SOP for Preparing Nasal Sprays with Hydrophilic APIs

Standard Operating Procedure for Preparing Nasal Sprays with Hydrophilic APIs

1) Purpose

The purpose of this SOP is to outline the procedures for preparing nasal sprays containing hydrophilic active pharmaceutical ingredients (APIs). Hydrophilic APIs readily dissolve in water, making them suitable for aqueous nasal spray formulations.

2) Scope

This SOP applies to all personnel involved in the formulation, preparation, and quality control of nasal sprays containing hydrophilic APIs at [Company Name]. It ensures compliance with internal and regulatory standards for nasal drug delivery.

3) Responsibilities

Operators: Responsible for formulating nasal sprays with hydrophilic APIs, ensuring proper dissolution and homogeneous distribution of the API.
Quality Assurance (QA): Ensures that the final product meets quality standards, including API dissolution, pH, and sterility requirements.
Maintenance Team: Responsible for maintaining and calibrating equipment used in the formulation process.

4) Procedure

4.1 Selection of Ingredients

4.1.1 Hydrophilic API Selection

Select a hydrophilic active pharmaceutical ingredient (API) that is suitable for nasal delivery. The API should have adequate solubility in water to ensure complete dissolution in the nasal spray formulation.
Choose excipients such as buffers, stabilizers, and

preservatives that enhance the stability of the hydrophilic API without causing irritation to the nasal mucosa.

4.1.2 Weighing and Handling of Ingredients

Weigh the API and excipients using a calibrated balance. Ensure that all ingredients are weighed to within ±2% of the target weight. Document the measured quantities in the Batch Manufacturing Record (BMR).
Ensure the formulation area is free from contaminants to prevent cross-contamination during ingredient handling.

4.2 Mixing and Formulation

4.2.1 Preparing the Aqueous Phase

Dissolve the excipients (e.g., buffers and preservatives) in Water for Injection (WFI). Ensure that the solution is free from air bubbles and foam by stirring gently.
Maintain the solution at a controlled temperature (20-25°C) to ensure proper dissolution of the excipients.

4.2.2 Incorporating the Hydrophilic API

Add the hydrophilic API to the aqueous phase. Stir continuously to ensure that the API dissolves completely in the solution. If necessary, use a magnetic stirrer to achieve uniform dissolution.
Check for the absence of undissolved particles using a visual inspection or filtration method. Record the mixing parameters in the BMR.

4.2.3 pH Adjustment

Measure the pH of the solution using a calibrated pH meter. Adjust the pH using a buffer solution to match the optimal pH range for nasal administration (typically pH 4.5-7).
Record the pH adjustment process, including the initial and final pH values, in the BMR.

4.3 Filtration and Sterilization

4.3.1 Sterilization of Equipment

Ensure that all equipment used in the formulation and filling process, including mixing vessels and filling machines, is sterilized using autoclaving or other validated methods.

4.3.2 Filtration of the Formulation

Filter the nasal spray formulation through a 0.22-micron filter to remove microbial contaminants and ensure sterility.
Record the filtration process, including the integrity test of the filter, in the BMR.

4.4 Filling and Packaging

4.4.1 Filling Process

Transfer the sterile formulation to a filling machine. Fill each nasal spray container with the required volume (e.g., 100 µL per spray), ensuring that each unit is filled accurately and consistently.
Test the fill accuracy by weighing a sample of 10 filled containers. Ensure that the fill accuracy is within ±5% of the target volume. Record the results in the BMR.

4.4.2 Sealing and Packaging

Seal the filled containers with sterile 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 appropriate secondary packaging that protects the product from environmental factors such as light and humidity.

4.5 Quality Control Testing

4.5.1 API Content Uniformity

Test the content uniformity of the API in the nasal spray formulation to ensure that each spray contains the appropriate amount of API. Perform this test on a sample of 10 units.
Record the API content uniformity results in the content uniformity log.

4.5.2 Sterility Testing

Perform sterility testing on the final product to ensure that it is free from microbial contamination. Use validated methods for sterility testing such as membrane filtration.
Record the sterility test results in the microbial testing log.

4.6 Documentation

Document all steps of the formulation, mixing, pH adjustment, filtration, and filling processes in the BMR.
Ensure QA reviews and approves all documentation before the batch is released for distribution.

4.7 Equipment Cleaning and Calibration

4.7.1 Equipment Calibration

Calibrate all equipment used in the formulation process, including balances, pH meters, and filling machines, according to the calibration schedule. Record the calibration data in the calibration log.

4.7.2 Cleaning Equipment

Follow the cleaning validation protocol to clean and sterilize all equipment used in the formulation and filling processes. Document the cleaning process in the cleaning log.

5) Abbreviations, if any

API: Active Pharmaceutical Ingredient
QA: Quality Assurance
BMR: Batch Manufacturing Record
WFI: Water for Injection

6) Documents, if any

Batch Manufacturing Record (BMR)
Content Uniformity Log
Microbial Testing Log
Calibration Log
Cleaning Log

7) References, if any

ICH Q6A – Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products
FDA Guidance for Nasal Drug Products

8) SOP Version

Version 1.0

Annexure

1. Content Uniformity Log Template


  
    Date
    Formulation
    API Content (mg/spray)
    Test Method
    Operator Initials
    QA Approval
  
  
    DD/MM/YYYY
    Formulation Name
    API Content
    Method
    Operator Name
    QA Name

Date	Formulation	API Content (mg/spray)	Test Method	Operator Initials	QA Approval
DD/MM/YYYY	Formulation Name	API Content	Method	Operator Name	QA Name

2. Microbial Testing Log Template


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

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

3. Calibration Log Template


  
    Date
    Equipment ID
    Calibration Procedure
    Calibration Results
    Operator Initials
    QA Approval
  
  
    DD/MM/YYYY
    Equipment Name/ID
    Procedure
    Pass/Fail
    Operator Name
    QA Name

Date	Equipment ID	Calibration Procedure	Calibration Results	Operator Initials	QA Approval
DD/MM/YYYY	Equipment Name/ID	Procedure	Pass/Fail	Operator Name	QA Name

4. Cleaning Log Template


  
    Date
    Equipment ID
    Cleaning Procedure
    Operator Initials
    QA Approval
  
  
    DD/MM/YYYY
    Equipment Name/ID
    Procedure
    Operator Name
    QA Name