Professional Documents
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QUALITY
ASSURANCE
QUESTION
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MOST FREQUENTLY ASKED QUESTIONS
1. What is the definition of SOP?
SOPs are detailed written instructions for the operations routinely performed in the course of
any activities associated with pharmaceutical manufacturing.
Or
A written authorized procedure which gives instructions for performing operations not
necessarily specific to a given product / material, but of a more general nature the equipments
preventive maintenance and cleaning; recall of products; purchasing; cleaning of premises and
environmental control; sampling and inspection etc.
Or
These are guidelines which describe how the activity is to be performed. To achieve uniformity
of results by each individual, it is mandatory to follow these guidelines. SOP is like a “TELL and
SHOW” concept.
Tell – means to establish and teach how the activity is to be carried out.
Show – means to provide the documented proof for the activity carried out.
2. What are the contents of the SOP?
Objective/Purpose, Scope, Responsibility, Accountability, Procedure, List of formats/Annexure,
Abbreviations, Reference, Revision History
3. Which information should master document carry on every page not just one of the pages to
meet GMP?
Page number, document reference number and authorizing signatures
4. How many SOPs required for equipment and what are those?
Operation, Cleaning, Preventive maintenance/ Calibration, Sampling procedure
5. What is the Batch production and control record (BPCR)?
BPCR are prepared for each intermediate and API and include the complete information
relating to the completion of each significant step in the Batch production.
6. What is the Master production & control record (MPCR)?
To ensure the uniformity from batch to batch, master production instructions for each
intermediate and API are prepared, dated and signed by one person, immediately checked,
dated and signed by a person in the quality unit.
7. What are the content of the MPCR?
The name of the intermediate or API being manufactured and an identifying document
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reference code, if applicable
A complete list of raw materials and intermediates designated by names or codes
sufficiently specific to identify any special quality characteristics.
An accurate statement of the quantity or ratio of each raw material or intermediate to
be used, including the unit of measure. Where the quantity is not fixed, the calculation
for each batch size or rate of production should be included. Variations to quantities
should be included where they are justified
The production location and major production equipment to be used
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Australia (AS 1386): 0.035, 0.35, 3.5, 35, 350, 3500
Germany (VDI 2083): 1, 2, 3, 4, 5, 6
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its pre-determined specifications and quality attributes.
Process validation is three types:
1. Prospective process validation
2. Concurrent process validation
3. Retrospective process validation
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e.g: The protocol for manufacturing process identifies process equipments, critical process
parameters, and / or operating range, product characteristics, sampling, test data to be
collected, number of validations runs and acceptance test results.
Contents:
Protocol Approval
Table of contents
Objective
Scope
Responsibility
Accountability
Validation team
Brief manufacturing process (Description, Flow chart, Reaction scheme)
Selection of batches
List of equipments used in the manufacturing process
List of raw materials used in the manufacturing process
Critical operations with justification
In-process controls with acceptance criteria
Sampling & testing plan with frequency
Stability programm
Data to be complied
Acceptance criteria
Intermediate & final products quality & yield
Stability specification
Document review
Conclusion
Revalidation criteria
21. What is the definition of the procedure?
A documented description of the operation to be performed, the precautions to be taken, and
measures to be applied directly or indirectly related to the manufacture of an intermediate /
API (Reference: ICH Q7A).
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22. What is the master document?
Master document is a formally authorized source document relating to specifications, and / or
manufacturing / analytical methods, which is protected from un-authorized access or
amendment.
Documents required describing the quality system requirements in the organization.
Documents required describing the process or product characteristics.
Documents required by various regulatory agencies as part of compliance to GMP
requirements.
Documents required for legal/ regulatory supports of the organization to meet the local
regulations.
Any other documents required by government / regulatory agency.
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Should be of appropriate design, adequate size and have smooth surface.
31. How are cGMP implemented?
Training, compliance to SOPs, control on operations, following procedures / systems,
monitoring through compliance audits.
32. What is solvent?
An organic or inorganic liquid used as a vehicle for the preparation of solutions or suspensions
in the manufacturing of an intermediate / API.
33. What are the classifications of residual solvents?
Residual solvents are classified into three class based on the possible risk to human health:
Class-I (Solvents to be avoided)
Class-II (Solvents to be limited)
Class-III (Solvents with low toxic potential)
34. What is the difference between Responsibility and Accountability?
Responsibility: Personnel directly associated with the implementation of the procedure
Accountability: Person directly associated with the implementation of the system under which
the procedure falls.
35. Write the names of the different countries regulatory body (Like for India, USA, UK, Australia,
South Africa, Brazil, Hungary, Germany, Philippines etc.)
India – Schedule M
United Status of America – USFDA (United state Food and Drug Administration)
Australia – TGA (Therapeutic Goods Administration)
United Kingdom – MHRA (Medicines & Health care products Regulatory Agency)
South Africa – MCC (Medicine Control Council)
Brazil – ANVISA (Brazilian Health Surveillance Agency or National Sanitary Surveillance Agency)
Hungary - PIC/S (Pharmaceutical Inspection Convention or Pharmaceutical Inspection Co-
operation Scheme)
Germany – NIP (National Institute of Pharmacy)
Philippines – BFAD (Beaureu of Food & Drug)
36. What is the abbreviation of MSDS and how many contents are mentioned & what are those?
MSDS means Material Safety Data Sheet and it contains 16 contents. Those are given below:
1. Product Identification
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2. Composition / Information on Ingredients
3. Hazards identification
4. First Aid measures
5. Fire fighting measures
6. Accidental release measures
7. Handling & storage
8. Exposure controls / Personal protection
9. Physical & Chemical properties
10. Stability & Reactivity
11. Toxicological information
12. Ecological information
13. Disposal consideration
14. Transport information
15. Regulatory information
16. Other information
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Investigating problems
Continual improvement of performance
Assessing for Registration
Reducing cost of operation
Legal requirement
Types: 1. Study/test based inspection
2. Facility based inspection
3. Process based inspection
40. Why nitrogen gas used in the manufacturing area at room temperature and why not other gas?
Because of nitrogen is chemically less reactive and does not react with other elements at
ordinary temperature. It is due to strong bonding in its molecule.
41. What are the different types of cleanings?
There are three types of cleanings:
Batch to Batch cleaning
Periodically cleaning
Product change over cleaning
iii. Preventing changes that could adversely affect product quality or conflict with
registration or regulatory requirement.
iv. Providing an assessment of change and monitors the impact of change.
Level 1 (Minor): Are those that are unlikely to have any detectable impact on the quality
attributes of the product.
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Level 2 (Major): Are those that are likely to have a significant impact on the
quality attributes of the product.
The type of reasons for change control:
- Regulatory requirement
- GMP implementation / enhancement
- Quality improvement
- Capacity enhancement
- Introduction of new product in existing facility
- Cost reduction
- Automation
- Aging of facility
- To manage the unavoidable situation
- Market requirement
47. What is contamination and cross-contamination?
Contamination: The undesired introduction of impurities of a chemical or Microbiological
nature, or of foreign matter, in to or onto a raw material, intermediate, or API during production,
sampling, packaging or repackaging, storage or transport.
Cross-contamination: Contamination of a material or of a product with another material or
product.
55. What is the ICH? Write its aim/purpose and names of the different parties & different regions?
ICH means “International conference on harmonization”.
Aim/Purpose: “Ensure good quality, safety and effective medicines are developed and
registered in the most effective manner, through harmonization of technical requirements”
Different Parties:
1. European commission – European Union (EMEA)
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2. European Federation of Pharmaceutical Industries & Association (EFPIA)
3. Minister of health, Labour & Welfare, Japan (MHLW)
4. Japan Pharmaceutical Manufactures Association (JPMA)
5. US Food & drugs Administration (FDA)
6. Pharmaceutical Research & Manufactures of America (PhRMA)
Different regions:
1. European Union (EMEA)
2. United states of America (USFDA)
3. Japan (MHLW)
56. What URS, DS, FAT, SAT, DQ, IQ, OQ, PQ?
URS:
DS:
FAT:
SAT:
DQ:
Installation Qualification (IQ): Establishing a high degree of confidence that the equipment as
installed is consistent with manufacture’s requirements and specifications.
Operating Qualification (OQ): Establishing a high degree of confidence that the equipment as
installed is able to consistently operate within established limits and tolerances.
Performance Qualification (PQ): Establishing a high degree of confidence, with appropriate
testing that the equipment, under normal operating conditions, will consistently produce a
quality product.
57. Difference between validation & testing?
Both are not same. Testing is defined as the identification of errors (difference between
expected & actual results) in a system. Validation is defined as documented evidence that a
system performance as expected. Validation includes testing but it is more – for instance,
checking the documents for completeness & correctness.
58. Why water is used extensively as a coolant in heat exchange equipments?
Because of the abundance and high heat capacity, water is used as coolant in heat exchange
equipment.
59. What are the different characteristics of the fluid are to be considered while deciding its
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route in a heat exchanges?
The following characteristic of the fluid are to be considered while deciding its route in a heat
exchanger: a) Viscosity b) Fouling c) Corrosiveness d) Pressure
60. When steam distillation recommended?
a) To separate appreciable quantities of higher boiling materials.
b) To separate relatively small amounts of volatile impurity from a large amount of
material.
c) Where use of direct-fired heaters is detrimental to the materials.
d) Where the material is to be subjected to distillation is thermally unstable or will react
with other component associated with it at the boiling temperature.
e) Where the material cannot be distilled by in-direct heating even under low pressure
because of the high boiling temperature.
61. What is the difference between instrument & equipment?
Instrument: A device that takes a physical measurement and displays a value or has no control
or analytical functions. e.g.: Stop watch, timers & thermometer.
[A device <chemical, electrical, hydraulic, magnetic, mechanical, optical, pneumatic> used to
test, observe, measure, monitor, alter, generate, record, calibrate, manage or control physical
properties, movements, or other characteristics].
Equipment: A device or collection of components that perform a process to produce a result.
[The collective analytical measurement instruments in conjunction with firmware, assembled
to perform a mechanical process]
62. What is HVAC?
The HVAC is designed to circulate the air in the area after passing it over cooling & heating
coils to maintain the required environmental conditions & passing it through the series of
filters to maintain desired cleanliness level in the area. The air in-take and out-take of the
system is designed to maintain certain degree of pressure gradient in the area as per
requirements.
Or
HVAC system function is to condition (heating & cooling), replace (makeup, fresh air, oxygen
replacement), and pressurize (contaminant) and clean (filter) the air in the environment to
meet the required operational conditions.
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To achieve this objective, electrical, mechanical & electronic components are arranged in
several configurations such that they produce the expected results.
63. What is the meaning of Q, S, E, M in the ICH?
“Q” stands for Quality; “S” stands for Safety, “E” stands for Efficacy and “M” stands for Multi
dispensary
64. How many guidelines are present in Q & what are those, describe in detail?
In Quality (Q), total 10 guidelines are present. Those are as follows:
1. Q1 - Stability
2. Q2 - Analytical Method validation
3. Q3 - Impurities
4. Q4 - Pharmacopoeia
5. Q5 - Biotechnological quality
6. Q6 - Specification
7. Q7 - Good Manufacturing Practice (GMP)
8. Q8 - Pharmaceutical Development
9. Q9 - Quality Risk Management
10. Q10 - Pharmaceutical Quality System
65. How many types of raw material and packing material?
Raw materials are classified into two types. Those are as follows:
1. Key raw material
2. Other raw material
Packing materials are classified into two types. Those are as follows:
1. Primary Packing material
2. Secondary Packing material
66. Define the Key raw material/ starting material & primary packing material?
Key raw material/starting material:
Starting material shall be defined as that which is
Incorporated as a significant structural fragment of the API / Drug Intermediate and
Having significant effect on the Quality and Yield of the product.
Starting material shall be identified in TDP.
Primary Packing material: Packing material, which come in direct contact with the
API/Intermediate are considered as Primary packing material.
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67. What is cleaning validation?
Cleaning validation is documented evidence that an approved cleaning procedure will provide
equipment which is suitable for processing of pharmaceutical products or APIs.
Cleaning validation is the confirmation of reliable cleaning products so that the analytical
monitoring may be omitted or reduced to a minimum in the routine phase.
It describes the validation of cleaning procedures for the removal of contaminants associated
with the previous products, residues of cleaning agents as well as the control of potential
microbial contaminants.
68. What are the sampling techniques used in the cleaning validation?
Swab sampling: Areas which are reasonably accessible & hardest to clean can be evaluated,
leading to level of contamination or residue per gives surface area.
Rinse sampling: Large areas or parts of equipments which could not be swabbed should be
rinse sampled or directly extracted by solvent. Tubes, nozzles, pipes or containers with surface
those are not reasonably accessible for direct surface sampling have to be rinsed with solvent.
In addition, inaccessible areas of equipment that cannot be routinely disassembled can be
evaluated.
69. What parameters considered during performance qualification of HVAC?
The following parameters are to be considered during the performance qualification of HVAC:
1. Calibration test certificates of instruments
2. Training records of validation team
3. Pressure drop across the HEPA & fine filters
4. Air velocity measurement & calculation of Air changes
5. Integrity test of HEPA filter
6. Differential pressure test
7. Temperature & Relative Humidity test
8. Air flow direction test
9. Cleanliness class verification (Non-viable particle count)
10. Sound level test
11. Light level test
12. Air borne viable particle monitoring
13. Recovery Study
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70. What are the contents in the BPCR?
BPCR contains the following contents, but not limited:
1. Product Name 2. Stage
3. BPCR Document Number 4. MPCR Reference Number
5. Batch Number 6. Date of Manufacturing
7. Date of Expiry/Re-test 8. Batch release details
9. List of equipments used 10. List of raw materials & Quantity with UOM
11. General instructions, Control & Safety instructions
12. Detailed step wise written manufacturing procedures
13. Actual results record for critical process parameters
14. Identity of In-process & Laboratory test results
15. Signatures of person performing details along with supervising details
16. Description of Packaging details
17. Yield calculation
18. Representative of labels for intermediates / raw materials
19. Deviation details
20. Batch starting & completion date
71. What is OOT and define?
“OOT” stands for Out Of Trend. It means any test results obtained for a particular batch that is
markedly different the results of the batches in a series obtained using a same validated
method.
72. How will you prevent cross-contamination between two different products manufactured in
the one production block?
By maintaining the proper pressure differential between the rooms with two Air handling units
(if re-circulation) / one Air handling unit (if 100% fresh air)
73. What is limit of Temperature and relative humidity in the pharma area?
Temperature: 25±2˚C & Relative Humidity: 50±5%
74. What is the difference between dedicated and non-dedicated equipments?
Dedicated equipment: It is used solely for the production of a single product or product line.
Concerns over cross-contamination with other products are markedly reduced. Dedicated
equipments must be clearly identified with the restrictions of use in order to prevent potential
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errors during cleaning and preparation.
Non-dedicated equipment: Where the same piece of equipment is utilized for a range of
products formulations. The prevent of cross-contamination between products becomes the
main objective in the cleaning validation effort. Clearly, cleaning non-dedicated equipments
represents a more significant obstacle to overcome.
75. Which instrument is used for the measuring of RPM?
Techo meter is used for the measurement of RPM.
76. Why three batches consider for the validation?
Because of First one is for information, Second one is for confirmation and Third one is for
evidence.
77. If one batch is failed during the validation, then what will you do for completion of validation?
When a quality parameter fails with respect to the specification, a deviation report shall
be raised and the investigation shall be conducted immediately for the identification of
failure.
If the reason for failure is identified, one more consecutive batch shall be considered for
the validation run by taking preventive actions to avoid those failures (If necessary
revise the MPCR and BPCR).
If the reason is unidentified, another three consecutive batches shall be taken for
validation
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Heavy Metals NMT 0.1 ppm
Conductivity (At 25˚C) NMT 5.1ms.cm-1
Total viable aerobic count NMT100 CFU /ml
Pathogens :
E. coli Absent
Salmonella Absent
Pseudomonas Absent
Staphalococcus aureus Absent
79. Write the different storage conditions as per any guidelines (specify the name of guideline)?
The different storage conditions are given below as per USP:
Freezer : -25°C to -10°C
Cold : Any temperature not exceeding 8°C
Refrigerator : Between 2°C and 8°C
Cool : 8°C to 15°C
Room temp. : The temperature at prevailing working area.
CRT : 20°C to 25°C
Warm : 30°C to 40°C
Excessive heat : Above 40°C
80. What is Fumigation?
92. Do you have any idea about schematic diagram of HVAC system?
Fresh Air
Filtering of Air with Pre filter
Cooling & Heating coil
Filtering of Air with Fine filter
Filtering of air with HEPA filter, If required
Suction of air through return ducts from the process area using some pre filters as per
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requirements
Air is exhausted to atmosphere after filtration wherever required
Portion of air then passes through a dehumidifier wherever dehumidifier is required
In the mixing chamber, return Air & Fresh air get mixed
Process repeats from
93. If two different products are manufacturing in two modules of one production block, then will
you accept the common air handling unit for both pharma area? Write “Yes” or “No” with
reason?
No, because of cross-contamination (if re-circulation of return air)
Yes, if 100% of fresh air is circulated through the respective area.
94. Why blending validation is required? What quality parameters of product are considered for
validation and what parameters of equipment are to be considered during validation?
Because of to provide sufficient documented evidence to assure that the blending operation of
product is capable of repeatedly and reliably producing a homogeneous material to meet
established specifications when operated under defined standard conditions.
The following Quality parameters are to be considered, but not limited:
a) Loss on Drying / Water content
b) Bulk density / tapped density
c) Residual solvent
d) Particle size
The following parameters are to be considered for the equipment during validation, but not
limited:
a) Blender capacity
b) RPM of the blender
c) Occupancy of the blender
d) Number of individual batches to be taken for each blend
e) Mixing time
95. What is the formula for calculation of “Air changes per hour” during HVAC validation?
Total CFM of the blower/Filter x 60
Air changes per hour= ----------------------------------------------------
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Total room volume
96. During the performance qualification in the vacuum tray dryer, how many temperature probs
used?
Total 16 to 24 temperature probes are to be kept during the performance qualification of the
vacuum tray dryer (or number of probes specified in the protocol)
97. What is the formula for the calculation of “MACO” while cleaning between one API to another
API?
Minimum therapeutic dosage of previous product X Minimum batch size of next
product
MACO = -----------------------------------------------------------------------------------------------------------
Safety factor X Maximum therapeutic dosage of the next product
98. What is the limit for “Individual unknown Impurity” in API as per ICH Q2A?
The limit of the “Any individual unknown Impurity” is not more than 0.1%
99. What are the class-I solvents as per ICH Q3C?
Benzene - 2 ppm Carbon tetrachloride - 4 ppm
1,2-Dichloroethane - 5 ppm 1,1-Dichloroethene - 8 ppm
1,1,1-Trichloroethane - 1500 ppm
100. What is the abbreviation of CAS Number?
CAS Number : Chemical Abstract Service Number
101. What is the specific gravity of Methylene chloride?
Specific gravity of Methylene chloride is 1.308 g/ml
102. If equipment is cleaned with water, then finally it should be rinse with suitable solvent as per
guidelines, why?
Because of the last step of the cleaning procedures involve drying with solvent or flushing with
nitrogen, thus ensuring that there is no opportunity for microbial growth.
103. What is mean by “4M”?
“4M” means Man, Machine, Method and Material
104. If supposed your pharma area is class 100000, then what is the maximum light and sound
level as per guidelines?
The light & sound level limits are given below for class 100,000 / ISO 8:
Light Level : Not less than 300 Lux
Sound Level : Not more than 80 decibels
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105. Write the classification of contaminants in clean rooms?
Substance:
Physical : Dust, Dirt, Grit, Fiber, Lint & Fly ash
Chemical : Organic compound, Inorganic salts, vapor, mist, fume & smoke
Biologic : Bacteria, Fungus, Spore, Pollen, Virus, Human skin & cells
Energy:
Energy : Thermal, Light, Electromagnetic (EMI), Electrostatic (ESD), Radiation &
Electrical
106. What is mean by “Clean-in-Place” and “Clean-out-Place”?
Clean-in-Place: The cleaning of large pieces of equipment may be performed in the
equipments permanent location. Generally, in a configuration very similar to that in which it is
utilized for production. This procedure widely known as Clean-in-Place (CIP)
Clean-out-Place: The smaller items are frequently transported to a designated cleaning or
washing area where the cleaning procedures is performed. This practice is known as clean-out
-place (COP)
107. What is the name of the instrument, which is used for measuring of vacuum (in Tars) during
high vacuum distillation?
Macleod gauge
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- Personnel
- Warehouse
- Safety & Environment
- Engineering
- Estate Management
- Info tech
111. Why do we conduct trainings?
It brings awareness and helps us in becoming competent.
112. What is personal hygiene?
Each personal should:
- Wear clean uniform
- Take bath daily
- Report illness or injury
- Be medically fit
- Develop good hygiene habits
113. What are cGMP requirements for building and facilities?
Following are the cGMP requirements:
- Suitable size, construction and location
- Facilitate cleaning, maintenance and proper operation
- Adequate space
- Defined areas of adequate size
- Water supply: continuous and of good quality
- Power supply: continuous
- Adequate lighting, ventilations, air filtration, plumbing sewage, toilet facilities
114. What is mean by designated area?
By designated area we mean:
- Specific area for a specific operation: e.g. packing operation shall be carried out only in
packing room and not elsewhere.
115. How do we know that the gauges are ok?
Gauges are periodically calibrated and they bear the calibration status tag.
116. What is in-process control?
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Monitoring the manufacturing process at different stages is called in-process control.
In-process control of the process provides an acceptable and achievable level of built in quality
assurance for the product. This is possible through appropriate GMP during all manufacturing
steps.
Or
Checks performed during production in order to monitor and, if necessary to adjust the
process and / or to ensure that the intermediate or API conforms to its specifications.
117. What is critical process parameter?
A process parameter whose variability has an impact on a critical quality attribute and
therefore should be monitored or controlled to ensure the process produces the desired quality.
Or
A process condition or material or a test when it is essential to maintain a predetermined rage
in order to reproducibly meet the specification is called critical parameter. Critical parameters
have direct impact on the quality of a product.
118. What precautions are to be observed while working in the powder processing room?
Following precautions should be observed while working in the powder processing rooms:
- Absolute discipline w.r.t complete uniform
- Bunny suit, clean shoe covers, hand loves, snoot mask etc. and SOPs compliance
- Positive pressure
- House keeping
- Avoid foreign objects (pens, pencils, tools etc.)
- Identification / status card on materials
- Stage slips on equipments
- Temperature (less than 25°C)
- Avoid extraneous contamination from dust, insects, micro-organism, foreign particles etc.
- Check the condition of sieves used in multi mill and sifter
- Cleaning and calibration of weighing balances
- Usage of fresh, clean drums and poly bags for final packing.
119. What precautions do we take during storage of API?
All APIs are stored under controlled conditions of temperature and humidity in their designated
area.
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Records of temperature and humidity are maintained on daily basis.
House keeping is done on daily basis and records are kept for the same.
Insects, pests and rodent control procedures are follows.
120. What is mean by the word “Quality”?
Quality is basically customer’s satisfaction through sensitivity.
Or
A measure of a product’s or service’s ability to satisfy the customer’s stated or implied needs.
121. Inspection can be of three types, what are those?
Inspections are three types:
- Study /test based inspection
- Facility based inspection
- Process based inspection
122. Define stability study and its necessity?
Stability study is defined as “stability testing is to provide evidence how quality varies with time
under influence as: temperature, humidity & light”
- Establish re-test period for drug substance
- Establish shelf life for drug product
- Recommended storage conditions
123. Write the different types of stability study conditions as per ICH guidelines?
General storage conditions:
Name Temperature (°C) Relative humidity (%)
Long term 25±2 60±5
Intermediate 30±2 65±5
Accelerate 40±2 75±5
Storage in a Refrigerators:
Long term 5±3 NA
Accelerate 25±2 60±5
Storage in a Freezer:
Long term -20±5 NA
124. What do you mean by “Reference standard” and “Working standard”?
Reference Standard: A substance that has been shown by an extensive set of analytical tests
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to be authentic material that should be of high purity. This standard may be obtained from an
officially recognized source or may be prepared by independent synthesis or by further
purification of existing production material.
Working Standard: A substance of established quality and purity, as shown by comparison to a
primary reference standard, used as a reference standard for routine laboratory analysis
125. What is abbreviation of CTD?
“CTD” means Common Technical Document. This is addressed in the ICH guidelines in the
section of “M” and in the part of “M4”
126. What do you mean by market complaint?
Any communication, written or verbal, received regarding the quality, packing directly from any
traders or product manufacturer and marketing staff or any other such complaints shall be
considered as a Market Complaint.
127. What is maximum time period for the sending of the final response to concerned customer
regarding the market complaint?
Within 30 days or as specified in the Market compliant SOP
128. Describe the categories of the market complaints?
Market complaints are categorized into three types and are as follows:
Critical: Complaints related to suspected contamination, adulteration and mislabeling.
Major: Complaints related to the product not meeting its pre-determined critical specifications
and damage to primary packaging.
Minor: Complaints related to the product not meeting non-critical quality attributes, or damage
to secondary packaging or shortages etc.
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Minor: Those findings that require corrective action plan as agreed between the Auditee
department Head and Quality Assurance.
130. How many phases are divided the performance qualification of purified water system and
write the duration of each phase?
Performance qualification of purified water system is divided into the three phases and
described below:
Phase-I: (a) Develop & finalize operating, preventive maintenance, sanitization procedures.
(b) Demonstrate production & delivery of water of required quality.
(c) To finalize SOP on sanitization, Alert & Action limits.
(d) Phase – I shall be conducted for 30 days.
Phase-II: (a) Demonstrate consistent operation within established ranges.
(b) Demonstrate consistent production & delivery of water of required quality.
(c) Phase – II shall be conducted for 30 days.
Phase-III: (a) Demonstrate extended performance.
(b) Ensure that potential seasonal variations are evaluated & treated.
(c) Phase-III shall be conducted for 10 - 12 months
131. What is the abbreviation of “TDP” and its contents?
“TDP” means Technical Data Package and shall contain the following contents, but not limited:
Brief manufacturing process
Solvents used in the manufacture
Impurity profile
Working standard profile (If any)
Characterization data (if any)
Specifications and test procedures of the supplier
TSE / BSE free Certificate
Stability studies/ Hold time data
Storage conditions
Packing details
MSDS
Certificate Of Analysis (COA)
DMF Number (if any)
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MOST FREQUENTLY ASKED QUESTIONS
132. What are the QA activities during the vendor qualification for Key starting raw material, give
flow chart?
New Vendor
Receive Vendor
Questionnaire/ TDP
Lab/Plant
trial/stability Ok?
Reject Vendor
Information
Approve Vendor Update approved
adequate?
vendor List
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MOST FREQUENTLY ASKED QUESTIONS
134. What are the QA activities during the vendor qualification for Primary packing material, give
flow chart?
New
Vendor Data shall be Compliance
Certificate
available for 3
for
consignments 21 CFR?
1º
Packagi
ng
Quality
complie
s/
Food
Grade
certificati
Organic Vendor
Polymeri samples
c quality OK?
Non
Polymeric
Material
Approved
Reject vendor
Vendor
Page 32 of 32
MOST FREQUENTLY ASKED QUESTIONS
When more than one equipment is involved (equipment chain) for rinsing, suitable
quantity of solvent shall be used and the rinse volume shall be measured.
As per EU GMP:
Maximum permitted number of particles/m3 equal or above
Grade At Rest In Operation
> 0.5 μm >5.0 μm > 0.5 μm >5.0 μm
A 3500 0 3500 0
B 3500 0 350000 2000
C 350000 2000 3500000 20000
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MOST FREQUENTLY ASKED QUESTIONS
D 3500000 20000 Not defined Not defined
Page 37 of 37
MOST FREQUENTLY ASKED QUESTIONS
of the DMF.
152. What are the types of DMF?
There are four types of DMF. They are referred to by their numbers in Roman numerals:
Type-II: DMF is for companies who supply drug substances, drug products, intermediates &
material used in their manufacture.
Type-III: DMF is for companies who supply packaging (container closure system) for human
drugs & biologics.
Type-IV: DMF is for companies who supply excipients
Type-V: DMF is for companies who supply clinical services, sterile manufacturing etc.
Type-I: Is an obsolete number once used for a category that no longer exists because it was
found to easily fit into and overlap with the other four categories.
153. What are the possible reasons for the Non-conformities?
The following are the possible reasons, but not limited:
- Management attitude
- Ineffective documentation
- Lack of trained personnel
- Lack of co-ordination / co-operation within or among departments.
154. What do you mean by Critical Quality Attributes?
A critical quality attributes is a physical, chemical, biological or microbiological property or
characteristic that should be within an appropriate limit, range, or distribution to ensure the
desired product quality.
155. What are the test parameters in the nitrogen gas validation?
Test parameters during validation and its frequency are given below:
a) Test for oil mists - Every 6 months once
b) Test for moisture content - Every 6 months once
c) Particulate count (Non-viable) - Every 6 months once
d) Sterility test (Aseptic area locations) - Every 6 months once
e) Bio burden test (Controlled area locations) - Every 6 months once
* Perform the nitrogen gas sampling & testing for three consecutive days.
f) Purity of nitrogen gas (Based on manufacturer COA)
156. What do you mean by Non-conformity?
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MOST FREQUENTLY ASKED QUESTIONS
Non-conformity is non-fulfillment of a specified or implied requirement of the quality
management system or of a quality work product.
157. Describe the method of testing for checking of MOC of SS material (Molybdenum test)?
Procedure:
i) Put one drop of electrolyte solution of molybdenum test kit on clean metal surface,
which is to be tested.
ii) Switch on the detector and touch the metal tip of the detector on metal surface &
carbon point in electrolyte solution.
iii) Do not pass the current for more than 3 to 4 seconds
iv) If the red color appears and is stable for more than 2 seconds then it can be
concluded that MOC of the part being tested is SS-316.
v) If the solution remains colorless or green color appears then it can be concluded
that MOC of the part being tested is SS-304.
vi) If the black color appears & is stable for more than 2 seconds then it can be
concluded that MOC of the part being tested is SS-302.
158. What do you mean by production?
All operations involved in the preparation of an API from receipt of material through processing
and packaging of an API.
159. Define Bio burden?
The level & type (i.e. objectionable or not) of micro organisms that can be present in raw
materials, API starting materials, intermediates or APIs. Bio burden should not be considered
contamination unless the levels have been exceeded or defined objectionable organisms have
been detected.
160. What is the necessity of analytical method validation?
The principle purpose of analytical validation is to ensure that a selected analytical procedure
will give reproducible and reliable results that are adequate for the intended purpose. It is thus
necessary to define properly both the conditions in which the procedure is to be used & the
purpose for which it is intended.
161. What is the solubility data as per any Pharmacopoeia?
Approximately volume of solvent in ml per gram of solute at
20° to 30° C
Page 39 of 39
MOST FREQUENTLY ASKED QUESTIONS
------------------------------------------------------------------------------
Very soluble : Less than 1
Freely soluble : From 1 to 10
Soluble : From 10 to 30
Sparingly soluble : From 30 to 100
Slightly soluble : From 100 to 1000
Very slightly soluble : From 1000 to 10000
Insoluble / practically soluble : More than 10000
Example: Very soluble means one gram of solute substance will require less than 1 ml
of solvent.
162. What are the different types of safety factors used in the pharmaceutical industries?
1/10 to 1/100th of normal daily dose = Topical products
1/100 to 1/1000th of normal daily dose = Oral products
1/1000 to 1/10000th of normal daily dose = Inject able & Ophthalmic products
1/10000 to 1/100000th of normal daily dose = Research, investigational products.
163. What do you mean by reconciliation?
A comparison, making due allowance for normal variation, between the amount of product or
material theoretically & actually produced/used.
164. What are the contents of Annual product quality review (APQR)?
S.
Contents
No.
1.0 Introduction
3.0 Review of out put for all Isolated Intermediates and Finished Products
6.0 List of Deviations and a brief description of deviations and action taken.
List of customer complaints; Return goods and Recalled goods along with
7.0
description and actions taken
Number of Reprocessed and Reworks batches in all stages during the year-
8.0
2009
15.0 Status of Drug Master File (if any),Drug Master File new updates
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MOST FREQUENTLY ASKED QUESTIONS
165. Which solvents are categorized in the organic volatile impurities (OVI)?
Methylene chloride - 600 ppm
Chloroform - 60 ppm
1,1,2-Tri chloro ethylene - 80 ppm
1,4-Dioxane - 380 ppm
166. What do you mean by customer satisfaction?
Customer’s perception of the degree to which the customer’s requirements have been fulfilled
Any customer wants three things:
- Good product
- Timely feedback
- Timely supply
167. What is the QMS?
It is the quality management system to direct and control an organization with regard to quality.
168. What do you mean by pre-determined acceptance criteria?
The criteria assigned, before undertaking testing to allow evaluation of test results to
demonstrate compliance with a test phase of delivery requirement.
169. What is Master validation Plan (VMP)?
A document providing information on the company’s validation work program. It should define
details of and timescales for the validation work to be performed. Responsibilities relating to
the plan should be stated.
170. What do you mean by product recall?
Products recall means removal or withdraw of marketed material due to violation in laws &
regulations as per regulatory authorities or not conforming to the customers’ specifications.
171. What do you mean by residual solvent?
These are the traces of the solvents left during the manufacturing of drug substances or drug
products. Residual solvents are not completely removed by practical manufacturing
techniques.
172. How can we avoid contaminations in warehouse?
Contamination can be avoided by:
- Proper segregation / identification of different RMs
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MOST FREQUENTLY ASKED QUESTIONS
- Following good house keeping procedures
- Having dedicated sampling tools for each RM
- Segregated rejected materials
- Segregated storage of penicillin RMs
- Separate sampling booth/enclosure for RMs
173. What is retention sample & why retention sample is preserved?
A part of the sample which is representative of the released batch of a finished product
preserved beyond its shelf life.
It is preserved for future reference / reanalysis in cases of market complaints or development
work or any other clarification about the released batch.
174. What will happen if cGMP are not followed?
Non-compliance to cGMP may lead to:
- Poor quality of product / services
- Batch failure
- Market complaints and product recalls
- Company’s reputation affected
- Business will be affected
- Regulatory action
- Injuries or accidents
- Equipment failures
175. What are the safety systems in the plant?
Some of the safety systems used in the plant are:
- Eye washer, safety showers
- Fire extinguishers
- Fire hydrants
- Face shields
- Goggles
- Helmets
- Nose masks
- Safety shoes
- Safety belts
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MOST FREQUENTLY ASKED QUESTIONS
- Hand gloves
- Training on safety rules and use of safety equipments.
176. Would you like to recommend any precautions while operating the equipment?
Following precautions are recommended:
- Make sure that each equipment is numbered and its log is maintained.
- Check whether the equipment is cleaned as per SOP
- Always follow product changeover procedure during product changeover
- Take care of safety rules
- Monitor operating conditions
177. What are the contents of ICH Q7A GMP guidelines?
I. INTRODUCTION
A. Objective
B. Regulatory Applicability
C. Scope
II. QUALITY MANAGEMENT
A. Principles
B. Responsibilities of the Quality Unit(s)
C. Responsibility for Production Activities
D. Internal Audits (Self Inspection)
E. Product Quality Review
III. PERSONNEL
A. Personnel Qualifications
B. Personnel Hygiène
C. Consultants
IV. BUILDINGS AND FACILITIES
A. Design and Construction
B. Utilities
C. Water
D. Containment
E. Lighting
F. Sewage and Refuse
G. Sanitation and Maintenance
V. PROCESS EQUIPMENT
A. Design and Construction
B. Equipment Maintenance and Cleaning
C. Calibration
D. Computerized Systems
VI. DOCUMENTATION AND RECORDS
A. Documentation System and Specifications
B. Equipment Cleaning and Use Record
C. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials
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MOST FREQUENTLY ASKED QUESTIONS
D. Master Production Instructions (Master Production and Control Records)
E. Batch Production Records (Batch Production and Control Records)
F. Laboratory Control Records
G. Batch Production Record Review
VII. MATERIALS MANAGEMENT
A. General Controls
B. Receipt and Quarantine
C. Sampling and Testing of Incoming Production Materials
D. Storage
E. Re-evaluation
VIII. PRODUCTION AND IN-PROCESS CONTROLS
A. Production Operations
B. Time Limits
C. In-process Sampling and Controls
D. Blending Batches of Intermediates or APIs
E. Contamination Control
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MOST FREQUENTLY ASKED QUESTIONS
XVI. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)
XVII. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS
A. Applicability
B. Traceability of Distributed APIs and Intermediates
C. Quality Management
D. Repackaging, Re-labeling, and Holding of APIs and Intermediates
E. Stability
F. Transfer of Information
G. Handling of Complaints and Recalls
H. Handling of Returns
Page 47 of 47
MOST FREQUENTLY ASKED QUESTIONS
Module-2 (QOS):
Module-3 (Quality):
Table of Contents
Body of Data
Page 48 of 48
MOST FREQUENTLY ASKED QUESTIONS
3.2. S Drug Substance
3.2 S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
3.2. S.2 Manufacture
3.2.S.2.1 Manufacturers
3.2.S.2.2 Description of Manufacturing Process and Process Controls
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development
3.2. S.3 Characterization
3.2.S.3.1 Elucidation of Structure and other Characteristics
3.2.S.3.2 Impurities
3.2. S.4 Control of Drug substance
3.2.S.4.1 Specification
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification
3.2. S.5 Reference standards or materials
3.2. S.6 Container Closure system
3.2. S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
3.2.S.7.2 Post approval Stability Protocol and Stability Commitment
3.2.S.7.3 Stability Data
179. What annexure are to be submitted while submitting the Drug Master File?
The following annexure are to be submitted during the initial submission wherever applicable:
Annexure- 1 : Letter of Authorization
Annexure-2 : Letter of Agreement (Where the manufacturer is not intended holder of a
certificate of suitability)
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MOST FREQUENTLY ASKED QUESTIONS
Annexure-3a : Letter of declaration of manufacture according to the presented dossier
and to GMP rules for APIs for Human / Veterinary use.
Annexure-3b : Letter of declaration of manufacture according to the presented Dossier
and to GMP rules and/or a quality assurance system.
Annexure-4 : Letter of declaration of willingness to be inspected according to the
presented dossier and to the GMP rules.
Annexure-5 : Letter of declaration of manufacture regarding the use of material of
human or animal origin including substances at risk of transmitting agents
of animal spongiform Encephalopathy.
Annexure-6 : Letter of commitment to provide samples of required by the EDQM.
180. Write the different parts of 21 CFR and details of different subparts of 21 CFR 211?
21 CFR Part 11 : Electronic records, Electronic signatures, Electronic copies of electronic
record
21 CFR Part 58 : GLP for Non-clinical Laboratory studies regulation
21 CFR Part 210 : cGMP in manufacturing, processing, packing / holding of drug
21 CFR Part 211 : cGMP regulations for finished pharmaceuticals
21 CFR Part 820 : GMP regulations for Medical devices
Subpart A (General Provisions):
21 CFR Section 211.1 : Scope
21 CFR Section 211.3 : Définitions
Subpart B (Organization and Personnel):
21 CFR Section 211.22 : Responsibilities of Quality unit
21 CFR Section 211.25 : Personnel Qualification
21 CFR Section 211.28 : Personnel Responsibilities
21 CFR Section 211.34 : Consultants
Subpart C (Building and Facilities):
21 CFR Section 211.42 : Design & construction features
21 CFR Section 211.44 : Lighting
21 CFR Section 211.46 : Ventilation, Air filtration, Air heating & cooling
21 CFR Section 211.48 : Plumbing
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MOST FREQUENTLY ASKED QUESTIONS
21 CFR Section 211.50 : Sewage and refuse
21 CFR Section 211.52 : Washing and Toilet facilities
21 CFR Section 211.56 : Sanitation
21 CFR Section 211.58 : Maintenance
Subpart D (Equipments):
21 CFR Section 211.63 : Equipment design, size and location
21 CFR Section 211.65 : Equipment construction
21 CFR Section 211.67 : Equipment cleaning and maintenance
21 CFR Section 211.68 : Automatic, Mechanical and Electronic equipment
21 CFR Section 211.72 : Filters
Subpart E (Control of components and drug product container and closures):
21 CFR Section 211.80 : General Requirements
21 CFR Section 211.82 : Receipt and storage of untested components, drug product
containers and closures.
21 CFR Section 211.84 : Testing and approval / rejection of components, drug product
containers and closures
21 CFR Section 211.86 : Use of approved components, drug product containers and
closures
21 CFR Section 211.87 : Retesting of approved components, drug product containers &
closures
21 CFR Section 211.89 : Rejected components, drug product containers & closures
21 CFR Section 211.94 : Drug product containers and closures
Subpart F (Production and process controls):
21 CFR Section 211.100 : Written procedures and deviations
21 CFR Section 211.101 : Charge-in of components
21 CFR Section 211.103 : Calculation of yield
21 CFR Section 211.105 : Equipment identification
21 CFR Section 211.111 : Time limitation on production
21 CFR Section 211.115 : Re-processing
Subpart G (Packaging and labeling control):
21 CFR Section 211.122 : Materials examination and usage criteria
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MOST FREQUENTLY ASKED QUESTIONS
21 CFR Section 211.125 : Labeling issuance
21 CFR Section 211.130 : Packing and labeling operations
21 CFR Section 211.132 :Tamper-evident packing requirements for over-the-counter <OTC>
human drug products
21 CFR Section 211.134 : Drug product inspection
21 CFR Section 211.137 : Expiration dating
Subpart H (Holding and distribution):
21 CFR Section 211.142 : Warehousing procedures
21 CFR Section 211.150 : Distribution procedures
21 CFR Section 211.160 : General Requirements
Subpart I (Laboratory controls):
21 CFR Section 211.165 : Testing and release for distribution
21 CFR Section 211.166 : Stability Testing
21 CFR Section 211.167 : Special testing requirements
21 CFR Section 211.170 : Reserve samples
21 CFR Section 211.173 : Laboratory animals
21 CFR Section 211.176 : Penicillin contamination
Subpart J (Records and Reports):
21 CFR Section 211.180 : General requirements of records and reports
21 CFR Section 211.182 : Equipments cleaning and usage log
21 CFR Section 211.184 : Components, drug product containers, closures and labeling
records
21 CFR Section 211.186 : Master production and control record
21 CFR Section 211.188 : Batch production and control record
21 CFR Section 211.192 : Production records review
21 CFR Section 211.194 : Laboratory records
21 CFR Section 211.196 : Distribution records
21 CFR Section 211.198 : Complaints files
Subpart K (Returned and salvaged drug products):
21 CFR Section 211.204 : Returned drug products
21 CFR Section 211.208 : Drug product salvaging
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MOST FREQUENTLY ASKED QUESTIONS
181. What parameters are to be considered during the analytical method validation of related
substance or Residual solvents?
The following parameters are considered during the analytical method validation of related
substances or Residual solvents:
S. No. PARAMETERS
1. Demonstration of precision
0
1.1 System precision / System suitability
1.2 Sample precision
2. Solution stability
0
3. Limit Of Detection (LOD)
0
4. Limit Of Quantification (LOQ)
0
4.1 Precision at LOQ level
4.2 Accuracy at LOQ level
4.3 Linearity at LOQ level
5. Accuracy
0
6. Linearity
0
7. Ruggedness
0
7.1 On the same column at spiked level
7.2 Variability from analyst to analyst
7.3 Variability from system to system
7.4 Variability from column to column
8. Robustness
0
8.1 Variability of column initial oven temperature
8.2 Variability of carrier gas flow rate
9. Different Batch analysis
0
182. What parameters are to be considered during the analytical method validation of Assay?
S. No. PARAMETERS
1. System suitability
0
Page 53 of 53
MOST FREQUENTLY ASKED QUESTIONS
2. System precision
0
3. Sample precision
0
4. Solution stability and Mobile Phase stability
0
5. Assay Content
0
6. Accuracy
0
7. Linearity
0
8. Ruggedness
0
8.1 With same analyst, same system, same column
8.2 With same analyst, same system, but different column
8.3 With same analyst, same column, but different system
8.4 With same system, same column, but different analyst
9. Robustness
0
9.1 Effect of temperature variation on the column
9.2 Effect of flow variation
9.3 Effect of variation in mobile phase organic composition
9.4 Effect of pH variation in mobile phase
1 Different Batch analysis
0.
0
183. What are the different conditions conducted during the forced degradation study?
The following conditions are conducted during forced degradation study:
a) Thermal degradation
b) Photo degradation (Direct sunlight)
c) Acid hydrolysis
d) Base hydrolysis
e) Oxidation
f) Ultra-violet exposure
184. What is clean zone and clean room?
Clean zone: A defined space in which the concentration of air borne particles is controlled to
Page 54 of 54
MOST FREQUENTLY ASKED QUESTIONS
meet a specified air borne particulate cleanliness class
Clean room: A room in which the concentration of air borne particles is controlled and contains
one or more clean zone.
185. What is As-built clean room (facility)?
A clean room (facility) that is complete and ready for operation, with all services connected
and functional, but without equipment or operational personnel in the facility.
186. What is At-rest clean room (facility)?
A clean room (facility) that is complete and ready for operation, with all services functioning
and with equipment installed and operable or operating, as specified, but without operating
personnel in the facility.
187. What is Operational clean room (facility)?
A clean room (facility) in normal operation, with all services functioning and with equipment
and personnel, if applicable, present and performing their normal work functions in the facility.
Some other terms used in the clean rooms:
188. What is unidirectional and non-unidirectional air flow?
Unidirectional air flow: Airflow having generally parallel steam lines, operating in a single
direction, and with uniform velocity over its cross section; previously referred to as “laminar”
air flow
Non-unidirectional air flow: Air flow which does not meet the definition of unidirectional air
flow, previously referred as “Turbulent or Non-Laminar” air flow.
Page 55 of 55
MOST FREQUENTLY ASKED QUESTIONS
G. Sanitation Intermediates
H. Maintenance F. Time Limits on Production of APIs
IV. Process Equipment and Intermediates
A. Equipment Design, Size, and G. Control of API Contamination
Location H. Blending of APIs and
B. Equipment Construction and Intermediates
Installation VII. Packaging and Labeling Controls
C. Equipment Cleaning and A. Materials Examination and Usage
Maintenance Procedures Criteria
D. Equipment Cleaning Methods B. API Label Issuance
E. Validation of Equipment Cleaning C. Packaging and Labeling
Methods Operations
F. Clean in Place Methods D. API Packaging Materials
G. Automatic, Mechanical, Electronic, E. Expiration or Retest Dating
and Computer VIII. Holding and Distribution of APIs
V. Control of Raw Materials and Intermediates
A. General Controls A. Warehousing Procedures
B. Receipt, Sampling, Testing, and B. Distribution Procedures
Approval of Raw Materials IX. Laboratory Controls
C. Use and Reevaluation of A. General Controls
Approved Raw Materials B. Testing and Release for
D. Rejected Raw Materials Distribution
E. Control of Recovered Solvents, C. Stability Testing
Mother Liquors, and Second Crops D. Reserve Samples
F. Process Water Quality E. Laboratory Animals
VI. Production and Process Controls X. Records and Reports
A. Written Procedures and A. General Controls
Deviations B. Equipment Cleaning and Use
B. Raw Material Weighing and Record
Measuring C. Raw Material, API Packaging
C. Calculation of Yield Materials, and Labeling Records
D. Equipment Identification D. Master Production and Control
E. In-Process Controls, Records
Sampling/Testing of APIs and E. Batch Production and Control
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MOST FREQUENTLY ASKED QUESTIONS
Records A. Reprocessing by Repeating a
F. Production Record Review Chemical Reaction
G. Laboratory Records B. Reprocessing by Physical
H. Distribution Records Manipulations
I. Complaint Files C. Reworking of APIs and
J. Returned APIs and Intermediates Intermediates
K. API and Intermediate Salvaging XIV. Control of Chemical, Biological, and
XI. Validation Physical Contaminants
A. Process Validation Strategy XV. APIs for Clinical Trials
B. The Validation Protocol A. Quality Assurance Measures
C. Prospective Validation B. Quality Control Unit
D. Concurrent Validation C. Equipment and Facilities
E. Retrospective Validation D. Control of Raw Materials
XII. Change Control/Revalidation E. Production and Process Controls
A. Change-Control System F. Process Validation
B. Change-Control Classification G. Change Documentation
XIII. Reprocessing/Reworking of APIs H. Laboratory Controls
and Intermediates I. Documentation
190. What are the contents of South Africa (MCC) GMP Guidelines?
Chapter 1: Quality Management
Principles
Quality Assurance
Good Manufacturing Practice
Quality Control
Audits
Quality Evaluation Audits
Critical Procedures
Chapter 5: Manufacturing
Principle
Validation
Dispensing
Manufacturing Operations
In-process Control
Contamination
Reprocessing
Chapter 6: Packaging
Principles
Component Issue
Packaging Operations
In-process Control
Contamination
Finished Product Release
Chapter 7: Quality Control
Principles
Responsibilities
Equipment
Personnel
Sampling
Testing
Standards, reagents
Documentation
Stability
Chapter 8: Documentation
Principles
Preparation, Issue and Use of Documents
Master Specifications
Master Manufacturing Instructions
Master Packaging Instructions
Batch Records (Starting Materials)
Batch Records (Packaging Materials)
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MOST FREQUENTLY ASKED QUESTIONS
Batch Records (Manufacturing)
Batch Records (Packaging)
Other Procedures and Records
Analytical Records
Other Documentation Required
Chapter 9: Validation
Principles
Validation Master Plan
Validation Protocol
Validation Report
Qualification
Process Validation
Analytical Method Validation
Cleaning Validation
Computer System Validation
Validation of specific dosage forms
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MOST FREQUENTLY ASKED QUESTIONS
Documentation and Control
191. What are the contents of Korean Drug Master File (KDMF)?
Section Contents
1.0 Facilities of Manufacturing site
1.1 Drawings of the whole site plan (each production, laboratory, storage area and
other accessory facilities for production should be labeled for area names, gates,
and corridor)
1.2 A simple plan showing the classification of the rooms (e.g. Class I, II, III, IV) using
different colors according to cleanliness
1.3 Schematic Drawings of air-ventilation system
2.1.1 Origin, finding and developmental history (including when, where, from
what and who extracted, isolated or synthesized the drug, what became the
fundamental source of such finding and when and where the non-clinical
studies and the clinical trial started)
2.1.2 Data on structure elucidation, physico-chemical properties and biological
properties
2.1.3 In case any patent has been acquired in Korea or foreign countries, data
including a copy of the patent register, etc.
2.2 Data on stability
2.2.1 As data in conformity with the "Guidance on Stability Test of Drugs, etc." as
stipulated by the FDA Commissioner, specific analytical methods shall be
described and raw data shall be attached.
2.2.2 Test Methods
Section Contents
3. Data on the manufacturing processes, packaging, containers, cautions in handling, etc.
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MOST FREQUENTLY ASKED QUESTIONS
3.1 Manufacturing processes
3.1.1 The overall manufacturing process flow shall be described in detail, and
such description shall include matters relating to in-process controls by
each manufacturing step. And data on starting materials, solvents,
reagents, etc. used in each manufacturing process, such as synthesis
(fermentation), isolation, purification, etc. shall be attached.
6.1 The sample drug substances for the test of three times shall be provided unless
otherwise justified
192. What do you mean by site master file (SMF) and write its contents as per MHRA or PIC/S
guidelines?
The Site Master File is prepared by the manufacturer and contains specific information about
the quality assurance, the production and/or quality control of pharmaceutical manufacturing
operations carried out at the named site and any closely integrated operations at adjacent and
nearby buildings.
The Site Master File provides information on the manufacturer’s operations and procedures
that can be useful in the efficient planning and undertaking of a GMP inspection.
S. No. Contents
C. General Information
1
C.1. Brief information on the firm (including name and address), relation to other sites and,
1 particularly, any information relevant to understand the manufacturing operations
C.1.
Pharmaceutical manufacturing activities as licensed by the Competent Authorities
2
C.1.
Any other manufacturing activities carried out on the site
3
C.1. Name and exact address of the site, including telephone, fax and 24 hrs telephone
4 numbers
Type of actual products manufactured on the site and information about specifically toxic
C.1.
or hazardous substances handled, mentioning the way they are manufactured (in
5
dedicated facilities or on a campaign basis).
C.1. Short description of the site (size. location and immediate environment and other
6 manufacturing activities on the site).
C.1. Number of employees engaged in the quality assurance, production, quality control,
7 storage and distribution
C.1. Use of outside scientific, analytical or other technical assistance in relation to
8 manufacture and analysis
C.1. Short description of the quality management system of the firm responsible for
9 manufacture
C. Personnel
2
C.2. Organization chart showing the arrangements for quality assurance, including production
1 and quality control
C.2.
Qualification, Experience and Responsibilities of key personnel
2
C.2.
Outline of arrangements for basic and in-service training and how records are maintained
3
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MOST FREQUENTLY ASKED QUESTIONS
S. No. Contents
C.2.
Health Requirements for personnel in the production
4
C.2.
Personnel Hygiene requirements, including clothing
5
C. Premises and Equipment
3
C.3. Simple plan or descriptions of manufacturing areas with indication of scale architectural
1 or engineering drawings are not required).
C.3.
Nature of Construction and finishes
2
C.3.
Heat Ventilation & Air Conditioning System (HVAC)
3
C.3.
Handling of Toxic, Hazardous and Sensitizing Chemicals
4
C.3. Brief description of water systems (schematic drawings of the systems are desirable)
5 including sanitation
C.3. Maintenance (description of planned preventive maintenance programmes and recording
6 system
C.3.
Brief description of major production and control laboratories equipment
7
C.3. Maintenance (description of planned preventative maintenance programmes and
8 recording system).
C.3. Qualification and calibration, including recording system. Arrangements for computerized
9 systems validation
C.3.1 Availability of written specifications and procedures for cleaning manufacturing areas
0 and equipment
C.
Documentation
4
C.4. Arrangements for the preparation, revision and distribution of necessary documentation
1 for manufacture
C.4. Any other documentation related to product quality which is not mentioned elsewhere
2 (e.g. microbiological controls on air and water)
C.
Production / Manufacturing
5
Brief description of production operations using, wherever possible, flow sheets and
C.5.
charts specifying important parameters (see at Appendix the list of products
1
manufactured)
C.5. Arrangements for the handling of starting materials. Packaging materials, bulk and
2 finished products, including sampling, quarantine, release and storage
C.5.
Arrangements for Reprocessing and Rework
3
C.5.
Arrangements for the Handling of Rejected Materials & Products
4
C.5.
Brief Description of General Policy for Process Validation
5
C.
Quality Control
6
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MOST FREQUENTLY ASKED QUESTIONS
S. No. Contents
C.6. Description of the Quality Control system and of the activities of the Quality Control
1 Department Procedures for the release of finished products
C.
Contract Manufacturers and Analytical Laboratories
7
C.
Distribution, Compliance and Product Recall
8
C.8.
Arrangements and Recording System for Distribution
1
C.8.
Arrangements for handling of Complaints and Recalls
2
C.
Short description of the Self Inspection system
9
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MOST FREQUENTLY ASKED QUESTIONS
EDI, just as in conventional ion exchange, cations and anions in the feed water are exchanged for
hydrogen and hydroxyl ions in the ion exchange resins, producing de-mineralized water. The key
operational difference is that with EDI, the ion exchange resin is regenerated continuously, while with
conventional ion exchange, chemical regeneration is performed intermittently.
Continuous regeneration in EDI is achieved electrochemically by means of ion conducting membranes
and an imposed electric current. The hydrogen and hydroxyl ions necessary for regeneration are
formed in-situ, without the addition of chemical reagents, by means of the familiar water dissociation
reaction, sometimes called water splitting:
H2O H+ + OH-
With EDI, feed water is fed through ion exchange resin in the diluting chambers bordered by anion- and
cation-conducting membranes. At the same time, electrodes at each end of the unit impose an electric
potential which drives the water splitting reaction and causes the ions in the ion exchange resins to
migrate to the selectively permeable membranes, where they are transported into the adjacent
concentrating chambers. Once in the concentrating chambers, the ions are carried away by the
concentrate flow. Note that just as in conventional ion exchange, EDI benefits from the excellent mass
transfer and de-ionizing characteristics of modern ion exchange resins.
Pre-Treatment Plant
EDI System
UV TREATMENT
USER POINT
The validation of purified water generation shall be done in three phases. The purpose and sampling plan is
described as below:
The initial phase (phase-I) typically begins only after successfully completion of operational qualification.
The water generated during the second phases will be used for the manufacturing as long as the water
meets the specifications.
PHASE- I
During this phase daily samples were taken and analysed for chemical and microbiological quality.
Sampling should be after each step in the treatment process and from each point of use. The incoming
feed water will also be tested to verify the compliance with the specifications. The phase-I shall be
performed for a minimum period of 30days.
At the end of this phase alert and action limits will be established. These alert and action limits
will be used during phase-II and beyond.
The data obtained during phase-I should be used to develop the SOP and confirm that, the operational
SOPs are adequate.
Alert and Action limits shall be calculated based on the phase-1 study.
PHASE- II
This phase is to demonstrate that the system consistently operates within predetermined operating ranges
and delivers the water of the required quality (as specified) when operated in accordance with the SOPs.
The sampling plan will be the same as phase -I, and this activity will continue for 30 days after completion
of phase-I.
PHASE- III
This phase will be continued for 10months to verify the extended performance of system procedures on
the quantity and quality of water despite possible seasonal variations of feed water.
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MOST FREQUENTLY ASKED QUESTIONS
At the end of this phase the performance qualification is considered as completed and on going monitoring
will be established a continuous record of water quality. This activity is under progress. During this phase
purified water samples are collected daily from minimum one point of use, covering all points in a week.
PHASE PRIMARY OBJECTIVES
Develop & Finalize operating, preventive maintenance, sanitization
procedures.
I
Demonstrate production and delivery of water of the required quality
To finalize the SOP on sanitization, Alert & Action Limit.
Demonstrate consistent operation within established ranges.
II Demonstrate consistent production and delivery of water of the required
quality.
Demonstrate extended performance.
III
Ensure that potential seasonal variations are evaluated and treated.
Phase-I: samples shall be collected daily from all user points and tested for chemical and Microbiological
parameters. Chemical parameters like pH, TOC, Conductivity, Nitrates and Heavy metals were tested. For
Microbiology use high nutrient and low nutrient media to isolate the stressed organism.
The rationale of being low nutrient agar (R2A) being used during the validation of purified water was to
enumerate and isolate any adverse microorganisms, which are either slow growing or injured during
preliminary stages of water treatment. The bio-flim formed by the endogenous microorganism adsorbed
on to the surface is also indicative of surviving in low nutrient medium.
The samples tested using high nutrient agar were incubated at 30-35°C for 5 days and those tested using
low nutrient agar were incubated at 20-25°C for 7 days
Analyse the sample as per the Standard Operating Procedure. Phase-I will be started and duration of study
is minimum 30 days.
Phase-II: samples shall be collected daily from all user points and tested for Chemical and Microbiological
parameters. Chemical parameters like pH, TOC, Conductivity, Nitrates and Heavy metals were tested. For
Microbiology use high nutrient and low nutrient media to isolate the stressed organism.
The rationale of being low nutrient agar (R2A) being used during the validation of purified water was to
enumerate and isolate any adverse microorganisms, which are either slow growing or are injured during
preliminary stages of water treatment. The bioflim formed by the endogenous microorganism adsorbed on
to the surface are also indicative of surviving in low nutrient medium.
The samples tested using high nutrient agar were incubated at 30-35°C for 5 days and those tested using
low nutrient agar were incubated at 20-25°C for 7 days
For Microbiology use high nutrient and low nutrient media to isolate the stressed organism. Analyse the
sample as per the Standard Operating Procedure. Duration of Phase-II study is minimum 30 days.
Phase-III: samples are collected daily from minimum one point of use, covering all points in a week for
Page 69 of 69
MOST FREQUENTLY ASKED QUESTIONS
Chemical and Microbiological parameters. For Microbiology use high nutrient media to isolate the stressed
organism. Analyse the sample as per the Standard Operating Procedure.
The samples tested using high nutrient agar was incubated at 30-35°C for 5 days. Duration of Phase-III
study is 10 months which also includes the seasonal variations.
194. What microbial & chemical parameters are to be considered during the nitrogen gas
validation?
195. What microbial & chemical parameters are to be considered during the compressed air
validation?
Page 71 of 71