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QA Hand Book Part-3

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0% found this document useful (0 votes)
139 views45 pages

QA Hand Book Part-3

Uploaded by

Tohidur Rahman
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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QA

HAND
BOOK
A Compendium of Guidelines and Related
Materials

EDITION – I
(PART-3)

PHARMACEUTICAL
FORMULATIONS

Ajay Thakur
QA HAND BOOK

Basic Concepts
&
Their
Questions& Answers

Page 492 of 535


QA HAND BOOK
What do you mean by Quality Assurance?
The sum total of the organized arrangements made with the objects of ensuring that all
products are of quality required for their intended use and the quality systems are maintained.

What is Standard Operating Procedure (SOP)?


SOP is a document used for routine or repetitive administrative and technical activities to
facilitate consistency in the quality and integrity of the product/activity. SOP is a written,
controlled document used to describe process, procedure or practice which is required to be
consistently performed.

What is the list SOPs required in QA department?


 SOP for SOP.
 SOP for format preparation.
 Change Control.
 Deviation.
 Non-conformance product.
 Market Complaints.
 Product Recalls.
 Returned Goods.
 Vendor Qualification.
 Preparation of BMR&BPR.
 Assigning of Manufacturing & Expiring date.
 Annual Product Review.
 Corrective & Preventive Action.
 Process Validation.
 Cleaning Validation.
 Equipment Qualification.
 Glossary of terms.
 Document Control.
 Review of BMR/BPR & analytical reports.
 Batch Numbering System.
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 Labeling Practice.
 Personnel Training.
 BMR/BPR Issue & Retrieval.
 Batch Release.
 Internal Audit.
 File Numbering System.
 Preparation of Organogram.
 Preparation of COA.
 Specimen Signatures.
 Technology transfer.
 Measurable Quality Objectives etc.

Which information should master document carry on every page not just one of
the pages to meet GMP?
 Page Number.
 Document Reference Number.
 Authorizing signatures.

What is clean room?


Clean rooms are defined as especially constructed, environmentally controlled enclosed
spaces with respect to airborne particulates, temperature, humidity, air pressure, air flow
patterns, air motion, and vibration, noise, viable and lighting.

What are the classifications of clean rooms?


Generally clean rooms are classified into the following types as per different guidelines:

Schedule M

 Grade A.
 Grade B.
 Grade C.
 Grade D.
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USFDA (US 209E)

 Class 1.
 Class 10.
 Class 100.
 Class 1000.
 Class 10000.
 Class 100,000.

WHO 2002

 Grade A.
 Grade B.
 Grade C.
 Grade D.

EU GMP

 Grade A.
 Grade B.
 Grade C.
 Grade D.

ISO 14644-1

 ISO-3.
 ISO-4.
 ISO-5.
 ISO-6.
 ISO-7.
 ISO-8.
 ISO-9.

Australia (AS 1386)

 0.035.
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QA HAND BOOK
 0.35.
 3.5.
 35.
 350.
 3500.

Germany (VDI 2083)

 1
 2
 3
 4
 5
 6

What is the difference between GMP & CGMP?


GMP

GMP is the part of Quality assurance which ensures that products are consistently produced
and controlled to the quality standards appropriate to their intended use and as required by
the marketing authorization. GMP is aimed primarily at diminishing the risks inherent in any
pharmaceutical production.

Such risks are essentially of two types:

 Cross Contamination.
 Mix-ups.

CGMP

Current Good Manufacturing Practices. This means any procedure/ system adopted by the
manufacturer which proves to be necessary and important for identity, strength and purity of
a product.

What is the difference between Qualification and Validation?

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Qualification is equipment/instrument oriented but validation is process oriented.

What do you mean by validation protocol and its contents of process validation?
A written plan stating, how validation will be conducted and defining acceptance criteria e.g.
The protocol for manufacturing process identifies process equipment’s, critical process
parameters and / or operating range, product characteristics, sampling, test data to be
collected, number of validation 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 equipment’s used in the manufacturing process.
 Critical operations with justification.
 In-process controls with acceptance criteria.
 Sampling & testing plan with frequency.
 Stability program.
 Data to be compiled.
 Acceptance criteria.
 Intermediate & Final Products Quality & Yield.
 Stability Specification.
 Document Review.
 Training Record.
 Conclusion.
 Revalidation Criteria.

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What is 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.

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
amendments.

 Document 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.
 Document required for legal/ regulatory supports of the organization to meet the local
regulations.
 Any other document required by government/ regulatory agency.

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.

What is MSDS and how many contents are mentioned & what are those?

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MSDS means Material Safety Data Sheet and it contains 16 contents. Those are given below:

 Product Identification.
 Composition/ Information on Ingredients.
 Hazards Identification.
 First Aid Measures.
 Fire Fighting Measures.
 Accidental Release Measures.
 Handling & Storage.
 Exposure Controls / Personal Protection.
 Physical & Chemical Properties.
 Stability & Reactivity.
 Toxicological information.
 Ecological Information.
 Disposal Consideration.
 Transport Information.
 Regulatory Information.
 Other Information.

What are the different types of Qualifications?


Qualifications are as follows:

 Design Qualification.
 Installation Qualification.
 Operational Qualification.
 Performance Qualification.

What are the different types of cleanings?


There are three types of cleanings:

 Batch to Batch Cleaning.


 Periodically Cleaning.
 Product Change over cleaning.
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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 seriesof
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.

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 equipment’s 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.

What does the term HEPA mean?


HEPA is an acronym for “High Efficiency Particulate Air” or “High Efficiency Particulate
Arrestance”. This acronym refers to a filter that is manufactured, tested and certified to meet
Institute of Environment Sciences and Technology (IEST) construction, performance and
certification standards as currently published in IEST RP-CC001.3.

How long have HEPA filters been in use?


The first HEPA filters were developed for the Atomic Energy Commission during World War II
for use in facilities manufacturing components for the Manhattan (atomic bomb) project.
These HEPA filters were originally designed to capture microscopic radioactive particles too
small for effective removal by existing type of filters.
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HEPA filters used today are much more efficient and economical than the products made in
the 1940’s.

Where are HEPA filters used today?


HEPA filters are generally specified for application where microscopic airborne particles or bio
pollutants could cause human health or product quality problems.

Typical users include military, nuclear, pharmaceutical, electronics, biological and medical
facilities.

What is that makes HEPA filters so efficient?


The ultra-fine glass-fiber medium captures microscopic particles that can easily pass through
other filters by a combination of diffusion, interception and inertial impaction.

To qualify as a Type A HEPA filter, the filter must capture at least 99.97% (9,997 out of 10,000)
of particles 0.3 microns in size-about 300 times smaller than the diameter of a Human hair,
and 25 to 50 times smaller than we can see.

To a HEPA filter, catching a one-micron particle (1/1,000,000 of a meter) is like stopping a


cotton ball with a door system.

Does HEPA filter efficiency decrease as the filter gets dirty?


No, unlike electronic air cleaners and other air purification technologies that experience
substantial loss of efficiency as they become dirty, exactly the opposite typically happens with
HEPA filters.

In fact, the dirtier a HEPA filter gets, the more efficient it can become.

What is RLAF?
RLAF stands for “Reverse Laminar Air Flow”, CRESCENDDO make RLAF Bench finds a major
application in sampling and dispensing. Majorly used for mixed airflow stream to control the
hazardous emission of dust powder during dispensing or sampling process.

Or
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RLAF is a purifying apparatus fitted with a high efficiency HEPA filter to ensure maximum
protection from airborne contaminants produced at the time of powder handling operations
such as sampling and dispensing.

RLAF filters and its magnehelic gauge reading


 Pre-filter = 10microne- 2 to 8mm of WC
 Intermediate filter = 5 micron- 2 to 8mm of WC
 HEPA filter = 0.3 micron – 7 to 15mm of WC

Where,
As mm of WC = millimeter of water columns

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.

What is QMS?
It is the quality management system to direct and control an organization with regard to
quality.

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.

Why used opacifier in tablet coating?


Opacifier is used to make the ensuring system opaque, given excellent heat insulation when
compacted under pressure.

What are the commonly used opacifiers?


 Titanium dioxide.
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 Aluminium hydroxide.
 Aluminium silicate.

Which excipients are used in enteric coated tablet?

 CAP.
 PVAP.
 Kollicoat (Methacrylic acid Ethyl Acrylate Copolymer (1:1)).

Why plasticizer used in coating solution?


 To increase the plasticity and flexibility.
 To reduce the glass transition temperature (Tg) facilitating transition.

What are the commonly used plasticizers in coating solution?


 Castor oil.
 Glycerin.
 PEG 1000.
 PEG 1450.
 PEG 3350.

Why magnesium stearate is added in the last stage before compression?


Magnesium stearate is added at the last stage of mixing due to prevent the adversely effect on
compressibility and dissolution characteristics.

What type of measurement should be taken for hygroscopic material?


 RH should be under control.
 Wet granulation should be omitted.

Which parameter should be checked after granulation?


 Assay (Blend Homogeneity).
 Granule size (PSD).
 Granules flow ability (BD, TD) etc.
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Which water soluble lubricants are used in pharmaceutical products?
 Sodium lauryl Sulphate.
 Magnesium lauryl Sulphate.

What are Diluent and its properties?


Diluents are fillers used to make required bulk of the tablet when the drug dosage itself is
inadequate to produce the bulk. Secondary reason is to provide better tablet properties such
as improve cohesion, to permit use of direct compression manufacturing or to promote flow.
A diluent should have following properties.

 They must be nontoxic.


 They must be commercially available in acceptable grade.
 Their cost must be low.
 They must be physiologically inert.
 They must be physically & chemically stable by themselves & in combination with the
drugs.
 They must be free from all microbial contamination.
 They do not alter the bioavailability of drug.
 They must be color compatible.

What are additives or excipients?


In addition to active ingredients, tablet contains a number of inert materials known as
additives or excipients.

Different excipients are:

 Diluent.
 Binder and adhesive.
 Disintegrants.
 Lubricants & Glidants.
 Coloring Agents.
 Flavoring Agents.
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 Sweetening Agents.

What are In-Process checks?


In-process checks are checks performed during an activity, In order to monitor and if necessary
to adjust the process to ensure that product confirms to its specification.

What is 21 CFR part 11?


Title 21 CFR Part 11 of the Code of Federal Regulations deals with the Food and Drug
Administration (FDA) guidelines on electronic records and electronic signatures in the United
States. Part 11, as it is commonly called, defines the criteria under which electronic signatures
are considered to be trustworthy, reliable and equivalent to paper records.

What are User Requirements?


User requirements specification describes what users require from the system. User
requirement specifications are written early in the validation process, typically before the
system owner and end users, with input from Quality Assurance.

Requirements outlined in the URS are usually tested in the PQ. 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 requirement outlined in the URS.

Why water for pharmaceutical use is always kept in close loop in continuous
circulation?
Water is best medium for many microorganism can be a highly pathogenic which causes
serious diseases (many disease are water born), these pathogens infect after consumption of
contaminated water, microorganism 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.

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Water for pharmaceutical use shall be free cations, anions and other impurities
why?
Water for pharmaceutical must be free from inorganic as well as organic impurities 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 reactions 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 colors dies tend to fed in presence of chlorine as most of the dies
used are diazo compound 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 use shall be free heavy metals why?


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.

Explain in detail about qualification of pharmaceutical water system?


Qualification of pharmaceutical water system involves three phases:

 Phase 1.
 Phase 2.
 Phase 3.

Phase 1

A test period of 2 to 4 weeks should be spent for monitoring the system intensively. During
this period the system should operate continuously without failure of performance deviation.

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Water cannot be used for pharmaceutical manufacturing in this phase. The following should
be included in testing approach.

 Undertake 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 SOPs for operation, maintenance, sanitization and trouble shooting.
 Verify provisional alert and action levels.
 Develop and refine test failure procedure.

Phase2

A further test period of 2 to 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 quanity.

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 7 Phase 2.

Explain about Revalidation Criteria of AHU system?


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

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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.

What needs to be check during AHU validation?


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.

Briefly explain about ICH climatic zones for stability testing &long term storage
conditions?
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:

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 ASEAN testing conditions hot/ higher humidity.
 Long term storage condition.
 Climatic zone.
 Temperature.
 Humidity.

MINIMUM DURATION
Zone I Zone II Zone III Zone Iva Zone IVb
 21°C ± 2°C.  25°C ± 2°C.  30°C ± 2°C.  30°C ± 2°C.  30°C ± 2°C.
 45% RH ±  60% RH ±  35% RH ±  65% RH ±  65% RH ±
5% RH. 5% RH. 5% RH. 5% RH. 5% RH.
 12  12  12  12  12
Months. Months. Months. Months. Months.
Refrigerated
 5°C ± 3°C.
 No
Humidity
 12
Months.
Frozen
 -15°C ±
3°C.
 No
Humidity
 12
Months.

How can define the commissioning in qualification of equipment and


instruments?
Commissioning is the documented process of verifying the equipment and systems are
installed according to specifications, placing the equipment into active service and verifying its
proper action. Commissioning takes place at the conclusion of project construction but prior to
validation.

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What are the selection criteria during clean area classification that should be
addressed at the design and qualification stages?
The following criteria will be addressed during design and qualification stages of clean area
classification in order to achieve an efficient clean area.

 Building finishes and structure.


 Air filtration.
 Air change rate of flushing rate.
 Room pressure.
 Location of air terminals and direction airflow.
 Temperature.
 Humidity.
 Material Flow.
 Equipment movement process being carried out.
 Outside air conditions.
 Occupancy.
 Type of product.

What is the selection criteria of type of filters for required ambient quality air, air
change rates and return air quality during design and qualification stages of
clean area classification?
The type of filters required for different applications depends on levels of protection that is
briefing in below table

Level of Protection and Recommended Filtration

Level of Protection Recommended Filtration


Level 1  Primary filters only (e.g. EN779G4 filters)
 Production facility operating on 100% outside air:
Level 2 and 3 primary plus.
 Secondary filters (e.g. EN779 G4 plus F8 filters).

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Level 2 and 3  Production facility operating on recirculated plus
ambient air,
 where potential for cross-contamination exists:
primary plus secondary plus tertiary filters (e.g.
EN779G4 plus F8 plus EN1822H13 filters)

Note

The filter classifications referred to above relate to the EN1822 and EN779 test standards
(EN779 relates to filter classes G1 to F9 and EN1822 relates to filter classes H10 to U16).

Examples of Levels of Protection

Level 1 Area

General area with normal, housekeeping and maintenance, e.g. warehousing, secondary
packing.

Level 2 Area

Protected area in which steps are taken to protect the exposed pharmaceutical starting
material or product from contamination or degradation, e.g. manufacturing, primary packing,
dispensing.

Level 3 Area

Controlled area in which specific environmental conditions are defined, controlled and
monitored to prevent contamination or degradation of the pharmaceutical starting material or
product.

What parameter should be considered to achieve targeted air changes rates in


area?
The following parameter should be considered to achieve the required air changes per hour in
area that is:

 Level of protection required.


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 The quality and filtration of the supply air.
 Particulates generated by the manufacturing process.
 Configuration of the room and air supply and extract locations.
 Sufficient air to achieve containment effect.
 Sufficient air to cope with the room heat load.
 Sufficient air to maintain the required room pressure.

What is cross contamination?


Contamination of a starting material, intermediate product or finished product with another
starting material or material during production.

How to control the cross-contamination in clean room?


Following measures assist in preventing cross-contamination that is

 Correct directional air movement.


 A pressure cascade system.
 The displacement concept (low pressure differential, high airflow).
 The pressure differential concept (high pressure differential, low air flow).
 The physical barrier concept.

Note

 Contaminants may result from inappropriate premises (e.g. poor design, layout or
finishing), poor cleaning procedures, contaminants brought in by personnel and a poor
HVAC system.
 Airborne contaminants should be controlled through effective ventilation.
 External contaminants should be removed by effective filtration of the supply air.
 Internal contaminants should be controlled by dilution and flushing of contaminants in
the room, or by displacements airflow.

What is relative humidity?

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The ratio of the actual water vapor pressure of the air to the saturated water vapor pressure
of the air at the same temperature expressed as a percentage. It is the ratio of the mass of
moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature.

What is unidirectional airflow (UDAF)?


Unidirectional airflow should be used to provide product protection by supplying a clean air
supply over the product, minimizing the ingress of contaminants from surrounding areas and
also provide protection to the operator from contamination by the product.

Sampling of materials, primary packaging materials and products, should be carried out in the
unidirectional airflow environmental conditions that are required for the further processing of
the product in a dispensing booth situation.

Dispensing booth should be provided with unidirectional airflow for protection of the product
and operator.

What is the flow direction of pressure differential in manufacturing facilities?


Manufacturing facilities should be maintained at a +ve pressure relative to the outside, to limit
the ingress of contaminants.

Where facilities are to be maintained at negative pressures relative to the ambient pressure to
prevent the escape of harmful products to the outside.

Negative pressure zones should, as far as possible, be encapsulated by surrounding areas with
clean air supplies, so that only clean area can infiltrate into the controlled zone.

What is NDC Code (National Drug Code)?


Each listed drug product listed is assigned a unique 10 digit, 3 segment numbers. This number,
known as the NDC, identifies the labeler, product and trade package size.

 The first segment the labeler code is assigned by the FDA. A labeler is any firm that
manufacturers (including repackers or relabelers) or distribute (under its own name) the
drug.

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 The second segment the product code identifies a specific strength, dosage form and
formulations for a particular firm.
 The third segment the package code identifies package sizes and types. Both the
product and package codes are assigned by the firm.

The NDC Code will be in one of the following configurations: 4-4-2, 5-3-2 or 5-4-1.

What are different types of patents listed in Orange Book?


Patents that are listed in Orange Book include:

 Patents that claim the active ingredients or ingredients.


 Drug product patents which include formulation-composition patents.
 Use patents for a particular approved indication or method of using the product.

The Bolar amendment to the Drug Price Competition and Patent Term Restoration Act allows a
pharmaceutical manufacturer (sponsor) to seek approval from FDA to market a generic drug
before the expiration of a patent relating to the brand name drug upon which the generic
based.

As part of the ANDA, the sponsor must consider the pertinent patents and provide the results
to the FDA. The Act requires patent information to be cled with all newly submitted section
505 drug applications and that no NDA may be approved after September 24, 1984, without
the submission of pertinent patent information to the FDA. The ANDA sponsor must provide a
certification that, in the opinion of the sponsor and to the best of the sponsor’s knowledge
with respect to each patent that claims the listed drug, some or all of the following
certification may be submitted:

Paragraph I: That such patent information has not been filed;


Paragraph II: That such patent has expired;
Paragraph III: Of the date on which such patent will expire; or
Paragraph IV: That such patent is invalid or will not be infringed by the manufacture,
use, or sale of the new drug for which the application is submitted.

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A certification under Paragraph I or II permits the ANDA to be approved immediately, if it is
otherwise eligible.

A certification under paragraph III indicates that the ANDA may be approved on the patent
expiration date.

If the Orange Book lists one or more unexpired patents, the sponsor of the ANDA who seeks
effective approval prior to the patent’s expiration must either:

 Challenge the listing of the patent (e.g., file a Paragraph IV Certification that the patent
is invalid or will not be infringed by the manufacture, use or sale of the drug product).
 File a statement that the application for use is not claimed in the listed patent.

What is Dissolution?
Dissolution rate may be defined as amount of drug substance that goes in the solution per unit
time under standard condition of liquid/solid interface, temperature and solvent composition.
It can be considered as a specific type of certain heterogeneous reaction in which a mass
transfer results as a net effect between escape and deposition of solute molecules at a solid
surface.

Importance (Need of Dissolution)

 Result from in-vitro dissolution rate experiments can be used to explain the observed
differences in in-vivo availability.
 Dissolution testing provides the means to evaluate critical parameters such as adequate
bioavailability and provide information necessary to formulator in development of more
efficacious and therapeutically optimal dosage forms.
 Most sensitive and reliable predictors of in-vivo availability.
 Dissolution analysis of pharmaceutical dosage forms has emerged as single most
important test that will ensure quality of product.
 It can ensure bioavailability of product between batches that meet dissolution criteria.
 Physicochemical properties of model can be understood needed to mimic in in-vivo
environment.

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 Such models can be used to screen potential drug and their associated formulations for
dissolution and absorption characteristics.
 Serve as quality control procedures, once the form of drug and its formulation have
been finalized.

An IR product is considered rapidly dissolving when a mean of 85 percent or more of the


labeled amount of the drug substance dissolves within 30 minutes, using Unites States
Pharmacopoeia (USP) Apparatus 1 at 100 RPM (or at 75 RPM when in each of the following
media:

 0.1 N HCL or Simulated Gastric Fluid USP without enzymes;


 A pH 4.5 buffer, and
 A pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.

An IR product is considered very rapidly dissolving when a means of 85 percent or more of the
labeled amount of the drug substance dissolves within 15 minutes, using the above mentioned
conditions.

Define the Airlock system in Pharmaceutical industry?


Airlock systems play an important role in pharmaceutical industries to protect clean rooms
from contaminants and to prevent cross-contamination. As the name indicates, airlock means
a locking system which is produced by utilizing air pressure. In simple words, Airlock system is
air locking system for the protection of clean areas from contaminants which can
contaminated the clean rooms during men and material flow.

An airlock is produced by creating differential pressure between two areas and differential
pressure is produced by HVAC. According to WHO a differential pressure of 10 to 15 Pascal’s
should be maintained. To produce a higher differential pressure cost of the system is also
increased.

What is the purpose of Airlock system?


 The main purpose of the airlock system is to prevent cross-contamination.
 To prevent the entry of contaminants from less classified area to a highly classified area.
 In a sterile area prevent the entry of less clean air to high clean area.
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 In a sterile area prevent the entry of microbes from the less clean area to the high clean
area.
 In oral solid dosage forms, manufacturing areas prevent the outflow of powders.

In most of the pharmaceutical industries, a common airlock system is used for the entry of
men and materials it is wrong practice.

Personnel Airlock (PAL)

The airlocks which are used for the entry of personnel into the cleanroom is called personnel
airlock (PAL).

Material Airlock (MAL)

The airlock which is used for transferring of materials is called Material Air lock (MAL).

What are the designs of the Air lock?


The airlock is a closed room between two cleanrooms of different classes for example
between Cleanroom Class B and Cleanroom Class C and same way between Class C and Class
D.

Air lock is usually with two doors one door open in one clean room like in class C and other
door opens in another class area like in class D. So if we want to enter from Class D to Class C,
first of all, we will enter from Class D into Airlock and then the airlock to Class C.

Both doors of airlock should not be opened simultaneously. First of all open and enter into
airlock from Class D then close that door and open other door to enter into Class C.
Interlocking system should be installed in airlocks to prevent the opening of both door at the
same time. An alarm system should be installed which give an alert if both doors are opened
at the same time.

The doors of airlock should be opened towards higher pressure side so that it can easily be
closed by air pressure. The airlock should always be free from any furniture, chairs, table, shoe
covers etc.

What is the Principle of Air lock and define its types?


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As it is a general role that air moves from an area of higher pressure towards the area of lower
pressure. So all airlocks work on the same principle just we have to change the pressure in
airlocks on in adjacent areas to change the type of airlock either it is a bubble, sink or cascade.

Types of Air lock

There are three types of an airlock system:

 Bubble Airlock.
 Sink Airlock.
 Cascade Airlock.

Bubble Airlock

In bubble airlock pressure inside the airlock is high or positive and in adjacent sides, the
pressure is less or negative.

For example, in airlock pressure is 20 Pa and in both the sides, the pressure is 10 PA so air
moves form 20 Pa to 10 Pa in adjacent sides. Mean air moves from the airlock to the primary
manufacturing area and in the same way from the airlock to the corridor. Higher air changes
are produced in the airlock. It is called bubble because it pushes air outside from the airlock.

Sink Airlock

In sink airlock, the pressure inside airlock is negative and in adjacent areas pressure is positive
so air moves from higher pressure area to lower pressure mean from adjacent rooms to the
airlock.

For example, in airlock pressure is 10Pa and in both sides, the air pressure is 20 Pa so air
moves from adjacent to 10Pa in airlock. Mean air moves from adjacent areas to airlock e.g.
from the primary manufacturing area to airlock and in the same way from the corridor the
airlock. It is called sink because the air from both sides come into the airlock.

Cascade Airlock

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In cascade airlock system pressure increases or decreases in ascending or descending order for
example from 30Pa to 20Pa to 10Pas to 20Pa to 30Pa. So air moves from higher pressure to
lower pressure side and prevent cross-contamination.

Example

Take the example of a simple layout; we have one primary room where we want to
manufacture the product for example granulation area of tablet manufacturing section.
Outside the primary room is a corridor and on other side of the corridor is compression room
so we want to prevent cross-contamination of granulation area to compression room or from
compression room to granulation room. We will build an airlock room between granulation
room and corridor and in the same way between corridor and compression room.

Processing Area Airlock Corridor


Cascade 15Pa 30Pa 45Pa
Bubble 15Pa 30Pa 15Pa
Sink 30Pa 15Pa 30Pa

How to prevent cross contamination through airlock system?


We can prevent cross-contamination either by maintaining Bubble or cascaded airlock system.

For Bubble Air Lock

 To prevent cross contamination by Bubble airlock for granulation area, build an airlock
room between granulation area and corridor and create positive in airlock pressure by
supplying more air through HVAC say it is 20Pa.
 In granulation room produce 10Pa so when we will open the door, clean air will move
from airlock to granulation area and powders from granulation will not enter to airlock
because of differential pressure.
 In the same way in corridor create 10Pa so when we will enter from corridor the clean
air from airlock will move into the corridor.If inside granulation room is positive e.g.
20Pas and in the lock is 10Pa the powder from granulation area will enter in the airlock
and if in the corridor is 8Pa then this powder will move from airlock to corridor and will
contaminate other areas.
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For Cascade Airlock

Cross contamination can also be prevented by creating a cascade airlock.

 For cascade airlock inside of granulation area is maintained negative for example at
10Pa and airlock is maintained at 30Pa means highly positive.
 According to principle air will move higher pressure to lower pressure so air will move
from corridor to airlock and from airlock to manufacturing area. In this case, the
corridor will be cleaned corridor having high air changes.

In oral solid dosage form areas, we keep inside of the manufacturing area at negative pressure
to prevent our flow of powders.

So critical monitoring of air pressure maintenance is required in all areas because any drop or
increase in the pressure of any area may result in cross contamination.

What is the formula for calculating number of air changes in an area?


A number of air changes/hour in an area is:

Total Room Airflow in CFM x 60 / Total Volume of room in cubic feet


 For calculating Total Room Airflow in CFM, first calculate air flow of individual filter.
Formula is given below.
 Air flow (in CFM) = Avg. air velocity (in feet / Minute) x Effective area of filter Then find
Total air flow.
 Formula is Total Air flow = Sum of air flow of individual filter. Air flow Velocity can be
measured with the help of Anemometer.

What is preventive maintenance?


It is periodic inspection and minor repairs of equipment as per schedule given in the SOP.

This enables smooth operation and long life of the equipment. It also avoids major breakdown
of the equipment during manufacturing of the product.

There are two types of maintenance.


Preventive maintenance
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Schedule maintenance before any breakdown of machinery which prevents the machine
breakdown.
Breakdown maintenance

Maintenance was done after stopping machine breakdown weekly, Monthly, Quarterly, Half
yearly and Yearly preventive maintenance.

What is HVAC?
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.
To achieve this objective, electrical, mechanical & electronic components are arranged in
several configurations such that they produce the expected results.

What is the difference between dedicated and non-dedicated equipment’s?


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 equipment’s must be
clearly identified with the restrictions of use in order to prevent potential errors during
cleaning and preparation.
Non-dedicated equipment

Where the same piece of equipment is utilized for a range of products formulations. To
prevent the cross-contamination between products becomes the main objective in the
cleaning validation effort. Clearly, cleaning non-dedicated equipment’s represents a more
significant obstacle to overcome.

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.
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 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 the reason is unidentified, another three consecutive batches shall be taken for
Validation.
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:
 Loss on Drying / Water content.
 Bulk density / tapped density.
 Residual solvent.
 Particle size.
The following parameters are to be considered for the equipment during validation, but not
limited:
 Blender capacity.
 RPM of the blender.
 Occupancy of the blender.
 Number of individual batches to be taken for each blend.
 Mixing time.

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 equipment’s 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

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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).

What do you mean by worst case?

A condition or set of conditions encompassing upper and lower processing limit and
circumstances, within standard operating procedures, which poses the greatest chance of
product or process failure when compared to ideal conditions. Such conditions do not
necessarily induce product or process failure.

What is the difference between specification and Limit?

Specification
A document giving a description of a starting material, packaging material, intermediate, bulk
or finished product in terms of its chemical, physical & possibly biological characteristics. A
specification normally includes description clauses & numerical clauses, the latter stating
standards & permitted tolerances.
Or
Lists of detailed requirements with which the products/ materials used or obtained during
manufacture have to conform. They serve as a basis for quality evaluation.

Limit

The point, edge or lines beyond which something cannot or may not be proceed. The
boundary surrounding a specific area, bounds.

What are the advantages of Swab sampling?

 Dissolves & physically removes sample.


 Adaptable to a wide variety of surfaces.
 Economical & widely available.
 May allow sampling of a defined area.
 Applicable to active, microbial & cleaning agent residues.

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What are the advantages of Rinse sampling?

 Adaptable to on line monitoring.


 Easy to sample.
 Non-intrusive.
 Less technique dependent that swab.
 Applicable for active, cleaning agents & excipients allow sampling of a large surface.
 Allows sampling of unique (e.g. porous) surface.

Why do we consider three consecutive runs/batches for process validation? Why


not two or four?
The number of batches produced in the validation exercise should be sufficient to allow the
normal extent of variation and trends to be established and to provide sufficient data for
evaluation and reproducibility.

 First batch quality is accidental (co-incidental).


 Second batch quality is regular (accidental).
 Third batch quality is validation (conformation).

In 2 batches we cannot assure the reproducibility of data, 4 batches can be taken but the time
and cost are involved.

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.

What are the different types of cleanings?


There are three types of cleanings:

• Batch to Batch cleaning.

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• Periodically cleaning.

• Product changeover cleaning.

What is expiry date & re-test date?


Expiry date

The date place on the container / labels of an API designated the time during which the API is
expected to remain within established shelf life specifications if stored under defined
conditions and after which it should not be used.

Re-test date

The date when a material should be re-examined to ensure that it is still suitable for use. The
period of time during which the drug substance is expected to remain within its specifications
and therefore, can be used in the manufacturing of the drug product, provided that drug
substance has been stored under the defined conditions.

What is Batch number and batch?


Batch Number

A unique combination of numbers, letters, and/or symbols which identifies a batch (or lot) and
from which the production and distribution history can be determined

Batch

A specific quantity of material produced in a process or series of processes so that it is


expected to be homogeneous within specified limits. In the case of continuous production, a
batch may correspond to a defined fraction of the production. Batch size may be defined
either by a fixed quantity or the amount produced in a fixed time interval.

What is quarantine?
The status of materials isolated physically or by other effective means pending a decision on
their subsequent approval or rejection.

What is definition of critical process parameters?


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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.

What is the difference between theoretical and expected yield?


Theoretical yield

The quantity that would be produced at any appropriate phase of production, based upon the
quantity of material to be used, in the absence of any loss or error in actual production.

Expected yield

The quantity of material or the percentage of theoretical yield anticipated at any appropriate
phase of production based on previous laboratory, pilot scale, or manufacturing data.

What is the difference between the 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.

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.


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The collective analytical measurement instruments in conjunction with firmware, assembled
to perform a mechanical process.

What is the difference between dedicated and non-dedicated equipment’s?


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 equipment’s must be
clearly identified with the restrictions of use in order to prevent potential errors during
cleaning and preparation.

Non-dedicated equipment

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 equipment’s represents a more significant obstacle to
overcome.

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 BMR and BPR).
 If the reason is unidentified, another three consecutive batches shall be taken for
Validation.

What are ISO 9001, ISO 14001, ISO 18001, and ISO 22001?
ISO 9001:Quality Standard Management.

ISO 14001:Environmental Standard Management.

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ISO 18001:Safety & Health Standard Management

ISO 22001:Hazop Standard Management.

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

Thermal, Light, Electromagnetic (EMI), Electrostatic (ESD), Radiation & Electrical.

Define stability study and its necessity?


Stability study is defined as “stability testing is to provide evidence how quality varies with
timeunder influence as: temperature, humidity & light”

 Establish re-test period for drug substance.


 Establish shelf life for drug product.
 Recommended storage conditions.

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 to be authentic
material that should be of high purity. This standard may be obtained from an officially

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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

What do you mean by Non-conformity?


Non-conformity is non-fulfillment of a specified or implied requirement of the quality
management system or of a quality work product.

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.

Describe the method of testing for checking of MOC of SS material (Molybdenum


test)?
 Put one drop of electrolyte solution of molybdenum test kit on clean metal surface,
which is to be tested.
 Switch on the detector and touch the metal tip of the detector on metal surface &
carbon point in electrolyte solution.
 Do not pass the current for more than 3 to 4 seconds
 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.
 If the solution remains colorless or green color appears then it can be concluded that
MOC of the part being tested is SS-304.
 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.
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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.

What are the safety systems in the pharmaceutical manufacturing plant?


 Some of the safety systems used in the plant is;
 Eye washer, safety showers.
 Fire extinguishers.
 Fire hydrants.
 Face shields.
 Goggles.
 Helmets.
 Nose masks.
 Safety shoes.
 Safety belts.
 Hand gloves.
 Training on safety rules and use of safety equipment’s.

What is clean zone and clean room?


Clean zone

A defined space in which the concentration of air borne particles is controlled to meet a
specified air borne particulate cleanliness class.

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Clean room

A room in which the concentration of air borne particles is controlled and contains one or
more clean zone.

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.

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.

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.

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.

What is Quality Manual?


The quality manual is a statement of the Company’s Quality Policy and Quality Objectives of
the organization.

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Which Guideline follows for preparation of Quality Manual?
Eudralex Volume 4 (Chapter – 1 Pharmaceuticals Quality System), ICH Q8, Q9 and Q10,
Schedule M.

Contents of Quality Manual

 Introduction, Scope, Basics of Quality Management System.


 Quality Policy, Quality Objective Quality Risk Management Policy.
 Company Profile, Organization, Regulatory Basics.
 Documentation for the Quality Management System.
 Document Structure Production of Quality Management System.
 Accompanying Quality Management System.
 Design/Project Management, Qualification and Validation.
 Maintenance, Health requirements, Personnel hygiene requirements, including clothing.
 Complaints, Product Recall, Customer Management.
 Product Documentation, Labeling and Packaging Control.
 Product Quality Review, References.

Review Period

Every Two Years

Storage Period

Perpetual

What are Contamination, Cross Contamination and Mix - UP?


Contamination

In any product, presence of a substance other than product manufacturing formula is called

Contamination.

Cross Contamination

Contamination of one product to another is called cross contamination.


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Mix - Up

Undesirable mixing of material, product/ batch, unintentionally or accidently is called Mix-up.

Which types of PassBox?


 Dynamic Pass Box
 Static Pass Box

DYNAMIC PASS BOX

For Material transfer from unclassified area to classified area. This Pass box having HEPA filter
and UV Light. Frequency of Validation is every six month

Test

 Air Velocity
 Filter Integrity
 Particle count

STATIC PASS BOX

For Material transfer from classified area to classified area.

Difference between Water Content and LOD?

Water Content

Water Content determined by the Karl Fischer method and it consists of only i.e. water
content. The result does not contain other volatile matter.

Loss on drying (LOD)

LOD is determined by heating the sample below its melting point in an oven and it includes all
volatile matter including water content and solvent.

Loss on Drying is an unspecific analytical technique removing not only water but all other
volatile impurities like alcoholetc. From a sample.

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The degree of drying is dependent on,

 Temperature
 Drying time

LOD or water content of pharmaceutical products can include both bound (e.g. water of
hydration) and free water. In case there are additional traces of other volatile impurities
present, like alcohol: LOD ma be higher than water content. In other cases, LOD may be lower
than water content, as bound crystal water may not be removed by heating

%LOD = %water content - %Water molecule in API

What is Commissioning?
Commissioning is the documented process of verifying that the equipment and systems are
installed according to specifications, placing the equipment into active service and verifying its
proper action. Commissioning takes place at the conclusion of project construction but prior to
validation.

What is Design condition?


Design condition relates to the specified range or accuracy of a controlled variable used by the
designer as a basis for determining the performance requirements of an engineered system.

What is Operating range?


Operating range is the range of validated critical parameters within which acceptable products
can be manufactured.

What is Turbulent flow?


Turbulent flow, or non-unidirectional airflow, is air distribution that is introduced into the
controlled space and then mixes with room air by means of induction.

What is pressure cascade?


A process whereby air flows from one area, which is maintained at a higherpressure, to
another area at a lower pressure.
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“As the Pharmaceutical Industry is an “OCEAN” so it’s impossible to
cover all the topics in a single Hand Book. That’s why this QA HAND
BOOK is considered as Edition-I. In future I will again write a QA
HAND BOOK which will be Edition-II”.

THANKS
“AND GO CHALLENGE THOSE
WHO SAY’S YOU DIDN’T
HAVE KNOWLEDGE”

AJAY KUMAR
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