Standard Operating Procedure

PROCEDURE FOR CONCURRENT PROCESS VALIDATION

SOP NO.

Dated

Effective

Revision

QD-3-PD-000

01

Replaces

Pages
11

Dated
-

All previous SOPs in this context

PREPARED BY

CHECKED BY

REVIEWED BY

APPROVED BY

Azmat Ali
MPD

Ahmad Shehryar
SMPD

Waseem Shamsi
SMQC

Dr. Ajmal Nasir

EDT

Circulation
EDT, EDQO, SM (PD), SM (QC) CM (Production)

1.0

PURPOSE
To define and document a procedure for Concurrent Process Validation.

2.0

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

3. 0

RESPONSIBILITES
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, compilation of data and preparation the validation report
Circulation of the validation report to all the concerned department 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
NO. QD-9-0018
IPC
Assist in the development of the validation protocol

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Check and review the validation protocol

Over all 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
4.0

PROCEDURE

4.1

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
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

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- 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 in the same manner as
described above.

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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 of 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 CRITEIA
Stage wise suitability requirement 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 MANUFACTRUING

The list consist 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

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Manufacturer
Function
Percentage in the formulation
mg per tablet
kg per batch

H.

MANUFACTURING PROCESS FLOW CHART

The chart shows the diagrammatic over view of the manufacturing process.

I.

IN PROCESS CONTROL AND CHECKS WITH ACCEPTANCE CRITERIA AND

FREQUENCY
a. The various control parameters and their specifications are defined at each section in the
experimental plan
b. In order to consider the process validated, the validation batches must comply with each
and every specification included in the experimental plan
c. Any data outside specifications must be studied individually and recorded in the final
report
d. Environmental control should also be monitored especially in case of sensitive products
e.g. temperature and humidity

J.

PROCESSES 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 tabletting
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 diagrammes.

L.

4.2

ASSOCIATED DOCUMENT
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 MANUCTURING 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

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4.2.1

CHECKS AND CONTROLS MONITORED DURING TABLET MANUCTURING PROCESS

The following parameters are monitored and tested during different stages of the tabletting
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 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

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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 Tablet Coating stage
- Percent weight gain
- Elegance (appearance defects)
- Dissolution
- Assay
- Degradation Level

4.2.2

CHECKS AND CONTROLS MONITORED DURING CAPSULE MANUCTURING

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

PARAMETERS MONITORED AND TESTED DURING CAPSULE

BLENDING
The following parameters are monitored during Capsule Powder Blending
- Blender - make, model, size
- Blender load
- Blender Speed
- Blending Time

POWDER

The following tests are performed at 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

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4.2.3

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 Encapsulation stage

- Dose Uniformity
- Weight Control
- Elegance of Filled Capsules
- Capsule closure (Fit and length of capsule)
- Assay
- Dissolution
- Microbial Count
CHECKS AND CONTROLS MONITORED DURING LIQUID MANUCTURING
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 formulation / Compounding stage of Liquid and
Semi-solid dosage forms
- Mix Uniformity
- Assay of the Solution
- pH
- Density
- Viscosity
- Water Content

5.0.

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
Characteristics
Identification
Average weight
Weight uniformity
Disintegration
Friability
Assay
Hardness
Dissolution

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Applicable to
Tablets, Capsules, Granules
Tablets, Capsules, Granules
Tablets, Capsules
Tablets
Tablet, Capsules
Tablets
Tablets, Capsules, Granules
Tablets
Tablets, Capsules, Granules
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Moisture
Residual solvent
Related substances

Tablets, Capsules, Granules

Tablets, Capsules, Granules
Tablets, Capsules, Granules

Study parameters for Liquid and Semi-Solid Dosage Forms are

Parameters
Characteristics
Identification
Density
Viscosity
Assay
Water Content
Related substances
Sterility Test

Applicable to
Liquids, Semisolids
Liquids, Semisolids
Liquids, Semisolids
Liquids, Semisolids
Liquids, Semisolids
Liquids, Semisolids
Liquids, Semisolids
Liquids, Semisolids

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

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6.0

MICROBIOLOGICAL CONTAMINATION CONTROL

Quality Control determines microbial contamination with the following parameters
PARAMETERS

SPECIFICATIONS

- Total aerobes
Bacteria
Fungi
- E. coli

Complies USP, BP, or Eur. Ph. Limits

Complies USP, BP, or Eur. Ph. Limits
Complies USP, BP, or Eur. Ph. Limits

Microbiological Controls are carried out on the Finished Pharmaceutical Product. Copies of the
corresponding Analysis Certificates are attached with the validation report for record.
7.0

VALIDATION REPORT
On completion of the activities described in the protocol, 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.

8.0

RE VALIDATION POLICY
Revalidation will carried out only in case of change of
Formulation
Manufacturing process
Batch size (if extremes are not validated during initial validation)
Equipments (if the working principle is different form the previous ones)

Reference:
FDA, Guidance for Industry, Powder Blends and Finished Dosage Units Stratified In-Process Dosage Unit Sampling and
Assessment

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ANNEX 1

QD-3-PD-002/00-12-2003

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