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 products.

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 the 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 the 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

1. Validation team
2. Execution team

B.  Validation Protocol

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

1. Acceptance criteria
2. Frequency
3. Environmental controls

• Processes validation
• Granulation

1. Processing step
2. Purpose
3. Tests
4. Sampling plan
5. Acceptance criteria

• Compression

1. Processing step
2. Purpose
3. Tests
4. Sampling plan
5. Acceptance criteria

• Coating

1. Processing step
2. Purpose
3. Tests
4. Sampling plan
5. 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 for manufacturing the Pharmaceutical Product.

C.  Scope

• This protocol covers all the operations involved in manufacturing 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:

1. Granulation: The granulation must comply with the HNL content uniformity specifications
2. Compression: The tablets must comply with the HNL specification for compression of that particular product
3. 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

1. < 4% - Readily passable
2. < 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 Equipment and Areas of Manufacturing

The list consists of the following information

• Equipment / Area
• Number (Asset)
• Qualification number

G.  Formulation Details

Mention the following details regarding the formulation:

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

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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

• 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 the 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.

1. Granulation
2. Compression
3. Coating
4. Other (for other dosage forms)

K.  Sampling Plan

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

1. Sampling Technique
2. Sampling Locations
3. Sampling Tools
4. Number of Samples
5. Sample Quantity
6. Sampling frequency

Where appropriate, explain the sampling plan using schematic diagrams.

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

1. Granulation
2. Compression
3. Coating
4. 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
• The appearance of the granulation
• Blender, auger or chopper speed
• Amount of granulating fluid (wet granulation)
• The feed rate of the 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
• The humidity of incoming and Exhaust air
• The porosity of filter bag

The following tests are performed at the 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 the Milling stage

• Particle size/size distribution
• Bulk densities, Loose and tapped

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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

ALSO READ: Checklist for Analytical Method Validation

The following tests are performed at the Encapsulation stage

• Dose Uniformity
• Weight Control
• The elegance of Filled Capsules
• Capsule closure (Fit and length of capsule)
• Essay
• 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 the 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 comply 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 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

• Formulation
• Manufacturing process
• Batch size (if extremes are not validated during initial validation)
• Equipment (if the working principle is different from the previous ones)

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