2022

QA
HAND
BOOK
A Compendium of Guidelines and Related
Materials

EDITION - I

PHARMACEUTICAL
FORMULATIONS

Ajay Thakur
 QA HAND BOOK
INDEX
S.No. QUALITY ASSURANCE BASIC PAGE NO.
1. QUALITY ASSURANCE 63 to 64
2. STANDARD OPERATING PROCEDURE 65 to 65
3. SITE MASTER FILE 66 to 66
4. DRUG MASTER FILE 66 to 66
5. PROCESS VALIDATION 66 to 68
6. VALIDATION MASTER PLAN 69 to 69
7. CHANGE CONTROL 70 to 74
8. DEVIATION 75 to 81
9. CORRECTIVE AND PREVENTIVE ACTION 82 to 85
10. COMPLAINTS AND RECALLS 86 to 93
11. CLEANING VALIDATION 94 to 100
12. ANNUAL PRODUCT QUALITY REVIEW 101 to 105
13. QUALITY RISK MANAGEMENT 106 to 116
14. DOCUMENT & DATA COLLECTION, RECORD, CONTROL 117 to 122
& MANAGEMENT
15. VENDOR MANAGEMENT 123 to 130
16. QUALITY / FACILITY AUDITS 131 to 141
17. OOS/ OOT 142 to 154
18. PHARMACOPOEIA 151 to 161
TABLET’S MANUFACTURING UNIT OPERATION
19. IPQA 164 to 164
20. WAREHOUSE 165 to 176
21. GRANULATION 177 to 227
22. COMPRESSION 228 to 302
23. COATING 302 to 349
24. PACKING 349 to 404
25. CALIBRATION 404 to 422
26. SAMPLING 423 to 434
27. GUIDELINES 435 to 491

BASIC CONCEPTS & THEIR QUESTIONS & ANSWERS

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DEFINITIONS
A

Accelerated Testing
Studies designed to increase the rate of chemical degradation or physical change of a drug
substance or drug product by using exaggerated storage conditions as part of the formal stability
studies.

Data from these studies, in addition to long term stability studies, can be used to assess longer
term chemical effects at non-accelerated conditions and to evaluate the effect of short term
excursions outside the label storage conditions such as might occur during shipping. Results
from accelerated testing studies are not always predictive of physical changes.

Acceptance Criteria
Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical
procedures.

Accuracy
The accuracy of an analytical procedure expresses the closeness of agreement between the value
which is accepted either as a conventional true value or an accepted reference value and the
value found. This is sometimes terms trueness.

Active Ingredient
An active pharmaceutical ingredient (API) is the chemical substance contained in a
pharmaceutical dosage form, which is responsible for its therapeutic effect.

Adverse Reaction (Adverse Drug Reaction), ADR

An adverse drug reaction is a response to a medicinal product which is noxious and unintended
and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of
disease or for the restoration, correction or modification of physiological function.

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the incorporation of binders to improve compatibility. The granulation step and the drying step
may be performed consecutively (typically using high shear granulation and fluid bed drying)
or concurrently (typically using fluid bed granulation). Continuous wet granulation is
increasingly being used to aid throughput in pharmaceutical processing factories.

There are no terms under “X”.

Yield, Expected
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.

Yield, Theoretical
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.

Z-Value
The number of degrees of temperature change necessary to change the D-value by factor of 10.

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QUALITY
ASSURANCE
BASIC

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Why Companies Have Difficulties

Analyze

Verify

Review

Implement

Identify

Why? Incorrect Root Cause Identified

Analyze: Not done

Verify: Problem recurrence

Review: Preventive Action does not work

Implement: Corrective Action wrong

Identify: Problem but not root cause

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CLEANING VALIDATION
It is a document act of demonstrating that cleaning procedure for the equipment used in the
fabrication/packaging will reduce to an acceptable level of all residues the (product & cleaning
agent) and to demonstrating that routine cleaning & storage of equipment does not allow
microbial proliferation.

Importance of Cleaning Validation

• “Particular attention should be accorded to the validation of … cleaning procedures”
(WHO)
• “Cleaning validation should be performed in order to confirm the effectiveness of a
cleaning procedure” (PIC/s)
• “The data should support a conclusion that residues to an acceptable level” (FDA)

Cleaning validation Studies

Following cleaning validation related studies shall be carried out:

Cleaned Equipment Hold Time Study (CEHT)

Hold time study shall be carried out to ensure the suitability of cleaned equipment, stored in
its prescribed storage conditions, and does not increase the microbial contamination level
more than the limit for freshly cleaned equipment.

Dirty Equipment Hold Time Study (DEHT)

The dirty equipment hold time studies shall be carried out to ensure the microbial
proliferation over a period of time and the same shall be possible to clean.

Sampling Techniques
Direct Surface sampling (Swab method)

Rinse Samples (Indirect method)

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Repository

The Life-cycle of a regulated document

Document Control
Each manufacturer shall establish and maintain procedures to control all documents that are
required. The procedure shall provide for the following:

Document Approval and Distribution

Each manufacturer shall designate and individuals(s) to review for adequacy and approve prior
to issuance all documents established to meet the requirements of this part.

The approval, including the date and signature of the individuals approving the document,
shall be documented.

Documents established to meet the requirement of regulatory agency shall be available at all
locations for which they designated, used, or otherwise necessary, and all obsolete documents
shall be promptly removed from all points of use or otherwise prevented from unintended
use.
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Audit Report and Technical • API: 4 years from NA
Agreement date of the audit.

• KRM/KE/Primary
and Printed PM: 6
years from the date
of audit.

Table B: Documents/ Activities require for qualification of New Vendor

Documents/Activities required for Qualification of New vendor

S.No. Requirement Input Material
√ = Mandatory Raw Material Packaging Material
● = Desirable API KRM Excipie RM other Primary Printed
□ = NA nt other than
than KE KRM
1 Vendor Information √ √ √ √ √ √
(VIF)
2 Process Flow Diagram ● ● ● ● ● ●
3 TSE/BSE Declaration/ √ √ √ √ √ √
TSE / BSE risk
evaluation
questionnaire (if
applicable)
4 Residual solvent √ √ √ ● □ □
declaration
5 Stability Data / Shelf ● ● ● ● ● ●
Life Declaration / Retest
or Reevaluation Period
Declaration
6 Regulatory / CGMP √ √ √ □ √ √
Certificate
7 Audit of Vendor √ ● □ □ √ √
Manufacturing Site
Prior to
Commercialization
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Table D: Documents / Activities required for Qualification of existing Vendor for
New Vendor

Documents/Activities required for Qualification of Existing Vendor for New

vendor
S.No. Requirement Input Material
√ = Mandatory Raw Material Packaging Material
● = Desirable API KRM KE Excipient RM Primary Printed
□ = NA other than other
KE than
KRM
1 Vendor Information
(VIF) Ensure the Validity
2 GMP Certificate
3 Technical Agreement
4 Stability data/ Shelf life ● ● ● ● ● ● ●
declaration/ Retest or
Reevaluation period
Declaration
5 Process Flow Diagram ● ● ● ● ● ● ●
6 Residual solvent √ √ √ √ ● □ □
Declaration
7 TSE / BSE Declaration / √ √ √ √ √ √ □
TSE / BSE risk
Evaluation
questionnaire (if
applicable)

Audit of Suppliers
Based on the questionnaire evaluation, if any Supplier is performing repacking activity, audit of
such Supplier shall be a part of approval procedure.

Corporate QA shall prepare a supplier audit schedule at the beginning of each calendar year
for those suppliers who perform the repacking activity.

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Quality / Facility Audits
Audits are conducted to ascertain the validity and reliability of the information; also to provide
an assessment of the internal control of a system.

It provides management with information on the efficiency with which the company controls
the quality of its processes and products.

In FDA & ISO environments, auditing of both compliance and performance is essential.

Pharmaceutical audit experience includes the drafting and revision of validation policies,
guidelines and SOP from project qualification to performance evaluation phases.

If implemented correctly; it can be one of the most effective means of improvement.

Goals of Audit
The simple goal of this complex process is to evaluate existing activities and documentation
and determine if they meet the established standards.

An audit will evaluate the strengths and weaknesses of Quality control & Quality Assurance
processes, the results of which will help us to improve processes and build a better system for
the benefit of the company.

With proper preparation and planning, the audit itself must easily achieve the intended
purpose.

Effective auditing and proper compliance with standards will help build brand reputation and
avoid the negative effects of non-compliance, such as fines, bad public relations and court
proceedings.

Objectives
Audit objectives may include:

• Evaluating conformity of requirements to ISO 9001

• Evaluating conformity of documents to ISO 9001
• Judging conformity of implementation to documentation.
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PHARMACOPOEIA
“A pharmacopoeia is a legally binding collection of standards and quality specifications for
medicines used in a country or region”.

The term Pharmacopoeia first appears as a distinct title in a work published in Basel,
Switzerland in 1561 by Dr. A.Foes, but does not appear to have come into general use until the
beginning of the 17th century. Today’s pharmacopoeias focus mainly on assurance of quality of
products by various tools of analytical sciences.

The aim to achieve a wide global harmonization of quality specifications for selected
pharmaceutical products, excipients and dosage forms came with increased globalization and
reciprocal collaboration.

History of these approaches goes back to 1902-1925 when agreements established a “Unified”
Pharmacopoeia. In 1929 the “Brussels Agreement” stipulated the League of Nations to carry
out related administrative functions.

Eight year later in 1937, the first meeting of the “Technical commission of Pharmaceutical
Experts” was held. An important date in the history of quality assurance of medicines is 1948,
when the First World Health Assembly (WHA) approved the Expert Committee on Unification
of Pharmacopoeias to continue this work. One year later, the WHA renamed it the Expert
Committee on International Pharmacopoeia.

Each country has legislation on pharmaceutical preparations which sets a standards and
required quality indices for medicament, raw materials and preparations employed in the
manufacturer of drugs.

These regulations are presented in separate articles. General and specific matters relating to
individual drugs are published in the form of a book called a Pharmacopoeia.

On 15th December 1820, the first United States Pharmacopoeia (U.S.P) was released.

In 1864, the first British Pharmacopoeia (B.P) was published.

In 1955, the first Indian Pharmacopoeia (IP) was published.

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two supplements between
the editions after JP12 and
partial revision at any time if
immediate necessity.
United State of America (Ph. United State Pharmacopoeia Annually, with 2 supplements
Eur. Obs.) (USP) per year
Argentina (Ph. Eur. Obs.) Farmacopea Argentina Undetermined, intended
biannually
Korea* The Korean Pharmacopoeia Currently revised in every 5
year term.

IPQA
TABLET’S
MANUFACTURING
Question UNIT
OPERATION

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Answer
What is IPQA department?
The main goal of IPQA department is to help create a quality product. Their Job is not only bug
searching and regular product testing, but to also prevent defects accordingly. They ensure the
high quality of the development process and its results.

What is IPQA Chemist?

IPQA is determined by quality proceedings in standards and specifications of manufactured
products to prevent mistakes, problems to customer services.

What are the IPQA activities?

• Verify the area label with the process going on in the area.
• Verify the cleanliness of area and operation.
• The status label verification of the equipment with process stage.
• Verify whether the activities are carried out in accordance with relevant SOPs and
instructions in BMR & BPR.
• Verify timely completion of batch documents.
• Personal practices verification including gowning.
• Verify pressure differential of areas and shall be within limits defined on the respective
Magnehelic gauge.
• The temperature and relative humidity of areas shall be in compliance as per SOP.
• Verify status label where relevant.
• Verify the calibration status and records of the balances.
• Verify the Equipment Re-Qualification status.
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• To verify the Inward and Outward entries of material.
• To perform the calibration of the Instruments i.e. DT, Friability, Hardness tester,
Moisture Analyzer.
• To perform the In-Process at various stages as per frequency.
• To maintain the GMP on the shop floor.
• To perform the sampling at various stages.

Ware House
The Warehouse plays a pivotal role in manufacturing quality products, as it is responsible for
all incoming goods (including labeling and packaging) and for releasing finished products.
Therefore there are GMP rules in place to ensure that materials are handled and stored
properly, while appropriate documentation is maintained.

Once a finished product is received into the warehouse, it does not undergo any further
inspections or quality control tests. If the product is degraded or damaged at this point, there
is nothing that stops it from being given to the patient. The Warehouse must rely upon
procedures and well trained staff to ensure that product arrives safely and with the same
quality as when they left manufacturing.

There have been many cases of product being affected by poor warehouse storage conditions
or rough handling on transport. Biopharmaceutical products have temperature sensitive active
ingredients that breakdown or degrade if exposed to heat or lights, thus becoming ineffective.

A pharmaceutical warehouse must be expertly managed and run in compliance in order for
the company to protect and distribute a quality product.

These compliant practices include control over receiving goods, quality control, storing
materials, components and products, fulfilling picking requests and shipping the product to
the market place. These practices must be completely traceable in order to protect the
integrity and stability of the product and its packaging.

What is the role of IPQA in Warehouse?

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In process Quality Assurance (IPQA) plays a prominent role in every activity in warehouse and
ensures that the results produced meets the GMP specifications.

• IPQA is responsible for affixing hold labels to the damaged packs.

• Ensuring the recording of temperature and RH in storage areas.
• To identify the documentation errors wherever found out.
• Identification of approved vendors and new vendors.
• Ensuring the status of the materials i.e. Quarantine, Approved and rejected.
• Ensuring that the materials stored in appropriate storage areas.

IPQA giving Line clearance for the dispensing of batches and verification of weighing balances,
Calibration and cross contamination of the materials can be prevented by the role of IPQA.

What is GWP vs. GDP?

GWP refers to the practices specifically within the company warehouse. GDP refers specifically
to the transport and distribution of the product.

• Good Distribution Practice (GDP) and Good Warehousing Practices (GWP) are each
special parts of GMP. GDP refers specifically to the transport and distribution of the
product. GWP refers to the practices specifically within the company warehouse.
• GDP and GWP each have their own legal definition and regulations. These regulations
recognize that product quality can be significantly impacted offer manufacturing and
packaging has taken place.
• GMP for the warehouse incorporates practices, rules, and regulations spanning GMP,
GDP, and GWP.

What are the GMP rules for the Warehouse?

• Protect medicines from damage during storage and transport.
• Prevent degradation of the product by exposure to adverse temperature conditions.
• Avoid mix-ups and contamination by other materials.
• Maintain product identity and traceability.
• Prevent time-expired or damaged material or product from being used.

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What comes into the Warehouse?
The following goods generally do not appear on any production bill of materials, and have a
simplified check and release. Often, they do not have an in-house lot number applied, but this
varies from company to company.

• Non-production consumables (non-GMP material), e.g. toilet paper, Stationery.

• Production materials consumed in processing e.g. filters.
• Laboratory reagents e.g. Buffers, Chemicals.

The last two items above will usually have their own QC approval processes.

The following goods will always appear on any production or packaging bill of materials. They
are each governed by GMP quality control and release procedure. All these goods will be
issued with unique lot numbers.

• Manufacturing starting materials and chemical.

• Packaging components, e.g. blister pack film, bottles, caps, vials, seals.
• Printed matter, e.g. labels, cartons, inserts/leaflets, pre-printed tubes.

How the Warehouses are classified?

Warehouses are typically classified by the types of material they contain, For example, Raw
materials, Packaging materials, Intermediate or Bulk product and Finished product.

A typical warehouse will contain some or all of the areas described below.

• Quarantine area for storing goods that have not yet been inspected or tested. Materials
stored in Quarantine cannot be used or released until approved by QC.
• Some warehouses have a Dangerous Goods storage area to ensure the safety of staff
and the facility. For example, Flammable goods such as ethanol would be stored in this
area. Special storage conditions, such as Flame Proof Cabinets, are used here.
• Some warehouses have a locked area for restricted goods, such as poisons and drug of
addiction. This area is restricted to specifically authorized staff.
• A separate area for isolating faulty or recalled goods, ensuring that they are not issued
or sold by mistake.
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Color & Flavor

API

Granulation
Granulation is a process of producing granules generally. In pharmaceutical manufacturing,
granulation process implies the techniques that are used to combine powdered particles to
from relatively bigger ones called granules. This process is used for commercial production of
tablets.

The granulation process of size enlargement used within the pharmaceutical industry has its
roots in ancient times. The practice of delivering medicinal powder by hand rolling into pill by
using honey or sugar has been used for centuries. It is still the practice to deliver the botanical
and herbal extract in homeopathic and ayurvedic branches of medicines, which are still
practiced in India along with allopathic medicine.

The term “granulated” material is derived from the Latin word “granulatum” meaning grained.
The granulated material can be obtained by direct size enlargement of primary particles, or
size reduction from dry compacted material. In modern times, granulation technology has
been widely used by a wide range of industries, such as coal, mining, and agrochemical. These
industries employ agglomeration techniques to reduce dust, provide ease of handling, and
enhance the material’s ultimate utility.

The development of pharmaceutical granulation was driven by the invention of the tablet
press by W. Brockedon in 1843. Subsequent improvements in the tablet machinery were
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patented in the United States by J. A McFerran 1874, T.J. young 1874, and J. Dunton 1876. The
demands on the granulation properties were further enhanced in the 1970s as high speed
tablet and capsule filling machine with automated controls were introduced.

The continuous refinements in the regulatory requirements such as low-dose products

requiring blend uniformity/ content uniformity necessitated knowledge and technology to
produce the required granule characteristics. The high speed compression and capsule filling
machines require a uniform flow of material to the dies or filling stations that produce
pharmaceutical dosage form.

Granulation methods can be divided into two major types: Wet methods which utilize some
form of liquid to bind the primary particles, and dry methods which do not utilize any liquid.

What are the types of Granulation?

There are two types of granulation

(1) Dry Granulation

(2) Wet Granulation

Dry Granulation

• Dry Granulation is the process of forming granules without using any liquid solution.
• Involves the direct compression of a finely ground powder.
• Requires finely powdered compound and tablet pressers or roll compactors.
• Required when producing tablets from highly moisture and heat sensitive compounds.

Wet Granulation

• Wet granulation is the process of forming granules by adding a granulating liquid.

• Involves mixing the powder with a granulating fluid, followed by forcing through a sieve
to make tablets.
• Requires powder particles, a granulating fluid and a sieve.
• Required to avoid the destruction of active components in the powder.

What are the reasons for Granulation?

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• Good flow properties.
• Binding capacity to from tablets of low friability.
• Adequate hardness.

What is the difference between wet granulation and dry granulation?

There are three types of granulations as dry granulation, wet granulation, and direct blending.
The main difference between dry and wet granulation is that dry granulation is the formation
of granules without using any liquid solution whereas wet granulation is the formation of
granules by adding a granulating liquid.

What is dry granulation?

Dry granulation is a powder agglomeration process used in the pharmaceutical industry to
improve the flow ability of powders by increasing the particle size (granules).

What is roll compactor?

Roller compaction is a dry granulation process used to make coarse granules prior to final
compression. Typical excipients used in roller compaction are Lactose, Microcrystalline
Cellulose, and Magnesium Stearate as the lubricant.

What is dry granulation process?

Basic principles of Dry Granulation and Roller Compaction Technology Granulation is a process
in which powder particles are made to adhere to each other, resulting in larger, multi-particle
entities, so called granules. If such a process is performed without adding liquids, this is called
dry granulation.

What is dry granulation method?

Dry granulation is a simple and low cost method, once extremely common and again becoming
more popular because of its simplicity and cost efficiency. Dry granulation helps to increase
the size of granules within powders, making it easier to form them into tablets or capsules.

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Sifting:Active Pharmaceutical Ingredient (API) and excipients are sifted, usually through a 40
mass or 60 mass sieve. When API and excipients are sifted they mix together.

Mixing:In order to mix them up more thoroughly, the dry mixing process is utilized. Once the
mixing is complete, granulating fluid is added to RMG (Rapid Mixer Granulator).

Drying:The materials are then dried in a dryer, usually a fluid bed dryer or a tray dryer. When
constitutes have dried, they are then milled using 16 mass or 20 mass sieves.

Lubrication:The final step is lubrication in order to make the particles adhere firmly together.
This is done with the addition of a lubricating agent. The use of lubricating agents is particular
to the types of API and excipients used. The most commonly used lubricating agent is
magnesium stearate. The material formed is thus ready for further compression and
manufacturing.

(2) Dry Granulation

Dry granulation does not involve the use of a liquid lubricating agent. This is because
constituents utilized might chemically react with the agent used, thus dry granulation
equipment technique is used.

Dispensing: The first step in dry granulation is dispensing of the API and excipients used, in
specified amount.

Dry mixing or Blending:Once both constitutes are dispensed, API and intragranular excipients
are mixed together through dry mixing.

Compaction:After dry mixing of the materials, they are passed through roller powder
compactors for compaction. This results in the formation of slugs. Slugs are the rough form of
tablets, usually quite large in size.

Milling or crushing:The slugs are then milled or crushed until the required granule size is
obtained. Depending upon the product requirement, sieves are used to attain granules of the
right size. At this stage, further mixing is done with the addition of extra granular excipients.

Extra granular excipients do not form the part of the main mixture; instead they are added
after the granulation has taken place. Extra granular excipients include diluents, disintegrating
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Generally, purging air is used to flush the industrial process equipment with clean air. Purging
air helps to keep the surfaces of RMG clean and help in maintaining its effective performance.

What is torque in RMG?

Torque is a measure of the amount of energy needed to rotate the impeller. Therefore, torque
depends on the resistance of the mass against rotation of the impeller (2-4). In the wet mixing
process, changes in torque occur as the result of a change in the cohesive force of the granules
in the wet powder bed.

How to measure tip speed of RMG?

Blade speed (tip speed), measures how far a point on the outer most edge of the disperse
blade travels in a given amount of time. You may remember from early math classes that the
circumference of a circle is equal to:

So if we take a 1 foot diameter (D) blade and turn it one complete revolution, a point on its
edge would have travelled pi(π)3.14 feet. By multiplying by rpm (n) we get the Tip speed
formula:

Tip speed= π x D x n

Where:

• Tip speed – Impeller tip speed (RPM)

• D – Impeller diameter (ft.)
• n – Impeller rotation speed (fpm)

Why we measure RMG in liters?

Because every powder product has different bulk density so we can’t mention it in kg. We
always mention in liters and products can be calculated in kg by factor.

What is Kneading?
Kneading time is a wet mixing process after addition of binder solution in any of the mixer
either RMG or low shear mixer granulator.

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• Filters to exhaust air may be choked so results in a pressure drop.

Solution

• In the case of a tray dryer, reduce the tray load or in the words reduce the thickness of
the product layer in trays.
• Improve Hot air circulation in tray dryer for uniform drying for this check blower speed.
• Load the product trolley according to its capacity.
• In FBD increase fan motor speed for proper fluidization.
• Use stirrer to properly mix granules in product trolley for uniform drying.
• Use shakers or blowback systems to prevent filter clogging during drying.

Mottling/Color Migration
Mottling or color migration is a defect that occurs during the drying of granules in which we
use color.

Reason

• Dye colors are water soluble and migrate along with the evaporation of water.
• Excessive drying without stirring the granules in the product trolley.
• Most products dried in a tray dryer show a mottling effect.

Solution

• The use of lake colors prevents color migration because lakes are not soluble in water
• Do not over-dry the granules.
• Use a stirring mechanism during drying which brings new surfaces in contact with heat.
• The use of microcrystalline cellulose in product formulation prevents color migration.

Problems during Sieving of Dried Mass

Dry sieving is the process in which we convert dried granules into uniformly sized granules
using a specified mesh or sieve in an oscillating granulator or dry mill.

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CPP & CQA of Granulation stage
Sr. No. Unit Operation Critical Process Parameters Critical Quality Attributes
• Order of addition. • Particle size
• Mixer load level. distribution.
• Impeller speed and time. • Bulk/tapped density.
1. Mixing • Chopper speed and • Moisture Content.
time. • Flow Properties.
• Chopper On/OFF
pattern.
• Mixing time.
• Impact/ cutting/ • Particle Size.
screening mills direction. • Particle Shape.
2. Milling • Speed of mill. • Flow Properties.
• Screen size. • Polymorphic form.
• Feeding rate.
• Pre-binder addition mix • Blend Uniformity Flow.
time. • Moisture Content.
• Impeller Speed and ON • Particle Size and
time. distribution.
• Chopper speed and ON • Granule Size and
time. distribution.
3. Wet Granulation • Binder fluid • Granule strength and
(RMG) temperature. uniformity solid form.
• Binder addition rate and
time.
• Post granulation mix
time.
• Spray nozzle type and • Blend uniformity flow.
location. • Moisture content.
• Binder addition rate and • Particle size and
time. distribution addition.
• Bowl temperature. • Granule size and
• Fluid bed granulations distribution.
mixing time spray nozzle • Granule strength and
(type/ quantity/ uniformity solid form
4. Spray Granulation pattern/ configuration). moisture content.
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stroke machines and Manesty tooling was not changeable with Stroke machines. Manesty
named its small machines B3B and large machines D3a.
In the start of 1900 unique model of Kilian was developed in Italy by Kilian Gmbh. The Kilian
machine was different from B and D standards. In Kilian compression machine the traditional
punch head system which guides the upper punch was not used instead it has its own punch
shape in which punch is guided by cam angle on side of upper punch barrel.
In 1997 unique model was developed by “Ima called ima comprise” using a unique feeding
system based on centrifugal forces created by the rotation of the turret. In Ima machine tablet
ejection system was also unique; the tablet is ejected from the bottom of the die cavity using
the force of gravity.

In 2005 Fette developed most advance high-speed machines with the concept of segmented
dies. Segmented dies reduce set up hours.

What is aTablet?
Tablets are solid dose pharmaceutical preparation containing drug substances usually
prepared with the aid of suitable pharmaceutical excipients. That may vary in size, shape,
weight, hardness, thickness, disintegration, and dissolution characteristics and in other
aspects, depending on their intended use and method of manufacture.

It has been estimated that solid dosage forms constitute approximately 90% of all dosage
forms clinically used to provide systematic administration of therapeutic agents. The
widespread use of tablets has been achieved as a result of their convenience and also the
diversity of tablets types.

Tablets are prepared primarily by compression of granules or powder blends, with a limited
number prepared by molding. Most tablets are used in the oral administration of drugs. Many
of these are prepared with colorants and coatings of various types. Other tablets, such as
sublingual, buccal, or vaginal tablets, are prepared to have features most applicable to their
particular route of administration.

Define general properties of Tablets?

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• Various mathematical equations have been used to describe the compaction process.
• Kawatika equation is modified form of heckel’s equation.

What is Powder Porosity?

Ratio of the volume of voids between particles, plus the volume of pores, to the volume
occupied by the powder, including voids and pores.

Which factor influence the Flow properties of powders?

Flow properties of powders are basically mechanical properties. The behaviors of bulk
powders are very much similar to the non-Newtonian fluids due to its plastic flow and
dilatancy. The iteration of particles is influenced by the attractive forces, such as van der
Waals, particle size, shape, porosity, moisture content and bulk density.

Define Flow Property?

Good flow property of a pharmaceutical powder is essential to ensure proper die fill during
compression, especially in direct compaction process.

Angle of repose is commonly used to measure flow of powders, and is the maximum angle
between the plane of powder and horizontal surface.

Flow Property Carr’s Index (%) Hausner’s ratio

Excellent ≤ 10􋯠 1.00-1.11
Good 11-15 1.12-1.18
Fair 16-20 1.19-1.25
Passable 21-25 1.26-1.34
Poor 26-31 1.35-1.45
Very Poor 32-37 1.46-1.59
Very, very poor >38 >1.60

Flow Property Angle of repose

Excellent 25-30
Good 31-35
Fair-aid not needed 36-40

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Passable 41-45
Poor 46-55
Very Poor 56-65
Very, very poor >66

What is angle of repose?

The angle of repose is an engineering property of granular materials. It is the maximum angle
of a stable slope of pile formed on horizontal surface.

When bulk granular materials are poured onto a horizontal surface, a conical pile will form.
The internal angle between the surface of the pile and the horizontal surface is known as the
angle of repose and is related to the density, surface area, and coefficient of friction of the
material.

Material with a low angle of repose forms flatter piles than material with a high angle of
repose. The exact angle depends upon conditions such as a size, shape, and density of the
powder, sorting or mixture of sizes and the height of fall of the powders.

What is compression machine?

Tablets are being formed by compressing the granules using the compression machines.
Different innovations to tablet compression machines are being done to improve the
production rates and now it is possible to produce more than 5000,000 tablets per hour. A
tablet formation takes place by the combined pressing action of two punches and a die.

What is the principle of Compression machine?

The basic principle behind the tablet compression machine is hydraulic pressure. The pressure
is transmitted unreduced through the static fluid. Any externally applied pressure is
transmitted via static fluid to all the directions in the same proportion. It also makes it possible
to multiply the force as needed.

What are the different stages of compression machine process?

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Tablet press hoppers come in a wide range of shapes and designs. Whatever the shapes and
designs. Whatever the shape, it should be such that material can flow seamlessly into the
tablet compression chamber.

Again, since it is one station that is in direct contact with the material, it is made of stainless
steel. Depending on the design of a tablet press machine, you can fill the powder manually or
using other automated systems.

As tablet press machine manufacturer, we put every measure in place to ensure there is a
consistent flow of powder from the hopper to compression systems.

Here are major concerns that are addressed so far:

• Hoppers may feature optimal flow angles to facilitate flow, especially where it is nearly
impossible to adjust formulation.
• Some hoppers may feature vibratory rods. This is done carefully to enhance product
flow and to prevent possible product separation.

At any given point, the design of these tablet compression machine parts aim to eliminate
possible feeder starvation.

Feeder System

This yet another critical part of the tablet compression process. Remember, at any given time,
the design of the system should be such that it allows an accurate and consistent amount of
powder to flow to the punch and die system.

Compression machine feeder system is made up two critical components:

1. Feeder Housing

Material from the hopper will enter the die system through the housing. The feeding process
should be consistent and accurate to produce high quality tablets.

The feeding housing is made of Stainless steel SS 316L since it is in contact with the product.
Also, the product must not stick on the feeder housing as it will cause inconsistence during the
feeding process.

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• Use good quality tooling.
• Properly adjust the lower punch position.

Chipping

Tablet chipping is a problem or defect in which the edges of the tablet chip during tablet
compression.

Reasons for Tablet Chipping

• Worn out, punches and dies.

• The lower punches position is not adjusted properly.
• The highlight of the scrapper blade is high over the turret.

Solution

• Regularly inspect punches and dies.

• Adjust lower punches and scrapper blade.

Tablet Sticking and Picking

There is a difference between sticking and picking but the reasons for both problems are
almost the same.

Sticking

Sticking is a tablet defect in which powder or granules stick to the surface of a punch or on the
walls of dies.

Picking

Picking is a tablet compression defect where powders of granules stick to the embossing on
the punches.

Formulation Related Reasons for Tablet Sticking & Picking

• Higher moisture content in the blend.

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Modified Release Tablet Modified Release Tablet Extended Release Tablet
Soluble Tablet Soluble Tablet Soluble Tablet
Effervescent Tablet Effervescent Tablet Effervescent Tablet
For use in mouth (Chewable, For use in mouth (Chewable, Chewable/Buccal, Sublingual
Lozenges, Sublingual) Lozenges, Sublingual)
Orodispersible Orodispersible Orodispersible

What is Content Uniformity?

Content uniformity is a test used to evaluate the equality of the dosage of a pharmaceutical
drug. The method is applicable for tablets which contain the active ingredient in less than
10mg or 10% w/w.

Also, this test is not applicable to multivitamin drugs or trace elements. During this test, 10
tablets can be taken randomly from a sample in order to determine the amount of active
pharmaceutical ingredient in them.

Then the mean value can be calculated. The mean value of an active pharmaceutical
ingredient has to be within 85-115% or 75-125% of the average value.

After that same test is performed for another 20 tablets if 2-3 tablets are out of range.

The sample is not considered as fulfilling the required does if the total sample of 30 tablets has
more than three tablets that are out of the range of 85 to 115% or more than three tablets
that are out of range of 75 to 125%.

What is an Assay?
An assay is another analytical procedure used to characterize the main functional component
of a sample. Also, an assay can be an either quantitative and/ or qualitative test.

Moreover, the original application of assays is widely used in pharmaceutical industry to

characterize the active pharmaceutical ingredient.

In addition, assays are widely used in other areas including laboratory medicine,
pharmacology, environmental biology, immunology, molecular biology and biochemistry.

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Sampling with AQL addressed these concerns. By pulling a sample of bullets randomly from a
lot, the military was able to test part of the lot and use those results to estimate the quality of
the total lot.

What is Critical defect in AQL?

It is one that will affect the quality of the finished product (unsafe) and cause a potential risk
to the patient. The AQL for critical defects is very low i.e. 0.0%.

What is a Major defect in AQL?

It is one that will likely to cause non-conformance of product during manufacturing/packaging,
testing, shipment, storage or use. Such failures do not constitute a potential risk to the
patient. The AQL for major defects normally ranges from 0.0 to 2.5%.

What are Minor defects in AQL?

It is one that will not affect the quality of the finished product (unsafe) and cause no potential
risk to the patient. The AQL for minor defects normally ranges from 0.0 to 6.5%.

What are the classifications of compression critical, major & minordefects for
AQL?
In critical defects

Defect Definition
Embedded Specks / Hair Particles, which are foreign, extraneous, or contaminant particles
embedded / Fiber. to the tablet. The particles are embedded in or in the surface of
the tablets, which cannot be wiped or blown off.
Capped/ Layer separation The complete separation of a portion of upper or lower tablet.
(For Bi layer)
Incorrect description/ Incorrect identification of product and Incorrect color/ size / shape
Incorrect identification. per specification.
Foreign product. Presence of different products other than the desired product.
Contaminated Presence of foreign matter
Misprinted/ debossed/ Incorrect imprint.
Embossing.
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Dissolution
Dwell Time Thickness, Hardness,
Dissolution
Feeder Speed Weight variation, Hardness,
Thickness
Upper Punch entry Hardness, Thickness
Tooling type used Hardness, Thickness
Verification of tooling before use Product Mix-up

COATING
The use of coating material for solid dosage form is very old and its first reference is found in
Islamic literature where Rhazes describe the coating of pills.

Tablet coating is a common pharmaceutical technique of applying a thin polymer-based film to

a tablet or a granule containing API. Solid dosage forms are coated for a number of reasons,
the most important the most of which is controlling the release profiles.

Tablets are usually coated in horizontal rotating pans with the coating solution sprayed onto
the free surface of the tablet bed. The advantages of the tablet coating are taste masking,
physical and chemical protection, protect the drug from gastric environment etc.

There are various techniques for tablet coating such as sugar coating, film coating and enteric
coating. Recent trends in pharmaceutical technologies are the development of coating
methods which overcomes the various disadvantages associated with solvent based coatings.

In these latest technologies coating materials are directly coated on the surface of the solid
dosage for without using any solvent. Various solvent less coatings are available such as
electrostatic dry coating, magnetically assisted impaction coating, compression coating, hot
melt coating, powder coating and supercritical coating.

“Panning” was the original word for the process of adding a coating to a tablet. The word
panning is still a common term which is used in the confectionary business. In past years
coating perform basically using a rotating drum (pan) on a stand.
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A coating solution was added, while the rotation of the pan distributed the solution
throughout the bed of tablets. The main disadvantage of this technology was slow waiting for
coating solution to dry; and the trick was to get it to dry evenly.

With the advent of film coating a film or thin membrane, usually representing 1-3% of the total
tablet weight, was sprayed on using a perforated pan. To decrease the overall process time,
holes were made through the pan so that treated air (hot or cold) could be pulled through the
pan so that treated air (hot or cold) could be pulled through the pan, much like a clothes dryer,
allowing the tablets to dry more quickly.

With this advent of improved drying came the ability to switch the film coating solution from a
solvent based solution to a water based solution.

Coating of pharmaceutical dosage forms has been practiced for many centuries. The historical
development of coating technique is mentioned below.

LAST 40 YEARS

Features

• Introduction of the side-vented tablet coating pans (with perforations).

• Evolution was required for the introduction of aqueous based film coating polymers to
the pharmaceutical industry.
• Carbon steel construction except for pan.
• Many screws, not welded in places.
• Does not complywith GMP.

LAST 30 YEARS

Introduction of reliable microprocessor based process control systems required to insure

process control and repeatability.

Features

• Improved design spray nozzles for tablet coating.

• Specific applications (all stainless steel).
• Improved air preparation systems required for consistent aqueous process drying.
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Evaporation of organic solvent requires less heat. Organic solvent are costly so the cost of this
process us increased.

Aqueous + Organic Solvent Coating

In the aqueous + organic solvent coating, the solvent used is a mixture of water and organic
solvent. Usually, 90% organic solvent and 10% water is used.

(3) Plasticizers

• Plasticizers are one of the important components of coating suspension.

• Plasticizers are low molecular weight materials and are used to increase the film forming
capacity of polymers.
• Polymers are long chain molecules and plasticizers break the long-chain polymer-
polymer interaction and rearrange them to enhance their film forming capacity.
• Plasticizers decrease the glass transition temperature of polymers.

When the coating film is peeled from the surface of the tablet it is due to the fact that coating
suspension does not have a plasticizer or the amount of plasticizer is low.

(4) Colorants

• Color may be added to the formulation depending upon the requirements.

• Color gives an attractive and appealing look to the tablets.
• Different colors are used for different strengths of the same product to prevent mix up.
• FD&C or D&C type colors are used.
• For coating lakes and dyes are used.
• Dyes are water soluble so when the heat is applied dye migration occurs and these
results in color variation.
• Lakes are water insoluble so during drying they are resistant to migration and prevent
the problem of color variation.

Classifications of Colors

Colors are classified into following classes,

• Organic dyes and their lakes.

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Surfactants

Surfactants are added to the coating suspension to enhance the solubility of poorly soluble or
insoluble ingredients.

Example,

• Spans
• Tweens

Antimicrobial Preservatives

Some coating suspension formulations may promote microbial growth so antimicrobial

preservatives can be added to the coating formulation to enhance the stability of suspension.

What is the Principle of Tablet Coating?

A solution or suspension of polymer or film former is sprayed over the moving bed of hot
tablets by atomization; the solvent is evaporated by the heat leaving behind the thin layer of
polymer or film former over the tablet. This is a cyclic process and the cycle is repeated until
the desired level of polymer film thickness over the tablet surface is achieved.

What are the general coating processes in pharmaceutical industry?

The steps involved in the coating of tablets in the pharmaceutical industry are as follow,

• Line Clearance/ Batch Identification

• Preparation of coating solution
• Tablets loading into a coating pan
• Tablet warming
• Application of coating solution
• Monitoring of weight gain
• Cooling
• Unloading of tablets

Line Clearance/ Batch Identification

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Minimum capacity of coating pan = Brim volume of pan (Liters) x BD of tablets (g/ml) x 60/100

Minimum capacity = 160 x 0.72 x 60/100 = 69.12 kg.

Bulk density depends on the tablet shape and size. Small tablets of same formulation have
higher bulk density in the compression of large tablet. So that maximum and minimum
capacity of coating pan (48) will different if the shape and size of tablets are different.

What is the coating equipment’s which are being used?

For the coating process use of one of the 3 types of following equipment’s,

• Conventional Coating Pan.

• The Perforated Coating Pan.
• The Fluidized bed coater.

Conventional Coating Pan

The conventional coating pan is simple unit, which employs the principle of rolling a batch of
tablets in an oval shape pan, spraying the coating solution on it and passing hot air across the
tablet bed. An exhaust blower may be used to carry away the excess fumes generated during
the coating and drying process.

Improvements in conventional pan are pellegrini system which has a baffled pan and diffuser
which improves the drying efficiency and can be suitable for sugar coating process.

The immersion sword system which includes a metal sword that will immerse in the tablet bed
and during drying process it will introduce drying which flows through perforated metal sword
then upwards towards bed.

The immersion tube system which includes a tube that will immerse in the tablet bed and this
tube has a spray nozzle that delivers both the hot air and coating solution. This is suitable for
both sugar coating and film coating.

Perforated Coating Pan

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Unit Operation CPP CQA
Stirrer Mixing Speed Viscosity, appearance of
tablets, dissolution pattern in
case of functional coating.
Coating Suspension Stirrer Mixing Time Viscosity, appearance of
Preparation tablets
Milling Time in Colloidal Mill Viscosity, appearance of
tablets
Spray Rate Weight Gain, DT
Atomization air pressure Appearance
Pan RPM Appearance
Pre Warming time Appearance
Coating Inlet Air Appearance
Product Bed Temperature Appearance
Gun to Bed Distance Appearance
Number of guns Appearance
Spray Nozzle Diameter Appearance

PACKING
The earliest containers for medicine or pharmaceuticals were made of stone. They were
porous, difficult to craft, and easy to break. Although not the ideal solution, these stoneware
containers were transportable and made for decent early storage.

By the early 17th century, glass medical and prescription bottles were becoming more
common. They offered relative durability, impermeability and some options for
customizability. They came in several shades and, over the years, they became less expensive
to produce. The glass was still breakable under certain conditions, but innovative glass-
blowing machines produced glass bottles quickly and with high uniformity.

Looking at today’s plastics, you’d be forgiven for thinking that plastics became less expensive.
As production costs went down, they became the ideal options for pharmaceutical packaging.
They offered durability, a sterile interior, customizable designs, and affordable production.

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Today’s plastic bottles are everywhere in the pharmaceutical field. They offer tamper proof,
child safe options. They provide a straight forward, easy to use option for patients, and they
are resistant to heat, water, and impact.

Look at the history of blister packs most sources point to the contraceptives of the 60s as the
origin point for blister packaging. Since then, blister packs have become one of, if not the
most, used option in pharmaceutical packaging. Blister packs are convenient. They provide
clear evidence of any tampering if a seal is broken or a tablet is missing. They’re impressively
durable for their size and their production costs are typically lower than the bottled
alternative.

Blister packs sprang into popularity in the 80s when pharmacists and physicians realized that
blister packs eliminated the chance for dispersing errors. They made it much simpler to
dispense the accurate amount of medication from bulk supplies. The blister pack was also an
obvious way for patients to track their intake, how much medication they had left, and when
their course of treatment was over.
Over the last decade, the pharmaceutical packaging landscape has seen a lot of changes.
The introduction of new technologies has paved the way for companies to explore more
innovative solutions, improve their operations, and drive efficiencies across the supply chain.

Serialization will also continue to be a huge focus in pharmaceutical packaging throughout

2018, as the EU FMD deadline of February 2019 and delayed enforcement date of the DSCSA
get closer. Serialization has been widely discussed across the industry since the regulations
were first announced and it is likely that the implementation of new systems to meet
legislation will have a lasting effect on the industry.

The introduction of mandatory barcodes and the management and transfer of the huge
amounts of data generated increases the complexity of pharmaceutical packaging and means
that companies are faced with refining their operations to meet these needs.

That being said, it’s vital that companies look beyond the initial implementation challenges.
Serialization and full track and trace systems, such as those that will eventually be required in
the US, will not only lead the industry towards a safer and more secure supply chain, but could
ultimately help to connect the whole ultimately help to connect the whole industry from
manufacturer to patient.
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Define Packing and Pharmaceutical Packaging?
Packing

Packing consists of enclosing an individual item, or several item, in a container, usually for
shipment or delivery. This operation is mostly done by hand and machine.

Pharmaceutical Packaging

Pharmaceutical packaging means the combination of components necessary to contain,

preserve, protect & deliver a safe, efficacious drug product, such that at any time point before
expiration date of the drug product, a safe & efficacious dosage form is available.

What are the different types of Packaging Systems?

Generally there are three types of packaging systems such as mentioned below,

Primary Package System

Primary package made up of those package components & subcomponents that come into
direct contact with the product, or those that may have direct effect on product shelf life.

Secondary or Tertiary Package System

Secondary & tertiary package includes cartons, corrugated shippers & pallets.

What are the ideal requirements of packaging?

• Protect the preparation from environmental conditions.
• Non-reactive with the product and so does not alter the identity of the product.
• Does not impart tastes or odors to the product.
• Nontoxic.
• FDA approved.
• Protect the dosage form from damage or breakage.
• Meet tamper-resistance requirements, wherever applicable.
• Adaptable to commonly employed high-speed packaging equipment’s.

What are the criteria for the selection of package type and package material?
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• In the newer technology “Co-Extrusion” a number of plastic plies are extruded in
combination to produce cheaper laminations.

Uses of Films, Foils, Laminations:

• Strip Packs
• Blister Packs
• Sachets
• Diaphragm seals for bottles
• Liners for boxes either attached or loose bag-in-box systems & bags.

Foil Blisters

When sealed with a metal foil-cover, the blister can provide a hermetic pack i.e. an isolated
system, which excludes any exchange of gases between the product & surrounding
atmosphere.

(6) Rubber based components

Mostly used to make stoppers and bulbs for dropper assemblies.

Examples of rubber for pharmaceutical products include:

• Natural Rubber
• Neoprene Rubber
• Nitrile Rubber
• Butyl Rubber
• Chlorobutyl Rubber
• Bromobutyl Rubber
• Silicone Rubber

(7) Cotton

Package Type Remarks

Wadding In Solid preparations to prevent the collision of individual units or to
absorb moisture etc.
As Desiccant To prevent absorption of moisture particularly by tablets & capsules
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FDA’S Current Focus

• CMC CC PACKAGING TECHNICAL COMMITTEE.

• PACKAGING GUIDANCE COMMITTEE.
• CMC CC RECENT PACKAGING INITIATIVE.

CMC CC: Chemistry, Manufacturing and Control Coordinating Committee.

CMC CC Packaging Technical Committee: It includes various offices from CDER, CBER and CVM.

CDER- Centre for Drug Evaluation and Research

• Office of New Drug Chemistry.

• Office of Generic Drug.
• Office of Compliance.
• Office of Testing and Research.
• Quality Implementation Staff.
CBER- Center for Biological Evaluation and Research
• Office of Compliance and Biological Quality.
CVM – Centre for veterinary Medicine
• Office of New Animal Drug Evaluation.

Packaging Guidance Committee

• Disentwining the packaging information to CDER, CBER and CVM.

• Reviewing pharmacopoeial forum packaging proposal.
• Internal guidance and comment to
Reviewer
CMC CC committee
CTDQ document
• External guidance via CMC CC PACKAGING equivalency test.
• Drafting revision to packaging guidance bulk container, Q and A format.

Pharmacopoeial Forum

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If any products are found defective during manual scanning, the same carton is replaced with
another good one.

What is Serialization in Pharmaceutical industry?

In pharmaceutical industries serialization is assigning a unique code to the packaging of each
drug and printing this code on the packaging by any method. There are two main points in this
definition. The first is the unique code and the second is the drug packaging.

The definition and structure of the unique code are defined within the regulations of the
countries. The unique code definition within the regulations of all countries is larger similar to
each other and follows GS1 standards. The areas that differ are generally the codes and
cryptography preferences of the reimbursement institutions.

Serialization at different packaging stages

Primary Packaging

Primary packaging is the packaging in contact with the drug. The serialization of the primary
packaging is not a requirement in any market other than the American and Indian markets.
Because only in these markets even if it is exceptional, the patient can purchase the primary
packaging.

Secondary Packaging

It is the packaging that contains the primary packages medicine or medicines. The best
example of this packaging is the carton. On average, 80% of the medicines in the world are
sold in a carton. The serialization of this packaging is a must for regulations compliance. Some
regulations, such as EU-FMD, require Tamper Evident, along with serialization, to guarantee
that the medicine is first opened by the patient.

Tertiary Packaging

The B2B operations can carry out in the supply chain by making medicines into a whole with
tertiary packaging are bundles, cases and pallets. The serialization of the tertiary packaging is
the most important point to ensure traceability in the supply chain.

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Servos also are available in a wide variety of sizes. A thumb sized servo motor can integrate an
absolute encoder with a resolution of 131,072 pulses per revolution.

How many servo motors are in the blister machine?

Blister Quick through Servo has a total of 5 servo motors:

• Main Cam.
• Feeding drum.
• Printing Drum.
• Puller Drum.
• Punching Cam.

What is the principle of Blister Packing Machine (BQS)?

For BQS (in the case of the heating plate and sealing plate) works on the principle of flat
sealing and flat forming.

For Blister machine (in the case of the heating plate and sealing roller) works on flat forming
and roller sealing.

How many sensors were used in the BQS machine?

• Lidding Foil sensor.
• Sensor for forming foil.
• Inlet water sensor.
• Hopper sensor for check product level.
• Heating plate sensor.

Name of sensors used in Cartonator machine?

• Product magazine sensor.
• Product count sensor.
• Carton Call.
• Low carton call.
• Pusher call.
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CALIBRATION
Calibration establishes a relation between the quantity value provided by a measurement
standard and the corresponding indication provided by a measuring instrument or system.
Calibration also requires determination of the uncertainties associated with the
measurements performed. A calibration can be executed either on a measuring instrument (or
system) or on a measurement standard.

The calibration of a measuring instrument allows determining the deviation of the indication
of the measuring instrument from a known value of the measurand provided by the
measurement standard, with associated measurement uncertainty. In other words, the
deviation of the indication of an instrument from the conventional “true value” of the
measurand is established and documented.

The calibration of a measurement standardcan be performed by comparing its quantity value

and associated measurement uncertainty to a reference indication (with associated
measurement uncertainty) obtained by a calibrated measuring system.

For instance a measuring system calibrated by a primary reference standard can be used to
calibrate a secondary measurement standard. Also a comparison between two measurement
standards can be viewed as a calibration if the comparison is used to check (and, if necessary,
to correct) the quantity value and measurement uncertainty attributed to one of the two
measurement standards.

Calibration should not be confused with verification nor with adjustment. Verification in fact is
the “provision of objective evidence that a given item fulfills specified requirements”.
Adjustment on the other hand is “the set of operations carried out on a measuring system so
that it provides prescribed indications corresponding to given values of a quantity to be
measure”.

Calibration must be repeated at appropriate intervals. A measurement instrument, for

example, should be periodically recalibrated because changes in its characteristics can occur
during its use and after some time. Recalibration on appropriate intervals ensures detection of
these possible changes.

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What is Calibration?
Calibration is important wherever measurements are important. It gives you confidence in
your instruments and the results that they monitor, record and control. Calibration is the
process of comparing a reading on one instrument, with another instrument that has been
calibrated and referenced to a known set of parameters. The equipment used as a reference
should be directly traceable to equipment that is calibrated to the national standard.

Calibration of your measurement instruments has two objectives. Firstly, it checks the
accuracy of the instrument. Secondly, it determines the traceability of the measurement. In
practice, calibration also includes repair of the device if it is out of calibration.

Another definition:

Calibration is a process by means of which deviation of the display value from the actual value
is determined and documented for a given measuring instrument, or deviation of the output
quantity from the nominal value for a given test instrument.

Why is Calibration important?

An instrument’s measurement accuracy degrades over time. This is typically caused by wear
and tear. However, changes in accuracy can be caused by both electric and mechanical shocks
and the environment the instrument is in. The bottom line is, calibration of an instrument
improves the accuracy of the measuring device so the instrument user can have confidence in
their results.

Why do we need to Calibrate instruments?

Regular calibration provides you with:

• Knowledge and evidence of how your instrument measures now and over time.
• The confidence that you know your instrument works correctly.
• To know the uncertainty that can be achieved with the measuring instrument.
• To confirm whether or not there has been any alteration of the measuring instrument
that could create doubt about the results.
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• For the calibration of thickness go to the thickness from the sub menu calibration and
enter.
• Place the 10 mm gauge between the movable jaws and press enter.
• To check the accuracy of thickness calibration with 3 different gauges.
• And receive actual value.
• Finished Calibration: Ok.
• Take Printout.

Calibration of Hardness

• Place the machine in vertical position & place the calibration clamp if required and shall
ready for calibration.
• Start Calibration.
• Place after keeping 5 kg weight without jerks/ on the plate form.
• Wait for few seconds to finish the vibrations.
• Finished Calibration: Ok
• Take Printout.

After completion of calibration perform the verification of Thickness, Diameter & Hardness &
take printout of each and attach with the calibration format.

Acceptance Criteria

For 5 kg weight, the tolerance limit is 49.03 ± 0.5 N.

What is vernier Calliper?

The vernier calliper is a precision instrument that can accurately measure internal & external
dimensions & the outside measuring faces used to measure external dimensions of an object.

Define the parts of the Vernier Calliper?

The various parts of the vernier calliper are described below,

Outside Measuring Faces

• Used to measure external dimensions of an object.

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Whereas, “Disintegration” is defined as that state in which no residue of the tablet remains on
the screen of the apparatus or, if a residue remains, it may be consist of a fragment of
insoluble coating of the tablet or is a soft mass with no palpable core.

Define the Disintegration apparatus assembly?

The various parts of the disintegration apparatus are described below,

Rigid Baskets

• Rack assembly supports six cylindrical glass tubes, 77.5 ± 2.5 mm long, 21.5 mm in
internal diameter, and a wall thickness of about 2 mm.

The Tube

• The tube is held vertically by two superimposed, transparent plastic plates, 90mm in
diameter and 6 mm thick, perforated by six holes having the same diameter as tubes.
• The hole is equidistant from the center of the plate and is equally spaced from one
another.
• Attached to the underside of the lower plate is a piece of woven gauge made from
stainless steel wire.
• These are 635 mm in diameters and having nominal mesh apertures of 2.00 mm.
• The upper plate is secured with a tempered stainless steel circle punctured by six gaps,
each around 22 mm in breadth, accommodating the cylinders and holding them
between the plastic plates.
• The hole coincides with those of the upper plastic plate and the upper open ends of
glass tubes.

The Plates

• Plates are held inflexibly in position and 77.5 mm separated by vertical metal rods on
the outskirts.
• The upper plate center is fixed to the metal rod enable the assembly to be attached to a
mechanical device capable of raising and lowering it quickly at a constant frequency of
between 29 to 32 cycles per minute as per USP and 28 to 32 as per IP criteria through a
distance of 55 ± 2 mm.
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• Out of the 10 numbers of containers, sampling can be done randomly from top, middle
and bottom portion of any container.

Systematic Sampling

• In this method of sampling, at a particular and regular interval sampling can be done.
The interval may be timer or a number.

Example

• If 10 numbers of containers are to be sampled out of 50 numbers of containers, then

each container can be selected at every 10th no. of container, e.g. 10th, 20th, 30th, 40th&
50th.
• Another example where a particular time interval can be chosen as a method of
systematic sampling is that sampling can be done at a regular time interval such as 30
minutes, 60 minutes or 120 minutes to collect composite sample of a particular batch
during its processing.

Stratified Sampling

• Stratified sampling is the process of sampling dosage units at predefined intervals and
collecting representatives samples from specifically targeted locations in the
compression operation that have the greatest potential to yield extreme highs and lows
in test results.
• The term “Stratified” means dividing in to sub groups (Strata). Strata should be
identified as worst locations from which if sample is collected have the greatest chance
of failure. If the samples collected from the strata pass the predefined acceptance
criteria, then we can say that the whole batch passes the acceptance criteria. Generally
the stratified sampling is done during process performance qualification (PPQ) or
validation of products.
• Regular interval used in case of systematic sampling is slightly different than that used in
case of stratified sampling in a way that in systematic sampling is done for regular
batches and stratified sampling is done in PPQ or validation batches and one composite
sample is prepared in case of systematic sampling while in stratified sampling individual
samples taken at regular intervals are analysed separately.
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• After completion of compression of a batch, sample shall be collected from all the
containers randomly in a polybag & make a composite sample as per sampling plan.
• Alternatively, another sampling procedure can be adopted. Sampling frequency and
numbers of samples required at each sampling interval can be decided based on the
batch size of a product and compression machine speed and the required quantity of
sample as per sampling plan.
• As per the sampling frequency, samples can be collected in a container or fresh polybag
to make a composite sample.
• The sampling frequency must include start and end of the total batch run time.

Coated Tablet

• Sampling of coated tablets can be performed after completion of the coating process
directly from the coating pan or from the containers after unloading of the coated
tablets.
• Collect the sample as per sampling plan in a fresh polybag to make a composite sample.

Finished Product Sampling

• Finished product sampling shall be done at secondary packing at start, middle and end
of the packing operation.
• Sample shall be collected as per sampling plan.
• The sampling plan may include samples such as but not limited to sample for QC
analysis, microbiological analysis, control sample & stability sample.

Process Validation Sampling

Blending Stage

• Sampling shall be performed from the blending stage in which the product is blended.
• As per sampling plan, sampling shall be performed from top, middle and bottom of the-
blender using a sampling rod and required size of dies from different locations
depending upon the design of the blender and regulatory requirements.
• Sample size may vary from 1x to 3x of the average weight of one unit dose.
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1 9 2 7

5 6

10
Discharging Chute

How to collect the rinse water sample from different manufacturing area?
Rinse water sample shall be collected in the area where the equipment cleaning been done.
Rinse water sample shall be collected after B type cleaning randomly by IPQA persons based
on visual inspection and also rinse water sampling shall be done as per given equipment’s.

Sampling Procedure

• Inspect the area, equipment and all its parts thoroughly for any visible contamination.
• Rewash if visible contamination in notice.
• Rinse the equipment with purified water and collect in the SS tray.
• Collect approximately 100 ml rinse water container from SS tray.
• Rinse water to be collected from only single hard to clean part of machine on basis of
visual inspection assessment by considering worst case, not from every cleaned part.

How to select the sampling die during sampling?

• Firstly took the result of Bulk density from QC.
• If we didn’t have the BD result than consider the BD as 0.5.

Formula: Bulk Density = Mass / volume.

Die size is in CC and 1 CC = 1ml.

GUIDELINES
Regulatory affairs in pharmaceutical industry aim at the production of human health. People
and government spent money on drugs because of the role they can play in saving lives,
restoring health, preventing diseases and stopping epidemics. But in order to do so, drug must
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Drug Regulatory Agencies in India
India has emerged as one of the leading markets for pharmaceutical products. Increase in the
private healthcare infrastructure, widening rural markets, and inclusion of newer technologies
have placed healthcare as an independent sector in India. With privatization of healthcare, the
medical devices sector is growing too.

In order to regulate the import, manufacture, distribution and sale of drugs and cosmetics, the
Drugs and Cosmetics Act, 1940 (“D&C, Act”) was introduced in India in 1940. However, no
separate regulation has been enacted for regulating the import, manufacture, distribution or
sale of medical devices in India till date by the Government of India.

Drugs and Health is in concurrent list of Indian Constitution. It is governed by both Centre and
State Governments under the Drugs & Cosmetics Act, 1940.

Organizational Structure

Ministry of Health

CDSCO

Drug Controller General India (DCGI)

Assistant Drugs Controller India

Medical Device Division Diagnostic Division

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• Licensing and classification of medical devices are handled by the Central Licensing
Approval Authority (CLAA). The CLAA is also responsible for setting and enforcing safety
standards, appointing notified bodies to oversee conformity assessment, conducting
post-market surveillance and issuing warnings and recalls for adverse events.
• The CDSCO establishes safety, efficacy and quality standards for pharmaceuticals and
medical devices. It publishes and updates the Indian Pharmacopoeia, a list of regulated
pharmaceuticals and medical devices.
• For all drugs and device application, the CDSCO appoints notified bodies to perform
conformity assessment procedures, including testing, in order to ensure compliance
with their standards.
• The CDSCO is also divided into several zonal offices which do pre-licensing and post-
licensing inspections, post-market surveillance, and recalls when necessary.
• In addition to its regulatory functions, the CDSCO offers technical guidance, trains
regulatory officials and analysts, and monitors adverse events.
• The CDSCO work with the World Health Organization (WHO) to promote Good
Manufacturing Practice (GMP) and international harmony.

National Institute of Health and Family Welfare (NIHFW)

• NIHFW is an Apex Technical Institute, funded by Ministry of Health and Family Welfare,
for promotion of health and family welfare programmers in the country through
education, training, research, evaluation, consultancy and specialized services. The
NHIFW was established on March 9, 1977 by a merger of the National Institute of Health
Administration and Education (NIHAE) with the National Institute of Family Planning
(NIFP).

List of governing body members of NIHFW:

• 18 Members.
• 1 Chairman (ex-officio).
• 1 Vice Chairman (ex-officio)
• 9 Member (ex-officio).
• 6 Members.
• 1 Member Secretary (ex-officio).
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• The GMP requirements in schedule M are for pharmaceutical products. It specify GMP
requirements for premises such as buildings, air conditioning, waste management,
sanitation of workers, record keeping etc. for pharmaceutical products.
• Part 1 A deal with the specific requirements for sterile ophthalmic preparations.
• Part 1 B has specific requirements for manufacture of oral solid dosage forms (Tablet
and Capsule).
• Part 1 C has specific requirements for the manufacture of oral liquids. (Syrup, Elixirs,
Emulsions and Suspensions).
• Part 1 D specific requirement for manufacture of topical products, i.e. External
preparations (creams, ointments, pastes, emulsions, lotions, solutions, dusting powders
and identical products).
• Part 1 E specific requirement for manufacture of metered-dose-inhalers (mdi).
• Part 1 F specific requirements of premises, plant and materials for manufacture of API
(bulk drugs).

Schedule M-1

• Schedule M-1 is titled “Good Manufacturing Practices and Requirements of Premises,

Plant and Equipment for Homeopathic Products.
• It specify GMP requirements for premises such as buildings, quality control etc. for
Homeopathic medicines.
• Schedule M1 prescribe basic equipment and facilities for different sections such as
potentiation section, container section, lotions section, ophthalmic preparation section
etc.

Schedule M-2

• Schedule M2 is titled “Requirements of factory Premises for Manufacture of Cosmetics”.

• The GMP requirements in schedule M2 are for Cosmetic products.
• It specifies GMP requirements for premises such as buildings, equipment’s, basic
sanitation etc. for cosmetic products.
• Schedule M2 prescribe basic equipment and facilities for different sections such as
creams, nail polishes, lipsticks, hair dyes and powders etc.

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Schedule M-3

• Schedule M3 is titled “Quality Management System – For Notified Medical Devices and
In-vitro Diagnostics”.
• The GMP requirements in schedule M3 are for notified medical devices.
• It specifies GMP requirements for premises such as buildings, equipment, design and
development validation, record keeping etc. for medical devices and diagnostic
products.
• Schedule M3 also has Annexures from A to C.

Define the guidelines which come under the Schedule M?

The parts of schedule M are:

• Part 1: Good Manufacturing Practices for Premises and Materials.

• Part 2: Good manufacturing Practices for specific requirements of Plant and Equipment.

Part 1: Good Manufacturing Practices for Premises and Materials

1. General Requirements

1.1 Location and Surrounding.

1.2 Building and Premises.

1.3 Water System.

1.4 Disposal of Waste.

2. Warehousing Area

3. Production Area

4. Ancillary Area

5. Quality Control Area

6. Personnel

7. Health, Clothing and Sanitation of Workers

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• Helping the public get the accurate science-based information they need to use
medicines, devices and foods to improve their health.

What is 21 CFR? Define the guidelines for parts 210 & 211?
21

Short for “Title 21” which is the section of the CFR that applies to food and drugs. The CFR
contains 50 “titles”.

CFR

Short for “Code of Federal Regulations” which is coded (numbers and letters) set of laws
published by the federal government of the United States.

Part 210 – Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or

Holding of Drugs.

§210.1 Status of Current Good Manufacturing practice regulations.

§210.2 Applicability of Current Good Manufacturing practice regulations.

§210.3 Definitions

Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals.

There are total 11 subparts of 21 CFR Part 211.

Subpart A – General Provisions.

§211.1 – Scope.

§211.3 – Definitions.

Subpart B – Organization and Personnel.

§211.22 – Responsibilities of Quality Control Unit.

§211.25 – Personnel Qualifications.

§211.28 – Personnel Responsibilities.

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Transplantation, Pharmaceuticals and Pharmaceutical Care. In 1996 The European Directorate
for the Quality of Medicines (EDQM) is created.

Define the guidelines of EU for pharmaceutical industry?

The rules governing medicinal products in the European Union contains guidance for the
interpretation of the principles and guidelines of good manufacturing practices for medicinal
products for human and veterinary use laid down in Commission Directives 91356/EEC, as
amended by Directive 2003/94/EC, and 91/412/EEC respectively.

Eudralex – Volume 4 – Good Manufacturing Practice (GMP) Guidelines

Introduction

Part I – Basic Requirement for Medicinal Products

• Chapter 1 – Pharmaceutical Quality System.

• Chapter 2 – Personnel.
• Chapter 3 – Premise and Equipment.
• Chapter 4 – Documentation.
• Chapter 5 – Production.
• Chapter 6 – Quality Control.
• Chapter 7 – Outsourced Activities.
• Chapter 8 – Complaints and Product Recall.
• Chapter 9 – Self Inspection.

Part II – Basic Requirement for Active Substances Used as Starting Materials

• Basic Requirement for Active Substances Used as Starting Materials.

Part III – GMP Related Documents

• Site Master File.

• Q9 Quality Risk Management.
• Q10 Note for Guidance on Pharmaceutical Quality System.
• MRA Batch Certificate.

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Drug Regulatory Agencies in UK
The Medicines and Healthcare Products Regulatory Agency (MHRA) is an executive agency of
the Department of Health and Social Care in the United Kingdom which is responsible for
ensuring that medicines and medical devices work and are acceptably safe.

The MHRA was formed in 2003 with the merger of the Medicines Control Agency (MCA) and
the Medical Devices Agency (MDA). In April 2013, it merged with the National Institute for
Biological Standards and Control (NIBSC) and was rebranded, with the MHRA identity being
used solely for the regulatory center within the group.

MHRA Activities

• Operate post-marketing surveillance – in particular the Yellow Card Scheme – for

reporting, investigating and monitoring of adverse drug reactions to medicines and
incidents with medical devices.
• Assess and authorize of medicinal products for sale and supply in the UK.
• Oversee the Notified Bodies that ensure medical device manufacturers comply with
regulatory requirements before putting devices on the market.
• Operate a quality surveillance system to sample and test medicines to address quality
defects and to monitor the safety and quality of unlicensed products.
• Investigate internet sales and potential counterfeiting of medicines, and prosecute
where necessary.
• Regulate clinical trials of medicines and medical devices.
• Monitor and ensure compliance with statutory obligations relating to medicines and
medical devices.
• Promote safe use of medicines and devices.
• Manage the Clinical Practice Research Data link and the British Pharmacopoeia..

The MHRA hosts and supports a number of expert advisory bodies, including the British
Pharmacopoeia Commission, and the Commission on Human Medicine which replaced the
Committee on the Safety of Medicines in 2005.The MHRA manages the Early Access to
Medicines Scheme (EAMS), which was created in 2014 to allow access to medicines prior to
market authorization where there is clear unmet medical need.

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• Glossary
PART II

1. Introduction.

2. Quality Management.

3. Personnel.

4. Building and Facilities.

5. Process Equipment.

6. Documentation and Records.

7. Materials Management.

8. Production and In-Process Controls.

9. Packaging and Identification Labeling of APIs and Intermediates.

10. Storage and Distribution.

11. Laboratory Controls.

12. Validation.

13. Change Control.

14. Rejection and Re-use of Materials.

15. Complaints and Recalls.

16. Contract Manufacturers (Including Laboratories).

17. Agents, Brokers, Traders, Distributors, Repackers, and Relabelers.

18. Specific Guidance for APIs Manufactured by Cell Culture/ Fermentation.

19. APIs for use in Clinical Trials.

20. Glossary.
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ICH Guidelines
ICH Guidelines were created by the International Council for Harmonization of Technical
Requirements for Pharmaceuticals for Human Use (ICH).

ICH aims to provide uniform standards for technical requirements for pharmaceuticals for
human use. They are developed by regulatory and pharma industry authorities. The purpose
of ICH guidelines is to ensure safe, effective and high quality medicines are developed and
registered efficiently.

ICH is a joint initiative involving both regulators and research based industry representatives of
the EU, Japan and the US in scientific and technical discussions of the testing procedures
required to assess and ensure the safety, quality and efficacy of medicines.

The ICH secretariat is based in Geneva. The biennial meetings and conferences of the ICH
Steering Committee rotate between the EU, Japan and the USA.

The ICH guidelines consist of four topics;

• Quality.
• Efficacy.
• Safety.
• Multidisciplinary.

Quality

A quality topic is those relating to chemical and pharmaceutical Quality Assurance (Stability
Testing, Impurity Testing etc.

Efficacy

An Efficacy topic is those relating to clinical studies in human subject (Dose response studies,
Good clinical practices etc.

Safety

A safety topic is those relating to in vitro and in vivo pre-clinical studies (Carcinogenicity
Testing, Genotoxicity testing etc.).
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Multidisciplinary

A multidisciplinary topic is cross-cutting topics which do not fit uniquely into one of the above
categories.

Define the ICH guidelines?

The ICH guidelines are dived into 14 parts from Q1A to Q14.

Q1 Stability
Q1A (R2) – Stability Testing of New Drug Substances and Products.

Q1B – Stability Testing: Photo stability Testing of New Drug Substances and Products.

Q1C – Stability Testing for New Dosage Forms.

Q1D – Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products.

Q1E – Evaluation of Stability Data.

Q1F – Stability Data Package for Registration Applications in Climatic Zones III and IV.

Q2 Analytical Validation
Q2 (R1) – Validation of Analytical Procedures: Text and Methodology.

Q2 (R2) Q14 – Analytical Procedure Development and Revision of Q2 (R1) Analytical

Validation.

Q3 Impurities
Q3 A (R2) – Impurities in New Drug Substances.

Q3 B (R2) – Impurities in New Drug Products.

Q3 C (R8) – Guideline for Residual Solvent.

Q3 C (R9) – Maintenance of the Guideline for Residual Solvents.

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A consumer usually cannot detect (through smell, touch, or sight) that a drug product is safe or
if it will work. While CGMPs require testing, testing alone is not adequate to ensure quality.In
most instances testing is done on a small sample of a batch, so that most of the batch can be
used for patients rather than destroyed by testing.

Therefore, it is important that drugs are manufactured under conditions and practices
required by the CGMP regulations to assure that quality is built into the design and
manufacturing process at every step.

Facilities that are in good condition, equipment that is properly maintained and calibrated,
employees who are qualified and fully trained, and processes that are reliable and
reproducible are a few examples of how CGMP requirement help to assure the safety and
efficacy of drug products.

What is the difference between GMP and CGMP?

Availability

The applications of GMP are broader when compared to the applications of CGMP. That’s
mainly because some of the manufacturers do not use the latest available technology due to
availability and cost implications.

Usage

GMP is widely being used in the world when compared to CGMP. In fact, more than 100
different countries out there in the world tend to use GMP. However, only handful countries
adhere to the guidelines of CGMP.

Applicability

GMP is widely applicable to a large number of situations out there in the world, when
compared to CGMP. These applications span across a large number of industries as well.

For example, GMP is used in ensuring different areas of a business, which include book
keeping, ensuring cleanliness, meeting personnel qualifications and manufacturing equipment.

GMP can also be used to define quality in procedures followed by a business. However the
applicability of CGMP is somewhat limited. It can mainly be used for manufacturing goods.
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Basic Concepts
&
Their
Questions& Answers

USV PRIVATE LIMTED BADDI - I

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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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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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• 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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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 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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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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