QUALITY CONTROL (Q.

C)

Quality control is an essential operation of the pharmaceutical industry. It is the sum of testing
and assessment. It is a part of Quality Assurance. Quality Control Department at Popular
Pharmaceuticals Ltd is to keep the quality up at their products and responsible for the day-by-
day control at quality within the company. This department is stuffed with qualified personnel
and technicians who assess and assure that the product is safe, effective, stable, and acceptable to
every consumer and satisfy all the aspects of GMP.

Major responsibilities of QC

• Sampling of the new raw & packaging materials that arrived at the factory
premises
• Issuing release, reject or quarantine tag for each batch of raw material & final
product.

• Ensuring precision & accuracy of all testing methods

• Testing of any return goods
• Stability tests for finished products
• Control of laboratory reagents

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Working Divisions in QC

Analytical section
Analytical section of quality control department performs the tests:

For Raw materials-

 Raw materials in each batch must request that the materials comply with the necessary
requirements with a complete certificate of analysis which is a definite binding on the
part of the supplier.

 After receiving the raw materials, a GRN (Goods Receive Note) recorded with details
such as: material’s name, supplier’s name, total quantity, number of containers,
manufacturer’s batch number.

 Sampling- It is important that during sampling, the QC staff independently inspect the

containers, is performed if there are large numbers of containers.

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  The raw materials should be released in a batch fashion and with proper status labeling.
Approved raw materials are marked green and available to warehouse staffs.

If the raw materials don’t comply with specifications, they are rejected and marked red
label.

For Packaging materials:

 Packets
• Printing error test,
• Length, width of secondary packing materials,
• Lock bottom test,

• Defection of gluing,

• Wide color variation.

 Cap
• Color
• Printing

• Weight,

• Length, diameter of wad,

• Length from top to the cut mark.
 Bottle
• Length,
• Diameter of neck and body,
• Weight,
• Over flow capacity,
• Light transmission test.
• Aluminum Foil
• Thickness of Al foil,
• Weight at gm / sq. inch,

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  Label
• Conditions of color printing
• Quality of paper

For Finished Products:

 Solid Preparation
• Description
• Dissolution & Disintegration time
• Weight Variation
• Assay

 Liquid Preparation
• Weight per ml
• Microbiological Limit Test
• pH

Final testing of finished product is made in the quality control laboratories. The testing of
finished product for compliance with predetermined standards is a critical factor for product
release.

Instrument used in the Quality Control department

Serial Equipment Company Origin Use

no.

1 HPLC Shimadzu Japan • Identification

(Quaternary)- 2sets • Qualification

• Separation

2 HPLC (Isocratic) Shimadzu Japan • Identification

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 • Qualification

• Separation

3 HPLC (Quaternary) Agilent Germany • Identification •

Qualification Separation

4 HPLC Barnstead USA Water conductivity and

reduce the particle size
(Quaternary)- of water

5 Atomic Shimadzu Japan To identify and measure

absorption minerals.
spectrophotometer

6 Pressure machine Shimadzu Japan To prepare the disc for

IR

7 Fourier Transform Shimadzu Japan Material identification &

(FTIR) infrared purity test
spectrophotometer

8 TOC-analyzer Shimadzu Japan To measure total organic

carbon in

purified water

9 Visible UV Shimadzu Japan For both qualitative &

quantitative analysis
spectrophotometer

10 Conductivity tester Sartorius Germany To test conductivity

11 Vibratory sieve Fritsch Germany Sieve analysis

shaker

12 Automatic Atago Japan To determine the optical

polarimeter rotation

13 Viscometer Brookfield Viscosity determination

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 14 pH meter Mettler Toledo Switzerland To determine pH

15 Dissolution tester Pharma test Germany Dissolution testing

16 Melting point Mettler Toledo Switzerland Identification

analyzer

17 Refractometer Atago Japan Determine refractive

index

18 Water bath GEL Germany Controlled temperature

reaction

Ultrasonic water Hawsin Korea Controlled temperature

bath reaction
19

20 Centrifuge machine Hermle Germany Separation technique

21 Furness muffle Linn Hitherm Germany To determine ash content

22 Microscope Olympus Japan Identification

23 Precision oven Channel Germany Drying

24 Vacuum drying Binder Germany Drying

oven

25 Drying oven Memmert Germany Drying

26 Horizontal shaker GEL Germany Shaking

27 Weighing balance Mettler Toledo Switzerland Analytical weighing

28 Potentiometer Mettler Toledo Switzerland Potentiometer titration

for ions

29 Karl Fisher titrator Mettler Toledo Switzerland Moisture determination

30 Tap density tester Pharmatest Germany Tap density

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 measurement

Mechanism of HPLC:

Mechanism of GC:

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GLP rules and Regulations:
APPROPRIATE FACILITY

Separation between work areas, test systems, and other such things are stipulated by the GLPs.
The purpose of the facility rules is to ensure that interference between test articles and test
systems does not occur, and also to ensure that the laboratory is generally well organized.

CLEAR ROLES

The Study Director is the person who is responsible for running the study, the Study Sponsor is
the person who requests the testing, the Quality Assurance Unit is the person (or group of
people) who audit the study and final report, the Archivist is the person who maintains study
records, and Management is the person (or group of people) who choose the Study Director and
supervise both the Quality Assurance Unit and the Study Director. Everybody involved in a GLP
study has various levels of accountability with regard to GLP compliance.

AGREED-UPON STUDY PROTOCOL

Before a GLP study is run, a full and detailed study protocol is signed by both the Sponsor (the
person paying for the study) and the Study Director (the person conducting the study). Changes
to the study protocol require a clear record of when, how, and why the study was changed.
Changes to and deviations from the protocol are OK, but they must be documented!

RECORD-KEEPING:

Arguably the most important aspect of GLP regulation pertains to record keeping. The GLP
regulations are intended to provide the government with a fully auditable study record, allowing
them to reconstruct every study done per the GLPs. For that reason, all records and raw data that
have to do with GLP studies are maintained for long periods of time. Changes to raw data are
made in such a way so as not to obscure the original entry. Additionally, the person who entered
the data must be identified. Lastly, a safe archive of data must be maintained. The archive is
typically fire and theft resistant.

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SOPS:

One critical element of GLP is the concept of an SOP, or Standard Operating Procedure. SOPs
are simply documents that describe how a particular scientific task is performed when it is
outside of the scope of the signed GLP study protocol. For example, Eurofins CRL maintains
SOPs on everything from media preparation to equipment maintenance.

CALIBRATED INSTRUMENTATION:

Accuracy of instruments is critical to experimental accuracy. Thus, the GLPs stipulate calibration
requirements for all data generating equipment. For example, Eurofins CRL regularly calibrates
thermometers, balances, and pipettes.

QUALITY OF MEDIA AND REAGENTS:

All media and reagents used for GLP studies must undergo documented quality testing. For
example, agar used for studies at Eurofins CRL is analyzed for both growth promotion of target
microorganisms and sterility.

TRAINING RECORDS FOR STUDY PERSONNEL:

Obviously, it's important for the people conducting a study to be educated, trained, and skilled
with respect to the study at hand. As such, GLPs stipulate extensive training records be kept for
all staff involved in GLP studies. One very unique aspect of Eurofins CRL is the skill and
expertise of the staff - literally all scientific personnel have college degrees in the biological
sciences, typically in microbiology proper. In addition, many have years of hands-on industry
experience.

INDEPENDENT QUALITY ASSURANCE AUDIT AND REVIEW:

Another important aspect of a GLP study is the auditing process. GLP regulations require an
"independent" audit of all studies to ensure study integrity. Typically, study auditors are
employed by the laboratory, but are removed from participation in the study. At Eurofins CRL,
GLP studies are audited at least once during the "critical phase," which means the conduct of the
actual study. In addition, study reports are audited to ensure that raw data matches that which is
reported, calculations are correct, and so on.

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DOCUMENTATION:
Documentation is an important parameter in any pharmaceutical industry. Quality compliance is
a department basically who deals with the quality of the product and keep all the document to
ensure the present and future safety along with all related problems of a drug for maintaining.

Figure: Parameters of documentation

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MICROBIOLOGY

Generally, pharmaceutical microbiology provides knowledge and understanding with regards to

the significance of the presence of bacteria, yeasts, molds, viruses and toxins in pharmaceutical
raw materials, intermediates, products and pharmaceutical production environments, as well as
the microbiological control of pharmaceutical products, production environments and people.

One of the key objectives of pharmaceutical microbiology is to ensure safety and efficacy of
pharmaceutical products. It embraces the processes like the validation of disinfectants,
evaluation of the efficacy of disinfectants in suspension, on surfaces, and through field trials.
Pharmaceutical microbiology offers protocols and techniques associated with the operation and
assurance of clean-room, aseptic-room and controlled environments for preventing any possible
microbial contamination, and introduces risk assessment and practical contamination control
strategies.

People trained in pharmaceutical microbiology, often known as pharmaceutical microbiologists,

mainly work in quality control and assurance and department in pharmaceutical companies, and
their primary role is to ensure the quality of raw materials before they are processed in the
production area, monitor the microbiological quality of environment and water, and validate the
assay methods used in testing finished products. As pharmaceutical microbiologists focus
fundamentally on quality control to ensure a supply of life-saving drugs and vaccines that are
free from microbial contamination, continuing research in pharmaceutical microbiology, and
subsequent relevant training are much needed.

Machines used in quality control department:

Serial No. Name of Machine No. of Machine Origin

01 Incubator 02 Germany

02 Cooled Incubator 01 Germany

03 Laminar Air Flow 01 Singapore

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 04 Top Loading 01 Japan
Autoclave
05 Dry Heat Sterilizer 02 Germany

06 Water Bath 01 Germany

07 Flocculation 01 India
Water Bath
08 Compound 01 Japan
Microscope
09 Centrifuge 01 Germany

10 Analytical Balance 01 Switzerland

Activities performed by Microbiology section are:

A. Floor/Environment Monitoring:
• Air Particle Count
• Settle Plate Count
• Swab Test
• Personnel Hygiene

B. Microbiology Lab Work:

• Sterility Test
• Bacterial Endotoxin Test/LAL Test
• Microbial Assay
• Microbial Limit Test
• Bioburden Test
• Water Treatment

Following techniques generally employed for monitoring:

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 A. Airborne particle count (non-microbiological):
This is done by using a particle counter.

1. Settle plate technique:

Petri dishes containing sterile microbiological growth media in agar are
exposed to the production area. Then it is incubated for 5 days at 30°c. This
visualizes the microbial growth.

2. Surface swabs technique:

Sterilized swabs of cotton buds are moistened in sterile diluents or a suitable
liquid culture media. A specific area is then swabbed and the organism
sampled from the surface is then smoothly rubbed over the supporting agar
surface and incubated. This technique is employed to evaluate solid surfaces,
garments, equipment, personnel for microbiological growth.

B. Air sampling: Done for microbial growth in air.

• Laboratory test:
A. Sterility test: It is done for raw materials and product materials. 14 days are
required for the sterility test. Two types:
1. Direct method.

2. Filtration method (mostly used).

The condition requires for microorganism test given below:

Type of Organism Time Temperature

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 Fungus 5 days 22°C – 25°C

Bacteria 3 days 30°C – 35°C

B. Limit test/Contamination test:

1. This test is done for checking raw materials. Three types:
2. Pour plate
3. Spread plate.
4. Filtration.

C. Endotoxin test/LAL test: It is an in-vitro test method for pyrogen, has been
developed utilizing the gelling property of the lysate of amoebocytes of
Limulus Polyphemus.

Single test

0.25 ml in LAL and dissolve Incubation at 37° C for 1 hr

Gel formation

Indicate the presence of

endotoxins

Bioburden Test: Bioburden is normally defined as the number of bacteria living on a

surface that has not been sterilized. The term is most often used in the context of
bioburden testing, also known as microbial limit testing, which is performed on
pharmaceutical products and medical products for quality control purposes. It is done for
terminal products & also aseptic products. Two types of the plate are used one pours
plate and another is a split plate. For media tryptone soya agar (TSA) is used.

Test for water:

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The procedure of filtration method by using test for microorganism is as follows

(Filter paper and filtration apparatus to be sterile for filtration method)

 Cellulose filter membrane + Apparatus is sterilized

 To set a filter paper in the filtration apparatus
 The liquid to be tested is added in the filter funnel
 The liquid is passed through the filter paper
 Filter paper is removed from the filtration apparatus by forceps
 Filter paper is cut through scissor
 Added to the media
 Filter papers with media keep the incubator ( 7 to 14 days)
 Observe the microbial growth
 No turbidity
 Sterility passed

QUALITY ASSURANCE
Quality Assurance includes all operations from design, development, manufacturing, installation
and maintenance to documentation. It includes control of the quality of raw materials, goods and
components, production related services and production and inspection management processes.

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Quality assurance ensures

Issuing and
Management of
controlling master
GMP training standard operating
documentation
procedures
record

Change control
system CAPA tracking QA product release

Vendor auditing and Customer

approval complaints

Role of QA in pharmaceutical industry

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Functions of QA department in different areas:

 Ware house
• Visual inspection of incoming raw and packaging materials.
• Sampling of raw and packaging materials for the following test.
• Amoy
• Microbial test
• Retention
• Released /rejection of raw and packaging materials on the basis analysis

 Dispensing area

QA dispensing officer monitors dispensing process in the dispensing area and attaches
dispensing card to materials

 Packaging area
• Before the start of packaging, the machine and rooms are checked for proper cleaning.

During packaging.

• QA department checks the following.

• Humidity of packaging area.
• Leak test of package
• Appearance of tablet and capsule
• Labeling of tripper and inner and outer carton

 In printing area

• Batch printing
• Inner and shipping carbon at regular time interval

 Documentation

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Documentation is most important task of the quality assurance department. The purpose of
documentation is to record import information with evidence. GXP requires that complete and
accurate records of all raw/packaging materials, finished product, BMR, BPR, have to maintain
for any necessary forcing back of any time.

The following documents are maintained in QA department-

• Production sheet order

• BMR (Batch manufacturing record)
• BPR (Batch packaging record)
• Coated tablet inspection sheet
• Leak test record sheet
• Packaging order sheet
• Retention sample quality

Risk management

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Retention sample
QA department preserve the samples of cover batch in the archive rooms in normal temperature
and process for reviewing the quality of product. If any complain comes from any source, they
check the sample of the same batch staring in the archive room.

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VALIDATION
It can be defined as the documented act of providing that any procedure, process, equipment,
material, activity system will consistently lead to the expected result. Qualification, calibration,
validation are the main concept of validation for any kind of production.

Basically, validation department of General Pharmaceuticals works in numerous ways. At

beginning, pre assurance of production, utilities etc. This department also ensures quality of
machine, environment of production room.

Validation master plan

It is also referred as VMP, outlines the principals involved in the qualification of a facility,
defining the areas and systems are validated, and provide a written program for achieving and
maintained the qualified facility. It is a key document in the GMP regulated pharmaceutical
industry as it drives a structure approach to validation process. Validation master plan for

General Pharmaceuticals Limited is designed to demonstrate that quality features built into the
facility and processes ensure that they remain functional as designed and perform consistently to
confirm the requirements of current GMP. Manager of validation lead the activities with the
support of following areas: R&D, engineering, production, QC, microbiology, QA, validation,
warehouse and so on. This team is responsible for ultimate safe, potent and good quality drugs.

Types of Process Validation

The guidelines on general principles of process validation mentions four types of validation:

 Prospective validation (or premarket validation)

 Retrospective validation
 Concurrent validation  Revalidation

 Prospective validation

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 Establishing documented evidence prior to process implementation that a system does what it
proposed to do based on preplanned protocols. This approach to validation is normally
undertaken whenever the process for a new formula (or within a new facility) must be
validated before routine pharmaceutical production commences.

 Retrospective validation
Retrospective validation is used for facilities, processes, and process controls in operation use
that have not undergone a formally documented validation process. Validation of these
facilities, processes, and process controls is possible using historical data to provide the
necessary documentary evidence that the process is doing what it is believed to do. It is used
only for the audit of a validated process.

 Concurrent validation
Concurrent validation is used for establishing documented evidence that a facility and
processes do what they purport to do, based on information generated during actual
imputation of the process. This approach involves monitoring of critical processing steps and
end product testing of current production, to show that the manufacturing process is in a state
of control.

 Revalidation
Revalidation means repeating the original validation effort or any part of it, and includes
investigative review of existing performance data. This approach is essential to maintain 74
the validated status of the plant, equipment, manufacturing processes and computer systems.

In-Process Control
In-process quality control tests are simply routine checks that are performed during production.
They are those tests carried out before the manufacturing process is completed to ensure that
established product quality is met before they are approved for consumption and marketing. The
function of in-process quality control is monitoring and if necessary, the adaptation of the
manufacturing processes to ensure that the product conforms to its specifications. This may
include the control of equipment and the environment also. In-process quality control may be
performed at regular intervals during a process step (e.g., tableting or encapsulation) or at the end
of a process step (e.g. granulation, blending). The tests allow the formulation scientist to identify
and follow all changes that may occur during applied technological procedures. It gives the
formulation scientist security that the finished products fulfill all quality requirements, most of
all that all the products should be safe for the patients.

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 Manufacturing IPC
process

Tablets

Dispensing • Temperature and humidity within specification.

• Weighing accurately as per BMR

Granulation • Granule size

• Uniformity of granules.
Drying • LOD

Compression • Appearance

• Room condition
• Uniformity of weight
• Average weight
• Thickness
• Hardness

• Friability

• Disintegration time

Coating • Sticking

• Filling

• Absence of bridging
• Color variation
Capsule
Encapsulation • Appearance of shell

• Room condition

• Uniformity of weight
• Average weight
• Disintegration time
Liquids and semi-solids

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 Bulk • pH

• Color

• Odor

• Appearance
Filling • Sealing

• Fill volume
• Presence of foreign material
• The appearance of liquid product
Ophthalmic
Filling • Fill volume

Powder for suspension

Bulk • Color

• Odor

• Appearance
Filling • Reconstituted volume
• Fill volume\room condition
• Sealing of cap
Blisters and Leak test
PP
infusion bags

• Chronological Batch Record:

✓ Production order sheet
✓ Batch manufacturing record
✓ (If applicable) Tablet inspection sheet
✓ (If applicable) Capsule inspection sheet
✓ Volume inspection sheet
✓ (If applicable) Production order sheet coating
✓ (If applicable) Record coating batch manufacturing
✓ (If applicable) Coated tablet visual inspection sheet

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 ✓ Finished product test record sheet
✓ Packaging order sheet
✓ Batch packaging record
✓ Catch cover/level//leaflet/inner carton
✓ Leak test record sheet
✓ Relative humidity record sheet
✓ Retention sample quantity
✓ QA checklist for product release

Site Master File

The site master file contains the complete layout and detailed information about the
company’s structure, engineering & plant’s machinery.

1. General introduction
▪ Manufacturing licenses
▪ Manufacturing activities
▪ Manufacturing site
▪ Number of employees
▪ Outside technical assistance
▪ Quality management system
2. Personnel
▪ Key personnel
▪ Training
▪ Health checkup
3. Premises and equipment

▪ Plant layout

▪ HVAC system
▪ Water system
▪ Major equipment
▪ Sanitation

4. Documentation

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 ▪ Preparation, distribution, authorization, revision.
▪ Document list related to product manufacturing.
5. Production
▪ Production operation
▪ Material handling
▪ Reprocessing and rework
▪ Handling rejected materials
▪ Process validation

6. Quality control
7. Toll manufacturing
8. Product release, distribution, complaint handling
9. Audit.

• Qualification & Calibration:

Calibration is done by QC and Qualification is done by QA& PD. Design
Qualification (DQ) is done by the vendor and the company they arranging the details
of a machine. After that Installation Qualification (IQ) Operational Qualification
(OQ) & Performance Qualification (PQ) takes place. Finally, the machine gets
qualified in pursuit of validation. In a validation process, critical parameters are
optimized.
Stability tasting: 2 types
✓ Accelerate: In accelerated stability testing, a product is stressed at several high
(warmer than ambient) temperatures and the amount of heat input required to cause
product failure is determined. This is done to subject the product to a condition that
accelerates degradation. This information is then projected to predict shelf life or
used to compare the relative stability of alternative formulations. This usually
provides an early indication of the product shelf life and thus shortening the
development schedule.
Temperature 40 ° c RH 75 ° c

✓ Real-Time Stability Tasting: Real-time stability testing is normally performed for

longer duration of the test period in order to allow significant product degradation
under recommended storage conditions. The period of the test depends upon the
stability of the product which should be long enough to indicate clearly that no
measurable degradation occurs and must permit one to distinguish degradation from
inter-assay variation.
Temperature 30 ° c RH 65 ° c

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 • Media Fill Validation: This is done for the aseptic product.

• Documentation: Primarily, the role of documentation in quality assurance would

be to keep a record. This record shows all the activities done in the development of
software. In addition, it can also serve as a reference. This is in case something
happens to the software which has happened before. Documentation makes it possible
for the quality assurance team to go over past details. This will enable them to see if
they find anything helpful in resolving a current software issue.

• Importance of QA Documentation: Documentation plays a very important part

is quality assurance. It can save an organization a lot in terms of money and time. A
client can review software processes easily, all because of proper documentation.
Documentation is important because it includes details that are helpful in quality
assurance and software development. Among the information and detail found in the
documentation are:
✓ System Specifications
✓ Test Designs, plans, cases, and conditions and results
✓ Program listings
✓ Bug reports
✓ Operator Manuals
✓ User Manuals
✓ Configuration of the software
✓ Flow charts
✓ Status report of the processes

• Deviation & Change Control:

If there are any types of departure from the standard, deviation form. Then QA took
Corrective Action & Prevention Action. Change Control is done if any type of changes,
required changes are written in a form and submitted to QA. After investigation of risk
assessment get signed by the head of QA.

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