Monday, April 21, 2008
Saturday, April 19, 2008
INJECTIONS FORMULA AND PROCEDURE
MASTER FORMULA
COMPOSITION
Each 2ml Vial Contains:
· ACTIVE INGREDIENT
Amikacin USP ………………………..………………..…. 100mg
(As Amikacin Sulphate)
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 3.5 and 5.5
Water for Injection BP/USP…………..…………... Q.S to 2.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards Equipments/machinery used for the manufacturing of
Injections / Infusions
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
1. R O Plant
2. Water Deionizer
3. Distillation Plant
4. WFI Storage Tank
5. Mixing Tank
6. Pressure Regulator with Microbial Filter
7. Vial Washing Machine
8. Vial Sterilizer
9. Vial filling Machine
10. Vial sealing Machine
11. Ampoule Washing Machine
12. Ampoule Sterilizer
13. Ampoule Filling/Sealing Machine
14. Pressure Tank
15. Filtration Unit
The physical parameter carried out for the releases of the product
(In process)
1. PHYSICAL VERIFICATION OF INGREDIENTS FOR QUALITY AND QUANTITY.
2. FOLLOWING CHECK ARE CARRIED OUT FOR INPROCESS CONTROL OF PARENTRALS.
a. Av. Volume of ampoules/bottles/vials.
b. pH of the solution.
c. Identifications of Active drug.
d. Code. No. for infusions.
e. Deformation of ampoules/bottles / vials.
f. Particles in ampoules / vials / bottles.
g. LAL test.
3. IN HOUSE PACKAGING CHECKS FOR PARENTRALS.
a. Product name
b. Batch No.
c. Manufacture Date
d. Expiry Date
e. Manufacturing License No.
f. Registration No.
g. Price
h. Labeling
i. Printing
j. Over all view.
k. Grammage of carton
Source of Water
Ground Water
1. Fit for drinking approved by PCSIR.
2. Copy of Certificate Attached.
ENCLOSURE – 09(a)
Water for Injection (BP/USP)
Equipment/Machinery used for the preparation of
“Water For Injection (BP/USP)”
1. Filters
2. De – Ionizer
3. RO – Plant
4. Distillation Plant
5. WFI Storage Tank
Specifications:
Sr. #
TEST PARAMETERS
SPECIFICATIONS
01
Description
A clear, odourless and tasteless liquid.
02
Acidity or Alkalinity
Must be complies to BP.
03
Ammonium
Not more than 0.2 PPM.
04
Calcium/Magnesium
Not more than 0.5 ml of 0.01 EDTA Should be used to produce blue color.
05
Heavy metals
Not more than 0.1 PPM.
06
Chloride
Solution remains clear within 15 minutes or not more than 5 PPM.
07
Nitrate
Not more than 2PPM.
08
Sulphate
No change in appearance within 1 hour.
09
Oxidisable Substance
The solution should remain faintly pink.
10
Residue on evaporation
Should not more than 0.001%.
11
Bacterial Endotoxins
NMT 0.25 units/ml.
12
Conductivity at 25C
NMT 1.3 mS/cm
(Master Formula)
COMPOSITION
Each 1ml contains:
· ACTIVE INGREDIENT
ARTEMETHER BAN..………………….………… 80 mg
(As Sodium)
· INACTIVE INGREDIENT
Edetate Sodium BP/USP…….……….……………….... 1.0mg
NaOH BP/USP….. Q.S to adjust pH between 11.0 and 12.5
Water for Injection BP/USP………… Q.S to
DESCRIPTION OF METHOD OF MANUFACTURE
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared the Q.C stickers is available.
Rinse the container with freshly prepared pyrogen free distilled water.
Measure the water quantity, record the temperature and bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of NaOH solution keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid.
Transfer the prepared solution to the sterilized apyrogenized vials equivalent to 40mg of Omeprazole and shift to the Lyophilization chamber (freezed dryer).
After the completion of Lyophilization process transfer the vial to the quarantine area.
Request the Q.C to draw the sample.
Inspect vial visually to ensure the contents are free of any particulate matter.
Pack in accordance with laid down GMP standards.
METHOD OF ANALYSIS
Injection NN 80mg/1ml
Ø Description:
A clear to light yellow colour solution in glass ampoule.
Ø Identification: (Artemether)
The chromatogram of the assay preparation exhibits a major peak for Artemether and , the retention time of which corresponds to the exhibited in the chromatogram of standard preparation as obtained in the assay.
Ø Assay:- (HPLC)
Mobile Phase: Prepare a mixture of acetonitrile and distilled water in the ratio of 70 volumes of acetonitrile and 30 volume of water and 0.05 ml of glacial acetic acid/100ml. filter and degassed mixture of the prepared solution.
Sample preparation:
Mix the contents of 10 ampoules, take sample equivalent to 160mg and make up volume 100ml with mobile phase. Filter through 0.45 micron filter.
Standard preparation:
Weigh accurately Artemether and ref. standard and prepare equal concentrations as mentioned above.
Procedure:
Inject the standard preparations and sample preparation, the tailing factor should not be more than 2% and calculate the contents of active ingredients.
Flow rate 2.0 ml
Pressure 350 Kg
Wave length 215 nm
Column Length 150 mm
Column I.D. 4.6 mm
Injection volume 20 ul
OBSERVATIONS & CALCULATIONS:
Peak area / height of Artemether sample preparation = A
Peak area / height of Artemether standard preparation = B
Limit:
Artemether 90 ----- 110 % of the labeled amount.
The physical parameter carried out for the releases of the product
(In process)
4. PHYSICAL VERIFICATION OF INGREDIENTS FOR QUALITY AND QUANTITY.
5. FOLLOWING CHECK ARE CARRIED OUT FOR INPROCESS CONTROL OF PARENTRALS.
a. Av. Volume of ampoules/bottles/vials.
b. pH of the solution.
c. Identifications of Active drug.
d. Code. No. for infusions.
e. Deformation of ampoules/bottles / vials.
f. Particles in ampoules / vials / bottles.
g. LAL test.
6. IN HOUSE PACKAGING CHECKS FOR PARENTRALS.
a. Product name
b. Batch No.
c. Manufacture Date
d. Expiry Date
e. Manufacturing License No.
f. Registration No.
g. Price
h. Labeling
i. Printing
j. Over all view.
k. Grammage of carton
COMPOSITION
Each vial contains:
q ACTIVE INGREDIENT:
Azithromycin USP…….…………………...…..….. 500mg
(As Dihydrate)
q IN-ACTIVE INGREDIENT:
Citric Acid Anhydrous BP/USP …..………………413.6 mg
NaOH BP/USP………………………………………114 mg
pH …………………………………………………4.0 --- 6.0
Water for Injection BP/USP (re – constitution) ……... 10ml
Method of analysis
AZIT 500mg/vial
COMPOSITION: Each vial contains:
AZITHROMYCIN USP ………………………….500mg
DESCRIPTION: White to pale yellow powder in glass vials.
IDENTIFICATION: - To 1 g powder in test tube, add 5 ml of 1 M hydrochloric acid, shake well, add 0.5 ml of 0.05 M iodine solution, and shake vigorously. Brown precipitates appear which convert to brown black tinny particles.
pH (When constituted as directed): Between 4.0 and 6.0
STERILITY TEST: Conforms to USP
Bacterial Endotoxin: Confirms to USP
ASSAY:-
METHOD OF ANALYSIS:
Sample Preparation:
Reconstitute the average dry powder for injection, take sample equivalent to 200 mg Azithromycin USP. Transfer to a separatory funnel, add 10 ml of water and extract with 3 x 30 ml of chloroform. Collect the chloroform layer and evaporate it on water bath at 50 – 60 C to dryness. Dissolve the residue in 50 ml of glacial acetic acid, Titrate with 0.1M perchloric acid using 0.05 ml crystal violet solution as indicator till the bluish green colour is produced.
Each ml of 0.1M perchloric acid is equivalent to 37.45.mg of Azithromycin.
Blank:
To 50 ml of glacial acetic acid, Titrate with 0.1M perchloric acid using 0.05 ml crystal violet solution as indicator till the bluish green colour is produced.
Observations & Calculations:
Sample taken = 200 mg
Volume of 0.1M perchloric acid used for sample. = A
Volume of 0.1M perchloric acid used for blank. = B
Net volume of 0.1M perchloric acid used for sample. = A - B
Azithromycin % = D X 37.45 X 100
200
Limit: The contents of Azithromycin should be 90.0 --- 110.0% of the label claim.
MASTER FORMULA
COMPOSITION
Each 1ml Ampoule Contains:
· ACTIVE INGREDIENT
Buprenorphine HCl BP ………………..….….0.324mg
Equivalent to Buprenorphine BP …………..…….0.3mg
· INACTIVE INGREDIENT
Dextrose (Anhydrous) BP/USP…….……….……50mg
HCl BP/USP….. Q.S to adjust pH between 3.5 and 5.5
Water for Injection BP/USP…………..….. Q.S to 1.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
PHARMACOLOGICAL & CLINICAL DATA
A. DESCRIPTION
XX is a synthetic opioid agonist-antagonistic analgesic. The active ingredient of XX is Buprenorphine hydrochloride, [N-cyclopropylmethyl-7alpha-(1-(S)-hydroxy-1,2,2-trimethylpropyl- 6-,14-endoethano-6,7,8,14-tetrahydronororipavine hydrochloride].
Buprenorphine hydrochloride is a highly lipophilic ring C bridges oripavine derivative of thebaine.
B. CHEMICAL STRUCTURE
C. INDICATIONS
Strong analgesic for short-term (not more than 1 week) relief of moderate to severe pain, including post-operative and terminal pain. XX Injection should be employed when sublingual administration is not practical e.g. pre- or peri-operatively. It is not recommended for use in children.
Buprenorphine does not have an approved role in opioid dependence rehabilitation programs.
D. CLINICAL PHARMACOLOGY
XX is a parenteral opioid analgesic with 0.3 mg XX being approximately equivalent to 10 mg morphine sulfate in analgesic and respiratory depressant effects in adults. Pharmacological effects occur as soon as 15 minutes after intramuscular injection and persist for 6 hours or longer. Peak pharmacologic effects usually are observed at 1 hour. When used intravenously, the times to onset and peak effect are shortened.
The limits of sensitivity of available analytical methodology precluded demonstration of bioequivalence between intramuscular and intravenous routes of administration. In postoperative adults, pharmacokinetic studies have shown elimination half-lives ranging from 1.2-7.2 hours (mean 2.2 hours) after intravenous administration of 0.3 mg of Buprenorphine. A single, ten-patient, pharmacokinetic study of doses of 3 µg/kg in children (age 5-7 years)
showed a high inter-patient variability, But suggests that the clearance of the drug may be higher in children than in adults. This is supported by at least one repeat-dose study in postoperative pain that showed an optimal inter-dose interval of 4-5 hours in pediatric patients as opposed to the recommended 6-8 hours in adults.
Buprenorphine, in common with morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. Studies in patients anesthetized with 0.5% halothane have shown that this anesthetic decreases hepatic blood flow by about 30%.
Mechanism of Analgesic Action: XX exerts its analgesic effect via high affinity binding to µ subclass opiate receptors in the central nervous system. Although XX may be classified as a partial agonist, under the conditions of recommended use it behaves very much like classical µ agonists such as morphine. One unusual property of XX observed in in vitro studies is its very slow rate of dissociation from its receptor. This could account for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence.
Narcotic Antagonist Activity: Buprenorphine demonstrates narcotic antagonist activity and has been shown to be equipotent with naloxone as an antagonist of morphine in the mouse tail flick test.
Cardiovascular Effects: XX may cause a decrease or, rarely, an increase in pulse rate and blood pressure in some patients.
Effects on Respiration: Under usual conditions of use in adults, both XX and morphine show similar dose-related respiratory depressant effects. At adult therapeutic doses, XX (0.3 mg Buprenorphine) can decrease respiratory rate in an equivalent manner to an equianalgesic dose of morphine (10 mg).
E. CONTRA-INDICATIONS
Pregnancy and Lactation (see Use in Pregnancy and Use in Lactation).
XX should not be administered to patients who have been shown to be hypersensitive to Buprenorphine.
F. WARNINGS
Because of the narcotic antagonist activity of Buprenorphine, use in individuals dependent on other opioids may result in withdrawal effects.
Use in Pregnancy
Category C. Narcotic analgesics may cause respiratory depression in the newborn infant. Therefore, during the last 2-3 hours before expected delivery, these products should only be used after weighing the needs of the mother against the risk to the foetus.
Buprenorphine readily crosses the placental barrier. The safety of Buprenorphine in pregnancy has not been established and therefore it should not be used in women who are pregnant or who are likely to become pregnant unless the potential benefits outweigh the possible risks.
Australian categorisation definition of:
Category C
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying text above should be consulted for further details.
Use in Lactation
It is not known whether Buprenorphine is secreted in breast milk and safety in the new born has not been established. Therefore, it should not be given to nursing mothers.
G. PRECAUTIONS
Cardiovascular Effects: Buprenorphine may cause a slight reduction in pulse rate and blood pressure in some patients.
Head Injury and Increased Intracranial Pressure: Although there is no clinical experience in patients with elevated cerebrospinal fluid (CSF) pressure caused by head injury or intracranial lesions, Buprenorphine should be used with caution. Experience with other opioid analgesics indicates that respiratory depressant effects may elevate CSF pressure due to vasodilation from the CO2 retention. This may be markedly exaggerated with pre-existing elevation of CSF pressure or head injury or intracranial lesions. Furthermore, Buprenorphine produces miosis and may change the level of consciousness, thus interfering with patient evaluation. The miosis is more marked than with morphine and persists for more than 24 hours.
Respiratory Depression: As with most analgesic drugs acting at the opiate receptor, Buprenorphine may cause respiratory depression and whilst this is rarely of clinical significance, it should be used with caution in patients with either compromised respiratory function or those given respiratory depressant drugs, especially as there is no fully effective antagonist.
Respiratory depression following sublingual Buprenorphine is more likely to occur with doses exceeding 0.4 mg.
Should respiratory depression occur to clinically undesirable degree, supportive measures should be used to maintain adequate ventilation and oxygenation. The effects of Buprenorphine are only partially reversed by standard narcotic reversal agents, such as naloxone.
Hepatic Dysfunction: Because Buprenorphine is metabolised by the liver, the intensity and duration of its action may be altered in those individuals with impaired hepatic function.
H. OVERDOSAGE
Symptoms: There is limited experience of accidental or intentional overdosage at the present time, But doses in the range 3 to 7 mg have been administered intravenously without producing clinically significant respiratory effects. Extrapolating from the animal pharmacology of the agent, respiratory depression is likely to occur in the event of overdosage, together with cardiovascular depression and some CNS effects, such as sedation. Therefore, the respiratory and cardiac status of the patient should be carefully monitored.
Treatment: Primary attention should be given to the re-establishment of adequate respiratory exchange. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Intravenous naloxone given repeatedly may be partially effective.
I. DRUG INTERACTIONS
(a) Monoamine Oxidase Inhibitors: Until further information is available, Buprenorphine should be used with caution in patients receiving monoamine oxidase inhibitors as these may intensify its adverse effects.
(b) CNS Depressants: Buprenorphine may cause some drowsiness, and this could be potentiated by other centrally-acting agents such as long acting benzodiazepines, volatile anaesthetics and certain induction agents. Hence, amBulant patients should be warned not to drive or operate machinery if affected.
(c) Narcotic Antagonist Activity: Buprenorphine demonstrates narcotic antagonist activity and has been shown to reverse the effects of peri-operatively administered narcotics. It may, therefore, precipitate mild withdrawal symptoms in narcotic addicts and it should be given with care, initially, to patients previously treated with narcotic analgesics.
J. ADVERSE REACTIONS
Drowsiness, or sleep from which the patient can easily be aroused, occurs in most patients, particularly in the post-operative period.
Gastrointestinal System: Nausea and vomiting have been reported in 9% and 7% of patients respectively, and may be worse in amBulatory patients. Administering a lower dose, or having the patient lie down may alleviate these effects.
Dry mouth and constipation have rarely been reported.
Central Nervous System: Often associated with nausea and vomiting, But less frequently, are headache and symptoms of dizziness (1%) and sweating (1%). Improved mood or mild euphoria has been reported in 0.28% of cases.
Hallucinations and other psychotomimetic effects have rarely been reported.
Respiratory System: Significant respiratory depression has been observed infrequently and is rarely of clinical significance.
Genito-urinary: Difficulty in urination has occurred in less than 1% of patients.
Cardiovascular: Slight bradycardia and hypotension occur. Tachycardia and hypertension have been rarely reported.
Other: For XX Injection, localised skin reactions at the injection site and hypersensitivity symptoms have been rarely reported, with one reported case of anaphylactic reaction.
Gastrointestinal System: Nausea and vomiting have been reported in 9% and 7% of patients respectively, and may be worse in amBulatory patients. Administering a lower dose, or having the patient lie down may alleviate these effects.
Dry mouth and constipation have rarely been reported.
Central Nervous System: Often associated with nausea and vomiting, But less frequently, are headache and symptoms of dizziness (1%) and sweating (1%). Improved mood or mild euphoria has been reported in 0.28% of cases.
Hallucinations and other psychotomimetic effects have rarely been reported.
Respiratory System: Significant respiratory depression has been observed infrequently and is rarely of clinical significance.
Genito-urinary: Difficulty in urination has occurred in less than 1% of patients.
Cardiovascular: Slight bradycardia and hypotension occur. Tachycardia and hypertension have been rarely reported.
Other: For XX Injection, localised skin reactions at the injection site and hypersensitivity symptoms have been rarely reported, with one reported case of anaphylactic reaction.
MASTER FORMULA
COMPOSITION
Each 2ml ampoule Contains:
· ACTIVE INGREDIENT
CIMETIDINE BP ………………………..………………..…. 200mg
(As HCl)
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 3.8 and 6.0
Water for Injection BP/USP…………..…………... Q.S to 2.0ml
MASTER FORMULA
COMPOSITION
Each 50ml vial contains:
· ACTIVE INGREDIENT
Ciprofloxacin USP …….…….………..………… …100mg
(As Lactate)
· INACTIVE INGREDIENT
Sodium Chloride BP/USP……………….………….…….… 0.9g
Lactic Acid BP/USP….……Q.S to adjust pH between 3.5 and 4.5
Water for Injection BP/USP…….….………..…..….. Q.S to 50ml
PHARMACOLOGICAL & CLINICAL DATA
A. Chemical Structure
B. Description
A fluoroquinolone is the salt of 1-cyclopropyl-6-fluora-1, 4-dihydro-4-oxa-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is C17H18FN3O3.
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-drhydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4 It is a faintly yellowish to light yellow crystalline substance.
Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-position.
C. Indications and Usage
UTI, respiratory, ENT, eye, skin and soft tissue, bone, joint, pelvic, biliary tract, intra-abdominal and Gl infection. Gonorrhoea. Severe systemic infection. Gram-negative pneumonia (not for first line treatment in pneumococcal pneumonia). Prophylaxis in upper Gl surgery or endoscopy.
D. Warnings
NOT FOR OPHTHALMIC USE. NOT FOR INJECTION.
XX should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported
in patients receiving systemic quinolones. Serious acute hypersensitivity reactions may require immediate emergency treatment.
E. Precautions
Do not use this medicine if you have had a severe allergic reaction to this medicine or another fluoroquinolone antibiotic. A severe reaction includes a severe rash, hives, breathing difficulties, or dizziness. If you experience difficulty breathing; tightness of chest; swelling of eyelids, face, or lips; or if you develop a rash or hives, tell your doctor immediately. For women: if you plan on becoming pregnant, discuss with your doctor the benefits and risks of using this medicine during pregnancy. It is unknown if this medicine is excreted in breast milk. Do not breast-feed while taking this medicine.
F. Adverse Reactions
In Phase 3 clinical trials, a total of 564 patients were treated with XX. Adverse events with at least remote relationship to treatment included headache (1.2%) and pruritus (0.4%). The following treatment-related adverse events were each reported in a single patient: migraine, hypesthesia, paresthesia, fungal dermatitis, cough, rash, urticaria, and alopecia.
G. Storage Conditions:
Store below 30°C. Keep out of reach of children.
DOSAGE AND ADMINISTRATION
DOSAGE AND DIRECTIONS FOR USE:
Dosage and Duration of Treatment:
The dosage of XX IV is determined by the severity and type of infection, the sensitivity of the causative organism(s) and the age, mass and renal function of the patient. The usual dose is 100 mg - 200 mg IV every 12 hours. For severe and/or complicated infections 400 mg may be administered every 12 hours (i.e. bd). Intravenous therapy should be discontinued as soon as oral ciprofloxacin therapy can be substituted. The normal duration of intravenous therapy is up to 7 days.
Cystic fibrosis:
In cystic fibrosis patients the normal dose is 200 mg IV twice daily. The low body mass of these patients should, however, be taken into consideration when determining dosage (5-10 mg/kg/day).
Directions for Intravenous Administration:
XX IV should be administered by intravenous infusion over a period of 60 minutes. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation. The infusion solution can be infused either directly or after mixing with the other compatible infusion solutions.
The XX IV infusion solution is compatible with physiological saline, Ringer solution and Ringer lactate solution, 5% and 10% glucose solutions, 10% fructose solution, and 5% glucose solution with 0.225% NaCl or 0.45% NaCl. When ciprofloxacin infusion solutions are mixed with compatible infusion solutions, for microbiological reasons and light sensitivity these solutions should be administered shortly after admixture.
Important incompatibilities:
Unless compatibility with other infusion solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding and discolouration.
Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solution (e.g. penicillins, heparin solutions), especially on combination with solutions adjusted to an alkaline pH (pH of the ciprofloxacin infusion solutions: 3.9-4.5).
Any remaining solution should be discarded.
Impaired Renal or Liver Function:
In patients with reduced renal function, the half-life of ciprofloxacin is prolonged and the dosage needs to be adjusted.
For patients with changing renal function or patients with renal impairment and hepatic insufficiency, monitoring of drug serum levels provides the most reliable basis for dose adjustment.
MASTER FORMULA
COMPOSITION
Each 2ml contains:
· ACTIVE INGREDIENT
TOBRAMYCIN USP ….………...……………...……….… .20mg
(as TOBRAMYCIN Sulphate)
· INACTIVE INGREDIENT
1. Benzyl alcohol USP .…………………………………. 18mg
2. Sodium Metabisulphite BP ..………………………….. 6.4mg
3. Disod. Edetate BP/USP ……………………………… 0.1mg
4. Sulfuric acid BP/USP……QS to adjust pH between 3.0 to 6.5
5. Water for Injection BP/USP .……………………………QS to 2ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
MASTER FORMULA
COMPOSITION
Each 2ml Ampoule Contains:
· ACTIVE INGREDIENT
TRAMADOL HCl BP …………………………..100mg
· INACTIVE INGREDIENT
Dextrose (Anhydrous) BP/USP…….……….……50mg
HCl BP/USP….. Q.S to adjust pH between 3.0 and 5.5
Water for Injection BP/USP…………..….. Q.S to 2.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards
MASTER FORMULA
COMPOSITION
Each 5ml Ampoule Contains:
· ACTIVE INGREDIENT
Tranexamic Acid USP ………………………..………………..….250mg
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 6.5 and 8.0
Water for Injection BP/USP…………..…………... Q.S to 5.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standar METHOD OF ANALYSIS
Injection T 250mg/5ml
Ø Description:
A clear colourless solution.
Ø Identification: (Tranexamic Acid)
The chromatogram of the assay preparation exhibits a major peak for Tranexamic Acid and, the retention time of which corresponds to the exhibited in the chromatogram of standard preparation as obtained in the assay.
Ø pH 6.5 -------------8.0
Ø Sterility Testing (Confirms to USP)
Ø Assay:- (HPLC)
Mobile Phase: Prepare a mixture of acetonitrile and distilled water in the ratio of 70 volumes of acetonitrile and 30 volume of water and 0.05 ml of glacial acetic acid/100ml. filter and degassed mixture of the prepared solution.
Sample preparation:
Mix the contents of 10 ampoules, take sample equivalent to 20mg of Tranexamic Acid and make up volume 50ml with mobile phase. Filter through 0.40 micron filter.
Standard preparation:
Weigh accurately Tranexamic Acid and ref. standard and prepare equal concentrations as mentioned above.
Procedure:
Inject the standard preparations and sample preparation, the tailing factor should not be more than 2% and calculate the contents of active ingredients.
Flow rate 2.0 ml
Pressure 350 Kg
Wave length 420 nm
Column Length 150 mm
Column I.D. 4.6 mm
Injection volume 20 ul
OBSERVATIONS & CALCULATIONS:
Peak area / height of Tranexamic Acid sample preparation = A
Peak area / height of Tranexamic Acid standard preparation = B
MASTER FORMULA
COMPOSITION
Each 1ml Ampoule Contains:
· ACTIVE INGREDIENT
SODIUM HYALURANATE BP…………………..10mg
· INACTIVE INGREDIENT
Sodium Chlorid BP/USP…….……….…………8.5mg
Monobasic Sod. Phosphate BP/USP…….……….0.1mg
Dibasic Sod. Phosphate BP/USP…….……….… 1.2mg
NaOH BP/USP….. Q.S to adjust pH between 6.8 and 8.0
Water for Injection BP/USP…………..….. Q.S to 1.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
MASTER FORMULA
COMPOSITION
Each 2ml Ampoule Contains:
· ACTIVE INGREDIENT
Ranitidine USP ………………………..………………..…. 50mg
(As HCl)
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 6.7 and 7.3
Water for Injection BP/USP…………..…………... Q.S to 2.0ml
DESCRIPTION OF METHOD OF MANUFACTURE
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture for method
The ingredients are weighed in the presence of Production Pharmacist and Q.C inspector and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the BP standard before formulation and ensure that it is freshly prepared the Q.C stickers is available.
Rinse the container with freshly prepared pyrogen free distilled water.
Measure the water quantity, record the temperature and bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized vials under sterile conditions.
Inspect vials visually to ensure the contents are free of any particulate matte.
Pack in accordance with laid down GMP standards.
The packed batch is sent under controlled conditions.
METHOD OF ANALYSIS
Infusion XX 100mg/50ml
Description: Clear greenish yellow, solution in glass vials.
pH: between 3.5 and 4.6
Identification: The retention time of sample solution corresponds to the retention time of standard
solution in assay.
STERILITY TEST: - Conforms to USP.
ENDOTOXIN/PYROGEN TEST: Confirms to USP
Assay (Ciprofloxacin): 90 — 110 % of the label’s claim
(as Lactate)
Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) dilute a quantity of the intravenous infusion with sufficient of the mobile phase to produce a solution containing the equivalent of 0.5% w/v of Ciprofloxacin. Solution (2) contains 0.058% w/v ciprofloxacin hydrochloride EPCRS in the mobile phase. Solution (3) contains 0.025% w/v of ciprofloxacin impurity C EPCRS (ethylene-diamine compound) in solution (2). For solution (4) dilute 1 volume of solution (3) to 100 volumes with the mobile phase.
The chromatographic procedure may be carried out using (a) a stainless steel column (150mm x 4.6mm) packed with stationary phase C (5um) (Nucleosil C18 is suitable), (b) as the mobile phase with a flow rate of 1.5ml per minute a mixture of 13 volumes of acetonitrile and 87 volumes of a 0.245% w/v solution of orthophosphoric acid the pH of which has been adjusted to 3.0 with triethylamin and (c) a detection wavelength of 278nm. Maintain the temperature of the column at 40o.
The assay is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to ciprofloxacin and ciprofloxacin impurity C is at least 1.5.Calculate the content of C17H18FN3O3 in the intravenous infusion using the declared content of C17H19CIFN3O3 is equivalent to 0.9010mg of C17H18FN3O3.
(MASTER FORMULA)
COMPOSITION
Each vial contains:
· ACTIVE INGREDIENT
RABEPRAZOLE INN..…………………...………… 20 mg
(As Sodium)
· INACTIVE INGREDIENT
Edetate Sodium BP/USP…….……….……………….... 1.0mg
NaOH BP/USP….. Q.S to adjust pH between 11.0 and 12.5
Water for Injection BP/USP………… Q.S to form the solution
for Lyophilization
DESCRIPTION OF METHOD OF MANUFACTURE
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared the Q.C stickers is available.
Rinse the container with freshly prepared pyrogen free distilled water.
Measure the water quantity, record the temperature and bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of NaOH solution keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid.
Transfer the prepared solution to the sterilized apyrogenized vials equivalent to 40mg of Omeprazole and shift to the Lyophilization chamber (freezed dryer).
After the completion of Lyophilization process transfer the vial to the quarantine area.
Request the Q.C to draw the sample.
Inspect vial visually to ensure the contents are free of any particulate matter.
Pack in accordance with laid down GMP standards.
PHARMACOLOGICAL & CLINICAL DATA
A. Description:
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H 2 -receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H + K + ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide.
B. Indications:
It is an alternative in patients for whom oral administration of Rabeprazole is not indicated.
GHI i.v . is indicated in the treatment of :
1. .Sequential-therapy(step-up) from oral GHI, e.g. A patient previously on oral GHI who is temporarily unable to
take oral medication for any reason.
2. .Active duodenal ulcer with bleeding or severe erosions.
3. .Active gastric ulcer with bleeding or severe erosions.
4. .Short-term treatment of erosive or ulcerative gastroesophageal reflux disease (GERD)
5. .Prevention of acid-aspiration .
6. .Stress-induced mucosal injury in critical care.
7. .Pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
C. Contra-Indications:
Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation.
D. Warnings And Precautions:
It is an alternative in patients in whom oral administration of rabeprazole is not indicated.Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
E. Side-Effects:
Adverse events with rabeprazole are mild to moderate in intensity and included malaise, diarrhoea, nausea, skin eruptions, headache and dizziness. Abnormal laboratory findings (increased hepatic enzymes, LDH, blood urea nitrogen) with rabeprazole were similar in incidence and severity with comparator agents and reversible with cessation of therapy.
F. Drug Interactions:
Rabeprazole sodium undergoes an almost complete, mainly non-enzymatic metabolism with renal elimination of the metabolites, CYP 450 enzymes contributed to the fraction of metabolism mediated enzymatically. Rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin, theophylline, diazepam and phenytoin.
G. Overdosage:
Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
H. Storage:
Store below 30°C. Protect from light.
MASTER FORMULA
COMPOSITION
Each 5ml Ampoule Contains:
· ACTIVE INGREDIENT
PIRACETAM BP ………………………..………………... 1.0gm
· INACTIVE INGREDIENT
Sodium Metaby Suphite BP/USP……………………….… 10mg
NaOH BP/USP……………..…… Q.S to Adjust pH 5.5 and 7.0
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 5.5 and 7.0
Water for Injection BP/USP…………..…………... Q.S to 5.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
METHOD OF ANALYSIS
Injection HIL 1.0gm/5ml
Ø Description:
A clear to light yellow colour solution in glass ampoule.
Ø Identification: (Piracetam)
The chromatogram of the assay preparation exhibits a major peak for Piracetam and , the retention time of which corresponds to the exhibited in the chromatogram of standard preparation as obtained in the assay.
Ø Assay:- (HPLC)
Mobile Phase: Prepare a mixture of acetonitrile and distilled water in the ratio of 70 volumes of acetonitrile and 30 volume of water and 0.05 ml of glacial acetic acid/100ml. filter and degassed mixture of the prepared solution.
Sample preparation:
Mix the contents of 10 ampoules, take sample equivalent to 100mg of Piracetam and make up volume 100ml with mobile phase. Filter through 0.45 micron filter.
Standard preparation:
Weigh accurately Piracetam and ref. standard and prepare equal concentrations as mentioned above.
Procedure:
Inject the standard preparations and sample preparation, the tailing factor should not be more than 2% and calculate the contents of active ingredients.
Flow rate 2.0 ml
Pressure 350 Kg
Wave length 205 nm
Column 150 mm x BDS x C18 x 5 micron
Column I.D. 4.6 mm
Injection volume 20 ul
OBSERVATIONS & CALCULATIONS:
Peak area / height of Piracetam sample preparation = A
Peak area / height of Piracetam standard preparation = B
Limit:
Piracetam 90 ----- 110 % of the labeled amount.
PHARMACOLOGICAL & CLINICAL DATA
I. Description:
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H 2 -receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H + K + ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide.
J. Indications:
It is an alternative in patients for whom oral administration of Rabeprazole is not indicated.
GHI i.v . is indicated in the treatment of :
8. .Sequential-therapy(step-up) from oral GHI, e.g. A patient previously on oral GHI who is temporarily unable to
take oral medication for any reason.
9. .Active duodenal ulcer with bleeding or severe erosions.
10. .Active gastric ulcer with bleeding or severe erosions.
11. .Short-term treatment of erosive or ulcerative gastroesophageal reflux disease (GERD)
12. .Prevention of acid-aspiration .
13. .Stress-induced mucosal injury in critical care.
14. .Pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
K. Contra-Indications:
Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation.
L. Warnings And Precautions:
It is an alternative in patients in whom oral administration of rabeprazole is not indicated.Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
M. Side-Effects:
Adverse events with rabeprazole are mild to moderate in intensity and included malaise, diarrhoea, nausea, skin eruptions, headache and dizziness. Abnormal laboratory findings (increased hepatic enzymes, LDH, blood urea nitrogen) with rabeprazole were similar in incidence and severity with comparator agents and reversible with cessation of therapy.
N. Drug Interactions:
Rabeprazole sodium undergoes an almost complete, mainly non-enzymatic metabolism with renal elimination of the metabolites, CYP 450 enzymes contributed to the fraction of metabolism mediated enzymatically. Rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin, theophylline, diazepam and phenytoin.
O. Overdosage:
Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
P. Storage:
Store below 30°C. Protect from light.
DOSAGE AND ADMINISTRATION
DOSAGE AND DIRECTIONS FOR USE:
The intravenous administration is recommended only in cases where the oral administration is not indicated. As soon as an oral therapy is possible the intravenous therapy should be discontinued.
Recommended dose is intravenous administration of the content of one vial ( 20 mg rabeprazole ) Once daily. Parenteral routes of administration other than intravenous are not recommended.
Injection: The content of the vial needs to be reconstituted with 5 ml sterile water for injection, which should be given slowly over 5-15 min.
Infusion: For intravenous infusion the reconstituted solution should be further diluted and administered as short-term infusion over 15-30 min.
Compatibility with various I.V. fluids
GHI I.V. is compatible with Dextrose injection, Dextrose saline injection.
Dosage In Special Populations: No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of rabeprazole to patients with mild to moderate liver impairment results in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in these patients.
Reconstitution
To reconstitute add 5 ml of sterile water for injection to make a solution.
After preparation, the reconstituted solution must be used within 4 hours and the unused portion discarded. As with all parenteral admixtures, the reconstituted or further diluted solution should be examined for change in colour, precipitation, haziness or leakage .The unused portion should be discarded.
pH of the reconstituted solution : Between 11.2-12.5
(Master Formula)
COMPOSITION
Each 1ml ampoule contains:
· ACTIVE INGREDIENT
PIROXICAM USP..………………….………………… 20 mg
· INACTIVE INGREDIENT
Propylene Glycol BP/USP …………………………….. 0.4ml
Sodium metabysulphite BP/USP ………………………. 4.0mg
Edetate Sodium BP/USP…….……….……………….... 1.0mg
NaOH BP/USP……... Q.S to adjust pH between 5.0 and 7.0
Water for Injection BP/USP……… Q.S to form 1ml ampoule
.
MASTER FORMULA
COMPOSITION
Each 2ml Vial Contains:
· ACTIVE INGREDIENT
Amikacin USP ………………………..………………..…. 100mg
(As Amikacin Sulphate)
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 3.5 and 5.5
Water for Injection BP/USP…………..…………... Q.S to 2.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards Equipments/machinery used for the manufacturing of
Injections / Infusions
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
1. R O Plant
2. Water Deionizer
3. Distillation Plant
4. WFI Storage Tank
5. Mixing Tank
6. Pressure Regulator with Microbial Filter
7. Vial Washing Machine
8. Vial Sterilizer
9. Vial filling Machine
10. Vial sealing Machine
11. Ampoule Washing Machine
12. Ampoule Sterilizer
13. Ampoule Filling/Sealing Machine
14. Pressure Tank
15. Filtration Unit
The physical parameter carried out for the releases of the product
(In process)
1. PHYSICAL VERIFICATION OF INGREDIENTS FOR QUALITY AND QUANTITY.
2. FOLLOWING CHECK ARE CARRIED OUT FOR INPROCESS CONTROL OF PARENTRALS.
a. Av. Volume of ampoules/bottles/vials.
b. pH of the solution.
c. Identifications of Active drug.
d. Code. No. for infusions.
e. Deformation of ampoules/bottles / vials.
f. Particles in ampoules / vials / bottles.
g. LAL test.
3. IN HOUSE PACKAGING CHECKS FOR PARENTRALS.
a. Product name
b. Batch No.
c. Manufacture Date
d. Expiry Date
e. Manufacturing License No.
f. Registration No.
g. Price
h. Labeling
i. Printing
j. Over all view.
k. Grammage of carton
Source of Water
Ground Water
1. Fit for drinking approved by PCSIR.
2. Copy of Certificate Attached.
ENCLOSURE – 09(a)
Water for Injection (BP/USP)
Equipment/Machinery used for the preparation of
“Water For Injection (BP/USP)”
1. Filters
2. De – Ionizer
3. RO – Plant
4. Distillation Plant
5. WFI Storage Tank
Specifications:
Sr. #
TEST PARAMETERS
SPECIFICATIONS
01
Description
A clear, odourless and tasteless liquid.
02
Acidity or Alkalinity
Must be complies to BP.
03
Ammonium
Not more than 0.2 PPM.
04
Calcium/Magnesium
Not more than 0.5 ml of 0.01 EDTA Should be used to produce blue color.
05
Heavy metals
Not more than 0.1 PPM.
06
Chloride
Solution remains clear within 15 minutes or not more than 5 PPM.
07
Nitrate
Not more than 2PPM.
08
Sulphate
No change in appearance within 1 hour.
09
Oxidisable Substance
The solution should remain faintly pink.
10
Residue on evaporation
Should not more than 0.001%.
11
Bacterial Endotoxins
NMT 0.25 units/ml.
12
Conductivity at 25C
NMT 1.3 mS/cm
(Master Formula)
COMPOSITION
Each 1ml contains:
· ACTIVE INGREDIENT
ARTEMETHER BAN..………………….………… 80 mg
(As Sodium)
· INACTIVE INGREDIENT
Edetate Sodium BP/USP…….……….……………….... 1.0mg
NaOH BP/USP….. Q.S to adjust pH between 11.0 and 12.5
Water for Injection BP/USP………… Q.S to
DESCRIPTION OF METHOD OF MANUFACTURE
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared the Q.C stickers is available.
Rinse the container with freshly prepared pyrogen free distilled water.
Measure the water quantity, record the temperature and bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of NaOH solution keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid.
Transfer the prepared solution to the sterilized apyrogenized vials equivalent to 40mg of Omeprazole and shift to the Lyophilization chamber (freezed dryer).
After the completion of Lyophilization process transfer the vial to the quarantine area.
Request the Q.C to draw the sample.
Inspect vial visually to ensure the contents are free of any particulate matter.
Pack in accordance with laid down GMP standards.
METHOD OF ANALYSIS
Injection NN 80mg/1ml
Ø Description:
A clear to light yellow colour solution in glass ampoule.
Ø Identification: (Artemether)
The chromatogram of the assay preparation exhibits a major peak for Artemether and , the retention time of which corresponds to the exhibited in the chromatogram of standard preparation as obtained in the assay.
Ø Assay:- (HPLC)
Mobile Phase: Prepare a mixture of acetonitrile and distilled water in the ratio of 70 volumes of acetonitrile and 30 volume of water and 0.05 ml of glacial acetic acid/100ml. filter and degassed mixture of the prepared solution.
Sample preparation:
Mix the contents of 10 ampoules, take sample equivalent to 160mg and make up volume 100ml with mobile phase. Filter through 0.45 micron filter.
Standard preparation:
Weigh accurately Artemether and ref. standard and prepare equal concentrations as mentioned above.
Procedure:
Inject the standard preparations and sample preparation, the tailing factor should not be more than 2% and calculate the contents of active ingredients.
Flow rate 2.0 ml
Pressure 350 Kg
Wave length 215 nm
Column Length 150 mm
Column I.D. 4.6 mm
Injection volume 20 ul
OBSERVATIONS & CALCULATIONS:
Peak area / height of Artemether sample preparation = A
Peak area / height of Artemether standard preparation = B
Limit:
Artemether 90 ----- 110 % of the labeled amount.
The physical parameter carried out for the releases of the product
(In process)
4. PHYSICAL VERIFICATION OF INGREDIENTS FOR QUALITY AND QUANTITY.
5. FOLLOWING CHECK ARE CARRIED OUT FOR INPROCESS CONTROL OF PARENTRALS.
a. Av. Volume of ampoules/bottles/vials.
b. pH of the solution.
c. Identifications of Active drug.
d. Code. No. for infusions.
e. Deformation of ampoules/bottles / vials.
f. Particles in ampoules / vials / bottles.
g. LAL test.
6. IN HOUSE PACKAGING CHECKS FOR PARENTRALS.
a. Product name
b. Batch No.
c. Manufacture Date
d. Expiry Date
e. Manufacturing License No.
f. Registration No.
g. Price
h. Labeling
i. Printing
j. Over all view.
k. Grammage of carton
COMPOSITION
Each vial contains:
q ACTIVE INGREDIENT:
Azithromycin USP…….…………………...…..….. 500mg
(As Dihydrate)
q IN-ACTIVE INGREDIENT:
Citric Acid Anhydrous BP/USP …..………………413.6 mg
NaOH BP/USP………………………………………114 mg
pH …………………………………………………4.0 --- 6.0
Water for Injection BP/USP (re – constitution) ……... 10ml
Method of analysis
AZIT 500mg/vial
COMPOSITION: Each vial contains:
AZITHROMYCIN USP ………………………….500mg
DESCRIPTION: White to pale yellow powder in glass vials.
IDENTIFICATION: - To 1 g powder in test tube, add 5 ml of 1 M hydrochloric acid, shake well, add 0.5 ml of 0.05 M iodine solution, and shake vigorously. Brown precipitates appear which convert to brown black tinny particles.
pH (When constituted as directed): Between 4.0 and 6.0
STERILITY TEST: Conforms to USP
Bacterial Endotoxin: Confirms to USP
ASSAY:-
METHOD OF ANALYSIS:
Sample Preparation:
Reconstitute the average dry powder for injection, take sample equivalent to 200 mg Azithromycin USP. Transfer to a separatory funnel, add 10 ml of water and extract with 3 x 30 ml of chloroform. Collect the chloroform layer and evaporate it on water bath at 50 – 60 C to dryness. Dissolve the residue in 50 ml of glacial acetic acid, Titrate with 0.1M perchloric acid using 0.05 ml crystal violet solution as indicator till the bluish green colour is produced.
Each ml of 0.1M perchloric acid is equivalent to 37.45.mg of Azithromycin.
Blank:
To 50 ml of glacial acetic acid, Titrate with 0.1M perchloric acid using 0.05 ml crystal violet solution as indicator till the bluish green colour is produced.
Observations & Calculations:
Sample taken = 200 mg
Volume of 0.1M perchloric acid used for sample. = A
Volume of 0.1M perchloric acid used for blank. = B
Net volume of 0.1M perchloric acid used for sample. = A - B
Azithromycin % = D X 37.45 X 100
200
Limit: The contents of Azithromycin should be 90.0 --- 110.0% of the label claim.
MASTER FORMULA
COMPOSITION
Each 1ml Ampoule Contains:
· ACTIVE INGREDIENT
Buprenorphine HCl BP ………………..….….0.324mg
Equivalent to Buprenorphine BP …………..…….0.3mg
· INACTIVE INGREDIENT
Dextrose (Anhydrous) BP/USP…….……….……50mg
HCl BP/USP….. Q.S to adjust pH between 3.5 and 5.5
Water for Injection BP/USP…………..….. Q.S to 1.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
PHARMACOLOGICAL & CLINICAL DATA
A. DESCRIPTION
XX is a synthetic opioid agonist-antagonistic analgesic. The active ingredient of XX is Buprenorphine hydrochloride, [N-cyclopropylmethyl-7alpha-(1-(S)-hydroxy-1,2,2-trimethylpropyl- 6-,14-endoethano-6,7,8,14-tetrahydronororipavine hydrochloride].
Buprenorphine hydrochloride is a highly lipophilic ring C bridges oripavine derivative of thebaine.
B. CHEMICAL STRUCTURE
C. INDICATIONS
Strong analgesic for short-term (not more than 1 week) relief of moderate to severe pain, including post-operative and terminal pain. XX Injection should be employed when sublingual administration is not practical e.g. pre- or peri-operatively. It is not recommended for use in children.
Buprenorphine does not have an approved role in opioid dependence rehabilitation programs.
D. CLINICAL PHARMACOLOGY
XX is a parenteral opioid analgesic with 0.3 mg XX being approximately equivalent to 10 mg morphine sulfate in analgesic and respiratory depressant effects in adults. Pharmacological effects occur as soon as 15 minutes after intramuscular injection and persist for 6 hours or longer. Peak pharmacologic effects usually are observed at 1 hour. When used intravenously, the times to onset and peak effect are shortened.
The limits of sensitivity of available analytical methodology precluded demonstration of bioequivalence between intramuscular and intravenous routes of administration. In postoperative adults, pharmacokinetic studies have shown elimination half-lives ranging from 1.2-7.2 hours (mean 2.2 hours) after intravenous administration of 0.3 mg of Buprenorphine. A single, ten-patient, pharmacokinetic study of doses of 3 µg/kg in children (age 5-7 years)
showed a high inter-patient variability, But suggests that the clearance of the drug may be higher in children than in adults. This is supported by at least one repeat-dose study in postoperative pain that showed an optimal inter-dose interval of 4-5 hours in pediatric patients as opposed to the recommended 6-8 hours in adults.
Buprenorphine, in common with morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. Studies in patients anesthetized with 0.5% halothane have shown that this anesthetic decreases hepatic blood flow by about 30%.
Mechanism of Analgesic Action: XX exerts its analgesic effect via high affinity binding to µ subclass opiate receptors in the central nervous system. Although XX may be classified as a partial agonist, under the conditions of recommended use it behaves very much like classical µ agonists such as morphine. One unusual property of XX observed in in vitro studies is its very slow rate of dissociation from its receptor. This could account for its longer duration of action than morphine, the unpredictability of its reversal by opioid antagonists, and its low level of manifest physical dependence.
Narcotic Antagonist Activity: Buprenorphine demonstrates narcotic antagonist activity and has been shown to be equipotent with naloxone as an antagonist of morphine in the mouse tail flick test.
Cardiovascular Effects: XX may cause a decrease or, rarely, an increase in pulse rate and blood pressure in some patients.
Effects on Respiration: Under usual conditions of use in adults, both XX and morphine show similar dose-related respiratory depressant effects. At adult therapeutic doses, XX (0.3 mg Buprenorphine) can decrease respiratory rate in an equivalent manner to an equianalgesic dose of morphine (10 mg).
E. CONTRA-INDICATIONS
Pregnancy and Lactation (see Use in Pregnancy and Use in Lactation).
XX should not be administered to patients who have been shown to be hypersensitive to Buprenorphine.
F. WARNINGS
Because of the narcotic antagonist activity of Buprenorphine, use in individuals dependent on other opioids may result in withdrawal effects.
Use in Pregnancy
Category C. Narcotic analgesics may cause respiratory depression in the newborn infant. Therefore, during the last 2-3 hours before expected delivery, these products should only be used after weighing the needs of the mother against the risk to the foetus.
Buprenorphine readily crosses the placental barrier. The safety of Buprenorphine in pregnancy has not been established and therefore it should not be used in women who are pregnant or who are likely to become pregnant unless the potential benefits outweigh the possible risks.
Australian categorisation definition of:
Category C
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying text above should be consulted for further details.
Use in Lactation
It is not known whether Buprenorphine is secreted in breast milk and safety in the new born has not been established. Therefore, it should not be given to nursing mothers.
G. PRECAUTIONS
Cardiovascular Effects: Buprenorphine may cause a slight reduction in pulse rate and blood pressure in some patients.
Head Injury and Increased Intracranial Pressure: Although there is no clinical experience in patients with elevated cerebrospinal fluid (CSF) pressure caused by head injury or intracranial lesions, Buprenorphine should be used with caution. Experience with other opioid analgesics indicates that respiratory depressant effects may elevate CSF pressure due to vasodilation from the CO2 retention. This may be markedly exaggerated with pre-existing elevation of CSF pressure or head injury or intracranial lesions. Furthermore, Buprenorphine produces miosis and may change the level of consciousness, thus interfering with patient evaluation. The miosis is more marked than with morphine and persists for more than 24 hours.
Respiratory Depression: As with most analgesic drugs acting at the opiate receptor, Buprenorphine may cause respiratory depression and whilst this is rarely of clinical significance, it should be used with caution in patients with either compromised respiratory function or those given respiratory depressant drugs, especially as there is no fully effective antagonist.
Respiratory depression following sublingual Buprenorphine is more likely to occur with doses exceeding 0.4 mg.
Should respiratory depression occur to clinically undesirable degree, supportive measures should be used to maintain adequate ventilation and oxygenation. The effects of Buprenorphine are only partially reversed by standard narcotic reversal agents, such as naloxone.
Hepatic Dysfunction: Because Buprenorphine is metabolised by the liver, the intensity and duration of its action may be altered in those individuals with impaired hepatic function.
H. OVERDOSAGE
Symptoms: There is limited experience of accidental or intentional overdosage at the present time, But doses in the range 3 to 7 mg have been administered intravenously without producing clinically significant respiratory effects. Extrapolating from the animal pharmacology of the agent, respiratory depression is likely to occur in the event of overdosage, together with cardiovascular depression and some CNS effects, such as sedation. Therefore, the respiratory and cardiac status of the patient should be carefully monitored.
Treatment: Primary attention should be given to the re-establishment of adequate respiratory exchange. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Intravenous naloxone given repeatedly may be partially effective.
I. DRUG INTERACTIONS
(a) Monoamine Oxidase Inhibitors: Until further information is available, Buprenorphine should be used with caution in patients receiving monoamine oxidase inhibitors as these may intensify its adverse effects.
(b) CNS Depressants: Buprenorphine may cause some drowsiness, and this could be potentiated by other centrally-acting agents such as long acting benzodiazepines, volatile anaesthetics and certain induction agents. Hence, amBulant patients should be warned not to drive or operate machinery if affected.
(c) Narcotic Antagonist Activity: Buprenorphine demonstrates narcotic antagonist activity and has been shown to reverse the effects of peri-operatively administered narcotics. It may, therefore, precipitate mild withdrawal symptoms in narcotic addicts and it should be given with care, initially, to patients previously treated with narcotic analgesics.
J. ADVERSE REACTIONS
Drowsiness, or sleep from which the patient can easily be aroused, occurs in most patients, particularly in the post-operative period.
Gastrointestinal System: Nausea and vomiting have been reported in 9% and 7% of patients respectively, and may be worse in amBulatory patients. Administering a lower dose, or having the patient lie down may alleviate these effects.
Dry mouth and constipation have rarely been reported.
Central Nervous System: Often associated with nausea and vomiting, But less frequently, are headache and symptoms of dizziness (1%) and sweating (1%). Improved mood or mild euphoria has been reported in 0.28% of cases.
Hallucinations and other psychotomimetic effects have rarely been reported.
Respiratory System: Significant respiratory depression has been observed infrequently and is rarely of clinical significance.
Genito-urinary: Difficulty in urination has occurred in less than 1% of patients.
Cardiovascular: Slight bradycardia and hypotension occur. Tachycardia and hypertension have been rarely reported.
Other: For XX Injection, localised skin reactions at the injection site and hypersensitivity symptoms have been rarely reported, with one reported case of anaphylactic reaction.
Gastrointestinal System: Nausea and vomiting have been reported in 9% and 7% of patients respectively, and may be worse in amBulatory patients. Administering a lower dose, or having the patient lie down may alleviate these effects.
Dry mouth and constipation have rarely been reported.
Central Nervous System: Often associated with nausea and vomiting, But less frequently, are headache and symptoms of dizziness (1%) and sweating (1%). Improved mood or mild euphoria has been reported in 0.28% of cases.
Hallucinations and other psychotomimetic effects have rarely been reported.
Respiratory System: Significant respiratory depression has been observed infrequently and is rarely of clinical significance.
Genito-urinary: Difficulty in urination has occurred in less than 1% of patients.
Cardiovascular: Slight bradycardia and hypotension occur. Tachycardia and hypertension have been rarely reported.
Other: For XX Injection, localised skin reactions at the injection site and hypersensitivity symptoms have been rarely reported, with one reported case of anaphylactic reaction.
MASTER FORMULA
COMPOSITION
Each 2ml ampoule Contains:
· ACTIVE INGREDIENT
CIMETIDINE BP ………………………..………………..…. 200mg
(As HCl)
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 3.8 and 6.0
Water for Injection BP/USP…………..…………... Q.S to 2.0ml
MASTER FORMULA
COMPOSITION
Each 50ml vial contains:
· ACTIVE INGREDIENT
Ciprofloxacin USP …….…….………..………… …100mg
(As Lactate)
· INACTIVE INGREDIENT
Sodium Chloride BP/USP……………….………….…….… 0.9g
Lactic Acid BP/USP….……Q.S to adjust pH between 3.5 and 4.5
Water for Injection BP/USP…….….………..…..….. Q.S to 50ml
PHARMACOLOGICAL & CLINICAL DATA
A. Chemical Structure
B. Description
A fluoroquinolone is the salt of 1-cyclopropyl-6-fluora-1, 4-dihydro-4-oxa-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is C17H18FN3O3.
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-drhydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4 It is a faintly yellowish to light yellow crystalline substance.
Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-position.
C. Indications and Usage
UTI, respiratory, ENT, eye, skin and soft tissue, bone, joint, pelvic, biliary tract, intra-abdominal and Gl infection. Gonorrhoea. Severe systemic infection. Gram-negative pneumonia (not for first line treatment in pneumococcal pneumonia). Prophylaxis in upper Gl surgery or endoscopy.
D. Warnings
NOT FOR OPHTHALMIC USE. NOT FOR INJECTION.
XX should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported
in patients receiving systemic quinolones. Serious acute hypersensitivity reactions may require immediate emergency treatment.
E. Precautions
Do not use this medicine if you have had a severe allergic reaction to this medicine or another fluoroquinolone antibiotic. A severe reaction includes a severe rash, hives, breathing difficulties, or dizziness. If you experience difficulty breathing; tightness of chest; swelling of eyelids, face, or lips; or if you develop a rash or hives, tell your doctor immediately. For women: if you plan on becoming pregnant, discuss with your doctor the benefits and risks of using this medicine during pregnancy. It is unknown if this medicine is excreted in breast milk. Do not breast-feed while taking this medicine.
F. Adverse Reactions
In Phase 3 clinical trials, a total of 564 patients were treated with XX. Adverse events with at least remote relationship to treatment included headache (1.2%) and pruritus (0.4%). The following treatment-related adverse events were each reported in a single patient: migraine, hypesthesia, paresthesia, fungal dermatitis, cough, rash, urticaria, and alopecia.
G. Storage Conditions:
Store below 30°C. Keep out of reach of children.
DOSAGE AND ADMINISTRATION
DOSAGE AND DIRECTIONS FOR USE:
Dosage and Duration of Treatment:
The dosage of XX IV is determined by the severity and type of infection, the sensitivity of the causative organism(s) and the age, mass and renal function of the patient. The usual dose is 100 mg - 200 mg IV every 12 hours. For severe and/or complicated infections 400 mg may be administered every 12 hours (i.e. bd). Intravenous therapy should be discontinued as soon as oral ciprofloxacin therapy can be substituted. The normal duration of intravenous therapy is up to 7 days.
Cystic fibrosis:
In cystic fibrosis patients the normal dose is 200 mg IV twice daily. The low body mass of these patients should, however, be taken into consideration when determining dosage (5-10 mg/kg/day).
Directions for Intravenous Administration:
XX IV should be administered by intravenous infusion over a period of 60 minutes. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation. The infusion solution can be infused either directly or after mixing with the other compatible infusion solutions.
The XX IV infusion solution is compatible with physiological saline, Ringer solution and Ringer lactate solution, 5% and 10% glucose solutions, 10% fructose solution, and 5% glucose solution with 0.225% NaCl or 0.45% NaCl. When ciprofloxacin infusion solutions are mixed with compatible infusion solutions, for microbiological reasons and light sensitivity these solutions should be administered shortly after admixture.
Important incompatibilities:
Unless compatibility with other infusion solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding and discolouration.
Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solution (e.g. penicillins, heparin solutions), especially on combination with solutions adjusted to an alkaline pH (pH of the ciprofloxacin infusion solutions: 3.9-4.5).
Any remaining solution should be discarded.
Impaired Renal or Liver Function:
In patients with reduced renal function, the half-life of ciprofloxacin is prolonged and the dosage needs to be adjusted.
For patients with changing renal function or patients with renal impairment and hepatic insufficiency, monitoring of drug serum levels provides the most reliable basis for dose adjustment.
MASTER FORMULA
COMPOSITION
Each 2ml contains:
· ACTIVE INGREDIENT
TOBRAMYCIN USP ….………...……………...……….… .20mg
(as TOBRAMYCIN Sulphate)
· INACTIVE INGREDIENT
1. Benzyl alcohol USP .…………………………………. 18mg
2. Sodium Metabisulphite BP ..………………………….. 6.4mg
3. Disod. Edetate BP/USP ……………………………… 0.1mg
4. Sulfuric acid BP/USP……QS to adjust pH between 3.0 to 6.5
5. Water for Injection BP/USP .……………………………QS to 2ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
MASTER FORMULA
COMPOSITION
Each 2ml Ampoule Contains:
· ACTIVE INGREDIENT
TRAMADOL HCl BP …………………………..100mg
· INACTIVE INGREDIENT
Dextrose (Anhydrous) BP/USP…….……….……50mg
HCl BP/USP….. Q.S to adjust pH between 3.0 and 5.5
Water for Injection BP/USP…………..….. Q.S to 2.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards
MASTER FORMULA
COMPOSITION
Each 5ml Ampoule Contains:
· ACTIVE INGREDIENT
Tranexamic Acid USP ………………………..………………..….250mg
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 6.5 and 8.0
Water for Injection BP/USP…………..…………... Q.S to 5.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standar METHOD OF ANALYSIS
Injection T 250mg/5ml
Ø Description:
A clear colourless solution.
Ø Identification: (Tranexamic Acid)
The chromatogram of the assay preparation exhibits a major peak for Tranexamic Acid and, the retention time of which corresponds to the exhibited in the chromatogram of standard preparation as obtained in the assay.
Ø pH 6.5 -------------8.0
Ø Sterility Testing (Confirms to USP)
Ø Assay:- (HPLC)
Mobile Phase: Prepare a mixture of acetonitrile and distilled water in the ratio of 70 volumes of acetonitrile and 30 volume of water and 0.05 ml of glacial acetic acid/100ml. filter and degassed mixture of the prepared solution.
Sample preparation:
Mix the contents of 10 ampoules, take sample equivalent to 20mg of Tranexamic Acid and make up volume 50ml with mobile phase. Filter through 0.40 micron filter.
Standard preparation:
Weigh accurately Tranexamic Acid and ref. standard and prepare equal concentrations as mentioned above.
Procedure:
Inject the standard preparations and sample preparation, the tailing factor should not be more than 2% and calculate the contents of active ingredients.
Flow rate 2.0 ml
Pressure 350 Kg
Wave length 420 nm
Column Length 150 mm
Column I.D. 4.6 mm
Injection volume 20 ul
OBSERVATIONS & CALCULATIONS:
Peak area / height of Tranexamic Acid sample preparation = A
Peak area / height of Tranexamic Acid standard preparation = B
MASTER FORMULA
COMPOSITION
Each 1ml Ampoule Contains:
· ACTIVE INGREDIENT
SODIUM HYALURANATE BP…………………..10mg
· INACTIVE INGREDIENT
Sodium Chlorid BP/USP…….……….…………8.5mg
Monobasic Sod. Phosphate BP/USP…….……….0.1mg
Dibasic Sod. Phosphate BP/USP…….……….… 1.2mg
NaOH BP/USP….. Q.S to adjust pH between 6.8 and 8.0
Water for Injection BP/USP…………..….. Q.S to 1.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
MASTER FORMULA
COMPOSITION
Each 2ml Ampoule Contains:
· ACTIVE INGREDIENT
Ranitidine USP ………………………..………………..…. 50mg
(As HCl)
· INACTIVE INGREDIENT
Sodium Meta Bisulfite BP/USP……………………….……1.3mg
Sodium Citrate BP/USP……………………………………. 5.0mg
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 6.7 and 7.3
Water for Injection BP/USP…………..…………... Q.S to 2.0ml
DESCRIPTION OF METHOD OF MANUFACTURE
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture for method
The ingredients are weighed in the presence of Production Pharmacist and Q.C inspector and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the BP standard before formulation and ensure that it is freshly prepared the Q.C stickers is available.
Rinse the container with freshly prepared pyrogen free distilled water.
Measure the water quantity, record the temperature and bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized vials under sterile conditions.
Inspect vials visually to ensure the contents are free of any particulate matte.
Pack in accordance with laid down GMP standards.
The packed batch is sent under controlled conditions.
METHOD OF ANALYSIS
Infusion XX 100mg/50ml
Description: Clear greenish yellow, solution in glass vials.
pH: between 3.5 and 4.6
Identification: The retention time of sample solution corresponds to the retention time of standard
solution in assay.
STERILITY TEST: - Conforms to USP.
ENDOTOXIN/PYROGEN TEST: Confirms to USP
Assay (Ciprofloxacin): 90 — 110 % of the label’s claim
(as Lactate)
Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) dilute a quantity of the intravenous infusion with sufficient of the mobile phase to produce a solution containing the equivalent of 0.5% w/v of Ciprofloxacin. Solution (2) contains 0.058% w/v ciprofloxacin hydrochloride EPCRS in the mobile phase. Solution (3) contains 0.025% w/v of ciprofloxacin impurity C EPCRS (ethylene-diamine compound) in solution (2). For solution (4) dilute 1 volume of solution (3) to 100 volumes with the mobile phase.
The chromatographic procedure may be carried out using (a) a stainless steel column (150mm x 4.6mm) packed with stationary phase C (5um) (Nucleosil C18 is suitable), (b) as the mobile phase with a flow rate of 1.5ml per minute a mixture of 13 volumes of acetonitrile and 87 volumes of a 0.245% w/v solution of orthophosphoric acid the pH of which has been adjusted to 3.0 with triethylamin and (c) a detection wavelength of 278nm. Maintain the temperature of the column at 40o.
The assay is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to ciprofloxacin and ciprofloxacin impurity C is at least 1.5.Calculate the content of C17H18FN3O3 in the intravenous infusion using the declared content of C17H19CIFN3O3 is equivalent to 0.9010mg of C17H18FN3O3.
(MASTER FORMULA)
COMPOSITION
Each vial contains:
· ACTIVE INGREDIENT
RABEPRAZOLE INN..…………………...………… 20 mg
(As Sodium)
· INACTIVE INGREDIENT
Edetate Sodium BP/USP…….……….……………….... 1.0mg
NaOH BP/USP….. Q.S to adjust pH between 11.0 and 12.5
Water for Injection BP/USP………… Q.S to form the solution
for Lyophilization
DESCRIPTION OF METHOD OF MANUFACTURE
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared the Q.C stickers is available.
Rinse the container with freshly prepared pyrogen free distilled water.
Measure the water quantity, record the temperature and bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of NaOH solution keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid.
Transfer the prepared solution to the sterilized apyrogenized vials equivalent to 40mg of Omeprazole and shift to the Lyophilization chamber (freezed dryer).
After the completion of Lyophilization process transfer the vial to the quarantine area.
Request the Q.C to draw the sample.
Inspect vial visually to ensure the contents are free of any particulate matter.
Pack in accordance with laid down GMP standards.
PHARMACOLOGICAL & CLINICAL DATA
A. Description:
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H 2 -receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H + K + ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide.
B. Indications:
It is an alternative in patients for whom oral administration of Rabeprazole is not indicated.
GHI i.v . is indicated in the treatment of :
1. .Sequential-therapy(step-up) from oral GHI, e.g. A patient previously on oral GHI who is temporarily unable to
take oral medication for any reason.
2. .Active duodenal ulcer with bleeding or severe erosions.
3. .Active gastric ulcer with bleeding or severe erosions.
4. .Short-term treatment of erosive or ulcerative gastroesophageal reflux disease (GERD)
5. .Prevention of acid-aspiration .
6. .Stress-induced mucosal injury in critical care.
7. .Pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
C. Contra-Indications:
Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation.
D. Warnings And Precautions:
It is an alternative in patients in whom oral administration of rabeprazole is not indicated.Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
E. Side-Effects:
Adverse events with rabeprazole are mild to moderate in intensity and included malaise, diarrhoea, nausea, skin eruptions, headache and dizziness. Abnormal laboratory findings (increased hepatic enzymes, LDH, blood urea nitrogen) with rabeprazole were similar in incidence and severity with comparator agents and reversible with cessation of therapy.
F. Drug Interactions:
Rabeprazole sodium undergoes an almost complete, mainly non-enzymatic metabolism with renal elimination of the metabolites, CYP 450 enzymes contributed to the fraction of metabolism mediated enzymatically. Rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin, theophylline, diazepam and phenytoin.
G. Overdosage:
Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
H. Storage:
Store below 30°C. Protect from light.
MASTER FORMULA
COMPOSITION
Each 5ml Ampoule Contains:
· ACTIVE INGREDIENT
PIRACETAM BP ………………………..………………... 1.0gm
· INACTIVE INGREDIENT
Sodium Metaby Suphite BP/USP……………………….… 10mg
NaOH BP/USP……………..…… Q.S to Adjust pH 5.5 and 7.0
Sulfuric Acid BP/USP …………….Q.S to Adjust pH 5.5 and 7.0
Water for Injection BP/USP…………..…………... Q.S to 5.0ml
DESCRIPTION OF METHOD OF MANUFACTURE.
PROCEDURE:
All the ingredients are checked and released prior to issue for manufacture.
The ingredients are weighed in the presence of Production Pharmacist and rechecked at the time of formulation, and the weights are recorded in the formula card
The ingredients are transferred to the formulation area.
The equipment utensils and the area‘s are checked for proper cleanliness and insured that no trace of foreign matter is visible and that there is no trace of any chemical left behind of any previous product.
Check that the quality of water meets the USP standard before formulation and ensure that it is freshly prepared and the Q.C stickers is available.
Rinse the container with freshly prepared Pyrogen free distilled water.
Measure the water quantity, record the temperature and Bubble Nitrogen through water to remove the traces of Oxygen in a mixing tank and add while mixing the preservatives.
Transfer the active medicament to the tank while stirring and record the temperature and pH. of the solution.
Adjust the pH of the solution slowly by intermittent additions of Hydrochloric Acid keeping the temperature of liquid at a desirable level. Adjust the volume with remaining quantity of water for injection and record pH.
Request the Q.C to draw the sample and after released by the QC, filter the liquid aseptically through 0.2 micron filter in sterile container under Nitrogen blanket and fill the liquid in sterilized Ampoule under sterile conditions.
Inspect Ampoule visually to ensure the contents are free of any particulate.
Pack in accordance with laid down GMP standards.
METHOD OF ANALYSIS
Injection HIL 1.0gm/5ml
Ø Description:
A clear to light yellow colour solution in glass ampoule.
Ø Identification: (Piracetam)
The chromatogram of the assay preparation exhibits a major peak for Piracetam and , the retention time of which corresponds to the exhibited in the chromatogram of standard preparation as obtained in the assay.
Ø Assay:- (HPLC)
Mobile Phase: Prepare a mixture of acetonitrile and distilled water in the ratio of 70 volumes of acetonitrile and 30 volume of water and 0.05 ml of glacial acetic acid/100ml. filter and degassed mixture of the prepared solution.
Sample preparation:
Mix the contents of 10 ampoules, take sample equivalent to 100mg of Piracetam and make up volume 100ml with mobile phase. Filter through 0.45 micron filter.
Standard preparation:
Weigh accurately Piracetam and ref. standard and prepare equal concentrations as mentioned above.
Procedure:
Inject the standard preparations and sample preparation, the tailing factor should not be more than 2% and calculate the contents of active ingredients.
Flow rate 2.0 ml
Pressure 350 Kg
Wave length 205 nm
Column 150 mm x BDS x C18 x 5 micron
Column I.D. 4.6 mm
Injection volume 20 ul
OBSERVATIONS & CALCULATIONS:
Peak area / height of Piracetam sample preparation = A
Peak area / height of Piracetam standard preparation = B
Limit:
Piracetam 90 ----- 110 % of the labeled amount.
PHARMACOLOGICAL & CLINICAL DATA
I. Description:
Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H 2 -receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H + K + ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion. In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide.
J. Indications:
It is an alternative in patients for whom oral administration of Rabeprazole is not indicated.
GHI i.v . is indicated in the treatment of :
8. .Sequential-therapy(step-up) from oral GHI, e.g. A patient previously on oral GHI who is temporarily unable to
take oral medication for any reason.
9. .Active duodenal ulcer with bleeding or severe erosions.
10. .Active gastric ulcer with bleeding or severe erosions.
11. .Short-term treatment of erosive or ulcerative gastroesophageal reflux disease (GERD)
12. .Prevention of acid-aspiration .
13. .Stress-induced mucosal injury in critical care.
14. .Pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
K. Contra-Indications:
Rabeprazole is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles or to any component of the formulation.
L. Warnings And Precautions:
It is an alternative in patients in whom oral administration of rabeprazole is not indicated.Symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy.
M. Side-Effects:
Adverse events with rabeprazole are mild to moderate in intensity and included malaise, diarrhoea, nausea, skin eruptions, headache and dizziness. Abnormal laboratory findings (increased hepatic enzymes, LDH, blood urea nitrogen) with rabeprazole were similar in incidence and severity with comparator agents and reversible with cessation of therapy.
N. Drug Interactions:
Rabeprazole sodium undergoes an almost complete, mainly non-enzymatic metabolism with renal elimination of the metabolites, CYP 450 enzymes contributed to the fraction of metabolism mediated enzymatically. Rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin, theophylline, diazepam and phenytoin.
O. Overdosage:
Rabeprazole is extensively protein bound and is not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.
P. Storage:
Store below 30°C. Protect from light.
DOSAGE AND ADMINISTRATION
DOSAGE AND DIRECTIONS FOR USE:
The intravenous administration is recommended only in cases where the oral administration is not indicated. As soon as an oral therapy is possible the intravenous therapy should be discontinued.
Recommended dose is intravenous administration of the content of one vial ( 20 mg rabeprazole ) Once daily. Parenteral routes of administration other than intravenous are not recommended.
Injection: The content of the vial needs to be reconstituted with 5 ml sterile water for injection, which should be given slowly over 5-15 min.
Infusion: For intravenous infusion the reconstituted solution should be further diluted and administered as short-term infusion over 15-30 min.
Compatibility with various I.V. fluids
GHI I.V. is compatible with Dextrose injection, Dextrose saline injection.
Dosage In Special Populations: No dosage adjustment is necessary in elderly patients, in patients with renal disease or in patients with mild to moderate hepatic impairment. Administration of rabeprazole to patients with mild to moderate liver impairment results in increased exposure and decreased elimination. Due to the lack of clinical data on rabeprazole in patients with severe hepatic impairment, caution should be exercised in these patients.
Reconstitution
To reconstitute add 5 ml of sterile water for injection to make a solution.
After preparation, the reconstituted solution must be used within 4 hours and the unused portion discarded. As with all parenteral admixtures, the reconstituted or further diluted solution should be examined for change in colour, precipitation, haziness or leakage .The unused portion should be discarded.
pH of the reconstituted solution : Between 11.2-12.5
(Master Formula)
COMPOSITION
Each 1ml ampoule contains:
· ACTIVE INGREDIENT
PIROXICAM USP..………………….………………… 20 mg
· INACTIVE INGREDIENT
Propylene Glycol BP/USP …………………………….. 0.4ml
Sodium metabysulphite BP/USP ………………………. 4.0mg
Edetate Sodium BP/USP…….……….……………….... 1.0mg
NaOH BP/USP……... Q.S to adjust pH between 5.0 and 7.0
Water for Injection BP/USP……… Q.S to form 1ml ampoule
.
Monday, April 14, 2008
GOOD MANUFACTURING PRACTICE AUDIT
(GMP AUDIT – CHECK LIST)
For Pharmaceutical Manufacturing Facilities
Good Manufacturing Practice – GMP Audit Checklist
Sr # (Contents) Page #
1. Quality Assurance ……… 03
2. Premises………. 04
3. Personnel………. 05
4. Validation………. 06
5. Documentation / Records………. 07
6. Vendor Qualification………. 09
7. Change Control Program……… 09
8. Sample………… 09
9. Stability Studies………… 10
10. Drug Recall……… 10
11. Annual Product Review…….. 10
12. Audits……… 11
13. Quality Control Departments………. 12
14. Manufacturing Area……….. 13
14.1 Equipment…………. 13
14.1.6 Equipment Calibration………. 13
14.1.7 Material / Component ……….. 14
14.2 Raw Material………. 14
14.3 Purified and Water for Injection Systems……… 16
14.4 Depack / Preparation component room……….. 19
14.5 Sterilizer / Oven Loading Room ……… 20
14.6 Equipment Airlock…….. 21
14.7 Washroom / Grown change room……… 22
14.8 Manufacturing (Sterile Product) ……….. 23
14.9 Aspectic Batching Area………. 25
14.11 Filling room………. 27
14.14 Terminal Sterilization………. 30
14.15 Packaging……….. 31
14.16 Manufacturing (Oral dosages) ……… 32
14.17 Packaging… 34
15. Reprocessing ……… 35
16. Finished Product Control…….. 35
17. Warehouse / Distribution……… 36
18. Environment, Health & Safety 37
GOOD MANUFACTURING PRACTICE (GMP AUDIT- CHECK LIST)
(FOR PHARMACETICAL MANUFACTURING FACILITIES)
SR #
CRITERIAS
Yes
No
Not Applicable
RATING
(1-10)
(1=low 10=high)
REMARKS
(To be filled by Auditee)
(To be filled by Auditor)
To be filled by Auditor
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
QUALITY ASSURANCE
Does the company have mission statement and the quality policy?
Is the company ISO certified?
Was the company previously audited (GMP audit)?
Are pharmaceutical products designed and developed according to the requirement of GMP & other associated codes such as good laboratory practice (GLP) and good clinical practice (GCP)?
Are production and control operations clearly specified in a written form and GMP requirements are adopted?
Are managerial responsibilities clearly specified in job descriptions?
Are all necessary controls on starting materials, intermediate products and other in-process controls, calibrations and validation carried out?
Are finished products correctly processed and checked according to the defined procedures?
Are satisfactory arrangements existed to store in appropriate storage conditions?
2.0
2.1
2.1.1
2.1.2
2.1.3
2.1.4
2.2
2.3
2.4
2.5
2.5.1
2.5.2
2.5.3
2.5.4
2.5.5
2.6
2.6.1
2.6.2
PREMESIS
(DESIGN & LAYOUT OF FACILITIES)
Does the facility have proper design, layout and finishes based on contemporary standards to:
Manufacture high quality medicine.
Avoidance of cross contamination.
Proper cleaning, drainage and sanitizing.
Ventilation, air conditioning and maintenance.
Is there emergency power supply available to take care of entire energy demand or at least critical areas?
Does the facility have appropriate controls to maintain required parameters e.g. temperature, relative humidity and pressure differentials etc?
Are the doors, windows, walls, ceiling and floor such that no holes or cracks evident (other than those intended by design)?
PLANT SAFETY & SECURITY
Does the facility have safety program?
Are safety procedures written?
Do employees receive safety orientation before working in the plant area?
Does the facility have a formal, written security policy?
Is access to the facility restricted?
SANITATION
Is written sanitation program available on the premises?
Is sanitation program is implemented and effective in preventing conditions?
3.0
3.1
3.2
3.3
3.4
3.5
3.6
3.6.1
3.6.2
3.6.3
3.6.4
3.6.5
PERSONNEL (STAFFING PLAN, STAFF QUALIFICATION, EXPERIENCE , ON THE JOB TRAINING & HYGIENE)
Has the facility provided sufficient qualified personnel to fulfill all its responsibilities required under the rule?
Has the facility provided Organization Chart?
Does the company have qualified, trained and experience staff required for managing?
Does the company have “On the job training program” for technical staff?
Is the technical staff, including supervisors and operations certified (and documented) in specialized training e.g. aseptic technique, sterilizing, washing, depyrogenation, visual inspection, standard operating procedure etc.
HYGIENE
Are all the personal under gone health examination to prior to employment?
Are all the personnel provided health examination during employment?
Are workers conducting visual inspections under gone periodic eye examination?
Are the record maintained?
Are all personal aware about of the principles of GMP and received initial and continued training including hygiene instructions?
4.0
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
5.0
5.1
5.2
5.3
5.4
5.5
5.6
5.6.1
5.6.2
5.6.3
5.6.4
5.6.4.1
5.6.4.2
5.6.4.3
5.6.4.4
5.6.4.5
5.6.4.6
5.6.4.7
5.6.4.8
5.6.4.9
5.6.5
5.6.5.1
5.6.5.2
5.6.5.3
5.6.5.4
5.6.5.5
5.6.5.6
5.6.5.7
5.6.5.8
5.6.5.9
5.7
5.7.1
VALIDATION
Is validation properly documented and include Validation Master Plan, Validation Protocols, Validation Reports and Equipment Qualified?
Are validation studies conducted in accordance with pre-defined protocols?
Have production procedures been validated?
Does the process control address an issue to ensure identity, strength, quality and purity of product?
Does the procedure include formulation that is written to yield not less than 100% of established amount of active ingredients?
Are all weighing and measuring performed by one qualified person and observed by a second person and is dully signed by both of them on record sheet?
Validation of New Master Formula:
Is new master formula or method of preparation adopted and steps taken to demonstrate its suitability for routine processing, process defined materials and equipment specified?
Validation of Equipment & Materials:
Are significant amendments to the manufacturing process, including any change in equipment and materials affecting product quality or re-productivity of process validated?
Are validation records properly maintained?
DOCUMENTATION / RECORDS
Are documentation meticulously maintained as per rules and regularly reviewed and kept up to date?
Is documentation accurate, clear & neat. Does it define specifications and procedures for all materials & methods of manufacture & control?
Are all the specifications, testing procedures, master formulae, packing instructions and standard operating procedures (SOPs) available, current & being followed?
Do the records provide existence of documented evidence, traceability, and an audit trial that will permit investigation?
Does the record provide batch processing & packaging details including receiving sample, processing equipment, analytical testing and laboratory instrument records?
LABELS
Are labels to the containers, equipment or premises applied un-ambiguously according to company’s agreed format?
Are labels of different colors indicating the status such as “Quarantined”, “Accepted”, “Rejected”, or “Clear” used?
Are all finished products are labeled as per specification?
PROCESS DOCUMENTS / RECORDS
· Are following documents / record are available:
Starting material re-assy.
Specifications for intermediate and bulk products
Batch processing records
Record for process operation
Batch packaging records
Record for packaging operation
Record of Batch numbers
Analytical records of the batch
Record for finished product release procedure
STANDARD OPERATING PROCEDURES (SOPS)
· Are SOPS and associated records of actions, conclusions
reached available for the following at the premises?
Equipment assembly and validation
Analytical apparatus and calibration
Maintenance, cleaning and sanitization
Personnel matters including qualification, training, clothing and hygiene
Environmental monitoring
Pest control
Complaints
Drug recalls
Drug returns
EQUIPMENT LOG BOOKS
Are log books for major & critical equipments identified by company kept?
6.0
6.1
6.2
7
7.1
8.0
8.1
8.2
VENDOR QUALIFICATION
Do you have list of approved vendors?
Are the vendors supplying raw material (both active & inactive ingredients), empty gelatin capsules, primary packaging & printed packaging components audited & found to be satisfactory?
CHANGE CONTROL PROGRAM
Is there a formal change control program in place supported by an SOP to initiate, review & approve changes in material, sources, processes, products packaging, equipment, batch size changes etc.
SAMPLE
Does the company retain a sample of lot or batch of the packaged / labeled drug for a period of at least one year after the expiration date on the label of the drug?
Does the company retain a sample of each lot or batch of a raw material (including both active and inactive ingredients)?
9.0
9.1
9.2
9.3
10.0
10.1
10.2
11.0
11.1
11.2
STABILITY STUDIES
Does the company have a prospective and concurrent stability studies program based on SOP and utilizing proper equipment i.e. climatic chambers maintained at 30° C / 65% RH for ambient and 40° C / 75% RH for stress conditions and continuously monitored for temperature & RH?
Is stability of finished products evaluated and documented prior to marketing?
Does the stability data support shelf life assigned to the product. Are any deviations in data reviewed and appropriate steps taken in case of stability issues?
DRUG RECALL
Do you have SOP for drug recalls?
If answer yes to the above did you have any drug recall in the past 2 year? (Please also mention the name of products)
ANNUAL PRODUCT REVIEW
Is there a process in place to review statistical data (i.e.: trend analysis, reworks, rejects, customer complaints) of all the products manufacture during the year?
Provide name of the products manufactured by you along with price list.
11.3
11.4
12.0
12.1
12.1.1
12.1.2
12.2
12.3
13.0
13.1
13.2
13.3
13.4
13.5
13.6
13.7
13.8
13.9
13.10
Provide the source of raw material for individual products.
Do you export your products, if so then to whom and mention the name of the products?
AUDIT / COMPLAINTS
INTERNAL GMP AUDITS
Do you have an effective internal GMP inspection program to audit all the manufacturing areas, activities & QC lab at specific defined periods?
Is there a process in place to fill the gaps / observation / non-conformance found during the internal GMP audits?
QUALITY AUDITS
Is quality audit conducted by outside or independent specials or a team designated by the management for the purpose?
COMPLAINTS
Are complaints and other information concerning potentially defective products carefully reviewed according to the written procedures?
QUALITY CONTROL DEPARTMENT
Does the QC lab have SOPs to cover all the functional areas?
Are adequate facilities and equipments available for the physical, chemical & microbiological testing?
Are approved written procedures available for sampling, inspecting and testing raw materials, packaging materials, in process drugs, bulk drugs and finished products?
Are samples of starting material, packaging material, intermediate products, bulk products and finished products taken by methods and personnels approved by QC department?
Are in-process materials tested at appropriate phases for identity, strength, quality, purity and are they approved or rejected by Quality Control?
Are records of in- process controls maintained?
Does each batch of drug product prior to release confirms compliance of finished product specification?
Are validated & stability indicating assay methods used?
Are reference standards used for the assay?
Are accurate, clear & neat records maintained along with the raw data for the entire analytical work?
14.0
14.1
14.1.1
14.1.2
14.1.3
14.1.4
14.1.5
14.1.6
14.1.6.1
14.1.6.2
14.1.6.3
MANUFACTURING AREA
EQUIPMENTS, MATERIAL / COMPONENT
EQUIPMENTS
Does the company have suitable equipments capable of producing consistent quality products?
Do the equipments meet contemporary standards for the manufacture of pharmaceuticals i.e. smooth finishes, right quality construction material for the intended purpose, easy to clean, wash, sterilize etc.
Are the following pieces of equipments suitable in their design/size & capacity? (Blendes, Conveyors, Tablet presses, Capsule fillers, Bottle fillers etc)
Does the equipments & facilities have appropriate controls to maintain required parameters e.g. temperature, relative humidity, pressure differentials etc?
Is the equipment cleaned promptly after use?
EQUIPMENT/INSTRUMENTS CALIBRATION & PREVENTIVE MAINTENANCE
Are written records maintained on equipment cleaning, sanitizing and maintenance on or near each piece of equipment?
Does the facility have approved written procedures for checking and calibration of each piece of measurement equipment?
Are records of calibration checks and inspections maintained in a readily retire able manner?
14.1.7
14.1.7.1
14.1.7.2
14.1.7.3
14.2
14.2.1
14.2.2
14.2.3
14.2.4
14.2.5
14.2.6
14.2.7
14.2.8
14.2.9
14.2.10
14.2.11
14.2.12
14.2.13
14.2.14
14.2.15
MATERIAL/COMPONENT
All handling of material and products such as receipt, quarantine, sample storage, tracking, labeling, dispensing, processing, packaging and distribution is done in accordance with approved written procedure, or instruction and recorded?
All incoming materials and finished products quarantined immediately after receipt or processing until they released for use or distribution?
Are all materials handled in such a way to prevent contamination?
RAW MATERIAL
Were the premises designed for storing the raw material?
Does the store premises allow storage of raw materials at various temperatures?
If answer yes to the above what are the controls to log any irregularities?
What is the source of the active ingredient used?
What are the source of additives used?
Is any documentation done at the time of receiving the raw materials?
What is the process of communication with the laboratory for sampling of the raw material?
Is there a quarantine for storing unreleased raw materials?
If so, what is the process?
What is the process of storage after the raw material is released for use?
What is the process of issue of raw material for manufacturing?
Who is responsible of issuing?
What is the process of revalidation of balances?
What is the process of revalidation of raw materials?
Do you have a standard operational procedural manual for stores?
14.3
14.3.1
14.3.2
14.3.3
14.3.4
14.3.5
14.3.6
14.3.7
14.3.8
14.3.9
14.3.10
14.3.11
14.3.12
14.3.13
14.3.14
14.3.8
14.3.9
14.3.10
14.3.11
14.3.12
14.3.13
14.3.14
14.3.15
14.3.16
14.3.17
14.3.18
14.3.19
14.3.20
14.3.21
14.3.22
14.3.23
14.3.24
14.3.25
14.3.26
14.3.27
14.3.28
14.3.29
14.3.30
14.3.31
14.3.32
14.3.33
14.3.34
14.3.35
14.3.36
14.3.37
14.3.38
14.3.39
PURIFIED AND WATER FOR INJECTION SYSTEM
Does the facility have proper Purified and Water for Injection System available?
Is water circulating in a continuous loop and maintained at 80° C, 24/07/365?
Is quality of water monitored chemically & biologically on daily basis?
Is purified water used in all oral preparation & washing of equipment?
Is water for injection used for all sterile preparation, clean steam generation for autoclaving, final rinse of machine parts and sterile container?
Are deionizers that feed water for injection of two bed design and able to provide for continous flow?
Are stills constructed of stainless steel?
If yes what type?
Are still equipped with devices which measure, record and automatically control conductivity
Have the stills been passivated?
Are the holding tanks electropolished and passivated?
Are the holding tanks electro polished and passivated?
Are the holding tanks equipped with heated or jacketed 0.2 micron hydrophobic filter?
Are the holding tanks capable of steam sterilization at a minimum of 121° C?
Are holding tanks equipped tanks equipped to maintain WFI at 80 °C?
Are the holding tanks equipped to supply nitrogen through a 0.2 micron hydrophobic vent filter?
If WFI system constructed of stainless steel 316 L or equivalent?
Is WFI system electro polished and passivated?
Is there a continous loop, single pass system?
Is the system sloped with dead legs no larger than 6 pipe diameters?
Is the system fitted with diaphragm values ?
Is the system capable of steam sterilization?
Is the system capable of being maintained at 80 °C with continous temperature monitoring devices?
Is the conductivity of WFI monitored on return loop?
Are pumps constructed of stainless steel, 316 L or equivalent?
Do the pumps use WFI as seal lubricant?
Are pumps able to be completely drained?
What is the source of water to the facility?
Well / City water / Treated / Untreated
Is testing performed on dionized water system which supplies the NFI system?
What tests are performed?
How frequently are they performed?
Are the results documented?
Are there heat exchangers with in WFI system?
What is the type of heat exchangers 316 L / Double sheet type/ double concentric tube type?
What is the type and porosity of filters within WFI system?
Which department performs the validation of WFI system?
Was the validation approved by QC/QA?
Was the report issued and forwarded to world wide QC/QA?
Do you have SOP written for WFI?
Is WFI tested when used as raw material as per testing standard Z 5576 requirements?
Are the results documented?
Are the all use points in WFI system tested as per testing standard Z 5576 on weekly basis?
Are the results documented?
Have microbial limits been established for WFI samples?
What action plan exists in the event the microbial limits exceed?
Are the investigation documented?
What is the porosity of membrances used in microbiological testing?
What nutrient media is used?
14.3.40
14.3.41
14.3.42
14.3.43
14.3.44
14.3.45
14.3.46
14.3.47
At what temperature and for how long are WFI samples incubated?
After incubation how are results documented?
Are any micro organisms that are isolated from positive WFI samples gram stained and/or identified to genus / species?3
Are standardized and validated autoclave loads for nutrient media used for WFI testing?
Are growth support testes performed on each lot of nutrient media that is used for WFI testing?
How is sterility verified for each lot of nutrient media that is used for WFI testing?
How is nutrient media stored prior to use?
Are there established routine maintenance / calibration programs for deionized and WFI systems?
14.4
14.4.1
14.4.2
14.4.3
14.4.4
14.4.5
14.4.6
14.4.7
14.4.8
14.4.9
14.4.10
14.4.11
14.4.12
14.4.13
DEPACK / PREPARATION COMPONENT ROOM
Is the depack room separate from the component preparation room?
Does depack room have air conditioning and local exhaust for dust control?
Is there a pass through between the depack room and the component preparation room?
Is there a uniform change room outside of the preparation component room?
Is access to the preparation component room restricted?
What is the preparation component room designated class?
What is the efficiency of filters? __________ %
How many air changes occur per hour?
What type of water is supplied to washer and sinks?
What is the validation process for the washing of stopper & vials?
How are the silicone vials and stopper tested for use?
Are Stopper and vials tagged with lot numbers as such through sterilization/depyrogenation and on through filling
How frequently are efficiency filters and laminar flow hood heap filters tested?
Are the garments made of non-shredding material?
What is the frequency of the garments being sterilized?
14.5
14.5.1
14.5.2
14.5.3
14.5.4
14.5.5
14.5.6
14.5.7
14.5.8
14.5.9
14.5.10
14.5.11
14.5.12
14.5.13
14.5.14
14.5.15
14.5.16
14.5.17
14.5.18
14.6
14.6.1
14.6.2
14.6.3
14.6.4
14.6.5
14.6.6
14.6.7
14.7
14.7.1
14.7.2
14.7.3
14.7.4
14.7.5
14.7.6
14.7.7
14.7.8
STERILIZER / OVEN LOADING ROOM
What is the sterilizer / oven loading room designated class?
What is the efficiency of filters?
How many air changes occur per hour?
Does the sterilizer meet the following criteria:
a. Is it capable of maintaining an empty chamber temperature distribution of +/- 1° C at a steady state?
b. Is there a double door design with interlock?
c. What is the size of vent filter?
d. Is it capable of using thermocouples in the chamber for measuring load temperatures?
e. Is it equipped with a recording device for checking temperature and pressure?
f. Is it equipped with a vacuum pump for the removal of air from the load?
g. Is it equipped with a clean steam?
Does the oven meet the following criteria?
a. Is it equipped with hepa filtered air?
b. Are there 2 inter locking doors?
c. Are there recirculating fans located upstream of the Hepa filters?
d. Does it have the resistance temperature device in the return air duct for control temperature?
e. Can it maintain an empty chamber temperature distribution of +/- 25 °C at 300 °C when utilized for depyrogeration and at a 90 °C +/- 20 °C for sterilization?
f. Is it equipped with a temperature recorder?
g. Can be fitted with additional temperature probes for measuring loaded materials?
How frequently are the sterilizer and oven calibrated and the results documented?
How frequently are the efficiency filters integrity tested?
Are the results of the testing documents?
Are the garments made of non sharedding material?
Are the garments washed and sterilized after use?
How frequently are they sterilized?
Are the procedures validated for the sterilized/depyrogenated stoppers and components?
Are biological or chemical indicators used?
Are stoppers and components used for a given lot of product traceable via a lot number to a specific sterilizer/oven load?
How long can the of sterilized/depyrogenated components be stored prior use?
Are the processes for storage of sterilized /depyrogenated components validated?
Are the sterilizer and oven charts reviewed by Quality Control prior to the release of sterile products?
Have restrictions been established for the number of times that components may be sterilized /depyrogenated?
EQUIPMENT AIRLOCK
Are the air lock doors interlocked double room concept?
Is the airlock designated class 100,000?
Are there low level air returns?
What is the air flow from?
Does the airlock have lights?
a) Ultraviolet b) Infra Red
Is the airlock equipped for spray sanitization?
What sanitizing agent is used?
WASHROOM / GOWN CHANGE ROOM
Is the wash room equipped with sink and hot air hand drivers?
Does the wash room have lights?
a) Ultraviolet b) Infra Red
Does the wash room have interlocked doors?
Is there an airlock entry from the grown change room into the
Sterile rooms?
Is the grown change room designed as class 100,000?
Are garments made of non-shredding material?
How frequently are they sterilized?
What sanitization agent is used?
14.8
14.8.1
14.8.2
14.8.3
14.9
14.9.1
14.9.2
14.9.3
14.9.4
14.9.5
14.9.6
14.9.7
14.9.8
14.9.9
MANUFACTURING
(STERILE PRODUCTS)
Does the company have adequate sterilizing, deprogenating, sterile, filteration, processing, filling and packaging equipment available?
Is there an adequate control of viable, non-viable micro-organisms and effective routine monitoring of sterile area and aseptic practices through use of reliable equipment?
Are sterile area air handling unit run 24/7 except for shut down due to routine maintenance to maintain sterile environment?
ENVIRONMENTAL MONITORING
Are laminar flow hood and HVAC system which serve the sterile operations areas validated?
Which department performs the validation?
Was the validation approved by QC/QA?
Was the report issued?
If yes, was the report forwarded to worldwide QC/QA?
Is there an environmental monitoring program for the aseptic batching area, sterile filling room, sterile filling line and ancillary areas?
Is non viable particulate sampling performed?
How is viable air sampling performed?
How is surface sampling performed?
Is environmental monitoring equipment on a maintenance / calibration program?
14.9.10
14.9.11
14.9.12
14.9.13
14.9.14
14.9.15
14.9.16
At what temperature for how long are environmental monitoring samples incubated?
After incubation how are test results documented?
What nutrient media is used for environmental monitoring?
Are there standardized and validated autoclave loads for nutrient media used for environmental monitoring?
Are growth support tests performed on each lot of nutrient media that is used for environmental monitoring?
How is sterility verified for each lot of nutrient media that is used for environmental monitoring?
How is nutrient media stored prior to use?
14.10
14.10.1
14.10.2
14.10.3
14.10.4
14.10.5
14.10.6
14.10.7
14.10.8
14.10.9
14.10.10
14.10.11
14.10.12
14.10.13
14.10.14
14.10.15
14.10.16
14.10.17
14.10.18
14.10.19
14.10.20
14.10.21
14.10.22
14.10.23
14.10.24
14.10.25
14.10.26
14.10.27
14.10.28
14.10.29
ASCEPTIC BATCHING AREA
Is the area designated as class 10,000?
Are there terminal Hepa filters?
What is the minimum of air changes per hour?
Is the area capable of complying with the maximum temperature (68° F) and humidity limits (50% RH)?
Do the laminar flow hoods provide class 100 air over the product?
Is all the product contact equipment in the aseptic batching area sterilizable by hot air or steam?
Are the walls, floors and ceilings non porous and sanitizable?
Are the doors self closing without door knobs?
Are the light fixtures and motors totally sealed and enclosed?
Are the room air pressure, temperature, humidity and filter pressure drop automatically monitored, alarmed and recorded?
Do personnel sanitize their gloved hands?
Are Hepa filters and laminar flow hoods integrity tested?
If yes, how frequently?
Are equipment status labeled?
Are the results documented for the equipments calibrated?
Are sterilization/clarification filters integrity tested and results documented
What is the quality of water used for equipment cleaning?
Are tanks, hoses etc sterilized prior to use and are these procedures user validated?
Are tanks labeled during processing indicating status of product?
Are asceptic operations performed using laminar flow hoods?
Is sterile bulk sampled and tested as per testing standard requirements?
Are sampling and testing complete prior to or concurrent with the filling operation?
Is bulk held under positive pressure after final filtration / sterilization?
How are gases sterilized?
Is sterile gas filters integrity tested before and / or after use?
How is bulk yield determined?
Are batches reprocessed?
If so, what are the written procedures?
Is rework material routinely added to batches?
14.11
14.11.1
14.11.2
14.11.3
14.11.4
14.11.5
14.11.6
14.11.7
14.11.8
14.11.9
14.11.10
14.11.11
14.11.12
14.11.13
14.11.14
14.11.15
14.11.16
14.11.17
14.11.18
14.11.19
14.11.20
14.11.21
14.11.22
14.11.23
14.11.24
14.11.25
14.11.26
14.11.27
14.11.28
14.11.29
14.11.30
14.11.31
14.11.32
14.11.33
14.11.34
14.11.35
14.11.36
14.11.37
14.11.38
14.11.39
14.11.40
FILLING ROOMS
Is the filling room designated as class 10,000?
What are the minimum air changes per hour
Are environmental systems designed to run continuously?
Is the area capable of complying with maximum temperature (68 °F) and humidity limits (50%RH)?
Do this laminar flow hoods provide class 100 air over product?
Is the product contact equipment sterilize by hot air or steam?
Are the walls, floors and ceilings non-porous and sanitizable ?
Are the doors self closing without door knobs?
Are the light fixtures and motors totally sealed and enclosed?
Are room air pressure, temperature, humidity and filter pressure drop automatically monitored, alarmed and recorded?
Are the filling lines designed with laminar flow hoods to provide class 100 air at the rate of 90feet/minute at the product height?
Are surfaces of laminar flow hood made of stainless steel?
Is the filling line equipped with continous non-hinged, non-shedding sanitizable belt or conveyor system?
Is the filling line equipped with automatic filling and stoppering equipment?
What sanitizing agent is used to sanitize gloved hands?
Are Hepa filters and laminar flow hoods integrity tested?
If yes, how frequently?
How is the product delivered from aseptic batching area to the filling lines?
Is the sterile bulk filtered on line?
Is the sterile filter integrity tested before and/or after use?
Is the porosity and type of filter included with the batch records?
Are results of filter integrity test included with the batch records?
Is bulk held under positive pressure during filling operation?
How are gases sterilized?
Are asceptic operations performed using laminar flow hoods?
How is the filling figure determined?
Is the fill volume checked during filling operation?
Are the results documented?
What action is taken when filling limits are exceeded?
Are vials flooded with nitrogen?
Where are the vials capped?
Are rejected vials reprocessed?
If so what are the written procedures?
Is QC/QA informed of manufacturing problems that could affect product quality? (Alert Notice System).
What is the quality of water used for equipment cleaning?
What filling equipment parts are sterilized /depyrogenated inan autoclave oven prior to use?
Have these processes been validated?
How frequently are the filling line (including accessories) sanitzed?
What sanitization agents are used?
Are the procedures validated and documented?
Is a filling line use record kept?
14.12
14.12.1
14.12.2
14.12.3
14.12.4
14.12.5
14.12.6
14.12.7
14.12.8
SANITIZATION OF STERILE ROOMS
How frequently is the sterile area sanitized?
What areas are sanitized?
Floor / Wall / Ceilings
What sanitizing agents are used?
Are sanitizing agents rotated?
Are sanitizing agents prepared with WFI and filter sterilized prior to use?
How is it applied to surfaces?
Is sanitization agent allowed to dry and then rinsed off with WFI?
Is sanitization documented?
14.13
14.13.1
14.13.2
14.13.3
14.13.4
14.13.5
.14.13.6
14.13.7
14.13.8
14.13.9
14.14
14.14.1
14.14.2
14.14.3
14.14.4
INSPECTION
Are filled vials inspected for particulars and container defects prior to packing?
What percentage of batch is inspected?
Are the types of rejected vials documented?
Are rejected vials reprocessed?
Is there a written procedure for handling rejected vials?
Are inspectors trained?
Is the training documented?
Do inspectors receive an eye examination?
If yes, how frequently?
TERMINAL STERILIZATION
Are any products terminally sterilized?
Are these processes validated?
Is each sterilization cycle recorded on a time-temperature chart?
Are biological indicators used in sterilization process?
14.15
14.15.1
14.15.2
14.15.3
14.15.4
14.15.5
14.15.6
14.15.7
14.15.8
14.15.9
14.15.10
14.15.11
14.15.12
PACKAGING
Is the packaging line equipped with capping equipment?
If so then with semi-automatic or automatic?
Are line, clearances performed and documented?
Is there adequate packing indicating status of product?
Is the line labeled during packing indicating status of product?
Are QC inspectors checking and documenting the packaging operations?
Are rejected vials reprocessed?
Are the number of packaged containers reconciled with the amount of filled containers that were delivered for packaging?
Is the reconciliation documented?
Upon completion of packaging, are the labels, inserts and cartons reconciled?
Is QC/QA informed in writing of manufacturing problems that could affect product quality?
How frequently is the area cleaned / sanitized?
14.16
14.16.1
14.16.2
14.16.3
14.16.4
14.16.5
14.16.6
14.16.7
14.16.8
14.16.9
14.16.10
14.16.11
14.16.12
14.16.13
14.16.14
MANUFACTURING
(ORAL DOSAGE FORM)
What is the receiving process of raw material from the stores?
Where is the raw material stored after being issued from the stores?
Does the QC validate the water used during the manufacturing process?
What is the source of water?
What are the SOP for the dryers used?
What are the controls for the temperature logging of the dryers?
What are SOP to eradicate cross contamination?
What procedures are adopted for storing of granules checked by QC for releasing the batch for compression?
Are the granules checked by QC for releasing the batch for compression?
During compression what are the SOP followed?
How frequent does QC inspector verifies the compression process?
How many compression machines are handled by one operator?
If answer to above is more than one what precautions are in force to avoid cross contamination between different products?
How are the compressed tablets stored before the batch is released for packaging?
14.16.15
14.16.16
14.16.17
14.16.18
14.16.19
14.16.20
14.16.21
14.16.22
14.16.23
14.16.24
14.16.25
14.16.26
14.16.27
14.17
14.17.1
14.17.2
14.17.3
14.17.4
14.17.5
14.17.6
14.17.7
14.17.8
14.17.9
14.17.10
Are there temperature log sheets maintain during the manufacturing cycle?
What safety measures are adopted for the personnel working in manufacturing?
Do you manufacture capsule dosage form
What types of humidifiers are used at the point of capsule filling?
Is filling done on an automatic, semi-automatic or manual machine?
How is the polishing of filled capsules done?
What are the SOP for liquid manufacturing?
What is the process of bottle washing?
What is the type of water used in bottle washing?
How is the batch released by QC?
How are the stainless steel tanks washed after completion of a product?
Check on yields and reconciliation of quantities are carried out at appropriate stages of the process to ensure that yields are within acceptable limits.
Are the deviations from the expected yield are recorded and investigated?
PACKAGING
What is the glass type of the bottles used?
What are SOP for
Packaging Materials
Packaging Operation
Labels and Labeling
How frequent does the QC inspector visits the packaging area?
Is the integrity of the batch maintained during the packaging process?
Is there SOP for packaging Material?
Is there SOP for Packaging Operations?
Is there SOP for Labels & Labeling?
All products and packaging materials to be used are checked on receipt by the packaging department for quality, identity and conformity with the packaging instructions?
The name and batch number of the product being handled is displayed at each packaging station or line?
15.0
15.1
15.2
16.0
16.1
16.2
16.3
REPROCESSING
Do written procedures identify steps for reprocessing batches?
Does QC testing confirms that reprocessed batches conforms to established specification?
FINISHED PRODUCT CONTROL
Do written procedures indicate how and who verifies that correct containers and packages are used for finished product during there finishing operation?
Has the formulation of each product been tested for stability based on a written protocol?
Are written sampling and testing procedures and acceptance criteria available for each product to ensure conformance to finished product specification?
17.0
17.1
17.2
17.3
17.4
17.5
17.6
17.7
17.8
17.9
17.10
17.11
17.12
WAREHOUSING / DISTRIBUTION
Are material stored under conditions as per the storage instructions on the label?
Is there adequate space for the orderly storage of material?
Is there a segregation of quarantined, approved & rejected materials?
Are there separate stores for raw material, packaging material, labels and finished products?
Are materials stored on pallets, shelves, or racks, off the floor and off the walls in all stores?
Are minimum and maximum temperatures in the store recorded?
Are air-conditioned and cold room facilities available?
Are flammable and hazardous chemicals stored in safe conditions?
Are there no expired raw materials in the raw material store(s)?
Are materials dispensed according to prescribed SOP meeting GMP requirements?
After release by quality control, are raw materials and packaging materials released on a FIFO (first in first out) basis?
Do distribution records in the finished good store enable specific batches to be traced?
18.0
18.1
18.2.
18.3
18.4
18.5
18.6
18.7
18.8
ENVIRONMENT, HEALTH & SAFETY
Does the company monitor and maintain incident / accident data etc to create awareness and develop improvement plans?
Does the company industrial hygiene sampling / monitoring program, do the employees use appropriate personnel protective equipment?
Does the company have fire fighting facility having fire hydrants, sprinkler system & trained people to handle the emergency?
Does the company have a proper hazardous and non-hazardous material storage and disposal system? (E.g. explosion proof cabinets & manufacturing suites, flammable storage area, solid waste incineration and waste water treatment)?
Are drains and routine cleaning procedures sufficient to prevent standing water inside the facility?
Is lighting adequate in all areas?
Is the control of air pressure, dust humidity and temperature adequate for the manufacturing, processing storage or testing of the drug products?
If air filters are used is there a written procedure specifying the frequencies of inspection and replacement?
(GMP AUDIT – CHECK LIST)
For Pharmaceutical Manufacturing Facilities
Good Manufacturing Practice – GMP Audit Checklist
Sr # (Contents) Page #
1. Quality Assurance ……… 03
2. Premises………. 04
3. Personnel………. 05
4. Validation………. 06
5. Documentation / Records………. 07
6. Vendor Qualification………. 09
7. Change Control Program……… 09
8. Sample………… 09
9. Stability Studies………… 10
10. Drug Recall……… 10
11. Annual Product Review…….. 10
12. Audits……… 11
13. Quality Control Departments………. 12
14. Manufacturing Area……….. 13
14.1 Equipment…………. 13
14.1.6 Equipment Calibration………. 13
14.1.7 Material / Component ……….. 14
14.2 Raw Material………. 14
14.3 Purified and Water for Injection Systems……… 16
14.4 Depack / Preparation component room……….. 19
14.5 Sterilizer / Oven Loading Room ……… 20
14.6 Equipment Airlock…….. 21
14.7 Washroom / Grown change room……… 22
14.8 Manufacturing (Sterile Product) ……….. 23
14.9 Aspectic Batching Area………. 25
14.11 Filling room………. 27
14.14 Terminal Sterilization………. 30
14.15 Packaging……….. 31
14.16 Manufacturing (Oral dosages) ……… 32
14.17 Packaging… 34
15. Reprocessing ……… 35
16. Finished Product Control…….. 35
17. Warehouse / Distribution……… 36
18. Environment, Health & Safety 37
GOOD MANUFACTURING PRACTICE (GMP AUDIT- CHECK LIST)
(FOR PHARMACETICAL MANUFACTURING FACILITIES)
SR #
CRITERIAS
Yes
No
Not Applicable
RATING
(1-10)
(1=low 10=high)
REMARKS
(To be filled by Auditee)
(To be filled by Auditor)
To be filled by Auditor
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
QUALITY ASSURANCE
Does the company have mission statement and the quality policy?
Is the company ISO certified?
Was the company previously audited (GMP audit)?
Are pharmaceutical products designed and developed according to the requirement of GMP & other associated codes such as good laboratory practice (GLP) and good clinical practice (GCP)?
Are production and control operations clearly specified in a written form and GMP requirements are adopted?
Are managerial responsibilities clearly specified in job descriptions?
Are all necessary controls on starting materials, intermediate products and other in-process controls, calibrations and validation carried out?
Are finished products correctly processed and checked according to the defined procedures?
Are satisfactory arrangements existed to store in appropriate storage conditions?
2.0
2.1
2.1.1
2.1.2
2.1.3
2.1.4
2.2
2.3
2.4
2.5
2.5.1
2.5.2
2.5.3
2.5.4
2.5.5
2.6
2.6.1
2.6.2
PREMESIS
(DESIGN & LAYOUT OF FACILITIES)
Does the facility have proper design, layout and finishes based on contemporary standards to:
Manufacture high quality medicine.
Avoidance of cross contamination.
Proper cleaning, drainage and sanitizing.
Ventilation, air conditioning and maintenance.
Is there emergency power supply available to take care of entire energy demand or at least critical areas?
Does the facility have appropriate controls to maintain required parameters e.g. temperature, relative humidity and pressure differentials etc?
Are the doors, windows, walls, ceiling and floor such that no holes or cracks evident (other than those intended by design)?
PLANT SAFETY & SECURITY
Does the facility have safety program?
Are safety procedures written?
Do employees receive safety orientation before working in the plant area?
Does the facility have a formal, written security policy?
Is access to the facility restricted?
SANITATION
Is written sanitation program available on the premises?
Is sanitation program is implemented and effective in preventing conditions?
3.0
3.1
3.2
3.3
3.4
3.5
3.6
3.6.1
3.6.2
3.6.3
3.6.4
3.6.5
PERSONNEL (STAFFING PLAN, STAFF QUALIFICATION, EXPERIENCE , ON THE JOB TRAINING & HYGIENE)
Has the facility provided sufficient qualified personnel to fulfill all its responsibilities required under the rule?
Has the facility provided Organization Chart?
Does the company have qualified, trained and experience staff required for managing?
Does the company have “On the job training program” for technical staff?
Is the technical staff, including supervisors and operations certified (and documented) in specialized training e.g. aseptic technique, sterilizing, washing, depyrogenation, visual inspection, standard operating procedure etc.
HYGIENE
Are all the personal under gone health examination to prior to employment?
Are all the personnel provided health examination during employment?
Are workers conducting visual inspections under gone periodic eye examination?
Are the record maintained?
Are all personal aware about of the principles of GMP and received initial and continued training including hygiene instructions?
4.0
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
5.0
5.1
5.2
5.3
5.4
5.5
5.6
5.6.1
5.6.2
5.6.3
5.6.4
5.6.4.1
5.6.4.2
5.6.4.3
5.6.4.4
5.6.4.5
5.6.4.6
5.6.4.7
5.6.4.8
5.6.4.9
5.6.5
5.6.5.1
5.6.5.2
5.6.5.3
5.6.5.4
5.6.5.5
5.6.5.6
5.6.5.7
5.6.5.8
5.6.5.9
5.7
5.7.1
VALIDATION
Is validation properly documented and include Validation Master Plan, Validation Protocols, Validation Reports and Equipment Qualified?
Are validation studies conducted in accordance with pre-defined protocols?
Have production procedures been validated?
Does the process control address an issue to ensure identity, strength, quality and purity of product?
Does the procedure include formulation that is written to yield not less than 100% of established amount of active ingredients?
Are all weighing and measuring performed by one qualified person and observed by a second person and is dully signed by both of them on record sheet?
Validation of New Master Formula:
Is new master formula or method of preparation adopted and steps taken to demonstrate its suitability for routine processing, process defined materials and equipment specified?
Validation of Equipment & Materials:
Are significant amendments to the manufacturing process, including any change in equipment and materials affecting product quality or re-productivity of process validated?
Are validation records properly maintained?
DOCUMENTATION / RECORDS
Are documentation meticulously maintained as per rules and regularly reviewed and kept up to date?
Is documentation accurate, clear & neat. Does it define specifications and procedures for all materials & methods of manufacture & control?
Are all the specifications, testing procedures, master formulae, packing instructions and standard operating procedures (SOPs) available, current & being followed?
Do the records provide existence of documented evidence, traceability, and an audit trial that will permit investigation?
Does the record provide batch processing & packaging details including receiving sample, processing equipment, analytical testing and laboratory instrument records?
LABELS
Are labels to the containers, equipment or premises applied un-ambiguously according to company’s agreed format?
Are labels of different colors indicating the status such as “Quarantined”, “Accepted”, “Rejected”, or “Clear” used?
Are all finished products are labeled as per specification?
PROCESS DOCUMENTS / RECORDS
· Are following documents / record are available:
Starting material re-assy.
Specifications for intermediate and bulk products
Batch processing records
Record for process operation
Batch packaging records
Record for packaging operation
Record of Batch numbers
Analytical records of the batch
Record for finished product release procedure
STANDARD OPERATING PROCEDURES (SOPS)
· Are SOPS and associated records of actions, conclusions
reached available for the following at the premises?
Equipment assembly and validation
Analytical apparatus and calibration
Maintenance, cleaning and sanitization
Personnel matters including qualification, training, clothing and hygiene
Environmental monitoring
Pest control
Complaints
Drug recalls
Drug returns
EQUIPMENT LOG BOOKS
Are log books for major & critical equipments identified by company kept?
6.0
6.1
6.2
7
7.1
8.0
8.1
8.2
VENDOR QUALIFICATION
Do you have list of approved vendors?
Are the vendors supplying raw material (both active & inactive ingredients), empty gelatin capsules, primary packaging & printed packaging components audited & found to be satisfactory?
CHANGE CONTROL PROGRAM
Is there a formal change control program in place supported by an SOP to initiate, review & approve changes in material, sources, processes, products packaging, equipment, batch size changes etc.
SAMPLE
Does the company retain a sample of lot or batch of the packaged / labeled drug for a period of at least one year after the expiration date on the label of the drug?
Does the company retain a sample of each lot or batch of a raw material (including both active and inactive ingredients)?
9.0
9.1
9.2
9.3
10.0
10.1
10.2
11.0
11.1
11.2
STABILITY STUDIES
Does the company have a prospective and concurrent stability studies program based on SOP and utilizing proper equipment i.e. climatic chambers maintained at 30° C / 65% RH for ambient and 40° C / 75% RH for stress conditions and continuously monitored for temperature & RH?
Is stability of finished products evaluated and documented prior to marketing?
Does the stability data support shelf life assigned to the product. Are any deviations in data reviewed and appropriate steps taken in case of stability issues?
DRUG RECALL
Do you have SOP for drug recalls?
If answer yes to the above did you have any drug recall in the past 2 year? (Please also mention the name of products)
ANNUAL PRODUCT REVIEW
Is there a process in place to review statistical data (i.e.: trend analysis, reworks, rejects, customer complaints) of all the products manufacture during the year?
Provide name of the products manufactured by you along with price list.
11.3
11.4
12.0
12.1
12.1.1
12.1.2
12.2
12.3
13.0
13.1
13.2
13.3
13.4
13.5
13.6
13.7
13.8
13.9
13.10
Provide the source of raw material for individual products.
Do you export your products, if so then to whom and mention the name of the products?
AUDIT / COMPLAINTS
INTERNAL GMP AUDITS
Do you have an effective internal GMP inspection program to audit all the manufacturing areas, activities & QC lab at specific defined periods?
Is there a process in place to fill the gaps / observation / non-conformance found during the internal GMP audits?
QUALITY AUDITS
Is quality audit conducted by outside or independent specials or a team designated by the management for the purpose?
COMPLAINTS
Are complaints and other information concerning potentially defective products carefully reviewed according to the written procedures?
QUALITY CONTROL DEPARTMENT
Does the QC lab have SOPs to cover all the functional areas?
Are adequate facilities and equipments available for the physical, chemical & microbiological testing?
Are approved written procedures available for sampling, inspecting and testing raw materials, packaging materials, in process drugs, bulk drugs and finished products?
Are samples of starting material, packaging material, intermediate products, bulk products and finished products taken by methods and personnels approved by QC department?
Are in-process materials tested at appropriate phases for identity, strength, quality, purity and are they approved or rejected by Quality Control?
Are records of in- process controls maintained?
Does each batch of drug product prior to release confirms compliance of finished product specification?
Are validated & stability indicating assay methods used?
Are reference standards used for the assay?
Are accurate, clear & neat records maintained along with the raw data for the entire analytical work?
14.0
14.1
14.1.1
14.1.2
14.1.3
14.1.4
14.1.5
14.1.6
14.1.6.1
14.1.6.2
14.1.6.3
MANUFACTURING AREA
EQUIPMENTS, MATERIAL / COMPONENT
EQUIPMENTS
Does the company have suitable equipments capable of producing consistent quality products?
Do the equipments meet contemporary standards for the manufacture of pharmaceuticals i.e. smooth finishes, right quality construction material for the intended purpose, easy to clean, wash, sterilize etc.
Are the following pieces of equipments suitable in their design/size & capacity? (Blendes, Conveyors, Tablet presses, Capsule fillers, Bottle fillers etc)
Does the equipments & facilities have appropriate controls to maintain required parameters e.g. temperature, relative humidity, pressure differentials etc?
Is the equipment cleaned promptly after use?
EQUIPMENT/INSTRUMENTS CALIBRATION & PREVENTIVE MAINTENANCE
Are written records maintained on equipment cleaning, sanitizing and maintenance on or near each piece of equipment?
Does the facility have approved written procedures for checking and calibration of each piece of measurement equipment?
Are records of calibration checks and inspections maintained in a readily retire able manner?
14.1.7
14.1.7.1
14.1.7.2
14.1.7.3
14.2
14.2.1
14.2.2
14.2.3
14.2.4
14.2.5
14.2.6
14.2.7
14.2.8
14.2.9
14.2.10
14.2.11
14.2.12
14.2.13
14.2.14
14.2.15
MATERIAL/COMPONENT
All handling of material and products such as receipt, quarantine, sample storage, tracking, labeling, dispensing, processing, packaging and distribution is done in accordance with approved written procedure, or instruction and recorded?
All incoming materials and finished products quarantined immediately after receipt or processing until they released for use or distribution?
Are all materials handled in such a way to prevent contamination?
RAW MATERIAL
Were the premises designed for storing the raw material?
Does the store premises allow storage of raw materials at various temperatures?
If answer yes to the above what are the controls to log any irregularities?
What is the source of the active ingredient used?
What are the source of additives used?
Is any documentation done at the time of receiving the raw materials?
What is the process of communication with the laboratory for sampling of the raw material?
Is there a quarantine for storing unreleased raw materials?
If so, what is the process?
What is the process of storage after the raw material is released for use?
What is the process of issue of raw material for manufacturing?
Who is responsible of issuing?
What is the process of revalidation of balances?
What is the process of revalidation of raw materials?
Do you have a standard operational procedural manual for stores?
14.3
14.3.1
14.3.2
14.3.3
14.3.4
14.3.5
14.3.6
14.3.7
14.3.8
14.3.9
14.3.10
14.3.11
14.3.12
14.3.13
14.3.14
14.3.8
14.3.9
14.3.10
14.3.11
14.3.12
14.3.13
14.3.14
14.3.15
14.3.16
14.3.17
14.3.18
14.3.19
14.3.20
14.3.21
14.3.22
14.3.23
14.3.24
14.3.25
14.3.26
14.3.27
14.3.28
14.3.29
14.3.30
14.3.31
14.3.32
14.3.33
14.3.34
14.3.35
14.3.36
14.3.37
14.3.38
14.3.39
PURIFIED AND WATER FOR INJECTION SYSTEM
Does the facility have proper Purified and Water for Injection System available?
Is water circulating in a continuous loop and maintained at 80° C, 24/07/365?
Is quality of water monitored chemically & biologically on daily basis?
Is purified water used in all oral preparation & washing of equipment?
Is water for injection used for all sterile preparation, clean steam generation for autoclaving, final rinse of machine parts and sterile container?
Are deionizers that feed water for injection of two bed design and able to provide for continous flow?
Are stills constructed of stainless steel?
If yes what type?
Are still equipped with devices which measure, record and automatically control conductivity
Have the stills been passivated?
Are the holding tanks electropolished and passivated?
Are the holding tanks electro polished and passivated?
Are the holding tanks equipped with heated or jacketed 0.2 micron hydrophobic filter?
Are the holding tanks capable of steam sterilization at a minimum of 121° C?
Are holding tanks equipped tanks equipped to maintain WFI at 80 °C?
Are the holding tanks equipped to supply nitrogen through a 0.2 micron hydrophobic vent filter?
If WFI system constructed of stainless steel 316 L or equivalent?
Is WFI system electro polished and passivated?
Is there a continous loop, single pass system?
Is the system sloped with dead legs no larger than 6 pipe diameters?
Is the system fitted with diaphragm values ?
Is the system capable of steam sterilization?
Is the system capable of being maintained at 80 °C with continous temperature monitoring devices?
Is the conductivity of WFI monitored on return loop?
Are pumps constructed of stainless steel, 316 L or equivalent?
Do the pumps use WFI as seal lubricant?
Are pumps able to be completely drained?
What is the source of water to the facility?
Well / City water / Treated / Untreated
Is testing performed on dionized water system which supplies the NFI system?
What tests are performed?
How frequently are they performed?
Are the results documented?
Are there heat exchangers with in WFI system?
What is the type of heat exchangers 316 L / Double sheet type/ double concentric tube type?
What is the type and porosity of filters within WFI system?
Which department performs the validation of WFI system?
Was the validation approved by QC/QA?
Was the report issued and forwarded to world wide QC/QA?
Do you have SOP written for WFI?
Is WFI tested when used as raw material as per testing standard Z 5576 requirements?
Are the results documented?
Are the all use points in WFI system tested as per testing standard Z 5576 on weekly basis?
Are the results documented?
Have microbial limits been established for WFI samples?
What action plan exists in the event the microbial limits exceed?
Are the investigation documented?
What is the porosity of membrances used in microbiological testing?
What nutrient media is used?
14.3.40
14.3.41
14.3.42
14.3.43
14.3.44
14.3.45
14.3.46
14.3.47
At what temperature and for how long are WFI samples incubated?
After incubation how are results documented?
Are any micro organisms that are isolated from positive WFI samples gram stained and/or identified to genus / species?3
Are standardized and validated autoclave loads for nutrient media used for WFI testing?
Are growth support testes performed on each lot of nutrient media that is used for WFI testing?
How is sterility verified for each lot of nutrient media that is used for WFI testing?
How is nutrient media stored prior to use?
Are there established routine maintenance / calibration programs for deionized and WFI systems?
14.4
14.4.1
14.4.2
14.4.3
14.4.4
14.4.5
14.4.6
14.4.7
14.4.8
14.4.9
14.4.10
14.4.11
14.4.12
14.4.13
DEPACK / PREPARATION COMPONENT ROOM
Is the depack room separate from the component preparation room?
Does depack room have air conditioning and local exhaust for dust control?
Is there a pass through between the depack room and the component preparation room?
Is there a uniform change room outside of the preparation component room?
Is access to the preparation component room restricted?
What is the preparation component room designated class?
What is the efficiency of filters? __________ %
How many air changes occur per hour?
What type of water is supplied to washer and sinks?
What is the validation process for the washing of stopper & vials?
How are the silicone vials and stopper tested for use?
Are Stopper and vials tagged with lot numbers as such through sterilization/depyrogenation and on through filling
How frequently are efficiency filters and laminar flow hood heap filters tested?
Are the garments made of non-shredding material?
What is the frequency of the garments being sterilized?
14.5
14.5.1
14.5.2
14.5.3
14.5.4
14.5.5
14.5.6
14.5.7
14.5.8
14.5.9
14.5.10
14.5.11
14.5.12
14.5.13
14.5.14
14.5.15
14.5.16
14.5.17
14.5.18
14.6
14.6.1
14.6.2
14.6.3
14.6.4
14.6.5
14.6.6
14.6.7
14.7
14.7.1
14.7.2
14.7.3
14.7.4
14.7.5
14.7.6
14.7.7
14.7.8
STERILIZER / OVEN LOADING ROOM
What is the sterilizer / oven loading room designated class?
What is the efficiency of filters?
How many air changes occur per hour?
Does the sterilizer meet the following criteria:
a. Is it capable of maintaining an empty chamber temperature distribution of +/- 1° C at a steady state?
b. Is there a double door design with interlock?
c. What is the size of vent filter?
d. Is it capable of using thermocouples in the chamber for measuring load temperatures?
e. Is it equipped with a recording device for checking temperature and pressure?
f. Is it equipped with a vacuum pump for the removal of air from the load?
g. Is it equipped with a clean steam?
Does the oven meet the following criteria?
a. Is it equipped with hepa filtered air?
b. Are there 2 inter locking doors?
c. Are there recirculating fans located upstream of the Hepa filters?
d. Does it have the resistance temperature device in the return air duct for control temperature?
e. Can it maintain an empty chamber temperature distribution of +/- 25 °C at 300 °C when utilized for depyrogeration and at a 90 °C +/- 20 °C for sterilization?
f. Is it equipped with a temperature recorder?
g. Can be fitted with additional temperature probes for measuring loaded materials?
How frequently are the sterilizer and oven calibrated and the results documented?
How frequently are the efficiency filters integrity tested?
Are the results of the testing documents?
Are the garments made of non sharedding material?
Are the garments washed and sterilized after use?
How frequently are they sterilized?
Are the procedures validated for the sterilized/depyrogenated stoppers and components?
Are biological or chemical indicators used?
Are stoppers and components used for a given lot of product traceable via a lot number to a specific sterilizer/oven load?
How long can the of sterilized/depyrogenated components be stored prior use?
Are the processes for storage of sterilized /depyrogenated components validated?
Are the sterilizer and oven charts reviewed by Quality Control prior to the release of sterile products?
Have restrictions been established for the number of times that components may be sterilized /depyrogenated?
EQUIPMENT AIRLOCK
Are the air lock doors interlocked double room concept?
Is the airlock designated class 100,000?
Are there low level air returns?
What is the air flow from?
Does the airlock have lights?
a) Ultraviolet b) Infra Red
Is the airlock equipped for spray sanitization?
What sanitizing agent is used?
WASHROOM / GOWN CHANGE ROOM
Is the wash room equipped with sink and hot air hand drivers?
Does the wash room have lights?
a) Ultraviolet b) Infra Red
Does the wash room have interlocked doors?
Is there an airlock entry from the grown change room into the
Sterile rooms?
Is the grown change room designed as class 100,000?
Are garments made of non-shredding material?
How frequently are they sterilized?
What sanitization agent is used?
14.8
14.8.1
14.8.2
14.8.3
14.9
14.9.1
14.9.2
14.9.3
14.9.4
14.9.5
14.9.6
14.9.7
14.9.8
14.9.9
MANUFACTURING
(STERILE PRODUCTS)
Does the company have adequate sterilizing, deprogenating, sterile, filteration, processing, filling and packaging equipment available?
Is there an adequate control of viable, non-viable micro-organisms and effective routine monitoring of sterile area and aseptic practices through use of reliable equipment?
Are sterile area air handling unit run 24/7 except for shut down due to routine maintenance to maintain sterile environment?
ENVIRONMENTAL MONITORING
Are laminar flow hood and HVAC system which serve the sterile operations areas validated?
Which department performs the validation?
Was the validation approved by QC/QA?
Was the report issued?
If yes, was the report forwarded to worldwide QC/QA?
Is there an environmental monitoring program for the aseptic batching area, sterile filling room, sterile filling line and ancillary areas?
Is non viable particulate sampling performed?
How is viable air sampling performed?
How is surface sampling performed?
Is environmental monitoring equipment on a maintenance / calibration program?
14.9.10
14.9.11
14.9.12
14.9.13
14.9.14
14.9.15
14.9.16
At what temperature for how long are environmental monitoring samples incubated?
After incubation how are test results documented?
What nutrient media is used for environmental monitoring?
Are there standardized and validated autoclave loads for nutrient media used for environmental monitoring?
Are growth support tests performed on each lot of nutrient media that is used for environmental monitoring?
How is sterility verified for each lot of nutrient media that is used for environmental monitoring?
How is nutrient media stored prior to use?
14.10
14.10.1
14.10.2
14.10.3
14.10.4
14.10.5
14.10.6
14.10.7
14.10.8
14.10.9
14.10.10
14.10.11
14.10.12
14.10.13
14.10.14
14.10.15
14.10.16
14.10.17
14.10.18
14.10.19
14.10.20
14.10.21
14.10.22
14.10.23
14.10.24
14.10.25
14.10.26
14.10.27
14.10.28
14.10.29
ASCEPTIC BATCHING AREA
Is the area designated as class 10,000?
Are there terminal Hepa filters?
What is the minimum of air changes per hour?
Is the area capable of complying with the maximum temperature (68° F) and humidity limits (50% RH)?
Do the laminar flow hoods provide class 100 air over the product?
Is all the product contact equipment in the aseptic batching area sterilizable by hot air or steam?
Are the walls, floors and ceilings non porous and sanitizable?
Are the doors self closing without door knobs?
Are the light fixtures and motors totally sealed and enclosed?
Are the room air pressure, temperature, humidity and filter pressure drop automatically monitored, alarmed and recorded?
Do personnel sanitize their gloved hands?
Are Hepa filters and laminar flow hoods integrity tested?
If yes, how frequently?
Are equipment status labeled?
Are the results documented for the equipments calibrated?
Are sterilization/clarification filters integrity tested and results documented
What is the quality of water used for equipment cleaning?
Are tanks, hoses etc sterilized prior to use and are these procedures user validated?
Are tanks labeled during processing indicating status of product?
Are asceptic operations performed using laminar flow hoods?
Is sterile bulk sampled and tested as per testing standard requirements?
Are sampling and testing complete prior to or concurrent with the filling operation?
Is bulk held under positive pressure after final filtration / sterilization?
How are gases sterilized?
Is sterile gas filters integrity tested before and / or after use?
How is bulk yield determined?
Are batches reprocessed?
If so, what are the written procedures?
Is rework material routinely added to batches?
14.11
14.11.1
14.11.2
14.11.3
14.11.4
14.11.5
14.11.6
14.11.7
14.11.8
14.11.9
14.11.10
14.11.11
14.11.12
14.11.13
14.11.14
14.11.15
14.11.16
14.11.17
14.11.18
14.11.19
14.11.20
14.11.21
14.11.22
14.11.23
14.11.24
14.11.25
14.11.26
14.11.27
14.11.28
14.11.29
14.11.30
14.11.31
14.11.32
14.11.33
14.11.34
14.11.35
14.11.36
14.11.37
14.11.38
14.11.39
14.11.40
FILLING ROOMS
Is the filling room designated as class 10,000?
What are the minimum air changes per hour
Are environmental systems designed to run continuously?
Is the area capable of complying with maximum temperature (68 °F) and humidity limits (50%RH)?
Do this laminar flow hoods provide class 100 air over product?
Is the product contact equipment sterilize by hot air or steam?
Are the walls, floors and ceilings non-porous and sanitizable ?
Are the doors self closing without door knobs?
Are the light fixtures and motors totally sealed and enclosed?
Are room air pressure, temperature, humidity and filter pressure drop automatically monitored, alarmed and recorded?
Are the filling lines designed with laminar flow hoods to provide class 100 air at the rate of 90feet/minute at the product height?
Are surfaces of laminar flow hood made of stainless steel?
Is the filling line equipped with continous non-hinged, non-shedding sanitizable belt or conveyor system?
Is the filling line equipped with automatic filling and stoppering equipment?
What sanitizing agent is used to sanitize gloved hands?
Are Hepa filters and laminar flow hoods integrity tested?
If yes, how frequently?
How is the product delivered from aseptic batching area to the filling lines?
Is the sterile bulk filtered on line?
Is the sterile filter integrity tested before and/or after use?
Is the porosity and type of filter included with the batch records?
Are results of filter integrity test included with the batch records?
Is bulk held under positive pressure during filling operation?
How are gases sterilized?
Are asceptic operations performed using laminar flow hoods?
How is the filling figure determined?
Is the fill volume checked during filling operation?
Are the results documented?
What action is taken when filling limits are exceeded?
Are vials flooded with nitrogen?
Where are the vials capped?
Are rejected vials reprocessed?
If so what are the written procedures?
Is QC/QA informed of manufacturing problems that could affect product quality? (Alert Notice System).
What is the quality of water used for equipment cleaning?
What filling equipment parts are sterilized /depyrogenated inan autoclave oven prior to use?
Have these processes been validated?
How frequently are the filling line (including accessories) sanitzed?
What sanitization agents are used?
Are the procedures validated and documented?
Is a filling line use record kept?
14.12
14.12.1
14.12.2
14.12.3
14.12.4
14.12.5
14.12.6
14.12.7
14.12.8
SANITIZATION OF STERILE ROOMS
How frequently is the sterile area sanitized?
What areas are sanitized?
Floor / Wall / Ceilings
What sanitizing agents are used?
Are sanitizing agents rotated?
Are sanitizing agents prepared with WFI and filter sterilized prior to use?
How is it applied to surfaces?
Is sanitization agent allowed to dry and then rinsed off with WFI?
Is sanitization documented?
14.13
14.13.1
14.13.2
14.13.3
14.13.4
14.13.5
.14.13.6
14.13.7
14.13.8
14.13.9
14.14
14.14.1
14.14.2
14.14.3
14.14.4
INSPECTION
Are filled vials inspected for particulars and container defects prior to packing?
What percentage of batch is inspected?
Are the types of rejected vials documented?
Are rejected vials reprocessed?
Is there a written procedure for handling rejected vials?
Are inspectors trained?
Is the training documented?
Do inspectors receive an eye examination?
If yes, how frequently?
TERMINAL STERILIZATION
Are any products terminally sterilized?
Are these processes validated?
Is each sterilization cycle recorded on a time-temperature chart?
Are biological indicators used in sterilization process?
14.15
14.15.1
14.15.2
14.15.3
14.15.4
14.15.5
14.15.6
14.15.7
14.15.8
14.15.9
14.15.10
14.15.11
14.15.12
PACKAGING
Is the packaging line equipped with capping equipment?
If so then with semi-automatic or automatic?
Are line, clearances performed and documented?
Is there adequate packing indicating status of product?
Is the line labeled during packing indicating status of product?
Are QC inspectors checking and documenting the packaging operations?
Are rejected vials reprocessed?
Are the number of packaged containers reconciled with the amount of filled containers that were delivered for packaging?
Is the reconciliation documented?
Upon completion of packaging, are the labels, inserts and cartons reconciled?
Is QC/QA informed in writing of manufacturing problems that could affect product quality?
How frequently is the area cleaned / sanitized?
14.16
14.16.1
14.16.2
14.16.3
14.16.4
14.16.5
14.16.6
14.16.7
14.16.8
14.16.9
14.16.10
14.16.11
14.16.12
14.16.13
14.16.14
MANUFACTURING
(ORAL DOSAGE FORM)
What is the receiving process of raw material from the stores?
Where is the raw material stored after being issued from the stores?
Does the QC validate the water used during the manufacturing process?
What is the source of water?
What are the SOP for the dryers used?
What are the controls for the temperature logging of the dryers?
What are SOP to eradicate cross contamination?
What procedures are adopted for storing of granules checked by QC for releasing the batch for compression?
Are the granules checked by QC for releasing the batch for compression?
During compression what are the SOP followed?
How frequent does QC inspector verifies the compression process?
How many compression machines are handled by one operator?
If answer to above is more than one what precautions are in force to avoid cross contamination between different products?
How are the compressed tablets stored before the batch is released for packaging?
14.16.15
14.16.16
14.16.17
14.16.18
14.16.19
14.16.20
14.16.21
14.16.22
14.16.23
14.16.24
14.16.25
14.16.26
14.16.27
14.17
14.17.1
14.17.2
14.17.3
14.17.4
14.17.5
14.17.6
14.17.7
14.17.8
14.17.9
14.17.10
Are there temperature log sheets maintain during the manufacturing cycle?
What safety measures are adopted for the personnel working in manufacturing?
Do you manufacture capsule dosage form
What types of humidifiers are used at the point of capsule filling?
Is filling done on an automatic, semi-automatic or manual machine?
How is the polishing of filled capsules done?
What are the SOP for liquid manufacturing?
What is the process of bottle washing?
What is the type of water used in bottle washing?
How is the batch released by QC?
How are the stainless steel tanks washed after completion of a product?
Check on yields and reconciliation of quantities are carried out at appropriate stages of the process to ensure that yields are within acceptable limits.
Are the deviations from the expected yield are recorded and investigated?
PACKAGING
What is the glass type of the bottles used?
What are SOP for
Packaging Materials
Packaging Operation
Labels and Labeling
How frequent does the QC inspector visits the packaging area?
Is the integrity of the batch maintained during the packaging process?
Is there SOP for packaging Material?
Is there SOP for Packaging Operations?
Is there SOP for Labels & Labeling?
All products and packaging materials to be used are checked on receipt by the packaging department for quality, identity and conformity with the packaging instructions?
The name and batch number of the product being handled is displayed at each packaging station or line?
15.0
15.1
15.2
16.0
16.1
16.2
16.3
REPROCESSING
Do written procedures identify steps for reprocessing batches?
Does QC testing confirms that reprocessed batches conforms to established specification?
FINISHED PRODUCT CONTROL
Do written procedures indicate how and who verifies that correct containers and packages are used for finished product during there finishing operation?
Has the formulation of each product been tested for stability based on a written protocol?
Are written sampling and testing procedures and acceptance criteria available for each product to ensure conformance to finished product specification?
17.0
17.1
17.2
17.3
17.4
17.5
17.6
17.7
17.8
17.9
17.10
17.11
17.12
WAREHOUSING / DISTRIBUTION
Are material stored under conditions as per the storage instructions on the label?
Is there adequate space for the orderly storage of material?
Is there a segregation of quarantined, approved & rejected materials?
Are there separate stores for raw material, packaging material, labels and finished products?
Are materials stored on pallets, shelves, or racks, off the floor and off the walls in all stores?
Are minimum and maximum temperatures in the store recorded?
Are air-conditioned and cold room facilities available?
Are flammable and hazardous chemicals stored in safe conditions?
Are there no expired raw materials in the raw material store(s)?
Are materials dispensed according to prescribed SOP meeting GMP requirements?
After release by quality control, are raw materials and packaging materials released on a FIFO (first in first out) basis?
Do distribution records in the finished good store enable specific batches to be traced?
18.0
18.1
18.2.
18.3
18.4
18.5
18.6
18.7
18.8
ENVIRONMENT, HEALTH & SAFETY
Does the company monitor and maintain incident / accident data etc to create awareness and develop improvement plans?
Does the company industrial hygiene sampling / monitoring program, do the employees use appropriate personnel protective equipment?
Does the company have fire fighting facility having fire hydrants, sprinkler system & trained people to handle the emergency?
Does the company have a proper hazardous and non-hazardous material storage and disposal system? (E.g. explosion proof cabinets & manufacturing suites, flammable storage area, solid waste incineration and waste water treatment)?
Are drains and routine cleaning procedures sufficient to prevent standing water inside the facility?
Is lighting adequate in all areas?
Is the control of air pressure, dust humidity and temperature adequate for the manufacturing, processing storage or testing of the drug products?
If air filters are used is there a written procedure specifying the frequencies of inspection and replacement?
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