Nasal Spray Formulations : SOP for Manufacturing Nasal Sprays for Pediatric Use

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SOP for Manufacturing Nasal Sprays for Pediatric Use

Standard Operating Procedure for Manufacturing Nasal Sprays for Pediatric Use

1) Purpose

The purpose of this SOP is to outline the process of manufacturing nasal sprays formulated specifically for pediatric patients, taking into account the safety, dosage, and specific regulatory requirements for this patient population.

2) Scope

This SOP applies to personnel involved in the formulation, preparation, testing, and packaging of nasal sprays intended for pediatric use at [Company Name].

3) Responsibilities

Operators: Responsible for accurately weighing and mixing ingredients according to pediatric-specific formulations.
Quality Assurance (QA): Ensures the pediatric nasal spray meets regulatory standards and quality control specifications, including safety and dosage limits.
Maintenance Team: Responsible for ensuring all equipment used in the formulation process is clean, sterilized, and calibrated.

4) Procedure

4.1 Preparation of Materials

4.1.1 Selection of Ingredients

Select ingredients that are safe for pediatric use. The active pharmaceutical ingredient (API) must be selected based on efficacy and safety data specific to pediatric patients.
Use appropriate excipients that are free from preservatives, irritants, or other components that may cause adverse reactions in pediatric patients.

4.1.2 Weighing of Ingredients

Weigh the API and excipients using a calibrated balance. Ensure that the API concentration is appropriate for pediatric use, typically lower than adult formulations.
Document the weighed amounts in the batch manufacturing record (BMR).

4.2 Mixing and Formulation

4.2.1 Mixing the Aqueous Phase

Prepare the aqueous phase by dissolving excipients such as buffers and stabilizers in water. Use pre-sterilized water for injection (WFI) to ensure sterility.
Maintain the mixing temperature between 20-25°C to avoid degradation of sensitive ingredients.

4.2.2 Incorporating the Active Ingredient

Slowly add the API to the aqueous phase while stirring continuously. Ensure that the API dissolves completely and uniformly.
Use a homogenizer if necessary to ensure even distribution of the API throughout the solution.
Record the stirring speed, time, and temperature in the BMR.

4.2.3 pH Adjustment

Adjust the pH of the formulation using pre-approved buffers. Ensure that the final pH is within the specified range (typically pH 4.5-7) for pediatric nasal administration.
Test the pH and record the results in the BMR.

4.3 Filtration and Sterilization

4.3.1 Filtration Process

Filter the prepared formulation through a 0.22-micron sterilizing filter to remove any microbial contaminants or particulates.
Document the filtration process, including the filter integrity test, in the BMR.

4.3.2 Sterilization

Ensure that all equipment, containers, and closures used in the filling process are pre-sterilized using autoclaving or another validated sterilization method.

4.4 Filling and Packaging

4.4.1 Filling Process

Transfer the sterile nasal spray formulation into a filling machine. Set the machine to dispense the pediatric dose (e.g., 50 µL per spray).
Test the fill accuracy by weighing 10 randomly selected filled containers. Ensure that the variation does not exceed ±5% of the target volume.
Document the fill weight results in the BMR.

4.4.2 Packaging and Labeling

Seal the containers with sterile nasal spray nozzles or caps. Ensure that the containers are leak-proof and properly labeled with batch numbers, expiration dates, and storage instructions.
Package the nasal sprays in child-resistant secondary packaging to ensure safety during storage and handling.

4.5 Quality Control Testing

4.5.1 Microbiological Testing

Conduct microbiological testing to ensure the pediatric nasal spray is free from microbial contamination. Perform tests such as total microbial count and endotoxin testing.
Record the results in the microbiological testing log.

4.5.2 Dosage Testing

Test the dosage accuracy of the nasal spray by dispensing a set number of sprays into a graduated cylinder. Ensure that the dose falls within the specified range for pediatric use.
Document the dosage test results in the dosage testing log.

4.6 Documentation

Document all steps of the pediatric nasal spray manufacturing process, including ingredient weighing, mixing, pH adjustment, filtration, and filling, in the BMR.
Ensure that QA reviews and approves all documentation before the product is released for distribution.

4.7 Equipment Cleaning and Calibration

Calibrate all equipment, including balances, homogenizers, and filling machines, according to the calibration schedule. Document the calibration results in the calibration log.
Clean and sterilize all equipment according to the cleaning validation protocol to prevent cross-contamination between batches.

5) Abbreviations, if any

API: Active Pharmaceutical Ingredient
QA: Quality Assurance
BMR: Batch Manufacturing Record

6) Documents, if any

Batch Manufacturing Record (BMR)
Microbiological Testing Log
Dosage Testing Log
Calibration Log
Cleaning Log

7) References, if any

ICH Q1A – Stability Testing Guidelines
FDA Guidance for Nasal Drug Products
Pediatric-specific Regulatory Guidelines

8) SOP Version

Version 1.0

Annexure

1. Microbiological Testing Log Template

Date	Formulation	Microbial Test	Results	Operator Initials	QA Approval
DD/MM/YYYY	Formulation Name	Microbial Test	Results	Operator Name	QA Name

2. Dosage Testing Log Template

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Date	Formulation	Dosage Volume (µL)	Test Method	Operator Initials	QA Approval
DD/MM/YYYY	Formulation Name	Volume	Method	Operator Name	QA Name

3. Calibration Log Template

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Standard Operating Procedure for Manufacturing Nasal Sprays for Pediatric Use

1) Purpose

The purpose of this SOP is to describe the step-by-step process for the preparation, formulation, and packaging of nasal sprays designed specifically for pediatric patients, ensuring safety, proper dosage, and regulatory compliance for this sensitive age group.

2) Scope

This SOP applies to all personnel responsible for the formulation, testing, and packaging of pediatric nasal sprays at [Company Name]. It ensures that formulations meet the pediatric safety and efficacy standards set forth by regulatory bodies.

3) Responsibilities

Operators: Responsible for measuring, mixing, and filling ingredients according to pediatric-specific requirements.
Quality Assurance (QA): Ensures product meets quality and safety standards, including microbial and chemical stability, before product release.
Maintenance Team: Ensures all equipment used in the formulation is sterilized, calibrated, and functioning properly.

4) Procedure

4.1 Preparation of Materials

4.1.1 Selection of Ingredients

Choose pediatric-safe active pharmaceutical ingredients (APIs) with known safety and efficacy profiles for this age group.
Use excipients that are non-toxic and do not cause irritation in pediatric patients. Preservatives should be minimized or avoided when possible.

4.1.2 Weighing of Ingredients

Weigh the API and excipients using a calibrated balance with precision. Ensure the concentration of the API is appropriate for the pediatric population and document it in the Batch Manufacturing Record (BMR).

4.2 Mixing and Formulation

4.2.1 Preparing the Aqueous Phase

Mix the excipients such as buffers and stabilizers into Water for Injection (WFI) in a sterile vessel.
Maintain the solution at a controlled temperature (20-25°C) to prevent degradation of sensitive ingredients.

4.2.2 Incorporation of API

Gradually add the API into the aqueous phase while continuously stirring. Ensure that the API is fully dissolved or dispersed in the formulation.
Use a homogenizer if necessary to achieve uniform distribution of the API.
Record the mixing parameters such as speed, time, and temperature in the BMR.

4.2.3 pH Adjustment

Adjust the pH of the formulation to fall within the acceptable range for nasal administration (typically pH 5.5 - 6.5 for pediatric use) using pre-approved buffers.
Record pH adjustments and the final pH in the BMR.

4.3 Sterilization and Filtration

4.3.1 Sterilization of Equipment

Ensure that all equipment used in the formulation process is sterilized, including vessels, filling machines, and storage containers. Use autoclaving or other validated sterilization methods.

4.3.2 Filtration

Filter the nasal spray solution using a 0.22-micron filter to remove any microbial contaminants. Ensure the filter integrity is maintained throughout the process.
Document the filtration process in the BMR, including the filter integrity test.

4.4 Filling and Packaging

4.4.1 Filling the Nasal Spray Containers

Transfer the sterile formulation into a filling machine pre-calibrated for pediatric doses (e.g., 50 µL per spray).
Test the fill accuracy by randomly selecting and weighing 10 filled containers. The variation must not exceed ±5% of the target dose. Document the results in the BMR.

4.4.2 Sealing and Packaging

Seal the filled containers with pre-sterilized nozzles or caps. Inspect for any leaks or defects before proceeding to packaging.
Label each container with the appropriate batch number, expiration date, and storage instructions, ensuring child-resistant packaging is used to prevent accidental exposure.

4.5 Quality Control Testing

4.5.1 Microbial Testing

Conduct microbial tests, including sterility and endotoxin tests, to ensure the nasal spray meets pediatric safety standards.
Record all microbial test results in the microbial testing log.

4.5.2 Dosage Accuracy Testing

Perform dosage accuracy tests by dispensing a set number of sprays into a graduated cylinder. Ensure that the dispensed volume is within the accepted range for pediatric dosage.
Document the dosage accuracy results in the dosage testing log.