PROCESS VALIDATION

PROCESS VALIDATION

To define a procedure for validation of process to demonstrate its effectiveness and reproducibility including the preparation of protocols and report. It also outlines the personnel responsibilities and other qualification documents required for performing the validation activities.

SCOPE:

This SOP is applicable for execution of process validation activity.

RESPONSIBILITY & ACCOUNTABILITY:

RESPONSIBILITY:

Quality Assurance Team.

Officer/Executive: preparation of Protocol and Report.

IPQA officer/Executive: Sampling, Execution, verification compilation of final report and approval of validation program.

Production Team: checking of protocol and report. Execution of process validation as per the approved protocol.

Quality Control Team: To analyze in-process samples and preparation of report.

Engineering Team: To provide technical support during validation activity.

Production Head: For implementation of SOP.

QA Head- To ensure compliance of this SOP being followed.

ACCOUNTABILITY:

The Accountability of implementation and compliance of the SOP is of QA Head.

PROCEDURE:

Definition:

Process Validation is defined as the collection and evaluation of data, from the process design

stage throughout commercial production which establishes scientific evidence that a process is

capable of consistently delivering a product meeting its pre-determined specifications quality product.

General Information:

Classification:

Types of Process Validation.

Process Validation can be categorizes as Prospective, Concurrent, Continuous Process Verification and Revalidation.

Prospective Validation:

Establishing documented evidence to demonstrate that systems during the development stage on the Lab scale or pilot scale batches of the products that are under pipeline to be manufactured on a large scale.

Ongoing/ Continuous Process Verification:

Ongoing process verification is carried out for continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. After completion of first 03 batches validate all parameter shall be verified by analysis. The verification shall be done till 10 batches of a product. Sampling parameters shall be remaining same as initial batch or process validation. Sampling point shall be reduced with proper justification. After completion of 10 batch process validation trend shall be prepared as per trend data the test parameter shall be reduce & fixed for continuous batches manufacturing.

Concurrent Validation:

Validation carried out during routine production of products intended for sale.

Prerequisites for Process Validation:

Ensure Equipment/Area/Utilities are qualified and intended instruments are calibrated.

Approved Specifications, Test Procedures and Validated Analytical Methods are in place.

Master Formula Record/Batch manufacturing records/Batch Packing records and process validation protocol in place.

Sampling plan and intended in-process controls with acceptance criteria is defined in the protocol.

SOP´s stating the process activities are in place.

Training has been imparted to all concerned.

Process/Operating Parameters:

The conditions under which a process is performed. It can be physical or chemical (i.e. pH, temperature, pressure, agitator, rpm, flow rate, etc.).

Critical Process Parameter:

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.

Validation Protocol:

A written protocol or plan stating how validation, testing and sampling will be conducted, defining roles and responsibilities, and defining acceptance criteria.

Process Validation Policy:

Process Validation shall be carried out for the following reasons:

A new product is manufactured in the facility.

An existing product is transferred from one manufacturing location to another.

Changes of raw materials (physical properties such as density, viscosity, particle size distribution may affect the process or product).

Change in existing formula or process.

Change in equipment, which has a direct impact on the manufacturing process.

In case of different batch size of similar product, maximum and minimum batch size shall validate.

Change in Production area (areas with equipments of different make / capacity / working principle) and major changes in the support system as identified by the validation committee members.

As per the Regulatory body requirement.

Approach for validation studies:

Pre-Validation Phase or the Qualification Phase (Prospective Validation):

Developmental trials shall be used to identify critical process parameters and critical controls.

Processing conditions are adjusted until optimization of the process is achieved. Critical  process parameters and analytical data of optimization batches are reviewed and these batches are subjected to accelerated stability studies. After optimization, the product or process can be considered as established and shall be validated.

The batch size of these batches shall be minimum 1/10th of the intended commercial batch size.

Process Validation Phase (Process Qualification phase):

This phase is evaluated to determine if the process is capable of reproducible commercial manufacturing. All the prerequisite and precautions applicable to the product under study, as mentioned in manufacturing document shall be followed.

All documents and raw data generated during validation activity shall be considered as GMP documentation for retention/archiving purposes.

A predefined number of validation batches “Conformance batches = at least three consecutive batches” shall be manufactured to demonstrate that, under normal conditions and defined ranges of operating parameters, the commercial scale process appears to make an acceptable product.

Process Validation shall ensure by testing that a process is capable of repeatedly and reliably producing a formulated product of the required quality under conditions to be used for routine manufacture.

Size of validation batches shall not exceed 10 times of optimization batch.

For Ongoing Process Verification, one batch from product of lower strength shall be taken for study every one year.

Loss of material and product shall be characterized and established at all stages of manufacturing during process validation.

Validation protocol shall be prepared by QA, reviewed by Production, QC, approved by Production, QC and QA Head.

Validation batches may be commercialized only after the product quality is found satisfactory. However stability studies are continued and reviewed periodically.

Sigma Calculation: If measured the same thing many times and draw a straight line for every result or value. A statistical measurement “standard deviation or sigma” Sigma calculation and evaluation of sigma values obtained are explained as below.

Validation batch shall be identified by marking “validation batch” on batch records.

Sampling plans shall be predetermined and documented in the validation protocol with respect to the dosage form and process variability.

All Critical process parameters shall be identified and monitored to keep them within proven acceptable range.

Validation Report:

A written report that summarizes the raw data and evaluates the validation work against the acceptance criteria defined in the Validation Protocol. It includes a clear conclusion as to whether the validation has been completed and successful or not.

Content of Process validation protocol shall include but not limited to:

• APPROVAL
• OBJECTIVE
• SCOPE
• RESPONSIBILITIES
• PRODUCT DETAILS
• Master Formula
• EXECUTION TEAM
• PREREQUISITES FOR THE VALIDATION
• VALIDATION APPROACH
• REVALIDATION CRITERIA
• PRECAUTION
• VALIDATION PROCEDURE
• Process flow diagram
• Brief description of manufacturing process
• Equipment /instrument details
• Sampling and testing plan
• Sampling location diagram
• ACCEPTANCE CRITERIA
• DEVIATION & CORRECTIVE ACTION
• SUMMARY & CONCLUSION
• ABBREVIATIONS
• REFERENCES
• FLOW CHART
• ANNEXURES

Validation Procedure:

Based on company’s decision to introduce a new product or based on the work order and considering the availability of raw & packing material, production will be planned.

Initial checks for Process Validation:

All equipment’s used for validation programme must be Qualified and wherever necessary calibrated and verified.

Availability of approved process validation protocol.

All Analytical methods used for testing of the product have been validated.

All related Master Documents like: MFR, BMR, BPR and FPS are available.

All SOP’s related to the validation program are available.

Trained personnel to carryout the validation.

All the Raw materials and Primary Packing Materials are Tested and Released by quality control.

Process validation protocol shall include manufacturing flow chart with detailed description of manufacturing procedure, drawing of sampling plan with respect to equipment involved during the process, in process test to be performed and its acceptance criteria. The process validation protocol shall also include the critical parameters identified based on the initial formulation which shall be optimized and validated.

Quality assurance representative in consultation with Head production / Regulatory /Head quality assurance will prepare the process validation Protocol and Report.

The Header comprises of:

• Company Logo on Right top corner of page.
• Process Validation Protocol
• For restricted circulation only
• PV Number
• Product Name: (As per name mentioned in the MFR/BMR of the product)
• Generic Name: Generic name of product.
• Issued By QA
• Doc. No. : (indicate current version number of the PV)
• Effective Date: (effective date of the process validation)
• Product Code: Product Code of product.
• Page No.: X of Y.
• Supersedes No.: To write the number of previous version of the PV number.

The footer on first page comprises of Signatures of Prepared By (Quality assurance),

Checked By (Production, Quality Control) and Approved By (Quality Assurance).

The Quality Assurance Department assigns tracking number to PVP as follows

PVP No.: C/TB/YYY/DDD/NN-VV

Where,

C stands for Cephalosporin Block

TB indicates the department / dosage form.

YYY indicates the type of document.

e.g.:- PVP:-Process validation protocol

PVR:-Process validation Report

DDD indicates the product code

NN indicates the serial number as per Batch size.

VV indicates the version number.

The protocol will be reviewed and Authorized by Production, quality control and quality assurance personnel.

Upon receiving BMR request, quality assurance will issue a controlled copy of BMR   and the validation protocol for the said product.

Material will be dispensed as per quantities given in BMR and validation protocol.

Dispensed material is then taking for further manufacturing processes.

The manufacturing process will be carried out stepwise.

As per protocol, quality assurance officer will keep ready required sampling bags,

identification labels and sampling tools.

Quality assurance officer will do extensive sampling of the process stage wise as mentioned in the validation protocol.

These samples are transferred to quality control department for analysis along with test request form and validation protocol.

After completion of testing, quality control will record the results of each process in  the data recording sheets provided in the validation protocol.

After getting compliance report from quality control, Production department should start next process stage.

In process validation Sampling shall be done as per the sampling plan illustrated in the diagram during each in process steps.

Test shall be performed at each stage during the process and results shall be compared with the acceptance criterion.

Replicate studies must be conducted on minimum of three consecutive batches.

Note:

In the case of manufacturing process validation where batch is manufactured on common blend concept, the lowest strength will be considered for process validation.

The Challenging (i.e. subjected   to   sampling   at different   time   limits) of the critical Parameters (e.g.Mixing time, RPM, Lubrication Time, and Hardness Challenges at compression stages) will be done only on optimization batches (Prospective Validation)

During concurrent validation the sampling shall be done at fixed time interval as mentioned in Batch documents.

In case if BMR is having provision of multiple equipment’s, ensure that each equipment is validated by taking three consecutive batches.

For Example: If in BMR of XYZ 10mg, both 27 and 27 station compression machines included. Validate the 27 station compression machine on first three batches(A, B, C) and 27 station compression machines on next three batches (D, E, F).

In case validation of batches cannot be completed as per approved protocol due to less marketing requirement or is discontinued due to other justifiable reason then an ‘Interim Report’ shall be generated to give the status of various parameters tested during validation studies. However, process validation studies shall be deemed to be completed only on successful completion of three batches.

In cases where it is unlikely that second and / or Third batch of the product will be manufactured for a period of time, generate interim reports on batch to batch basis till such time the process validation study is completed.

Deviations to Validation Protocol:

Any deviation from the approved protocol must be documented and authorized.

In the event of acceptance criteria not being met, an investigation shall be carried out to identify the root cause and to provide corrective actions. If the investigation results in a change to a process parameter or operations the replication sequence shall start again and shall be conducted on three batches.

Conclusion and Summary:

If results of three batches are within acceptance parameters, giving the product of desired quality, the process stands valid.

After completion of three validation batches, a conclusion will be written with summary of results, duly certified by validation team for formal acceptance.

Recommendation:

Recommendation if any, necessary for routine production should be incorporated in the Batch Manufacturing / Packing Record.

If any of the three batches do not meet acceptance criteria, revalidation should be done.

Revalidation Criteria:

Change of any major equipment in the chain of equipments which may affect the earlier validation study.

Any major modification to the equipment, which may affect the earlier validation status.

Based on any request from customer or regulatory agency.

The validated batches shall be charged for stability as per ICH Guideline.

REFERENCE:

SOP FOR SOP

WHO Technical Report Series, No. 863 – Annexure 6

EU guidance Annexure -15

FDA guideline Process Validation: General Principles and Practices

ABBREVIATION:

Abbreviation

SOP Standard Operating Procedure

QA Quality Assurance

QC Quality Control

PVP Process Validation Protocol

PVR Process Validation Report

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