Process Validation of Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup

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Product Name :  
Generic Name :  

Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup

 

 
Type of Validation : Concurrent Validation
Reason for Validation :  
Batch Size :  
Effective Date:  

 

TABLE OF CONTENTS

S. No. Subject Page No.
1.        Pre-Approval  
2.        Purpose  
3.        Scope  
4.        Validation team  
5.        Personnel Responsibility  
6.        Procedure  
7.        Product details  
8.        Batches selected for validation study  
9.        Reference documents  
10.    List of raw material for formulation:  
11.    Manufacturing Process flow chart  
12.    Equipments Used For Process  
13.    Qualification status of equipment’s  
14.    Manufacturing Process  
15.    Critical process parameters:  
16.    Sampling, test parameters, acceptance criteria  
17.    Certificate of analysis  
18.    Mixing time validation  
19.    Machine set up & filling & sealing checks  
20.    Stability study Sample  
21.    Acceptance criteria  
22.    Change control / revalidation criteria  
23.    Deviation  
24.    Evaluation of the Results  
25.    Yield  
26.    Summary and Conclusion  
27.    Post approval  

 

 PROTOCOL APPROVAL

   Prepared By:

 

Functional Area Name Designation Signature/Date
Quality Assurance      

 

Checked By:

 

Functional Area Name Designation Signature/Date
 Quality Assurance      
Head Production      
Head-Quality Control      

 

Approved By:

 

Functional Area Name Designation Signature/Date
Head-QA      

 

 

 

 

2. PURPOSE:
  To demonstrate that the manufacturing process of Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup has been consistently producing the product, that meets its predetermined specifications and quality attributes.
3. SCOPE:
  Three consecutive batches of the Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup have been manufactured according to the method of manufacture to re-confirm the standard manufacturing process parameters.
4. VALIDATION TEAM :
  A representative from following Departments:

·         Quality Assurance

·         Quality Control

·         Production

·         Engineering
5. PERSONEL RESPONSIBILITIES
   

S. No. Designation Responsibility
1. QA Executive Preparation of the protocol, Report and their execution.
2. Production Manager Execution of protocol
3. QC Head To furnish all the analysis reports for compilation.
4. QA Head Final Authorization of the report.
6 PROCEDURE:
  During execution of 3 consecutive batches of the product as per the Batch Manufacturing Record, sampling at critical stages was done as per the protocol. Results of all parameters have to be compiled in this report.

 
7. PRODUCT DETAILS:
   

Product Name : Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup
Composition  

:

 Each 5ml contains:

Terbutaline Sulphate               IP 1.25mg

Ambroxol HCl                                    IP 15mg

Guaiphenesin                          IP 50mg

Menthol                                   IP 2.5mg

In a Flavoured Syrupy base         q.s.

Colour: Sunset Yellow FCF
Shelf Life : 24 months from the date of manufacturing.
No. Of Batches to be Considered for Validation : 03 Batches
Net fill volume : 60 ml.
Batch Size : 1000 Ltr.
Type of Validation : Concurrent
8. BATCHES SELECTED FOR VALIDATION STUDY:

S. No. Batch No. Batch Size Mfg. Date Exp. Date
       1.        
       2.        
       3.        
9. REFERENCE DOCUMENTS

 

1 Analytical Reports (Raw materials, In-process & Finished product)
2 Batch Manufacturing Records & Master Formula Record.

 

 

 

 
10. LIST OF RAW MATERIAL FOR FORMULATION:

RAW MATERIALS FOR BATCH SIZE: 1000 Ltr.
   

S. No. Ingredients Spec. Label Claim Quantity required

(1000 ltr.)
1 Terbutaline Sulphate* IP 1.25mg  
2 Ambroxol HCl* IP 15mg  
3 Guaiphenesin* IP 50mg  
4 Menthol* IP 2.5mg  
5 Sugar IP —  
6 Citric Acid Monohydrate IP —  
7 Xantham Gum (Gyp Gr) USP —  
8 Sodium Benzoate IP —  
9 Bronopol IP —  
10 Aspartam IP —  
11  Saccharin Sodium IP —  
12 Neotame IP —  
13 Citric acid mono IP —  
14 EDTA Sodium IP —  
15 Acrysol K-150 IP —  
16 Sunset Yellow Supra Colour IH —  
17 Orange Liquid Flavour IH —  
  *The Quantity of API may vary depending on potency / Assay & %LOD /Water/ Moisture content.

** The Quantity of Purified water may vary according to API.
11. MANUFACTURING PROCESS FLOW CHART: –

 

Equipment                                Critical Process                    Process Variables                  Tests

 

                                                                                                                            

                                                                                                                                                                             

pH

 

                                                                                                                                                           

                                                                                                                                         

 

 
12. EQUIPMENTS USED FOR PROCESS:

 

S. No. Equipment Name Equipment No. Capacity
1 Manufacturing Tank    
2 Storage Tank    
3 Storage Tank    
4 Pre mixing Tank    
5 Bottle filling and sealing machine    
13. QUALIFICATION STATUS OF EQUIPMENTS

 

S. No. Equipment Name         Equipment No. Qualification Status
1 Manufacturing Tank   Qualified
2 Storage Tank   Qualified
3 Storage Tank   Qualified
4 Pre mixing Tank   Qualified
5 Bottle filling and sealing machine   Qualified
14. Manufacturing Process:
  Raw Material weight verification:

The balance calibration & their record found well within the set acceptance. The weight of all the ingredients was verified as per bill of material given in batch manufacturing record & found satisfactory.
  Mixing:
  Mixing of the Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup with the specified ingredients has been done for 30, 40 & 50 minutes in manufacturing tank. Samples have been taken from 02 different locations (from Top and Bottom) for testing as per details given in the process validation protocol. The content of assay of Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup after 30-50 minute of mixing found well within the acceptance limit (90.0 to 110.0 % of labeled amount).
  Filling and Sealing:
  Samples were collected & tested from filling and sealing machine as per frequency set in the protocol. During filling and sealing, all the parameter found well within the acceptance criteria at a speed of 50 and 150 BPM. All the  parameter e.g. average net volume, uniformity of filled volume, pH, leak test were performed on the samples taken at initial, middle & end of filling and sealing process and found consistent & well within the limit prescribed in  the in-process specification of filling and sealing stage. The content of assay of Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup found well within the acceptance criteria (90-110% of the labeled amount respectively) at 50 & 150 BPM and at initial, middle and end of the filling and sealing process.
  For The Process Parameter:

 

Stage Standard Requirement Observation
Raw Material Dispensing As per bill of materials given in BMR Balance Calibration and raw materials weight found complies to the standard requirement
Mixing As per process validation protocol All the parameter found as per set acceptance criterion
Bottle Filling & Sealing As per process validation protocol All the parameter found as per set acceptance criterion
  For Analytical Parameter:

Stage Standard Requirement Observation
Mixing As per in process spec. & STP All analytical data found within specification limit
Bottle Filling & Sealing As per in process spec. & STP All analytical data found within specification limit
  During manufacturing & packing process temperature & relative humidity have been checked & found as per environment requirement.
15. CRITICAL PROCESS PARAMETERS:

Step Sampling Plan Sampled Quantity

 

 Test Parameters &

Quality Control

 Acceptance Limits
Syrupy base  Preparation Determination on each sample, for temperature, & Clarity NA Solution of Clarity Clear solutions observed
Manufacturing After addition of all active / non-active completed, draw the sample after final mixing and volume make up Draw sample from Top and Bottom of tank for 30min,40min,50min Description Orange colour liquid.
pH 5.0 – 7.0
Wt. /ml 1.0±0.2gm/ml
Assay
Terbutaline Sulphate, 90.0% to 110.0%
Ambroxol HCl, 90.0% to 110.0%
Guaiphenesin 90.0% to 110.0%
Menthol 90.0% to 110.0%
Filter through Nylon cloth Solution clarity

 

 

 Visually Pre-integrity test Visually found ok
Post integrity test Visually found ok
Filtration Filtered solution After, and Before Pre-Filtration Test Visually found ok
Filling & Sealing Initial, middle & End time of filling. Sample size:

One  bottles at each nozzle,

 

 Volume and

Quality sealing

  

 

Ok

 
Leak Testing After every hour As per Batch Complete seal To be Complies
Visual Inspection At start time of visual,

Middle and end time

 —- Clarity free from black particle, white particle, Fiber, Sealing rejects, Breakage
16. SAMPLING, TEST PARAMETERS, ACCEPTANCE CIRTERIA:

 

Step Sampling Plan

 

 Sampled Quantity

 

 

 Test Parameters &

Quality Control

 Acceptance Limits
Sugar Syrup Preparation Determination on each sample, for temperature, & Clarity NA Solution of Clarity Clear solutions observed
Manufacturing After addition of all active / non-active completed, draw the sample after final mixing and volume make up Draw sample from Top and Bottom of tank for 30min,40min,50min Description Orange colour liquid.
pH 5.0 – 7.0
Wt. /ml 1.0±0.2gm/ml
Assay
Terbutaline Sulphate, 90.0% to 110.0%
Ambroxol HCl, 90.0% to 110.0%
Guaiphenesin 90.0% to 110.0%
Menthol 90.0% to 110.0%
Filter through Nylon cloth  

Solution clarity

 

 

 Visually Pre-integrity test Visually found ok
Post integrity test Visually found ok
Filtration Filtered solution After, and Before Pre-Filtration Test Visually found ok
Filling & Sealing Initial, middle & End time of filling. Sample size:

One  bottles at each nozzle,

 Volume and

Quality sealing

  

 

Ok

 
Leak Testing After every hour As per Batch Complete seal To Complies
Visual Inspection At start time of visual,

Middle and end time

 —- Clarity free from black particle, white particle, Fiber, Sealing rejects, Breakage

 

 

 

 

Where:

TL: Top Left

TC: Top centre

TR: Top Right

CL: Centre Left

CC: Centre Centre

CR: Centre Right

LC: Lower Centre

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Target 10.00 ml 30.00 ml 50.00 ml 60.00 ml 100.00 ml
Minimum 10.00 ml 30.00 ml 50.00 ml 60.00 ml 100.00 ml
Maximum 10.50 ml 32.00 ml 53.00 ml 63.00 ml 103.00 ml

 
17. CERTIFICATE OF ANALYSIS:
  Certificate of analysis for under process validation study below the table maintained

 

Sr. No. Tests Specification
1 Description Orange colour liquid.
ASSAY: Each 5ml contains,
1 Terbutaline Sulphate, 90.0% to 110.0 %
2 Ambroxol HCl, 90.0% to 110.0 %
3 Guaiphenesin 90.0% to 110.0 %
4 Menthol 90.0% to 110.0 %
18. MIXING TIME VALIDATION: 

BATCH NO:

Assay (in %) Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup
Specified Time 30 minutes 40 minutes 50 minutes
Sampling points Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol
Top                        
Bottom                        
  BATCH NO:

Assay (in %) Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup
Specified Time 30 minutes 40 minutes 50 minutes
Sampling points Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol
Top                        
Bottom                        
  BATCH NO:

Assay (in %) Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup
Specified Time 30 minutes 40 minutes 50 minutes
Sampling points Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol Terbutaline Sulphate Ambroxol HCl Guaiphenesin Menthol
Top                        
Bottom                        
19. MACHINE SET UP & FILLING & SEALING CHECKS:

BOTTLE FILLING AND SEALING M/C ID: 

BATCH NO:    
TEST MACHINE SPEED (BOTTLE/MINUTE): ………… BPM
50 BPM

(Low speed)

 100 BPM

(Optimum speed)

 150 BPM

(High speed)
Description      
Average net volume      
Uniformity of filled volume      
pH      
Leak test      
Assay (in %)
Terbutaline Sulphate      
Ambroxol HCl      
Guaiphenesin      
Menthol      
 
BATCH NO:    
TEST MACHINE SPEED (BOTTLE/MINUTE): ………… BPM
50 BPM

(Low speed)

 100 BPM

(Optimum speed)

 150 BPM

(High speed)
Description      
Average net volume      
Uniformity of filled volume      
pH      
Leak test      
Assay (in %)
Terbutaline Sulphate      
Ambroxol HCl      
Guaiphenesin      
Menthol      
 
BATCH NO:    
TEST MACHINE SPEED (BOTTLE/MINUTE): ………… BPM
50 BPM

(Low speed)

 100 BPM

(Optimum speed)

 150 BPM

(High speed)
Description      
Average net volume      
Uniformity of filled volume      
pH      
Leak test      
Assay (in %)
Terbutaline Sulphate      
Ambroxol HCl      
Guaiphenesin      
Menthol      
  BOTTLE FILLING AND SEALING M/C:

BATCH NO:    
TEST FILLING AND SEALING RUN
Initial

 

 Middle

 

 End

 
Description      
Average net volume      
Uniformity of filled volume      
pH      
Leak test      
Assay (in %)
Terbutaline Sulphate      
Ambroxol HCl      
Guaiphenesin      
Menthol      
 
BATCH NO:    
TEST FILLING AND SEALING RUN
Initial

 

 Middle

 

 End

 
Description      
Average net volume      
Uniformity of filled volume      
pH      
Leak test      
Assay (in %)
Terbutaline Sulphate      
Ambroxol HCl      
Guaiphenesin      
Menthol      
 
BATCH NO:    
TEST FILLING AND SEALING RUN
Initial

 

 Middle

 

 End

 
Description      
Average net volume      
Uniformity of filled volume      
pH      
Leak test      
Assay (in %)
Terbutaline Sulphate      
Ambroxol HCl      
Guaiphenesin      
Menthol      
20. STABILITY STUDY SAMPLES:

Three Consecutive validated batches of Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup shall be subjected for Stability Study at following conditions:

  1. Accelerated Stability Study at condition 40 + 20 C, RH 75% + 5% for period of 0,3 and 6 months. Sample qty.-Require 10 bottle for each station.

2.      Long Time stability study at condition 30 + 20 C, RH 75% + 5% for period of 3, 6, 9, 12, 18, 24, months. MLT Performed 0, 3, 6, 9, 12, 18, 24 months. Sample qty.-Require 10 bottle for each station.
21. ACCEPTANCE CRITERIA:
  The process validation study of Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup shall be carried out on three Consecutive commercial batches following parameters shall be considered as acceptance criteria for process validation study
  These batches shall be manufactured & complied as per Master Production and Control records.
  The equipment utilized for the manufacturing and processing of these batches shall be as per list of qualified equipment’s mentioned in Master Production and Control Record.
  The raw material used for manufacturing process shall be produced from approved vendors only and shall be approved by Quality Control.
  The critical process parameters of the process shall be evaluated with respect to quality attributes of the products
  Sampling for in-process control samples is to be carried as per established sampling plan.
  Critical in-process control shall be evaluated with respect to the laid down specifications.

Finished drug product of these Batches shall be analyzed and meet as per Pre determined specification & it shall be in compliance with the same.
22. CHANGE CONTROL / REVALIDATION CRITERIA:
  The manufacturing process for the Terbutaline Sulphate, Ambroxol HCl, Guaiphenesin and Menthol Syrup Syrup shall be revalidated when there is change in following parameters.

1.      Change in facilities or plant.

2.      Change or replacement in a critical piece of equipment.

3.      Change in source of active pharmaceutical ingredient.

4.      Change in batch size.

5.      Sequential batches that fail to meet product and process specification on the basis of trend analysis data of one year.
  The implementation of these changes shall be carried out through change control system.
23. DEVIATION:

In case of any deviation(s) are observed they shall be noted down in the deviation report immediately. The deviation shall be noted in succession throughout the process along with the corrective action.

 
24. EVALUATION OF THE RESULTS:
  After review, the results shall be evaluated for achievement of the acceptance criteria. In case of any deviation, effect of deviation shall be evaluated on the process and quality of the product.
25. Yield:

The yield after filling and sealing was ……………% and it was well within the acceptance criteria (NLT 98.0%).
26. Summary & Conclusion:

 

 
27. POST APPROVAL:
  Prepared By:

 

Functional Area Name Designation Signature/Date
Quality Assurance      

 

Checked By:

 

Functional Area Name Designation Signature/Date
 Quality Assurance      
Head Production      
Head-Quality Control      

 

Approved By:

 

Functional Area Name Designation Signature/Date
Head-QA      

 

Analytical Method Validation