single batch to an alternatemanuacturing process due to a ailure to meet predetermined specifications.Reworking is an unexpected occurrence and is not pre-approved as part o themarketing authorization.

self-contained area. Premises which provide complete and totalseparation o all aspects o an operation, including personnel and equipmentmovement, with well established procedures, controls and monitoring. Tisincludes physical barriers as well as separate air-handling systems, but does notnecessarily imply two distinct and separate buildings.

specification. A list o detailed requirements with which the products ormaterials used or obtained during manuacture have to conorm. Tey serve asa basis or quality evaluation.

standard operating procedure (SOP). An authorized written procedure

giving instructions or perorming operations not necessarily specific to a givenproduct or material (e.g. equipment operation, maintenance and cleaning;

validation; cleaning o premises and environmental control; sampling andinspection). Certain SOPs may be used to supplement product-specific masterand batch production documentation.



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Te attainment o this quality objective is the responsibility o seniormanagement and requires the participation and commitment o staff

in many different departments and at all levels within the company,the company’s suppliers and the distributors. o achieve this qualityobjective reliably there must be a comprehensively designed and correctlyimplemented pharmaceutical quality system (PQS) incorporating GMPand QRM

1.2 Senior management has the ultimate responsibility to ensure an effectivePQS is in place, is adequately resourced, and that roles, responsibilities,and authorities are defined, communicated and implemented throughout

the organization. Senior management’s leadership and active participationin the PQS is essential. Tis leadership should ensure the support andcommitment o staff at all levels and sites within the organization to the PQS.

1.3 Quality management is a wide-ranging concept covering all mattersthat individually or collectively influence the quality o a product. It isthe totality o the arrangements made with the object o ensuring thatpharmaceutical products are o the quality required or their intendeduse. Quality management, thereore, incorporates GMP and other actors,

including those outside the scope o this guide, such as product designand development.

1.4 GMP applies to the lie-cycle stages rom the manuacture o investigationalmedicinal products, technology transer, and commercial manuacturing,through to product discontinuation. Te PQS can extend to thepharmaceutical development lie-cycle stage and should acilitate innovationand continual improvement and strengthen the link between pharmaceuticaldevelopment and manuacturing activities. All parts o the PQS should

be adequately resourced and maintained, including being provided withsufficient competent personnel, suitable premises, equipment and acilities.

1.5 Te PQS appropriate to the manuacture o pharmaceutical products shouldensure that:

a) product realization is achieved by designing, qualiying, planning,implementing, maintaining and continuously improving a systemthat allows the consistent delivery o products with appropriate

quality attributes;b) product and process knowledge is managed throughout all lie-

cycle stages;

c) pharmaceutical products are designed and developed in a way thattakes account o the requirements o GMP and other associated codes



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such as those o good laboratory practice (GLP) and good clinicalpractice (GCP);

d) production and control operations are clearly specified in a writtenorm and GMP requirements are adopted;

e) managerial responsibilities are clearly specified in job descriptions;

) arrangements are made or the manuacture, supply and use o thecorrect starting and packaging materials, the selection and monitoringo suppliers and or veriying that each delivery is the correct materialrom the approved supply chain;

g) all necessary controls on starting materials, intermediate products,

and bulk products and other in-process controls, calibrations and validations are carried out;

h) the finished product is correctly processed and checked, accordingto the defined procedures;

i) pharmaceutical products are not sold or supplied beore theauthorized persons (see also sections 9.11 and 9.12) have certifiedthat each production batch has been produced and controlled inaccordance with the requirements o the marketing authorization and

any other regulations relevant to the production, control and releaseo pharmaceutical products;

j) processes are in place to assure the management o outsourcedactivities;

k) satisactory arrangements exist to ensure, as ar as possible, that thepharmaceutical products are stored, distributed and subsequentlyhandled so that quality is maintained throughout their shel-lie;

l) there is a procedure or sel-inspection and/or quality audit thatregularly appraises the effectiveness and applicability o the PQS;

m) product and processes are monitored and the results taken intoaccount in batch release, in the investigation o deviations and, witha view to taking preventive action to avoid potential deviationsoccurring in the uture;

n) arrangements are in place or the prospective evaluation and approvalo planned changes and their approval prior to implementationtaking into account regulatory notification and approval whererequired. Afer implementation o any change, an evaluation is

undertaken to confirm that the quality objectives were achieved andthat there was no unintended adverse impact on product quality;

o) regular reviews o the quality o pharmaceutical products areconducted with the objective o veriying the consistency o theprocess and identiying where there is a need or improvement;



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p) a state o control is established and maintained by developingand using effective monitoring and control systems or process

perormance and product quality;q) continual improvement is acilitated through the implementation

o quality improvements appropriate to the current level o processand product knowledge;

r) there is a system or QRM;

s) deviations, suspected product deects and other problems arereported, investigated and recorded. An appropriate level o rootcause analysis is applied during such investigations. Te most likely

root cause(s) should be identified and appropriate corrective actionsand/or preventive actions (CAPAs) should be identified and taken.Te effectiveness o CAPAs should be monitored.

1.6 Tere should be periodic management reviews, with the involvement osenior management, o the operation o the PQS to identiy opportunities orcontinual improvement o products, processes and the system itsel. Unlessotherwise justified, such reviews should be conducted at least annually.

1.7 Te PQS should be defined and documented. A quality manual or equivalentdocumentation should be established and should contain a description othe quality management system including management responsibilities.

Quality risk management1.8 QRM is a systematic process or the assessment, control, communication

and review o risks to the quality o the medicinal product. It can be appliedboth proactively and retrospectively.

1.9 QRM should ensure that:

– the evaluation o the risk to quality is based on scientific knowledge,experience with the process and ultimately links to the protection othe patient;

– the level o effort, ormality and documentation o the QRM processis commensurate with the level o risk.

Product quality review

1.10 Regular, periodic or rolling quality reviews o all pharmaceutical products,including export-only products, should be conducted with the objective o

veriying the consistency o the existing process and the appropriatenesso current specifications or both starting materials and finished product,to highlight any trends and to identiy product and process improvements.



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Such reviews should normally be conducted and documented annually,taking into account previous reviews, and should include at least:

a) review o starting materials and packaging materials used or theproduct, especially those rom new sources and in particular thereview o supply chain traceability o active substances;

b) a review o critical in-process controls, and finished product results;

c) a review o all batches that ailed to meet established specification(s)and their investigation;

d) a review o all significant deviations or non-conormances, therelated investigations and the effectiveness o resultant CAPAs taken;

e) a review o all changes made to the processes or analytical methods;

) a review o dossier variations submitted, granted or reused;

g) a review o the results o the stability monitoring programme andany adverse trends;

h) a review o all quality-related returns, complaints and recalls andthe investigations perormed at the time;

i) a review o adequacy o any other previous corrective actions on

product processes or equipment; j) post-marketing commitments or new dossiers and variations tothe dossiers;

k) the qualification status o relevant equipment and utilities, e.g. heating, ventilation and air-conditioning (HVAC), water or compressedgases and a review o the results o monitoring the output o suchequipment and utilities;

l) a review o technical agreements to ensure that they are up to date.

Te manuacturer and, where different, marketing authorization holder,should evaluate the results o the review and an assessment should be made as towhether CAPA or any revalidation should be undertaken, under the PQS. CAPAsshould be completed in a timely and effective manner, according to documentedprocedures. Tere should be procedures or the ongoing management and reviewo these actions, and the effectiveness o these procedures should be verifiedduring sel-inspection. Quality reviews may be grouped by product type, e.g.solid dosage orms, liquid dosage orms, or sterile products, where scientifically

justified. Where the marketing authorization holder is not the manuacturer, there

should be a technical agreement in place between the various parties that definestheir respective responsibilities in producing the quality review. Te authorizedperson responsible or final batch certification, together with the marketingauthorization holder, should ensure that the quality review is perormed in atimely manner and is accurate.



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2. Good manufacturing practices for

pharmaceutical products2.1 GMP is that part o quality management which ensures that products are

consistently produced and controlled according to the quality standards

appropriate to their intended use and as required by the marketing

authorization, clinical trial authorization or product specification. GMP

is concerned with both production and QC. GMP is aimed primarily at

managing and minimizing the risks inherent in pharmaceutical manuacture

to ensure the quality, saety and efficacy o products. Under GMP:

a) all manuacturing processes are clearly defined, systematically

reviewed or associated risks in the light o scientific knowledge and

experience, and shown to be capable o consistently manuacturing

pharmaceutical products o the required quality that comply with

their specifications;

b) qualification and validation are perormed;

c) all necessary resources are provided, including:

(i) sufficient and appropriately qualified and trained personnel,

(ii) adequate premises and space,

(iii) suitable equipment and services,

(iv) appropriate materials, containers and labels,

(v) approved procedures and instructions,

(vi) suitable storage and transport,

(vii) adequate personnel, laboratories and equipment or

in-process controls;

d) instructions and procedures are written in clear and unambiguous

language, specifically applicable to the acilities provided;

e) procedures are carried out correctly and personnel are trained to

do so;

) records are made (manually and/or by recording instruments)

during manuacture to show that all the steps required by the defined

procedures and instructions have in act been taken and that thequantity and quality o the product are as expected. Any significant

deviations are ully recorded and investigated with the objective o

determining the root cause and appropriate corrective and preventive

action is implemented;



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g) records covering manuacture and distribution, which enable the

complete history o a batch to be traced, are retained in a

comprehensible and accessible orm;

h) the proper storage and distribution o the products minimizes any

risk to their quality and takes account o good distribution

practices (GDP);

i) a system is available to recall any batch o product rom sale or supply;

j) complaints about marketed products are examined, the causes o

quality deects investigated and appropriate measures taken in respect

o the deective products to prevent recurrence.

3. Sanitation and hygiene

3.1 A high level o sanitation and hygiene should be practised in every aspect o

the manuacture o medicines. Te scope o sanitation and hygiene covers

personnel, premises, equipment and apparatus, production materials and

containers, products or cleaning and disinection, and anything that could

become a source o contamination to the product. Potential sources o

contamination should be eliminated through an integrated comprehensive

programme o sanitation and hygiene. (For Personal hygiene see section 11,

and or sanitation see section 12, “Premises”.)

4. Qualification and validation

4.1 In accordance with GMP, each pharmaceutical company should identiy

what qualification and validation work is required to prove that the critical

aspects o their particular operation are controlled.

4.2 Te key elements o a qualification and validation programme o a company

should be clearly defined and documented in a validation master plan.

4.3 Qualification and validation should establish and provide documentary

evidence that:

a) the premises, supporting utilities, equipment and processes have

been designed in accordance with the requirements or GMP(design qualification or DQ);

b) the premises, supporting utilities and equipment have been built and

installed in compliance with their design specifications (installation

qualification or IQ);



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5.3 Tere should be written procedures describing the action to be taken,including the need to consider a recall, in the case o a complaint concerning

a possible product deect.

5.4 Special attention should be given to establishing that the product that gaverise to a complaint was deective.

5.5 Any complaint concerning a product deect should be recorded with all theoriginal details and thoroughly investigated. Te person responsible or QCshould normally be involved in the review o such investigations.

5.6 I a product deect is discovered or suspected in a batch, consideration should

be given to whether other batches should be checked in order to determinewhether they are also affected. In particular, other batches that may containreprocessed product rom the deective batch should be investigated.

5.7 Where necessary, appropriate ollow-up action, possibly including productrecall, should be taken afer investigation and evaluation o the complaint.

5.8 All decisions made and measures taken as a result o a complaint should berecorded and reerenced to the corresponding batch records.

5.9 Complaints records should be regularly reviewed or any indication ospecific or recurring problems that require attention and might justiy therecall o marketed products.

5.10 Te competent authorities should be inormed i a manuacturer is consideringaction ollowing possibly aulty manuacture, product deterioration, a suspectproduct or any other serious quality problems with a product.

6. Product recalls6.1 Principle. Tere should be a system to recall rom the market, promptly and

effectively, products known or suspected to be deective.

6.2 Te authorized person should be responsible or the execution andcoordination o recalls. He or she should have sufficient staff to handle allaspects o the recalls with the appropriate degree o urgency.

6.3 Tere should be established written procedures, which are regularly reviewed

and updated, or the organization o any recall activity. Recall operationsshould be capable o being initiated promptly down to the required level inthe distribution chain.

6.4 An instruction should be included in the written procedures to store recalledproducts in a secure segregated area while their ate is decided.



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6.5 All competent authorities o all countries to which a given product hasbeen distributed should be promptly inormed o any intention to recall the

product because it is, or is suspected o being, deective.

6.6 Te distribution records should be readily available to the authorizedperson, and they should contain sufficient inormation on wholesalers anddirectly supplied customers (including, or exported products, those whohave received samples or clinical tests and medical samples) to permit aneffective recall.

6.7 Te progress o the recall process should be monitored and recorded.

Records should include the disposition o the product. A final report shouldbe issued, including a reconciliation between the delivered and recoveredquantities o the products.

6.8 Te effectiveness o the arrangements or recalls should be tested andevaluated rom time to time.

7. Contract production, analysis and other activities

7.1 Principle. Contract production, analysis and any other activity covered byGMP must be correctly defined, agreed and controlled in order to avoidmisunderstandings that could result in a product, or work or analysis, ounsatisactory quality.

General7.2 All arrangements or contract production and analysis, including

technology transer and any proposed changes in technical or otherarrangements, should be in accordance with the marketing authorizationor the product concerned.

7.3 Te contract should permit the contract giver to audit the acilities andactivities o the contract acceptor or mutually agreed subcontractors.

7.4 In the case o contract analysis, the final approval or release must be givenby the authorized person in accordance with GMP and the marketingauthorization as specified in the contract.

The contract giver7.5 Te PQS o the contract giver should include the control and review o any

outsourced activities. Te contract giver is responsible or assessing thelegality, suitability and competence o the contract acceptor to successullycarry out the work or tests required, or approval or contract activities,



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and or ensuring by means o the contract that the principles o GMPincorporating QRM principles are ollowed.

7.6 Te contract giver should provide the contract acceptor with all theinormation necessary to carry out the contracted operations correctlyin accordance with the marketing authorization and any other legalrequirements. Te contract giver should ensure that the contract acceptoris ully aware o any hazards associated with the product, work or tests thatmight pose a risk to premises, equipment, personnel, other materials orother products.

7.7 Te contract giver should review and assess the records and results related tothe outsourced activities. Te contract giver should ensure that all productsand materials delivered by the contract acceptor have been processed inaccordance with GMP and the marketing authorization; comply with theirspecifications and that the product has been released by the authorizedperson in accordance with GMP and the marketing authorization.

7.8 Te contract giver should monitor and review the perormance o thecontract acceptor including the implementation o any needed improvementsand their effectiveness.

7.9 Te contract giver is responsible or ensuring that the contract acceptorunderstands that his or her activities may be subject to inspection bycompetent authorities.

The contract acceptor7.10 Te contract acceptor must have adequate premises, equipment, knowledge,

experience and competent personnel to satisactorily carry out the work

ordered by the contract giver. Contract manuacture may be undertakenonly by a manuacturer who holds a valid manuacturing authorization.

7.11 Te contract acceptor should not pass to a third party any o the workentrusted to him or her under the contract without the contract giver’s priorevaluation and approval o the arrangements. Arrangements made betweenthe contract acceptor and any third party should ensure that inormationand knowledge, including that rom assessments o the suitability o thethird party, are made available in the same way as between the original

contract giver and contract acceptor.7.12 Te contract acceptor should rerain rom any activity (including

unauthorized changes outside the terms o the contract) that may adverselyaffect the quality o the product manuactured and/or analysed or thecontract giver.



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The contract

7.13 Tere must be a written contract between the contract giver and thecontract acceptor which clearly establishes the responsibilities o each party,

covering the outsourced activities, the products or operations to which they

are related, communication processes relating to the outsourced activities

and any technical arrangements made in connection with it.

7.14 Te contract must clearly state the way in which the authorized person, in

releasing each batch o product or sale or issuing the certificate o analysis,

exercises his or her ull responsibility and ensures that each batch has been

manuactured in, and checked or, compliance with the requirements othe marketing authorization.

7.15 echnical aspects o the contract should be drawn up by competent

persons with suitable knowledge o pharmaceutical technology, analysis

and GMP.

7.16 All arrangements or production and analysis must be in accordance with

the marketing authorization and agreed by both parties.

7.17 Te contract should clearly describe who is responsible or contracted

activities, e.g. knowledge management, technology transer, supply chain,

subcontracting, testing and releasing materials and undertaking production

and QC, including in-process controls, and who has responsibility or

sampling and analysis. In the case o contract analysis, the contract should

state whether or not the contract acceptor should take samples at the

premises o the manuacturer.

7.18 Manuacturing, analytical and distribution records, and reerence samples,should be kept by, or be available to, the contract giver. Any records relevant

to assessing the quality o a product in the event o complaints or a suspected

deect, or to investigating in the case o a suspected alsified product or

laboratory raud, must be accessible and specified in the procedures o the

contract giver.

7.19 Te contract should describe the handling o starting materials, intermediate,

bulk and finished products, i they are rejected. It should also describethe procedure to be ollowed i the contract analysis shows that the tested

product must be rejected.



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8. Self-inspection, quality audits and

suppliers’ audits and approval8.1 Principle. Te purpose o sel-inspection is to evaluate the manuacturer’s

compliance with GMP in all aspects o production and QC. Te sel-inspection programme should be designed to detect any shortcomings inthe implementation o GMP and to recommend the necessary correctiveactions. Sel-inspections should be perormed routinely, and may be, inaddition, perormed on special occasions, e.g. in the case o product recallsor repeated rejections, or when an inspection by the health authorities

is announced. Te team responsible or sel-inspection should consisto personnel who can evaluate the implementation o GMP objectively.All recommendations or corrective action should be implemented. Teprocedure or sel-inspection should be documented, and there should bean effective ollow-up programme.

Items for self-inspection8.2 Written instructions or sel-inspection should be established to provide

a minimum and uniorm standard o requirements. Tese may includequestionnaires on GMP requirements covering at least the ollowing items:

(a) personnel;

(b) premises including personnel acilities;

(c) maintenance o buildings and equipment;

(d) storage o starting materials and finished products;

(e) equipment;

() production and in-process controls;

(g) QC;

(h) documentation;

(i) sanitation and hygiene;

(j) validation and revalidation programmes;

(k) calibration o instruments or measurement systems;

(l) recall procedures;

(m) complaints management;

(n) labels control;

(o) results o previous sel-inspections and any corrective steps taken.



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Self-inspection team

8.3 Management should appoint a sel-inspection team consisting o expertsin their respective fields who are amiliar with GMP. Te members o theteam may be appointed rom inside or outside the company.

Frequency of self-inspection8.4 Te requency with which sel-inspections are conducted may depend on

company requirements but should preerably be at least once a year. Terequency should be stated in the procedure.

Self-inspection report8.5 A report should be made at the completion o a sel-inspection. Te report

should include:

(a) sel-inspection results;

(b) evaluation and conclusions;

(c) recommended corrective actions.

Follow-up action8.6 Tere should be an effective ollow-up programme. Te company

management should evaluate both the sel-inspection report and thecorrective actions as necessary.

Quality audit8.7 It may be useul to supplement sel-inspections with a quality audit. A

quality audit consists o an examination and assessment o all or part oa quality system with the specific purpose o improving it. A quality auditis usually conducted by outside or independent specialists or a teamdesignated by the management or this purpose. Such audits may also beextended to suppliers and contractors (see section 7, “Contract productionand analysis”).

Suppliers’ audits and approval8.8 Te person responsible or QC should have responsibility, together with

other relevant departments, or approving suppliers who can reliably supplystarting and packaging materials that meet established specifications.

8.9 Beore suppliers are approved and included in the approved suppliers’ listor specifications, they should be evaluated. Te evaluation should take into



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account a supplier’s history and the nature o the materials to be supplied.I an audit is required, it should determine the supplier’s ability to conorm

with GMP standards.

9. Personnel

9.1 Principle. Te establishment and maintenance o a satisactory system o QAand the correct manuacture and control o pharmaceutical products andactive ingredients rely upon people. For this reason there must be sufficientqualified personnel to carry out all the tasks or which the manuacturer

is responsible. Individual responsibilities should be clearly defined andunderstood by the persons concerned and recorded as written descriptions.

General9.2 Te manuacturer should have an adequate number o personnel with

the necessary qualifications and practical experience. Te responsibilitiesplaced on any one individual should not be so extensive as to present anyrisk to quality.

9.3 Responsible staff should have its specific duties recorded in writtendescriptions and adequate authority to carry out its responsibilities. Itsduties may be delegated to designated deputies with a satisactory levelo qualifications. Tere should be no gaps or unexplained overlaps in theresponsibilities o personnel concerned with the application o GMP. Temanuacturer should have an organization chart.

9.4 All personnel should be aware o the principles o GMP that affect themand receive initial and continuing training, including hygiene instruction,

relevant to their needs. All personnel should be motivated to support theestablishment and maintenance o high quality standards.

9.5 Steps should be taken to prevent unauthorized people rom enteringproduction, storage and QC areas. Personnel who do not work in theseareas should not use them as a passageway.

Key personnel9.6 Key personnel include the heads o production, the head(s) o quality

unit(s) and the authorized person. Te quality unit(s) typically comprisethe quality assurance and quality control unctions. In some cases, thesecould be combined in one department. Te authorized person may also beresponsible or one or more o these quality unit(s). Normally, key postsshould be occupied by ull-time personnel. Te heads o production and



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quality unit(s) should be independent o each other. In large organizations,it may be necessary to delegate some o the unctions; however, the

responsibility cannot be delegated.

9.7 Key personnel responsible or supervising the production and qualityunit(s) or pharmaceutical products should possess the qualifications o ascientific education and practical experience required by national legislation.Teir education should include the study o an appropriate combination o:

(a) chemistry (analytical or organic) or biochemistry;

(b) chemical engineering;

(c) microbiology;

(d) pharmaceutical sciences and technology;

(e) pharmacology and toxicology;

() physiology;

(g) other related sciences.

Tey should also have adequate practical experience in the manuactureand QA o pharmaceutical products. In order to gain such experience, apreparatory period may be required, during which they should perorm theirduties under proessional guidance. Te scientific education and practicalexperience o experts should be such as to enable them to exercise independentproessional judgement, based on the application o scientific principles andunderstanding to the practical problems encountered in the manuacture andQC o pharmaceutical products.

9.8 Te heads o the production and the quality unit(s) generally have someshared, or jointly exercised, responsibilities relating to quality. Tese mayinclude, depending on national regulations:

(a) authorization o written procedures and other documents,including amendments;

(b) monitoring and control o the manuacturing environment;

(c) plant hygiene;

(d) process validation and calibration o analytical apparatus;

(e) training, including the application and principles o QA;

() approval and monitoring o suppliers o materials;

(g) approval and monitoring o contract manuacturers;

(h) designation and monitoring o storage conditions or materialsand products;



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(i) perormance and evaluation o in-process controls;

(j) retention o records;

(k) monitoring o compliance with GMP requirements;

(l) inspection, investigation and taking o samples in order to monitoractors that may affect product quality.

9.9 Te head o production generally has the ollowing responsibilities:

(a) to ensure that products are produced and stored in accordance withthe appropriate documentation in order to obtain the required quality;

(b) to approve the instructions relating to production operations, includingthe in-process controls, and to ensure their strict implementation;

(c) to ensure that the production records are evaluated and signed by adesignated person;

(d) to check the maintenance o the department, premises and equipment;

(e) to ensure that the appropriate process validations and calibrationso control equipment are perormed and recorded and the reportsmade available;

() to ensure that the required initial and continuing training oproduction personnel is carried out and adapted according to need.

9.10 Te head(s) o the quality unit(s) generally have the ollowing responsibilities:

(a) to approve or reject starting materials, packaging materials, andintermediate, bulk and finished products in relation to theirspecifications;

(b) to evaluate batch records;

(c) to ensure that all necessary testing is carried out;

(d) to approve sampling instructions, specifications, test methods andother QC procedures;

(e) to approve and monitor analyses carried out under contract;

() to check the maintenance o the department, premises and equipment;

(g) to ensure that the appropriate validations, including those oanalytical procedures, and calibrations o control equipment arecarried out;

(h) to ensure that the required initial and continuing training o qualityunit personnel is carried out and adapted according to need;

(i) establishment, implementation and maintenance o the quality system;

(j) supervision o the regular internal audits or sel-inspections;



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(k) participation in external audit (vendor audit);

(l) participation in validation programmes.

Other duties o QC are summarized in sections 17.3 and 17.4.

9.11 Te authorized person is responsible or compliance with technical or

regulatory requirements related to the quality o finished products and theapproval o the release o the finished product or sale or supply.

9.12 Assessment o finished products should embrace all relevant actors,including the production conditions, the results o in-process testing,

the manuacturing (including packaging) documentation, compliancewith the specification or the finished product, and an examination o the

finished pack.

9.13 No batch o product is to be released or sale or supply prior to certification

by the authorized person(s). In certain countries, by law, the batch release

is a task o the authorized person rom production together with the

authorized person rom QC.

9.14 Te authorized person responsible or approving a batch or release shouldalways ensure that the ollowing requirements have been met:

(a) the marketing authorization and the manuacturing authorization

requirements or the product have been met or the batch concerned;

(b) the principles and guidelines o GMP, as laid down in the guidelines

published by WHO, have been ollowed;

(c) the principal manuacturing and testing processes have been validated;

(d) all the necessary checks and tests have been perormed and accounttaken o the production conditions and manuacturing records;

(e) any planned changes or deviations in manuacturing or QC have

been notified in accordance with a well-defined reporting system

beore any product is released. Such changes may need notification

to, and approval by, the medicines regulatory authority;

() any additional sampling, inspection, tests and checks have been

carried out or initiated, as appropriate, to cover planned changes

and deviations;(g) all necessary production and QC documentation has been completed

and endorsed by supervisors trained in appropriate disciplines;

(h) appropriate audits, sel-inspections and spot-checks are carried out

by experienced and trained staff;



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(i) approval has been given by the head o QC;

(j) all relevant actors have been considered, including any notspecifically associated with the output batch directly under review(e.g. subdivision o output batches rom a common input, actorsassociated with continuous production runs).

9.15 Te unction o the approval o the release o a finished batch or a productcan be delegated to a designated person with appropriate qualifications andexperience who will release the product in accordance with an approvedprocedure. Tis is normally done by QA by means o batch review.

10. Training

10.1 Te manuacturer should provide training in accordance with a writtenprogramme or all personnel whose duties take them into manuacturingareas or into control laboratories (including the technical, maintenance andcleaning personnel) and or other personnel as required.

10.2 Besides basic training on the theory and practice o GMP, newly recruitedpersonnel should receive training appropriate to the duties assigned to them.

Continuing training should also be given, and its practical effectivenessperiodically assessed. Approved training programmes should be available.raining records should be kept.

10.3 Personnel working in areas where contamination is a hazard, e.g. cleanareas or areas where highly active, toxic, inectious or sensitizing materialsare handled, should be given specific training.

10.4 Te concept o QA and all the measures which aid its understanding and

implementation should be ully discussed during the training sessions.10.5 Visitors or untrained personnel should preerably not be taken into the

production and QC areas. I this is unavoidable, they should be givenrelevant inormation in advance (particularly about personal hygiene) andthe prescribed protective clothing. Tey should be closely supervised.

10.6 Consultant and contract staff should be qualified or the services theyprovide. Evidence o this should be included in the training records.

11. Personal hygiene

11.1 All personnel, prior to and during employment, as appropriate, shouldundergo health examinations. Personnel conducting visual inspectionsshould also undergo periodic eye examinations.



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11.2 All personnel should be trained in the practices o personal hygiene. A highlevel o personal hygiene should be observed by all those concerned with

manuacturing processes. In particular, personnel should be instructedto wash their hands beore entering production areas. Signs to this effectshould be posted and instructions complied with.

11.3 Any person shown at any time to have an apparent illness or open lesionsthat may adversely affect the quality o products should not be allowedto handle starting materials, packaging materials, in-process materials ormedicines until the condition is no longer judged to be a risk.

11.4 All employees should be instructed and encouraged to report to theirimmediate supervisor any conditions (relating to plant, equipment orpersonnel) that they consider may adversely affect the products.

11.5 Direct contact should be avoided between the operator’s hands and startingmaterials, primary packaging materials and intermediate or bulk product.

11.6 o ensure protection o the product rom contamination, personnel shouldwear clean body coverings appropriate to the duties they perorm, includingappropriate hair covering. Used clothes, i reusable, should be stored in

separate closed containers until properly laundered and, i necessary,disinected or sterilized.

11.7 Smoking, eating, drinking, chewing, and keeping plants, ood, drink,smoking material and personal medicines should not be permitted inproduction, laboratory and storage areas, or in any other areas where theymight adversely influence product quality.

11.8 Personal hygiene procedures, including the wearing o protective clothing,should apply to all persons entering production areas, whether they aretemporary or ull-time employees or non-employees, e.g. contractors’employees, visitors, senior managers and inspectors.

12. Premises

12.1 Principle. Premises must be located, designed, constructed, adapted andmaintained to suit the operations to be carried out.

General12.2 Te layout and design o premises must aim to minimize the risk o errors

and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up o dust or dirt, and in general, any adverse effecton the quality o products.



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12.3 Where dust is generated (e.g. during sampling, weighing, mixing andprocessing operations, or packaging o powder), measures should be

taken to avoid cross-contamination and acilitate cleaning.

12.4 Premises should be situated in an environment that, when consideredtogether with measures to protect the manuacturing process, presentsminimum risk o causing any contamination o materials or products.

12.5 Premises used or the manuacture o finished products should be suitablydesigned and constructed to acilitate good sanitation.

12.6 Premises should be careully maintained, and it should be ensured thatrepair and maintenance operations do not present any hazard to the qualityo products.

12.7 Premises should be cleaned and, where applicable, disinected accordingto detailed written procedures. Records should be maintained.

12.8 Electrical supply, lighting, temperature, humidity and ventilation shouldbe appropriate and such that they do not adversely affect, directly orindirectly, either the pharmaceutical products during their manuacture

and storage, or the accurate unctioning o equipment.

12.9 Premises should be designed and equipped so as to afford maximumprotection against the entry o insects, birds or other animals. Tere shouldbe a procedure or rodent and pest control.

12.10 Premises should be designed to ensure the logical flow o materialsand personnel.

Ancillary areas12.11 Rest and rereshment rooms should be separate rom manuacturing and

control areas.

12.12 Facilities or changing and storing clothes and or washing and toiletpurposes should be easily accessible and appropriate or the number ousers. oilets should not communicate directly with production orstorage areas.

12.13 Maintenance workshops should i possible be separated rom productionareas. Whenever parts and tools are stored in the production area, theyshould be kept in rooms or lockers reserved or that use.

12.14 Animal houses should be well isolated rom other areas, with separateentrance (animal access) and air-handling acilities.



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Storage areas

12.15 Storage areas should be o sufficient capacity to allow orderly storage othe various categories o materials and products with proper separationand segregation: starting and packaging materials, intermediates, bulk andfinished products, products in quarantine, and released, rejected, returnedor recalled products.

12.16 Storage areas should be designed or adapted to ensure good storageconditions. In particular, they should be clean, dry, sufficiently lit andmaintained within acceptable temperature limits. Where special storage

conditions are required (e.g. temperature, humidity) these should beprovided, controlled, monitored and recorded where appropriate.

12.17 Receiving and dispatch bays should be separated and should protectmaterials and products rom the weather. Receiving areas should bedesigned and equipped to allow containers o incoming materials to becleaned, i necessary, beore storage.

12.18 Where quarantine status is ensured by storage in separate areas, theseareas must be clearly marked and their access restricted to authorizedpersonnel. Any system replacing the physical quarantine should giveequivalent security.

12.19 Segregation should be provided or the storage o rejected, recalled, orreturned materials or products.

12.20 Highly active and radioactive materials, narcotics, other dangerousmedicines, and substances presenting special risks o abuse, fire orexplosion should be stored in sae and secure areas.

12.21 Printed packaging materials are considered critical to the conormity othe pharmaceutical product to its labelling and special attention shouldbe paid to sampling and the sae and secure storage o these materials.

12.22 Tere should normally be a separate sampling area or starting materials.(I sampling is perormed in the storage area, it should be conducted insuch a way as to prevent contamination or cross-contamination.)

Weighing areas12.23 Te weighing o starting materials and the estimation o yield by weighing

should be carried out in separate weighing areas designed or that use, orexample, with provisions or dust control. Such areas may be part o eitherstorage or production areas.



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Production areas

12.24 In order to minimize the risk o a serious medical hazard due to cross-contamination, dedicated and sel-contained acilities must be availableor the production o particular pharmaceutical products, such as highlysensitizing materials (e.g. penicillins) or biological preparations (e.g.live microorganisms). Te production o certain other highly activeproducts, such as some antibiotics, hormones, cytotoxic substances andcertain non-pharmaceutical products, should not be conducted in thesame acilities. In exceptional cases, the principle o campaign workingin the same acilities can be accepted provided that specific precautions

are taken and the necessary validations (including cleaning validation)are made. Te manuacture o technical poisons, such as pesticides andherbicides, should not be allowed in premises used or the manuacture opharmaceutical products.

12.25 Premises should preerably be laid out in such a way as to allowthe production to take place in areas connected in a logical ordercorresponding to the sequence o the operations and to the requisitecleanliness levels.

12.26 Te adequacy o the working and in-process storage space should permitthe orderly and logical positioning o equipment and materials so as tominimize the risk o conusion between different pharmaceutical productsor their components, to avoid cross-contamination, and to minimize therisk o omission or wrong application o any o the manuacturing orcontrol steps.

12.27 Where starting and primary packaging materials and intermediate or bulkproducts are exposed to the environment, interior suraces (walls, floors

and ceilings) should be smooth and ree rom cracks and open joints,should not shed particulate matter, and should permit easy and effectivecleaning and, i necessary, disinection.

12.28 Pipework, light fittings, ventilation points and other services shouldbe designed and sited to avoid the creation o recesses that are difficultto clean. As ar as possible, or maintenance purposes, they should beaccessible rom outside the manuacturing areas.

12.29 Drains should be o adequate size and designed and equipped to preventback-flow. Open channels should be avoided where possible, but i they arenecessary they should be shallow to acilitate cleaning and disinection.

12.30 Production areas should be effectively ventilated, with air-control acilities(including filtration o air to a sufficient level to prevent contamination



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and cross-contamination, as well as control o temperature and, wherenecessary, humidity) appropriate to the products handled, to the operations

undertaken and to the external environment. Tese areas should beregularly monitored during both production and non-production periodsto ensure compliance with their design specifications.

12.31 Premises or the packaging o pharmaceutical products should bespecifically designed and laid out so as to avoid mix ups, contaminationor cross-contamination.

12.32 Production areas should be well lit, particularly where visual online

controls are carried out.

Quality control areas12.33 QC laboratories should be separated rom production areas. Areas where

biological, microbiological or radioisotope test methods are employedshould be separated rom each other.

12.34 QC laboratories should be designed to suit the operations to be carriedout in them. Sufficient space should be given to avoid mix ups and cross-

contamination. Tere should be adequate suitable storage space orsamples, reerence standards (i necessary, with cooling), solvents, reagentsand records.

12.35 Te design o the laboratories should take into account the suitabilityo construction materials, prevention o umes, and ventilation. Tereshould be separate air supply to laboratories and production areas.Separate air-handling units and other provisions are needed or biological,microbiological and radioisotope laboratories.

12.36 A separate room may be needed or instruments to protect them againstelectrical intererence, vibration, contact with excessive moisture andother external actors, or where it is necessary to isolate the instruments.

13. Equipment

13.1 Equipment must be located, designed, constructed, adapted and maintainedto suit the operations to be carried out. Te layout and design o equipment

must aim to minimize the risk o errors and permit effective cleaning andmaintenance in order to avoid cross-contamination, build-up o dust ordirt, and, in general, any adverse effect on the quality o products.

13.2 Equipment should be installed in such a way as to minimize any risk oerror or o contamination.



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13.3 Fixed pipework should be clearly labelled to indicate the contents and,

where applicable, the direction o flow.

13.4 All service pipework and devices should be adequately marked and special

attention paid to the provision o non-interchangeable connections or

adaptors or dangerous gases and liquids.

13.5 Balances and other measuring equipment o an appropriate range and

precision should be available or production and control operations and

should be calibrated according to a fixed schedule.

13.6 Production equipment should be thoroughly cleaned according to afixed schedule.

13.7 Laboratory equipment and instruments should be suited to the testing

procedures undertaken.

13.8 Washing, cleaning and drying equipment should be chosen and used so

as not to be a source o contamination.

13.9 Production equipment should not present any hazard to the products.

Te parts o the production equipment that come into contact with theproduct must not be reactive, additive, or absorptive to an extent that

would affect the quality o the product.

13.10 Deective equipment should be removed rom production and QC areas. I

this is not possible, it should be clearly labelled as deective to prevent use.

13.11 Closed equipment should be used whenever appropriate. Where open

equipment is used or equipment is opened, precautions should be taken

to minimize contamination.

13.12 Non-dedicated equipment should be cleaned according to validated

cleaning procedures between being used or production o different

pharmaceutical products to prevent cross-contamination.

13.13 Current drawings o critical equipment and support systems should

be maintained.

14. Materials

14.1 Principle. Te main objective o a pharmaceutical plant is to produce

finished products or patients’ use rom a combination o materials

(starting and packaging).



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14.2 Materials include starting materials, packaging materials, gases, solvents,process aids, reagents and labelling materials.

General14.3 No materials used or operations such as cleaning, lubrication o

equipment and pest control should come into direct contact with theproduct. Where possible, such materials should be o a suitable grade(e.g. ood grade) to minimize health risks.

14.4 All incoming materials and finished products should be quarantined

immediately afer receipt or processing, until they are released or useor distribution.

14.5 All materials and products should be stored under the appropriateconditions established by the manuacturer, and in an orderly ashion, topermit batch segregation and stock rotation by a first-expire, first-out rule.

14.6 Water used in the manuacture o pharmaceutical products should besuitable or its intended use.

Starting materials14.7 Te purchase o starting materials is an important operation that should

involve staff who have a particular and thorough knowledge o the productsand suppliers.

14.8 Starting materials should be purchased only rom approved suppliers and,where possible, directly rom the producer. It is also recommended that thespecifications established by the manuacturer or the starting materialsbe discussed with the suppliers. It is beneficial or all critical aspects othe production and control o the starting material in question, includinghandling, labelling and packaging requirements as well as complaints andrejection procedures, to be contractually agreed between the manuacturerand the supplier.

14.9 For each consignment, at a minimum, the containers should be checked atleast or integrity o package and seal and or correspondence between theorder, the delivery note, and the supplier’s labels.

14.10 All incoming materials should be checked to ensure that the consignmentcorresponds to the order. Containers should be cleaned where necessaryand labelled, i required, with the prescribed inormation. Where additionallabels are attached to containers, the original inormation should notbe lost.



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14.11 Damage to containers and any other problem that might adversely affect

the quality o a material should be recorded and reported to the QC

department and investigated.

14.12 I one delivery o material is made up o different batches, each batch must

be considered as separate or sampling, testing and release.

14.13 Starting materials in the storage area should be appropriately labelled.

Labels should bear at least the ollowing inormation:

(a) the designated name o the product and the internal code reerence

where applicable;(b) the batch number given by the supplier and, on receipt, the control

or batch number given by the manuacturer, i any, documented so

as to ensure traceability;

(c) the status o the contents (e.g. in quarantine, on test, released, rejected,

returned, recalled);

(d) where appropriate, an expiry date or a date beyond which retesting

is necessary. When ully validated computerized storage systems are

used, not all o the above inormation need be in a legible orm onthe label.

14.14 Tere should be appropriate procedures or measures to ensure the identity

o the contents o each container o starting material. Bulk containers

rom which samples have been drawn should be identified.

14.15 Only starting materials released by the QC department and within their

shel-lie should be used.

14.16 Starting materials should be dispensed only by designated persons,

ollowing a written procedure, to ensure that the correct materials are

accurately weighed or measured into clean and properly labelled containers.

14.17 Each dispensed material and its weight or volume should be independently

checked and the check recorded.

14.18 Materials dispensed or each batch o the final product should be kept

together and conspicuously labelled as such.

Packaging materials14.19 Te purchase, handling and control o primary and printed packaging

materials should be as or starting materials.



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14.20 Particular attention should be paid to printed packaging materials. Teyshould be stored in secure conditions so as to exclude the possibility o

unauthorized access. Roll eed labels should be used wherever possible. Cutlabels and other loose printed materials should be stored and transportedin separate closed containers so as to avoid mix ups. Packaging materialsshould be issued or use only by designated personnel ollowing anapproved and documented procedure.

14.21 Each delivery or batch o printed or primary packaging material should begiven a specific reerence number or identification mark.

14.22 Outdated or obsolete primary packaging material or printed packagingmaterial should be destroyed and its disposal recorded.

14.23 All products and packaging materials to be used should be checked ondelivery to the packaging department or quantity, identity and conormitywith the packaging instructions.

Intermediate and bulk products14.24 Intermediate and bulk products should be kept under appropriate conditions.

14.25 Intermediate and bulk products purchased as such should be handled onreceipt as though they were starting materials.

Finished products14.26 Finished products should be held in quarantine until their final release,

afer which they should be stored as usable stock under conditionsestablished by the manuacturer.

14.27 Te evaluation o finished products and the documentation necessary orrelease o a product or sale are described in section 17, “Good practicesin quality control”.

Rejected, recovered, reprocessed and reworked materials14.28 Rejected materials and products should be clearly marked as such and

stored separately in restricted areas. Tey should either be returned tothe suppliers or, where appropriate, reprocessed or destroyed in a timelymanner. Whatever action is taken should be approved by authorizedpersonnel and recorded.

14.29 Te reworking or recovery o rejected products should be exceptional.It is permitted only i the quality o the final product is not affected, i



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the specifications are met, and i it is done in accordance with a definedand authorized procedure afer evaluation o the risks involved. A record

should be kept o the reworking or recovery. A reworked batch should begiven a new batch number.

14.30 Te introduction o all or part o earlier batches, conorming to therequired quality standards, into a batch o the same product at a definedstage o manuacture should be authorized beorehand. Tis recoveryshould be carried out in accordance with a defined procedure aferevaluation o the risks involved, including any possible effect on shel-lie.Te recovery should be recorded.

14.31 Te need or additional testing o any finished product that has beenreprocessed, reworked or into which a recovered product has beenincorporated, should be considered by the QC department.

Recalled products14.32 Recalled products should be identified and stored separately in a secure

area until a decision is taken on their ate. Tis decision should be made as

soon as possible.

Returned goods14.33 Products returned rom the market should be destroyed unless it is certain

that their quality is satisactory; in such cases they may be consideredor resale or relabelling, or alternative action taken only afer they havebeen critically assessed by the QC unction in accordance with a writtenprocedure. Te nature o the product, any special storage conditions it

requires, its condition and history, and the time elapsed since it was issuedshould all be taken into account in this assessment. Where any doubt arisesover the quality o the product, it should not be considered suitable orreissue or reuse. Any action taken should be appropriately recorded.

Reagents and culture media14.34 Tere should be records or the receipt and preparation o reagents and

culture media.

14.35 Reagents made up in the laboratory should be prepared according towritten procedures and appropriately labelled. Te label should indicatethe concentration, standardization actor, shel-lie, the date when re-standardization is due, and the storage conditions. Te label should besigned and dated by the person preparing the reagent.



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14.36 Both positive and negative controls should be applied to veriy the

suitability o culture media each time they are prepared and used. Te size

o the inoculum used in positive controls should be appropriate to thesensitivity required.

Reference standards14.37 Whenever official reerence standards exist, these should preerably

be used.

14.38 Official reerence standards should be used only or the purpose described

in the appropriate monograph.

14.39 Reerence standards prepared by the producer should be tested, released

and stored in the same way as official standards. Tey should be kept under

the responsibility o a designated person in a secure area.

14.40 Secondary or working standards may be established by the application o

appropriate tests and checks at regular intervals to ensure standardization.

14.41 Reerence standards should be properly labelled with at least the ollowing

inormation:

(a) name o the material;

(b) batch or lot number and control number;

(c) date o preparation;

(d) shel-lie;

(e) potency;

() storage conditions.

14.42 All in-house reerence standards should be standardized against an

official reerence standard, when available, initially and at regular intervals

thereafer.

14.43 All reerence standards should be stored and used in a manner that will

not adversely affect their quality.

Waste materials14.44 Provision should be made or the proper and sae storage o waste

materials awaiting disposal. oxic substances and flammable materials

should be stored in suitably designed, separate, enclosed cupboards, as

required by national legislation.



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14.45 Waste material should not be allowed to accumulate. It should be collectedin suitable receptacles or removal to collection points outside the

buildings and disposed o saely and in a sanitary manner at regular andrequent intervals.

Miscellaneous14.46 Rodenticides, insecticides, umigating agents and sanitizing materials

should not be permitted to contaminate equipment, starting materials,packaging materials, in-process materials or finished products.

15. Documentation

15.1 Principle. Good documentation is an essential part o the quality assurancesystem and, as such, should exist or all aspects o GMP. Its aims are todefine the specifications and procedures or all materials and methodso manuacture and control; to ensure that all personnel concernedwith manuacture know what to do and when to do it; to ensure thatauthorized persons have all the inormation necessary to decide whether

or not to release a batch o a medicine or sale; to ensure the existence odocumented evidence, traceability, and to provide records and an audittrail that will permit investigation. It ensures the availability o the dataneeded or validation, review and statistical analysis. Te design and useo documents depend upon the manuacturer. In some cases some or allo the documents described below may be brought together, but they willusually be separate.

General15.2 Documents should be designed, prepared, reviewed and distributed with

care. Tey should comply with the relevant parts o the manuacturingand marketing authorizations.

15.3 Documents should be approved, signed and dated by the appropriateresponsible persons. No document should be changed without authorizationand approval.

15.4 Documents should have unambiguous contents: the title, nature and

purpose should be clearly stated. Tey should be laid out in an orderlyashion and be easy to check. Reproduced documents should be clearand legible. Te reproduction o working documents rom masterdocuments must not allow any error to be introduced through thereproduction process.



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15.5 Documents should be regularly reviewed and kept up to date. When a

document has been revised, a system should exist to prevent inadvertent

use o the superseded version. Superseded documents should be retainedor a specific period o time.

15.6 Where documents require the entry o data, these entries should be clear,

legible and indelible. Sufficient space should be provided or such entries.

15.7 Any alteration made to a document should be signed and dated; the

alteration should be done in such a way as to permit the reading o the

original inormation. Where appropriate, the reason or the alteration

should be recorded.

15.8 Records should be made or completed when any action is taken and in

such a way that all significant activities concerning the manuacture o

pharmaceutical products are traceable. Records should be retained or at

least one year afer the expiry date o the finished product.

15.9 Data (and records or storage) may be recorded by electronic data-

processing systems or by photographic or other reliable means. Master

ormulae and detailed SOPs relating to the system in use should be availableand the accuracy o the records should be checked. I documentation is

handled by electronic data-processing methods, only authorized persons

should be able to enter or modiy data in the computer system, and there

should be a record o changes and deletions; access should be restricted

by passwords or other means and the entry o critical data should be

independently checked. Batch records stored electronically should be

protected by back-up transer on magnetic tape, microfilm, electronic

discs, paper printouts or other means. It is particularly important that,during the period o retention, the data are readily available.

Documents requiredLabels

15.10 Labels applied to containers, equipment or premises should be clear,

unambiguous and in the company’s agreed ormat. It is ofen helpul in

addition to the wording on the labels to use colours to indicate status (e.g.

quarantined, accepted, rejected, clean).

15.11 All finished medicines should be identified by labelling, as required by the

national legislation, bearing at least the ollowing inormation:

(a) the name o the medicines;



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(b) a list o the active ingredients (i applicable, with the INN), showingthe amount o each present and a statement o the net contents (e.g.

number o dosage units, weight, volume);(c) the batch number assigned by the manuacturer;

(d) the expiry date in an uncoded orm;

(e) any special storage conditions or handling precautions that maybe necessary;

() directions or use, and warnings and precautions that maybe necessary;

(g) the name and address o the manuacturer or the company or the

person responsible or placing the product on the market.

15.12 For reerence standards, the label and/or accompanying document shouldindicate potency or concentration, date o manuacture, expiry date,date the closure is first opened, storage conditions and control number,as appropriate.

Specifications and testing procedures

15.13 esting procedures described in documents should be validated in the

context o available acilities and equipment beore they are adopted orroutine testing.

15.14 Tere should be appropriately authorized and dated specifications,including tests on identity, content, purity and quality, or starting andpackaging materials and or finished products; where appropriate, theyshould also be available or intermediate or bulk products. Specificationsor water, solvents and reagents (e.g. acids and bases) used in productionshould be included.

15.15 Each specification should be approved, signed and dated, and maintainedby the QC or QA units. Specifications or starting materials, intermediates,bulk, finished products and packaging materials are reerred to in sections15.18–15.21.

15.16 Periodic revisions o the specifications may be necessary to comply withnew editions o the national pharmacopoeia or other official compendia.

15.17 Pharmacopoeias, reerence standards, reerence spectra and other

reerence materials should be available in the QC laboratory.

Specifications for starting and packaging materials

15.18 Specifications or starting, primary and printed packaging materials shouldprovide, i applicable, a description o the materials, including:



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(a) the designated name (i applicable, the INN) and internal codereerence;

(b) the reerence, i any, to a pharmacopoeial monograph;

(c) qualitative and quantitative requirements with acceptance limits.

Depending on the company’s practice other data may be added to thespecification, such as:

(a) the supplier and the original producer o the materials;

(b) a specimen o printed materials;

(c) directions or sampling and testing, or a reerence to procedures;

(d) storage conditions and precautions;

(e) the maximum period o storage beore reexamination.

Packaging material should conorm to specifications, and should becompatible with the material and/or with the medicines it contains. Te materialshould be examined or compliance with the specification, and or deects as wellas or the correctness o identity markings.

15.19 Documents describing testing procedures should state the required

requency or re-assaying each starting material, as determined by itsstability.

Specifications for intermediate and bulk products

15.20 Specifications or intermediate and bulk products should be available.Te specifications should be similar to specifications or starting materialsor or finished products, as appropriate.

Specifications for finished products15.21 Specifications or finished products should include:

(a) the designated name o the product and the code reerence,where applicable;

(b) the designated name(s) o the active ingredient(s) (i applicable,with the INN(s));

(c) the ormula or a reerence to the ormula;

(d) a description o the dosage orm and package details;

(e) directions or sampling and testing or a reerence to procedures;

() the qualitative and quantitative requirements, with acceptance limits;

(g) the storage conditions and precautions, where applicable;

(h) the shel-lie.



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Master formulae

15.22 A ormally authorized master ormula should exist or each product andbatch size to be manuactured.

15.23 Te master ormula should include:

(a) the name o the product, with a product reerence code relating toits specification;

(b) a description o the dosage orm, strength o the product andbatch size;

(c) a list o all starting materials to be used (i applicable with the INNs),with the amount o each, described using the designated name and areerence that is unique to that material (mention should be made oany substance that may disappear in the course o processing);

(d) a statement o the expected final yield with the acceptable limits,and o relevant intermediate yields, where applicable;

(e) a statement o the processing location and the principal equipmentto be used;

() the methods, or reerence to the methods, to be used or preparingand operating the critical equipment, e.g. cleaning (especially afer achange in product), assembling, calibrating, sterilizing, use;

(g) detailed step-wise processing instructions (e.g. checks on materials,pretreatments, sequence or adding materials, mixing times,temperatures);

(h) the instructions or any in-process controls with their limits;

(i) where necessary, the requirements or storage o the products,

including the container, the labelling, and any special storageconditions;

(j) any special precautions to be observed.

Packaging instructions

15.24 Formally authorized packaging instructions should exist or each product,pack size and type. Tese should normally include, or make reerence to:

(a) the name o the product;(b) a description o its pharmaceutical orm, strength and, where

applicable, method o application;

(c) the pack size expressed in terms o the number, weight or volume othe product in the final container;



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(d) a complete list o all the packaging materials required or a

standard batch size, including quantities, sizes and types, with the

code or reerence number relating to the specifications or eachpackaging material;

(e) where appropriate, an example or reproduction o the relevant

printed packaging materials and specimens, indicating where the

batch number and expiry date o the product have been marked;

() special precautions to be observed, including a careul examination

o the packaging area and equipment in order to ascertain the line

clearance beore and afer packaging operations;

(g) a description o the packaging operation, including any significant

subsidiary operations, and equipment to be used;

(h) details o in-process controls with instructions or sampling and

acceptance limits.

Batch processing records

15.25 A batch processing record should be kept or each batch processed. It should

be based on the relevant parts o the currently approved specifications onthe record. Te method o preparation o such records should be designed to

avoid errors. (Copying or validated computer programs are recommended.

ranscribing rom approved documents should be avoided.)

15.26 Beore any processing begins a check should be made that the equipment

and work station are clear o previous products, documents, or materials

not required or the planned process, and that the equipment is clean and

suitable or use. Tis check should be recorded.

15.27 During processing, the ollowing inormation should be recorded at the

time each action is taken, and afer completion the record should be dated

and signed by the person responsible or the processing operations:

(a) the name o the product;

(b) the number o the batch being manuactured;

(c) dates and times o commencement, o significant intermediate

stages, and o completion o production;

(d) the name o the person responsible or each stage o production;

(e) the initials o the operator(s) o different significant steps o

production and, where appropriate, o the person(s) who checked

each o these operations (e.g. weighing);



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() the batch number and/or analytical control number and the quantity

o each starting material actually weighed (including the batch

number and amount o any recovered or reprocessed material added);

(g) any relevant processing operation or event and the major

equipment used;

(h) the in-process controls perormed, the initials o the person(s)

carrying them out, and the results obtained;

(i) the amount o product obtained at different and pertinent stages o

manuacture (yield), together with comments or explanations or

significant deviations rom the expected yield;(j) notes on special problems including details, with signed authorization

or any deviation rom the master ormula.

Batch packaging records

15.28 A batch packaging record should be kept or each batch or part batch

processed. It should be based on the relevant parts o the approved

packaging instructions, and the method o preparing such records should

be designed to avoid errors. (Copying or validated computer programs arerecommended. ranscribing rom approved documents should be avoided.)

15.29 Beore any packaging operation begins, checks should be made that the

equipment and work station are clear o previous products, documents

or materials not required or the planned packaging operations, and that

equipment is clean and suitable or use. Tese checks should be recorded.

15.30 Te ollowing inormation should be recorded at the time each action is

taken, and the date and the person responsible should be clearly identifiedby signature or electronic password:

(a) the name o the product, the batch number and the quantity o bulk

product to be packed, as well as the batch number and the planned

quantity o finished product that will be obtained, the quantity

actually obtained and the reconciliation;

(b) the date(s) and time(s) o the packaging operations;

(c) the name o the responsible person carrying out the packaging

operation;

(d) the initials o the operators o the different significant steps;

(e) the checks made or identity and conormity with the packaging

instructions, including the results o in-process controls;



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(d) the supplier’s name and, i possible, manuacturer’s name;

(e) the manuacturer’s batch or reerence number;

() the total quantity, and number o containers received;

(g) the batch number assigned afer receipt;

(h) any relevant comment (e.g. state o the containers).

15.34 Tere should be SOPs or the internal labelling, quarantine and storage ostarting materials, packaging materials and other materials, as appropriate.

15.35 SOPs should be available or each instrument and piece o equipment (e.g.

use, calibration, cleaning, maintenance) and placed in close proximity tothe equipment.

15.36 Tere should be SOPs or sampling, which speciy the person(s) authorizedto take samples.

15.37 Te sampling instructions should include:

(a) the method o sampling and the sampling plan;

(b) the equipment to be used;

(c) any precautions to be observed to avoid contamination o thematerial or any deterioration in its quality;

(d) the amount(s) o sample(s) to be taken;

(e) instructions or any required subdivision o the sample;

() the type o sample container(s) to be used, and whether they are oraseptic sampling or or normal sampling, and labelling;

(g) any specific precautions to be observed, especially in regard to the

sampling o sterile or noxious material.

15.38 Tere should be an SOP describing the details o the batch (lot) numberingsystem, with the objective o ensuring that each batch o intermediate,bulk or finished product is identified with a specific batch number.

15.39 Te SOPs or batch numbering that are applied to the processing stage andto the respective packaging stage should be related to each other.

15.40 Te SOP or batch numbering should ensure that the same batch numberswill not be used repeatedly; this applies also to reprocessing.

15.41 Batch-number allocation should be immediately recorded, e.g. in alogbook. Te record should include at least the date o allocation, productidentity and size o batch.



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16. Good practices in production

16.1 Principle. Production operations must ollow clearly defined proceduresin accordance with manuacturing and marketing authorizations, with theobjective o obtaining products o the requisite quality.

General16.2 All handling o materials and products, such as receipt and cleaning,

quarantine, sampling, storage, labelling, dispensing, processing, packagingand distribution should be done in accordance with written procedures or

instructions and, where necessary, recorded.

16.3 Deviation rom instructions or procedures should be avoided as aras possible. I deviations occur, they should be in accordance withan approved procedure. Te authorization o the deviation should beapproved in writing by a designated person, with the involvement o theQC department, when appropriate.

16.4 Checks on yields and reconciliation o quantities should be carried out asnecessary to ensure that there are no discrepancies outside acceptable limits.

16.5 Operations on different products should not be carried out simultaneouslyor consecutively in the same room or area unless there is no risk o mix upor cross-contamination.

16.6 At all times during processing, all materials, bulk containers, major itemso equipment, and, where appropriate, the rooms and packaging lines beingused, should be labelled or otherwise identified with an indication o theproduct or material being processed, its strength (where applicable) and the

batch number. Where applicable, this indication should also mention thestage o production. In some cases it may be useul to also record the nameo the previous product that has been processed.

16.7 Access to production premises should be restricted to authorized personnel.

16.8 Normally, non-medicinal products should not be produced in areas or withequipment destined or the production o pharmaceutical products.

16.9 In-process controls are usually perormed within the production area. Te

perormance o such in-process controls should not have any negative effecton the quality o the product or another product (e.g. cross-contaminationor mix up).



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Prevention of cross-contamination and bacterialcontamination during production16.10 When dry materials and products are used in production, special

precautions should be taken to prevent the generation and dissemination

o dust. Provision should be made or proper air control (e.g. supply and

extraction o air o suitable quality).

16.11 Contamination o a starting material or o a product by another material

or product must be avoided. Tis risk o accidental cross-contamination

arises rom the uncontrolled release o dust, gases, particles, vapours, sprays

or organisms rom materials and products in process, rom residues onequipment, rom intruding insects, and rom operators’ clothing, skin, etc.

Te significance o this risk varies with the type o contaminant and o the

product being contaminated. Among the most hazardous contaminants

are highly sensitizing materials, biological preparations such as living

organisms, certain hormones, cytotoxic substances, and other highly active

materials. Products in which contamination is likely to be most significant

are those administered by injection or applied to open wounds and those

given in large doses and/or over a long time.16.12 Cross-contamination should be avoided by taking appropriate technical

or organizational measures, or example:

(a) carrying out production in dedicated and sel-contained areas

(which may be required or products such as penicillins, live

vaccines, live bacterial preparations and certain other biologicals);

(b) conducting campaign production (separation in time) ollowed

by appropriate cleaning in accordance with a validatedcleaning procedure;

(c) providing appropriately designed airlocks, pressure differentials,

and air supply and extraction systems;

(d) minimizing the risk o contamination caused by recirculation or

reentry o untreated or insufficiently treated air;

(e) wearing protective clothing where products or materials are handled;

() using cleaning and decontamination procedures o known

effectiveness;

(g) using a “closed system” in production;

(h) testing or residues;

(i) using cleanliness status labels on equipment.



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16.13 Measures to prevent cross-contamination and their effectiveness should bechecked periodically according to SOPs.

16.14 Production areas where susceptible products are processed shouldundergo periodic environmental monitoring (e.g. or microbiological andparticulate matter, where appropriate).

Processing operations16.15 Beore any processing operation is started, steps should be taken to ensure

that the work area and equipment are clean and ree rom any startingmaterials, products, product residues, labels or documents not requiredor the current operation.

16.16 Any necessary in-process controls and environmental controls should becarried out and recorded.

16.17 Means should be instituted o indicating ailures o equipment or oservices (e.g. water, gas) to equipment. Deective equipment shouldbe withdrawn rom use until the deect has been rectified. Afer use,production equipment should be cleaned without delay according to

detailed written procedures and stored under clean and dry conditions ina separate area or in a manner that will prevent contamination.

16.18 ime limits or storage o equipment afer cleaning and beore use shouldbe stated and based on relevant data.

16.19 Containers or filling should be cleaned beore filling. Attention should begiven to avoiding and removing any contaminants such as glass ragmentsand metal particles.

16.20 Any significant deviation rom the expected yield should be recordedand investigated.

16.21 Checks should be carried out to ensure that pipelines and other pieceso equipment used or the transportation o products rom one area toanother are connected in the correct manner.

16.22 Pipes used or conveying distilled or deionized water and, whereappropriate, other water pipes should be sanitized and stored according

to written procedures that detail the action limits or microbiologicalcontamination and the measures to be taken.

16.23 Measuring, weighing, recording, and control equipment and instrumentsshould be serviced and calibrated at prespecified intervals and recordsmaintained. o ensure satisactory unctioning, instruments should be



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checked daily or prior to use or perorming analytical tests. Te date ocalibration and servicing and the date when recalibration is due should

be clearly indicated on a label attached to the instrument.

16.24 Repair and maintenance operations should not present any hazard to thequality o the products.

Packaging operations16.25 When the programme or packaging operations is being set up, particular

attention should be given to minimizing the risk o cross-contamination,mix ups or substitutions. Different products should not be packagedin close proximity unless there is physical segregation or an alternativesystem that will provide equal assurance.

16.26 Beore packaging operations are begun, steps should be taken to ensurethat the work area, packaging lines, printing machines and otherequipment are clean and ree rom any products, materials or documentsused previously and which are not required or the current operation. Teline clearance should be perormed according to an appropriate procedureand checklist, and recorded.

16.27 Te name and batch number o the product being handled should bedisplayed at each packaging station or line.

16.28 Normally, filling and sealing should be ollowed as quickly as possible bylabelling. I labelling is delayed, appropriate procedures should be appliedto ensure that no mix ups or mislabelling can occur.

16.29 Te correct perormance o any printing (e.g. o code numbers or expiry

dates) done separately or in the course o the packaging should bechecked and recorded. Attention should be paid to printing by hand,which should be rechecked at regular intervals.

16.30 Special care should be taken when cut labels are used and whenoverprinting is carried out off-line, and in hand-packaging operations.Roll-eed labels are normally preerable to cut labels in helping to avoidmix ups. Online verification o all labels by automated electronic meanscan be helpul in preventing mix ups, but checks should be made to

ensure that any electronic code readers, label counters, or similar devicesare operating correctly. When labels are attached manually, in-processcontrol checks should be perormed more requently.

16.31 Printed and embossed inormation on packaging materials should bedistinct and resistant to ading or erasing.



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16.32 Regular online control o the product during packaging should include ata minimum checks on:

(a) the general appearance o the packages;

(b) whether the packages are complete;

(c) whether the correct products and packaging materials are used;

(d) whether any overprinting is correct;

(e) the correct unctioning o line monitors.

Samples taken away rom the packaging line should not be returned.

16.33 Products that have been involved in an unusual event during packagingshould be reintroduced into the process only afer special inspection,investigation and approval by authorized personnel. A detailed recordshould be kept o this operation.

16.34 Any significant or unusual discrepancy observed during reconciliationo the amount o bulk product and printed packaging materials and thenumber o units produced should be investigated, satisactorily accounted

or, and recorded beore release.16.35 Upon completion o a packaging operation, any unused batch-coded

packaging materials should be destroyed and the destruction recorded. Adocumented procedure requiring checks to be perormed beore returningunused materials should be ollowed i uncoded printed materials arereturned to stock.

16.36 Production records should be reviewed as part o the approval process obatch release beore transer to the authorized person. Any divergence orailure o a batch to meet production specifications should be thoroughlyinvestigated. Te investigation should, i necessary, extend to otherbatches o the same product and other products that may have beenassociated with the specific ailure or discrepancy. A written record othe investigation should be made and should include the conclusion andollow-up action.

17. Good practices in quality control

17.1 QC is the part o GMP concerned with sampling, specifications andtesting, and with the organization and documentation which ensure thatthe necessary and relevant tests are actually carried out and that materialsare not released or use, nor products released or sale or supply, until their



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quality has been judged to be compliant with the requirements. QC is not

confined to laboratory operations, but may be involved in many decisions

concerning the quality o the product.

17.2 Te independence o QC rom production is considered undamental.

17.3 Each manuacturer should have a QC unction. Te QC unction should

be independent o other departments and under the authority o a person

with appropriate qualifications and experience. Adequate resources must

be available to ensure that all the QC arrangements are effectively and

reliably carried out. Te basic requirements or QC are as ollows:

(a) adequate acilities, trained personnel and approved procedures must

be available or sampling, inspecting, and testing starting materials,

packaging materials, and intermediate, bulk, and finished products,

and where appropriate or monitoring environmental conditions or

GMP purposes;

(b) samples o starting materials, packaging materials, intermediate

products, bulk products and finished products must be taken by

methods and personnel approved by the QC department;(c) qualification and validation;

(d) records must be made (manually and/or by recording instruments)

demonstrating that all the required sampling, inspecting and testing

procedures have actually been carried out and that any deviations

have been ully recorded and investigated;

(e) the finished products must contain ingredients complying with the

qualitative and quantitative composition o the product described in

the marketing authorization; the ingredients must be o the requiredpurity, in their proper container and correctly labelled;

() records must be made o the results o inspecting and testing the

materials and intermediate, bulk and finished products against

specifications; product assessment must include a review and

evaluation o the relevant production documentation and an

assessment o deviations rom specified procedures;

(g) sufficient samples o starting materials and products must be

retained to permit uture examination o the product i necessary;the retained product must be kept or the appropriate time in its

final pack unless the pack is exceptionally large, in which case one

that is equivalent to the marketed packaging system may be used.



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17.4 Other QC responsibilities include:

(a) establishing, validating and implementing all QC procedures;(b) evaluating, maintaining and storing reerence standards

or substances;

(c) ensuring the correct labelling o containers o materials

and products;

(d) ensuring that the stability o the active pharmaceutical ingredients

and products is monitored;

(e) participating in the investigation o complaints related to the quality

o the product;

() participating in environmental monitoring;

(g) participation in QRM programmes.

Tese activities should be carried out in accordance with written

procedures and, where necessary, recorded.

17.5 QC personnel must have access to production areas or sampling and

investigation as appropriate.

Control of starting materials and intermediate,bulk and finished products

17.6 All tests should ollow the instructions given in the relevant written test

procedure or each material or product. Te result should be checked by

the supervisor beore the material or product is released or rejected.

17.7 Samples should be representative o the batches o material rom whichthey are taken in accordance with the approved written procedure.

17.8 Sampling should be carried out so as to avoid contamination or other

adverse effects on quality. Te containers that have been sampled should

be marked accordingly and careully resealed afer sampling.

17.9 Care should be taken during sampling to guard against contamination or

mix up o, or by, the material being sampled. All sampling equipment that

comes into contact with the material should be clean. Some particularlyhazardous or potent materials may require special precautions.

17.10 Sampling equipment should be cleaned and, i necessary, sterilized beore

and afer each use and stored separately rom other laboratory equipment.



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17.11 Each sample container should bear a label indicating:

(a) the name o the sampled material;(b) the batch or lot number;

(c) the number o the container rom which the sample has been taken;

(d) the number o the sample;

(e) the signature o the person who has taken the sample;

() the date o sampling.

17.12 Out-o-specification results obtained during testing o materials or

products should be investigated in accordance with an approved procedure.Records should be maintained.

Test requirementsStarting and packaging materials

17.13 Beore releasing a starting or packaging material or use, the QC manager

should ensure that the materials have been tested or conormity with

specifications or identity, strength, purity and other quality parameters.

17.14 An identity test should be conducted on a sample rom each container

o starting material (see also section 14.14). It is permissible to sample

only a proportion o the containers where a validated procedure has been

established to ensure that no single container o starting material has been

incorrectly labelled. Tis validation should take account o at least the

ollowing aspects:

– the nature and status o the manuacturer and o the supplier and

their understanding o the GMP requirements;

– the QA system o the manuacturer o the starting material;

– the manuacturing conditions under which the starting material is

produced and controlled;

– the nature o the starting material and the medicinal products in

which it will be used.

Under such a system it is possible that a validated procedure or exemption

rom the requirement or identity testing o each incoming container o starting

material could be accepted or the ollowing:

– starting materials coming rom a single product manuacturer or

plant; or



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– starting materials coming directly rom a manuacturer, or in themanuacturer’s sealed container where there is a history o reliability,

and regular audits o the manuacturer’s QA system are conductedby the purchaser (the manuacturer o the medicinal product) or byan officially accredited body.

It is improbable that such a procedure could be satisactorily validatedor either:

– starting materials supplied by intermediaries, such as brokers, wherethe source o manuacture is unknown or not audited; or

– starting materials or use in parenteral products.

17.15 Each batch (lot) o printed packaging materials must be examinedollowing receipt.

17.16 In lieu o ull testing by the manuacturer, a certificate o analysis may beaccepted rom the supplier, provided that the manuacturer establishes thereliability o the supplier’s analysis through appropriate periodic validationo the supplier’s test results (see sections 8.8 and 8.9) and through on-siteaudits o the supplier’s capabilities. (Tis does not affect section 17.15.)

Certificates must be originals (not photocopies) or otherwise have theirauthenticity assured. Certificates must contain at least the ollowinginormation (7 ):

(a) identification (name and address) o the issuing supplier;

(b) signature o the competent official, and statement o his orher qualifications;

(c) the name o the material tested;

(d) the batch number o the material tested;(e) the specifications and methods used;

() the test results obtained;

(g) the date o testing.

In-process control

17.17 In-process control records should be maintained and orm a part o thebatch records (see section 15.25).

Finished products

17.18 For each batch o medicines, there should be an appropriate laboratorydetermination o satisactory conormity to its finished productspecification prior to release.



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17.19 Products ailing to meet the established specifications or any other relevantquality criteria should be rejected.

Batch record review17.20 QC records should be reviewed as part o the approval process o batch

release beore transer to the authorized person. Any divergence or ailureo a batch to meet its specifications should be thoroughly investigated.Te investigation should, i necessary, extend to other batches o thesame product and other products that may have been associated with thespecific ailure or discrepancy. A written record o the investigation should

be made and should include the conclusion and ollow-up action.

17.21 Retention samples rom each batch o finished product should be kept orat least one year afer the expiry date. Finished products should usuallybe kept in their final packaging and stored under the recommendedconditions. I exceptionally large packages are produced, smaller samplesmight be stored in appropriate containers. Samples o active startingmaterials should be retained or at least one year beyond the expiry dateo the corresponding finished product. Other starting materials (other

than solvents, gases and water) should be retained or a minimum o twoyears i their stability allows. Retention samples o materials and productsshould be o a size sufficient to permit at least two ull reexaminations.

Stability studies17.22 QC should evaluate the quality and stability o finished pharmaceutical

products and, when necessary, o starting materials and intermediateproducts.

17.23 QC should establish expiry dates and shel-lie specifications on the basiso stability tests related to storage conditions.

17.24 A written programme or ongoing stability determination should bedeveloped and implemented to include elements such as:

(a) a complete description o the medicine involved in the study;

(b) the complete set o testing parameters and methods, describingall tests or potency, purity, and physical characteristics anddocumented evidence that these tests indicate stability;

(c) provision or the inclusion o a sufficient number o batches;

(d) the testing schedule or each medicine;

(e) provision or special storage conditions;



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() provision or adequate sample retention;

(g) a summary o all the data generated, including the evaluation andthe conclusions o the study.

17.25 Stability should be determined prior to marketing and ollowing anysignificant changes, or example, in processes, equipment or packagingmaterials.

References

1. Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on

Specifications for Pharmaceutical Preparations. Thirty-seventh report . Geneva, World Health

Organization, 2003 (WHO Technical Report Series, No. 908), Annex 4.

2. Validation of analytical procedures used in the examination of pharmaceutical materials. In: WHO

Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report . Geneva,

World Health Organization, 1992 (WHO Technical Report Series, No. 823), Annex 5.

3. EudraLex – Volume 4. Good manufacturing practice (GMP) Guidelines. European Commission.

(http://ec.europa.eu/health/documents/eudralex/vol-4/ index_en.htm).

4. Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme (PIC/S).

In: Guide to good manufacturing practice for medicinal plants. Geneva, PIC/S Secretariat, 2000.

5. Quality assurance of pharmaceuticals. WHO guidelines, related guidance and GXP training modules.Geneva, World Health Organization, 2013 (CD-ROM).

6. Good manufacturing practices for pharmaceutical products, Part one. In: WHO Expert Committee

on Specifications for Pharmaceutical Preparations. Thirty-second report . Geneva, World Health

Organization, 1992 (WHO Technical Report Series, No. 823), Annex 1; and in: Quality assurance of

pharmaceuticals. A compendium of guidelines and related materials. Vol. 2, 2nd updated edition.

Good manufacturing practices and Inspection. Geneva, World Health Organization, 2007; and in:

Quality assurance of pharmaceuticals. WHO guidelines, related guidance and GXP training modules.

Geneva, World Health Organization, 2013 (CD-ROM).

7. Model certificate of analysis. In: WHO Expert Committee on Specifications for Pharmaceutical

Preparations. Thirty-sixth report . Geneva, World Health Organization, 2002 (WHO Technical

Report Series, No. 902), Annex 10.

WHO good manufacturing practices for pharmaceutical products: main principles

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