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59Testing of Raw Materials, Intermediate, and Finished Products
Tablet hardness acts as a basis to direct the development of products and as a
quality-control requirement. Tablets should not be too soft or too hard.
Tablet hardness testing is a laboratory method which is applied to measure the
breaking point of a tablet.
Most tablet hardness testers operate through a simple movement of a jaw or bar
which squeezes the tablet between two rigid plates.
Thus, causing it to fracture under the pressure and hence, establishing the force
needed.
There exist several varying tablet hardness testers, all operating around the same
primary principle.
Hardness testers spun from simple handheld equipment to fully automated
appliances.
Procedure
Place the tablet at in contact with the stationary jaw as indicated below. Measure the
hardness of ten individual tablets, unless otherwise specied.
Calculate the mean, range, and if required, the relative standard deviation of the
ten tested tablets. The calculated mean value must fall within the acceptable range as
outlined in the Product Specications.
PLaceMent of tabLets
Round Tablets: Place the tablet in contact with the stationary jaw, with score line (if
present) perpendicular to the stationary jaw.
FIGURE5.4 Friabilator.
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60 Basics of Pharmaceutical Manufacturing and Quality Operations
Oval, Capsule Shaped, Elongated hexagon, and/or Rectangular Tablets: Place the
tablet lengthwise, face down in contact with the stationary jaw.
Multi-edge (Polygonal) tablet: Place the tablets such that one at edge is in contact
with the stationary Tablets: jaw and a parallel at edge is facing the moving jaw.
If the tablet shape does not correspond to any of the above shapes or conditions,
refer to the specication of the product.
FRIABILITY
Tablet Friability is the physical condition that describes the tendency of tablets to
break into smaller pieces or to detach a percentage of powder or powder loss from
the tablet’s outer surface under mechanical and physical stress.
During transportation and handling, tablets are subjected to mechanical shocks,
which can lead to chipping and, in extremes, breaking, or capping. So, the tablet must
be formulated to withstand this stress. It is also crucial that loosely packed powder
does not erode from the tablets, which could cause a handling hazard.
A weak tablet could be due to several factors, including poor tablet design, low
moisture content, insufcient binder, and over-lubrication.
The Friability tester is known as the friabilator. It consists of a drum, with an
internal diameter between 283 and 291 mm and a depth between 36 and 40 mm,
of a transparent synthetic polymer with polished internal surfaces and is subject to
minimum static build-up. One side of the drum is removable. The tablets are tumbled
at each turn of the drum by a curved projection with an inside radius between 75.5
and 85.5 mm that extends from the middle of the drum to the outer wall. The outer
diameter of the central ring is between 24.5 and 25.5 mm. The drum is attached to
the horizontal axis of a device that rotates at 25 ± 1 rpm. Drums with dual scooping
projections or an apparatus with more than one drum for the running of multiple
samples at one time are also permitted (Figure5.4).
If a single tablet weight is less than 650 mg, take 6.5 g tablets or as near as possible
to 6.5
g. For tablets with more than 650mg/Tablet, take 10 tablets and weigh them.
The tablets should be carefully deducted before testing with air pressure or a soft
brush. Accurately weigh the tablets and place them in a friabilator wheel. Rotate
the wheel 100 times (i.e. approximately 4minutes), unless otherwise specied and
remove the tablets. Remove any loose dust from the tablets as before, and accu-
rately weigh. In the case of hygroscopic tablets, a humidity-controlled environment
is required for testing. Calculate the percentage of Loss in Weight.
If tablet size or shape causes irregular tumbling, adjust the drum so that the base
forms about a 10° angle with the bench top and the tablets no longer bind together
when lying next to each other, which prevents them from falling freely.
%
Loss in weight
WW
W
100
12
1
=
−
W
1
= Net Weight (g) of tablets before
W
2
= Net Weight (g) of tablets after
If cracked, cleaved, or broken tablets are present in the tablet sample after tumbling,
the sample fails.
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61Testing of Raw Materials, Intermediate, and Finished Products
QUESTIONS AND ANSWERS
1. A 10.3256 g glass container was used to determine LOD. Container was
dried for 30minutes at 100°C. Sample was crushed in small particles
and placed in the same container. The weight of sample and container
was found to be 11.6521 g. The container containing the sample was
dried for 4 hours at 100°C. The weight after drying was 11.5896 g. The
specication for the test is “Not more than 5.0% for 4 hours at 100°C.
Calculate the %LOD and determine if the test meets the specication.
Answer:
Weight of empty container = 10. 3256 g
Weight of empty container + sample before drying = 11. 65 21 g
Weight of sample before drying = 1. 326 5 g
Weight of empty container + sample after drying = 11. 58 96 g
Weight of sample after drying = 1. 26 40 g
%
LOD
1.3265 1.2640
1.3265
100
4.7%
()
()
=
−
×=
The test meets the specication and passes.
2. How long, and in what condition is the weighing apparatus to be dried
before weighing the original sample?
Answer: The weighing bottle is to be dried for about 30minutes under the
same conditions to be employed in the determination.
3. How much sample should be weighed to determine the LOD?
Answer: 1–2 g of sample powder or as specied in the product monograph.
4. For the disintegration test what should be the temperature of the water
bath?
Answer: 15°C–25°C for dispersible tablets and for others 37°C ± 2°C.
5. How many tablets/capsules are used for initial testing for disintegration
test.
Answer: Six tablets or capsules.
6. What is considered as “Complete disintegration”?
Answer: Complete disintegration is dened as that state in which any residue
of the unit, except fragments of insoluble coating or capsule shell, remains on
the screen of the test apparatus or adhering to the lower surface of the disk
7. What are major parts of pH meter?
Answer:
1. Measuring Electrode
2. Suitable Reference Electrode
3. Voltage Measurement System
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62 Basics of Pharmaceutical Manufacturing and Quality Operations
8. If the pH of a solution is to be adjusted to 7.2 which two buffer will be
used to calibrate the pH meter?
Answer: Buffer 4.00 and 7.00
9 How will you dene the hardness?
Answer: Determine the breaking point and structural integrity of a tablet.
10. How and oval shaped tablet is placed at hardness tester?
Answer: It should be placed the lengthwise, face down in contact with the
stationary jaw
11. For friability test, if the weight of an individual tablet is less than 650 mg
how much sample to be weighed?
Answer: 6.5 g
12. A friability test was performed, the initial weight of the tablets was
6.6329 g. After rotating for 100 times, the weight remained at 6.6013 g,
and a broken tablet was found. The limit of the test is not more than
0.8%. Calculate the % loss. Is the test passed?
Answer:
%
loss
6.6329 6.6013
6.6329
100
()
=
−
×
=0.48%
The result is well within the limit of friability, since a broken table is found
overall results failed.
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6
Data Integrity
Regulatory Bodies all around the world have been observing a critical issue, Data
Integrity. Massive problems were found during inspections by the pharmaceutical
regulatory agency because mal practices had given rise to the product for patients
that was not safe for them to use. Data is established when various information and
results are collected together; however, this data is not much useful without integrity.
Accuracy and original data increase the chances of stability and performance of an
organization.
In the simplest words, Data Integrity could be explained as follows;
The raw data has to be complete, reliable, and accurate and no changes or dele-
tions could be introduced without appropriate authorization.
Authentication of Data Integrity is a critical part of the FDA’s mission to ensure
the safety, efcacy, and quality of human and veterinary drugs, biological products,
and medical devices. As such, the FDA expects that all data which is submitted to
the agency must fulll the denition of completeness, consistency, and accuracy and
should be attributable, legible, contemporaneously recorded, original or a true copy,
and reliable.
Data integrity must not be mistaken as data security. The difference between the
two terminologies should be clearly understood. Data Security refers to the preven-
tion of data corruption through the use of controlled access mechanisms as well as
ensuring that data is accessed only by its assigned users, thus ensuring the privacy
and protection of data.
Whereas Data Integrity refers to the quality of data, which assures that the data
is complete and has a whole structure and its prime motive is the validity of data.
SIGNIFICANCE OF DATA INTEGRITY IN GMP
Data Integrity plays a key role in all areas of GMP compliance and Health regulators
expect data to be meaningful, taking into consideration the design, operation, and
monitoring of systems and controls based on risk to patient, process, and product.
Data Integrity is highly important in any industry, but in pharmaceutical indus-
try, its signicance is further enhanced as any error in data could lead to serious
consequences.
Principles of Data Integrity had to be standardized in order to regulate them and
achieve better processes and higher quality products. This leads to ALCOA principle.
ALCOA is an acronym for the original ve principles of Data Integrity that should
be possessed by data in order to maintain the integrity.
The acronym “ALCOA” denes that data should be:
1. Attributable
2. Legible
63DOI: 10.1201/9781003366393- 6
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64 Basics of Pharmaceutical Manufacturing and Quality Operations
3. Contemporaneous
4. Original and
5. Accurate
ALCOA relates to all sorts of data, whether paper or electronic, and these principles
should be part of our data lifecycle, GDP, and Data Integrity initiatives.
It helps in developing strategies so that the integrity of the evidence is maintained
both in research and manufacturing. The aspects of ALCOA in pharmaceuticals have
been discussed below:
Attributable: To ensure accountability, the data should be attributable. This
means that every piece of data entered into the record must be capable of
being traced back to the person who has collected it. In other words, data
should clearly demonstrate who observed and recorded it, when it was
observed and recorded. This would further clarify that the person who
recorded or entered the data was qualied, experienced, and trained accord-
ingly to perform the desired responsibilities. Any changes made to records,
for example corrections, deletions, changes, etc., will also be governed by
this very principle.
Legible: This principle particularly applies on paper records that they should
be legible. The data should be readable, easy to understand, and recorded
permanently, and allows a clear picture of the sequencing of steps and origi-
nal entries should be preserved and non-erasable and are reliable through-
out the data lifecycle. This is very critical in the pharmaceutical industry
as a mistaken spelling could result in the administering of a completely
different drug.
For an electronic record to be considered legible, traceable, and perma-
nent, creation of data in temporary memory must be avoided as well as
immediately committing data to a permanent memory before moving on.
Contemporaneous: Contemporaneous could be explained as follows:
“Data should be recorded as it was observed and exactly at the time it was
ex e c u t ed”.
Basically, this factor provides the indication that the actions, events or
decisions taken were recorded as they took place. This documentation can
provide an accurate verication of what was done, or what was decided and
what inuenced the decision at that time.
Original: Source data should be accessible and preserved in its original form.
No matter whether the data paper based or electronic, the source in either
case is referred to as source data or primary data. For example, if the data
is related to validation, it should be originally recorded in an approved pro-
tocol or form or in a dedicated notebook and hence it should must remain
available in that state. The basic purpose is to preserve the content and
meaning of the original data where it is generated. Recording results in a
notebook for transcription later can introduce errors and if your original
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65Data Integrity
data is handwritten and needs to be stored electronically, ensure that a
“true copy” is generated, and the copy is veried for completeness and then
migrated into the electronic system.
Accurate: Data accuracy means ensuring the recorded data is free from errors,
complete, truthful, and reliable and conform to the protocol. If the data
is edited without logging, then it means that the accuracy of data is lost.
Therefore, editing should not be performed without documenting and anno-
tating the amendments. It is of vital importance to always record who, when,
and why changed the data record. ALCOA in pharmaceuticals helps both
the companies and the users making it sure that there are no record-keeping
errors due to which any product which is compromised on quality, efcacy,
and safety is released onto the market.
Many of the concepts for ALCOA have been captured in the regulations
as far back as 1978. Since that time, the industry has changed dramati-
cally. The generic-drug industry has grown and in the United States alone
accounts for more than 80% of the prescriptions written today. Coupled
with the emergence of biosimilars, virtual companies, contract manufac-
turing organizations, rapid advancements in automation and information
technology, and the globalization of the industry have resulted in reinter-
pretation of the attributes associated with maintaining the integrity of data
throughout the product lifecycle, whether those data are generated from
electronic, paper-based, or hybrid systems.
ALCOA+
The acronym ALCOA+ adds the concepts that, in addition to ALCOA, data also
needs to be complete, consistent, enduring, and available. It is important to under-
stand what each element of ALCOA+ means in order to apply the concepts appropri-
ately with respect to a company’s records. So when we talk of ALCOA+, we add up
more values to original set ALCOA as follows;
a. Complete: Information that is critical to recreating and understanding an
event. This would include any repeat or reanalysis performed on a labora-
tory test sample.
b. Consistent: The data is presented, recorded, dated, or time-stamped in the
expected and dened sequence.
c. Enduring: The data or information must be maintained, intact, and acces-
sible throughout their dened retention period.
d. Available: The data or information must be able to be accessed at any time
during the dened retention period.
In order to minimize Data Integrity risks, the following actions are recommended:
1. Follow a software development lifecycle
2. Ensure all computer systems are compliant to 21 CFR Part 11 requirements
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66 Basics of Pharmaceutical Manufacturing and Quality Operations
3. Implement error detection software
4. All computerized systems must be completely validated and qualied
5. Audit trails should be implemented effectively
6. There should be a backup and recovery procedure in place
7. The records should be secured with limited system access
8. The physical and logical security of systems must be protected
9. Design a Quality Management System with SOPs and logical controls
10. Establish a vendor management qualication program
11. Properly train users and maintain training records
12. Conduct internal audits to evaluate controls and procedures
QUESTIONS AND ANSWERS
1. What is Data Integrity?
Answer: Data Integrity could be explained in the following words;
“the raw data has to be complete, reliable, and accurate and no changes or
deletions could be introduced without appropriate authorization”.
2. Dene and explain ALCOA principles
Answer: ALCOA is an acronym for the original ve principles of Data
Integrity that should be possessed by all sorts of data, whether paper or
electronic, in order to maintain the integrity.
The acronym “ALCOA” denes that data should be;
Attributable: This means that every piece of data entered into the record
must be capable of being traced back to the person who observed and
recorded it and when it was observed and recorded. Also, changes made to
records, for example corrections, deletions, changes, etc., are also attributed
to the responsible person.
Legible: Legible means that the paper records should be readable, easy to
understand, and recorded permanently, and allows a clear picture of the
sequencing of steps and original entries should be preserved and not eras-
able and are reliable throughout the data lifecycle.
The electronic records must always be created in a permanent memory to be
considered as legible.
Contemporaneous: This factor provides the indication that the actions,
events, or decisions taken were recorded as they took place. In other words
data should be recorded as it was observed and exactly at the time it was
executed.
Original: Original means the source data whether paper based or electronic
should be accessible and preserved in its original form. For example, the
data should be always recorded in an approved protocol or form or in a
dedicated notebook and hence it should must remain available in that state
so that the content and meaning of the original data where it is generated,
could be preserved.
Accurate: This principle means that the recorded data is free from errors,
complete, truthful and reliable, and conform to the protocol. The data
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67Data Integrity
should not be edited without logging in and documenting and annotating
the amendments. It is of vital importance to always record who, when, and
why changed the data record.
3. What is an Audit trail?
Answer: In pharmaceutical industry, audit trail is a regulatory requirement.
It is a series of records of computer events, about an operating system, an
application, or user activities. Audit trail also contains in the record the
name of persons who performed any activity with the date and time. Audit
trail assures the record integrity and security.
A computer system may have several audit trails, each devoted to a particu-
lar type of activity.
4. What is the difference between ALCOA and ALCOA+?
Answer: The term ALCOA is an acronym, which stands for Attributable,
Legible, Contemporaneous, Original, and Accurate. Alcoa was then
expanded to Alcoa Plus (Alcoa +), by the addition of a few more concepts
which are Complete, Consistent, Enduring, and Available.
5. How does Data Security differ from Data Integrity?
Answer: There is a difference between the two terminologies that could be
explained as follows;
Data Security refers to the prevention of data corruption through the use of
controlled access mechanisms as well as ensuring that data is accessed only
by its assigned users, thus ensuring the privacy and protection of data.
Whereas data integrity refers to the quality of data, which assures the data
is complete and has a whole structure and it’s prime motive is the validity of
data.
https://t.me/med1917
7
Process Validation
According to the ICH guidelines Q7, Process validation can be dened as docu-
mented evidence that the process, operated within established parameters, can
perform effectively and reproducibly to produce a medicinal product meeting its pre-
determined specications and quality attributes.
Before stepping into the details of Process validation, let us understand rst why
Process Validation is important and why was it introduced to Pharmaceutical Good
Manufacturing practices.
Process Validation concept does not have a very old history as other good manu-
facturing practice (GMP) elements. It was only in 1987 when US Food and Drug
Administration released the process validation guidelines for the rst time and intro-
duced the pharmaceutical world with the term “Validation”.
Although initially the pharmaceutical products were manufactured under some
kind of process controls yet the controls were not strict enough to ensure and con-
trol the product quality to 100% and the manufacturing processes were still suscep-
tible to produce medicines with compromised quality which were given to patients
directly, resulting in obvious adverse consequences. These consequences led to
the introduction of Quality Control department and various analytical functions
related to it.
Establishing the regulatory agencies such as the US FDA, clinical testing prior to
approval of new products, GMPs, and other controls were also taken into measures
to prevent safety and efcacy adversities.
With the ever-growing pharmaceutical industry and complexity of the pro-
cesses, it became apparent that a reactive approach of testing the products was
not adequate. A proactive approach was then required to be applied and greater
emphasis needed to be placed to control the processes prior to the nished stage
of the products.
It was realized in the very beginning of biological products that many impor-
tant quality attributes of the product were not directly measurable for release testing
and that these attributes were critical to the product’s safety and efcacy. It was
therefore understood that a biopharmaceutical product is signicantly dened by its
manufacturing process and thus the process needed to be both tightly controlled and
validated.
This was the beginning of the concept of Process Validation.
The fundamental approach was testing the process to assure it worked, along with
periodic retesting of the manufacturing process to assure it was continuing to work.
The US FDA thus came out with the denition of Validation as follows:
PROCESS VALIDATION is establishing documented evidence which provides a high
degree of assurance that a specic process consistently produces a product meeting its
predetermined specications and quality attributes
68 DOI: 10.1201/9781003366393-7
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