SOP for Concurrent Process Validation

PURPOSE

To define and document a procedure for Concurrent Process Validation.

SCOPE

This procedure is applicable to concurrent process validation of new or revised manufacturing processes of pharmaceutical product.

RESPONSIBILITIES

The delegation of responsibilities regarding the concurrent process validation activity is given as follows;

Product Development

Preparation of the validation protocol according to the BMR (Batch Manufacturing Record)
Communication with all the departments involved in the execution of the validation protocol
Manufacturing of the batches to be validated jointly with the Production team
Records generation, a compilation of data, and preparation of the validation report
Circulation of the validation report to all the concerned departments and personnel for approval

Production

Assist in the development of validation protocol
Check and review the validation protocol
Manufacturing of the batches to be validated and following the controls described in the protocol jointly with Product Development Team

Quality Control and MDV

Assist in the development of the validation protocol
Check and review the validation protocol
Providing analytical support by testing the validation batches
Communicate the results to the Product Development Department after testing
Carry out the stability study with the products obtained from the validation batches as per SOP.

IPQC

Assist in the development of the validation protocol
Check and review the validation protocol
Overall management of the in-process control and checks during the manufacturing of the validation batches

EDT

Approves the validation protocol
Approves the validation report for circulation

EDQO

Authorize the validation protocol
Approves the validation report for circulation

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PROCEDURE

PREPARATION AND EXECUTION OF THE CONCURRENT VALIDATION PROTOCOL

The main contents of the Concurrent Validation Protocol are:

Project description
Title page
Table of contents
Protocol description
Approvals
Distribution list
Responsibilities

Validation team
Execution team

B. Validation Protocol

Introduction
Purpose
Scope
Acceptance criteria
Validation batches
List of equipments and areas of manufacturing
Formulation details
Manufacturing process flow chart
In-process controls and checks with

Acceptance criteria
Frequency
Environmental controls

Processes validation
Granulation

Processing step
Purpose
Tests
Sampling plan
Acceptance criteria

Compression

Processing step
Purpose
Tests
Sampling plan
Acceptance criteria

Coating

Processing step
Purpose
Tests
Sampling plan
Acceptance criteria

Detail of each step of the validation protocol is given in the proceeding sections. A specimen protocol is also attached for reference.

For liquid products, validation of all the critical steps will be carried out in the same manner as described above.

A. Introduction

The introduction covers the following points

Product
Pharmacological classification
Indication
Manufacturing history (if required)
Justification for validation
Stability requirements (as per SOP)
Validation requirement (as per SOP)

B. Purpose

Concurrent Process Validation of the manufacturing process is conducted to ensure that the given manufacturing process is suitable to manufacture the Pharmaceutical Product.

C. Scope

This protocol covers all the operations involved in manufacturing of three consecutive commercial batches of a pharmaceutical product, from receiving the raw materials to the achievement of the Bulk Pharmaceutical Product.
The finished products obtained from the validated batches are subjected to Stability studies.

D. Acceptance Criteria

Stage wise suitability requirements or acceptance criteria are mentioned under this heading. For example:

Granulation: The granulation must comply with the HNL content uniformity specifications
Compression: The tablets must comply with the HNL specification for compression of that particular product
Coating: The coated tablets must comply with the HNL specification for coating of that particular product.

RSD (Relative Standard Deviation) limits for these processes are

< 4% - Readily passable
< 6% - Marginally passable

E. Validation Batches

The following details regarding the three validation batches must be provided

Batch number
Manufacturing date
Expiry date
Shelf life
Batch size

F. List of Equipments and Areas of manufacturing

The list consists of the following information

Equipment / Area
Number (Asset)
Qualification number

G. Formulation Details

Mention the following detail regarding the formulation:

Component
Material code
QC specification number
Manufacturer
Function
Percentage in the formulation
mg per tablet
kg per batch

H. Manufacturing process flow chart

The chart shows the diagrammatic overview of the manufacturing process.

I. In process control and checks with acceptance criteria and frequency

The various control parameters and their specifications are defined at each section in the experimental plan

In order to consider the process validated, the validation batches must comply with each and every specification included in the experimental plan
Any data outside specifications must be studied individually and recorded in the final report
Environmental control should also be monitored especially in case of sensitive products e.g. temperature and humidity

J. Process to be Validated

Any critical process or step that may affect the quality of the final product must be validated. For example, final mixing/lubrication of the granulate, official and unofficial tableting parameters, coating process parameters, etc.

Granulation
Compression
Coating
Other (for other dosage forms)

K. Sampling Plan

A stepwise sampling plan should be designed and implemented in order to ensure reliability in the validation procedure. The main components of the sampling plan are as follows;

Sampling Technique
Sampling Locations
Sampling Tools
Number of Samples
Sample Quantity
Sampling frequency

Where appropriate, explain the sampling plan using schematic diagrams.

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L. Associated Documents

A comprehensive approved protocol
Completed BMRs of all the validation batches (Uncontrolled copies can be used for the record and reference)
Result formats

Granulation
Compression
Coating
Other (for other dosage forms)

Certificate of Analysis ( with Analytical Method Number)
Microbiological Control (Certificate of Analysis with Analytical Method Number)

CHECKS AND CONTROLS MONITORED DURING THE MANUFACTURING PROCESS

During the manufacturing process, the below-mentioned controls and tests applicable to the products/processes are carried out. The protocol, testing, and result formats and reports are compiled while following the requirements given as follows

A. Checks and Controls Monitored during Tablet Manufacturing Process

The following parameters are monitored and tested during different stages of the tableting process.

Parameters monitored and tested during Granulation

The following parameters are monitored during Granulation

Equipment
Batch size
Appearance of the granulation
Blender, auger or chopper speed
Amount of granulating fluid (wet granulation)
Feed rate of granulation fluid
Granulation time

The following tests are performed at the granulation stage

Loss on Drying or Water Content By KF (Karl Fischer) (if required)
Assay of the mixed powders (if required)

Parameters monitored and tested during Fluid bed Drying

The following parameters are monitored during Fluid Bed Drying

Bowl Type and charge
Inlet/exhaust air temp.
Product Temp.
Total drying Time
Inlet Air Volume
Humidity of incoming and Exhaust air
Porosity of filter bag

The following tests are performed at Fluid Bed Drying stage

Particle size / size distribution (if required)
Bulk densities, Loose and tapped (if required)
Powder Flow (if applicable) (if required)
Loss on Drying or Water Content By KF
Assay of the mixed powders (if required)

Parameters monitored and tested during Milling

The following parameters are monitored during Milling

Equipment
Screen Size
Mill (Blade), type, speed and orientation
Feed Rate

The following tests are performed at Milling stage

Particle size / size distribution
Bulk densities, Loose and tapped

Parameters monitored and tested during Lubricant Blending

The following parameters are monitored during Lubricant Blending

Blender Type
Blender Load
Blender Speed
Blending Time

The following tests are performed at the Lubricant Blending stage

Particle size / size distribution (if needed)
Bulk densities, Loose and tapped(if needed)
Flow Properties(if needed)
Content Uniformity (if needed)

Parameters monitored and tested during Tablet Compression

The following parameters are monitored during Tablet Compression

Tablet Press
Tablet Press Speed
Tooling
Fixed No. of stations
Pre-compression Force
Compression Force
Feed Frame (Open / Closed)

The following tests are performed during Tablet Compression

Weight Control
Hardness
Thickness
Friability
Disintegration
Dissolution
Assay / Dose Uniformity
Elegance (appearance defects)
Bulk holding testing, i.e. Bulk drug stability (if applicable)

Parameters monitored and tested during Tablet Coating

The following parameters are monitored during Tablet Coating

Equipment
Pan Load
Inlet Air Volumes
Inlet / Exhaust Humidities (If required)
Inlet / Exhaust Temperatures
Pan Speed
Spray Nozzle Size and number
Atomizing Air pressure
Spray rate and spray cycle
Gun to bed distance
Coating suspension viscosity
Coating efficiency

The following tests are performed at the Tablet Coating stage

Percent weight gain
Elegance (appearance defects)
Dissolution
Assay
Degradation Level

B. Checks and Controls Monitored during Capsule Manufacturing Process

The following parameters are monitored and tested during different stages of the Capsule Manufacturing Process.

Parameters monitored and tested during Capsule Powder Blending

The following parameters are monitored during Capsule Powder Blending

Blender - make, model, size
Blender load
Blender Speed
Blending Time

The following tests are performed at the Capsule Powder Blending stage

Blend Uniformity
Assay of the Blended powders (if required)
Dissolution on hand filled capsules (If appropriate)
Loss on Drying or Water Content By KF
Bulk densities, Loose and tapped
Flow Properties

Parameters monitored and tested during Encapsulation

The following parameters are monitored during Encapsulation

Capsule filling Machine Used
Number of station
Machine Speed
Powder Bed Height
Compaction Pressure
Dosator Volume Setting
Vacuum Level

The following tests are performed at the Encapsulation stage

Dose Uniformity
Weight Control
Elegance of Filled Capsules
Capsule closure (Fit and length of capsule)
Assay
Dissolution
Microbial Count

C. Checks and Controls Monitored during Liquid Manufacturing Process

The following parameters are monitored and tested during different stages of Liquid manufacturing.

Parameters monitored and tested after Liquid Compounding

The following parameters are monitored during formulation / Compounding of Liquid dosage forms

Type of Vessel
Mixer type
Mixing Time
Mixer speed
Mix volume
Dissolving solvent quantity
Filter type, Filtration time

The following tests are performed at the formulation / Compounding stage of Liquid and Semi-solid dosage forms

Mix Uniformity
Assay of the Solution
pH
Density
Viscosity
Water Content

BULK PHARMACEUTICAL ANALYSIS

Quality Control Lab performs the analyses listed below using a representative batch sample. The result of the analyses should complies with the BP, USP, Eur Ph. Limits or Limits mentioned in the Standard Product Specification.

Study parameters for Solid Dosage Forms are

Parameters	Applicable to
Characteristics	Tablets, Capsules, Granules
Identification	Tablets, Capsules, Granules
Average weight	Tablets, Capsules
Weight uniformity	Tablets
Disintegration	Tablet, Capsules
Friability	Tablets
Assay	Tablets, Capsules, Granules
Hardness	Tablets
Dissolution	Tablets, Capsules, Granules
Moisture	Tablets, Capsules, Granules
Residual solvent	Tablets, Capsules, Granules
Related substances	Tablets, Capsules, Granules

Study parameters for Liquid and Semi-Solid Dosage Forms are

Parameters	Applicable to
Characteristics	Liquids, Semisolids
Identification	Liquids, Semisolids
Density	Liquids, Semisolids
Viscosity	Liquids, Semisolids
Assay	Liquids, Semisolids
Water Content	Liquids, Semisolids
Related substances	Liquids, Semisolids
Sterility Test	Liquids, Semisolids

Copies of the corresponding Analysis Certificates are attached with the validation report for the record.

MICROBIOLOGICAL CONTAMINATION CONTROL

Quality Control determines microbial contamination with the following parameters

PARAMETERS

SPECIFICATIONS

Total aerobes

Bacteria
Fungi

Complies USP, BP, or Eur. Ph. Limits

E. coli

Microbiological Controls are carried out on the Finished Pharmaceutical Product. Copies of the corresponding Analysis Certificates are attached with the validation report for the record.

VALIDATION REPORT

On completion of the activities described in the protocol, the Product Development Department issues the corresponding Validation Report concluding as to whether the results obtained from the batches tested are repeatable and do not present significant variations against the parameters assigned in the Validation Protocol.
The Validation report includes annexes with tables duly compiling the data collected during the execution of the Protocol.
The validation report is signed by all the persons involved in the validation process and by the heads of the concerned departments.

RE VALIDATION POLICY

Revalidation will be carried out only in case of a change of