Cov tshuaj txhaj tshuaj yog siv dav hauv kev kho mob. Rau lawv cov kev npaj, ntau npaum li cas cov ntaub ntawv yog siv - kev daws teeb meem, ncua kev kawm ntawv, emulsions, hmoov, ntsiav tshuaj, ntxeem tau masses, yaj tam sim ntawd ua ntej parenteral tswj. Kev tsim cov tshuaj no yog ua los ntawm kev ua raws li cov cai ntawm kev ua kom tsis muaj menyuam, tsis yog pyrogenicity, tsis muaj cov khoom tsis huv thiab lub cev.
Technological scheme
Lub thev naus laus zis ntawm kev tsim cov tshuaj txhaj tshuaj thiab tshuaj raws li lawv suav nrog ntau theem:
- txheej txheem ua ntej: kev npaj cov ampoules, npaj cov ntim, vials, kaw cov khoom, cov kuab tshuaj, kev npaj ntawm thaj chaw, lim thiab cov neeg ua haujlwm.
- Kev tsim tawm ncaj qha ntawm cov kev daws teeb meem: dilution ntawm cov tshuaj tshuaj, stabilizers, preservatives thiab lwm yam auxiliary compounds; lim cov tshuaj.
- Ampouling - sau ampoules, vials, sealing lossis corking lawv.
- Sterilization.
- Leak test.
- Kev tswj hwm zoo.
- Sau, sau npe.
- Packaging thiab labeling of containers.
Requirements
Cov kev cai tseem ceeb rau kev txhaj tshuaj yog raws li hauv qab no:
- sterility (tsis muaj microbiological impurities tsis tau teev nyob rau hauv specifications);
- non-toxic;
- purity txheeb ze rau txhua yam impurities;
- non-pyrogenic (tsis suav cov khoom pov tseg ntawm cov kab mob, lossis pyrogens);
- physiological.
Lub cev ntawm cov kev daws teeb meem tau nkag siab tias yog kev sib xyaw ntawm ntau qhov tsis sib xws uas ua rau lawv siv tau rau tib neeg:
- isotonicity (osmotic siab);
- isohydricity (cov ntsiab lus ntawm qee yam ions thiab kab kawm);
- isoviscosity;
- isoionicity (constancy ntawm hydrogen ion concentration, pH ~ 7, 36).
Cov kev daws teeb meem zoo li no tuaj yeem pab txhawb kev ua haujlwm ntawm cov hlwb, cov ntaub so ntswg thiab cov kabmob thiab tsis ua rau muaj kev hloov pauv hauv tib neeg lub cev.
Aseptic mob
Kev npaj cov tshuaj txhaj tshuaj yog ua tiav ntawm qib siab ntawm purity ntawm ib puag ncig. Cov kev xav tau rau cov mob aseptic yog tswj hwm los ntawm thoob ntiaj teb GMP tus qauv. Kev faib tawm ntawm kev ua kom huv ntawm thaj chaw ua haujlwm raws li cov ntaub ntawv tswj hwm no tau ua nyob rau hauv ob lub xeev: nrog thiab tsis muaj cov neeg ua haujlwm. Chav A yog chav huv tshaj plaws.
Cov ntsiab lusmicrobiological Cheebtsam nyob rau hauv xws li cov chav yuav tsum tsis txhob ntau tshaj ib tug ntawm plaub tsis (units ntawm kev ntsuas yog qhia nyob rau hauv brackets):
- hauv huab cua (colony forming units per m³3);
- deposition ntawm wafer Ø90 mm (CFU rau 4 teev ntawm kev ntsuas);
- ntawm daim hlau tiv tauj Ø55 mm (CFU ib 1 phaj);
- ntawm tsib ntiv tes hnab looj tes (CFU).
Hauv thaj chaw ntawm pawg A, cov haujlwm hauv qab no ntawm kev tsim cov tshuaj txhaj tshuaj tau ua:
- unloading sterile ampoules (vials) thiab sealing cov ntaub ntawv;
- spill solutions;
- plug cov khoom;
- sib dhos ntawm cov lim rau kom tsis muaj menyuam;
- control sampling.
kev ruaj ntseg
Raws li kev ruaj ntseg ntawm cov tshuaj txhaj tshuaj yog nkag siab txog lawv cov cuab yeej kom tswj tau qhov muaj pes tsawg leeg thiab cov ntsiab lus ntawm cov khoom nquag hloov pauv raws li lub sijhawm teev tseg los ntawm cov txheej txheem txee lub neej. Nws tsuas yog nyob ntawm qhov ua tau zoo ntawm cov kuab tshuaj thiab cov tshuaj pib. Cov tshuaj uas yog ib feem ntawm cov kev daws teeb meem yuav tsum muaj qhov tsim nyog HCh - "tshuaj lom neeg", ChDA - "ntshiab rau kev tsom xam" lossis GDI - " haum rau kev txhaj tshuaj". Qhov ntsuas no tau qhia rau ntawm pob nrog cov tshuaj thiab hauv cov ntaub ntawv nrog.
Kev ruaj khov ntawm cov tshuaj txhaj tshuaj hauv kev tsim tshuaj siv tshuab tuaj yeem txhim kho ntau txoj hauv kev:
- Lub cev txoj kev: saturation ntawm txhaj dej nrog carbon dioxide, sau rau hauv ampoules hauvinert gas cua.
- Txhim kho qhov purity ntawm cov khoom pib: boiling txhaj dej thiab nws ceev ceev txias, recrystallization, kho nrog adsorbents.
- Taw qhia txog cov tshuaj tiv thaiv kab mob thiab cov stabilizers.
- Kev siv cov thev naus laus zis niaj hnub no - sublimation, nqus kom qhuav, khov tsis muaj dej thiab lwm yam.
Nyob rau hauv ib puag ncig alkaline thiab acidic heev, cov txheej txheem sterilization tuaj yeem ua rau muaj kev hloov tshuaj lom neeg. Yog li ntawd, rau cov tshuaj zoo li no, kev siv cov tshuaj stabilizers tshwj xeeb yog ib qho kev ntsuas uas yuav tsum tau zam.
Cov hom tseem ceeb hauv qab no ntawm stabilizers rau kev txhaj tshuaj yog siv hauv cov tshuaj:
- hydrochloric acid tov;
- sodium hydroxide thiab bicarbonate;
- antioxidants (rau cov tshuaj uas yooj yim oxidized, xws li ascorbic acid);
- tshwj xeeb stabilizers (cov kua qab zib thiab lwm yam).
Ua kom tsis muaj menyuam thiab pyrogenicity
Lub hauv paus tseem ceeb ntawm kev kis kab mob ntawm cov tshuaj nrog cov tshuaj microbial yog thaj chaw, khoom siv, cov khoom siv hauv huab cua, cov neeg ua haujlwm, cov cuab yeej siv kho mob thiab cov khoom siv, cov khoom siv yooj yim thiab cov khoom siv, cov kuab tshuaj. Cov kev cai rau kev txhaj tshuaj tiv thaiv kev ua kom tsis muaj menyuam (qhov tsis muaj cov kab mob ua haujlwm tau zoo thiab lawv cov spores hauv lawv) yog muab los ntawm kev ntsuas thev naus laus zis hauv qab no:
- filtering;
- adsorption ntawm sorbents;
- ua raws li qhov ntsuas kub;
- raug lub sijhawm xav tau thaum ua kom tsis muaj menyuam;
- ua raws li txoj cai aseptic hauv kev tsim khoom;
- ntxiv cov tshuaj tua kab mob.
Pyrogens, thaum lawv nkag mus rau hauv lub txaj vascular, tuaj yeem ua rau tus neeg ua npaws. Qhov no yog vim muaj cov endotoxins, uas muaj nyob rau hauv lub cell phab ntsa ntawm cov kab mob, fungi thiab kab mob.
Sterilization Methods
Kev ua kom tsis muaj menyuam ntawm cov tshuaj txhaj tshuaj yog ua tiav ntau txoj hauv kev thiab nyob ntawm cov tshuaj muaj pes tsawg leeg thiab cov khoom ntawm cov tshuaj txhaj tshuaj:
- Thermal (kub, cua). Yuav luag tag nrho cov kab mob pathogenic tuag los ntawm kev raug rau chav ntub dej. Kev ua haujlwm yog nqa tawm ntawm qhov siab tshaj thiab kub ntawm 120-132 ° C. Txoj kev tseem ceeb ntawm kev ua cov tshuaj txhaj tshuaj yog autoclaving hauv pre-sterilized vials. Cua sterilization yog nqa tawm nrog cua qhuav rhuab mus rau 200 ° C.
- Tshuaj (kev daws, roj av). Rau cov hom phiaj no, ethylene oxide thiab nws cov sib tov nrog carbon dioxide, freon, methyl bromide thiab lwm yam tebchaw feem ntau yog siv; hydrogen peroxide, peracetic thiab ua haujlwm acids.
- Kev lim. Txoj kev no yog siv rau cov kev daws teeb meem kub-rhiab thiab rau lub hom phiaj ntawm kev ntxuav los ntawm cov neeg kho tshuab impurities. Ib qho zoo tshaj plaws niaj hnub sterilization technologies yog ultrafiltration los ntawm membrane lim.
- Txoj kev tawg yog ua los ntawm irradiating cov tshuaj. Lub hauv paus yog radioisotope keeb lossis ib lub teeb hluav taws xob.
YAntioxidants
Oxidation thiab hloov pauv hauv cov khoom ntawm cov tshuaj txhaj tshuaj yuav tshwm sim nyob rau hauv lub zog ntawm cov pa oxygen muaj nyob rau hauv cov huab cua ntawm ampoule los yog vial, lub teeb, kub, acidity ntawm nruab nrab thiab lwm yam. Txhawm rau tiv thaiv qhov tshwm sim, cov haujlwm hauv qab no tau ua:
- qhia txog tshuaj antioxidants;
- siv cov complexones - cov khoom siv organic uas khi hlau ions rau hauv cov dej-soluble complexes ruaj khov;
- tsim kom muaj qib siab ntawm acidity ntawm nruab nrab;
- txo qis cov pa oxygen hauv ampoule;
- siv cov ntim tsis pom kev.
Cov kev cai tseem ceeb rau kev txhaj tshuaj nrog cov tshuaj antioxidants yog raws li hauv qab no:
- tsis muaj teeb meem ntawm cov tshuaj siv los tswj oxidation;
- muaj peev xwm ntawm daim ntawv thov hauv qhov tsawg kawg nkaus concentration;
- kev nyab xeeb ntawm cov khoom lag luam metabolic;
- zoo solubility.
Txhua hom tshuaj tua kab mob tau muab faib ua ob pawg loj:
- ncaj qha - txo cov neeg ua haujlwm, uas nws lub zog oxidizing ntau dua li cov tshuaj uas lawv tau siv;
- indirect (anti-catalysts), khi impurities nyob rau hauv daim ntawv ntawm hlau cations uas txhawb oxidative txheej txheem.
thawj pab pawg suav nrog cov tshuaj nrog cov txheej txheem hauv qab no:
- tso tseg kev tsim cov radicals (arromatic amines, phenols, naphthols);
- destructive hydroperoxides (sib xyaw nrog S, P, N atoms);
- cuam tshuam cov oxidation saw ntawm theem ntawm kev tsim cov alkyl radicals (molecular iodine, quinones, nitro compounds).
Cov tshuaj antioxidants uas nquag siv tshaj plaws yog cov khoom xws li: phenol derivatives, sodium sulfite thiab metabisulphite, aromatic amines, rongalit, trilon B, tocopherols, analgin, amino acids, unitiol, polybasic carboxylic thiab hydroxy acids (citric, salicylic, tartaric), thiourea, cysteine thiab lwm cov tshuaj.
Preservatives yog excipients uas pab tsim microbiological stability ntawm txhaj tshuaj. Cov kab mob microorganisms thiab lawv cov khoom lag luam metabolic uas nkag mus rau hauv kev txhaj tshuaj ua rau oxidation, hydrolysis thiab lwm yam kev cuam tshuam uas cuam tshuam rau cov tshuaj nquag. Kev xaiv ntawm preservative tsuas yog nyob ntawm cov khoom siv tshuaj ntawm cov tshuaj, pH ntawm qhov nruab nrab thiab txoj kev siv tshuaj. Lawv tau nkag mus rau hauv cov muaj pes tsawg leeg ntawm ob qho tib si ntau koob thiab ib koob tshuaj kho mob. Kev siv cov tshuaj tua kab mob tsis yog qhov hloov pauv rau cov kev cai aseptic.
Muaj kev faib tawm hauv qab no ntawm cov tshuaj ntawm pab pawg no (lawv qhov kev tso cai tso cai yog qhia hauv cov kab ke):
- Los ntawm hom kev ua: bacteriostatic - phenylethyl cawv (0.5%), merthiolate, methyl parahydroxybenzoate, benzoic, sorbic acids thiab lwm yam; Cov kab mob bactericidal - phenols, cresols.
- Los ntawm cov khoom siv tshuaj: inorganic - dej uas muaj nyiaj ions (1-10 mg / l); organometallic - merthiolate (0.02%),phenylmercury acetate (0.02%), phenylmercury nitrate (0.004%); organic - roj yam tseem ceeb (anise, laurel, lavender thiab lwm yam), cawv (phenylethyl, benzyl - 2%), hydroxybenzene (0.5%), benzoic acid esters (0.5%), organic acids (benzoic, sorbic - 0, 2%).
Cov kev cai hauv qab no siv rau cov khoom khaws cia:
- tsis muaj tshuaj lom, ua rau muaj kev cuam tshuam thiab ua rau khaus khaus nyob rau hauv cov ntawv thov concentration;
- broad antimicrobial spectrum;
- zoo solubility;
- tsis muaj tshuaj lom neeg cuam tshuam nrog lwm yam khoom ntawm cov tshuaj thiab ntim khoom;
- ruaj khov ntawm qhov sib txawv ntawm qhov nruab nrab acidity thiab kub;
- tsis cuam tshuam rau cov khoom organoleptic (xim, pob tshab).
Cov tshuaj tiv thaiv tsis raug tso cai hauv cov tshuaj xws li:
- intracavitary;
- intracardiac;
- intraocular;
- muaj kev nkag mus rau cerebrospinal kua;
- qauv nrog ib koob tshuaj ntau dua 15 ml.
dej txhaj tshuaj
Dej nrog qib siab ntawm kev huv yog siv rau kev npaj cov dej raws li kev daws teeb meem. Cov khoom siv niaj hnub no rau nws cov khoom tsim muaj xws li ntau theem ntawm kev ua:
- ua ntej ntxuav;
- reverse osmosis;
- deionization;
- filtration (los yog ultrafiltration thiab ultraviolet sterilization).
Npaj dej rau cov ntawv txhaj tshuaj yog khaws cia tom qab distillation tsis pub dhau ib hnub hauvkaw vials nyob rau hauv aseptic tej yam kev mob los tiv thaiv kev nkag ntawm microorganisms. Rau cov tshuaj uas tsis ua kom tsis muaj menyuam, siv cov dej tsis huv rau kev txhaj tshuaj, nchuav rau hauv cov yas lossis iav ampoules.
Non-aqueous solvents
Cov khoom xyaw hauv qab no yog siv los ua cov kuab tshuaj tsis muaj dej hauv kev tsim cov tshuaj txhaj tshuaj:
- Cov roj muaj roj (peach, apricot, almond thiab lwm yam). Lawv tau txais los ntawm lub cev qhuav dej thiab tom qab txias nias ntawm cov noob. Cov kua qaub ntawm cov roj yuav tsum tsis pub ntau tshaj 2.5, vim tias tus nqi siab dua ua rau cov hlab ntsha tawg.
- Mixed kuab tshuaj. Lawv suav nrog kev sib xyaw ntawm cov roj zaub thiab cov kua roj sib tov (ethyl oleate, propylene glycol, benzyl benzoate, glycerol esters, benzyl cawv). Lawv qhov zoo dua ntawm pab pawg dhau los yog lub zog tawg loj. Cov formulations no yog siv nyob rau hauv zus tau tej cov tshuaj nrog sparingly soluble tshuaj (hormones, vitamins, tshuaj tua kab mob, thiab lwm yam).
Qhov tsis zoo ntawm cov roj hnyav rau kev txhaj tshuaj suav nrog:
- nce viscosity;
- mob ntawm qhov chaw txhaj tshuaj;
- ncua kev nqus ntawm cov khoom xyaw;
- cov kev mob tshwm sim - kev loj hlob ntawm lipogranulomas (kev tsom mus rau qhov mob ntev).
Type of packages
Ntau hom ntim tau siv los daws:
- ampoules (lawv qhov loj tuaj yeem yog 0.3 txog 500 ml);
- vials (tsuas yog rau cov tshuaj tua kab mob thiab tshuaj organotherapeutic, kev daws teeb meem nrog cov viscosity siab);
- tubes nrog ob tus nres;
- koob txhaj tshuaj nrog rab koob;
- cov nkoj thiab ntim khoom ua los ntawm cov yas.
Cov tshuaj txhaj tshuaj hauv ampoules raws li qhov muaj feem thib ob tom qab ntsiav tshuaj. Ua 2 hom ampoules - qhib thiab kaw. Cov tom kawg yog qhov tseem ceeb tshaj plaws, txij li thaum lawv raug kaw, cov kev daws teeb meem raug cais tawm ntawm ib puag ncig, uas ua rau nws muaj peev xwm tsim cov tshuaj nrog lub neej txee ntev.
Kev tsim khoom ntawm ampoules
Feem ntau, ampoule iav yog siv rau ntim tshuaj thiab infusion daws. Muaj ob qhov tseem ceeb rau nws lub cev thiab tshuaj lom neeg:
- Txoj kev pom kev yooj yim ntawm kev tswj xyuas cov ntsiab lus (tsis muaj sediment, mechanical impurities, spoilage).
- tshuaj tiv thaiv.
Quartz iav muaj qhov ua tau zoo tshaj plaws hauv kev sib raug zoo rau qhov ntsuas tom qab, tab sis nws muaj qhov kub siab heev - 1,800 ° C. Txhawm rau txhim kho nws cov thev naus laus zis zoo, cov ntsiab lus hauv qab no tau ntxiv:
- sodium thiab potassium oxides uas txo cov refractoriness;
- CaO thiab MgO kom txhim kho cov tshuaj tiv thaiv;
- txhuas oxide thiab boron oxide kom zoo dua soldering thiab tiv thaiv tawg.
Thaum nyob rau hauv kev sib cuag nrog dej thiab txhaj tshuaj, sodium silicate yog ntxuav tawm ntawm lub iav ampoule, ib zaj duab xis uas muaj silicic acid yog tsim. tshwj xeeb tshaj yog muaj zogalkaline compounds corrode iav. Rau cov tshuaj formulations uas yog rhiab heev rau pH hloov (xws li alkaloids), tsuas yog chav kawm 1 iav yog siv.
Cov chaw tsim tshuaj niaj hnub tsim cov ampoules rau kev txhaj tshuaj siv cov thev naus laus zis hauv qab no:
- calibration ntawm iav raj (tso raws txoj kab uas hla, ntev thiab curvature);
- ntxuav hauv chav nrog dej kub lossis hauv da dej ultrasonic;
- ziab nrog cua kub lim;
- txiav cov hlab, ua rau ntawm lub khob-txheej tshuab lossis tshuab semi-automatic;
- kho cua sov (annealing hauv qhov cub) kom tshem tawm cov kev ntxhov siab seem;
- ib txheej ntawm ampoules nyob rau hauv cassettes, lawv sab nraud thiab sab hauv ntau qhov ntxhua (syringe, da dej, ultrasonic).
Control
Qhov zoo ntawm cov tshuaj txhaj tshuaj yog tshuaj xyuas los ntawm ntau qhov tsis muaj:
- transparency;
- xim;
- tsis muaj cov khoom tsis huv (tswj ob zaug - ua ntej thiab tom qab ua kom tsis muaj menyuam);
- authenticity (tshuaj ntsuam xyuas ntawm qhov muaj pes tsawg leeg ntawm cov khoom tseem ceeb thiab cov khoom pabcuam);
- pH;
- endotoxin, tsis muaj menyuam (tswj dej rau kev txhaj tshuaj, cov khoom siv tshuaj nruab nrab thiab zaum kawg);
- ntim ntawm lub nkoj ntim;
- ntim khoom nruj.
Kuaj xyuas cov tshuab suav nrog ua qhov muag pom. Txij li cov qauv no yog cov ntsiab lus, qhov kev txheeb xyuas qhov yuam kev yog siab thiab muaj txog li 30%. Tsis muaj cov khoom yog tswj nyob rau hauv lem ntawm ib tug dub keeb kwm yav dhau.(iav hmoov av, insoluble hais, zoo fibers los ntawm lim) thiab nyob rau hauv dawb (xim, tsaus inclusions, zuag qhia tag nrho kev ncaj ncees).
Hom kev kis kab mob tseem ceeb ntawm kev txhaj tshuaj yog iav hmoov av (txog 80% ntawm tag nrho). Nws yog tsim los ntawm cov theem tsim khoom hauv qab no:
- tsim tawm ntawm ampoules;
- txiav capillaries;
- kev kho cua sov.
iav me dua 1 micron nkag mus rau hauv cov hlab ntsha ntawm phab ntsa, thiab tom qab ntawd mus rau hauv yuav luag tag nrho cov ntaub so ntswg thiab lub cev. Ntxiv nrog rau cov iav, cov tshuaj txhaj tshuaj tuaj yeem muaj cov khoom siv los ntawm cov hlau, roj hmab, yas, uas yog vim lawv nkag los ntawm cov khoom siv, ntim khoom, los ntawm cov neeg ua haujlwm pabcuam.
Nyob rau theem kev npaj, ampoules thiab vials raug tso tseg yog tias lawv tsis ua raws li kev tsim khoom. Kev tswj cov tshuaj txhaj tshuaj yog ua tiav ntawm txhua theem ntawm cov txheej txheem thev naus laus zis. Tightness, zoo ntawm sealing thiab capping ntawm cov thawv raug kuaj nyob rau hauv ob peb txoj kev:
- nqus tsev;
- ntsuas kev daws teeb meem (rau kev txhaj tshuaj raws li dej);
- xab npum tov (roj raws li txhaj tshuaj);
- los ntawm lub teeb ntawm cov roj hauv lub nkoj txhaj tshuaj raws li qhov tshwm sim ntawm ionization nyob rau hauv qhov kev txiav txim ntawm hluav taws xob teb.
