How to conduct process validation studies

Process Validation - Process Validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality.

Validation Protocol: A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results.

Validation Report: Document reporting the validation activities, the validation data and the summary, conclusions drawn & Recommendation.

Critical Process Parameters: (CPP) - A process parameter, (e.g. temperature, time, speed,etc.) which can affect the critical quality attributes of a product.

Process validation study shall be carried out on the basis of pre-approved protocol as per following  guideline ....

• When receiving a new Master manufacturing formula , product packaging specification, Specification of API, Blend Specification, In-process specification & finished product specification, quality unit shall prepare validation protocol / report  along with new BMR/BPR followed by change control procedure.
• Protocol have information like protocol / report number, introduction, objective and scope. The protocol shall be prepared in either generic name or brand name of the product.
• The validation protocol / report for manufacturing activity shall be reviewed by Production unit, Quality control unit, Engineering, and warehouse and finally approved by Quality unit. the validation protocol /report can be prepared separately at manufacturing and packing stage.
• Details of responsibility of various departments in protocol preparation and approval shall be defined and same monitored, the detail review and comment /suggestion provided by all respective department shall be modified before final approval.
• Product Profile should include the name of the product, composition, shelf life, appearance and storage condition of product.
  
• Give list of equipment, identification number of the equipment, Calibration date, Calibration due date (If applicable) which are required for manufacturing of the product.
• Give list of raw materials (components), its specification, Grade/ Brand name/item codes, approved source and quantity used in the manufacturing.
  
• Draw process flow diagram indicating various steps involved in the manufacturing process, Equipment used and critical steps involved in the manufacturing process of the product.
  
• Explain various process steps – Mixing , Blending/mixing, compression/filling, coating and packing, control variables and measuring responses in detail.
  
• The critical process parameters and quality attributes shall be identified and monitored as per the continued process verification procedure.
  
• Sampling location diagram shall be draw at blending/mixing to explain the location of sampling points.  Sample quantity at each location shall be drawn as per define sampling plan in protocol(at least 10 location sample require) . Clearly define the time spent or the minimum quantity of unit pack like a strip/ a blister/ or a container or a pouch which shall be subjected under / for validation.
  
• Blend uniformity testing, sample quantity of unit dose shall be taken in between Xmg-3Xmg Where X is unit dose of that stage, but not limited to.
  
• Sieve analysis to be carried out at least 20,40,60,80,100 mesh sieve analysis or irrespective to validation protocol.
  
• Give details of punch specifications, compression parameters – such as Uniformity of weight, average weight, group weight, thickness, hardness, friability, disintegration time etc. along with the limits according to master manufacturing formula (MMF) and product specification.
  
• Give the study, test requirement and sampling details of the tablet compression machine at maximum and minimum hardness, Maximum speed and minimum speed and at various stages of compression viz., initial, middle and end stage at optimum hardness and optimum speed.
  
• Coating parameters – Atomizing pressure, Bed temperature, Inlet air temperature, Outlet temperature, Coating pan RPM, peristaltic pump speed, Distance of gun from the bed etc. (in case of tablets coating).
  
• Give the study and sampling details of the tablet-packing machine (Blister & strip) at high sealing temp with slow speed, low sealing temp with high speed and optimum temperature and optimum speed at initial, middle and end stage. During induction sealing, different height & different speed shall be mentioned for the validation.(if applicable).
  
• Give the study and sampling details of the Sachet packing machine at low speed low temperature, high speed low temperature, at low speed, high temperature, at high speed high temperature and at optimum speed and optimum temperature.(where applicable).
  
• Give the study and sampling details of the capsule packing machine (Blister & strip) at high sealing temp with slow speed, low sealing temp with high speed and optimum temperature and optimum speed at initial, middle and end stage.(where applicable).
  
• Give acceptance criteria for premix, blended material/mixed liquid, compressed tablets, coated tablets,  filled bottles and packed tablets/ Bottles filled sachets /filled capsules as mentioned in BMR/BPR and product specification.

1. At the time of execution each and every stage shall be recorded on line and if require wait for quality control testing result ,should wait after getting satisfactory results then proceed to next stage.
   
2. Minimum three batches shall be taken for process validation study for each existing product. The packing validation shall be scheduled for separate packs.
   
3. Sampling plan, which is a part of Process Validation Protocol, shall be prepared to cover the critical process parameters like blending time, drying temperature, compaction force, compression speed, packing, etc, and batches shall be manufactured and sampling shall be performed as per approved batch manufacturing/packing records and Process Validation Protocol.
   
4. Any deviation during validation in process or from specification observed shall be reported on batch records. Evaluation and justification shall be provided for any a typical result or deviations.
   
5. After completion of validation exercise, the results shall be compiled and evaluated,In case there is no change in the batch documentation or specification, same documents shall be used for intended purpose. Or any change observed /recommendation, documents shall be appropriately revised followed by,  evaluated and recorded through change control procedure.
   
6. The addendum to Process Validation Protocol shall be taken for in the cases where additional equipment needs to be included in the batch manufacturing/packing process and same  validation and stability study requirements shall be carried out.

Re-validation criteria 

Process re-validation shall under take when a change occurs in a previously validated process or an established process, the change, which could have an impact on product characteristics. the re-validation will be required in following cases but not limited to.....

• Change in the batch size.
  
• Area change/equipment change/location change.
  
• Process change.
  
• Observations of negative quality trends.
  
• Periodic re-validation
  

Following table also to be consider for re-validation criteria :

Sr. No.	Reason for re-validation	No.of Batches to be validated	Stage to be validated
1	Change in Manufacturing facility/location.	Three batches	All critical stages
2	Change in manufacturing process and product formula	Three batches	All critical stages
3	Change in critical equipment in manufacturing process	Three batches	All critical stages
4	Change in batch size	Three batches	All critical stages
5	Increase in batch  size(Existing)	Three batches & only one  batch in stability	All critical stages
6	As per recommendation of PQR	As per recommendation	As per recommendation

1. Change in API Vendor, process validation shall be carried out on the basis of risk assessment and if the root of the synthesis of the API material is different, otherwise only one batch stability study to be performed at accelerated as well as real time both condition.
2. During validation, samples shall be withdrawn in duplicate/triplicate. One set of samples shall be submitted to quality control for analysis. The other set, shall be preserved in quality unit. In case of failure results, the second set of samples shall be used for investigation.
3. During report preparation, the data generated shall be thoroughly reviewed with respect to acceptance criteria and designed parameters. The result of various parameters, deviations observed during manufacturing shall be reviewed by QA and Production and QC for evaluation. Corrective and preventative actions shall be suggested based on the results of evaluation.
4. Necessary changes, if any as recommended in report, after review in the process/parameters shall be done following change control procedure. If however, there are no changes in any of steps of parameters thereby not promoting revision of batch records, the same version of batch records may be used for further manufacturing.
   
5. After completion of process validation, a summary of validation shall be made as a part of the report stating various parameters/ ranges established during validation.
6. The protocol and report have unique identification number each product have individual protocol and report.If products for which less than three batches have been manufactured, an interim summary report shall be generated for filing purpose as when required, interim reports shall capture the details like no. of batches, mfg. and expiry dates, batch size, description of process, deviation or out of trend observations and Conclusion.