ࡱ> 24+,-./01a RGbjbj2F\F\a ccmj !55555}E[[[[6zT!|||||||$)ߍ4|U c '66'' |cc[[ *___'.c[c[|_'|__Vf@g[8Vf ||5H}g y_Fg6gl("#&_$%("("("||_"("("("}''''("("("("("("("("("I ):  Annex 2 WHO good manufacturing practices for pharmaceutical products: main principles DU_2 WHOoTGMP;NSR Introduction_ General considerations;`R Glossary/g Quality management in the medicines industry: philosophy and essential elements 6RoONv(ϑ{tGMPt_TW,gCQ } 1. Pharmaceutical quality system 6Ro(ϑSO| Quality risk management (ϑΘi{t Product quality review NT(ϑV~ 2. Good manufacturing practices for pharmaceutical products oTGMP 3. Sanitation and hygiene nmTkSu 4. Qualification and validation nxT 5. Complaints bɋ 6. Product recalls NTSV 7. Contract production, analysis and other activities YXbuN0hTvQN;mR General i The contract giver YXbe The contract accepter YXbe The contract T T 8. Self-inspection, quality audits and supplier s audits and approval h0(ϑ[0O^FU[TybQ Items for self-inspection hyv Self-inspection team hV Frequency of self-inspection hs Self-inspection report hbJT Follow-up action T~ce Quality audit (ϑ[ Suppliers audits and approval O^FU[TybQ 9. Personnel NXT General i Key personnel sQ.NXT 10. Training W 11. Personal hygiene NXTkSu 12. Premises S?b General i Ancillary areas R:SW Storage areas NP:SW Weighing areas yϑ:SW Production areas uN:SW Quality control areas QC:SW 13. Equipment Y 14. Materials ire General i Starting materials wYire Packaging materials SňPge Intermediate and bulk products -NSOTbT Finished products 6RBR Rejected, recovered, reprocessed and reworked materials NTeL&{T,gV[:_6Rĉ[vl_Tlĉ0 batch (or lot) A defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it is expected to be homogeneous. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch. In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave. In continuous manufacture, the batch must correspond to a defined fraction of the production, characterized by its intended homogeneity. The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval. yb (WN*N]zb]z|R-N @buNvĉ[ϑv(Wyr[P^QwQ gGWN'`vSe0SňPgeboT0_e S\NybRbr^\yb gT\vQTbN*N(ϑGWSvyb0S_gTmp̃e 1uؚSmp̃vRegQ[ybϑ0(Wޏ~uNǏ z-N yb_{&{TuNvNR v^wQ gGWN'`vyrp0ybv'Y\S1uN*NV[vϑegnx[_NSN1uN*NV[eQ@buNvϑegnx[0 batch number (or lot number) A distinctive combination of numbers and/or letters which uniquely identifies a batch on the labels, its batch records and corresponding certificates of analysis, etc. ybS (uN(Wh~{0ybU_Tv^vRgbJTUShƋv/UNvpeW[T/bW[kv~T0 batch records All documents associated with the manufacture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product. ybU_ N_SňNTbbTuNvsQv@b geN0vQcOkNybNTNSNNT(ϑvsQv@b gsXvSS0 bulk product Any product that has completed all processing stages up to, but not including, final packaging. _SňNT \*g[bg~SňFO][b@b gvQN]zekvNT0 calibration The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established. !hQ (Wĉ[agN Nnx[gNKmϑ$\cy͑ 0U_0c6RNhVb|~v:yeL0PX[T.UNSvsQvc6R(WQv@b gd\O0 manufacturer A company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals. uNFU [boTuN0Sň0͑eSň04~{T͑e4~{I{d\OvlQS marketing authorization (product licence, registration certificate) A legal document issued by the competent medicines regulatory authority that establishes the detailed composition and formulation of the product and the pharmacopoeial or other recognized specifications of its ingredients and of the final product itself, and includes details of packaging, labelling and shelf-life. .USuNS0lQfN V[oTv{:ggS^vlĉeN ~NTv~bTMe bTST*N~RvoxQhQbvQNSvchNSSň04~{T'ggv`0 master formula A document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process controls. ;NMe uNN[ϑvgNoT@bSPgevpeϑTSňPgeNS]zTlaNyvNNeNbNWYeN ؏Sb]zcNT-Nc6R0 master record A document or set of documents that serve as a basis for the batch documentation (blank batch record). ;NU_ :NybuNU_cOOncvNNeNbNWYeNzz}vybU_ 0 packaging All operations, including filling and labelling, that a bulk product has to undergo in order to become a finished product. Filling of a sterile product under aseptic conditions or a product intended to be terminally sterilized, would not normally be regarded as part of packaging. Sň _SňNTb:NbT@bv@b gd\Oek SbRňT4~{0FOẽuN]z-NNTvẽLpň NSg~mp̃NTvLpňI{ NƉ:NSň0 packaging material Any material, including printed material, employed in the packaging of a pharmaceutical, but excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product. SňPge oTSň@b(uv@b gPge SbpS7Rire FO NSbЏb9Џ@b(uvYSňPge0SňPge9hnc/f&Tvcc执NTRR:NQSňPgeTYSňPge0 pharmaceutical product Any material or product intended for human or veterinary use presented in its finished dosage form or as a starting material for use in such a dosage form, that is subject to control by pharmaceutical legislation in the exporting state and/or the importing state. oT NUO(uNNbRirvirebNT N6RBRb__b\O:NwYire(uN6RBRv 1uQSVT/bۏSVoTv{:ggc6R0 production All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing, packaging and repackaging, labelling and relabelling, to completion of the finished product. uN mSoTuNv@b gd\O Nirevc6e0uN0SňT͑eSň04~{T͑e4~{_0RbT0 qualification Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word  validation is sometimes extended to incorporate the concept of qualification. nx f@b gS?b0|~TNhVyvck8^ЏLv^_g~gvce0vaIN geibU\S+Tnxvi_0 quality assurance See Part One (6). (ϑO S,{NR6 quality control See Part One (6). (ϑc6R S,{NR6 quality unit(s) An organizational unit independent of production which fulfils both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. (ϑ [b(ϑOT(ϑc6RL#vrzNuNvN*N~~:gg0S9hnc~~:ggv'Y\bzUSrvQATQC _NSNbzUSrvQATQC\~0 quarantine The status of starting or packaging materials, intermediates, or bulk or finished products isolated physically or by other effective means while a decision is awaited on their release, rejection or reprocessing. _h I{_TeLvsQvNUOvQNlĉuNTc6Rvk*NuNyb (WcCgNnxMR N_ۏLoT.UbO^0 j) processes are in place to assure the management of outsourced activities; j)^ gOYS;mR{tvĉ z k) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored, distributed, and subsequently handled so that quality is maintained throughout their shelf-life; k) ^ gS_ce=\SnxOoTvPX[0.USTvYt ONT(ϑ(Wte*N'ggQOc NS0 l) there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the PQS; l) ^ ghT/b(ϑ[ z^ [gċNPQSv gHe'`T(u'`0 m) product and processes are monitored and the results taken into account in batch release, in the investigation of deviations and, with a view to taking preventive action to avoid potential deviations occurring in the future; m) yb>eL0OP]gNS:NMQ\o(WOP]vSu ǑS2cee^\NTT]zvvKm~gQ(WQ0 n) arrangements are in place for the prospective evaluation and approval of planned changes and their approval prior to implementation taking into account regulatory notification and approval where required. After implementation of any change, an evaluation is undertaken to confirm that the quality objectives were achieved and that there was no unintended adverse impact on product quality; n) gRSfvċ0ONybQvQY[c Ygv݋ vQ[eMRvybQ^\v{蕄vwNybQQ(WQ0[eNNUOSfT^_U\ċ0ONnx(ϑvhv[s NSl g[NTNua` N0Rvbq_T o) regular reviews of the quality of pharmaceutical products are conducted with the objective of verifying the consistency of the process and identifying where there is a need for improvement; o):NNnx]zvN'`NSƋ+R9eۏv0We ^[g_U\NT(ϑV~ p) a state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality; p)Ǐ_S0O(u gHevvKmTc6R|~:N]zyr'`TNT(ϑ^zv^~cc6Rr`0 q) continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge; q)Ǐ[eNS_MR]z0NTwƋv^v(ϑ9eUOۏc~9eۏ r) there is a system for QRM; r) ^S_^z(ϑΘi{t|~0 s) deviations, suspected product defects and other problems are reported, investigated and recorded. An appropriate level of root cause analysis is applied during such investigations. The most likely root cause(s) should be identified and appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken. The effectiveness of CAPAs should be monitored. s)bJT0gTU_OP]0ueϑT6eVϑKNvs^a0 6.8 The effectiveness of the arrangements for recalls should be tested and evaluated from time to time. 6.8 ^S_ehKmTċ0ONTSVYtv gHe'`0 7. Contract production, analysis and other activities 7 YXbuN0hTvQN;mR 7.1 Principle. Contract production, analysis and other activity covered by GMP must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality. 7.1 SR.:NMQS bvNT0]\Obhv GMP@bmvvYXbuN0RgTvQN;mR_{Qnxv[IN v^~Se TaTqQ Tvc0 General i 7.2 All arrangements for contract production and analysis, including technology transfer and any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization for the product concerned. 7.2 YXbuNThv@b gOS Sbb/glyTb/gbvQNeb@bZPvSf GW^&{T gsQNT.USvBl0 7.3 The contract should permit the contract giver to audit the facilities and activities of the contract acceptor or mutually agreed subcontractors. 7.3 T T^QYXbe[YXbebSe TavRSFUvuNeT;mR0 7.4 In the case of contract analysis, the final approval for release must be given by the authorized person in accordance with GMP and the marketing authorization as specified in the contract. 7.4 YXbhe ^1uSCgN9hncT T-Nĉ[vGMPT N^SQ[NTvg~>eL0 The contract giver YXbe 7.5 The PQS of the contract giver should include the control and review of any outsourced activities. The contract giver is responsible for assessing the legality, suitability and competence of the contract acceptor in successfully carrying out the work or tests required, for approval for contract activities, and for ensuring by means of the contract that the principles of GMP incorporating QRM principle are followed. 7.5 YXbevPQS^Sb[NUOYS;mRvc6RTV~0YXbe^#ċ0OYXbevTl'`0T'`NS/f&TwQYYvR[bYXbeBlvuNR]Th v^ǏT TnxOvQ%NeL0 7.8 The contract giver should monitor and review the performance of the contract acceptor including the implementation of any needed improvements and their effectiveness. 7.8 YXbe^vcT[8hYXbevgbL`Q SbNUO[ev9eۏNSNNvgbLHeg0 7.9 The contract giver is responsible for ensuring that the contract acceptor understands that his or her activities may be subject to inspection by competent authorities. 7.9 YXbe g#NnxOYXbef}vNNv;mRSOS0R;N{蕄vhg0 The contract acceptor YXbe 7.10 The contract acceptor must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the contract giver. Contract manufacture may be undertaken only by a manufacturer who holds a valid manufacturing authorization. 7.10 YXbe_{wQYvYvS?b0Y0wƋTuN~NS gD(vNXT cgqYXbevBl_U\]\O0S gwQY gHeoTuNSvuNFUMbbbYXbuN0 7.11 The contract acceptor should not pass to a third party any of the work entrusted to him or her under the contract without the contract givers prior evaluation and approval of the arrangements. Arrangements made between the contract acceptor and any third party should ensure that information and knowledge, including that from assessments of the suitability of the third party, are made available in the same way as between the original contract giver and contract acceptor. 7.11 YXbe(W*g~YXbeۏLċ0OTybQKNMR N_\YXbNRvNUO]\Ol~T Tĉ[v,{ Ne0^S_ǏS_v[cnxOYXbeN,{ NeKN_Oo`TDeve_NSYYXbeNYXbeKNve_v T Sb,{ NeT'`vċ0OvOo`TDe0 7.12 The contract acceptor should refrain from any activity (including unauthorized changes outside the terms of the contract) that may adversely affect the quality of the product manufactured and/or analysed for the contract giver. 7.12 YXbe^MQ[YXbeuNT/bhvNT bb(ϑq_Tv@b g;mRSbT Tag>kKNYv*gcCgvSf 0 The contract T T 7.13 There must be a written contract between the contract giver and the contract acceptor which clearly establishes the responsibilities of 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. 7.13 YXbeTYXbe_{~{fNbT T fnx^zSev#N SbYS;mR NYS;mRvsQvNTbd\O NYS;mRvsQvlAm zTNUONYS;mRvsQvb/g[c0 7.14 The contract must clearly state the way in which the authorized person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the marketing authorization. 7.14 T T^fnxĉ[cCgN>eLkybNTb~{SRgbJTUSve_ ^S_hQCg# NnxOkybNTvuN0h&{ToT.USvBl0 7.15 Technical aspects of the contract should be drawn up by competent persons with suitable knowledgeable of pharmaceutical technology, analysis and GMP. 7.15 T T gsQb/gebvag>k^1uwQY6Rob/g0oThTGMPwƋvNXTegwI0 7.16 All arrangements for production and analysis must be in accordance with the marketing authorization and agreed by both parties. 7.16 YXbuNThv@b geb_{&{ToT.USvBl v^~Se Ta0 7.17 The contract should clearly describe who is responsible for contracted activities, e.g. knowledge management, technology transfer, supply chain, subcontracting, testing and releasing materials and undertaking production and QC, including in-process controls, and who has responsibility for sampling and analysis. In the case of contract analysis, the contract should state whether or not the contract acceptor should take samples at the premises of the manufacturer. 7.17 T T^S_fnxĉ[YS;mRv#NN kY De{t0b/gly0O^0RS0irehKmN>eL0ۏLuNTQCSb-Nc6R v#NNNSS7hTRgv#NN0(WYXbhv`Q N T T^S_f/f&TAQYXbe(WuNFUvS?bQS7h0 7.18 Manufacturing, analytical, distribution records and reference samples, should be kept by, or be available to, the contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect, or to investigating in the case of a suspected falsified product or laboratory fraud, must be accessible and specified in the procedures of the contract giver. 7.18 uN0h0.UU_ThQT^S_1uYXbeOX[bY[f_0R0S_G0Rbɋb`uNT g:we NSS_mZ*O NTT[[ GPۏLge _{Y_NT(ϑċ0OvsQv@b gU_ v^(WYXbe{tĉ z-N~ĉ[0 7.19 The contract should describe the handling of starting materials, intermediate, bulk and finished products, if they are rejected. It should also describe the procedure to be followed if the contract analysis shows that the tested product must be rejected. 7.19 T T^S_[ NTeLybQ0 9.12 Assessment of finished products should embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product, and an examination of the finished pack. 9.12 g~NTvċ0O^S+T@b gvsQV } SbuNagN0-Nc6RhKm~g0uNeNSbSň g~NTvch&{T'`NSSňbTvhg0 9.13 No batch of product is to be released for sale or supply prior to certification by the authorized person(s). In certain countries, by law, the batch release is a task of the authorized person from production together with the authorized person from QC. 9.13 *g~SCgN[ N_>eL.UbO^vNUONybNT0(WgNV[ l_ĉ[yb>eL1ueguN蕄vSCgNTQCSCgNqQ TybQ0 9.14 The authorized person responsible for approving a batch for release should always ensure that the following requirements have been met: 9.14 SCgN#ybQ>eLvyb!k^S_nxOnN NBl (a) the marketing authorization and the manufacturing authorization requirements for the product have been met for the batch concerned; (a) vsQvyb!kn^:WcCgTuNcCgvvsQBl0 (b) the principles and guidelines of GMP, as laid down in the guidelines published by WHO, have been followed; (b) cgqWHOQHrvGMPcWSĉ[ u_GMPvSRTcWS0 (c) the principal manufacturing and testing processes have been validated; (c) Ǒ(uvuNThKmel~Ǐ0 (d) all the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records; (d) QuNagNTuNU_ [b@b g_vhgTKmՋ0 (e) any planned changes or deviations in manufacturing or QC have been notified in accordance with a well defined reporting system before any product is released. Such changes may need notification to, and approval by, the medicines regulatory authority; (e) (WNaNT>eLKNMR cgqĉ[vbJT|~bJTuNb(ϑc6R-NSuvNUORSfTOP]0dk{|SfSwoTvcw:ggv^_vQ[yb0 (f) any additional sampling, inspection, tests and checks have been carried out or initiated, as appropriate, to cover planned changes and deviations; (f) S_ۏLYvS7h0hg0hKmT[8h N/ecRSfTOP]0 (g) all necessary production and QC documentation has been completed and endorsed by supervisors trained in appropriate disciplines; (g) [b@b g_vuNTQCeN v^_0RǏv^f[yWv;N{vybQ0 (h) appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff; (h) 1u g~vv^~ǏWvXT][bS_v[0hTs:Whg0 (i) approval has been given by the head of QC; (i) ]1uQC[ybQ (j) all relevant factors have been considered, including any not specifically associated with the output batch directly under review (e.g. subdivision of output batches from a common input, factors associated with continuous production runs). (j) Q@b gvsQV } SbNNQyb!kl gvcsQTvV }OYegck8^bevNQyb!kv~R0Nޏ~uN_svsQvV } 9.15 The function of the approval of the release of a finished batch or a product can be delegated to a designated person with appropriate qualifications and experience who will release the product in accordance with an approved procedure. This is normally done by QA by means of batch review. 9.15 bTybbbNT>eLybQvLSNYXb~wQ gS_D(T~vNN dkN9hnc]ybQvĉ z>eLNT0ُNN,1uQA8^yb[8hve_[b0 10. Training 10 W 10.1 The manufacturer should provide training in accordance with a written programme for all personnel whose duties take them into manufacturing areas or into control laboratories (including the technical, maintenance and cleaning personnel) and for other personnel as required. 10.1 uSFU^S_ cgqfNb z^:N@b gۏeQuN:SWbc6R[[vXT]Sbb/g0~bTnmNXT NSvQN_vNXTcOW0 10.2 Besides basic training on the theory and practice of GMP, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness periodically assessed. Approved training programmes should be available. Training records should be kept. 10.2 dGMPtwƋT[vW@xWY eXT]؏^cS gsQvQ]\OL#vW0؏^[XT]c~W v^[gċ0O[EWHeg0^ gybQvWR0^S_OX[WU_0 10.3 Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, infectious or sensitizing materials are handled, should be given specific training. 10.3 ^S_[]\O(WؚalgΘi:SWvXT]ۏLyrkW YmQ:Sbؚ;m'`:SW0k'`0 Og'`bOea'`ireYt:S0 10.4 The concept of QA and all the measures which aid its understanding and implementation should be fully discussed during the training sessions. 10.4 (WWg ^[(ϑOvi_NS@b g gRNXۏvQt㉌TgbLvceۏLEQRv0 10.5 Visitors or untrained personnel should preferably not be taken into the production and QC areas. If this is unavoidable, they should be given relevant information in advance (particularly about personal hygiene) and the prescribed protective clothing. They should be closely supervised. 10.5 N^\S‰NXTT*g~ǏWvNXT&^eQuN:SWTQC:SW0 NSMQ ^S_cMR\vsQOo`yr+R gsQ*NNkSueb Tz4b2b gvBlJTɋNN0v^^[vQۏL[Rvcw0 10.6 Consultant and contract staff should be qualified for the services they provide. Evidence of this should be included in the training records. 10.6 ~TT TXT]^S_wQY@bcO gRvv^D(0 gsQُebvnc^S+T(WWU_-N0 11. Personal hygiene 11 *NNkSu 11.1 All personnel, prior to and during employment, as appropriate, should undergo health examinations. Personnel conducting visual inspections should also undergo periodic eye examinations. 11.1 @b gNXT(WǖcOKNMRTǖcOg^S_ۏLSOh0ۏLƉɉhKmvXT]_N^[gcSƉRhg0 11.2 All personnel should be trained in the practices of personal hygiene. A high level of personal hygiene should be observed by all those concerned with manufacturing processes. In particular, personnel should be instructed to wash their hands before entering production areas. Signs to this effect should be posted and instructions complied with. 11.2 ^[@b gNXTۏL*NNkSuvW0*NNkSuvؚhQ^NuN]zvsQv@b gNXT w0R0yr+R/f ^S_JTXT](WۏeQuN:SWMR_{mKb0^S_ _4mKbvh_Tc:y v^u[gbL0 11.3 Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials or medicines until the condition is no longer judged to be a risk. 11.3 NUOXT](WNUOePSs` gSq_TNT(ϑvuubSOhR$Oe (W[u` N[NTNuΘiMR N_NNYtSe0SňPge0-NNTboTvd\O0 11.4 All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment or personnel) that they consider may adversely affect the products. 11.4 ^YeTRXT];NRT N~bJTS[NTNubq_Tv`QNS?b0YbNXTvsQv 11.5 Direct contact should be avoided between the operator s hands and starting materials, primary packaging materials and intermediate or bulk product. 11.5 ^MQXT]vKbvcc扟SPge0QSňPgeT-NSOb_SňvNT0 11.6 To ensure protection of the product from contamination, personnel should wear clean body coverings appropriate to the duties they perform, including appropriate hair covering. Used clothes, if reusable, should be stored in separate closed containers until properly laundered and, if necessary, disinfected or sterilized. 11.6 :NnxONTMQSalg XT]^z4bN@bNN]\Ov^vmQ g Sb4Yi0zǏv gň YgSN͑ YO(u ^ۏLS_vnmv^X[>e(Wrz[핹[hV-N0_eۏLmkbmp̃0 11.7 Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines should not be permitted in production, laboratory and storage areas, or in any other areas where they might adversely influence product quality. 11.7 (WuN:SW0[[TX[P:SW bS[NT(ϑNubq_TvNavQN:SW N_8Tp0nߘ0U4l0TV N_{QI0X[>eߘir0neTp{|irTNS*NNoT0 11.8 Personal hygiene procedures including the wearing of protective clothing, should apply to all persons entering production areas, whether they are temporary or full-time employees or nonemployees, e.g. contractors employees, visitors, senior managers and inspectors. 11.8 *NNkSuĉ zSbz2b g ^(uN@b gۏeQuN:SWvNXT N{/f4NeXT]bhQLXT]bYegNXT OYT T]0S‰0ؚ~{tNXTT[XT0 12. Premises 12 S?b 12.1 Principle. Premises must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. 12.1 SR.S?bv @W00^ 09e T~b_{nxO(uN[Evd\O0 General i 12.2 The layout and design of premises must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and in general, any adverse effect on the quality of products. 12.2 :NMQNSalg pp\yZbalg ;`KN NUOS[NT(ϑNubq_TvV } S:Sv^@\T_{\Nu]vΘiMgNO v^NY gHenmT~b0 12.3 Where dust is generated (e.g. during sampling, weighing, mixing and processing operations, or packaging of powder), measures should be taken to avoid cross-contamination and facilitate cleaning. 12.3 Nupp\v0WeOYS7h0y͑0mTTR]d\O0|+gSň ^S_ǑSceMQNSalgTONnm0 12.4 Premises should be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of materials or products. 12.4 ~TQObuN]zvce S?b^YN[irebNTX[(Wg\algΘivsX0 12.5 Premises used for the manufacture of finished products should be suitably designed and constructed to facilitate good sanitation. 12.5 (uNoTuNvS?b^S_vT^ ONnmkSu0 12.6 Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products. 12.6 S?b^S_\_~b ^nxOS:Sv~OT~bd\O NX[(WNUOq_TNT(ϑvqS[0 12.7 Premises should be cleaned and, where applicable, disinfected according to detailed written procedures. Records should be maintained. 12.7 ^9hnc~vfNbĉ z[S?bnmTmk0nmU_^S_OX[0 12.8 Electrical supply, lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment. 12.8 S?bQ^ gS_vO5u0gqf0)n^0n^TΘ nxO NOb0vcbcq_TuNǏ zbPX[Ǐ z-NvoTbY'`0 12.9 Premises should be designed and equipped so as to afford maximum protection against the entry of insects, birds or other animals. There should be a procedure for rodent and pest control. 12.9 S:SvTMn^g'YP^2bkfk0{|bvQNRirvۏeQ0^S_^zc6RnU{|RirTuk[vĉ z0 12.10 Premises should be designed to ensure the logical flow of materials and personnel. 12.10 S?bv^OirAmSTNAmSR_0 Ancillary areas R:SW 12.11 Rest and refreshment rooms should be separate from manufacturing and control areas. 12.11 Oo`:ST6p[^S_NuNTc6R:SWR_0 12.12 Facilities for changing and storing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not communicate directly with production or storage areas. 12.12 (uNfcTPX[cirveNSnmTkSue^S_ONۏQ v^NO(uNpev^0kSu N^NuN:SWbPX[:SWvcvޏ0 12.13 Maintenance workshops should if possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use. 12.13 Y gS ~Of^NuN:SWR_0S_~O]wQTMN(WuN:SWX[>ee ^S_>en(WN g?bb]wQPg-N0 12.14 Animal houses should be well isolated from other areas, with separate entrance (animal access) and air-handling facilities. 12.14 Rire^NvQN:SW%NeTy N TvireTbTSbSPge0SňPge0-NSO0_SňTg~vNT0_NTT>eLNT0 NTe0 12.20 Highly active and radioactive materials, narcotics, other dangerous medicines, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas. 12.20 ؚ;m'`T>e\'`ire0T0vQNqSiirTTwQ gn(u0fqbfrΘivir(^X[>e(W[hQ:SW0 12.21 Printed packaging materials are considered critical to the conformity of the pharmaceutical product to its labelling and special attention should be paid to sampling and the safe and secure storage of these materials. 12.21 pS7RSňPge[oT-h~{vN'`/fsQ.v Vdk^yr+Rlaُ{|irevS7h0[hQTOX[0 12.22 There should normally be a separate sampling area for starting materials. (If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.) 12.22 8^^:NSPgeMYUSrvS7h:SW0Yg(WPX[:SS7h ^ǑSce2bkalgbNSalg Weighing areas y͑:SW 12.23 The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing areas designed for that use, for example, with provisions for dust control. Such areas may be part of either storage or production areas. 12.23 SPgevy͑NS:N0O{6es ۏLvy͑^S_(WN蕾v:SWۏL0Y 2\c6Rvĉ[0dk{|:SWS/fPX[:SbuN:SvNR0 Production areas uN:SW 12.24 In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms). The production of certain other highly active products, such as some antibiotics, hormones, cytotoxic substances and certain non-pharmaceutical products, should not be conducted in the same facilities. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations (including cleaning validation) are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products. 12.24 :N\NSalg_wv%N͑oTqS[MgNO z^ [NNyrkoTvuN _{Ǒ(uN蕄v\필vuNe OYؚOe'`oirOY R } buir6RBROY ;m'`_uir6RT 0NNvQNؚ;m'`oTvuN OYNNbu }0o }0~ހk }TgN^;SoNT N^O(u TNuNe0(Wyrk`Q N ǑSyr+R2bcev^~Ǐ_vSbnm SNcSO(u TNuNe[buN0]zkovuN Y@gkBRTdIBR N^(W(uNoTuNvS?bQuN0 12.25 Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels. 12.25 S?b^Tt^@\ O_uNY cgqv^vd\Oz^TBlvmQ~+RۏL0 12.26 The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination, and to minimize the risk of omission or wrong application of any of the manufacturing or control steps. 12.26 uN:ST-NirePX[:S^wQYYvzz AQYTire g^X[>e g'YP^vMNO N ToTb~RKNvmm MQNSalg g'YP^MNO@b guNbc6Rek1uNWob[e bvΘi0 12.27 Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ce  F H V ` b v jl11&1:14262|22264666@6P6R6777$8r8:h`P6CJOJQJ]h`PCJOJQJjh`P0JUh`PCJKHo(h`PCJKH\ h`PCJh`P5CJKH\o(h`P5CJKH\h`P5CJKHo(h`P5CJKHh`PCJKH7& <  V V  4 6 V   dp$ 9dp7$8$H$a$ dp7$8$H$ $dp7$8$H$a$V BvDDdzTv\ P dp $dp7$8$H$a$Dh(Rh.FtvDF dp7$8$H$  dp $dp7$8$H$a$F\^!!"X#Z$r$$$$&f&h&)j*N & Fdp7$8$EƀC H$hdp7$8$H$WDj^h` dp7$8$H$j*l* ,j,l,-.///1d2f2455J777: dp7$8$H$:z;\>>7$8$$ƀð$7$8$$ƀð$:;<<b=d=>>Z>\>r>>.?0???@N@d@@@XApAAAAXB`BbBfBpBrBBBBBJJKKKK MMMM4N6NOOPP Qƻٱh`P5CJKH\h`PB*CJOJQJaJph# h`PCJH*KHjh`P0JUh`P5CJKHo(h`P5CJKHh`PCJOJQJh`PCJKHo(h`PCJKHh`PCJOJQJh`PCJOJQJo(4>AB0BgLdp7$8$C$EƀCH$Ldp7$8$C$EƀCH$0BPBtBgLdp7$8$C$EƀCH$Ldp7$8$C$EƀCH$tBBBBBvFGGPIIIg^^^^^^^^ dp7$8$H$Ldp7$8$C$EƀCH$Ldp7$8$C$EƀCH$ IL4N6NrOOOOOOOP Q QZQISTTTT&W,WWWWYY dp7$8$C$H$ $dp7$8$H$a$ dp7$8$H$ QZQTTWWdZZR__,aHaZctctdd4hJhrjjj kLmhmoopqrrsssvvwwVyny2{L{|}6TPnHJpn4<Xz6Nd:Lrt >fԥ~h`PCJKH]h`P5CJKH\h`PCJKHo(h`P6CJKH]h`PCJKHh`P6CJKHNYbZdZZ]^P_R__``*a,aHabbXcZctc4d@drdtddgg $dp7$8$H$a$$  dp7$8$H$a$ dp7$8$H$g2h4hJhiipjrjjllJmLmhm6of ԥ$*|~ħVƪȪ$&<­ȭ02 $dp7$8$H$a$ dp7$8$H$~ħȪ&<2ҮԮ֮x'({ 67Sݻ޻(*2np| &(*68fjxȿퟔ픋⿨h`PCJH*KHh`PCJH*KHo(h`PCJKHo(h`P5CJKHo(h`P5CJH*KHo(h`P5CJKHh`P5CJKH\o(h`P5CJH*KH\o(h`P5CJKH\h`PCJKHh`P6CJKH]62֮Tرڱ(dtV & Fedp7$8$EƀC H$^e`hdp7$8$H$WDj^h` dp7$8$H$ dp7$8$H$ $dp7$8$H$a$ EFݻ(*,n~^Ldp7$8$C$EƀNC'H$ dp7$8$H$Ldp7$8$C$EƀKC'H$ ~*^Ldp7$8$C$EƀZC'H$Ldp7$8$C$Eƀ\C'H$ dp7$8$H$x"$"#lmTb&2,-jkFG&(,.8>,df h`PCJH*KHo(h`P6CJKH]o(h`PCJKHh`PCJKHo(UgLdp7$8$C$EƀuC'H$Ldp7$8$C$EƀfC'H$T(*&^^Ldp7$8$C$Eƀ{C'H$ dp7$8$H$Ldp7$8$C$EƀeC'H$&(,^Ldp7$8$C$EƀC'H$ dp7$8$H$Ldp7$8$C$EƀyC'H$,gLdp7$8$C$EƀC'H$Ldp7$8$C$EƀC'H$8: $dp7$8$H$a$dp7$8$ dp7$8$H$Ldp7$8$C$EƀC'H$~8:<PQ|:<>>@HNRT|*,\`bRTLNRT hhj 8: h`PCJo( h`PCJh`PCJKHo(h`PCJKHYP~JLdh7$8$C$EƀCGH$GdpC$EƀCGdp dp7$8$H$hdp7$8$H$WDj^h`:<<>R^^^Ldp7$8$C$EƀC'H$ dp7$8$H$Ldh7$8$C$EƀCGH$ gLdp7$8$C$EƀC'H$Ldp7$8$C$EƀC'H$fggLdp7$8$C$EƀC'H$Ldp7$8$C$EƀCGH$fh:ggLdp7$8$C$EƀC'H$Ldp7$8$C$EƀC'H$:>~-.op=>mnJLz| V-Jf9=jnln^`h`Ph`P5CJKH\h`P5CJKHo(h`PCJKHo(h`PCJKHT:z|g^^^ dp7$8$H$Ldp7$8$C$EƀC'H$Ldp7$8$C$EƀC'H$ngLdp7$8$C$EƀC'H$Ldp7$8$C$EƀUC'H$gLdp7$8$C$EƀC'H$Ldp7$8$C$EƀC'H$>Xg^ dp7$8$H$Ldp7$8$C$EƀC'H$Ldp7$8$C$EƀC'H$ +PN & Fdp7$8$EƀC H$ $dp7$8$H$a$ dp7$8$H$Ldh7$8$C$EƀCGH$ Znll^*RT $dp7$8$H$a$ dp7$8$H$*,TV<> `b$&PRT , 0 2 4 ^ `     N      d  ` l |    OP[\$.r|`hBZ[|jh`P5CJKHh`Ph`P5CJKH\h`PCJKHo(h`PCJKHUT:<^`$PR0 2     : <  $dp7$8$H$a$ dp7$8$H$<  np`b9hdp7$8$H$WDj^h` $dp7$8$H$a$ dp7$8$H$Jdp7$8$EƀC'H$ j##$"$&&&&^'`'''2(^(++h++F.../(191Q1\13"3$3p366NGpGxGGNNOO&O2O6OHOt[|[[[[kl llHlTlVlZlflhlplllllmnnnh`P5CJKH\o(h`P5CJKHh`P6CJKH]h`P6CJKHh`P5CJKH\h`PCJKHh`PCJKHo(IRT:`bXtvN t v    0!L!N! dp7$8$H$hdp7$8$H$WDj^h`N!!" "&#j#l#$2$4$'^(`() * *4+++*,^,`,->.@.t...y1 dp7$8$H$y133^3n3p35p5r56667j899::F;;;H<J<=f>h>hdp7$8$H$WDj^h` $dp7$8$H$a$ dp7$8$H$h>?.@0@AAAjBBBCCCDDEEFF GFGHGdGnGpGHdIfI dp7$8$H$ dp7$8$H$fIK\L^LM(N*NOJOLOQQQSTTUVV&WpWrWX>Y@Y[t[v[ $dp7$8$H$a$ dp7$8$H$v[[[[\]]^&_(_*aaabccd6e8egZh\hTjjjkkk dp7$8$H$ $dp7$8$H$a$kHlflhlLnnnnnnp0q2q\rrr*t~tttttvxx){|| dp7$8$H$ $dp7$8$H$a$nnnnnnzooppqqrXrrrrr~ssssHtht~ttLuNuuu v vvvx2xJx^xxxxxzzzz}}[~\~~~0FLXƀȀVX|҃h`PCJKH]o(h`PCJKH]h`P6CJKH]o(h`P5CJKH\h`PCJKHh`PCJKHo(K|*ƀȀz|ԃ GP  dp7$8$C$EƀvCGH$  dp7$8$C$H$P  dp7$8$C$Eƀ^CGH$ dp7$8$H$ X\`@^T` <@ňXjnx~ފZ&,NTV>@׎؎6HJΓГfp~TV\^fhFHڗh`PCJKHo(h`PCJKHh`P5CJKH\h`PCJKH]h`P6CJKH]R LVX68}*,FLNLdp7$8$C$EƀCGH$ dp7$8$H$ $dp7$8$H$a$BƓȓTV`0ΞОؠTV vR$ , dp7$8$H$a$ $dp7$8$H$a$ dp7$8$H$ڗܗ893jxzdk Z֞؞tvޠ\ ,^.tH^V{FnVX\c(zdt$h'h`PCJKH[EG* *$h'h`PCJKHREG* *h`P6CJKHh`P6CJKH]h`P5CJKH\h`PCJKHh`PCJKHo(BR\^Nޫ2NzȬN & Fdp7$8$EƀC()H$ dp7$8$H$$ , dp7$8$H$a$Ȭ@A.ZN & Fdp7$8$EƀC()H$N & Fdp7$8$EƀC()H$ dp7$8$H$.@TcN & Fdp7$8$EƀC()H$N & Fdp7$8$EƀC()H$TZjcN & Fdp7$8$EƀC()H$N & Fdp7$8$EƀC()H$jpvcN & Fdp7$8$EƀC()H$N & Fdp7$8$EƀC()H$vcN & Fdp7$8$EƀC ()H$N & Fdp7$8$EƀC ()H$cN & Fdp7$8$EƀC ()H$N & Fdp7$8$EƀC ()H$ȮcN & Fdp7$8$EƀC()H$N & Fdp7$8$EƀC ()H$Ȯ,.hrtFHv@ dp7$8$H$ $dp7$8$H$a$N & Fdp7$8$EƀC()H$@z´ >Rt\^z@TVj$ 9dp7$8$H$a$ $dp7$8$H$a$ dp7$8$H$jl2>@>npDF $dp7$8$H$a$$ ^dp7$8$H$a$ dp7$8$H$FblnDXZ-?k  " dp7$8$H$ $dp7$8$H$a$.LNt*,@`b.L dp7$8$H$LN&( JL5 Nv.0 $dp7$8$H$a$ dp7$8$H$$]AZG(|4v,Dpr( dp7$8$H$:>    ,`+,2,I,J,......0,03366@@bGGNNOOPPxZZ:]h]````&a'accjX)4)6/@/@2z2P3h3ȽȽUh`P6CJKH]h`PCJKH\o(h`PCJKH\h`P5CJKH\h`PCJKHo(h`PCJKH$h'h`PCJKH\EG* *E(jlpNP`vP|~PR dp7$8$H$ dp7$8$H$ :<  f      Lr ;dp7$8$H$ dp7$8$H$ "H"$N^`<>!"".$$$% $dp7$8$H$a$ dp7$8$H$%&&(L)N)T+++ -...../00$0*0,0&222V444j66 dp7$8$H$66788Z999: ;;8===6???V@@@@@@nAAA :dp7$8$H$ dp7$8$H$ $dp7$8$H$a$ApCCCEF FG`GbG~GGG IJJvM6N8N*PPPR*S,S TJTLTU dp7$8$H$UVW`XbXZvZxZZZZ\8]:]\]f]h]1acceeecghhd dp7$8$H$ilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection. 12.27 S_SPgeTQSňPge0-NSOb_SňNTf2(WsX-Ne ?bQhbX00WgT)Yg ^S_IQn0eˆTc%N[ e|'`ir(1= fNnm _emp̃0 12.28 Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas. 12.28 {S0gqfe0ΘSTvQNevT[ň^MQQsNnmvQwY0:NeO~bO{Q ^YNuN:SYۏeQ0 12.29 Drains should be of adequate size and designed and equipped to prevent back-flow. Open channels should be avoided where possible, but if they are necessary they should be shallow to facilitate cleaning and disinfection. 12.29 c4ll^'Y\[ v^TMY2bkPAmvňn0^=\SMQf nc4l Yg NSMQ NN^S_fNnmTmk0 12.30 Production areas should be effectively ventilated, with air-control facilities (including filtration of air to a sufficient level to prevent contamination and cross-contamination, as well as control of temperature and, where necessary, humidity) appropriate to the products handled, to the operations undertaken and to the external environment. These areas should be regularly monitored during both production and non-production periods to ensure compliance with their design specifications. 12.30 uN:S^Y[d\OT[Y萯sX gHevΘ ňYNNTvzzlc6ReSbY~+RvzzlǏn MQalgTNSalgNSsXTn^c6R YS 0(WuNT^uN6k ُN:SW^S_[gvcNOnvhQ0 12.31 Premises for the packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix ups, contamination or cross-contamination. 12.31 oTSňS?b^S_N蕾T^@\ NMQmm0algbNSalg0 12.32 Production areas should be well lit, particularly where visual online controls are carried out. 12.32 S:S^S_ gYvgqf yr+R/fۏLƉɉ(W~c6Rv:SW0 Quality control areas (ϑc6R:SW 12.33 QC laboratories should be separated from production areas. Areas where biological, microbiological or radioisotope test methods are employed should be separated from each other. 12.33 QC[[^S_NuN:SWR_0ۏLuir0_uirb>e\'` TMO }hKmv:SW^S_|_dkR_0 12.34 QC laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix ups and cross-contamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents and records. 12.34 QC[[v^S_T[vd\O0[[^ gYvzzNMQmmTNSalg0 Te؏^cOYvPX[:SW(uegX[>e7hT0hQT_e ^Qυ 0nBR0ՋBRTvsQU_0 12.35 The design of the laboratories should take into account the suitability of construction materials, prevention of fumes and ventilation. There should be separate air supply to laboratories and production areas. Separate air-handling units and other provisions are needed for biological, microbiological and radioisotope laboratories. 12.35 [[v^S_Q^Q{PgeNSΘT2pv(u'`0[[TuN:S^ grzvzzlO^0uir0_uirT>e\'` TMO }[[USrvzzlYt|~TvQNce0 12.36 A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture and other external factors, or where it is necessary to isolate the instruments. 12.36 ^zN蕄vNhV[ OvQMQS5uP[r^pb0/cR0cǏYv4lRTvQNYV } b_e y勾Y0 13. Equipment 13 Y 13.1 Equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design of equipment must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products. 13.1 Yv @W00gW09e T~b_{(uNuNd\O0Yv^@\T_{OSu]vΘiMgNOv^ gHevnmT~b NMQNSalg0pp\vXyT@b gq_TNT(ϑv NoV }0 13.2 Equipment should be installed in such a way as to minimize any risk of error or of contamination. 13.2 NhVv[ň^S_OSubalgvNUOΘiMgNO0 13.3 Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow. 13.3 V[{S^nZivhƋ hfQ[irTAmT Y(u0 13.4 All service pipework and devices should be adequately marked and special attention paid to the provision of non-interchangeable connections or adaptors for dangerous gases and liquids. 13.4 @b gO~{STe^4 NS_vh ^yr+RlaqSilSOTmSO O(u NSNbcvޏcňnbc4Y0 13.5 Balances and other measuring equipment of an appropriate range and precision should be available for production and control operations and should be calibrated according to a fixed schedule. 13.5 ^MYwQ gS_ϑ zT|[^v)Ys^TvQNKmϑY (uNuNTc6Rd\O v^^[g[vQ!hQ0 13.6 Production equipment should be thoroughly cleaned according to a fixed scheduled. 13.6 ^[g[uNY{_^nm0 13.7 Laboratory equipment and instruments should be suited to the testing procedures undertaken. 13.7 [[vYTNhV^S_NhKmelv^0 13.8 Washing, cleaning and drying equipment should be chosen and used so as not to be a source of contamination. 13.8 ^S_ bTO(u NO balgegnvnm0nmTr^qNhV0 13.9 Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive, or absorptive to an extent that would affect the quality of the product. 13.9 uNY N^[NT gNUOqS[0NNTvcc扄vuNYvR N^[NT(ϑNuq_T YNoTSuSf[S^0mR_irb8TD\O(u0 13.10 Defective equipment should be removed from production and QC areas. If this is not possible, it should be clearly labelled as defective to prevent use. 13.10 SuEevY^S_yQuN:SWTQC:SW0Y NS ^S_nZihQsEe 2bkO(u0 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. 13.11 S_veP ^O(u[NhV0S_O(u_>eNhVbNhVSb_e ^S_ǑS2ceMNOalg0 13.12 Non-dedicated equipment should be cleaned according to validated cleaning procedures between being used for production of different pharmaceutical products to prevent cross-contamination. 13.12 9hncvnmĉ z uN N ToTv^N(uY^nm MQNSalg0 13.13 Current drawings of critical equipment and support systems should be maintained. 13.13 s gvsQ.YTR|~vV~^S_OX[0 14. Materials 14 ire 14.1 Principle. The main objective of a pharmaceutical plant is to produce finished products for patients use from a combination of materials (starting and packaging). 14.1 SR.oSv;Nvv/fO(uireSPgeTSňPge v~TuNOuNO(uvoT0 14.2 Materials include starting materials, packaging materials, gases, solvents, process aids, reagents and labelling materials. 14.2ireSbSPge0SňPge0lSO0nBR0]ze0ՋBRTh~{Pge0 General i 14.3 No materials used for operations such as cleaning, lubrication of equipment and pest control, should come into direct contact with the product. Where possible, such materials should be of a suitable grade (e.g. food grade) to minimize health risks. 14.3 (uNnm0YvmnTuk[c6Rd\Ovire N^vcc执NT0 gSv݋ dk{|ire^S_0RS_v~+ROY ߘ(u~ O_eP^ΘiMgNO0 14.4 All incoming materials and finished products should be quarantined immediately after receipt or processing, until they are released for use or distribution. 14.4 @b gۏSireTbT(Wc6ebR]T^zsSnN_r` v0R>eLO(ub N^0 14.5 All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation by a first-expire, first-out rule. 14.5 @b gireTbT^(WuNFU6R[vagN N g^RybPX[ ^X[hTl cgqHQۏHQQSRgbL0 14.6 Water used in the manufacture of pharmaceutical products should be suitable for its intended use. 14.6 oTuN(u4l^S_&{TvQg(u0 Starting materials SPge 14.7 The purchase of starting materials is an important operation that should involve staff who have a particular and thorough knowledge of the products and suppliers. 14.7 SPgevǑ-/fN*N͑v]\O #XT]^S_[NTTO^FUwQ g~vhQbvN0 14.8 Starting materials should be purchased only from approved suppliers and, where possible, directly from the producer. It is also recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all critical aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements as well as complaints and rejection procedures, are contractually agreed between the manufacturer and the supplier. 14.8 SPgeSNybQvO^FUǑ- Sv݋ vcNuNFUǑ-0^uNFU TO^FUnx[SPgevch0uNFUg}Y TO^FUOSFU[SPgevuNTc6R SbYt04~{TSňBlNSbɋTb~ z^0 14.9 For each consignment, the containers should be checked at least for integrity of package and seal and for correspondence between the order, the delivery note, and the supplier s labels. 14.9 k!kS'e ^S_\hgSň[hVv[te'`T[\'` NShg'US0'USTO^FUh~{/f&TN0 14.10 All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled, if required, with the prescribed information. Where additional labels are attached to containers, the original information should not be lost. 14.10 @b gۏ:Wire^S_8h[NnxONS'USN0_e Sň[hV^S_nmT4~{ Y gBl h~{^D N~Oo`0S_Bl(WSň[hV ND NvQNh~{e SYOo` N^"Nc0 14.11 Damage to containers and any other problem that might adversely affect the quality of a material should be recorded and reported to the QC department and investigated. 14.11 Sň[hV_cOWTvQNSq_TNT(ϑv^S_U_ v^bJT~QC ۏLg0 14.12 If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing and release. 14.12 N!kN'vNT1upeyb~b kNyb^USrS7h0hKmT>eL0 14.13 Starting materials in the storage area should be appropriately labelled. Labels should bear at least the following information: (a) the designated name of the product and the internal code reference where applicable; (b) the batch number given by the supplier and, on receipt, the control or batch number given by the manufacturer, if any, documented so as to ensure traceability; (c) the status of the contents (e.g. on quarantine, on test, released, rejected, returned, recalled); (d) where appropriate, an expiry date or a date beyond which retesting is necessary. 14.13 PX[:SQvSPge^S_S_h0h~{ NvOo`\SbN NQ[ (a) NTvc[ TyTQireNxY g 0 (b) O^FU~NvybSTc6ee uNFU~Nvc6RbybS g ^OX[vsQU_OSn'`0 (c) irer`OY _0(Wh0>eL0 NTeLvN(W'ggQvSPge0 14.16 Starting materials should be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labeled containers. 14.16 cgqfNbĉ z SPgeS1uNNRM OcknxvireY|nxyϑbbeQnmv^ gh~{vSň[hVQ0 14.17 Each dispensed material and its weight or volume should be independently checked and the check recorded. 14.17 kNMSvireSvQ͑ϑbSOy^S_USrhg v^NNU_0 14.18 Materials dispensed for each batch of the final product should be kept together and conspicuously labelled as such. 14.18 (uN6RYNybbTv@b gire^Ɩ-NX[>e v^4 Nv^v>fWh~{0 Packaging materials SňPge 14.19 The purchase, handling and control of primary and printed packaging materials should be as for starting materials. 14.19 QSňPgeTpS7RPgevǑ-0R]Tc6R^TSPgeN7h0 14.20 Particular attention should be paid to printed packaging materials. They should be stored in secure conditions so as to exclude the possibility of unauthorized access. Roll feed labels should be used wherever possible. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by designated personnel following an approved and documented procedure. 14.20 [NpS7RSňPge^S_yr+RsQl0vQ^PX[(W[hQagN N 2bkNN*g~cCg aQeQ0^=\SO(uwSeh~{0RrR_h~{TvQNceňpS7RPge^S_R+RnN[핹[hVQPX[TЏ N2bkmm0SňPgeS1uNN cgq]ybQvfNbĉ zS>eO(u0 14.21 Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark. 14.21 k!kS'bpS7RvkNybpS7RbQSňPge^S_~Nyr[vybSbƋ+Rh0 14.22 Outdated or obsolete primary packaging material or printed packaging material should be destroyed and its disposal recorded. 14.22 Ǐgvb^_vQSňPgebpS7RSňPge^S_kv^U_0 14.23 All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the packaging instructions. 14.23 @b gNTTSňPge(WN~Sňe ^S_8h[vQpeϑ0hƋNSSňcNv&{T'`0 Intermediate and bulk products -NSOT_SňNT 14.24 Intermediate and bulk products should be kept under appropriate conditions. 14.24 -NSOT_SňNT^S_(WS_agN NOX[0 14.25 Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials. 14.25 Ǒ-v-NSOT_SňNT(Wc6ee^\O:NSPgeYt0 Finished products bT 14.26 Finished products should be held in quarantine until their final release, after which they should be stored as usable stock under conditions established by the manufacturer. 14.26 bT(Wg~>eLKNMR^S_YN_r` >eLT^ cuNFUĉ[vPX[agN\O:NTe0 14.27 The evaluation of finished products and the documentation necessary for release of a product for sale are described in section 17,  Good practices in quality control . 14.27 bTvċ0OTNT>eL.UveNz17 (ϑc6Rvo}Yĉ 0 Rejected, recovered, reprocessed and reworked materials NTeLv^NNl[hQTv Tve_PX[0hQT^1uNN#X[>e(W[hQv:SWQ0 14.40 Secondary or working standards may be established by the application of appropriate tests and checks at regular intervals to ensure standardization. 14.40 ^ǏǑ(uS_vhKmT[ghgN~hQTb]\OhQTNnxOvQhQ'`0 14.41 Reference standards should be properly labelled with at least the following information: (a) name of the material; (b) batch or lot number and control number; (c) date of preparation; (d) shelf-life; (e) potency; (f) storage conditions. 14.41 hQT^S_4~{ h~{Q[\SbN NOo` (a) ire Ty (b) yb!kbybSbc6RS (c) 6RYeg (d) gHeg (e) HeN (f) PX[agN 14.42 All in-house reference standards should be standardized against an official reference standard, when available, initially and at regular intervals thereafter. 14.42 @b gQhQT^S_(WgRT[g(ul[hQTۏLh[0 14.43 All reference standards should be stored and used in a manner that will not adversely affect their quality. 14.43 @b ghQT^S_N N_c[vQ(ϑve_PX[TO(u0 Waste materials ^_Pge 14.44 Provision should be made for the proper and safe storage of waste materials awaiting disposal. Toxic substances and flammable materials should be stored in suitably designed, separate, enclosed cupboards, as required by national legislation. 14.44 ^S_6R[_Yt^_irev gsQ[hQPX[ĉ[0k'`irTTfqire^ cgqV[lĉBlPX[N~p`S_0USrv[\g-N0 14.45 Waste material should not be allowed to accumulate. It should be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals. 14.45 NAQXy^_ire0^O(uTv[hV6eƖ^_ire S?bYv6eƖY v^[gNr^QkSuve_ۏL[hQYt0 Miscellaneous Bgir 14.46 Rodenticides, insecticides, fumigating agents and sanitizing materials should not be permitted to contaminate equipment, starting materials, packaging materials, in-process materials or finished products. 14.46 mp BR0@gkBR0qBRTmkBR N^[Y0SPge0SňPge0-NSObbT balg0 15. Documentation 15 eN 15.1 Principle. Good documentation is an essential part of the quality assurance system and, as such, should exist for all aspects of GMP. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control; to ensure that all personnel concerned with manufacture know what to do and when to do it; to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a medicine for sale, to ensure the existence of documented evidence, traceability, and to provide records and an audit trail that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. The design and use of documents depend upon the manufacturer. In some cases some or all of the documents described below may be brought together, but they will usually be separate. 15.1 SR.o}YveN|~/f(ϑO|~vW,gR ^S_vGMPv@b geb0vQvh/f6R[@b girev(ϑhQTĉ zNSuNTc6Rvel NOuNvsQv@b gNXTwS^ZPNHNNSUOeZPnxOcCgNN㉧NT@b gOo`NQ[NT/f&TybQ>eL OfNbU_vX[(W Sn'` OcOvsQU_T[*NOg0vQnxO0[gT~Rg@b gpencv gHe'`0eNYUOTO(uSQNuNFU0(WgN`Q N NbcveNvNRbhQS(WNw FONNT8^/fvNrzv0 General i 15.2 Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorizations. 15.2 eN^S_|_v06R[0hgTS>e0vQ^S_&{TuNST.USvsQRvBl0 15.3 Documents should be approved, signed and dated by the appropriate responsible persons. No document should be changed without authorization and approval. 15.3 eN^S_ gTv#NybQ0~{W[v^lfeg0l g_0RcCgTybQ NUOeN N_O9e0 15.4 Documents should have unambiguous contents: the title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 15.4 eNQ[^S_fnx^S_feN Ty0'`(Tvv0eN^@\^S_ g^ ONhg0 YpSeN^S_nZif0N;NeN YpS]\OeNe N_NuNUO]0 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 of the superseded version. Superseded documents should be retained for a specific period of time. 15.5 eN^S_[g[gv^Ocfe0S_eNOe ^ g2bkeHr,g(uv|~0eHr,gveN^S_OX[N[e0 15.6 Where documents require the entry of data, these entries should be clear, legible and indelible. Sufficient space should be provided for such entries. 15.6 S_eNeQpence ُNpencveQ^S_npf fT Nf"N1Y0ech^S_Yu gYvzzkXQُNpenc0 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 of the original information. Where appropriate, the reason for the alteration should be recorded. 15.7 echvNUOO9e^S_~{ Tv^hfegO9eY^OSYOo`npfS0S_e ^S_U_O9evt1u0 15.8 Records should be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records should be retained for at least one year after the expiry date of the finished product. 15.8 uNǏ z-NǑSvkNyce^S_[teU_ MbSnoTuN-NmSv@b gsQ.ek0U_^S_OX[NT gHegT\Nt^0 15.9 Data (and records for storage) may be recorded by electronic data processing systems or by photographic or other reliable means. Master formulae and detailed SOPs relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data-processing methods, only authorized persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions; access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records stored electronically should be protected by back-up transfer on magnetic tape, microfilm, paper print-outs or other means. It is particularly important that, during the period of retention, the data are readily available. 15.9 ^O(u5uP[pencYt|~bgqvbvQNS`ve_U_pencPX[U_ 0^ g;NMeTN|~vsQv~vSOPs U_vQnx'`^S_8hg0YgO(u5uP[elYteN S gcCgNYۏeQ5ubO9epenc ^ gSfT RdU_0^Ǐ[xbvQNe_P6RNN{vF sQ.pencveQ^1uNNۏL Y8h0(u5uP[elPX[vybU_^YN0Rx&^0)_wS0SbpS~bvQNN( N0$\vQ͑v/f (WOYug penc^S_fNg0 Documents required _veN Labels h~{ 15.10 Labels applied to containers, equipment or premises should be clear, unambiguous and in the company s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (e.g. quarantined, accepted, rejected, clean). 15.10 Sň[hV0YbS?bvh~{^npff v^Ǒ(ulQSybQve0O(u0kbV^?bv@b gpS7RSňPgeT_SňNTvpeϑTSgqSbhƋNSNTpeϑ NOۏLEQRvirea{0 Standard operating procedures and records hQd\Oĉ zTU_ 15.31 SOPs and associated records of actions taken or, where appropriate, conclusions reached should be available for: (a) equipment assembly and validation; (b) analytical apparatus and calibration; (c) maintenance, cleaning and sanitization; (d) personnel matters including qualification, training, clothing and hygiene; (e) environmental monitoring; (f) pest control; (g) complaints; (h) recalls; (i) returns. 15.31 ^ gSOPsTǑSvsQcevU_ _e^ g~ (a) NhV~ňT (b) RgNhVT!hQ (c) ~b0nmTkSu (d) NNvsQ SbD(0W0 gňTkSu (e) sXvc (f) uk[c6R (g) bɋ (h) SV (i) V 15.32 There should be SOPs and records for the receipt of each delivery of starting material and primary and printed packaging material. 15.32 [NkN*NSPge0QSňPgeTpS7RSňPge^ girec6evSOPsTU_0 15.33 The records of the receipts should include: (a) the name of the material on the delivery note and the containers; (b) the  in-house name and/or code of material if different from (a); (c) the date of receipt; (d) the supplier s name and, if possible, manufacturer s name; (e) the manufacturer s batch or reference number; (f) the total quantity, and number of containers received; (g) the batch number assigned after receipt; (h) any relevant comment (e.g. state of the containers). 15.33 irec6evU_^S_Sb (a) S'USTSň[hV Nvire Ty (b) lQSQO(uvire TyT/bNx, N TN(a) (c) c6eeg (d) O^FUv TyTuNFUv TySv݋ (e) uNFUvybSbSS (f) c6ev;`ϑTSň[hVvpeϑ (g) c6eTRMvybS (h) gsQfOY Sň[hVvf 15.34 There should be SOPs for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate. 15.34 ^S_ gsQNQh~{0SPge0SňPgeTvQNire_TPX[vSOPs0 15.35 SOPs should be available for each instrument and piece of equipment (e.g. use, calibration, cleaning, maintenance) and placed in close proximity to the equipment. 15.35 [NkN*NNhVTYY O(u0!hQ0nmT~b ^ gv^vSOP v^>e(Wk*NYvDяMOn0 15.36 There should be SOPs for sampling, which specify the person(s) authorized to take samples. 15.36 ^S_ gS7hvSOPs fnxcCgS7hvNXT0 15.37 The sampling instructions should include: (a) the method of sampling and the sampling plan; (b) the equipment to be used; (c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality; (d) the amount(s) of sample(s) to be taken; (e) instructions for any required subdivision of the sample; (f) the type of sample container(s) to be used, and whether they are for aseptic sampling or for normal sampling, and labelling; (g) any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material. 15.37 S7hcN^S_Sb (a) S7helTS7hR (b) @b(uY (c) MQirealgbNUO(ϑv`Sv@b glaNy (d) S7hϑ (e) R7hd\OcN (f) @b(u7hT[hVv{|W /fẽS7h[hV؏/fck8^S7h[hV v^4~{ (g) ^ǑSyrk2ce yr+R/fS_mSẽS7hb gkir(0 15.38 There should be an SOP describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number. 15.38 ^S_ gcybS6R|~vSOP NOkNyb-NSO0_SňNTTbT gyr[vybS0 15.39 The SOPs for batch numbering that are applied to the processing stage and to the respective packaging stage should be related to each other. 15.39 (uNuN6kTTSň6kybS6RvSOP^S_|_dkvNsQT0 15.40 The SOP for batch numbering should ensure that the same batch numbers will not be used repeatedly; this applies also to reprocessing. 15.40 ybS6RvSOP^S_nxO TNybS NO͑ YO(u ُ_N(uNԏ]yb!k0 15.41 Batch-number allocation should be immediately recorded, e.g. in a logbook. The record should include at least the date of allocation, product identity and size of batch. 15.41 ybSRMT^S_zsSU_ YU_(We_-N0U_^S_\SbRMeg0NThƋTybϑ0 15.42 There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded. 15.42 ^S_6R[(uN N TuN6kvireTNThKmvfNbhĉ z c@b(uvelTNhV0^S_U_[evhKm0 15.43 Analysis records should include at least the following data: (a) the name of the material or product and, where applicable, dosage form; (b) the batch number and, where appropriate, the manufacturer and/or supplier; (c) references to the relevant specifications and testing procedures; (d) test results, including observations and calculations, and reference to any specifications (limits); (e) date(s) and reference number(s) of testing; (f) the initials of the persons who performed the testing; (g) the date and initials of the persons who verified the testing and the calculations, where appropriate; (h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person. 15.43 hU_^\S+TN Npenc (a) irebNTv Ty Y(u ^SbBRW (b) ybS S_e uNS[T/bO^FUv Ty (c) vsQchThKmelvS (d) hKm~gT@bSgqvchP^ Sb‰[T{ (e) hKmvegTSS (f) hNXTvY T)Q (g) [h0{ۏL8h[vNvY T)Q v^lfeg0 (h) >eLbb~vfnxXfbvQNQ[ v^ gc[v#Nv~{ TTeg0 15.44 Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by an authorized person. 15.44 ^S_^zireTbTvfNb>eLTb~ z^0yr+R/f1ucCgNQ[bT.U>eLvfNb z^0 15.45 Records should be maintained of the distribution of each batch of a product in order, e.g. to facilitate the recall of the batch if necessary. 15.45 kNybNTv.UU_^S_OX[ OY _eeOv^yb!kvSV0 15.46 Records should be kept for major and critical equipment, as appropriate, of any validations, calibrations, maintenance, cleaning, or repair operations, including dates and the identity of the people who carried these operations out. 15.46 ͑TsQ.Y gsQ0!hQ0~b0nmb~Od\OvU_^S_OX[ U_Q[^Sb[eُNd\OvegTd\ON0 15.47 The use of major and critical equipment and the areas where products have been processed should be appropriately recorded in chronological order. 15.47 ͑TsQ.YvO(uNSYtNTv:SW^S_ cez^U_0 15.48 There should be written procedures assigning responsibility for cleaning and sanitation and describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used and facilities and equipment to be cleaned. Such written procedures should be followed. 15.48 ^S_ gRMnmTkSuNS~cnmR0el0@b(uvYTireNSnmvYTevfNbĉ z0dk{|fNbĉ z^S_u_0 16. Good practices in production 16 uNd\Oĉ 16.1 Principle. Production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality. 16.1 SR.:N_0R(ϑTe0R]0SňT.U^S_ cgqfNbĉ zbcN[e _e U_0 16.3 Deviation from instructions or procedures should be avoided as far as possible. If deviations occur, they should be in accordance with an approved procedure. The authorization of the deviation should be approved in writing by a designated person, with the involvement of the QC department, when appropriate. 16.3 ^=\SMQOPycNb z^vOP]Su0YSuOP] ^ cgqybQv z^Yt0OP]vybQ^1uc[vNN~{W[[yb _eQC蕄vSN0 16.4 Checks on yields and reconciliation of quantities should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. 16.4 _e ^S_ۏL6esv8hgTirevs^a{ NONϑl gQScSV0 16.5 Operations on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix up or cross-contamination. 16.5 N TNTvd\O N^(W TN?bb:SWQ TeۏLbޏ~ۏL d^l gmmbNSalgvΘi0 16.6 At all times during processing, all materials, bulk containers, major items of equipment, and where appropriate, the rooms and packaging lines being used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and the batch number. Where applicable, this indication should also mention the stage of production. In some cases it may be useful to also record the name of the previous product that has been processed. 16.6 uNg @b gire0_Sň[hV0sQ.uNY NS@b(uv?bTSň~^S_4~{bO(uvQNe_hfuNvNTbirevĉeb_uir_wv0ُyΘiv%N͑'`9hncalgv{|WTSalgvNTv N T N T0gwQqSi'`valgir/fؚOe'`ire uir6RBR OY uirSO0gNo }0~ހk'`ir(TvQNؚ;m'`ire0l\BR0_>e'`R$O(uoT'YBRϑNTNSgO(uvoTNTalgg%N͑0 16.12 Cross-contamination should be avoided by taking appropriate technical or organizational measures, for example: (a) carrying out production in dedicated and self-contained areas (which may be required for products such as penicillins, live vaccines, live bacterial preparations and certain other biologicals); (b) conducting campaign production (separation in time) followed by appropriate cleaning in accordance with a validated cleaning procedure; (c) providing appropriately designed airlocks, pressure differentials, and air supply and extraction systems; (d) minimizing the risk of contamination caused by recirculation or reentry of untreated or insufficiently treated air; (e) wearing protective clothing where products or materials are handled; (f) using cleaning and decontamination procedures of known effectiveness; (g) using a  closed system in production; (h) testing for residues; (i) using cleanliness status labels on equipment. 16.12 :NMQNSalg ^S_ǑSS_b/gb~~ce OY (a) (WN(uvTrzv:SWۏLuNR }{|0;muׂ0;m̃6RBRTgNvQNuir6RBR{|S (b) uN[kT ^ cgqvnm z^ۏLS_vnm0 (c) cOTvl0S]0zzlO^Tbc|~ (d) \1u_sO(ubTuN:SeQ*g~YtbYt NS_vzzl [valgΘiMgNO0 (e) (WNTTireYtv0We z4b2b g0 (f) O(u]w gHevnmTmdalgvel (g) uNǏ z-NO(u \|~ (h) kYuhKm (i) Y^O(unmr`h~{ 16.13 Measures to prevent cross-contamination and their effectiveness should be checked periodically according to SOPs. 16.13 cgqSOPsvBl [ghg2bkNSalgvceSvQ gHe'`0 16.14 Production areas where susceptible products are processed should undergo periodic environmental monitoring (e.g. for microbiological and particulate matter where appropriate). 16.14 uNOeaNTv:SW^[gۏLsXhKmOY _uirvcTS_e|ir(vvc 0 Processing Operations uNd\O 16.15 Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels or documents not required for the current operation. 16.15 (WuNd\O_YKNMR ^ǑSceO]\O:SWTYYNnmr` N^ gs:Wd\O NvNUOSPge0NT0NTkYuir0h~{beN0 16.16 Any necessary in-process controls and environmental controls should be carried out and recorded. 16.16 @b g_v-Nc6RTsXc6R^S_[ev^U_0 16.17 Means should be instituted of indicating failures of equipment or of services (e.g. water, gas) to equipment. Defective equipment should be withdrawn from use until the defect has been rectified. After use, production equipment should be cleaned without delay according to detailed written procedures and stored under clean and dry conditions in a separate area or in a manner that will prevent contamination. 16.17 ^^zh_hfQsEevNhVbvQMWYeOY 4l0l 0QsEevY^S_\PbkO(u v0REemd0O(u[kT uNY^zsS cgq~vfNbĉ zۏLnm v^PX[(Wnmr^qagN NvUSr:SWQ bN2bkalgve_PX[0 16.18 Time limits for storage of equipment after cleaning and before use should be stated and based on data. 16.18 YnmTTO(uMRvOX[e^9hncy/}vpencf0 16.19 Containers for filling should be cleaned before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles. 16.19 Lpň[hV(WLpňMR^S_nm0^laMQTSd@b gvalgir OYstxGrTё^\|0 16.20 Any significant deviation from the expected yield should be recorded and investigated. 16.20 OPyg6esv@b g͑'YOP]^S_U_Tg0 16.21 Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner. 16.21 ^[NTNN*N:SWЏ0RSN*N:SWvޏc{STЏYۏLhgNOޏccknx0 16.22 Pipes used for conveying distilled or deionized water and, where appropriate, other water pipes should be sanitized and stored according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 16.22 4lbSyP[4lTvQN4lv{S^S_ cgqfNbĉ zۏLmkTPX[ dkfNbĉ z^ gsQN_uiralgvLRPT^ǑSvce0 16.23 Measuring, weighing, recording, and control equipment and instruments should be serviced and calibrated at prespecified intervals and records maintained. To ensure satisfactory functioning, instruments should be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when recalibration is due should be clearly indicated on a label attached to the instrument. 16.23 ϑ0y͑0U_0c6RYTNhV^ cHQ[vhTghgT!hck v^OX[v^vU_0RgNhV^S_k)Yhgb(WۏLRgKmՋKNMRhgNnxOck8^ЏL0!hQT~OegNS͑e!hQveg^S_(Wh~{ NnZihf v^\h~{4(WNhV N0 16.24 Repair and maintenance operations should not present any hazard to the quality of the products0 16.24 OtT~Od\O N^[NT(ϑ gNUOqS[0 Packaging operations Sňd\O 16.25 When the programme for packaging operations is being set up, particular attention should be given to minimizing the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation or an alternative system that will provide equal assurance. 16.25 S_^zSňd\O z^T ^S_yr+Rla\NSalg0mmTfbcvΘiMgNO0 N TNTvSň N^(W4Nя:SW[b d^ girtybcOs^I{Ov b|~0 16.26 Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents used previously and which are not required for the current operation. The line clearance should be performed according to an appropriate procedure and checklist, and recorded. 16.26 (WSňd\O_YKNMR ^S_ǑSceO]\O:SW0Sň~0pS7R:ghVTvQNYYNnmr` N^ gvQNNT0irebKNMRO(uveNNSs:Wd\O NvQ[0^ cgqv^nm z^ThgnUS [bSň~vnmv^U_0 16.27 The name and batch number of the product being handled should be displayed at each packaging station or line. 16.27 NT TyTybSvYt^(Wk*NSňSbSň~ NۏL0 16.28 Normally, filling and sealing should be followed as quickly as possible by labelling. If labelling is delayed, appropriate procedures should be applied to ensure that no mix ups or mislabelling can occur. 16.28 8^ NTLpňT[\T^S_=\_4~{0Yg4~{^ߏ ^S_ǑSS_vcenxO NOSummT4h~{0 16.29 The correct performance of any printing (e.g. of code numbers or expiry dates) done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand, which should be rechecked at regular intervals. 16.29 ^hgUSrSbpSvbSňǏ z-NSbpSveW[Q[OY Nxb gHeg vcknx'`v^U_0^laKb]SbpS v^[vQ[gۏL8hg0 16.30 Special care should be taken when cut labels are used and when overprinting is carried out off-line, and in hand-packaging operations. Roll feed labels are normally preferable to cut labels in helping to avoid mix ups. Online verification of all labels by automated electronic means can be helpful in preventing mix ups, but checks should be made to ensure that any electronic code readers, label counters, or similar devices are operating correctly. When labels are attached manually, in-process control checks should be performed more frequently. 16.30 YgO(uRrR_h~{ bS_y~SbpSTKb]Sňe ^S_yr+Rla08^wSeh~{kRrR_h~{f gRN2bkmm0Ǒ(uꁨRS5uP[Kbk[@b gh~{ۏL(W~hg[MQmm/f g(uv FO^S_hgnxO@b g5uP[xhV0h~{pehVbvQN{|eLKNMR (W[_SňNTTpS7RSňPgevpeϑNSuNfS8h[eSsv͑'Yb_8^:w ^ۏLg ~QTtʑv^U_0 16.35 Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure requiring checks to be performed before returning unused materials should be followed if uncoded printed materials are returned to stock. 16.35 Sňd\O[be @b gpS gybSviRYOSňPge^S_kv^U_0\*gpS gybSvSňPgeV^?bKNMR ^%NeLybQ z^vNR ybU_(WN~cCgNKNMR ^ۏL[8h0@b gOP]T NTeLO(ubybQ N^0(ϑc6R NNPN[[d\O ؏SNNT(ϑ gsQvYQ[0 17.2 The independence of QC from production is considered fundamental. 17.2 (ϑc6R蕔^rzNuN ُ/fW,gSR0 17.3 Each manufacturer should have a QC function. The QC function should be independent of other departments and under the authority of 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. The basic requirements for QC are as follows: 17.3 k*NuNFU^ g(ϑc6R0(ϑc6R蕔^S_rzNvQN 1uwQ gS_D(T~vNXT{t0_{cOYvDnO(ϑc6Rv@b g]\O gHev^S`v[e0[(ϑc6R蕄vW,gBlY N (a) adequate facilities, trained personnel and approved procedures must be available for sampling, inspecting, and testing starting materials, packaging materials, and intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; (a) ^S_MYYve ~ǏWvNXTTybQv z^[bS7h0[gThKmSPge0SňPge0-NSO0_SňNTTbT Te؏vcsXagNN&{TGMPvBl0 (b) samples of starting materials, packaging materials, intermediate products, bulk products and finished products must be taken by methods and personnel approved of by the QC department; (b) SPge0SňPge0-NSO0_SňNTTbTvS7h_{1u(ϑc6RybQvN cĉ[vS7hel[b0 (c) qualification and validation; (c) nxT (d) records must be made (manually and/or by recording instruments) demonstrating that all the required sampling, testing procedures have actually been carried out and that any deviations have been fully recorded and investigated; (d) _{ gU_Kb]T/bO(uU_NhV hf@b gBlvS7h0hKm z^]hQ萞[e @b gOP]]U_v^g0 (e) the finished products must contain ingredients complying with the qualitative and quantitative composition of the product described in the marketing authorization; the ingredients must be of the required purity, in their proper container and correctly labelled; (e) bT_{S+T&{T^:WS@bcv['`T[ϑ~bvbRbR_{0RBlv~^ Sň(WTv[hVQv^cknx4~{0 (f) records must be made of the results of inspecting and testing the materials and intermediate, bulk and finished products against specifications; product assessment must include a review and evaluation of the relevant production documentation and an assessment of deviations from specified procedures; (f) 9hncchhKmvire0-NSO0_SňNTTbTv~g_{ gvsQU_0NTċ0O_{SbvsQuNeNv[gTċ0ONSOPyĉ[ z^vOP]vċ0O0 (g) sufficient samples of starting materials and products must be retained to permit future examination of the product if necessary; the retained product must be kept for 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. (g) ^S_OYuYvSPgeTNT7hT NY\eg_e[NTvhKm0Yu7h_{(Wg~Sň[hV-NOX[S_ve d^SňǏ'Y Ygُ7hRO(uN^.USň|~vS_vSň0 17.4 Other QC responsibilities include: (a) establishing, validating and implementing all QC procedures; (b) evaluating, maintaining and storing reference standards for substances; (c) ensuring the correct labelling of containers of materials and products; (d) ensuring that the stability of the active pharmaceutical ingredients and products is monitored; (e) participating in the investigation of complaints related to the quality of the product; (f) participating in environmental monitoring; (g) participation in QRM programmes. These activities should be carried out in accordance with written procedures and, where necessary, recorded. 17.4 QCvvQNL#Sb a ^z0T[e@b gQCĉ z b ċ0O0~bTPX[irevhQT c OireTNTSň[hVvcknx4~{ d OvcNTTSeov3z['` e SNNT(ϑvsQvbɋg f SNsXvc g SNQRMeHh0 @b gُNd\O^S_ cgqfNb z^[e _e U_0 17.5 QC personnel must have access to production areas for sampling and investigation as appropriate. 17.5 QCNXT_{ g_ۏeQuN:SWS7hTg0 Control of starting materials and intermediate, bulk and finished products SPge0-NSO0_SňNTTbTvc6R 17.6 All tests should follow the instructions given in the relevant written test procedure for each material or product. The result should be checked by the supervisor before the material or product is released or rejected. 17.6 @b gvhKm^S_ cgqkN*NireTNTvsQvfNbhKmĉ zۏL0(WireTNT>eLbb~KNMR hKm~g^S_1u;N{[8h0 17.7 Samples should be representative of the batches of material from which they are taken in accordance with the approved written procedure. 17.7 7hT^YNh,gybire S7hel^ cgq]ybQvfNb z^0 17.8 Sampling should be carried out so as to avoid contamination or other adverse effects on quality. The containers that have been sampled should be marked accordingly and carefully resealed after sampling. 17.8 S7he^MQalgb[NT(ϑbq_TvV }0]SǏ7hTv[hV^S_v^vhv^(WS7hT\_[\0 17.9 Care should be taken during sampling to guard against contamination or mix up of, or by, the material being sampled. All sampling equipment that comes into contact with the material should be clean. Some particularly hazardous or potent materials may require special precautions. 17.9 S7he ^ǑSce2bkalgTmm0vccirevS7hY^S_nm0NNyrkqSi'`bؚ;m'`vire^ǑSv^vN蕪ce0 17.10 Sampling equipment should be cleaned and, if necessary, sterilized before and after each use and stored separately from other laboratory equipment. 17.10 S7hY^S_nm _e (WS7hMRTۏLmk v^N[[vvQNYR_PX[0 17.11 Each sample container should bear a label indicating: (a) the name of the sampled material; (b) the batch or lot number; (c) the number of the container from which the sample has been taken; (d) the number of the sample; (e) the signature of the person who has taken the sample; (f) the date of sampling. 17.11 k*NS7h[hV^S_4 Nh~{ v^hf (a) S7hirev Ty (b) ybS (c) S7hS (d) 7hTS (e) S7hN~{ T (f) S7heg 17.12 Out-of-specification results obtained during testing of materials or products should be investigated in accordance with an approved procedure. Records should be maintained. 17.12 ireTNThKmǏ z-NQsh~ge ^S_ cgq]ybQv z^ۏLgv^OX[vsQvU_0 Test requirements hKmBl Starting and packaging materials SPgeTSňPge 17.13 Before releasing a starting or packaging material for use, the QC manager should ensure that the materials have been tested for conformity with specifications for identity, strength, purity and other quality parameters. 17.13 SPgebSňPge>eLO(uKNMR QC~t^S_Oire&{T(ϑhQ nxO]~ۏLNt+R0+Tϑ0~^TvQN(ϑSpe0 17.14 An identity test should be conducted on a sample from each container of starting material (see also section 14.14). It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled. This validation should take account of at least the following aspects: 17.14 ^[kNSň[hVQvSeS7hۏLt+RhKmSz14.14 0S_]~^z z^nxOk*NSe[hVcknx4~{e S[NRkOv[hVireS7h0^\QN Neb  the nature and status of the manufacturer and of the supplier and their understanding of the GMP requirements;  uNFUTO^FUv'`(T0WMONSNN[GMPBlvt0  the QA system of the manufacturer of the starting material;  SPgeuNFUv(ϑO|~  the manufacturing conditions under which the starting material is produced and controlled; and  SPgeuNTc6RvuNagN  the nature of the starting material and the medicinal products in which it will be used.  SPgev'`(T(uNTNyoT Under such a system it is possible that a validated procedure for exemption from the requirement for identity testing of each incoming container of starting material could be accepted for the following: (Wdk|~ N S_n NRagNe SNcSMQdk*NۏSSe[hVvt+RhKmBlv z^ starting materials coming from a single product manufacturer or plant; or  egꁎNUS*NNTvuNFUb]SvSPge starting materials coming directly from a manufacturer, or in the manufacturer s sealed container where there is a history of reliability, and regular audits of the manufacturer s QA system are conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body.  vceguNFUv0bX[P(WuNFU[\Sň[hVQvSPge dkSň[hVwQ gS`'` v^NuNS[vQA|~[g1upNeoTvuNS[ b[e:gg[g[0 It is improbable that such a procedure could be satisfactorily validated for either:  starting materials supplied by intermediaries, such as brokers, where the source of manufacture is unknown or not audited; or  starting materials for use in parenteral products. S_QsN N`Qe NS[t+RhKmv z^ۏLEQR0  SPgeegꁎN-NN:gg OYNtN uNvegn*gwbl gۏL[  SPge(uNl\BR 17.15 Each batch (lot) of printed packaging materials must be examined following receipt. 17.15 kybpS7RPge(Wc6ee_{ۏLhg0 17.16 In lieu of full testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes the reliability of the supplier s analysis through appropriate periodic validation of the supplier s test results (see sections 8.8 and 8.9) and through on-site audits of the supplier s capabilities. (This does not affect section 17.15.) Certificates must be originals (not photocopies) or otherwise have their authenticity assured. Certificates must contain at least the following information (7): (a) identification (name and address) of the issuing supplier; (b) signature of the competent official, and statement of his or her qualifications; (c) the name of the material tested; (d) the batch number of the material tested; (e) the specifications and methods used; (f) the test results obtained; (g) the date of testing 17.16 O^FUcOvCOASNSNuNFUvh MRc/fuNON[gO^FUvh~gz8.8T8.9 v^s:W[O^FUvRN^zO^FURgvS`'`0COA_{/fSN N/fkbcN &TR_{O YpSNvw['`0COA_{\S+TN NQ[7  (a) O^FUvhƋ TyT0W@W (b) l[[XTv~{ TSvQD(Xf (c) hirev Ty (d) hirevybS (e) O(uvchTel (f) hKm~g (g) hKmeg In-process control -Nc6R 17.17 In-process control records should be maintained and form a part of the batch records (see section 15.25). 17.17 -Nc6RU_^S_OX[ vQ/fybU_vNRSz15.25 0 Finished products bT 17.18 For each batch of medicines product, there should be an appropriate laboratory determination of satisfactory conformity to its finished product specification prior to release. 17.18 [NkNyboT (W>eLKNMR^ gS_v[[h nx[vQ&{TNTch0 17.19 Products failing to meet the established specifications or any other relevant quality criteria should be rejected. 17.19 N&{Te[chbvQNvsQ(ϑhQvNT^S_b~>eL0 Batch record review ybU_[8h 17.20 QC records should be reviewed as part of the approval process of batch release before transfer to the authorized person. Any divergence or failure of a batch to meet its specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. 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