Prospective Process Validation of Paracetamol Tablets

Paracetamol 

Paracetamol/acetaminophen is the most commonly used analgesic and antipyretic drug, It is the drug of choice in patients who cannot be treated with non-steroidal anti-inflammatory drugs (NSAID), such as people with bronchial asthma, peptic ulcer disease, hemophilia, salicylate-sensitized people, children under 12 years of age, pregnant or breastfeeding women. It is recommended as a first-line treatment of pain associated with osteoarthritis. The mechanism of action is complex and includes the effects of both the peripheral (COX inhibition), and central (COX, serotonergic descending neuronal pathway, L-arginine/NO pathway, cannabinoid system) antinociception processes and “redox” mechanism. Paracetamol is a well-tolerated drug and produces few side effects from the gastrointestinal tract, however, despite that, every year, has seen a steadily increasing number of registered cases of paracetamol-induced liver intoxication all over the world.

PROCESS VALIDATION PROTOCOL OF PARACETAMOL 500 MG CAPLTES

Batch size: 8,000,00Tablets (480.00 kg),

Shelf life: 36 Months

Reason for validation: Introduction of New Product at Site (8.0Lac.)

Table of Contents

• Pre-approval
• Objective
• Scope
• Responsibilities
• Reference documents
• Key equipment/instrument detail (qualification/calibration)
• Product detail
• Master Formula
• Process description
• Process flow
• Risk assessment for critical process parameters (CPPS) & critical quality attributes (CQA)
• Critical process parameters and its evaluation
• Sampling plan
• The rationale for selection of critical steps and its process parameters for validation
• Sampling procedure & location diagram
• Acceptance criteria
• Deviation detail
• Process validation report & summarization of test result
• Annexure
• Re-validation criteria
• Stability study
• Abbreviations

OBJECTIVE :

The protocol is intended to validate the critical process parameters by providing suitable documented evidence that the manufacturing process when operated in these validated parameters can supply a final product that fulfills the analytical specifications, quality attributes, and other release specifications. This Validation study is anticipated due to the introduction of the new product “Paracetamol 500 mg Tablets”.

SCOPE :

This protocol shall apply to the Process Validation of Paracetamol 500 mg manufactured as per current BMR.

This protocol shall be executed on three Validation Batches. If, for any reason, the critical process parameters of the manufacturing process are not validated on three Validation batches then three more batches can be taken for validation.

All the documents including analytical test reports including raw data as well as the other documentation specified in this protocol shall be archived separately. After Completion of the documentation specified in this protocol, the report shall be prepared, signed, dated, and authorized.

RESPONSIBILITIES

• Preparation of Validation protocol and Execution of process Validation with approved protocol:
• Validation Team
• Provide required utilities for process Validation activity: Head Engineering
• Execute manufacturing of product: Validation Team
• Sampling as per Sampling Plan: IPQA Personnel/Validation team
• Testing of Samples & Reporting: QC Personnel
• Review of Analytical Reports: Head QC
• Review and Approval of Process Validation Protocol: Head Production/Head QC/Head QA/Site Head/Marketing Authorization Holder

REFERENCE DOCUMENTS

• Master Formula Card Number
• Batch Manufacturing Record Number
• Finished Product Specification Number
• Process validation SOP

KEY EQUIPMENT / INSTRUMENT DETAIL (QUALIFICATION / CALIBRATION)

Dispensing

• Dispensing Booth
• Weighing Balance

Granulation

• Vibratory Sifter
• Sifter cum Multimills
• Binder Preparation Vessel
• RMG
• RMG
• Fluidized Bed Drier
• Tippler
• Bin Lifter
• Conta Blender

Compression

• Weighing Balance
• 37stn D Tooling Compression M/C
• De-dusting & Deburring unit
• Metal Detector
• Venire Caliper
• Friability Test Apparatus
• Disintegration Test Apparatus
• Hardness Tester
• Weighing Balance 

Note: Qualification/calibration status shall be verified before execution.

PRODUCT DETAIL

Product Name: Paracetamol 500 mg Tablets

Batch Size: 8, 000, 00 Tablets (480.00 kg)

Label Claim:

Each Uncoated Tablet Contains:

Paracetamol BP …………………….. 500 mg

Shelf Life: 36 months

Storage Condition: Store below 25 ºC

MASTER FORMULA

Dry Mixing

Paracetamol Qty. / Tab in mg Label Claim in mg/Tab 500.00, Qty. /Tab in mg 500.00.

Maize Starch (Maize Starch B) Qty. /Tab in mg 18.00

Pregelatinized Maize Starch: Qty. /Tab in mg 57.00

Vehicle

Purified Water —-q.s.

Lubrication

Maize Starch (Maize Starch 5%)

Maize Starch (Maize Starch 5%) Qty. /Tab in mg 19.00

Stearic Acid Qty. /Tab in mg 6.00

Tablets weight: 600.00 mg

PROCESS DESCRIPTION

• Sift the materials Paracetamol Ph. Eur (200.00kg) through 4#, Maize Starch (Maize Starch B) Ph. Eur (7.20kg) through 100#, and Pregelatinised starch Ph. Eur (22.80kg) through 40 # collect separately in a suitable lot wise in IPC or double lined polythene bags with proper labeling.
• Affix the dispensed labels in BMR on a separate Annexure.
• Repeat the procedure for the second Lot.

Preparation of Binding Solution

• Take Purified Water 64.00 Lts. in a Binder preparation vessel.
• Repeat the procedure for the second Lot.

Dry Mixing

• Charge the Pre Sifted Material contained in-process Container in RMG using the elevator.
• Close the lid of the RMG.
• Start the RMG with the Impeller at slow speed and the Chopper in Off Position for 10 Minutes.
• Repeat the procedure for the second Lot.

Wet Granulation

• Start the RMG with the Impeller at slow speed and chopper in the off position and charge the Binding Solution gradually contained in a planetary bowl in RMG using the elevator for 4 Minutes.
• After Completion of Binding, open the lid of RMG and scrape the side of the mixer, impeller Blade, and chopper blade with the help of S.S Spatula.
• Knead the wet mass with impeller at a slow speed and chopper in a slow position for 4 minutes
• After completion of kneading, open the lid of RMG and scrape the side of the mixer, impeller blade, and chopper blade with the help of S.S Spatula
• Add quantity of Purified Water and do additional kneading if required to get mass of appropriate consistency with the impeller at a slow speed and chopper on slow position. Record an additional quantity of Purified Water.
• When the desired consistency is attained, start the Co-mill and discharge approximately half the quantity of wet granules into the FBD bowl by opening the discharge port of the RMG with the impeller at creep mode and chopper in the off position.
• Discharge another half quantity of wet granules into another FBD bowl by opening the discharge port of the RMG with the impeller at creep mode and chopper in the off position.
• Stop the RMG after the maximum wet mass is unloaded, open the lid, and collect the wet mass adhered to the side of the RMG impeller blade, and chopper blade with the help of an S.S. spatula. Unload the collected wet mass in the FBD bowl.
• After complete removal of wet mass close the discharge port and lid of the RMG.
• Open the assembly of the co-mill and collect the mass adhered to the blade and side of the co-mill.
• Close the assembly of the Co Mill.
• Repeat the procedure for the second Lot.

Drying

• Place the FBD bowl containing the granular mass under the retarding chamber and ensure Proper locking with retarding chamber.
• Dry the granules at 50 – 60°C (Inlet temperature) till the outlet temperature reaches 30 ±3 °C with uniform raking whenever required.
• Set the Shaking Interval to after every 5min.and the shaking time to 30 sec.
• Collect the granules from the bowl and check the LOD.
• Continue drying till the specified level of LOD is achieved i.e.1.6 – 3.0% w/w (Target LOD   50% w/w),
• After the specified LOD is achieved cool the granules for 1 minute in Piston UP 2.5 sec., Piston down 2.5 sec.
• Shake the FBD bag for 30 sec. before removing the FBD bowl from the drying chamber.
• Wait for 5 min for the granular dust to settle down before taking out the bowl.
• Repeat the procedure for the second lot.

Grading of Dried Granules Using Sifter cum Multimills and Tippler

• Remove the FBD bowl with the dry granules from the FBD and take the bowl near the
• Fix the clamps of the Tippler to the FBD bowl and ensure that the FBD bowl is aligned properly with the tippler before lifting the Tippler upward to the required height.
• Mount the FBD bowl containing dried granules over the Sifter cum Multimills which is fitted with a 2.0 mm Screen for Sifter and a 2.0 mm Screen for the Multimills.
• Place a Bin at the Discharge end of the Sifter cum Multimills. Note down the weight of the bin used for collecting the graded granules.
• Start the Sifter cum Multimills and slowly load the dried granular mass by opening the pneumatic Butterfly valve of the Tippler.
• Repeat the procedure for the second Lot. 

Sifting of Lubricants

• Sift the Maize Starch (15.20kg) through 100# and stearic Acid (4.80 KG) through 60 # using a vibro sifter and collect them in Poly Bags and keep them separately.

Blending

    Procedure for Mixing of Un-lubricated Graded Granules

• Place the Contabin containing graded granules under the Contabin blender.
• Add the pre-sifted Maize starch into the blender containing granules.
• Run the blender for 19 min at a slow speed. 

Lubrication of Graded Granules

• Add the pre-sifted Stearic Acid into the blender containing granules.
• Run the blender for 4 min at slow speed.

Compression

• Ensure the Dust extractor is connected to the Compression Machine, ducting, and Deburring Machine.
• Switch on the Dust extractor.
• After the Machine setting run the Machine in Inching mode and check for any abnormal noise
• Feed the lubricated granules by operating a pneumatic valve attached below the bin through the “Y” chute into the hopper of the compression machine.
• Collect the first 2 Rounds of tablets (approximately 200 tablets) and destroy them.
• Set the machine to meet the required standard parameters.
• Collect 40 tablets from each side and check them individually for any damages on the upper and lower surfaces along with thickness Appearance and hardness.
• Check the Weight of 20 tablets, Uniformity of Weight, Disintegration, and Friability parameters at the below-mentioned frequency.
• Collect the tablets in clean labelled double polythene-lined HDPE drums.

RISK ASSESSMENT FOR CRITICAL PROCESS PARAMETERS (CPPS) & CRITICAL QUALITY ATTRIBUTES (CQA)

This study is to be carried out due to the Introduction of the new product Paracetamol 500 mg Caplets. Risk analysis was carried out to establish which critical process parameters are likely to have the greatest impact on product quality.

Risk Details

1. Step: Sifting

CPP: Sieve Size-    Sieve Integrity

Impacted CQA: Particle size distribution

Risk Level: Low

Risk Mitigation: BMR Shall be verified for procedural control (Sieve size & Sieve integrity)-    Process Validation Protocol shall be verified for procedural control (Sieve size & Sieve integrity)

2. Step: Binder Preparation

CPP: Continuous stirring

Impacted CQA: Appearance

Risk Level: Low

Risk Mitigation: BMR Shall be verified for procedural control (Appearance)-    Process Validation Protocol shall be verified for procedural control Appearance.

3. Step: Dry mixing

CPP: Mixing Time-    Speed of Chopper & Impeller

Impacted CQA: Blend uniformity-Assay

Risk Level: Low

Risk Mitigation: BMR Shall be verified for procedural control (Mixing Time, Speed of Chopper & Impeller)-    Process Validation Protocol shall be verified for procedural control (Mixing Time, Speed of Chopper & Impeller)

4. Step:  Wet Granulation

CPP:  Binder addition Time-    Kneading Time-    Speed of Impeller & Chopper,-    Amperage Load-    Discharge mode-    Additional Quantity of Water

Impacted CQA:  DT, Assay, Dissolution

Risk Level: Low

Risk Mitigation: BMR Shall be verified for procedural control (Binder addition Time, Kneading Time, Speed of Impeller & Chopper, Amperage Load, Discharge mode, Additional Quantity of water )-    Process Validation Protocol shall be verified for procedural control (Binder addition Time, Kneading Time, Speed of Impeller & Chopper, Amperage Load, Discharge mode).

5. Step:  Drying

CPP:  Inlet temperature-    Outlet temperature-    Drying time

Impacted CQA:  LOD of Granules

Risk Level: Low

Risk Mitigation:  BMR Shall be verified for procedural control (Inlet temperature, Outlet temperature, Drying time, LOD)-    Process Validation Protocol shall be verified for procedural control (Inlet temperature, Outlet temperature, Drying time, LOD).

6. Step: Size Reduction of Granules

CPP:  Screen size and integrity-    Knives direction-    VFD Speed

Impacted CQA:  Particle size distribution

Risk Level: Low

Risk Mitigation:  BMR Shall be verified for procedural control (Screen size and integrity, knife direction, VFD speed)- Process Validation Protocol shall be verified for procedural control (Screen size and integrity, knife direction, VFD speed)

7. Step: Sifting of Lubrication

CPP:  Sieve Size-    Sieve Integrity  

Impacted CQA: Particle size distribution

Risk Level: Low

Risk Mitigation:  BMR Shall be verified for procedural control (Sieve size & Sieve integrity)- Process Validation Protocol shall be verified for procedural control (Sieve size & Sieve integrity).

8. Step: Mixing of Un-Lubricated Graded granules

CPP:  Mixing Time-    Blender RPM

Impacted CQA: Blend uniformity

Risk Level: Moderate

Risk Mitigation:  BMR Shall be verified for procedural control (Mixing Time & Mixing Speed)-    Process Validation Protocol shall be verified for procedural control (Mixing Time, Mixing Speed).

9. Step: Lubrication

CPP:  Mixing Time-    Mixing Speed

Impacted CQA: Blend uniformity-    Flow of Granules-    Assay

Risk Level: Moderate

Risk Mitigation:  BMR Shall be verified for procedural control (Mixing Time & Mixing Speed)-    Process Validation Protocol shall be verified for procedural control (Mixing Time, Mixing Speed).

10. Step:  Compression

CPP:  Machine Speed, Compression Force

Impacted CQA: Physical(-Appearance -Length and Width-Thickness-Hardness-Friability-Disintegration time-Weight of 20 tablet-Average weight-Uniformity of weight Chemical-Assay -Dissolution.

Risk Level: Moderate

Risk Mitigation:  BMR Shall be verified for procedural control (Physical (e.g. Friability, Hardness, Uniformity of weight, Average weight, Thickness, etc.)- Process Validation Protocol shall be verified for procedural control [Physical (e.g. Friability, Hardness, Uniformity of weight, Average weight, Thickness, etc.) and chemical Parameters (e.g. Assay, Dissolution, etc.) of Tablet]-    Process Validation Protocol shall be verified for challenges for full hopper, Half Hopper, Quarter Hopper, Slow Speed, High Speed, High Hardness and Low Hardness.

CRITICAL PROCESS PARAMETERS AND THEIR EVALUATION

SAMPLING PLAN Compression stage

Acceptance Criteria :

• Appearance: White, Pillow Shaped Tablets(Caplets) with a single break bar on one Face
• Length and Width :Length: 17.2-18.0 mm, Width: 7.0-7.4 mm
• Thickness: 5.50-6.10mm 
• Hardness  : Target 8 – 10 Kp(No individual  tablet to be NLT 6 Kp)
• Friability: NMT 1.0% w/w
• Disintegration Time: NMT 10min.
• Weight of 20 Tablets: 11.76 gm to 12.24 gm
• Average Weight: 600 ± 2%(588.00 mg to 612.00 mg)
• Uniformity of weight:  Average weight ± 5.0%
• Dissolution: NLT 70.0 % should dissolve in  45 minutes
• Assay: Between 95.0% to 105.0% of the labeled amount
• Related Substance:4-Aminophenol:NMT0.1%4’-Chloracetanilide: NMT10 PPMAny Other Impurity: NMT 0.25% Test to be analyzed in Quality Control.

NOTE:

1. Batch Details and Sample Details are recorded as per Annexure I.
2. Challenges at the compression machine shall be performed as per the sampling plan and the in-process data as per Annexure-II. The executed Annexure shall be attached to the report as raw data for each challenge.

RATIONALE FOR SELECTION OF CRITICAL STEPS AND ITS PROCESS PARAMETERS  FOR VALIDATION :

A) Blending: This step involves mixing of granules with other Excipients and lubricants. The purpose of blending is to get a uniform distribution of Paracetamol to get good flow and anti-adhesion properties of the blend. Mixing speed and time are critical variables in this process. Since the speed of the blender is constant, the time required for proper mixing shall be determined. Mixing time is critical as less blending will result in a non-uniform distribution of drugs and poor flow whereas more blending will result in de-mixing leading to a non-uniform distribution of drugs and an increase in disintegration time.

In addition to this Following tests shall be carried out for information purposes. This shall be carried out on final time interval samples only.

1. Loss on drying
2. Bulk Density
3. Sieve analysis
4. Compressibility Index

B) Compression: This step involves the conversion of blended material into tablets as per specifications. The speed of the machine is a major variable. The following physical parameters are to be checked to establish the above-mentioned variables at regular intervals

• Appearance
• Average Mass
• A mass of 20 Tablets
• Resistance to Crushing
• Thickness
• Friability
• Disintegration time
• Length and Width

SAMPLING PROCEDURE & LOCATION DIAGRAM

At Compression Stage – Sampling Locations for Hopper Level

Procedure: Compression setting shall be done as per batch manufacturing record. During sampling ensure the hopper level as per the below-mentioned diagram. Initial sampling shall be performed for full Hopper and after that Half Hopper and then quarter Hopper.  Sampling shall be performed directly from the chute of the compression machine.

ACCEPTANCE CRITERIA

DEVIATION DETAIL

A summary of any incident and corresponding root cause, its impact on the study, any unexpected observation (if any), or deviation shall be captured in the report. A recommendation (if any) should be documented in the report.

PROCESS VALIDATION    REPORT & SUMMARIZATION OF TEST RESULT

A separate report shall be prepared for the manufacturing process Validation study. The report shall include a concise description and summary of all studies performed. A detailed result and discussion shall be the part of the report which contains observations and data results obtained during the Validation study and all the established process parameters shall be summarized in the report.

RE-VALIDATION CRITERIA

• Change Manufacturing process
• Change in Batch size
• Change in equipment
• Change in Formulation
• Any customer/regulatory specific requirement
• Change in the sources of API.
• Sequential batches that fail to meet product and process specifications based on trend analysis

Stability Studies of the validation batch shall be performed by the Stability Protocol.

DISINFECTANT VALIDATION