Quality Assurance Handbook.pdf

2022

QA
HAND
BOOK
A Compendium of Guidelines and Related
Materials
EDITION - I

PHARMACEUTICAL
FORMULATIONS

Ajay Thakur


QA HAND BOOK
INDEX
S.No.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.

14.
15.
16.
17.
18.

QUALITY ASSURANCE BASIC
QUALITY ASSURANCE
STANDARD OPERATING PROCEDURE
SITE MASTER FILE
DRUG MASTER FILE
PROCESS VALIDATION
VALIDATION MASTER PLAN
CHANGE CONTROL
DEVIATION
CORRECTIVE AND PREVENTIVE ACTION
COMPLAINTS AND RECALLS
CLEANING VALIDATION
ANNUAL PRODUCT QUALITY REVIEW
QUALITY RISK MANAGEMENT
DOCUMENT & DATA COLLECTION, RECORD, CONTROL
& MANAGEMENT
VENDOR MANAGEMENT
QUALITY / FACILITY AUDITS
OOS/ OOT
PHARMACOPOEIA

PAGE NO.
63 to 64
65 to 65

66 to 66
66 to 66
66 to 68
69 to 69
70 to 74
75 to 81
82 to 85
86 to 93
94 to 100
101 to 105
106 to 116
117 to 122
123 to 130
131 to 141
142 to 154
151 to 161

TABLET’S MANUFACTURING UNIT OPERATION
19.
20.
21.
22.
23.
24.
25.
26.
27.

IPQA
WAREHOUSE

GRANULATION
COMPRESSION
COATING
PACKING
CALIBRATION
SAMPLING
GUIDELINES
BASIC CONCEPTS & THEIR QUESTIONS & ANSWERS

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164 to 164
165 to 176
177 to 227
228 to 302
302 to 349
349 to 404
404 to 422
423 to 434
435 to 491


QA HAND BOOK
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.

X
There are no terms under “X”.

Y
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
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
Agreement

and

• API: 4 years from
date of the audit.

Technical

NA

• 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
√ = Mandatory
● = Desirable
□ = NA
1
2
3

4
5

6
7

Vendor Information
(VIF)
Process Flow Diagram
TSE/BSE Declaration/
TSE / BSE risk
evaluation
questionnaire (if
applicable)

Residual solvent
declaration
Stability Data / Shelf
Life Declaration / Retest
or Reevaluation Period
Declaration
Regulatory / CGMP
Certificate
Audit of Vendor
Manufacturing Site
Prior to
Commercialization

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API

√

Input Material
Raw Material
Packaging Material
KRM Excipie RM other Primary
Printed
nt other
than
than KE
KRM
√
√

√
√
√

●
√

●
√

●
√

●
√

●
√

●
√

√

√

√

●

□

□

●

●

●

●

●

●

√

√

√

□

√

√

√

●

□

□

√

√


QA HAND BOOK
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.

1
2
3
4

5
6
7

Requirement
√ = Mandatory
● = Desirable

□ = NA

Vendor Information
(VIF)
GMP Certificate
Technical Agreement
Stability data/ Shelf life
declaration/ Retest or
Reevaluation period
Declaration
Process Flow Diagram
Residual solvent
Declaration
TSE / BSE Declaration /
TSE / BSE risk
Evaluation
questionnaire (if
applicable)

API

KRM

Input Material
Raw Material
KE
Excipient
RM
other than
other

KE
than
KRM

Packaging Material
Primary
Printed

Ensure the Validity
●

●

●

●

●

●

●

●
√

●
√

●

√

●
√

●

●

●
□

√

√

√

√

√

●

□
√

□

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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United State of America (Ph.
Eur. Obs.)
Argentina (Ph. Eur. Obs.)

United State Pharmacopoeia
(USP)
Farmacopea Argentina

Korea*

The Korean Pharmacopoeia

two supplements between
the editions after JP12 and
partial revision at any time if
immediate necessity.
Annually, with 2 supplements
per year
Undetermined, intended
biannually

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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