Prospective Process Validation

by

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
  • 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 the suitable documented evidence that the manufacturing process when operated in these validated parameters is able to supply a final product which fulfills the analytical  specifications, quality attributes and other release specifications. This Validation study is anticipated due to introduction of new product “Paracetamol 500 mg Tablets”.

SCOPE :

This protocol shall be applicable 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 manufacturing process are not validate  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 labelling.
  • Affix the dispensed labels in BMR on separate Annexure.
  • Repeat the procedure for second Lot.

Preparation of Binding Solution

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

Dry Mixing

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

Wet Granulation

  • Start the RMG with Impeller at slow speed and chopper in off position and charge the Binding Solution gradually contained in planetary bowl in RMG using elevator for a period of 4 Minutes.
  • After Completion of Binding, open the lid of RMG and scrape the side of the mixer, impeller Blade, chopper blade with the help of S.S Spatula.
  • Knead the wet mass with impeller at slow speed and chopper in slow position for a period of 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 additional quantity of Purified Water and do additional kneading if required to get mass of appropriate consistency with the impeller at slow speed and chopper on slow position. Record additional quantity of Purified Water.
  • When the desired consistency is attained, start the Co-mill and discharge approximate half 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 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 off position.
  • Stop the RMG after maximum wet mass is unloaded, open the lid and collect wet mass adhered to the side of RMG impeller blade, chopper blade with the help of S.S spatula. Unload the collected wet mass in 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 co mill.
  • Close the assembly of the Co Mill.
  • Repeat the procedure for 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 Shaking Interval to after every 5min.and 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 specified LOD achieved cool the granules for 1minute in Piston UP 2.5 sec., Piston down 2.5 sec.
  • Shake the FBD bag for 30 sec. before removing the FBD bowl form drying chamber.
  • Wait for 5 min for the granular dust to settle down before taking out the bowl.
  • Repeat the procedure for 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 FBD bowl and ensure that the FBD bowl is aligned properly to the tippler before lifting the Tippler upward to the required height.
  • Mount the FBD bowl containing dried granules over Sifter cum Multimills which is fitted with

2.0 mm Screen for Sifter and 2.0 mm Screen for Multimills.

  • Place a Bin at the Discharge end of Sifter cum Multimills. Note down tare weight of 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 second Lot. 

Sifting of Lubricants

  • Sift the Maize Starch (15.20kg) through 100#, Stearic Acid (4.80 KG) through 60 # using vibro sifter and collect them in Poly Bags and keep 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 in to the blender containing granules.
  • Run the blender for 19 min at slow speed . 

Lubrication of Graded Granules

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

Compression

  • Ensure the Dust extractor is connected to Compression Machine, Dedusting and Deburring Machine.
  • Switch on the Dust extractor.
  • After Machine setting run the Machine in Inching mode and check for any abnormal noise
  • Feed the lubricated granules by operating pneumatic valve attached below the bin through “Y” chute in to the hopper of 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 upper and lower surface 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 Introduction of new product Paracetamol 500 mg Caplets. A Risk analysis was carried out to establish which critical process parameters are likely to have greatest impact on product quality.

Risk Details Risk Level Risk Mitigation
Step CPP Impacted CQA
Sifting –    Sieve Size-    Sieve Integrity Particle size distribution Low –    BMR Shall be verified for procedural control (Sieve size & Sieve integrity)-    Process Validation Protocol shall be verified for procedural control (Sieve size & Sieve integrity)
Binder Preparation –    Continuous stirring Appearance Low –    BMR Shall be verified for procedural control (Appearance)-    Process Validation Protocol shall be verified for procedural control Appearance
Dry mixing –    Mixing Time-    Speed of Chopper & Impeller -Blend uniformity-Assay Low –    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)
Wet Granulation –    Binder addition Time-    Kneading Time-    Speed of Impeller & Chopper,-    Amperage Load-    Discharge mode-    Additional Quantity of Water DT, Assay , Dissolution Low –     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)
Drying –    Inlet temperature-    Outlet temperature-    Drying time LOD of Granules Low –    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)
Grading of Granules –    Screen size and integrity-    Knives direction-    VFD Speed Particle size distribution Low –    BMR Shall be verified for procedural control (Screen size and integrity, Knives direction, VFD speed)-    Process Validation Protocol shall be verified for procedural control (Screen size and integrity, Knives direction, VFD speed)
Sifting of Lubrication –    Sieve Size-    Sieve Integrity Particle size distribution Low –    BMR Shall be verified for procedural control (Sieve size & Sieve integrity)-    Process Validation Protocol shall be verified for procedural control (Sieve size & Sieve integrity)
Mixing of Un-Lubricated Graded granules –    Mixing Time-    Blender RPM Blend uniformity Moderate –    BMR Shall be verified for procedural control (Mixing Time & Mixing Speed)-    Process Validation Protocol shall be verified for procedural control (Mixing Time, Mixing Speed).
Lubrication –    Mixing Time-    Mixing Speed –    Blend uniformity-    Flow of Granules-    Assay Moderate –    BMR Shall be verified for procedural control (Mixing Time & Mixing Speed)-    Process Validation Protocol shall be verified for procedural control (Mixing Time, Mixing Speed).
Compression –    Machine Speed-    Compression Force Physical(-Appearance -Length and Width-Thickness-Hardness-Friability-Disintegration time-Weight of 20 tablet-Average weight-Uniformity of weight Chemical-Assay -Dissolution Moderate –    BMR Shall be verified for procedural control (Physical (for e.g. Friability, Hardness, Uniformity of weight, Average weight, Thickness, etc.)-    Process Validation Protocol shall be verified for procedural control [Physical (for e.g. Friability, Hardness, Uniformity of weight, Average weight, Thickness, etc.) and chemical Parameters (for 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 ITS EVALUATION

Process Step Critical process parameter Critical Quality Attribute Reference specification/test method
Sifting Sieve Size, Sieve Integrity Particle size distribution  As per BMR
Dry mixing Mixing Time ,Speed of Chopper & Impeller Blend uniformity- Assay As per BMR
Wet Granulation Binder addition Time ,Kneading Time ,  Speed of Impeller & Chopper, Amperage Load, Discharge mode, Additional Quantity of water, Discharge time  DT, Assay-    Dissolution As per BMR
Drying Inlet temperature, Outlet temperature-    Drying time, Shaking time, Raking time  LOD of Granules  As per BMR
Grading of Granules Screen size and integrity, Knives direction-    VFD speed, Grading time Particle size distribution As per BMR / Analytical protocol
Sifting Sieve Size ,Sieve Integrity Particle size distribution As per BMR
Mixing of Un –Lubricated Graded Granules Mixing Time ,Speed Blend uniformity As per BMR / Analytical protocol
Lubrication Mixing Time ,Speed Blend uniformity, Flow of Granules ,  Assay As per BMR / Analytical protocol
Compression Machine Speed ,Compression force Physical (-Appearance -Length and Width-Thickness-Hardness-Friability-Disintegration time-Weight of 20 tablets-Average weight-Uniformity of weight Chemical-Assay -Dissolution –    As per BMR / Analytical protocol

SAMPLING PLAN Compression stage

Process Step Test Parameter Quantity of Samples ## Acceptance Criteria
Slow speed & High Hardness. Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width Dissolution* 136 tablets(68 RHS +68 LHS)36 tablets for *dissolution(composite from LHS & RHS) Appearance: White, Pillow Shaped Tablets(Caplets) with a single break bar on one FaceLength and Width :Length: 17.2-18.0 mmWidth : 7.0-7.4 mmThickness : 5.50-6.10mm
Hardness  : Target 8 – 10 Kp(No individual  tablet to be NLT6 Kp)
Friability  : NMT 1.0% w/w
Disintegration Time: NMT 10min.
Weight of 20 Tablets : 11.76 gm to 12.24 gmAverage 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
 Appearance: White, Pillow Shaped Tablets(Caplets) with a single break bar on one FaceLength and Width :Length: 17.2-18.0 mmWidth : 7.0-7.4 mmThickness : 5.50-6.10mmHardness  : Target 8 – 10 Kp(No individual  tablet to be NLT6 Kp)
Friability  : NMT 1.0% w/wDisintegration Time: NMT 10min.Weight of 20 Tablets : 11.76 gm to 12.24 gmAverage 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 minutesAssay : Between 95.0% to 105.0% of the labelled amountRelated Substance:4-Aminophenol:NMT0.1%4’-Chloracetanilide: NMT10 PPMAny Other Impurity :NMT 0.25%
High speed &Low hardness.  Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS
Slow Speed & Low Hardness Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS
High Speed & High Hardness Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width Dissolution* 136 tablets(68 RHS +68 LHS)36 tablets for *dissolution(composite from LHS & RHS)
At Full Hopper & optimum speed and optimum hardness Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS
Initial (Optimum Hardness & optimum speed.) Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS
*As per in-process specification + * Related Substances , *Assay and *Dissolution 250 tablets(Composite)
At Half Hopper & optimum speed and optimum hardness Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS)
At Middle stageOptimum speed and optimum hardness Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS Appearance: White, Pillow Shaped Tablets(Caplets) with a single break bar on one Face

Length and Width :Length: 17.2-18.0 mmWidth : 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 labelled amount

Related Substance:4-Aminophenol:NMT0.1%4’-Chloracetanilide: NMT10 PPMAny Other Impurity :NMT 0.25%
 
*As per in-process specification + *Related Substances, *Assay  and *Dissolution 250 tablets(Composite)
At Quarter Hopper  optimum speed and optimum hardness Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS
End (Optimum Hardness & optimum speed.) Appearance, Thickness, uniformity of weight,  Average weight, Weight of 20 tablets, Hardness, Friability,  Disintegration Time, Length  and Width 136 tablets(68 RHS +68 LHS
*As per in-process specification +* As per Product Specification, *Related Substances and *Dissolution + Microbiological Examination 250 tablets(Composite) +20 gm (Microbiological Analysis)

*Test to be analyzed in Quality Control.

NOTE:

  1. Batch Detail and Sample Details recorded as per Annexure I.
  2. Challenges at compression machine shall be performed as per the sampling plan and record the in-process data as per Annexure II. Executed Annexure shall be attached with the report as a raw data of 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 property of the blend. Mixing speed and time are critical variables in this process. Since speed of the blender is constant, time required for proper mixing shall be determined. Mixing time is critical as less blending will result in non uniform distribution of drug and poor flow whereas more blending will result in de-mixing leading to non uniform distribution of drug and increase in disintegration time.

In addition to this Following tests shall be carried out for information purpose. 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 conversion of blended material into tablets as per specifications. Speed of machine is major variable. Following physical parameters are to be checked to establish the above-mentioned variables at regular intervals

  • Appearance
  • Average Mass
  • 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 compression machine.

ACCEPTANCE CRITERIA

Test Parameter Acceptance Criteria
Drying
LOD 1.6 – 3.0% w/w
Grading of Dried Granules
Particle Size Distribution(20#,40#,60#, 80# & below 100#) For Information only
Bulk Density and Tapped Density For Information only
Mixing of Un-lubricated graded granules
Blend uniformity 90.0% to 110.0% (RSD NMT 5.0%)
Lubrication
Blend uniformity 90.0% to 110.0% (RSD NMT 5.0%)
Assay Between 95.0% to 105.0% of labeled amount
Bulk density For Information only
Tapped Density For Information only
Compressibility index For Information only
Hausner Ratio For Information only
Sieve Analysis(20#, 40# & 60#, 80#, 100#) For Information only
Compression
As per In-process specification
Appearance White, Pillow Shaped Tablets(Caplets) with a single break bar on one Face
Length and width Length: 17.2-18.0 mmWidth : 7.0-7.4 mm
Thickness 5.50mm-6.10mm
Hardness NLT to 6 Kp ( Target 8-10Kp)
Friability NMT 1.0% w/w
Disintegration time NMT 10 min.
Weight of 20 tablets 11.76gm –12.24gm
Average weight 588.0 mg  to 612.0 mg
Uniformity of weight ± 5% of  Average weight
Test Parameter Acceptance Criteria
As per product specification
Appearance White, Pillow Shaped Tablets(Caplets) with a single break bar on one Face
Identification
BY HPLC The retention time of Paracetamol peak in the chromatogram of the sample solution should correspond to that in the chromatogram of the standard solution as obtained in the Assay
BY IR The Infrared absorption spectrum of residue should be concordant with the reference spectrum of Paracetamol (RS 258).
PHYSICAL  PARAMETER
Average weight 588.0 mg To 612.0 mg
Dimension
Length 17.2 -18.0mm
Width 7.0-7.4 mm
Uniformity of mass NMT 2 of the individual masses should deviate from the average mass by more than 5% and none should deviate from the average mass by more than 10%
Hardness About 10 KP
Specific Test
Disintegration NMT15 minutes
Dissolution  NLT 70.0 % should dissolve in  45 minutes
Assay
Paracetammol (By HPLC) Between 95.0% to 105.0% of label  claim
Related Substance
By HPLC
4-aminophenol NMT 0.1%
4 – Chloroacetanilide NMT 10 ppm
Any Other impurity NMT 0.25%
Microbiological Examination
Microbial enumeration tests
Total Aerobic Microbial Count (TAMC) NMT 103 CFU/g.
Total combined Yeast/Moulds Count (TYMC) NMT 102 CFU/g
Test for specified microorganism
Escherichia coli Should be absent/g

DEVIATION DETAIL

A summary of any incident and corresponding root cause, its impact on study, any unexpected observation (if any), deviation shall be captured in 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 manufacturing process Validation study. Report shall include a concise description and summary of all studies performed. A detail result and discussion shall be the part of report which contains observations and data results obtained during the Validation study and all the established process parameters shall be summarized in 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 specification on basis of trend analysis

Stability Studies of validation batch shall be performed in accordance with Stability Protocol.