SOP for Preparation of Nasal Sprays for Targeted Brain Delivery

Standard Operating Procedure for Preparation of Nasal Sprays for Targeted Brain Delivery

1) Purpose

This SOP outlines the procedures for preparing nasal sprays that are specifically designed for targeted brain delivery. Such formulations aim to bypass the blood-brain barrier, utilizing the nasal-to-brain route for direct drug transport to the central nervous system (CNS).

2) Scope

This SOP applies to all personnel involved in the formulation, preparation, and quality control of nasal sprays intended for targeted brain delivery at [Company Name].

3) Responsibilities

Operators: Responsible for following specific guidelines for formulating nasal sprays for brain-targeted delivery, ensuring proper API incorporation and stability.
Quality Assurance (QA): Ensures that the nasal spray formulation meets the necessary requirements for CNS delivery, including particle size and drug release profile.
Maintenance Team: Responsible for maintaining and calibrating equipment used for manufacturing nasal sprays for brain delivery.

4) Procedure

4.1 Selection of Ingredients

4.1.1 Brain-Targeted API and Excipients

Select APIs that can effectively cross or interact with the nasal pathway to target the brain. These APIs should have demonstrated efficacy in CNS delivery through nasal administration.
Choose excipients that enhance permeability through the nasal epithelium and provide stability to the API during nasal-to-brain transport. Consider incorporating permeation enhancers, mucoadhesive agents, or nanoparticles for effective delivery.

4.1.2 Weighing of Ingredients

Weigh APIs and excipients using a calibrated balance, ensuring that the measured quantities fall within ±2% of the target weight. Record the weight in the Batch Manufacturing Record (BMR).

4.2 Mixing and Formulation

4.2.1 Preparing the Aqueous Phase

Dissolve the excipients (e.g., permeation enhancers, stabilizers, mucoadhesive agents) in Water for Injection (WFI) at room temperature, ensuring all excipients are fully dissolved.
Stir gently to avoid introducing air bubbles into the formulation.

4.2.2 Incorporating the API

Add the brain-targeted API to the aqueous phase while stirring continuously. Use a homogenizer or sonicator to ensure uniform dispersion of the API in the solution.
If necessary, use nanoparticle encapsulation or liposomal carriers to enhance drug delivery efficiency. Record the mixing parameters, such as time, speed, and temperature, in the BMR.

4.2.3 pH and Osmolality Adjustment

Measure and adjust the pH to fall within the physiological range (pH 5.5-7.0) suitable for nasal administration. Use a calibrated pH meter.
Check the osmolality of the solution to ensure it is isotonic (280-320 mOsm/kg) for safe nasal administration.
Record the pH and osmolality adjustment processes in the BMR.

4.3 Filtration and Sterilization

4.3.1 Filtration Process

Filter the nasal spray formulation through a 0.22-micron sterile filter to remove any microbial contamination.
Record the filtration process and the filter integrity test results in the BMR.

4.4 Filling and Packaging

4.4.1 Filling Process

Transfer the sterile formulation to a calibrated filling machine. Ensure that the machine is set to dispense the appropriate volume per spray (e.g., 50 µL or 100 µL).
Weigh 10 randomly selected filled containers to check fill accuracy, ensuring that the variance is within ±2% of the target volume. Record the results in the BMR.

4.4.2 Sealing and Packaging

Seal the filled containers with pre-sterilized nasal spray nozzles or caps. Ensure the packaging is secure, leak-proof, and labeled with batch numbers, expiration dates, and instructions for use.
Package the nasal sprays in secondary packaging with appropriate storage and transportation instructions.

4.5 Quality Control Testing

4.5.1 Drug Release Profile Testing

Test the in-vitro release profile of the API using an appropriate nasal delivery simulation to confirm that the drug is released in a controlled manner for targeted brain delivery.
Record the drug release profile data in the release profile log.

4.5.2 Stability Testing

Conduct stability testing under various environmental conditions to ensure the formulation remains stable over time. Record the stability test results in the stability testing log.

4.6 Documentation

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

4.7 Equipment Cleaning and Calibration

4.7.1 Equipment Calibration

Calibrate all equipment, including balances, pH meters, osmometers, and filling machines, as per the calibration schedule. Record the calibration data in the calibration log.

4.7.2 Cleaning Equipment

Clean and sterilize all equipment used in the formulation and filling processes according to the cleaning validation protocol. 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)
Drug Release Profile Log
Stability 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. Drug Release Profile Log Template


  
    Date
    Formulation
    Release Time (hours)
    Released API (%)
    Test Method
    Operator Initials
    QA Approval
  
  
    DD/MM/YYYY
    Formulation Name
    Time
    API Released
    Method
    Operator Name
    QA Name

Date	Formulation	Release Time (hours)	Released API (%)	Test Method	Operator Initials	QA Approval
DD/MM/YYYY	Formulation Name	Time	API Released	Method	Operator Name	QA Name

2. Stability Testing Log Template


  
    Date
    Formulation
    Storage Conditions
    Time Interval
    Stability Results
    Operator Initials
    QA Approval
  
  
    DD/MM/YYYY
    Formulation Name
    Temperature and Humidity
    1 month, 3 months, etc.
    Pass/Fail
    Operator Name
    QA Name

Date	Formulation	Storage Conditions	Time Interval	Stability Results	Operator Initials	QA Approval
DD/MM/YYYY	Formulation Name	Temperature and Humidity	1 month, 3 months, etc.	Pass/Fail	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