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219Role of Quality Control
Quality control is responsible for arranging sound and appropriate specications,
standards, sampling plans, and test procedures designed to assure that components,
drug product containers, closures, in-process materials, labelling, and drug products
conform to appropriate standards of identity, strength, quality, and purity.
PreParation and iMPLeMentation of standard oPeratinG Procedures (soP)
SOPs for pharmaceutical testing describe how to perform routine and expected tasks
in the laboratory environment.
SOPs provide clear instructions that describe when a task will be performed, how
a task will be performed, who will perform the task, why the task is necessary, any
limitations in performing the task, and what action to take when unacceptable devia-
tions or discrepancies occur.
SOPs must be reviewed regularly and updated as necessary. Auditing and verify-
ing compliance with established SOPs should be performed periodically. The SOP
should be specic to each device and process used in testing. Properly maintained
and implemented SOPs are vital to preparation quality.
coMPLiance With reGuLations
The pharmaceutical industry is highly regulated. Quality control ensures that pharma-
ceutical companies comply with various regulatory requirements and guidelines, such
as those set by the Food and Drug Administration (FDA) in the United States or the
European Medicines Agency (EMA) in Europe. It implements and maintains quality
systems that meet the current Good Manufacturing Practices (cGMP) standards.
test Methods and sPecifications
Management has to provide specic validated test methods for each test and product.
Test methods provide specic directions on properly executing a test procedure in
a standardized manner. A test method is specic to analysis and instrumental tech-
niques such as HPLC, UV, or GC. Specications generally accompany test methods
and provide criteria to pass or fail a particular test and acceptance criteria for a test
method, such as system suitability or control limits.
Laboratory testinG records
Sample and reagent preparation should be documented in laboratory notebooks.
Notebooks document the preparations of laboratory solutions, standards, and work-
ing reagents. It is important in a laboratory to provide accurate instructions and
records of these preparations.
Testing records include laboratory analyst notebooks, specic testing sheets, ana-
lytical printouts, electronic records such as chromatographs, and ancillary records
that support the laboratory’s compliance. Records would include calibration reports,
training records, and monitoring of the environment.
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220 Basics of Pharmaceutical Manufacturing and Quality Operations
traininG
A quality control program for testing medicines requires training documentation of
both training and skill competency.
Personnel involved in nonsterile or sterile testing requires additional, specic
training, and periodic retraining beyond the training needed for routine duties.
If testing is outsourced, the management must be assured of the credentials,
proper training, and continuing competency activities of the personnel in the con-
tract laboratory.
docuMentation
The purpose of documentation is to provide a record of all aspects of testing opera-
tions and procedures.
Information on the testing record should ideally be entered as the tasks are per-
formed or as testing data is received. testing records should be reviewed for accuracy
and completeness (as appropriate) and approved by QA personnel.
verification
Verication involves authoritatively signed assurance and documentation that a pro-
cess, procedure, or equipment is functioning properly and producing the expected
results. Verifying a testing procedure involves checking to ensure the calculations;
weighing and measuring, order of mixing, and testing techniques and equipment are
appropriate and accurately performed.
The quality of ingredients should be veried upon receipt. For example, Certicate
of Analysis, manufacturer’s label on commercial products, etc.
Equipment verication methods are sometimes available from specic equipment
manufacturers or can be developed in-house. The responsibility for verifying equip-
ment performance, including work completed by contractors.
testinG of raW MateriaLs
Quality control involves testing raw materials, packaging components, and in-process
and nished products used in pharmaceutical production. This includes testing the
identity, purity, potency, and quality of active pharmaceutical ingredients (APIs),
excipients, and other materials.
in‑Process controL
Quality control monitors the whole manufacturing process to ensure it is performed
correctly and meets specications. In-process control involves testing and verifying
critical parameters, such as temperature, pH, and moisture content, at different stages
of production. This helps detect and prevent any deviations from the expected qual-
ity, ensuring the consistency and quality of the nal product.
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221Role of Quality Control
finished Product testinG
Quality control conducts testing of nished pharmaceutical products to assess their
quality, safety, and efcacy. This includes various analytical tests, such as assay,
impurities, dissolution, stability, and microbial testing, to ensure the product meets
the predetermined standards and specications. Finished product testing helps iden-
tify deviations or abnormalities affecting the product’s quality and performance.
data interPretation
The collection of raw data from the testing process must be completed accurately. The
analyst must ensure that appropriate and valid descriptive statistics are used to analyze
the data and that the operating parameters of the analytical instruments are well-estab-
lished. Reference values, if available, should be provided with the analytical results. A
description of the analytical controls used by the laboratory is important for documen-
tation, as is the source of reference standards used to establish standard curves.
docuMentation and recordkeePinG
Quality control maintains detailed documentation and records of all testing activi-
ties, results, and procedures. This documentation is a critical reference for verifying
compliance with regulatory requirements and providing traceability throughout the
manufacturing process. It allows for a thorough investigation of quality issues or
recalls and provides evidence of product quality for regulatory audits.
corrective action and Preventive action (caPa)
The pharmaceutical company should have a system for implementing corrective
and preventive actions resulting from investigating complaints, product rejections,
non-conformances, recalls, deviations, audits, regulatory inspections and ndings,
and trends from process performance and product quality monitoring…
continuous iMProveMent
Quality control plays a crucial role in continuous improvement efforts within the
pharmaceutical industry. It monitors quality metrics, conducts trend analysis, and
identies areas for improvement. By implementing corrective and preventive actions
based on quality control data, pharmaceutical companies can enhance their manu-
facturing processes, reduce deviations, and enhance overall product quality.
chanGe controL systeM
The change control system ensures that continual improvement is undertaken
promptly and effectively. It should provide a high degree of assurance that the change
has no unintended consequences.
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222 Basics of Pharmaceutical Manufacturing and Quality Operations
storaGe reQuireMents
Storage requirements for samples and standards must be specied, including the type
of container, temperature, humidity, and light protection.
Before handling the sample, the effect(s) of any substance on the sample prepa-
ration that may interfere with or alter the results must be known. When sending a
preparation to a contract laboratory, they should provide the complete written for-
mulation so that the laboratory can quickly determine if any interfering substances
are present.
MicrobioLoGicaL testinG
Microbiological testing for pharmacy compounding includes sterility, endotoxin,
preservative effectiveness, and microbial limit testing.
steriLity testinG
Sterility tests may be conducted using commercial kits or by developing and verify-
ing USP sterility testing protocols.
QuaLity risk ManaGeMent
Quality risk management is a systematic process for the assessment, control, com-
munication, and review of risks to the quality of a drug across the product lifecycle.
It can be applied both proactively and retrospectively.
According to the “International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH)”, quality risk management
has two primary principles,
• Quality risk evaluation should be based on scientic knowledge, such as
data and research, and ultimately work towards the protection of consumers.
• The higher the risk level, the stronger a QRM process should be. The level
of effort, formality, and documentation should be equal to the risk level.
These principles can be seen in the examples provided below by the European
Commission in its Good Distribution Practice (GDP) Guidelines for Medicinal Products:
• Temperature mapping should be repeated according to the risk assessment
results.
• Equipment should be calibrated at dened intervals based on a risk and reli-
ability assessment.
• The scope and extent of key equipment qualication and/or key process val-
idation must be determined using a documented risk assessment approach.
•
All means available must be used to minimize the risk of falsied medicinal
products entering the supply chain.
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223Role of Quality Control
• Returned products must be handled according to a documented, risk-based
process.
• Risk assessment of delivery routes should be used to determine where tem-
perature controls are required.
WORK FLOW OF QC TESTING
saMPLe receivinG
The sample received in QC should be login. There should be a document /register
where sample identication, receiving date and time should be documented. This
should be a traceable record, and the sample could be tracked.
Work assiGnMent
The sample should be assigned to the analyst(s) for testing. The method, specica-
tion, and other resources should be provided to the analyst.
saMPLes/standard PreParation and instruMents. set uP
The test method should describe how to prepare the sample and standard. This may
involve sample dilution or extraction. A reference to the current test method should
be documented before setting up the sample.
testinG the saMPLe
Once the sample and standard are prepared, it is included in the test run. The sample
should be placed under controlled conditions to prevent any degradation. The sample
identication must be documented in instrument logbooks. All preparations must be
documented in the lab book as it was done.
verification of systeM suitabiLity
Instruments must be calibrated. The methods may have some system suitabil-
ity requirements. All those requirements must meet as per specication. The
test methods should describe how the integrity of particular test runs is veried.
Non-instrumental methods may also include control or equivalent verication
systems.
caLcuLation and resuLts
After running samples and standards on an instrument, the analyst should calculate
the nal results. Calculations should be double-checked, and all entries in the instru-
ment if the instrument does the calculation.
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224 Basics of Pharmaceutical Manufacturing and Quality Operations
out of sPecifications (oos)
There should be a written procedure if OOS results are produced. All OOS or atypi-
cal results must be informed to management to conduct the necessary investigation
and inform the concerned department to take appropriate action.
rePort resuLt
Once the sample has been run, either the instrument or the analyst will perform a
calculation to arrive at a result. It is essential to double-check all calculations before
nalizing sample results.
OVERALL SUMMARY
Quality is everyone’s job. Quality is important for every aspect of pharmaceutical
manufacture and packaging. Quality should not be tested into products; it must be
built in at each manufacturing step.
Quality must be followed during actual processing steps and in other areas such
as vendor assurance, personnel training, internal audits, change management, release
for supply, and QC sampling.
Pharmaceutical manufacturers must integrate the key functions of quality control
and regulations or GMP under quality assurance. QA is charged with preventing
defects and errors by overseeing all aspects of producing a quality product.
Overall, quality control is vital in the pharmaceutical industry to ensure that
pharmaceutical products are safe, effective, and high quality. It helps protect public
health, maintain regulatory compliance, and build trust in the industry.
QUESTIONS AND ANSWERS
1. Why Quality role is important?
Answer: The quality department is vital in the pharmaceutical industry to
ensure that pharmaceutical products are safe, effective, and of high quality.
It helps protect public health, maintain regulatory compliance, and build
trust in the industry.
2. What is the basic responsibility of Quality Control?
Answer: It involves various activities and processes to monitor and control
the quality of packaging components, raw materials, intermediate products,
and nished pharmaceutical products.
3. What is an SOP?
Answer: SOPs are clear instructions that describe when a task will be per-
formed, how a task will be performed, who will perform the task, why the
task is necessary, any limitations in performing the task, and what action to
take when unacceptable deviations or discrepancies occur.
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225Role of Quality Control
4. Who provides the test method? What does a test method describe?
Answer: Management has to provide specic validated test methods for
each test and product.
Test methods provide specic directions on properly executing a test pro-
cedure in a standardized manner. A test method is specic to analysis and
instrumental techniques such as HPLC, UV or GC.
5. If OOS results are produced, what are the responsibilities of analysts
and management?
Answer: If OOS results are produced the analyst will inform management.
Management will conduct the necessary investigation and inform the con-
cerned department to take appropriate action.
6. Why are nished products tested in QC?
Answer: Quality control conducts testing of nished pharmaceutical prod-
ucts to assess their quality, safety, and efcacy. This includes various ana-
lytical tests, such as assay, impurities, dissolution, stability, and microbial
testing, to ensure that the product meets the predetermined standards and
specications. Finished product testing helps identify deviations or abnor-
malities affecting the product’s quality and performance.
7. Why in‑process controls are important? What are the most common
tests being done during the in‑process?
Answer: In-process control involves testing and verifying critical param-
eters, such as temperature, pH, and moisture content, at different stages of
production. This helps detect and prevent any deviations from the expected
quality, ensuring the consistency and quality of the nal product.
8. What is quality risk management?
Answer: Quality risk management is a systematic process for the assess-
ment, control, communication, and review of risks to the quality of a
drug across the product lifecycle. It can be applied both proactively and
retrospectively.
9. What are the two principles of risk management of ICH?
Answer: (1) Quality risk evaluation should be based on scientic knowledge,
such as data and research, and ultimately work towards the protection of
consumers. (2) The higher the risk level, the stronger a QRM process should
be. The effort, formality, and documentation level should equal the risk level.
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18
Logistics–Cold
Chain Supply
Maintaining the quality of a pharmaceutical product is not just limited up to the
stage of manufacturing. It should never be considered that once the goods are out
of the premises of the manufacturing company, the responsibilities of the manufac-
turer to ensure a quality product to reach the customer or patient which maintains its
efcacy up to the end of the shelf life, are over. Because it is not. The manufacturer
has to make sure that during the transportation of the product, depending on the
dosage forms, different forms of liabilities still lie on their shoulders and it is their
job to ensure a safe and smooth transition of the products from their stores to the
distribution warehouse and from there when it goes to the market where they can
be picked up by a customer at some point of time, the quality of the product is never
compromised.
The quality of the product, especially a liquid or a sterile medicine, can be com-
promised in different ways. It’s not just the potency of the product but also the pack-
aging that matters when it reaches to the customer. To maintain the pharmaceutical
products’ integrity and safety, the products must stay within the recommended ranges
of temperature and humidity.
The smallest temperature or humidity variation can alter the product’s quality
which can put the customer’s health at risk and cost the pharmaceutical company a
signicant amount of money. During the supply chain process, there are many fac-
tors to consider in order to ensure the drugs and vaccines remain safe and follow
shipping regulations from both the manufacturer and the health regulatory bodies.
In order to keep pharmaceutical products safe during transport, companies have to
optimize their supply chain by ensuring that their goods are constantly stored under
suitable conditions. To meet these requirements, companies that transport pharma-
ceuticals use a process known as cold chain shipping, or cold chain pharma logis-
tics. Managing the pharmaceutical supply chain is complex with greater demands
for business innovation, security, reducing costs, and improving customer satisfac-
tion. Therefore, pharmaceutical companies have been facing increased challenges
presented by strict regulations, costly recalls, counterfeiting, and product protection
across the supply chain.
COLD CHAIN SUPPLY
The cold chain for pharmaceuticals requires uninterrupted temperature control on
the journey from their site of manufacture all the way to where they are admin-
istered. As a consequence, dedicated solutions are required for the freezing/thaw-
ing, packaging, tracking, and storing of these temperature-sensitive products.
Therefore, cold chain logistics are essential to transport the pharmaceutical and bio
226
DOI: 10.1201/9781003366393-23
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227Logistics – Cold Chain Supply
pharmaceutical products. High temperature may cause the degradation in these prod-
ucts which could harm the end user. Over the years the pharmaceutical industry has
used non-temperature specic drugs as pills for most of its purposes; however, the
usage of liquid and other sterile products like injectable and infusion solutions has
never been ceased either.
This is what a pharmaceutical company with the help of quality department has to
do in order to maintain the product’s quality throughout its transportation:
• They have to provide an ambient temperature, refrigeration control, and
cold chain support
• The full chain of custody, that is from collection to handover signature,
identity verication, and documented proof of the delivery, has to be
demonstrated
• Having professional drivers who can offer safe and secure delivery without
compromising on product safety, quality, and efcacy.
COLD CHAIN MANAGEMENT
It’s not that all pharmaceutical products require a temperature controlled transporta-
tion. In fact, it is approximately over 30% of pharmaceutical products which require
handling and transport at a controlled temperature so that they do not suffer any
alteration. Depending on the drug or product, the temperature will be one or the
other, and may range from negative to positive. For example, liquid nitrogen should
be kept at −190 °C and frozen products at −20 °C. Drugs that require refrigeration
will need temperatures between 2 °C and 8 °C, although there are also products that
require room temperature, which is about 20 °C.
The cold chain management starts from the company’s own warehouse where the
released batches of products are stored until they are ready to go to the market or
to the distributor’s warehouse. There are various requirements that the QA needs to
handle, given as follows:
1. Generate a Master plan of cold chain supply management.
2. Qualication of the company’s stores for maintaining the environmental
conditions like relative humidity and temperature.
3. Temperature mapping to determine the coldest and hottest points of the
warehouse and installation of data loggers based on the mapping.
4. Qualication of the loading and ofoading areas.
5. Usage and maintenance of calibrated data loggers.
6. Standard operating procedures for the functions stated above.
7. Qualication and temperature mapping of the transportation vehicles to
determine the coldest and hottest points.
8. Inspection, maintenance, and monitoring of transportation vehicles. The medi-
cines or pharma products are usually transported in a refrigerated or insulated
truck. These trucks undergo routine inspections to make sure that they are
under satisfactory conditions to keep inventory at the correct temperature.
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228 Basics of Pharmaceutical Manufacturing and Quality Operations
QUALITY ASSURANCE OWNERSHIP
The Quality Assurance department has the ownership of maintaining the cold chain
supply management standards.
It should not be forgotten that pharmaceutical transport is the most important part
in a logistics chain because the products being transported are for human consump-
tion. Therefore, it is necessary to have an exhaustive control of the whole distribution
chain to ensure that the medicines arrive to the consumer under perfect conditions.
The manufacturer of pharmaceutical products is going to require the logistics
operator that when handling and transporting this type of goods all the requirements
are met. Safety, traceability, and temperature maintenance in pharmaceutical trans-
port are critical elements that a logistics operator must guarantee.
Quality Assurance has the responsibility to have the data loggers installed in the
transportation vehicles as per the qualication and temperature mapping results,
monitor them, upload the data after the transportation process is accomplished and
analyze them to draw conclusion.
COLD CHAIN REGULATIONS
Good Distribution Practice is an important regulation that is required in the for manu-
facturers and transport companies or suppliers of logistics services. This regulation
guarantees safety and quality in the distribution of medicines, which are highly sensi-
tive. Therefore, it regulates aspects such as equipment and installations, documentary
follow-up, transport, vehicle cleaning, temperature monitoring, and inverse logistics.
QUESTIONS AND ANSWERS
1. What is the signicance of cold chain supply in pharmaceutical industry?
Answer: To maintain the pharmaceutical products’ integrity and safety,
the products must stay within the recommended ranges of temperature
and humidity. The smallest temperature or humidity variation can alter the
product’s quality which can put the customer’s health at risk and cost the
pharmaceutical company a signicant amount of money. In order to keep
pharmaceutical products safe during transport, companies have to optimize
their supply chain by ensuring that their goods are constantly stored under
suitable conditions. To meet these requirements, companies that transport
pharmaceuticals use a process known as cold chain shipping, or cold chain
pharma logistics.
2. Which department is the owner of the cold chain management standards?
Answer: The Quality Assurance department has the ownership of main-
taining the cold chain supply management standards. Quality Assurance
has the responsibility to have the data loggers installed in the transportation
vehicles as per the qualication and temperature mapping results, monitor
them, upload the data from the data loggers after the transportation process
is accomplished, and analyze them to draw conclusion.
https://t.me/med1917
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