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• Both Matrixing and Bracketing can be applied in VALIDATION studies.
• Matrixing
• Different strength of same product
• Different size of same equipment
• Bracketing - Evaluating EXTREMES
• Largest and smallest fill volumes
• FASTEST and slowest operating SPEEDS

PARTICLE SIZE of the drug substance:

• Bulk density of drug substance/excipients
• Powder load in granulator
• Amount & concentration of BINDER
• Mixer speed & mixing timings
• Granulation moisture content
• Milling conditions
• LUBRICANT blending times
• Tablet hardness
• COATING solution spray rate

Particle size of the drug substance:

ICH STABILITY ZONES:

Zone: Type of Climate

Zone I: Temperate zone

Zone II: Mediterranean/subtropical zone

Zone III: Hot dry zone

Zone IVA: Hot humid/tropical zone

Zone IVb:

• ASEAN testing conditions hot/higher humidity
• Long TERM Storage condition
• Climatic Zone
• Temperature
• Humidity

Minimum Duration:

Zone I: 

21ºC ± 2ºC

45% rH ± 5% rH

12 Months

Zone II:

25ºC ± 2ºC

60% rH ± 5% rH

12 Months

Zone III:

30ºC ± 2ºC

35% rH ± 5% rH

12 Months

Zone IV:

30ºC ± 2ºC

65% rH ± 5% rH

12 Months

Zone IVb:

30ºC ± 2ºC

75% rH ± 5% rH

12 Months

Refrigerated

5ºC ± 3ºC

No Humidity

12 Months

FROZEN

-15ºC ± 5ºC

No Humidity

12 Months

ICH STABILITY ZONES:

Zone: Type of Climate

Zone I: Temperate zone

Zone II: Mediterranean/subtropical zone

Zone III: Hot dry zone

Zone IVa: Hot humid/tropical zone

Zone IVb:

Minimum Duration:

Zone I: 

21ºC ± 2ºC

45% rH ± 5% rH

12 Months

Zone II:

25ºC ± 2ºC

60% rH ± 5% rH

12 Months

Zone III:

30ºC ± 2ºC

35% rH ± 5% rH

12 Months

Zone IV:

30ºC ± 2ºC

65% rH ± 5% rH

12 Months

Zone IVb:

30ºC ± 2ºC

75% rH ± 5% rH

12 Months

Refrigerated

5ºC ± 3ºC

No Humidity

12 Months

Frozen

-15ºC ± 5ºC

No Humidity

12 Months

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 for 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 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 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 trouble shooting.
• Verify provisional alert and action levels.
• Develop and refine test failure procedure.

Phase -2:

A further test period of 2-4 weeks. Sampling scheme will be same as Phase – 1.Water can be used for manufacturing process in this phase. Approach should also

• Demonstrate consistent operation within established ranges.
• Demonstrate consistent production & delivery of water of required quality and quantity.

Phase - 3:

Phase 3 runs for one year after satisfactory completion of phase-2.Water can be used for 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.

Qualification of pharmaceutical water system involves three phases:

Phase -1:

A test period of 2-4 weeks should be spent for 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 testing approach.

Phase -2:

A further test period of 2-4 weeks. Sampling scheme will be same as Phase – 1.Water can be used for manufacturing process in this phase. Approach should also

Phase - 3:

Phase 3 runs for one year after satisfactory completion of phase-2.Water can be used for manufacturing process during this process.

Objectives & Features of Phase -3:

During AHU VALIDATION, 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.

During AHU validation, following tests shall be carried out:

AHU system SHALL be revalidated periodically as mentioned in the regulatory standards.

AHU shall be revalidated in following cases also:

• When basic design of AHU is changed,
• When clean room VOLUME is changed,
• When new equipment is installed
• When a CONSTRUCTION is carried out, that CALLS for reconstruction of AHU system.

AHU system shall be revalidated periodically as mentioned in the regulatory standards.

AHU shall be revalidated in following cases also:

While collecting inprocess samples, avoid contamination of the product being sampled (Don’t COLLECT samples with bare HANDS) & avoid contamination of sample TAKEN.

While collecting inprocess samples, avoid contamination of the product being sampled (Don’t collect samples with bare hands) & avoid contamination of sample taken.

Immediately stop packing process and check for:

1. Sealing temperature
2. Verify for any possible changes like foil width,knurling etc.
3. Check & quarantine the isolated quantity of packed goods from last passed inprocess.
4. Collect RANDOM SAMPLES & do RETEST.
5. Blisters from the LEAK TEST passed containers shall allow to go further and rest must be deblistered/defoiled accordingly.

Immediately stop packing process and check for:

A 5% CHANGE in ASSAY for INITIAL VALUE.

A 5% change in assay for initial value.

Q1A- STABILITY testing of new drug SUBSTANCE & PRODUCTS

Q1A- Stability testing of new drug substance & products

PURIFIED WATER has a recommended bioburden limit of 100 CFU/mL, and water for INJECTION (WFI) has a recommen

Purified water has a recommended bioburden limit of 100 CFU/mL, and water for injection (WFI) has a recommen

A DEAD leg is defined as an area in a PIPING SYSTEM where LIQUID can BECOME stagnant and not be exchanged during flushing.

A dead leg is defined as an area in a piping system where liquid can become stagnant and not be exchanged during flushing.

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 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.

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 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.

BRAZIL,Cuba,CHINA,Brunei,Cambodia,Indonesia,MALAYSIA,Myanmar,Philippines,SINGAPORE,THAILAND

Brazil,Cuba,China,Brunei,Cambodia,Indonesia,Malaysia,Myanmar,Philippines,Singapore,Thailand

 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

 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

Forced degradation and stress testing are not 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. Photo stability testing should be an integral part of stress testing.

Forced degradation and stress testing are not 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. Photo stability testing should be an integral part of stress testing.

CHANGE in the size or SHAPE of the original container may not NECESSITATE the INITIATION of new stability STUDY.

Change in the size or shape of the original container may not necessitate the initiation of new stability study.

ZONE IVB (30 DEGREE celsius and 75% RELATIVE humidity)

Zone IVB (30 degree celsius and 75% relative humidity)

Heavy metals like lead and ARSENIC are highly cumulative neurotoxic metals, heavy metals are not eliminated out of our body easily like other drugs and molecules but heavy metals BIND with PROTEINS and tend to get accumulated in fatty tissues, nerve TISSUE is most likely to get DAMAGED by heavy metals, heavy metal causes nervous tissue damage there for water must be free from heavy metals.

Heavy metals like lead and arsenic are highly cumulative neurotoxic metals, heavy metals are not eliminated out of our body easily like other drugs and molecules but heavy metals bind with proteins and tend to get accumulated in fatty tissues, nerve tissue is most likely to get damaged by heavy metals, heavy metal causes nervous tissue damage there for water must be free from heavy metals.

Water for pharmaceutical must be free from inorganic as well as organic IMPURITIES, minerals, and heavy metals. Some impurities like calcium, magnesium, ferrous are responsible for degradation of drug molecule, many cations like ferrous and calcium magnesium act as catalysts in degradation reaction of drug molecule, anions like chloride are highly ACTIVE they participate in nucliophylic substitution reactions, where in they break a double bond between -C=C- in to a single bond as CL –CH-CH2- , which a reason why we observe that color dies tend to FED in presence of chlorine as most of the dies used are diazo compounds which has PLENTY of places for nucliophylic 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 must be free from inorganic as well as organic impurities, minerals, and heavy metals. Some impurities like calcium, magnesium, ferrous are responsible for degradation of drug molecule, many cations like ferrous and calcium magnesium act as catalysts in degradation reaction of drug molecule, anions like chloride are highly active they participate in nucliophylic substitution reactions, where in they break a double bond between -C=C- in to a single bond as CL –CH-CH2- , which a reason why we observe that color dies tend to fed in presence of chlorine as most of the dies used are diazo compounds which has plenty of places for nucliophylic 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 is a best medium for many MICROORGANISMS, microorganism can be a highly PATHOGENIC which causes serious diseases(many diseases are water born), these pathogens infect after consumption of CONTAMINATED water, microorganisms tend to settle on a surface if water is allowed to stand in a stagnant POSITION for few hours, these settled microorganism form a film over the surface of vessel and piping, such film formed by microorganisms is also called as biofilm, biofilms are very difficult of 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.

Water is a best medium for many microorganisms, microorganism can be a highly pathogenic which causes serious diseases(many diseases are water born), these pathogens infect after consumption of contaminated water, microorganisms tend to settle on a surface if water is allowed to stand in a stagnant position for few hours, these settled microorganism form a film over the surface of vessel and piping, such film formed by microorganisms is also called as biofilm, biofilms are very difficult of 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.

Water is a best medium for many microorganisms, MICROORGANISM can be a highly pathogenic which causes serious diseases(many diseases are water born), these PATHOGENS infect after consumption of contaminated water, microorganisms tend to settle on a SURFACE if water is allowed to stand in a stagnant position for few HOURS, these settled microorganism form a film over the surface of vessel and piping, such film formed by microorganisms is also called as biofilm, biofilms are very difficult of 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.

Water is a best medium for many microorganisms, microorganism can be a highly pathogenic which causes serious diseases(many diseases are water born), these pathogens infect after consumption of contaminated water, microorganisms tend to settle on a surface if water is allowed to stand in a stagnant position for few hours, these settled microorganism form a film over the surface of vessel and piping, such film formed by microorganisms is also called as biofilm, biofilms are very difficult of 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.

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.

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.

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

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:

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 tests requirements that were defined in the User Requirement Specification (or possibly the Functional Requirements). Due to the nature of performance qualifications, these tests are sometime conducted with POWER users as the system is being released.

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 tests requirements that were defined in the User Requirement Specification (or possibly the Functional Requirements). Due to the nature of performance qualifications, these tests are sometime conducted with power users as the system is being released.

Operational Qualifications are a collection of test cases used to verify the proper FUNCTIONING of a System. The operational qualification tests requirements DEFINED in the Functional Requirements. Operational Qualifications are usually PERFORMED before the system is RELEASED for use.

Operational Qualifications are a collection of test cases used to verify the proper functioning of a System. The operational qualification tests requirements defined in the Functional Requirements. Operational Qualifications are usually performed before the system is released for use.

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 and Performance Qualification.

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 and Performance Qualification.

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.

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

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.

Validation Plans can include:

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.

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.

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.

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.

Standard Operating Procedure (SOP) is a CERTAIN type of DOCUMENT that describes in a step-by-step 

Standard Operating Procedure (SOP) is a certain type of document that describes in a step-by-step