Process Validation Protocol for Oral Rehydration Salt

PRODUCT	Oral Rehydration Salts
LOCATION	PharmaGuide Limited (ORS Section)
BATCH SIZE	1000 Sachets
DOSAGE FORM	Powder (Sachet)
PROTOCOL NUMBER
PRODUCT CODE
SHELF LIFE	24 Months

LABEL CLAIM:

Each Sachet contains: Sodium Chloride BP 2.6 gm., Glucose anhydrous BP 13.5 gm., Potassium Chloride BP 1.5 gm., Trisodium Citrate, Dihydrate BP 2.9 gm.

PREPARED BY

DEPARTMENT	NAME	SIGNATURE	DATE
QA Executive

REVIEW BY

DEPARTMENT	NAME	SIGNATURE	DATE
QA Manager

APPROVED BY

DEPARTMENT	NAME	SIGNATURE	DATE
Pharmacist In-Charge

TABLE OF CONTENT

1. Introduction
2. Objective
3. Label claim
4. Scope
5. Responsibilities
6. Reference documents
7. Manufacturing formula
8. Process flow chart
9. Rationale for selection of critical steps and its process parameters for validation
10. List of equipment's and status
11. Validation procedure
12. Sampling procedure at different stage
13. Acceptance criteria for critical in-process controls and sampling plan
14. Prerequisites of process validation
15. Yield details
16. Process validation report
17. Deviation
18. Revalidation

1. INTRODUCTION

Sachets being manufactured at PharmaGuide Limited, so product needs to be validated for all critical stages.

ALSO READ: SOP for Concurrent Process Validation

2. OBJECTIVE

To establish documented evidence, which provides a high degree of assurance that the manufacturing process will consistently produce Sachets meeting its predetermined acceptance criteria and quality attributes.

3. LABEL CLAIM

Each sachet contains:

1. Sodium Chloride BP 2.6 gm.,
2. Glucose, anhydrous 13.5 gm.,
3. Potassium Chloride BP 1.5 gm.,
4. Trisodium Citrate Dihydrate BP 2.9 gm.

4. SCOPE

The scope of this protocol is applicable to the validation of manufacturing process of Sachets to be carried out at PharmaGuide Limited.

If any batch (es) fails due to process extrinsic causes or deviations from the batch manufacturing record / protocol the batch (es) will be disqualified for validation purpose and next three consecutive batches shall considered for validation.

5. RESPONSIBILITIES

Validation: To prepare, review and approve the process validation protocol and report.

Production: Execution of manufacturing process during validation.

Quality control: To analyze validation samples.

Pharmacist in Charge: To review the protocol and report from regulator perspective

Quality assurance: To monitor the validation activity and sampling as per the sampling plan of protocol, Review and approval of process validation protocol and report.

6. REFERENCE DOCUMENTS

Batch Manufacturing Record : 

Raw Material Specifications : As mentioned in the Manufacturing Formula

Finished Product Spec : 

Analytical Method : As per BP

7. MANUFACTURING FORMULA

Item code	Item	RM Specification No. #	Quantity / Sachet (gm.)	Quantity / Batch (Kg)	Function
	Glucose Anhydrous		13.500	13.500	Active ingredient
	Trisodium citrate, Dihydrate		2.900	2.900	Active ingredient
	Potassium Chloride		1.500	1.500	Active ingredient
	Sodium Chloride		2.600	2.600	Active ingredient

8. PROCESS FLOW CHART

9. RATIONALE FOR SELECTION OF CRITICAL STEPS AND ITS PROCESS PARAMETER FOR VALIDATION:

Blending: 

• This step involves mixing of sifted raw material. The purpose of blending is to get a uniform distribution of Sodium Chloride BP 2.6 gm., Glucose anhydrous 13.5 gm., Potassium Chloride BP 1.5 gm., Trisodium Citrate Dihydrate BP 2.9 gm. 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.
• Proper blending shall be established b checking content uniformity of drug at all the time intervals mentioned in protocol.
• 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. Assay
2. LOD

ALSO READ: Difference between Qualification and Validation

Sachet filling and sealing

• This step involves filling of blended material fill into sachets 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.

1. Appearance of sachets
2. Physical Appearance
3. Identification
4. pH
5. Loss on drying
6. Individual weight variation
7. Sealing of sachets
8. Leak test
9. Batch coding details
10. Assay

10. LIST OF EQUIPMENTS

S. No.	Equipment Name
1	Sifter
2	Double Cone Blender
3	Form Fill Seal Machine
4	Printing machine

11. VALIDATION PROCEDURE

• Three batches of 1000 Sachets to be manufactured as described in the Batch Manufacturing Record.
• Current version of standard operating procedures to be followed
• Record the yield after Blending, filling, Inspection and Packing.

12. SAMPLING PROCEDURE AT DIFFERENT STAGES

Note: Collect samples for content uniformity in three sets. One set of sample to be taken for analysis and other two sets are to be kept as a reserve sample. In case results are failed, use one set of the reserved sample set for analysis, otherwise, discard the reserve sample set.

Blending

Load sifted materials into the Double Cone Blender as per BMR. Start the blender in inch mode and check for any leakage of material. On ensuring that there is no leakage, blend for 25 and 30 minutes. Samples to be drawn from 3 locations from the blender. Collect samples step no.13.0 using sampling rod. The sample quantity shall be between 20.5g ± 1 g

Sachet filling

Sachet filling to be carried out as per batch manufacturing record form fill seal machine

Type of Machine: 

Automatic pouch form, fill and sealing machine

Carry out the testing of physical parameters as mentioned in the table.

Sr. No	Parameter	Standard	Number of Sachets to be taken for testing
1	Sachet Fill Weight	20.5 mg ± 5 % (19.50 gm. to 21.5 gm.)	20 Sachets
2	Batch Coding Details	Batch No., Mfg. Date, Exp. date	20 Sachets
3	Sachet sealing	Should be proper without leakage	20 Sachets
4	Leak test	Should not leak	5 Sachets

Run the Semi-auto capsule filling machine tablet speed at different speeds of 60 Sachets/Minute and collect the samples for physical appearance, identification, pH, loss on drying, uniformity of weight and assay testing at start of filling, middle and end of the filling.

ALSO READ: SOP for Continued Process Verification

13. ACCEPTANCE CRITERIA FOR CRITICAL INPROCESS CONTROL AND SAMPLING

PLAN: The below table gives the stage wise critical process variables (Parameters), and in-process controls (Acceptance Criteria) different tests with sample size and responsibility.

Stage	Process variables	Time	Tests to be performed	Approximate sample size	Acceptance criteria	Responsibility
Blending	Blending time	25 & 30 minutes	assay	3x3 samples each between 20.5±1 gm.	100 ± 10 % RSD NMT 5.0%	Production/QA / QC
Sachet filling machine	Speed of the machine	Batch start	Avg. wt., flow of powder, pH, Clarity, Leak test, Sealing of sachets, appearance, uniformity of weight and assay	25 Sachets	As per specification	Production / QA/QC
		Batch middle		25 Sachets
		Batch end		25 Sachets

14. PREREQUISITES OF PROCESS VALIDATION

• The batches shall be manufactured as per Batch Manufacturing Record.
• The equipment's utilized for manufacturing and processing of these batches shall be as per list of Equipment's.
• The raw material used for manufacturing shall be from approved vendors and shall be released 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 shall be carried as per established sampling procedure and plan.
• Critical in-process control shall be evaluated with respect to the laid down specification.
• Finished drug product of these batches shall be analyzed as per laid down test procedures and comply with respect to the predetermined specifications.

15. YIELD DETAILS

Record the yield at every stage as mentioned below.

Blending, Sachet filling, Inspection and Packing.

16. PROCESS VALIDATION REPORT

The process validations report shall be prepared by compiling the analytical results and raw data generated during validation. Analytical results and raw data shall be verified against acceptance criteria. A comparative report of validation data obtained, shall be prepared and checked by Validation (QA executive, Production, Quality Control Manager, and Quality Assurance shall approve this report.

17. DEVIATION

If there is any deviation with respect to the procedure mentioned in the protocol / BMR / BPR that shall be recorded in BMR / BPR and Report.

18. REVALIDATION

The manufacturing process of Sachets (Oral Rehydration Salts) shall be revalidated in one or more of following cases

• Change of formulation procedures or quality of pharmaceutical ingredients.
• Change of equipment, addition of new equipment, major breakdowns / maintenance that affect the performance of equipment's.
• Major changes of process parameters.
• Change in facilities.
• On appearance of negative quality trends.
• On appearance of new findings based on current knowledge.
• Batch size change.

Implementation of these changes shall be carried out as per change control system.

ALSO READ: Process Validation Protocol Template for Capsule Dosage Form