This Document describes (Standard Operating procedure) SOP for Measures Taken during carrying out process validation of drug products.

I. Purpose & Scope:

• The Purpose of this SOP is to lay down the procedure for Measures Taken for carrying out process validation of drug products.
• This procedure is applicable for Production and Quality assurance Department personnel for carrying out process validation of drug products.

II. Responsibilities:

• All production and Quality assurance personnel’s shall be responsible to follow and implement this SOP.

III . Introduction and Procedural Part :

• PROCEDURE:

• Definition:
  • • Validation

Collection and Evaluation of data from process design to Manufacturing process. In concern with documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.

• Prospective validation :

Validation carried out during the initial manufacturing of the new product by means of a risk analysis of the production process, which is broken down into individual steps, these are then evaluated on the basis of past experience (development stage) to determine whether they may lead to critical situations.

• Validation Protocol :

The validation protocol is a written plan stating how validation shall be conducted, including test parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results.

• Validation Report

The validation report is a written report on the validation activities, the validation data and the conclusions drawn.

• Revalidation:

Process revalidation is under taken when a change occurs in a previously validated process or an established process, the change, which could have an impact on product characteristics.

• Worst Case:

A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

• Quality by design:

A systematic approach that begins with predefined objectives and emphasizes  product and process understanding and process control, based on sound science and quality risk management.

 

 

• Continued Process Verification :

Collection and Evaluation of data from process design to Manufacturing process. In concern with documented evidence that the process remains in a state of control during commercial manufacture.

• Lifecycle :

All phases in the life of a product, equipment or facility from initial development or use through to discontinuation of use.

• Knowledge management :

A systematic approach to acquire, analyze, store and disseminate information. (ICH Q10).

• Critical process  parameter  (CPP) :

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

• Critical Quality Attribute (CQA)

A physical, chemical, biological or microbiological property or characteristic that should be within an approved limit, range or distribution to ensure the desired product quality.

• Prerequisites :
  • Validation shall be performed for new manufacturing processes, equipment and when major changes have been made or implemented to premises, systems, equipment, materials and /or processes.
  • Ensure that all relevant SOP’s are in place and training is completed on equipment operations, manufacturing instructions and sampling strategy are in place. Also that the operators and supervisory persons who will be running the validation batches have the understanding of the process.
  • The process validation requires that validated assays, calibrated instruments, and qualified production support systems shall be established with proper documentation prior to execution of process validation studies. Furthermore, the process shall be fully developed, optimized and documented. Process validation shall focus on process performance at the set-point of each operating parameter range.
  • When any new manufacturing formula or method of preparation is adopted, validation shall be done to demonstrate its suitability for routine processing.
  • Validation can be prospective or continuous process verification depending on when validation is performed but the type of validation shall be recorded in the respective validation protocol.
  • In case of prospective or continuous process verification studies, the protocol shall specify a sufficient number of replicate process runs to demonstrate reproducibility and provide an accurate measure of variability among successive runs.
  • The test conditions for the validation runs shall encompass upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure compared to ideal conditions.
    • For contract manufactured the validation protocol shall need approval from QP/ responsible person of the contract given.
    • In case of bracketing etc. in situation of multiple strength, the same shall only be done after the prior approval from QP/ authorized person of the contract giver or regulatory agency.
  • In case of prospective and concurrent validation, the process validation protocol shall be written in a standard format that would enable the user to demonstrate that a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the product meet it specifications.
  • The process validation protocol shall be prepared by the Quality Assurance department in consultation with the validation team.
  • The protocol shall be submitted for initial document approval prior to beginning of the execution in case of contract manufactured product.
• Content of Process Validation Protocol:

The Process validation protocol shall typically include, but not being limited to the    following contents as applicable:

• The Header of the protocol shall include:
  • Company logo and site
  • Protocol Number: Each protocol shall be identified by a unique code No.

Process Validation Protocol shall be numbered as PVPA/001/00

Process Validation Report shall be numbered as PVRB/001/00

Where,

PVP  or PVR	:	Process Validation Protocol or PVR – Process Validation Report
A	:	Formulation code such as T-Tablet, C-Capsule, O-Ointment, I-Injection,
001	:	Stands Serial number of MFR
00	:	Revision number

 

• Title: It shall describe the title of the process being validated.
• Date of Issue: Date of Issuance of the protocol is after the date of approval of the protocol for providing training before execution of the validation activity which shall appear on the first page of the protocol.
• Effective Date: Date of Implementation of the protocol after training for the execution of the validation activity. This shall appear on the first page of the protocol.
• Supersedes: It gives withdrawal of earlier version of the protocol No if applicable. If the protocol is prepared for the 1st time, it shall be written as “NA”. This shall appear on the first page of the protocol.
• Location: Location shall be specified on the first page of the protocol.

• Protocol Approval sheet: This shall mention the details for approval of protocol.
• Revision History: This shall describe the details of revision of the protocol.
• Abbreviations: This indicates the abbreviated form and definition of used in the protocol.
• Objective: This shall list the objective of the process validation study.
• Scope: This shall define the applicability of the protocol.
• Responsibilities: This shall include the specific responsibilities of the Personnel’s/Department involved in the execution of process Validation study.
• Training: Training of the concern personnel involved in the process shall be verified.
• Product Details: It shall indicate the details of the product like MMF No., BMR No., Batch size, stage, product name, and strength/dose of the product.
• List of Materials: This shall indicate the name of raw materials/Packaging material, QC reference number, Activity/function of the material in the product and quantity per batch used in the manufacturing of stage/process under validation.
• Equipment Details: This shall indicate the details of the equipments used in the manufacturing of product under process validation study.
• Reason for Validation: Shall be specified to record in the validation report.
• Process Description: A brief description of the process involved in validation study shall be mentioned along with the critical process stage.
• Process Flow chart: Flow chart shall include stages involved in the process under validation.
• Critical Process Parameters: This shall indicate the critical process parameters with a meaningful, narrow operating range to ensure that product attributes meet their specifications.
• Risk Assessment: This includes rationale for critical process parameters and critical in process parameters including the worst case scenario consideration or challenge study to be performed for the selection of critical process parameters.
  • Rationale for Critical Process Parameters: This shall indicate the rationale for the selection of critical process parameters.
  • Critical in process controls: This shall define the rationale for the selection of critical in process parameters used in the process validation study.
  • Worst case scenario or challenge study: This shall include the challenges during the process validation considering the probable failures or worst case parameters without affecting the quality attributes.
• Acceptance Criteria: It shall clearly describe objective, quantifiable parameter ranges or validation requirements the constitute completion of the protocol to consider the study successful. If the study doesn’t meet the acceptance criteria, then the validation lot fails. Criteria for determining consistency shall be defined. Statistical tools should be used whenever possible.
• Procedure: This shall define the procedure for the execution of the process validation study.
• Sampling Plan and testing summary: This shall indicate the details of the Samples to be collected for analysis during process validation study. Sampling plan shall have details like Sampling location, sample quantity, sampling procedure and analysis to be performed.
• Deviation Report: It shall contain the deviations encountered during the process validation study.
• Revalidation Criteria: This shall indicate the criteria for the revalidation of the process under validation study.
• Summary & Conclusion: Shall be specified to record in the validation report.

 

• Execution of process validation:
  • Nominate a team compromising user department, Quality Assurance, Quality Control and Engineering as defined in the validation master plan.
  • Initiate a plan for performance of studies based on production schedule.
  • The manufacturing process shall be monitored for critical process parameters; qualities of raw materials used, and yield of each stage of process as mentioned in the individual protocol.
  • Carry out the process validation as per the respective validation protocol and report.
  • The required samples are withdrawn by the Quality Assurance for each critical step & forwarded to the Quality Control department for analysis.
  • The various samples shall be collected and tested as mentioned in the respective protocol.
  • The samples shall be analyzed by the Quality Control and the results shall be forwarded to the Validation Team on approval of Head – Quality Control.
  • Summarize the findings, observations of the validation studies with conclusion.
  • Statistical methods can be used to interpret data obtained and provide meaningful information during validation exercise.
  • Necessary changes as recommended after review in the process parameters, if any shall be done following change control protocol.
  • In case of prospective and continuous verification process studies statistical tools needs to be used to evaluate the consistency, accuracy and capability of the process.
• Preparation of Process Validation Report :
  • Follow the steps 5.2.1 to 5.2.22 for the preparation of validation report to record the indicated parameters as mentioned in the validation protocol.
  • Reference protocol No. shall be recorded in the validation report.
  • The validation report format protocol shall be prepared before the validation. Execution of the process.
  • The signatures on report shall be by the same individuals who signed for the initial approval or by an authorized designee of the protocol.
  • The final approval shall be of Head-Quality Assurance.
  • The signature and date of the individual(s) performing the execution shall be recorded at the time of execution.
  • Recording formats shall be provided as per the validation protocol.
  • A summary of validation shall be made as a part of the report starting various parameters/range with graphical representations with respect to predetermined key quality attributes specifications established during validation.
  • Conclusion shall be made with relates the results back to the purpose of the study and compare them with the predefined acceptance criteria. The discussion shall provide support for any study conclusions. The impact of assay ranges and deviation shall be discussed if the affect the study results, and both a risk assessment and any follow up conclusions including corrective actions, as appropriate, should be stated.
  • All the above is applicable to prospective and continuous verification studies only.
• Criteria for Process Validation:
  • Following criteria and stages mentioned shall be used as a guidance to prepare specific validation protocols.

 

 

 

 

Type	Frequency	Manufacturing Stages
New product ( Tablet) (For Regulatory Products / PL Markets)	Initial three consecutive batches	Dry mixing Blending Compression Coating Inspection Packing
New product ( Capsule) (For Regulatory Products / PL Markets)	Initial three consecutive batches	Blending Capsule Filling Packing
New product ( External preparations ) (For Regulatory Products/ PL Markets )	Initial three consecutive batches	Homogenization Filling Packing
New product ( Dry Powder Injections) (For Regulatory Products/ PL Markets )	Initial three consecutive batches	Vial Washing Depyrogenation of vials Filling & Sealing Visual Inspection Labeling & Secondary Packing
Transferred product from Third Party/Contract Giver	As per Technical Agreement/ Initial three batches	As per Formulation Requirement and validation protocol of the contract giver
Others	As defined by Head QA	As per protocol

 

• Following criteria shall be followed for revalidation is given below:
• When there is change in formulation or Critical Process Parameters.
• Change in Batch size
• Change of critical Equipment/critical part of equipment, which is directly affecting the final Quality of the product.
• Change of Approved vendor source of Active Pharmaceutical Ingredient (API).( Applicable to regulated and PL related markets only)
• When there is a change in manufacturing site, the process is considered as new process and a full validation shall be carried out.
• A validated process shall be subjected to re-evaluation even if there is no change equipment, process or any other critical parameters. One batch shall be re-evaluated at a frequency of three years or as defined in the individual protocol.

• Criteria for manufacturing of Minimum Batch size and maximum batch size for Dry Powder Injections :
  • Processes shall be validated for all products as Minimum batch size and Maximum Batch size
  • In case, change in validated standard batch size follow the respective SOP  procedure and shall be  suspected product defects and other problems shall reported, investigated and recorded.
  • An appropriate level of root cause analysis is applied during such investigations. The most likely root cause(s) should be identified and appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken. The effectiveness of CAPAs should be monitored.
• Stability Study of Validation Batches:
  • The samples for stability shall be subjected to stability studies as per the individual protocol, or as per Change Control (if any).

• ANNEXURE:

Annexure No.	Format Name
Annexure – I	Process Validation Protocol for Tablets
Annexure – II	Process Validation Protocol for Ointment
Annexure – III	Process Validation Protocol for Injection
Annexure – IV	Process Validation Protocol for Capsule

Annexure – I

Process Validation Protocol for Tablets

PROCESS VALIDATION PRODUCT INFORMATION

 

Product Name
Product Code
Mfg. Lic. No.
Label Claim
Shelf life
Batch Size
Reference Master Formula No.
Reason for Validation

 

 

 

 

 

TABLE OF CONTENT (For TABLETS)

 

S. No.	Subject			Page No.
1.0	Objective
2.0	Scope
3.0	Validation Team
4.0	Responsibility
5.0	Revalidation Criteria
6.0	Acceptance criteria
7.0	Batch Under Validation
8.0	Equipment / Instrument summary
	8.1	List of Equipments / Instruments
	8.2	Equipment Cleaning & Clearance
	8.3	Qualification Status of Equipments
	8.4	Calibration Status of Instruments
9.0	Master formula
10.0	Process flow Diagram
11.0	Sampling plan
12.0	Process stage Control Variables & measuring responses
13.0	Manufacturing procedure and schematic diagram of sample location
	13.1		Sifting
	13.2		Granulation
	13.3		Drying
	13.6		Lubrication
14.0	Compression
	14.1		Machine setting
15.0	Compression of Tablets
16.0	Packing.
17.0	Data Compilation
18.0	Summary, conclusion & Report
19.0	Abbreviation

 

Annexure – II

Process Validation Protocol for Ointment

 

PROCESS VALIDATION PRODUCT INFORMATION

 

Product Name
Product Code
Mfg. Lic. No.
Label Claim
Shelf life
Batch Size
Reference Master Formula No.
Reason for Validation

 

 

 

 

 

TABLE OF CONTENT (For OINTMENT):

S. No.	Subject		Page No.
1.0	Objective
2.0	Scope
3.0	Validation Team
4.0	Responsibility
5.0	Revalidation Criteria
6.0	Acceptance criteria
7.0	Batch Under Validation
8.0	Equipment / Instrument summary
	8.1	List of Equipments / Instruments
	8.2	Equipment Cleaning & Clearance
	8.3	Qualification Status of Equipments
	8.4	Calibration Status of Instruments
9.0	Master formula
10.0	Process flow Diagram
11.0	Sampling plan
12.0	Process stage Control Variables & measuring responses
13.0	Manufacturing procedure and schematic diagram of sample location
14.0	Tube Filling
15.0	Filling of tube
16.0	Packing.
17.0	Data Compilation
18.0	Summary, conclusion & Report
19.0	Abbreviation

 

Annexure – III

Process Validation Protocol for Injection

 

PROCESS VALIDATION PRODUCT INFORMATION

 

Product Name
Product Code
Mfg. Lic. No.
Label Claim
Shelf life
Batch Size
Reference Master Formula No.
Reason for Validation

 

 

 

 

 

TABLE OF CONTENT (For INJECTION):

 

S. No.	Subject	Page No.
01	Approval Page
02	Objective
03	Scope
04	Reason for Validation
05	Process Validation Team and Responsibility
06	Process Validation Methodology
07	Training Detail
08	Master documents verification
09	Formula being Validated
10	Equipment Qualification/Instrument Calibration Verification
11	Process Flow Diagram With Validation Parameters
12	Description of Manufacturing Process
13	Monitoring of Process Parameters
14	Critical Parameters and Acceptance Criteria
15	Sampling Plan
16	Deviations
17	List of Attachments
18	Exhibits

Annexure – IV

Process Validation Protocol for Capsule

 

PROCESS VALIDATION PRODUCT INFORMATION

 

Product Name
Product Code
Mfg. Lic. No.
Label Claim
Shelf life
Batch Size
Reference Master Formula No.
Reason for Validation

 

 

 

 

 

TABLE OF CONTENT (For CAPSULES):

Sr. No.	Subject			Page No.
1.0	Objective
2.0	Scope
3.0	Validation Team
4.0	Responsibility
5.0	Revalidation Criteria
6.0	Acceptance criteria
7.0	Batch Under Validation
8.0	Equipment / Instrument summary
	8.1	List of Equipments / Instruments
	8.2	Equipment Cleaning & Clearance
	8.3	Qualification Status of Equipments
	8.4	Calibration Status of Instruments
9.0	Master formula
10.0	Process flow Diagram
11.0	Sampling plan
12.0	Process stage Control Variables & measuring responses
13.0	Capsule filling
	14.10		Machine setting
14.0	Packing.
15.0	Data Compilation
16.0	Summary, conclusion & Report
17.0	Abbreviation