PRODUCT PROCESS QUALIFICATION (PPQ)

December 18, 2024 shivpharma2016

PRODUCT PROCESS QUALIFICATION (PPQ)

PURPOSE: The purpose of this procedure is to provide a high degree of assurance of meeting all the predefined attributes and the process is capable of consistently delivering quality products.

SCOPE: This SOP is applicable for Process Qualification activities of drug products manufactured.

REFERENCE(S)

- ISPE, Volume 5, Commission & Qualification.
- Guidance for Industry: Process Validation: General Principles and Practices; U.S. Food and Drug Administration: 2011.
- Concept Paper on the Revision of the Guideline on Process Validation, EMA/CHMP/ QWP/809114/2009; European Medicines Agency: 2010.
- Guideline on Process Validation, EMA/CHMP/CVMP/QWP/70278/2012-Revl; European Medicines Agency: 2012.
- Eudralex: The Rules Governing Medicinal Products in the European Union: Volume 4 Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex. 15. Qualification and Validation; European Commission: 2014.
- Appendix 7. Non-sterile process validation (as published in TRS 992, Annex 3, 2015 (3).

CROSS-REFERENCE
- Quality Risk Management (QRM)
- SOP on Investigations
- SOP on In-Process
- SOP on Acceptable Quality Level
- SOP on Operation, Cleaning, and Handling of Sampling Rod & Dies
- Change Control Management
- Handling, management, and Investigation of Deviation.

ATTACHMENTS:

S.No.	Attachment No.	Attachment Title
1.	Attachment-I	Template for Product Process Qualification (PPQ) protocol
2.	Attachment-II	Template for Product Process Qualification Report (PPR)
3.	Attachment-III	Template for Process Optimization Protocol (POP)
4.	Attachment-IV	Template for Process Optimization Report (POR)
5.	Attachment-V	Documents Verification for Technology Transfer or Site Transfer or FDD for New Product or Existing Product.
6.	Attachment-VI	List of Product Process Qualification
7.	Attachment-VII	List of Process Optimization Batch or Trial Batch
8.	Attachment-VIII	Flow Chart of Qualification Approach
9.	Attachment-IX	Decision Tree for Routine Changes in Process
10.	Attachment-X	Sampling Plan During Product Process Qualification

DEFINITION
Manufacturing process: Transformation of starting materials into finished products through a single operation or a sequence of operations involving processing equipment, environmental control, personnel and documentation.
Validation: Validation is the documented act of proving that any procedure, process, equipment, material, activity or system actually leads to the expected result.
Process validation: Establishing documented evidence through collection and evaluation of data from process design stage to routine production, which establishes scientific evidence and provide high degree of assurance that a process is capable of consistently yield product meeting pre-determined specification and quality attribute.
Product life cycle: Stages through which a product moves from its inception till its discontinuation. It includes pharmaceutical development technology transfer and commercial production up to product discontinuation.
Performance Qualification (PQ): Defines that an integrated system or processing operation is capable of performing consistently to give an outcome that meets predetermined specifications.

RESPONSIBILITY

QA Executive and above shall be responsible for

Quality Assurance Dept. shall responsible for preparation of Product process qualification protocol, collection of process qualification sample (s) and preparation of Product Process Qualification report.

2. Production Executive and above shall be responsible for

Production shall responsible for execution of Product process qualification batches along with the QA personnel and office QA or above for sampling as per the protocol.

3. QC Executive and above shall be responsible for

Quality Control Dept. shall responsible for analysis of Process Qualification sample(s) and provide the data for process qualification report to Quality Assurance Dept.

4. User & Engineering department shall responsible for

Maintenance Dept. shall responsible for preventive maintenance and calibration of equipment and instruments respectively.

5. Head QA/Designee shall be responsible for

Head QA/Designee shall be responsible for approval of the protocol.

6. Plant Head shall be responsible for

The plant Head shall be responsible and accountable for approval of the protocol.

PROCEDURE:

SAFETY/PRECAUTION/EHS:

All Qualification Protocol/Report/Documents shall be prepare as per this SOP.
Only Approved copies of documents/protocol shall be made available at the time of Qualification activity.
Previous Qualification activity shall be documented & completed while performing next activity of qualification.
Movable items, like to like equipment’s shall be used after assurance of cleaning, if required as per activity. In such cases, QMS documents shall be raised by user department.
Movable items, like to like equipment’s shall be used after comparing qualification data and variance, in such case variance shall be log and describe and data shall be collected if any.

PROCESS QUALIFICATION METHODOLOGY:

This guidance describes the process validation activities in three stages:
Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities.
The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes majority of activities related to stage -1 shall be performed, suggested by site transfer team or FDD (Formulation Development Department).
Stage 2 – Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. This stage shall be done in two parts:
Design of the facility and qualification of the equipment and utilities: Qualification of utilities and equipment shall be covered under individual plans or as part of an overall project plan. The details of the same shall be mention in the Protocol. Qualification activities must be completed prior to startup of Process Performance Qualification (PPQ) stage.
Suitability of equipments and utilities must be documented in accordance with the process requirements in all the anticipated operating ranges.
Process Performance Qualification: During stage 2 and onwards, cGMP compliance must be followed. Successful completion of stage 2 is necessary before commercial distribution. Need of training shall be assessed prior to startup of PPQ batches.
During this stage, the process design is evaluated to determine if the process is capable to consistently manufacturing the product meeting predetermined acceptance criteria.
Process for new as well as existing products shall be qualified. Process qualification shall run according to approved protocol detailing sampling, timing, location, procedures along with analytical tests and acceptance criteria.
Product lifecycle approaches shall refer as per flow chart of qualification approaches as Attachment-VIII.
Three batches of commercial batch size shall be taken for qualification in accordance to the Process Qualification protocol and BMR. Sampling plan for PPQ batch as per Attachment-X .
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
During this stage continuous monitoring of process parameters and quality attributes at the level established during the process qualification stage shall be done.
This stage is applicable for Existing Products, Site Transfer Products and New Products.

Process Development and Trial Batch Plan:

Site transfer team / FDD shall generate knowledge and understanding about the manufacturing process and the product at the development stage.
Site transfer team / FDD shall issue a MFR and BMR to the manufacturing site defining manufacturing process, critical process parameters, in-process checks, specifications for input materials, intermediate products and final products.
Based on the requirement and risk assessment Site transfer team / FDD shall recommend for the trial batches manufacture prior to commercialization.
The batch/lot size of trial batch shall be decided based on the equipment occupancy level and other scientific rationale, so that the data, observation & experience from the trial batch will be useful for preparing the batch record and process qualification protocol/report for commercial batches.
The trial batch/lot size shall be atleast 1/10th of the intended commercial batch size, keeping the set of equipment same. Principle of operation shall be identical.
A trial or Optimization batch report shall be prepared as per the Attachment-IV.
The trial batch report shall be duly signed by the Production, QA, QC head and Quality head and shall be retained with QA for reference. The photo copy can be attached to the relevant BMR.
Based on the trial batch report & recommendations, the commercial batch manufacturing record & process qualification protocol can be prepared and the commercial batch manufacturing can be initiated.
Site transfer team / FDD shall revise and send the MFR/BMR to the site prior to post qualification BMR revision, if any revision is recommended /identify during execution of process qualification batches.

Process Qualification Pre-Requisites:.

Following prerequisite activities shall be completed before Process Qualification study.
Manufacturing Equipment and utilities has been qualified to meet cGMP requirements.
Utilities to be used in manufacture of the product (example – purified water, compressed air, HVAC system etc.) have been qualified.
Instruments used in processing have been calibrated (example – weighing balance, vernier calipers, hardness tester etc.).
Analytical methods for in-process testing and finished product analysis have been validated.
Personnel involved in manufacturing and testing of process qualification batches are appropriately trained.

Process Qualification Protocol:

On satisfactory completion of pre requisite activities, the Preparation of Process Qualification protocol shall be under taken as described below.
Process Qualification protocol shall be prepared by QA as per Attachment-I (applicable for commercial and for trial batches Attachment-III.
The Process Qualification Protocol and Report shall be reviewed by Production Head or designee, Quality control Head or designee & Quality assurance Head or designee and shall be approved by Site Quality head.
The Process Qualification team members of different departments (Production, QC & QA) shall review Process Qualification Protocol for the correctness of their relevant matter.
Designated person from Production shall ensure the suitability of the equipments listed in the protocol; whether the range and set point of process parameters is in line with measuring device available on the respective equipment / instrument; whether the equipment and measuring instruments are in calibrated status.
Designated person from QC shall verify whether the QC tests to be carried out at different process stages are correct and required testing methodology are available.
Validation team coordinator or AM /designee shall ensure the correctness of the process description, flow chart, critical process parameters, their range and set point, input material, their quantities, names of vendors stated in the protocol.
Designated person from QA shall verify whether Objective, Scope, Process description, Process flow, list of equipment, equipment qualification status, list of input materials, critical process parameters, in-process checks are correct; whether sampling plan is adequate to assess the capability of the process to consistently produce product meeting required specifications.
QA shall verify and ensure whether training is imparted up to the operator level prior to execution of process qualification activity.

Execution of Process Qualification:

A minimum of three consecutive batches shall be executed against the approved BMR and the Process Qualification protocol.
Where multiple batch sizes are available for a product, Process Qualification shall be done for each batch size. However, process qualification plan can be restricted to only those unit processes that are evaluated to have impact due to difference in batch size. For example, if there is no change in lot size at Granulation stage and only number of lots increased, process qualification of only Blending operation can be performed and the extent of validation study of other stages shall be decided based on the risk/impact assessment.
Where a product is manufactured in multiple strengths using a common blend, a matrix approach can be employed for Process Qualification. For example, if a product is manufactured as 10 mg, 20 mg and 40 mg by a common blend then the Process Qualification can include qualification up to blend stage with three batches of common blend and validation of subsequent unit processes like compression, coating etc. with three batches each strength. In such cases number of batches of different strength can be reduced with appropriate justification and necessary approval from CQC/site transfer team /FDD or quality head.
Samples shall be collected as per sampling plan defined in the process qualification protocol & tested in QC and results obtained shall be compiled for evaluation by the Process Qualification team.
Values of critical process parameters noted during in-process of the Qualification Batches shall be captured as per Protocol datasheets in Attachment-I (applicable for both commercial and for trial batches in Attachment-III.
The variations in the critical process parameters in lot to lot/batch to batch shall be justified with scientific logic and shall be captured in batch manufacturing record as well as process qualification report.
At compression stage Challenge study performs like Hopper study, Speed study and Cycle study ranges shall be done for the minimum, optimum and maximum ranges and shall be recorded in the attachment of respective batch number. For Liquid Top , Middle & Bottom at fixed speed and for Dry powder(FFS), Start middle & End cycle run & sealing temperature (Low, Middle & High)
Results from testing of in-process samples, intermediate product and final product of the process qualification Batches shall be checked by QC person for correctness and compliance to respective acceptance criteria. This shall be independently checked by QA person.
Variability ‘within’ a validation batch shall be assessed by QA by comparing the results of samples drawn from various locations / different intervals using the Relative Standard Deviation criteria pre-defined in the protocol.
Likewise, variability ‘between’ Validation Batches shall be assessed by QA by comparing the process parameters and test results of each batch at every stage of testing with the other process qualification batches. Results that are significantly different shall be investigated to determine the cause of variability.

OTHER RESOURCES: MASTER FORMULA OF PHENYLEPHRINE HYDROCHLORIDE,CETRAZINE DIHYDROCHLORIDE ,PARACETAMOL & CAFFEINE ANHYDROUS TABLETS

Process Qualification Report

The process qualification report shall be prepared by QA by compilation of BMR data and QC analytical report as per Attachment-II.
During execution of process qualification batches all the data shall be recorded as per test datasheet in protocol as per Attachment-I for each batch
Preparation of the interim report first, second and third after completion of manufacturing and packing process of respective batches.
Interim report shall be prepared by QA reviewed by Production department and approved by QA Head.
All finished product result shall be compiled as per acceptance criteria and shall be attached with reports.
Any deviation or event observed during execution of process qualification batches shall be handled as per Handling, Management and investigation of Deviation.
A process Qualification summary report shall be prepared after completion of process qualification batches as per Attachment-II.
Process qualification summary report shall be prepared by QA and reviewed by production and approved by QA Head.
Approved Process qualification summary report shall be shared with production department to freeze all the critical process parameters and revise the BMR.
Refer Decision tree for identification of PPQ batches as per Attachment-IX.
Release of Process Qualification batches for distribution.
Process qualification batches shall be released for distribution after:
Successful completion of process qualification activity and review, approval and signing off the process qualification interim report with supporting raw data.
Ensure no impact on product quality prior to release of each process qualification batch.
Re-Process Qualification criteria:
Change in Vendor of API & Excipients.
Change in manufacturing process.
Change in critical process parameters.
Change in batch size.
Change in make, model or capacity of manufacturing equipment.
Transfer product from one location to another.
Based on associated risk and impact analysis the extent of process qualification shall be decided which may include the entire process that is impacted.

Requirement for the introduction of new product in the facility:

Products shall be transferred to sites with minimum 3 months stability data (accelerated and long term) of 1 FDD batch/site transfer batch. This stability data should be part of Master Formula Record or (MFR) or Product Specific Test Procedure (STS) given by FDD or site transfer team.
A permanent change control shall be initiated by the user department and approved as per Change Control SOP.
Based on above satisfactory stability data by FDD or site transfer team shall give pre approval to site to start manufacturing one (1) optimization batch (scale up) and 3 commercial process qualification batches.
Scale up/ Optimization batches shall be monitored by production department in coordination with QA and Process Qualification team.
The details of execution of process optimization batch shall be recorded as per Attachment-III.
All the critical process parameters shall be identify in the protocol for the particular product and batch shall be manufactured by referring the tentative limit as provided in MFR/BMR/PPQ protocol (provided by site transfer team or document provided by FDD).
Note:-The critical process parameter and their control limit mentioned in the BMR are considered to be the tentative limit and any deviation observed during the manufacturing process shall be recorded in the respective BMR. Such deviations are to be verified by QA/ FDD representatives and appropriate remark shall be written in the concern page of BMR.
Parameters which are indicative and need to be established during process qualification shall be established / freezed after successful completion of process qualification
The actual reading obtained during wet granulation is likely to vary from the limit mentioned from the BMR. Similarly, the limits provided in BMR/MFR for Hardness/thickness/ yields are indicative only and need to be established during process qualification.
Final Yields of each stage of process manufacturing and packaging shall be freezed in BMR / BPR after evaluation of 10 batches meanwhile process manufacturing yield and packaging yield shall be tentatively mention in commercial batches on the basis of 3 process qualification batches.
After 10 batches yields shall evaluated by QA and Production both and shall revised by initiating change control for BMR / BPR for further commercial manufacturing batches. These yields at each stage shall be continue monitoring and evaluated in continue process verification of process validation Stage-3.
All identified Tentative/ indicative or to be established parameters can be highlighted by following Good Documentation Practices like application of Symbols and putting remarks against the symbol on the same page.
After successful monitoring of Scale up/Optimization batches, Process monitoring report shall be attached with respective BMR.
Process Optimization shall be prepared by production department, reviewed by Production head and shall formally approved by QA Head.
After successful completion of one (1) optimization batch (scale up), three (3) consecutive commercial process qualification batches shall be manufactured.
Three (3) commercial process qualification batches shall be charged on stability.
Optimization batch shall be considered as commercial batch, only if there is no change in manufacturing formula and process compared to 3 process qualification batches.
In case during optimization batch there is change, which can impact the stability of product like (but not limited to) change in batch size, change in equipment (different principle of operation), critical process step or change in manufacturing formula and process then optimization batch should not be considered as commercial batch.
Challenge study shall be performed during process qualification batches, which shall include Full Hopper, Half Hopper, Low Hopper, High Speed, Optimum Speed, Low Speed, Low Hardness & High Hardness (If Applicable) Based on findings, processing parameters shall be updated. For Liquid stirring time, Low, Middle & High Time.
Challenge study shall be performed at the start of the compression operation after initial machine setting verified by QA.
QA shall prepare the protocol for process qualification and carryout sampling and testing of physical parameter as per the approved protocol. QA shall verify the parameter and record in the protocol/BMR.
To monitor and record the CQAs and Process Parameters details at various stages (Granulation, Lubrication, Compression, Coating and Packing) of manufacturing in case of Tablet, (Granulation, Lubrication, Filling & Sealing and Packing) of manufacturing in case of Dry Powder and (Dispensing, sifting, Filtering, Mixing, Filling & Sealing and Packing) of manufacturing in case of Liquid.
Requirement of any of the process qualification batches shall be decided by FDD/QC/QA and shall be part of PPQ. Based on product, process, technical criticality, reduced sampling plan can be adopted and details shall be mentioned in the sampling plan of respective protocol.
Sample for chemical analysis or microbial analysis shall be collected and sent to QC/Micro by QA.
After completion of the analysis, QC or microbial shall submit the analytical reports/ microbial reports to QA and QA shall prepare the Process qualification report.
The Process qualification report shall be approved by QA Head and Quality head.
These commercial batches shall be released or launched to market only after receipt of satisfactory 6^th month stability data (accelerated and long term) of 1 FDD/ site transfer batch and satisfactory minimum 3 month stability data (accelerated and long term) of 3 commercial process qualification batches with final approval from Quality Head.
These Existing commercial batches or site transferred product shall be released or already launched to marketed only after evaluation of risk on process qualification data of 3 process qualification batches and satisfactory 3 month stability data (accelerated and long term with final approval from Quality Head.
After completion of process qualification report, BMR& BPR shall be revised.
QA shall maintain status of process qualification batches as per given Attachment-VI and for trial batches or optimization batches as per given Attachment-VII.
In case any discrepancies observed during processing of optimization batch at different stages like Granulation, Lubrication, Compression, Coating, or filling, sealing Process Optimization Protocol datasheet shall be used as per Attachment-III.
Process Optimization Protocol test datasheet shall be filled by production department, proposed changes against the existing system shall be filled with proper justification in consultation with Site Transfer team/FDD.
Product Process Qualification Protocol contains a numbering system