What is an SOP?
A Standard Operating Procedure (SOP) is a certain type of document that describes in a step-by-step outline form how to perform a particular task or operation. Everyone in a company must follow the same procedures to ensure that studies are performed consistently and correctly. Most companies have a wide variety of SOPs that describe how to do different tasks. In many companies, technicians and operators are trained in how to follow individual SOP's and their training record specifies which SOP's they are trained on and are authorized to use.
What is 21 CFR part 11?
Title 21 CFR Part 11 of the Code of Federal Regulations deals with the Food and Drug Administration (FDA) guidelines on electronic records and electronic signatures in the United States. Part 11, as it is commonly called, defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records.
What are user requirements?
User Requirements Specification describes what users require from the System. User requirement specifications are written early in the validation process, typically before the system is created. It is written by the System Owner and End Users, with input from Quality Assurance. Requirements outlined in the URS are usually tested in the Performance Qualification. User Requirements Specifications are not intended to be a technical document; readers with only a general knowledge of the system should be able to understand the requirements outlined in the URS.
What is a Validation Plan?
Validation Plans define the scope and goals of a validation project. Validation plans are written before a validation project and are specific to a single validation project.Â
Validation Plans can include:
- Deliverables (Documents) to be generated during the validation process
- Resources/Departments/Personnel to participate in the validation project
- Time-Line for completing the validation project
What is an IQ document?
Installation Qualifications are a collection of test cases used to verify the proper installation of a System. The requirement to properly install the system was defined in the Design Specification. Installation Qualifications must be performed before completing Operational Qualification or Performance Qualification.
What is an OQ Document?
Operational Qualifications are a collection of test cases used to verify the proper functioning of a System. The operational qualification tests requirements are defined in the Functional Requirements. Operational Qualifications are usually performed before the system is released for use.
What is a PQ Document?
Performance Qualifications are a collection of test cases used to verify that a System performs as expected under simulated real-world conditions. The performance qualification test requirements were defined in the User Requirement Specification (or possibly the Functional Requirements). Due to the nature of performance qualifications, these tests are sometimes conducted with power users as the system is being released.
What is a Validation Summary Report?
Validation Summary Reports provide an overview of the entire validation project. When regulatory auditors review validation projects, they typically begin by reviewing the summary report. The validation summary report should include:
- A description of the validation project
- All test cases performed, including if those test cases passed without issue
- All deviations reported, including how those deviations were resolved
What is a Change Request?
Change Control is a general term describing the process of managing how changes are introduced into a controlled System. In validation, this means how changes are made to the validated system. Change control is required to demonstrate to regulatory authorities that validated systems remain under control after system changes. Change Control systems are a favorite target of regulatory auditors because they vividly demonstrate an organization capacity to control its systems.
Why water for pharmaceutical use is always kept in a close loop in continuous circulation?
Water is the best medium for many microorganisms, the microorganism can be highly pathogenic which causes serious diseases(many diseases are water born), these pathogens infect after consumption of contaminated water, and microorganisms tend to settle on a surface if water is allowed to stand in a stagnant position for a few hours, these settled microorganisms form a film over the surface of vessel and piping, such film formed by microorganisms is also called biofilm, biofilms are very difficult to remove, once a biofilm is formed at a particular point then that point may form a biofilm again even after cleaning very easily as seed from this point is may not completely get removed effectively.
Biofilms then can become a source of microbial contaminations; therefore purified water after collection in a distribution system is always kept in a closed loop in a continuous circulation.
Continuous circulation is also not enough at some points, therefore it is aided by a high-temperature range from 65 °C to 80°C, a minimum temperature of 65 °C is considered a self-sanitizing, but a better assurance is obtained with a temperature of 80°C.
Purified water collected should be stored in a stainless still vessel which must facilitate distribution to the point of use in a closed loop of continuous circulation, the tank should be made of corrosion-free material of construction and must facilitate sanitization and easy cleaning.
Water for pharmaceutical use shall be free of cations, anions, and other impurities why?
Water for pharmaceuticals must be free from inorganic as well as organic impurities, minerals, and heavy metals. Some impurities like calcium, magnesium, and ferrous are responsible for the degradation of the drug molecules, many cations like ferrous and calcium magnesium act as catalysts in degradation reaction of the drug molecule, anions like chloride are highly active they participate in nucliophylic substitution reactions, where in they break a double bond between -C=C- into a single bond as CL –CH-CH2-, which is a reason why we observe that color dies to tend to be fed in presence of chlorine as most of the dies used are diazo compounds which have plenty of places for nucleophilic substitution reactions, which is also a reason why stability of drug is drastically affected in presence of cations and anions from mineral origin present in water.
Water for pharmaceutical use shall be free of heavy metals why?
Heavy metals like lead and arsenic are highly cumulative neurotoxic metals, heavy metals are not eliminated from our body easily like other drugs and molecules but heavy metals bind with proteins and tend to get accumulated in fatty tissues, and nerve tissue is most likely to get damaged by heavy metals, heavy metals cause nervous tissue damage there for water must be free from heavy metals.
Brazil falls under which climatic zone?
Zone IVB (30℃ and 75% relative humidity)
Change in the size or shape of the original container requires any stability study.
Change in the size or shape of the original container may not necessitate the initiation of a new stability study.
Forced degradation (stress testing) and accelerated stability testing are the same?
Forced degradation and stress testing are not the same. Stress testing is likely to be carried out on a single batch of the drug substance. The testing should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C) above that for accelerated testing), humidity (e.g., 75 percent relative humidity or greater) where appropriate, oxidation, and photolysis on the drug substance.
The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photostability testing should be an integral part of stress testing.
According to WHO guidelines, what is the storage condition of climatic zone IVa and zone IVb?
Zone IV a: 30°C and 65% RH (hot and humid countries)
Zone IV b: 30°C and 75% RH (hot and very humid countries
Countries come under climatic zone IVb?
Brazil,Â
Cuba,Â
China,Â
Brunei,Â
Cambodia,Â
Indonesia,Â
Malaysia,Â
Myanmar,
Philippines,
Singapore,
Thailand
What is the purpose of stress testing in stability studies?
Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating the power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved.
What is the formula for calculating the number of air changes in an area?
The number of air changes/hour in an area is
= Total Room Airflow In CFM x 60 / Total Volume of room in cubic feet
For calculating Total Room Airflow in CFM, first, calculate the airflow of the individual filter. The formula is given below.
Air flow (in cfm) = Avg.air velocity in feet/Minute x Effective area of filter
Then find the Total airflow. The formula is Total Airflow = Sum of airflow of the individual filter.
Airflow Velocity can be measured with the help of an Anemometer.
What is a dead leg?
A dead leg is defined as an area in a piping system where liquid can become stagnant and not be exchanged during flushing.
What are the recommended bioburden limits of purified water & WFI?
Purified water has a recommended bioburden limit of 100 CFU/mL, and water for injection (WFI) has a recommended bioburden limit of 10 CFU/100 mL.
Brief about ICH stability guidelines?
- Q1A- Stability testing of new drug substances & products
- Q1B- Photostability testing of new drug substances & products
- Q1C-Stability testing of new dosage forms
- Q1D-Bracketing & Matrixing designs for testing of new drug substances and products
- Q1E-Evaluation of stability data
- Q1F-Stability data package for registration applications in climatic zone III & IV (Withdraw)
What are significant changes in stability testing?
- A 5% change in an assay for the initial value.
- Any degradation products exceed its acceptance criterion.
- Failure to meet the acceptance criterion for appearance, physical attributes, and functionality test.
- Failure to meet acceptance criteria for dissolution for 12 units.
If the leak test fails during in-process checks what needs to be done?
- Immediately stop the packing process and check for
- Sealing temperature
- Verify for any possible changes like foil width, knurling etc.
- Check & quarantine the isolated quantity of packed goods from the last passed in-process.
- Collect random samples & do a retest.
- Blisters from the leak test passed containers shall allow going further and rest must be de-blistered/de-foiled accordingly.
How many Tablets shall be taken for checking friability?
For tablets with unit mass equal or less than 650 mg, take a sample of whole tablets corresponding to 6.5g. For tablets with a unit mass of more than 650mg, take a sample of 10 whole tablets.
What is the pass or fail criteria for the friability test?
Generally, the test is run for once. If any cracked, cleaved or broken tablets are present in the tablet sample after tumbling, the tablets fail the test. If the results are doubtful, or weight loss is greater than the targeted value, the test should be repeated twice and the mean of the three tests determined. A mean weight loss from the three samples of not more than 1.0% is considered acceptable for most of the products.
What is the standard number of rotations used for the friability test?
100 rotations
What is the fall height of the tablets in the friabilator during friability testing?
6 inches. Tablets fall from 6 inches eight in each turn within the apparatus.
Why do we check hardness during in-process checks?
To determine the need for pressure adjustments on the tableting machine. Hardness can affect the disintegration time. If tablet is too hard, it may not disintegrate in the required period of time. And if a tablet is too soft it will not withstand handling and subsequent processing such as coating, packing etc.
What needs to be checked during in-process QA checks?
- Environmental Monitoring
- Measured values obtained from the process equipment (ex: temperature, RPM etc.)
- Measured values obtained from persons (ex: timings, entries etc.)
- Process attributes (Ex: weight, hardness, friability etc.)
What precautions shall be taken while collecting in-process samples?
While collecting in-process samples, avoid contamination of the product being sampled (Don’t collect samples with bare hands) & avoid contamination of sample taken.
In a tablet manufacturing facility, ‘positive’ pressure is maintained in processing area or service corridors.
In tablet manufacturing facilities, pressure gradients are maintained to avoid cross-contamination of products through air. Usually, processing areas are maintained under positive pressure with respect to service corridors.
If sticking is observed during tablet compression what may the probable reason for the same?
- If the granules are not dried properly sticking can occur.
- Too little or improper lubrication can also lead to sticking.
- Sticking can occur because of too much binder or hygroscopic granular.
What checks shall be carried out while calibrating the DTÂ apparatus?
While calibrating the DT apparatus, the following checks shall be performed.
- Number of strokes per minute (Limit: 29-32 cycles/min)
- Temperature by probe & standard thermometer (Limit: 37 ± 1 °C).
- Distance traveled by basket (Limit: 53 -57mm)
ALSO READ:Â Frequently Asked Questions (FAQ): Data Integrity
What are In-process checks?
In-process checks are checks performed during an activity,In order to monitor and, if necessary, adjust the process to ensure that product confirms its specification.
What is the difference between disintegration and dissolution?
Disintegration is a disaggregation process, in which an oral dosage form falls apart into smaller aggregates. (Disintegration time is the ‘break up’ time of a solid dosage form).
Whereas dissolution is a process by which a solid substance enters in the solvent to yield a solution. It is controlled by the affinity between the solid substance and the solvent.
In other words, disintegration is a subset of dissolution.
Why do we calibrate qualified equipment/instruments on definite intervals?
Equipment or instrument can ‘drift’ out of accuracy between the time of qualification and actual use. So it is recommended to calibrate and recalibrate the measuring devices and instruments at predetermined time intervals, to gain confidence in the accuracy of the data.
Explain about revalidation criteria of the AHU system.
AHU system shall be revalidated periodically as mentioned in the regulatory standards. AHU shall be revalidated in the following cases also.
- When the basic design of AHU is changed,
- When clean room volume is changed,
- When new equipment is installed
- When construction is carried out, that calls for a reconstruction of the AHU system.
What needs to be checked during AHU validation?
During AHU validation, the following tests shall be carried out
- Filter efficiency test,
- Air velocity & number of air changes,
- Air flow pattern (visualization)
- Differential pressure, temperature and RH
- Static condition area qualification
- Dynamic condition qualification
- Non-viable count
- Microbial monitoring
- Area recovery and power failure study.
Position of oblong tablets to be placed in hardness tester to determine the hardness? Lengthwise/widthwise?
The position of oblong tablets should be length-wise because the probability of breakage is more in this position.
Explain in detail the qualification of the pharmaceutical water systems?
Qualification of pharmaceutical water system involves three phases
- Phase -1
- Phase -2
- Phase -3
Phase - 1
A test period of 2-4 weeks should be spent on monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. Water cannot be used for pharmaceutical manufacturing in this phase. The following should be included in the testing approach.
Under-take chemical & microbiological testing in accordance with a defined plan.
- Sample incoming feed water daily to verify its quality.
- Sample each step of the purification process daily.
- Sample each point of use daily.
- Develop appropriate operating ranges.
- Demonstrate production and delivery of product water of required quantity and quality.
- Use and refine the SOP’s for operation, maintenance, sanitization, and troubleshooting.
- Verify provisional alert and action levels.
- Develop and refine test failure procedure.
Phase - 2
A further test period of 2-4 weeks. The sampling scheme will be same as Phase – 1. Water can be used for the manufacturing process in this phase. Approach should also
- Demonstrate consistent operation within established ranges.
- Demonstrate consistent production & delivery of water of the required quality and quantity.
Phase - 3
Phase 3 runs for one year after the satisfactory completion of phase-2. Water can be used for the manufacturing process during this process.
Objectives & Features of Phase -3
- Demonstrate extensive reliable performance.
- Ensure that seasonal variations are evaluated.
- The sample locations, sampling frequencies and test should be reduced to the normal routine pattern based on established procedures proven during Phase -1 & phase - 2.
What is the difference between calibration and Validation?
Calibration is a demonstration that, a particular Instrument or device produces results within specified limits by comparisons with those produced by a reference or traceable standard over an appropriate range of measurements.
Whereas Validation is a documented program that provides high degree of assurance that a specific process, method or system consistently produces a result meeting pre-determined acceptance criteria.
In calibration performance of an instrument or device is compared against a reference standard. But in validation, such a reference standard is not used. Calibration ensures that instruments or measuring devices produce accurate results. Whereas validation demonstrates that a process, equipment, method or system produces consistent results (in other words, it ensures that uniform batches are produced).
Why do we consider three consecutive runs/batches for process validation? Why not two or four?
The number of batches produced in the validation exercise should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation and reproducibility.
- The first batch quality is accidental (co-incidental),
- The second batch quality is regular (accidental),
- The third batch quality is validation (confirmation).
In 2 batches we cannot assure the reproducibility of data, 4 batches can be taken but the time and cost are involved.
What is bracketing & matrixing in stability testing?
Both Matrixing & Bracketing are reduced stability testing designs
Bracketing
The design of a stability schedule, is such that only samples of extremes of certain design factors (ex: strength, package size) are tested at all time points as in full design. The designs assume that the stability of any intermediate level is represented by the stability of extremes tested.
Matrixing
The design of a stability schedule, such that a selected subset of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point. There for a given time point other than initial & final ones not every batch on stability needs to be tested.
What are the common variables in the manufacturing of tablets?
The particle size of the drug substance
- Bulk density of drug substance/excipients
- Powder load in a granulator
- Amount & concentration of binder
- Mixer speed & mixing timings
- Granulation moisture content
- Milling conditions
- Lubricant blending times
- Tablet hardness
- Coating solution spray rate
Whether bracketing & validation concepts can be applied in process validation?
Both Matrixing & Bracketing can be applied in validation studies.
Matrixing
Different strengths of the same product
Different sizes of the same equipment
Bracketing - Evaluating extremes
Largest and smallest fill volumes
Fastest and slowest operating speeds
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