S1 Seminar Tonicity Adjustment 2024 PDF

24.11.2023 Tonicity adjustment Assoc. Prof. PharmDr. Zdenka Sklubalova, Ph.D. Faculty of Pharmacy CUNI Department of Pharmaceutical Technology Šklubalová, Vraníková: Oční přípravky. Maxdorf. 2018. ISBN 978-80-7345-572-9 1 1 24.11.2023 Osmosis An aqueous solution in contact with body fluids and tissue membranes water movement through a semipermeable membrane isotonic  hypotonic  hypertonic  conclusion 2 2 24.11.2023 Osmotic pressure of solutions Vanꞌt Hoff equation   R Tmn … osmotic pressure (kPa) R… universal constant for gases (J/molK) T… absolute temperature (K) m… molality of a solution (mol/kg) n… number of particles resulting by dissolution of a substance 3 3 24.11.2023 Começo do áudio Modification for electrolytes Vanꞌt Hoff equation   R  T  m i Theorical calculation of I is very diﬃcult i… Vanꞌt Hoff’s factor for correction dissociation  number of particles (ions) concentration interionic attractions Influences the value of i and solvation 4 4 24.11.2023 Modification for electrolytes i… Vanꞌt Hoff’s factor for correction  influence of dissociation level i  1   n 1   … coefficient of dissociation n… number of particles (ions) existing in a solution an example The value of Vanꞌt Hoff’s factor i The actual value never reaches the theoretical one 5 5 24.11.2023 Colligative properties depend only on the number of particles in the solution osmotic pressure elevation boiling point elevation vapour pressure depression freezing point depression mostly used: 6 6 24.11.2023 Freezing point depression Freezing point depression of an aqueous solution Liso T  K f  i  m T…freezing-point depression Kf…molal freezing-point depression constant of water (cryoscopic constant) i…Vanꞌt Hoff’s factor for correction m… molality of a solution (mol/kg) Has larger volume than molarity, but molarity has higher concentration than molality To convert from morality to molar it’s we must know the density 7 7 24.11.2023 Estimation of ΔT For the diluted aqueous solutions the molal concentration m (mol/kg) can be replaced by molar concentration c (mol/L) Liso according to the valency of electrolyte electrolytes Liso value bi-bivalent 2.0 Very low value , due to non mono-monovalent 3.4 complet dissolution mono-bivalent 4.3 bi-monovalent 4.8 8 If the y have isotonic they have the same colligative properties 8 24.11.2023 Law of colligative properties Solutions having the same colligative properties ARE Isotonic An ……………………………………. solution exerts ………………………............. osmotic pressure as body fluids 9 9 24.11.2023 Law of colligative properties Tonicity adjustment is based on a comparison of the colligative properties with a standard Lacrimal fluid and human blood have an isotonicity value corresponding to that of comparison of …………………… 10 10 24.11.2023 Estimation of freezing-point depression isotonic solution of  T  L iso  c Remember, is the value for isotonic solutions of sodium chloride T  3.4. 0.154 = 0.520 standard freezing point depression Without this number we are not able to resulte certain equations T  0.520 any solution having ………………………………………………….. The same freezing point depression as the …………………………………………………… 9g/l solution of sodium chloride Isotonic IS ………………………… WITH BODY FLUIDS 11 Low concentration of osmoticly active particles- hypotonic What is the value of hipotonic solution It has lower value than the isotonic Hypotonic solutions we never use, we know it’s an hypotonic solution if the value is lower than the 0.520. 11 24.11.2023 Tonicity adjustment of eye drops 12 12 24.11.2023 Composition of eye drops Compounding of eye drops requires the addition of necessary excipients 1. following the general Pharmacopoeial requirements to adjust Isotonic it’s of a hypotonic solution (toxicity adjuster) - because we never use this hypotonic solution to prevent At the time of opening it must be sterile but to prevent the contamination in a multi dose container (preservatives) 2. according to the specific requirements of a practitioner to adjust to adjust 13 13 24.11.2023 Tonicity adjustment correction of a hypotonic solution to an isotonic solution the addition of the tonicity adjuster 14 14 24.11.2023 Tables The measured values of freezing-point depression (T, D-value) of the substance solution are tabulated in relationship to the PERCENT CONCENTRATION (w/w and/or w/v) 15 15 24.11.2023 Buffering of eye drops correction of a hypotonic solution to an isotonic solution having a suitable pH value by the addition of a suitable buffer 16 16 24.11.2023 The amount of tonicity adjusting agent can be determined by different methods the freezing-point depression method (T, D-value) the sodium chloride equivalent method (E-value) the isotonic solution method (V-value) 17 17 24.11.2023 Tonicity adjustment of eye drops Basic steps 1. estimation of a drug contribution 2. estimation of a „gap“ 3. estimation of an adjuster concentration 4. estimation of an adjuster mass 5. editing of eye drops prescription 18 18 24.11.2023 Prescription Pilocarpine hydrochloride 0.20 g Water for injection to 10.0 mL 19 19 24.11.2023 Tonicity adjustment 1. Contribution of a drug Determine the percent concentration of the drug Read D-value (ΔT) caused by a drug in a Table 1% ΔT = Calculate the D-value (ΔT) caused by the prescribed concentration of the drug ΔT = 20 20 24.11.2023 Tonicity adjustment 2. Estimation of a „gap“ Subtract this from the desired isotonic D-value (ΔT) Decide on an appropriate tonicity adjuster 21 21 24.11.2023 Tonicity adjustment 3. Concentration of the adjuster Read D-value (ΔT) caused by NaCl in the Table 1% ΔT = Calculate the concentration of sodium chloride needed to give the remaining freezing point depression (= to achieve isotonicity) 22 22 24.11.2023 Tonicity adjustment 4. Mass of adjuster Calculate the mass (g) of sodium chloride needed for the desired (prescribed) volume of a solution (10 mL) 23 23 24.11.2023 Editing of eye drops prescription multidose containers a suitable Calculate required mass (g) of................................... required for THE PRESCRIBED VOLUME of preparation 24 24 24.11.2023 Editing of eye drops prescription Write a total composition of eye drops Pilocarpine hydrochloride 0.20 g Water for injection to 10.0 mL 25 25 24.11.2023 4. Compounding 1. Tare a glass beaker 2. Weigh the prescribed mass of pilocarpine hydrochloride the required mass of ……………………………………….. pour into a beaker 3. Add the ………………… % aqueous solution of......... to make 10 mL of isotonic eye drops. 4. Dissolve substances by mixing. 5. 26 26 24.11.2023 TASK Prescription Homatropine hydrobromide 0.10 g Water for injection to 10.0 mL calculate the mass of tonicity adjuster boric acid edit the composition of multidose eye drops 27 27 24.11.2023 osmotic pressure==> concentration hypotonic ==> more dangerous for system Tonicity adjustment Assoc. Prof. PharmDr. Zdenka Sklubalova, Ph.D. Faculty of Pharmacy CUNI Department of Pharmaceutical Technology Šklubalová, Vraníková: Oční přípravky. Maxdorf. 2018. ISBN 978-80-7345-572-9 1 1 24.11.2023 Osmosis An aqueous solution in contact with body fluids and tissue membranes water movement through a semipermeable membrane isotonic  balance hypotonic  hydration ==> more dangerous hypertonic  dehydration conclusion aqueous solutions must be isotonic==>pharmacopoeia 2 2 24.11.2023 Osmotic pressure of solutions Vanꞌt Hoff equation => only works for non-electrolytes   R Tmn … osmotic pressure (kPa) R… universal constant for gases (J/molK) T… absolute temperature (K) m… molality of a solution (mol/kg) n… number of particles resulting by dissolution of a substance ==> if we have molecule or ion during dissolution 3 3 24.11.2023 Modification for electrolytes Vanꞌt Hoff equation ==> electrolyte   R  T  m i i… Vanꞌt Hoff’s factor for correction dissociation  number of particles (ions) concentration ==> more concentrwation we ahve less disociation we have interionic attractions and solvation ==> difficult to predict 4 4 24.11.2023 Modification fornotelectrolytes a good way to predict osmotic pressure i… Vanꞌt Hoff’s factor for correction for simple solution  influence of dissociation level !!!!!!  i  1   n 1  … coefficient of dissociation best in low conc n… number of particles (ions) existing in a solution an example low conc of NaCl==> I=2==> in ideal solution The value of Vanꞌt Hoff’s factor i 5 5 24.11.2023 Colligative properties depend only on the number of particles in the solution osmotic pressure elevation boiling point elevation vapour pressure depression freezing point depression !!!!used as value if we get one of these we can reach to others mostly used: change in freezing point depression==> for solving problems of tonisity adjustment 6 6 24.11.2023 Freezing point depression Freezing point depression of an aqueous solution Liso ==> depndent on electrolyte type 1.86==> always constant like 3.72 for NA CL T  K f  i  m T…freezing-point depression Kf…molal freezing-point depression constant of water (cryoscopic constant) ==> reflex to aqueius environment 1.86k.kg/mol i…Vanꞌt Hoff’s factor for correction m… molality of a solution (mol/kg) ==> concentration of solvent mol/l (of soln)==> has more conc than molality 7 7 24.11.2023 Estimation of ΔT For the diluted aqueous solutions the molal concentration m (mol/kg) can be replaced by molar concentration c (mol/L) delta T= Liso x c (mol/l) Liso according to the valency of electrolyte electrolytes Liso value bi-bivalent 2 mono-monovalent 3.4 mono-bivalent 4.3 bi-monovalent 4.8 8 8 24.11.2023 Law of colligative properties Solutions having the same colligative properties ARE ISOTONIC ==> TARGET we can compare ours collgative to standrard coligative An ……………………………………. isotonic solution exerts ………………………............. same osmotic pressure as body fluids same colligative properties 9 9 24.11.2023 Law of colligative properties Tonicity adjustment is based on a comparison of the colligative properties with a standard freezing point depression Lacrimal fluid and human blood have an isotonicity value corresponding to that of 0.9% w/v (9gr/l) sodium chloride solution==> same coligative proper comparison of …………………… delta T 10 10 24.11.2023 Estimation of freezing-point depression isotonic solution of  T  L iso  c T  3.4. 0.154==> 0.52 ==> remember this number standard freezing point depression T  0.52 ==> remember any solution having ………………………………………………….. same freezing point depression 9g/l solution NaCl as the …………………………………………………… isotonic IS ………………………… WITH BODY FLUIDS 11 freezing point of body fluid ==> -0.52c we only use the value as number 11 24.11.2023 delta T of 0==> pure water less than 0.52 ==> hypotonic (lower delta T) --> line of isotonic we can use hypertonic solution ==> delta T more than 0.52 we only solve hypotonic solution problem we use hypertonic ==> in parenteral nutrition Tonicity adjustment of eye drops 12 12 24.11.2023 Composition of eye drops Compounding of eye drops requires the addition of necessary excipients 1. following the general Pharmacopoeial requirements to adjust isotonisity of a hypotonic solution **** to prevent contamination by adding preservative(in multi- dose container) 2. according to the specific requirements of a practitioner Stability of the drug to adjust PH value (buffer) to adjust viscosity (viscosity increasing agent) 13 13 24.11.2023 Tonicity adjustment correction of a hypotonic solution to an isotonic solution the addition of the tonicity adjuster ==> NaCl, KI , mannitol if we cant use electrolyte sodium chloride is incompatible with silver ==>precipitation chloride cant mix with silver containing medication Sodium chloride Both are electrolytes (first two) if we are not able Potassium nitrate to use it we should use the mannitol Mannitol 14 Anything that contains silver it precipitates 14 24.11.2023 Tables The measured values of freezing-point depression (T, D-value) of the substance solution are tabulated in relationship to the PERCENT CONCENTRATION (w/w and/or w/v) 15 15 24.11.2023 by adding buffer change of PH value we change tonocity adjustment Buffering of eye drops correction of a hypotonic solution to an isotonic solution having a suitable pH value => for patient compliance + API stability by the addition of a suitable buffer ==>phsophate and borate are common for ophtalmic agent Hypotonic and convert to isotonic by addition of buﬀer - phsophste and borate, for pharmacy they are the most used. Buﬀer is solution of some substance that keeps the solution at some ph value When we add buﬀer the ph isn’t the only thing that changes but also the tonicity 16 16 24.11.2023 The amount of tonicity adjusting agent can be determined by different methods the freezing-point depression method (T, D-value) most common use the sodium chloride equivalent method (E-value) the isotonic solution method (V-value) 17 17 24.11.2023 Tonicity adjustment of eye drops Basic steps 1. estimation of a drug contribution 2. estimation of a „gap“ 3. estimation of an adjuster concentration 4. estimation of an adjuster mass 5. editing of eye drops prescription 18 18 24.11.2023 Prescription Pilocarpine hydrochloride 0.20 g Water for injection to 10.0 mL Pil HU 0120g 10mL 21 01138 0,276 double y 19 19 24.11.2023 Tonicity adjustment 1. Contribution of a drug Determine the percent concentration of the drug 2% Read D-value (ΔT) caused by a drug in a Table 1% ΔT = 0.138 Calculate the D-value (ΔT) caused by the prescribed concentration of the drug direct proportion ΔT = 0.276 is hypotonic 20 less than our target 20 24.11.2023 Tonicity adjustment 2. Estimation of a „gap“ Subtract this from the desired isotonic D-value (ΔT) 0.520-0.276=0.244 No units, only value We need to feel this gap with an excipient Decide on an appropriate tonicity adjuster ==> sodium chloride 21 21 24.11.2023 Tonicity adjustment 3. Concentration of the adjuster Read D-value (ΔT) caused by NaCl in the Table 1% ΔT = 0.576 Contribution of 1% gives us this value and we want only 0.244 Calculate the concentration of sodium chloride needed to give the remaining freezing point depression (= to achieve isotonicity) 0.424% Looking for the percentage since we know the contribution 22 22 24.11.2023 Tonicity adjustment 4. Mass of adjuster Calculate the mass (g) of sodium chloride needed for the desired (prescribed) volume of a solution (10 mL) 0.424/10 = x x 10==> 0.04gr of NaCl tp reach isotonicity Round to the second decimal place ***if we have D.S 3x or 2x or 1x a day ==> we need preservative (shows we have multi-dose) ===> benzalkoholium chloride efficient in 0.01% wide range of PH 23 best choice preservative 23 24.11.2023 Editing of eye drops prescription multidose containers a suitable preservative==> benzalkholium chloride 0.01% Calculate required mass (g) of................................... 0.001gr = 1mg required for THE PRESCRIBED VOLUME of preparation 24 24 24.11.2023 Editing of eye drops prescription Write a total composition of eye drops Pilocarpine hydrochloride 0.20 g sodium chloride 0.04gr benzalkoholium chloride 0.001gr Water for injection to 10.0 mL 25 25 24.11.2023 4. Compounding 1. Tare a glass beaker 2. Weigh the prescribed mass of pilocarpine hydrochloride sodium chloride the required mass of ……………………………………….. pour into a beaker Very small mass 3. Add the ………………… 0.01 benzalkoholium % aqueous solution of......... to make 10 mL of isotonic eye drops. chloride 4. Dissolve substances by mixing. 5. sterilization bacterial retentive filtration 26 26 24.11.2023 TASK Prescription Homatropine hydrobromide 0.10 g Water for injection to 10.0 mL calculate the mass of tonicity adjuster boric acid edit the composition of multidose eye drops 27 0,10g/10 ml Contribution of the drug is 0.10 at Direct contribution is 0.29 of boric acid Calculation of the gap - 0.520- 0.10= 0,42 1% is 0,29 1.45% 1.45/10=0,145 =150 mg =0,15 g 150 mg 27 Composition of infusions Assoc. Prof. PharmDr. Zdenka Sklubalova, Ph.D. Faculty of Pharmacy CUNI Department of Pharmaceutical Technology Šklubalová, Vraníková: Oční přípravky. Maxdorf. 2018. ISBN 978-80-7345-572-9 Infusions Direct application of substances into the central circulation aqueous solutions inactive substance it dependsontherouteof administration body compartent active substance verytypicalin infusionprep Effects of infusions on the inner balance effecton potent dissolvedparticles 1. hydration ms semi permeable membranethathas incontactwith membranesomemovement ofwater the water + ion water + molecule osmolality 286 mOsmol/kg  1% fluidvalue physiological verymannow nauge a verycommalled hyperosmolality ==> lose of water but not ion bythebody ms hormonesandmechanis both dangerous and inneed hypoosmolality ==> loose of ion without water ionnect colloidal osmotic pressure ==> effect of macromolecule colloid of macromolecule 2. acido-basis balance ABB weneedto use this prepenationto tonnect acidosis ==> more dangerous effect of ion and molecule mm alkalosis Stand and infusion therapy can influence hidnation andacid basicbalance Effect of infusions on hydration Osmotic effect Osmotic pressure pby temperature physical variable (measured) (colligative property) depends on the concentration molality Osmotic concentration ions molecluses osmotic effect of particles in infusions osmotic effect of 1 mol  1 Osmol we usually use miliosmol osmolality (osmol/kg) osmolarity (osmol/L) physical way solvent solution only in infusion can be measured by osmometer directly morepractialbut cannot be measured notpraticalfortheuse !!!!!!!! for conversion of osmolality and osmolarity we need to know density Theoretical osmolarity USP c os   c  n electrolyte dependson momelectrolyte c.... molarity of solution (mol/L) n... number of particles resulting from 1 mole non-electrolyte electrolyte glucose a remains as itis subs splitinto ions Theoretical osmolarity - example 55g/l gloucose==> 0.278 x 1 = 0.278 osmol/l ==> isotonic Cos C m 0,278 1 g is lay 0,278 osmof L 0127759 isotonic sodium chloride==>9g/l ==>==> 0.154 x 2==> 0.308 osmol/l ==> ideal situation TF osmolarity is greater than molarity in this case 58 0,154 Cos C M 0,154 2 0,308 osmal α Log theoretical osmolality we don't have 2particles this is the theonical value Theoretical osmolarity- example Mandatory We haveto expressbyosmolaritywhenexpressing us alot are prepare inhospitalpharmacy Labelbyosmolarity wehavetocalculate ear Estimation of osmolarity of Ringer-lactate solution substance we can summarise 1e Composition M Mw c n 1000 (g/l) (g/mol) (mmol/L) NaCl 6.00 58.44 102.66 2 205,3 Nad canbecharacterizedasexcipient KCl 0.30 74.55 4.024 2 8,048 CaCl26H2O 0.395 219.08 1.803 3 5 0409 Na lactate 3.09 112.06 27.57 2 55 14 total 273,9 osmolarity 274 mOsmol/l no isotonic even if we obtain _otdlIete zarb hamashoon issthnoade va baad jam kardaneshoon bicarbonate Laitatelastproducts water ifthepatienthashypenosmolarityyoucannot administerwarndirectlyinto theremote it isverydangerous Butifwe useprepenationsthat contained a lotofmetabolized substance youwillproduce waterbythe metabolism Patientnowhas a reliable wehave to have in consideration fontofwater Patientis able tometabolize Nowater dinently butwecare employthemetabolis Modified the rate by choosingthe substance we reducethe oftheconstantpantiles andreplacewithmetabolism some tan tombinethemtogether alipay.at h ganom we canalsousedirectlythesolution of sodiumacetatewithoutanyother substance o sodiumuptakeonglucoseas a isotonicsolution administration of water is toxic in hypertonicity Osmotic effect of dissolved substances affeit by marine ofsubstance Small molecules and ions non-metabolized after administration constant effect osmotic until its eliminated from body Na, K, Ca, Mg, Cl, … substance doesnotchangeinthemetabolism metabolized graduall decrease in effect via metabolism in body acetate, lactate, glucose ==> metabolize to bicarbonate and water rate of metabolism is different in between them decrease omostic effect if we need to add water==> we can use more the metabolizable substances and lower concentration of ions (hypoionic solution) theratedepends onwhat wechoose Osmotic effect of dissolved substances ==> doesnt affected by nature of substance just number Macromolecules (albumin) 11thpigmentsInwater becutethey important areresponsiblefortrapmentof minimum osmotic effect important circulation to pull water and keep it in central colloidal osmotic (oncotic) pressure moonionic is very important pressure Donnan equilibrium in the presence of ellectrolytes physic hydroxyethylstarch dextran plasma expander modified gelatin pegylated albumin with macrogol notend wehavetobecareful withtheadverseeffects verydangerous opioid Effect of infusions on ABB 2typeof jackground fluids immacel extracel Bodyfluid whichnation isthemostimportant inplasma Sodium Na 140 150 ran in anion is the mostimportant in plasma chlorine U 100 anions man banana managing theprepthatweusetoadministerinto infusiontherapydirectlyaffectsexmadu Chlorideis thebestdissolved substance ingeneral a thesystemwithoutanyproblems is isotonic fluid D but it doesnotaffectimmaceu salts aquossolution Bestforinfusion therapy If we haveoverload of A pp there's acidityeffect no bodyantivates fluidconnection system andthemostflexibleanion difference bythe ofA theanion that willdois Bicarbonate compartments No kt HPO n Natanda_ Electrolyte composition of the body Body Fluids and Fluid Compartments | Anatomy and Physiology II (lumenlearning.com) Administration of the isotonic sodium chloride infusion infusion Na : Cl 1:1 154mmol/l of both sodium and chloride plasma Na : Cl 1:4 140 mmol/l and 100mmol/l of chloride overload of Cl- : leads to lowering of bicarbonate and hence ==> acidosis==> used for correction of alkalosis Cl- ==> acidifying effect lactate==> for correction of acidosis darrow ==> used for loss of potassium patient Parenteral electrolyte infusions all are isotonic Infusion Content of ions (mmol/L) cos Na K Ca Mg Cl Lactate (mosm/l) Darrow’s 121 36 - - 104 53 314 He ftmEnat.am wimna aEltslllllef less than higher normal f Hartmann’s 130 5.4 0.9 1.0 112 27 276 im e miaem reduce and replaced by lactate==> no _FFddtldlLIls effect on acid-base ==> good for longer NaCl, isotonic 154 - - - ffgaasaaaanaaaa 154 therapy - 308 Ringer’s ==> acidifyes 147 4.0 2.3 - 156 - 309 i.it ttte nseeffe beacusei Maxwell’s of Cl- i.w 140 - 1.4 0.7 101 43 tonne normal Jolt tinger ==> shor-term carrier balanced maxwell ==> solution for dialysis==> close electrolyte to plasma==> we dont have kt potassium since body tries to excrete is==> add of potassium before therapy hartmann ==> good for long-term electrolyte therapy ringer ==> for alklosis Sterilisation of eye drops Too The mm Tamanduddhitmmammmmmeletollallelle Assoc. Prof. PharmDr. Zdenka Sklubalova, Ph.D. to dryheat air Faculty of Pharmacy CUNI Tllllllree DDradiation β fortleoff gama D bacteria name Almann Department of Pharmaceutical Technology forprevention t terminal offendination wetannotfilmatesomething in aclosed Šklubalová, asprit Vraníková: Oční přípravky. Maxdorf. 2018. ISBN 978-80-7345-572-9 finalcontainer conditions bacteria retentive filter==> no terminal filtration other 4 methods ==> terminal ==> closed container Sterilisation Eye preparations - Category I (Ph.Eur. 10.0) sterility validated method terminal sterilisation ==> first choice bacterial filtration => not terminal ==> must work aseptic condition==> for prevention of presence of contamination SAL stenility assurance Level byme expressed thatwehavesome doubt Not it'saboutprobability stemeasthattheabsoutlymothinglving DS.at doesit mean ofminimum 10 statisticalprobability that I Milnoongacouldsurvive in 1million Therule thatdescribes thedecreasinofnumber is the1storder Curve looksexponential I timedoesit Howmuch It never ashives taketoactive whatis theprinciple of validationwhatreference of mind 8 t of evenending we usethe most resistantorganisms if it worksonthemit willalsowork onthe giff isaimiuposoga.hngot iatt In moresensible ones inrealtimewehavedoubtsofithappenbutto beableto use thepreparationwehavetobesa ofit's sterility pexponential 1st ordered kinteic==> rate of MIO eradication SAL ==> sterility assurance level mn expression ofstaticsprobability IinImiltion.fmallthemethods istheminimum SAL of minimum 10-6 sterile devices no single use mosttime titterholder smallroots plasticsyninge singleuse container sterile membrane filter pore size 7 wehave diameter ofthefilterdependingonthemethod under 0.22 micrometer clean area no particle & MIO contamination Efficiency of bacteria retentive filtration depends on: the contamination level (bioburden) 2 we don'tknowtheN ofcontamination the filter reliability handtopredict capacity of a filter, batch size Thepressure isimportantwhenfiltration the filtration pressure limit ==> 5 bar drop by drop Tube is verythin if tomuchpressure is used themembranewillrupture follow the rules of aseptic processing Laminar air-flow cabinet (LAC) Class A ==> aseptic Hepa HEPA filter Filter 2ronditions laminar air flow Filtered Air Room Air Prefilter hospital pharmacy Fume Extraction Systems & Lab Safety Solutions - TION Aseptic technique rules Cleaning & disinfection ==> in small scale pharmacies laminar air current LAC should operate continuouslyshouldn't beturnedoff If turned off it must run for...........................minutes 15-30 to reestablish laminar air flow Before use all interior working surfaces should be disinfected LAC should be repeatedly disinfected................................... in the regular time intervals Cleaning & disinfection contamination goes to hepa filter Be carreful! The HEPA filter is protected by fragile mesh Nothing should be permitted to come in contact with the HEPA filter NO cleaning solution NO aspirate from syringes NO glass from ampules NO fluids, even if sterile we have no inforamtion about contamination level DO NOT touch HEPA filter Arrangement of devices correct wrong Only essential material they must ve next to eachother All aseptic manipulations should be carried out ==> in short time to prevent contamination at least …………………………………… 6 inches within the LAC to prevent contamination from room air entering the hood Sterilisation by filtration hand disinfection gloves, mask arrangement of the devices critical work place between the...............and HEPA filter.......................being sterile product prepared prevention of the contamination of sterilised products sealing of a container to show no one has opened the container in the past increase resistance of filter for air==> and if its seems blocked==> we can say the Test for filter integrity => with air filter worked properly 07.12.2023 in general 2category of pyrogen==> killed microorganism, product of microorganism infrared ==> source of heating in 250 degree focus is prevention from entering of pyrogen entering to the product Manufacturing of parenterals Assoc. Prof. PharmDr. Zdenka Sklubalova, Ph.D. Faculty of Pharmacy CUNI Department of Pharmaceutical Technology Šklubalová, Vraníková: Oční přípravky. Maxdorf. 2018. ISBN 978-80-7345-572-9 1 Principles misnoorgapartsofall is abacterialeuderox dead Sterile preparations pyrogen ophthalmic preparations parenteral preparations  pyrogen-free washearingto250 gugygyofapnoouitis elimination of pyrogen from product==> limited possibility==> prevention The entrances of microorganisms since final depyrogenation in most of cases is imposible iiE.is low initial bioburden ==> we reduce MIO in whole steps of manufacture meet ushastobecommuted I 111Tanguinon 2 by monotoningcontamination microonga asepticarea technologicaloperations 1 07.12.2023 Controlled working environment Clean rooms also validforpharmacists Air quality is defined in terms of total particulate counts of given size per cubic metre inprepofstenileprep.ee EU Guidelines to GMP (1.3.2009) non-working during night installed equipment no personnel working during the day routine workflow permissible number of personnel are valid for pharmacies preparing sterile preparations 3 Air quality not important numbers are not important they can be found in clusterMaximum permitted number of individual cells of bacteria particles/m3 Class non-working working ==> 1 or 2 order greater limit EU FDA 0.5m 5m 0.5m 5m !!!!! for embolism risk A, 100 3 520 20* 3 520 20* optimalmesarments laminar Iminoorgausdust 3 520 29* 352 000 2 900* B 100 C 10 000 352 000 2 900 3 520 000 29 000 Mesernsdifferent D 100 000 3 520 000 29 000 not given not given the wheightnear robe Mattie ge * … notserious problem for manufacturing estimated in FDA number is not that important only size is important 4 if we are near these limit, there must be a warning sign u cant ditinguish if its bacteria or in large scale production in class A==> there is no personell dust continious optical measurment ==> in class A and B for number of particles in class C,D ==> we measure the change in weight of filter 2 07.12.2023 CFU means lower than the average not 0 CFU==> colony forming unit Monitoring of microbiological contamination Limits of microbiological contamination Air sampling Air sampling Contact Glove Class (impingers) (settling) culture media CFU/m3 CFU/4 h CFU/plate CFU/ 1 hand A 1 1 1 1 no wedon't have themeant todetectlessreranacolony B 10 5 5 5 C 100 50 25 - D 200 100 50 - Limitations of Microbial Environmental Monitoring Methods in Cleanrooms | American Pharmaceutical Review - The Review of American Pharmaceutical Business & Technology is time consuming ==> 2 weeks ==> disadvantage that we cant use it during manufacturing 5 advantage u can detect the type and source of MIO ==> good for validation Design of the controlled environment gradient pressure most critical part C A C small very area terminal sterilisation if its possible or not if you can do it every thing is easier a logical and clearly defined workflow and you can go with C class sure minimum back-tracking==> if you have something sterilized, it must be marked and separated from non-sterilized things segregation of sterilised and non-sterilised material segregation aseptic areas from preparation areas pressure gradient highest air pressure is in zone A==> prevents entrance of non-clean air ***for suspension injection we cant use terminal sterilization and we must do everythin gin in zone A 6 3 07.12.2023 Aseptic area fashion HEPA filtration laminar air flow bad vertical not good for preparation Not used in large scale manufacturing goodfor horizontal drop eye combined ==> best horizontal ==> very good for eye drop zone A is very small area vertical cant be used when u are working with dangerous material Because it flows directly to our body, it’s harmful for is working wrong==> contamination goes to product the person manipulationing the materials wall doesnt end on floor==> free blow out of air in the zone **isolator unit is used for prevention of contamination and personell protection ==> mainly in hospital pharmacy 7 8 4 07.12.2023 Technological operations Preparation of working areas and equipment Validated hygiene and cleaning procedures washing & cleaning disinfection step by step we increase level sterilisation validated CIP/SIP procedure cleaning in place/steriliation in place !!!!!!! in large scale Preparation of containers & closures sterilisation, depyrogenization Preparation of a product vehicles and substances ==> they must be sterile and high quality WFI ==> distillation of water with same same steam as source of energy, change pressure--> save money solutions with terminal sterilisation suspensions without terminal sterilisation 9 Quality of the product In-process tests every ampule goes through it visible particulate contamination ==> 100s um optical control, white and black background integrity of the container ==> measuring resistance of glass extractable volume ==> excess of liquid ==>apparent volume(label), can be affected by viscosity Final tests sub-visible particulate contamination ==> microscopic checking test for sterility test for pyrogens or endotoxins ==> LAL, monocyte activation, injection and watching for inflammation in rabbit, recombinant factor (genetic modification of monocyte) trend is to avoid rabbit test by 2026 in europe 10 5

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