Kniga na apstrakti book of abstrcts

Retrospective validation of manufacturing process 
for Analgin tablets 500 mg
Sonja Maleva
1
, Sonja Ugarkovic
1
, Efta Linin
2
1
Research and Development Department,  
2
Solid Dosage Forms Department
, 
Alkaloid AD, blvd. Aleksandar Makedonski 12, Skopje, Macedonia, 
In the pharmaceutical and biotechnology industry, validation of drug manufacturing process refers to estab-
lishing documented evidence that a process or system, when operated within established parameters, can perform
effectively and reproducibly to produce a medicinal product meeting its pre-determined specifications and attributes.
Retrospective validation is performed for a product that has been on the market for a long time and is based
on statistical analysis and evaluation on large number of accumulated data from production process parameters, as
well as data from control testing.
Objective: To assure that the manufacturing process for Analgin tablets 500 mg, is capable of consistently
yielding a product of reproducible quality, which meets regulatory specifications and quality attributes, as well as
process capability.
Process validation: To validate the manufacturing process, results regarding process controls and control
tests were evaluated considering twenty industrial batches of Analgin tablets 500 mg. Descriptive statistics (Statistica
6.0, Industrial Statistics and Six Sigma, Process analysis, Graphs) was used for evaluation of the manufacturing
process for Analgin tablets 500 mg.
There were no rejected batches during the review period.There were no complaints registered against the
product during the review period. 
Analgin tablets 500 mg are prepared by wet granulation. Production includes four consecutive granulation
processes and mixing with extragranular excipients after merging of the prepared granulates.
Critical process/product parameters for each phase of the manufacturing process were taken into account:
time and speed of mixing of the ingredients, spray rate of binder solution, granulation time, wet mill speed and mesh
size of screen, drying time, drying temperature, tablet compression (force of compression and speed of tablet press).
All these parameters have influence on the physico-chemical properties of the final drug product (appearance, mass
uniformity, hardness, friability, disintegration, dissolution, content of active ingredient).
Statistical analysis and evaluation was performed on the results from in-process controls and control tests
of samples from final blend and tablets. All results were within specification limits.
Process capability for the manufacturing process was also demonstrated. Process capability is a measure of
the performance of the process against its specifications. A capable process is one where almost all the measurements
fall inside the specification limits. Capability index Cpk for this process is 1.16 (Cpk should be > 1 for capable process),
so this showed that the process is capable of producing product which meets its predetermined specifications.
Conclusion: The results from in-process controls, control tests, statistical analysis and process capability
analysis confirm that the manufacturing process for Analgin tablets 500 mg always gives product which meets its
predetermined specifications and quality attributes, so it can be considered validated.
Macedonian pharmaceutical bulletin 53 (1,2) 88-89 (2007)
PP - 34
88
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Retrospektivna validacija na proizvodniot proces 
na Analgin tableti 500 mg
Sowa Maleva
1
, Sowa Ugarkovi}
1
, Efta Linin
2
Istra`uvawe i razvoj
1
, Proizvodstvo cvrsti formi
2
, 
Alkaloid AD, bul. Aleksandar Makedonski 12, Skopje, Makedonija
Vo farmacevtskata i biotehnolo{kata industrija, validacija na proizvoden proces na lek podraz-
bira vospostavuvawe na dokumentiran dokaz deka nekoj proces ili sistem, koga se odviva pod to~no defi-
nirani uslovi i parametri, mo`e efektivno i reproducibilno da proizveduva medicinski proizvod koj
odgovara na prethodno definiran kvalitet i specifikacija.
Retrospektivna validacija se primenuva za proizvodi koi se dolgo vreme na pazarot i se bazira na
statisti~ka obrabotka i analiza na dovolen broj akumulirani podatoci od procesni parametri na proizvod-
stvo, kako i podatoci od testirawe i kontrola. 
Cel: Da se doka`e deka proizvodniot proces na Analgin tableti 500 mg, sekoga{ dava proizvod so
reproducibilen kvalitet koj odgovara na specifikacijata za kvalitetot so koja proizvodot e registri-
ran, kako i da se poka`e sposobnosta na procesot (process capability).
Validacija na procesot: Za validacija na proizvodniot proces, bea evaluirani rezultati od pro-
cesni kontroli i kontrolni testovi od dvaeset proizvedeni industriski serii na Analgin tableti 500 mg.
Za evaluacija na procesot be{e koristena Deskriptivna statistika (Statistica 6.0, Industrial Statistics and Six
Sigma, Process analysis, Graphs).
Vo periodot vo koj se proizvedeni odbranite serii za retrospektivna validacija nema{e otfr-
leni serii i reklamacii. 
Analgin tableti 500 mg se proizveduvaat so proces na vla`na granulacija. Proizvodstvoto vklu~uva
~etiri posledovatelni procesi na vla`na granulacija. ^etirite granulati potoa se spojuvaat i se me{aat
so ekstragranularni ekscipiensi. 
Bea razgledani kriti~nite parametri na procesot/proizvodot za sekoja faza od proizvodniot pro-
ces: vreme i brzina na me{awe na ingredientite, brzina na prskawe na rastvorot za vrzuvawe, vreme na gra-
nulirawe, brzina na vla`no seewe i golemina na otvori na sitoto na melnicata, vreme i temperatura na
su{ewe, tabletirawe (sila na kompresija i brzina na ma{inata za tabletirawe). Nabrojanite parametri
imaat vlijanie vrz fizi~ko-hemiskite svojstva na finalniot proizvod (izgled na tabletite, voedna~enost
na masa, cvrstina, tro{nost, dezintegracija, rastvorlivost i sodr`ina na aktivnata komponenta).
Rezultatite od procesnite kontroli i kontrolnite testovi na finalna me{avina i tableti bea
statisti~ki obraboteni i analizirani. Se poka`a deka site rezultati se vo granici na nivnata speci-
fikacija.
Sposobnosta na procesot (process capability) isto taka be{e prika`ana. Sposobnosta na procesot e
merka za negovata performansa vo odnos na negovite specifikacii. Sposoben proces e onoj proces kade
{to skoro site rezultati se vo granica na specifikacionite limiti. Indeksot Cpk so koj {to se izrazu-
va sposobnosta, za ovoj proces ima vrednost 1.16 ( Cpk treba da e > 1 za sposoben proces), pa so toa e potvr-
deno deka procesot e sposoben da proizveduva proizvod koj odgovara na negovata specifikacija.
Zaklu~ok: Rezultatite od procesnite kontroli, kontrolnite testovi, statisti~kata analiza i
analizata za sposobnost na procesot potvrduvaat deka proizvodniot proces na Analgin tableti 500 mg
sekoga{ dava proizvod koj odgovara na prethodno definiran kvalitet i specifikacija, pa procesot mo`e
da se smeta za validiran.
Macedonian pharmaceutical bulletin 53 (1,2) 88-89 (2007)
PP - 34
89
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Comparative methods for production 
of Natrii Hydrogencarbonatis Infundibile
Snezana Angeleska, D. Trombeva, T. Ilioska-Nabrezanec
1
Public Health Center – Hospital “Borka Taleski” – Prilep, Macedonia; 
Hospital pharmacy with Galen laboratory and Infusion ward; Laboratory of Biochemistry.
2
Public Health Center – Clinical Hospital “Trifun Panovski” – Bitola, Macedonia
Introduction:
Sodii Hydrogen carbonatis infundibile is used for treating acidosis, which is decreasing of the pH-value
(increasing of the H-ions) in the extra cellular liquid. The effect of Sodii Hydrogen carbonatis is quick, because
hydrogen carbonates, which are part of the content of the plasma and also the bicarbonate-puffer system which is
regulated through breathing and the kidneys, are directly consumed.
Different technological procedures have been adopted and modified for the production of Sodii Hydrogen
carbonatis infundibile. Along the aseptic manufacturing, some pharmacopeias prescribe adding CO
2
in the solution.
This is done in order to stabilize the concentration and the pH-value of the solution. During the autoclave steriliza-
tion, a hydrolysis of the Sodium Hydrogen Carbonate occurs and this moves the reaction towards basic pH-value
and transforms the sodium hydrogen carbonate into sodium carbonate and CO
2
is released.
That is why CO
2
is added into the solution, so the released CO
2
reunites in the solution.
Purpose of the study:
Analysis of the effect of adding CO
2
in the process of producing Sodii Hydrogen carbonatis infundibile 4,2
% (0,5 mol/l) on the quality of the final solution by:
1. Defining the content of the active component before and after sterilization;
2. Defining the pH-value before and after sterilization.
Materials and methods:
• Sodium Hydrogencarbonatis pulvis pro analysi, Merck – Germany;
• Aqua ad iniectabilia - Hospital pharmacy with Galen laboratory and Infusion ward, Prilep
• Infusion Bottles of 125 ml for single use
• Rubber lids – Seal Line Spa
• Tin Lids – Pharma Trade S.R.L.
• Devices for preparing sterile solutionsfrom the Sartopius company, with a 10l container and membrane 
filtration by saitz filters with 0,22µm widw pores.
Method of manufacturing:
The measured quantity of Sodii Hydrogen carbonatis infundibile (420g per 10l) is dissolved into injection
water cooled down at a temperature of 8-12°C with careful stiring. Secondly, CO
2
electricity is conducted in the
solution with duration of 10 min. until the pH-value of the solution decreases to 7-7,5. The solution is filtered and
poured in the infusion bottles up to ¾ of their volume. Bottles are closed and sterilised upside down in 120°C for 20
min. under pressure of 101,3 kPa. They are to be kept in a cool and dark place (2-8°C). Three series of the Sodii 
Macedonian pharmaceutical bulletin 53 (1,2) 90-93 (2007)
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3
NaHCO
  ¦ 
−
+
+
3
HCO
Na
 
2NaHCO
3
  t
0
 C 
NaHCO
3 
+ CO
2+ 
H
2
O
 

Hydrogen carbonatis concentratum ad infundibile produced in the Hospital pharmacy with Galen laboratory and
Infusion ward are used. There has been also a parallel production of solutions without conducting CO
2
. Five sam-
ples have been controlled.
Content: 42g/l NaHCO
3
(0,5 mol/l)
pH-value: 7-8,5
Ionic content: Na+ - 500mEg/l; HCO
3
- -500mEg /l
Theoretical osmolarity: 1000mOsm/l
Best before: 1 year from date of production
Analysis of the solution:
• Analysis of sterility: Bureau of Health Care – Prilep
• Analysis of pyrogenity: State Bureau of Health Care – Sector of Examination and control of Medicines
• Quantity Definition: 10ml of the solution is mixed with 5 drops of metylorange and titrated with 0,1mol/l HCl
(which equals 8,40mg NaHCO
3
). 1000ml has to contain 39,5-44,5g NaHCO
3
Summary:
Conducting CO
2
in the process of manufacturing of Sodii Hydrogen carbonatis infundibile affects the con-
tent of the active component and also th pH-value of the solution, preventing the transformation of NaHCO
3
in
Na
2
CO
3
. With this effect, the result is a solution whose pH-value and content of NaHCO
3
are in the allowed bound-
aries, which is not the case in the solution produced without adding CO
2
.
Macedonian pharmaceutical bulletin 53 (1,2) 90-93 (2007)
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Komparativni metodi na izrabotka 
na Natrii Hydrogencarbonatis infundibile
S. Angeleska
1
, D. Trombeva
2
, T. Ilieska-Nebre`anec
1
1
JZU Op{ta bolnica „BORKA TALESKI“ Prilep, 
- Bolni~ka apteka so galenska laboratorija i infuziono oddelenie - Biohemiska laboratorija
2
JZU Klini~ka bolnica -Trifun Panovski- Bitola - Analiti~ka laboratorija
Voved: 
Natrii Hydrogencarbonatis infundibile se primenuva za tretman na acidoza - termin {to ozna~uva namalu-
vawe na pH (zgolemuvawe na H-joni) vo ekstracelularnata te~nost. Deluvaweto na natrium hidrogen kar-
bonatot e brzo, bidej}i direktno se vnesuvaat hidrogen karbonati koi se sostaven del na plazmata i bikar-
bonatniot puferski sistem koj se regulira preku di{eweto i bubrezite.
Za izrabotka na Natrii Hydrogencarbonatis infundibile prifateni se i modificirani razni tehnolo{ki
postapki za izrabotka. Pokraj asepti~nata izrabotka, nekoi farmakopei prepi{uvaat i voveduvawe na
jagleroden dioksid vo rastvorot. Na ovoj na~in se vr{i stabilizacija na koncentracijata, a so toa i pH
na rastvorot. Pri sterilizacija so avtoklavirawe doa|a do hidroliza na Natrium Hydrogen Karbonat i pomes-
tuvawe na reakcijata kon bazna sredina.
i pominuvawe na natrium hidrogen karbonat vo natrium karbonat i osloboduvawe na jaglerod dioksid
Zaradi toa, vo rastvorot se vnesuva jaglerod dioksid, pa oslobodeniot jaglerod dioksid povtorno
se vrzuva vo rastvorot.
Cel na trudot:
Ispituvawe na na efektot na voveduvawe na jaglerod dioksid vo procesot na izraotka na Natrii
hydrogen carbonatis concetratum ad infundibile 4,2% (0,5 mol/l) vrz kvalitetot na dobieniot peparat preku:
1. opredeluvawe na sodr`inata na aktivnata komponenta pred i posle sterilizacija
2. odreduvawe na pH na rastvorot pred i posle sterilizacija
Materijal i metodi:
• Natrium Hydrogen Carbonatis Pulvis pro Analysi Merck - Germanija
• Aqua ad infectabilia - Bolni~ka apteka so galenska laboratorija i infuziono oddelenie
• Infuzioni {i{iwa od 125 ml za ednokratna upotreba Rocco Bormioli
• Gumeni zatvora~i Seal Line spa
• Limeni zatvara~i Pharma Trade s.r.l.
• Uredi za priprema na sterilni rastvori od firmata Sartorius, so kontejner so zafatnina od 10l i
membranska filtracija so Saitz filtri so golemina na pori 0,22 mm.
Metoda na izrabotka:
Odmerenata supstancija (420g za 10l) natrium hidrogenkarbonat se rastvora vo voda za inekcii
koja e naglo izladena na temperatura 8-12
o
C so vnimatelno me{awe. Vo rastvorot se propu{ta struja od
jagleroden dioksid vo traewe od 10 minuti, dodeka pH na rastvorot ne se namali na 7-7,5. Rastvorot se
filtrira i polni vo {i{iwa do 3/4 od nivnot volumen. Se zatvora i sterilizira vo obratna polo`ba na
{i{eto na 120
o
C 20 minuti i pritisok 101,2 kPa. Se ~uva na temno i ladno (2-8
o
C). Koristeni se 3 serii od
Macedonian pharmaceutical bulletin 53 (1,2) 90-93 (2007)
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3
NaHCO
  ¦ 
−
+
+
3
HCO
Na
 
2NaHCO
3
  t
0
 C 
NaHCO
3 
+ CO
2+ 
H
2
O
 

Natrii Hydrogencarbonatis Concetratum ad infundibile proizvedeni vo Bolni~ka apteka so galenska laboratori-
ja i infuziono oddelenie - Prilep. Paralelno se izraboteni preparati bez voveduvawe na jagleroden
dioksid.
Sodr`ina 42 g/l NaHCO
3
(0,5 mol/l) - dozvoleno otstapuvawe 94-106%
pH 7-8,5 Jonska sodr`ina Na
+
- 500 mEg/l HCO
3
- - 500 mEg/l
Teoriski osmolaritet - 1000 mOsm/l rok na upotreba 1 godina
Ispituvawe na preparat.
- Ispituvawe na sterilnost - Zavod za zdravstvena za{tita - Prilep
- Ispituvawe na pirogenost - Republi~ki zavod za zdravstvena za{tita - Sektor za ispituvawe i
kontrola na lekovi
- kvantitativno odreduvawe: 10 ml od rastvorot se me{a so 5 kapki metil oran` i se titrira so
0.1 mol/l HCl 1ml 0,1mol/l HCl odgovara na 8,40 mg NaHCO
3
.
1000 ml mora da sodr`i 39.5-44.5 NaHCO
3
sodr`ina na NaHCO
3
.
Ispituvana e sodr`ina i pH na 5 primeroci od 3 serii paralelno izraboteni so i bez CO
2
.
Zaklu~ok
Voveduvaweto na jagleroden dioksid vo procesot na prigotvuvawe na Natrii Hydrogencarbonatis
infundibile vlijae vrz sodr`inata na aktivnata komponenta, a so toa i na pH na rastvorot, spre~uvaj}i go
preminuvaweto na NaHCO
3
vo Na
2
CO
3
. So toa se dobiva preparat ~ii vrednosti na pH i sodr`ina na
NaHCO
3
se vo granicite na dozvolenite vrednosti, {to ne e slu~aj kaj rastvorot koj e izraboten bez vove-
duvawe na jagleroden dioksid.
Macedonian pharmaceutical bulletin 53 (1,2) 90-93 (2007)
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Selection of stable formulation of Risperidone solution 
in preformulation stage
S. Memed Sejfulah
1
, Lj. Krsteska
1
, S.Ugarkovic
1
, K. Brzilova
2
, 
1
Research and Development Department,  
2
Quality control department, 
Alkaloid AD, Blvd. Aleksandar Makedonski 12, Skopje, Macedonia
Risperidone is a serotonin antagonist approved for the treatment of psychic disorders. It belongs to the chem-
ical class of benzisoxazole derivate. 
Risperidone base is sparingly soluble in water. The solubility of risperidone base is increased upon the for-
mation of salt forms. Successful strategy for increasing solubility and stabilization of risperidone in oral solution
includes the use of different acids in preformulation development. 
The aim of this work is to establish stable risperidone oral solution and investigate the influence of differ-
ent acids or appropriate salts on physicochemical stability of solution in preformulation stage.
Preparation of oral solution is in accordance with general instruction for oral solution (Eur. Ph; USP)
In preformulation development three formulations of Risperidone oral solution 1mg/1ml are prepared. As
active substance risperidone base (Jubilant, Ph. Eur. grade) and different acids as tartaric acid, hydrochloric acid and
citric acid, were used. 
The stable solution of risperidone is defined if after storage for a period of up to 28 days at temperature of
80(±2)°C with a frequency every 7 days, the color is not changed, the residual amount of risperidone is 80% or more
from the initial concentration and the limit of total and any other individual impurities is accordance with specification.
Determination of colour was with spectrofotometric method; determination of assay of risperidon and total
and any other individual impurities of Risperidon oral solution 1mg/1ml were with HPLC method.
Results concerning discoloration, determination of assay and total and any other individual impurities for
three formulations were evaluated.
The summary data indicate that formulation 1 and 2 satisfy the criteria to qualify as stable composition.
Best results were achieved with hydrochloric acid which exhibited minimum variations of color, assay of
risperidone and total and any other individual impurities after storage (28 days under 80(±2)°C with a frequency
every 7 days) conditions which indicates a physicochemical stability of the system.
Macedonian pharmaceutical bulletin 53 (1,2) 94-95 (2007)
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Izbor na stabilna formulacija na
Risperidon rastvor vo predformulaciona razvojna faza
S. Memed Sejfulah
1
, Q. Krsteska
1
, Sowa Ugarkovi}
1
, K. Brzilova
2
1
Istra`uvawe i razvoj,  
2
Kontrola na lekovi, 
Alkaloid AD, bul. Aleksandar Makedonski 12, Skopje, Makedonija
Risperidonot e serotoninski antagonist i spa|a vo grupata na antipsihotici so benzioksazolska
struktura.
Risperidon e te{ko rastvorliv vo voda. Rastvorlivosta na risperidon se zgolemuva so formirawe
na soli. Vo predformulacionite studii, zgolemuvawe na rastvorlivosta i stabilizacija na risperidon vo
oralni rastvori e pratena so upotreba na razli~ni kiselini pri {to se formiraat razli~ni soli. 
Cel na trudot e da se dobie stabilen rastvor na risperidon, so ispituvawe na vlijanie na upotreba
na razli~ni kiselini i formirawe razli~ni soli so razli~na rastvorlivost.
Rastvorite se podgotvuvaat vo soglasnost so op{tite monografii (Eur .Ph; USP) za priprema na
oralni rastvori. 
Vo predformulacionata studii izraboteni se tri formulacii na rastvori so upotreba na risperi-
don (proizvoditel Jubilant, so kvalitet Eur. Ph.) i razli~ni kiselini i toa tartarna kiselina, hlorovodor-
odna kiselina i limonska kiselina.
Stabilen rastvor na risperidon se definira ako rastvorot postaven na ubrzana stabilnost na tem-
peratura od 80(±2)°C vo period od 28 dena so frekfencija na analiza od 7 dena nema promena na boja,
sodr`ina na aktivna supstancija e ne pomalku od 80% od pojdovnata koncentracija, a koncentracija na
raspadni produkti e vo barani granici. 
Ispituvani se parametrite boja (spektrofotometriska metoda) sodr`ina na aktivna supstanca i
raspadni produkti (bilo koe podine~no one~istuvawe i totalni one~istuvawa) so hromatografija pod
visok pritisok.
Od dobienite rezultati  e zaklu~eno deka formulaciite 1 i 2 gi zadovoluvaat postavenite grani-
ci za fizi~kohemiska stabilnost na rastvor.
Formulacija 2 na Risperidon oralen rastvor 1mg/1ml dava najdobri rezultati od ubrzana stabilnost
na temperatura od 80(±2)°C vo period od 28 dena so frekfencija na analiza od 7 dena, so najmala standardana
devijacija na sodr`ina na aktivna supstnca, promena na boja i koncentracija na raspadni produkti.
Macedonian pharmaceutical bulletin 53 (1,2) 94-95 (2007)
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