Pantoprazole Sodium 40 mg Tablets IP & Mechanism of action

Pantoprazole Sodium 40 mg Tablets IP & Mechanism of action

Pantoprazole is a proton pump inhibitor used to treat erosive esophagitis, and gastric acid hypersecretion, and to promote the healing of tissue damage caused by gastric acid.

Pantoprazole is a first-generation proton pump inhibitor (PPI) used for the management of gastroesophageal reflux disease (GERD), for gastric protection to prevent the recurrence of stomach ulcers or gastric damage from chronic use of NSAIDs, and for the treatment of pathological hypersecretory conditions including Zollinger-Ellison (ZE) Syndrome. It can also be found in quadruple regimens for the treatment of H. pylori infections along with other antibiotics including amoxicillin, clarithromycin, and metronidazole. Its efficacy is considered similar to other medications within the PPI class including omeprazole, esomeprazole, lansoprazole, dexlansoprazole, and rabeprazole.

Why is this medication prescribed?

Pantoprazole is used to treat damage from gastroesophageal reflux disease (GERD), a condition in which the backward flow of acid from the stomach causes heartburn and possible injury of the esophagus (the tube between the throat and stomach) in adults and children 5 years of age and older. Pantoprazole is used to allow the esophagus to heal and prevent further damage to the esophagus in adults with GERD. It is also used to treat conditions where the stomach produces too much acid, such as Zollinger-Ellison syndrome in adults. It works by decreasing the amount of acid made in the stomach.

Mechanism of action

Hydrochloric acid (HCl) secretion into the gastric lumen is a process regulated mainly by the H (+)/K (+)-ATPase of the proton pump, expressed in high quantities by the parietal cells of the stomach. ATPase is an enzyme on the parietal cell membrane that facilitates hydrogen and potassium exchange through the cell, which normally results in the extrusion of potassium and the formation of HCl (gastric acid).

Proton pump inhibitors such as pantoprazole are substituted benzimidazole derivatives, weak bases, which accumulate in the acidic space of the parietal cell before being converted in the canaliculi (small canal) of the gastric parietal cell, an acidic environment, to active sulfenamide derivatives. This active form then makes disulfide bonds with important cysteines on the gastric acid pump, inhibiting its function. Specifically, pantoprazole binds to the sulfhydryl group of H+, K+-ATPase, which is an enzyme implicated in accelerating the final step in the acid secretion pathway. The enzyme is inactivated, inhibiting gastric acid secretion. The inhibition of gastric acid secretion is stronger with proton pump inhibitors such as pantoprazole and lasts longer than with the H (2) antagonists.

Route of elimination

After a single oral or intravenous (IV) dose of 14C-labeled pantoprazole to healthy, normal metabolizing subjects, about 71% of the dose was excreted in the urine, with 18% excreted in the feces by biliary excretion. There was no kidney excretion of unchanged pantoprazole.

Toxicity

Rat Oral LD 50 747 mg/kg17

Tumorigenicity

Because of the chronic nature of GERD, there may be a potential for long-term administration of pantoprazole. In long-term rodent studies, pantoprazole was carcinogenic and its administration lead to rare types of gastrointestinal tumors. The relevance of these findings to tumor development in humans is unknown at this time.

Teratogenic Effects

This drug falls under the pregnancy category B category. Reproduction studies have been performed in rats at oral doses up to 88 times the recommended human dose (RHD), as well as in rabbits at oral doses up to 16 times the RHD, and have shown no evidence of impaired fertility or harm to the fetus caused by pantoprazole. No adequate and well-controlled studies on pregnant women have been completed. Because animal reproduction studies are not always predictive of human response, this drug should only be used during pregnancy if clearly required.

Nursing Mothers

Pantoprazole and its metabolites have been found to be excreted in the milk of rats. Pantoprazole excretion in human milk has been found in a study performed with a single nursing mother after one 40 mg oral dose. The clinical relevance of this finding is not known, however, it is advisable to take note of this finding when considering pantoprazole use during nursing. Many drugs excreted in human breastmilk have a risk for serious adverse effects in nursing infants.

Side Effects

Headache or diarrhea may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: symptoms of a low magnesium blood level (such as muscle spasms, irregular heartbeat, seizures), signs of lupus (such as rash on nose and cheeks, new or worsening joint pain).

This medication may rarely cause a severe intestinal condition due to a bacteria called C. difficile. This condition may occur during treatment or weeks to months after treatment has stopped. Tell your doctor right away if you develop: diarrhea that doesn’t stop, abdominal or stomach pain/cramping, blood/mucus in your stool.

If you have these symptoms, do not use anti-diarrhea or opioid products because they may make symptoms worse.

Precautions

Before taking pantoprazole, tell your doctor or pharmacist if you are allergic to it; or to similar drugs (such as lansoprazole, or omeprazole); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, and lupus.

Some symptoms may actually be signs of a more serious condition. Get medical help right away if you have: heartburn with lightheadedness/sweating/dizziness, chest/jaw/arm/shoulder pain (especially with shortness of breath, unusual sweating), or unexplained weight loss.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Proton pump inhibitors (such as pantoprazole) may increase your risk for bone fractures, especially with longer use, higher doses, and in older adults. Talk with your doctor or pharmacist about ways to prevent bone loss/fracture, such as by taking calcium (such as calcium citrate) and vitamin D supplements.

Older adults may be more sensitive to the side effects of this drug, especially bone loss, and fractures.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This medication passes into breast milk. Consult your doctor before breastfeeding.

Missed Dose

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.

Storage

Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

TABLE OF CONTENTS

1.0 PRODUCT DETAILS:

2.0 MANUFACTURING FORMULA:

3.0 LIST OF EQUIPMENT:                         

4.0 GENERAL PRECAUTIONS:

• API Description: A white to off-white powder. (Light Sensitive)
• All the Manufacturing Activities shall be performed under controlled conditions (temperature NMT 25 ⁰C and relative humidity NMT 60%).
• When working with Active Ingredients and drug products or a mixture of Active Ingredients and Excipients, wear gloves and a mask to avoid exposure and contact with any body parts.

Use Sodium Lamp and Black Poly-bags at every Step.

MANUFACTURING INSTRUCTIONS:

• All the Activities shall be performed as per current SOPs.
• Take the line clearance of every machine from QA before starting the manufacturing operation from batch to batch and product to product change over.
• Do not overwrite any entries. In case of mistake, cancel the entry by a single line with sign & date and make the correct entry.

6.0 MANUFACTURING PROCESS DETAILS:

6.1 GRANULATION:

   NOTE: Turn ON the sodium lamp and switch OFF all lights before starting the operation and use black polybags to store the materials.

STEP – I (SIFTING):

• Check Sieve Integrity (before sifting and after sifting).
• Set the Vibro Sifter (capacity: 30-inch dia) and sieve the Dispensed Materials as per Sieve Sizes mentioned below:

NOT

• Collect sifted Pantoprazole Sodium IP (22.600 kg), Mannitol IP (16.000 kg), Cross Carmellose Sodium IP (1.750 kg), and Sodium Carbonate (4.000 kg) into two Poly-lined HDPE Containers (capacity: 30 liters each).
• Collect sifted PVPK-30 IP (1.250 kg) in Polybag (capacity: 2 kg).
• Collect the sifted Talcum IP (1.400 kg), Cross Carmellose Sodium IP (1.750 kg), Crospovidone XL IP (2.500 kg), Aerosil IP (1.250 kg) in Polybag (capacity : 10 kg).
• Collect the sifted Calcium Stearate IP (2.500 kg) in Polybag (capacity: 5 kg)

STEP – II (BINDER PREPARATION):

• Take Isopropyl Alcohol (23.500 liters) in SS Container (capacity: 30 liters) and add PVPK-30 IP (1.250 kg) in it.  Mix together by Portable Stirrer continuously stirring till dissolved properly in IPA.
• Mixing Time: 10 minutes (To be validated in next batch)
• Filter the solution with filter cloth 100 # in SS Container (capacity: 30 liters).

STEP – III (DRY MIXING):

• Transfer the sifted Pantoprazole Sodium IP, Mannitol IP, Cross Carmellose Sodium IP, and Sodium Carbonate in Mass Mixer (capacity: 100 liters) and dry mix the materials till uniform mixing.
• Mixing Time: 10 minutes. (To be validated in next batch)
• Mixing Speed: 36 RPM
• Paddle (Blades) Timing: 05 minutes in clockwise direction & 05 minutes in anti-clockwise direction.

STEP –IV (BINDING OF DRY MIX MATERIAL):

• Slowly add the binder of Step-II in dry mix materials of Step-III and mix for 10 minutes till uniform binding and after binding, collect the wet mass into sixteen Trays (capacity: 3.000 kg each).
• Mixing Time: 10 minutes
• Mixing Speed: 36 RPM
• Paddle (Blades) Timing: 05 minutes in clockwise direction & 05 minutes in anti-clockwise direction.

STEP –V (DRYING):

• Dry the wet mass of Step -IV as follows:
• Load these sixteen trays in Tray Dryer.
• First air dries the granules for 30 minutes in a Tray Dryer. Ensure that Heaters are in OFF mode during air drying. After 30 minutes of air-drying, Switch ON the heaters and set the temperature at 35^oC, and dry the granules, until the LOD of granules is between 1.0 to 1.5% at 105^oC checked by Halogen Moisture Balance.
• Air Drying Time: 30 minutes (Heaters should be OFF)
• Drying Time: 04 to 05 hours. (To be validated in next batch)
• Drying Temperature: 35⁰C (After Air Drying)
• Raking Frequency: After every 30 minutes.

STEP-VI (SIZING/MILLING):

• Check Sieve Integrity (before sifting and after sifting).
• Set the Vibro Sifter and fix the sieve 40 # and sieve the dried material of Step-V. Collect the sized material into two Poly-lined HDPE containers (capacity: 30 liters each).

STEP – VII (PRE –LUBRICATION):

• Load the sized granules of Step-VI in Double Cone Blender (capacity: 200 liters) and add sifted Talcum IP, Cross Carmellose Sodium IP, Crospovidone XL IP, and Aerosil IP, mix properly till uniform mixing of sized material with Pre-Lubricating Material.
• Mixing Time: 30 minutes (15 minutes clockwise direction and 15 minutes anti-clockwise direction)
• Mixing Speed: 10 RPM

STEP – VIII (LUBRICATION):

• Add the sifted Calcium Stearate IP in Pre- Lubricated Material of Step-VII and mix properly till uniform mixing of materials with Calcium Stearate IP.
• Mixing Time: 05 minutes (clockwise direction)
• Mixing Speed: 10 RPM.

STEP- IX (BLEND SAMPLE ANALYSIS):

• After completion of lubrication, collect the composite blend sample (Qty. 10 gm) and send to QC for analysis according to the table below:

STEP – X:

• Take Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and unload the above-blended material from Double Cone Blender in Poly-lined HDPE Containers (capacity: 30 liters each) and weigh the material with containers and record the Gross Weight of the material and calculate the Net Weight of the material as per given formula:

Net Weight = Gross Weight – Tare weight

• Affix the status label with the following details – Product Name, Batch No., Batch Size, Mfg. Date, Exp. Date, Tare Weight, Gross Weight, and Net Weight on the Poly-lined HDPE Container.
• Batch Yield of Lubricated granules:
• Theoretical Batch Yield: 55.000 kg (100 %)
• Actual Batch Yield Limit NLT 54.450 kg (NLT 99 %) (To be established in next batch)

STEP – XI:

• Clean all equipment used in the granulation as per respective equipment cleaning SOP.

6.2 COMPRESSION:

   NOTE: Turn ON the sodium lamp and switch OFF all lights before starting the compression and use black polybags to store the tablets.

STEP – I:                                

• After receiving QC approval for the blend, verify the Net Weight of the received blend as per the status label in Granules Day Store.
• After confirmation continue the compression with 35 stations (B-Tooling) Compression Machine. Compress the blend as per the following parameters and In-Process checks under controlled environmental conditions.

• Collect the compressed tablets in SS Container (capacity: 20 liters each on both sides), when SS containers are filled with tablets, transfer the tablets in two Poly-lined HDPE Containers as given below in Step-III.

STEP – II:

• Send the composite sample of compressed tablets (Qty. 30 tablets) to the QC department for analysis.

STEP – III:

• Take Tare Weight of two Poly-lined HDPE Containers (capacity: 30 liters each), record the Tare Weight in BMR and transfer the compressed tablets in Poly-lined HDPE Containers (capacity: 30 liters each) and weigh the compressed tablets with containers and record the Gross Weight of the compressed tablets and calculate the Net Weight of the material as per given formula:

Net Weight = Gross Weight – Tare weight

• Affix the status label with the following details – Product Name, Batch No., Batch Size, Avg. Weight Mfg. Date, Exp. Date, Tare Weight, Gross Weight, and Net Weight on the Poly-lined HDPE Container.
• Batch Yield of Compressed Tablets:
• Theoretical Batch Yield: 55.000 kg (100 %)
• Actual Batch Yield Limit NLT 54.450 kg (NLT 99 %) (To be established in next batch)

STEP – IV:

• After completion of compression of tablets, clean the Compression Machine as per cleaning SOP.

NOTE: For this product, the lot size of 500000 tablets is taken which is divided into different sub lots (batches of different quantities) as per the order of the customers.

In order to standardize the Coating Procedure, we are taking the Batch Size of 100000 tablets for coating in this MFR.

6.3 COATING: FOR 100000 Tablets:

NOTE: Switch ON sodium lamp and Switch OFF all lights and use black polybags to store the tablets.

• Verify the Net Weight of the received compressed tablets for coating as per status label and after confirmation continues for tablet coating.

STEP – I (COATING MATERIALS SEAL COAT DETAILS):      

STEP – II (COATING MATERIALS ENTERIC COATING DETAILS):      

NOTE:

Color: As per packing material /according to the brands/products. The color and quantity of color to be used may vary from product to product as per the reference sample.

.STEP-III (LIST OF EQUIPMENT FOR COATING):

STEP – IV (PREPARATION OF SEAL COAT SOLUTION):

• Take Isopropyl Alcohol IP (0.630 liters) and Dichloromethane USP (1.470 liters) in SS Container (capacity: 10 liters) and add Instacoat Solution Transparent IC-S-1643 (0.110 kg), mix together by Portable Stirrer properly continuously stirring till uniform mixing achieved.
• Speed of stirrer: Constant.
• Mixing Time: 15 minutes (To be validated in next batch)
• Filter the seal coating solution with Filter Cloth 100 # in SS Container (capacity: 10 liters).
• Keep the solution for 10 minutes and after 10 minutes start the Seal Coating process with a Seal coating solution

STEP – V (COATING PROCEDURE FOR SEAL COAT OF TABLETS):

NOTE: Use sodium lamp and switch OFF lights and use black polybags to store the tablets.

• The coating will be done in one lot, take total compressed tablets for coating (11.000 kg).
• Load the tablets in coating pan (Capacity: 24″), start the hot air blower, set the inlet air temperature at 60°C to 65°C and start the exhaust fan & warm the tablets bed 30°C to 35°C.
• After warming up the tablets, take the weight of 100 warm tablets and also take the weight of 100 tablets after Seal Coat and record the weight in BMR for calculation of weight buildup of tablets after Seal Coat.
• Set the coating parameter as given in the below table and start the coating process by starting coating spray through the gun.
• After completion of Seal Coating, calculate the weight gain by using the below Formula in the table.

STEP – VI (PREPARATION OF ENTERIC COATING SOLUTION):

• Take Isopropyl Alcohol IP (6.270 liters) and Dichloromethane USP (14.630 liters) in SS Container (capacity; 30 liters) and add Instacoat EN Solution White IC-EN-001(1.100 kg), mix together by Portable Stirrer properly continuously stirring till uniform mixing achieved.
• Speed of stirrer: Constant.
• Mixing Time: 15 minutes (To be validated in next batch)
• After uniform mixing add color Yellow oxide of iron IP (0.055 kg) in the above solution and mix for 05 minutes with stirrer till uniform mixing is achieved.
• Filter the Enteric coating solution with Filter Cloth 100 # in one SS Container (capacity: 30 liters)
• Keep the solution, after completion of Seal Coating, start the enteric coating process with the enteric coating solution.

STEP – VII (COATING PROCEDURE FOR ENTERIC COATING OF TABLETS):

• Set the coating parameter as given in the below table and start the enteric coating process by starting coating spray through the gun.

• After completion of Enteric coating, take the weight of 100 Enteric-coated tablets and record the weight in BMR, and calculated the weight gain by using the Weight Gain Formula given in the above table of Step- VII

STEP – VII (COATING IN-PROCESS CHECK PARAMETERS):

• After completion of Enteric Coating perform the In Process checks as per the below parameters.

STEP – IX:

• Send the composite sample of coated tablets (Qty.30 tablets) to the QC department for analysis.

STEP – X:

• Take Tare Weight of one Poly-lined HDPE Containers (capacity: 30 liters), record the Tare Weight in BMR and transfer the coated tablets in Poly-lined HDPE Containers (capacity: 30 liters each) and weigh the coated tablets with containers and record the Gross Weight of the coated tablets and calculate the Net Weight of the material as per given formula:
• Net Weight = Gross Weight – Tare weight
• Affix the status label with the following details – Product Name, Batch No., Batch Size, Avg. Weight, Mfg. Date, Exp. Date, Tare Weight, Gross Weight, and Net Weight on the Poly-lined HDPE Containers.
• Batch Yield of Coated Tablets:
• Theoretical Batch Yield: 12.100 kg (100 %)
• Actual Batch Yield Limit NLT 11.979 kg (NLT 99 %) (To be established in next batch).

References:

Drug Bank Online

MedlinePlus (https://medlineplus.gov)

Web Med (https://www.webmd.com)