Question 1. What Is Process Validation?
EMA Definition: “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.”
USFDA Definition: “The collection and evaluation of data, from the process design stage throughout Production, which establishes scientific evidence that a process is capable of consistently delivering quality product.”
Question 2. Which Is The Latest Guidance Document For Process Validation Published By Usfda?
Process Validation: General Principles and Practices, (published on Jan.2011).
Question 3. According To Regulatory Guidelines (usfda), What Are The Stages Of Process Validation?
Process validation involves a series of activities taking place over the lifecycle of the product and process. There are three stages for process validation activities.
Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Question 4. How Many Batches To Be Considered For Process Validation?
The EMA draft guideline states “a minimum of three consecutive batches”, with justification to be provided (there are some exceptions to this statement).
The US FDA guidance states that the number of batches must be sufficient to provide statistical confidence of the process. It is a subtle, but important distinction in the approaches.
Question 5. Explain The Strategy For Industrial Process Validation Of Solid Dosage Forms?
- The use of different lots of raw materials should be included. i.e., active drug substance and major excipients.
- Batches should be run in succession and on different days and shifts (the latter condition, if appropriate).
- Batches should be manufactured in the equipment and facilities designated for eventual commercial production.
- Critical process variables should be set within their operating ranges and should not exceed their upper and lower control limits during process operation. Output responses should be well within finished product specifications.
- Failure to meet the requirements of the Validation protocol with respect to process input and output control should be subjected to process requalification.
Question 6. What Is Validation Protocol?
A written plan of actions stating how process validation will be conducted; it will specify who will conduct the various tasks and define testing parameters; sampling plans, testing methods and specifications; will specify product characteristics, and equipment to be used. It must specify the minimum number of batches to be used for validation studies; it must specify the acceptance criteria and who will sign/approve! Disapprove the conclusions derived from such a scientific study.
Question 7. What Should Be The Content Of Process Validation Protocol?
- General information
- Background/Pre validation Activities, Summary of development and tech transfer (from R&D or another Site) activities to justify in-process testing and controls; any Previous validations.
- List of equipment and their qualification status
- Facilities qualification
- Process flow charts
- Manufacturing procedure narrative
- List of critical processing parameters and critical excipients
- Sampling, tests and specifications
- Acceptance criteria
Question 8. In- Process Validation Studies What Should Be The Blend Sample Size?
1x – 3x dosage unit range on case to case basis. As per USFDA guidance, sampling size can be increased from 1x –10 xs with adequate scientific justification.
Question 9. According To Usfda Guidance How Many Sampling Points Should Be Considered For Collecting Blend Samples?
At least 10 sampling locations to be considered to represent potential areas of poor blending.
In tumbling blenders (ex: V-blenders, double cones, or drum mixers), samples should be selected from at least two depths along the axis of blender.
At least 20 locations are recommended to adequately validate connective blenders (ex: ribbon blender).
Question 10. What Will Be The Reason Of Within Location Variance Of Blend Data?
Inadequacy of blend mix, sampling error or agglomeration.
Question 11. Why Hopper Challenge Study Is Performing During Process Validation?
To evaluate effect of vibrations during compression on blend uniformity, hopper study shall be carried out.
Question 12. What Are The Critical Process Variables In Coating?
Pan RPM, inlet & exhaust temperature, spray rate, gun distance and air pressure.
Question 13. Why Blending Is A Critical Parameter In Tablet Manufacturing?
Less blending will result in non-uniform distribution of drug and poor flow whereas more blending will result in de-mixing leading to non-uniform distribution of drug and increase in disintegration time.
Question 14. What Are The Critical Parameters To Be Checked During Dry Mixing?
Mixing time and mixing speed.
Question 15. What Are The Critical Parameters To Be Checked During Binder Preparation And Addition?
Amount of binder solution and mixing time.
Question 16. What The Major Variables In Tablet Compression?
Speed of machine and hopper level is the major variables.
Question 17. What Is The Revalidation Criterion For Process Validation?
- Change in formulation, procedure or quality of pharmaceutical ingredients.
- Change of equipment, addition of new equipment and major breakdowns/maintenance, which affect the performance of equipment.
- Major change of process, parameters.
- Change in manufacturing site.
- On appearance of negative quality trends.
- On appearance of new findings based on current knowledge.
- Batch size change.
Question 18. What Are The Benefits Of Process Validation?
- Consistent through output.
- Reduction in rejections and reworks.
- Reduction in utility cost.
- Avoidance of capital expenditures.
- Fewer complaints about process related failure.
- Reduced testing process and finished goods.
- More rapid and accurate investigations into process deviation.
- More rapid and reliable start-up of new equipment.
- Easier scale-up from development work.
- Easier maintenance of equipment.
- Improve employee awareness of processes.
Question 19. What Are The Common Variables In The Manufacturing Of Tablets?
- Particle size of the drug substance
- Bulk density of drug substances/excipients
- Powder load in granulator
- Amount and concentration of binder
- Mixer speed & mixing timings
- Granulation moisture content
- Milling conditions
- Lubricant blending times
- Tablet hardness
- Coating solution spray rate
Question 20. What Is The Action Plan If A Test Failure Observed During Process Validation?
Any test during process validation shall investigate to determine the case of failure. Where the case of failure is not obvious, it may useful to us an investigation procedure to ensure that all the possible areas of potential failure are covered. Once the case of the process validation failure has been identified, the failure shall classify into the following categories.
Type I: where the failure can be attributed to an occurrence which is not intrinsic to the process for example, an equipment failure raw material that it can be agreed to complete the validation exercise substituting another batch for the one that failed. This investigation and the subsequent action shall be included in the validation report.
Type II: where the failure may be attribute failure or where the investigation is inconclusive than the validation exercise has failed. In this case the validation terms decide and justify the course of action to be taken, recording its justification and recommendations.
This decision shall consider:
- Re-testing – if investigation of the analytical results supports the decision.
- Introduction a change in operation parameters, process steps.
- Changing the process equipment or the procedure for using the equipment.
- Suspension of the process validation exercise until further technical evaluation and/or development has been carried out.
- Changing the sampling regime.
- Review of historical data.
- Change of the process validation acceptance criteria.
- Change to an analytical procedure.
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