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229Logistics – Cold Chain Supply
3. What are basic rules to maintain the products quality and integrity
during logistics?
Answer: Pharmaceutical companies have to adapt the following basic rules
in order to maintain the product’s quality throughout the 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 with-
out compromising on products safety, quality, and efcacy.
4. What are the functions that a pharmaceutical company should perform
in order to maintain product’s quality and during the logistics?
Answer: There are various requirements that the pharmaceutical company
management must ensure under the guidance of QA. These requirements
are 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
medicines 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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19
GMP for Biologics and
Similar Medicines
WHAT ARE BIOLOGICAL AND BIOSIMILAR MEDICINES?
Biological drugs or biopharmaceuticals are made from proteins and other substances
which exist in nature. To manufacture a biological product, a biological process is
utilized instead of a chemical process. It can be easily understood that the biologi-
cal drugs are a lot larger in size and more complicated than normal chemical drugs.
Some common examples of such products are steroids, 5-ASAs, and azathioprine.
A biosimilar is also a biologic drug that is highly similar to a biologic drug that
was already authorized for sale. The difference between biologics and biosimilar is
same as that between a generic drug and an original brand product. There are no
expected clinically meaningful differences in efcacy and safety between a biosimi-
lar and the biologic drug.
However, in order for a biosimilar to gain approval to be used, it has to meet strict
standards to show that it is as safe and effective as the original biologic drug, and to
have the same quality, although it may have small structural differences.
PREPARATION OF BIOLOGICAL AND BIOSIMILAR DRUGS
Biological drugs are made using living organisms, such as modied plant and animal
cells. The cells receive a gene (a piece of DNA) which instructs them to make a spe-
cic protein. The cell with the gene in it then multiplies, and produces the biological
protein which can be “harvested”. The cells that are the best at producing the protein
are identied and grown on an industrial scale–these special cells are called a “cell
line” and are unique to each manufacturer. The cell line is then grown in huge tanks,
and the nal product harvested. This is an extremely complex process, and very
small changes to it can lead to very large changes in the nal product. The biosimilar
manufacturer must develop a new cell line and manufacturing parameters that result
in a highly similar product.
GMP in bioLoGics/biosiMiLar
GMPs prevent or minimize errors or defects during the manufacturing process, min-
imize contamination, and maintain the integrity and stability of biologic products
just like all other pharmaceutical dosage forms. Therefore, the quality and safety of
biologics are also very important, because the human health can be impacted in a
number of ways by these products. Biologics are frequently sourced from other living
things, and act with human metabolism to enhance an existing biological process.
For example, vaccines enhance immune response, and hormones are administered
230
DOI: 10.1201/9781003366393-24
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231GMP for Biologics and Similar Medicines
to patients with endocrine insufciency. Therefore, it is essential that manufacturers
adhere to strict good manufacturing practices in order to ensure product quality and
safety, since failure to create a safe product has the potential to cause great harm.
difference in GMP for bioLoGics and other dosaGe forMs
How do the good manufacturing practices for biologics or biosimilar products differ
from solid dosage or any other pharmaceutical dosage form?
The answer to this question is not difcult. Although the biologics are different in
nature and in manufacturing processes from other medical products and may have
slightly different GMP requirements yet in a nutshell, the GMP does not signicantly
differ from that of other dosage forms. The reason is that the products, no matter manu-
factured in an entirely different way involving different types of processes instead of
regular pharma products but still used to provide therapy to human beings. GMP is
a system that assures that pharmaceutical and biological products are manufactured,
sampled, and tested consistently in accordance with specic quality standards.
In case of biologics, the ancillary materials manufacturers can provide GMP
quality by following all applicable GMP standards exactly the same way as advised
for pharmaceutical products. To understand this further, in biologics manufactur-
ing, ancillary materials are transfection reagents or a subset of critical raw materi-
als which are used for gene therapy product manufacturing. Although they are raw
ingredients that are not intended to be included in the nished product yet are vital
in its manufacture. The requirements for the collection, testing, and quality control
of ancillary materials are dened by a quality assurance system that is based on the
existence of a national structure, independent of manufacturers and adheres to GMP
principles and guidelines. Because the synthesis of biologically active substances and
biological medicinal products for human use requires some specic considerations
arising from the nature of the products and manufacturing processes, it is important
to take some special precautions. Some AMs may be authorized medicinal products
in their own right. Heparin and insulin are GMP-grade ingredients that are often
utilized in cell product manufacture.
Cell- and tissue-based therapies are often manufactured in specialized facilities
that contain equipment and methods for culturing, testing, and packaging live cells.
Biologics are manufactured in a living system such as a microbe, plant, or animal
cell. For cell product manufacturers, the nature of an Ancillary Material’s production
process is critical. Ancillary materials are also manufactured in accordance with all
relevant GMP guidelines, documented verication of purity, potency, consistency,
and stability. Therefore, GMP is one of the most important quality assurance systems
for ensuring the safety and high quality of ancillary materials. Biologic products are
typically more complex than traditional pharmaceuticals, due to the fact that they
originate from living organisms which introduce variability due to genetics, environ-
ment, diseases, and impurities inherent to naturally-occurring biochemistry in the
living thing. To understand the complexity of biologics, as an example, consider the
case of a recombinant insulin product which may undergo a series of manufacturing
steps, including fermentation to grow the cells generating the insulin, followed by
another series of purication steps to obtain the desired product. A product which
is derived from human blood may carry a risk of containing blood borne pathogens.
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232 Basics of Pharmaceutical Manufacturing and Quality Operations
Best Practices for Manufacturing Biologics under GMP
Quality standards are evolving in response to current GMP rules. The original GMP
regulations began with a focus on the product and quality control. The focus then
shifted to procedure and quality assurance. With the new model of quality systems,
pharmaceutical and biological rms are now facing a massive paradigm change. This
GMP paradigm shift will change the fundamental assumption of the manufacturing
process, radically shifting the regulatory and scientic emphasis by transferring the
regulatory anchor from xed processes to xed (constant) outputs.
Following the revision of GMP regulations and the implementation of new tech-
nological advancements, the FDA anticipates that manufacturers will continuously
maintain high-quality products and improve production efciency. The FDA believes
that this will help lower costs and minimize shortages of important medications
caused by failures that may result in product recalls. It’s indeed important to note
that the FDA believes that the CGMP rules necessitate a higher level of calibration
and maintenance than other non-pharmaceutical quality-system models.
Current GMP regulations will have a far greater impact on manufacturing and
development.
chaLLenGes in bioLoGicaL ManufacturinG under GMP
Since many AMs are complex biological materials, evaluating their qualities can be
challenging. Biologics are difcult to work with since they are derived from living
materials, which are naturally variable. As a result, the most difcult challenge from
a GMP standpoint is ensuring consistent product quality, which is dependent on both
incoming raw materials and manufacturing procedures. When additional complexity
is included, such as a non-traditional dose form, consistency becomes increasingly
challenging.
The complexity of biologics, as well as the application of emerging technology,
offer challenges for cGMP compliance. In general, complying with the FDA’s GMP
requirements is not difcult, but there are several intricacies that might provide a
barrier. For instance, it is simple to do gap analysis and conrm that processes are
in accordance with the regulations, guidelines and technical publications compris-
ing contemporary cGMPs. But still the complicated formulation work required in
biological products is quite challenging.
risks in bioLoGicaL Product ManufacturinG and MitiGation
It is evident that biologic products have numerous risks resulting from their inher-
ent nature. Due to this complexity and risk many additional GMP requirements are
needed to be met to achieve GMP compliance. For example, manufacturing facili-
ties used to produce biologics must be designed and constructed specically for this
purpose. In addition, all personnel working in these facilities must undergo rigorous
training. For example, personnel should not go to work in other areas outside the
biologics production facility in the same working day. In the following pages, let us
review the particular areas where specic precautions are to be taken to follow the
GMP and maintain compliance.
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233GMP for Biologics and Similar Medicines
FACILITIES AND EQUIPMENT
The following measures will be critical for GMP;
1. The design, construction, and maintenance of manufacturing facilities
and equipment should be in such a way that may minimize the risk of
contamination.
2. All production areas must be dedicated to prevent cross-contamination with
other processes.
3. Some equipment for biologics manufacturing may be highly-specialized,
and will require special testing to ensure that its use is suitable for making
biologic products.
PERSONNEL
1. All personnel working in manufacturing facilities must be properly trained
and qualied.
2. They must also follow all procedures and protocols for clothing require-
ments to minimize the risk of contamination.
3. Health monitoring process should be in place and strictly adhered to, to
prevent disease crossover into the product.
MATERIALS
1. The materials used in the manufacturing process must be of high quality
and free of contaminants.
2. All sterilization cycles are validated.
3. Specialized gowning process is followed.
4. Materials are segregated to ensure that they retain their purity through man-
ufacturing, holding, and distribution.
QUALITY CONTROL
Needless to say, Quality Control testing for biologic products is extensive, from raw
material receipt through the end product. Laboratory testing is just part of a compre-
hensive quality control program.
1. There must be a strict quality control program in place to ensure that all
products meet the required standards, including microbial control, stan-
dards for animal care, holding retain samples 6 months past expiration, and
temperature control during shipment.
2. The FDA requires reporting of deviations. Therefore all biological product
deviations are required to be investigated.
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234 Basics of Pharmaceutical Manufacturing and Quality Operations
Good Laboratory Practices in bioLoGics ManufacturinG
The safety and quality of biologic products are ensured by the GMP guidelines no
matter how overwhelming they may seem, they are essential. By following these
guidelines, manufacturers can be condent that their products will meet the highest
standards of quality and safety.
• Quality assurance work in biologics/biosimilar is very much like in other
pharmaceutical manufacturing, that involves assuring and verifying that
controls in the design of the biologic facility continue to perform as designed.
•
Apart from that, after release stability testing is also required.
• Quality Control also includes validation of laboratory testing as well as
the area where biologic material is harvested from animals, with specied
requirement for assuring cleanliness, including assurance of animal health
and preventing incursion of spore‑forming microorganisms.
• Laboratory test methods also require validation in much the same way that
validation is required for non‑biologic pharmaceuticals products, but the
specic laboratory tests required will differ.
• The types of test methods used for testing biologic products including
• In‑vitro assays
• Immunoassays
• Chromatography
• The choice of testing method will depend on the type of product being pro‑
duced, the scale of production, and regulatory requirements.
• Regardless of the testing method used, it is essential to ensure that all test‑
ing is carried out in a way that minimizes the risk of contamination, the
equipment used in testing is qualied, and the test methods are validated to
provide a true, reliable result.
•
Equipment sterilization requirements are specied in the standard, and ste‑
rility via equipment handling procedures to assure continued sterility.
• Tests may include screening for specied animal diseases, and reporting
certain diseases to the FDA if an outbreak is detected.
It is important for manufacturers to stay up‑to‑date with the current GMP
requirements. Failure to do so can result in subpar products and potential
safety risks for consumers, or products failing to meet the expected medical
state‑of‑the‑art.
QUESTIONS AND ANSWERS
1. What is a biosimilar drug?
Answer: A biosimilar drug is also a biologic drug that is highly similar to a
biologic drug that was already authorized for sale. The difference between
biologics and biosimilar is same as that between a generic drug and an orig‑
inal brand product. There are no expected clinically meaningful differences
in efcacy and safety between a biosimilar and the biologic drug.
https://t.me/med1917
235GMP for Biologics and Similar Medicines
However, in order for a biosimilar to gain approval to be used, it has to
meet strict standards to show it is as safe and effective as the original bio‑
logic drug, and to have the same quality, although it may have small struc‑
tural differences.
2. In what respect GMP is important in Biologics/Biosimilar drugs
manufacturing?
Answer: Good Manufacturing Practices prevent or minimize errors or
defects during the manufacturing process, minimize contamination, and
maintain the integrity and stability of the products just like all other phar‑
maceutical dosage forms. Therefore, the quality and safety of biologics are
also very important, because the human health can be impacted in a num‑
ber of ways by these products. Biologics are frequently sourced from other
living things, and act with human metabolism to enhance an existing bio‑
logical process. For example, vaccines enhance immune response, and hor‑
mones are administered to patients with endocrine insufciency. Therefore,
it is essential that manufacturers adhere to strict good manufacturing prac‑
tices in order to ensure product quality and safety, since failure to create a
safe product has the potential to cause great harm.
3. Describe Good Laboratory Practices in Biologics Manufacturing.
Answer: The GMP guideline work in biologics/biosimilar is very much
similar to other pharmaceutical manufacturing that involves assuring and
verifying that controls in the design of the biologic facility continue to
perform as designed. Apart from that, after release stability testing is also
required.
Quality Control also includes validation of laboratory testing as well as
the area where biologic material is harvested from animals, with specied
requirement for assuring cleanliness, including assurance of animal health
and preventing incursion of spore‑forming microorganisms.
https://t.me/med1917
20
QA/QC Release
Some of the responsibilities and functions discussed in this chapter are already men-
tioned, though briey, in Chapter 17. In this chapter those very functions will come
under detailed discussion in the context of batch release.
The Quality Control (QC) department is critical in ensuring pharmaceutical prod-
ucts’ safety, efcacy, and quality in the pharmaceutical industry. QC releases raw
materials, packaging components, in-process samples, and nished products.
The QC department ensures that these raw materials and packaging components
meet the required quality standards before they are used for production.
These materials are received and stored in the warehouse in a controlled
environment.
Raw materials are segregated based on their characteristics, such as active phar-
maceutical ingredients (APIs), excipients, solvents, or packaging materials.
If an investigation is required due to any reason, the material is kept in the quar-
antine area with the sticker “quarantine” signed by the QA ofcial. Similarly, if the
material is rejected, the material is kept in a rejected area with the sticker “rejected”
signed by the quality ofcial and later disposed as per policy.
Each raw material as well as nished product batch should be labelled with rel-
evant information such as name, batch number, manufacturing and expiration date,
and supplier details.
Records of incoming and outgoing materials, including certicates of analysis,
should be maintained. Good documentation practice is essential to maintain trace-
ability and regulatory compliance.
The containers should be opened, sampled, and closed to prevent contamination
of their contents and other components.
Additional safety measures should be taken if the raw materials include hazardous
substances.
Sterile equipment and aseptic sampling techniques shall be used when necessary.
These include proper labelling, storage in designated areas with appropriate
safety equipment, and adherence to regulations regarding the handling and disposal
of hazardous materials.
Materials received rst are used rst. Those materials are used rst, which have
less expiry period than others.
RECEIVING AND RELEASE OF RAW AND PACKAGING MATERIALS
Releasing raw materials and packaging components is critical to ensure the nal
product’s quality, safety, and efcacy in the pharmaceutical industry. The quality
control (QC) department plays a key role in this process.
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DOI: 10.1201/9781003366393-25
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237QA/QC Release
Let us take a look of the entire process as to how the Raw, packaging materials
and active pharmaceutical ingredients and excipients are received, stored, tested, and
then released in the QC Laboratory.
Packaging pharmaceutical products are bottles, blister packs, labels, inserts, and
outer cartons.
A representative sample is collected from the warehouse. Sampling methods fol-
low established guidelines and procedures to ensure that the sample accurately rep-
resents the bulk material.
Personnel working in manufacturing, processing, packing, or holding a drug
product should wear clean clothing appropriate for their duties. Personal protective
equipment, such as head, face, hand, and arm coverings, should be worn as necessary
to protect drug products from contamination. Personnel shall practice good sanita-
tion and health habits.
TESTING OF RAW MATERIAL
Quality Assurance personnel will collect and submit the sample to the QC depart-
ment. The submission has to be documented with the date and time the sample was
submitted. QC ofcials arrange required testing for materials.
The QA team reviews the documentation the supplier provided, including a cer-
ticate of analysis (CoA) that describes the test results and quality attributes of the
raw material.
The QA team veries the accuracy and completeness of the documentation.
The sample undergoes tests and analyses to evaluate its quality and compliance with
predened specications. These tests may include identication, physical, chemical,
microbiological, and other relevant tests for the specic material and its intended use.
THE FLOW OF QC WORK
After the QA personnel submits the samples to the quality control laboratory, the
ow of work occurs as discussed below;
saMPLes entry
The sample must be labelled with the name of the sample, lot number, and test
required. The sample is entered in a logbook or register. The sample identity, time,
and date of the sample submitted are entered in the logbook.
PLanninG
The laboratory supervisor or manager with other departments, such as Quality assur-
ance or Production, determines the upcoming workload and prioritize tasks accord-
ingly. This planning helps establish the overall schedule for the lab and ensures that
critical tasks are addressed promptly.
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238 Basics of Pharmaceutical Manufacturing and Quality Operations
In some companies, specic departments or groups deal with the samples of raw
materials, packaging components and in-process testing separately.
In-process testing is always prioritized since the production waits to proceed to
the next step of production.
Work orders/batch records creation
Once the work plan is established, specic work orders or batch records are created
for each task or project. These documents outline the required tests, methods, speci-
cations, and other relevant information for the analysis or quality control activities.
Work assiGnMent to anaLysts
The lab supervisor, manager, or designee assigns the work orders to individual
lab analysts or technicians based on their skills, expertise, and workload capacity.
Consideration is given to balancing the workload among team members and ensuring
all tasks are completed within the required timeframes.
The lab supervisor, manager, or designee create a sample request, which contains
the list of test to be performed and the method identication for each test. It also
contains the name of the analyst performing each test. Each analyst enters his name,
the date testing started, and date testing nished.
Before assigning tasks, it is crucial to ensure that lab personnel are properly trained
and qualied for the specic tests or analyses they perform. This includes compre-
hensive training on test methods, equipment operation, safety protocols, and Good
Laboratory Practices (GLP) or Good Manufacturing Practices (GMP) requirements.
Lab analysts receive clear instructions and guidelines regarding the assigned tasks.
These instructions may include details about sample preparation, testing procedures,
instrument usage, data recording, and any specic quality control requirements.
Effective communication ensures that analysts understand their responsibilities and
perform their work accurately.
Analysts maintain good documentation practice throughout the process, includ-
ing observations, test results, deviations, and other relevant information. Accurate
record-keeping is vital for traceability, quality assurance, and regulatory compliance.
In a quality control lab, internal quality control checks are performed to ensure
the accuracy and reliability of test results. This involves verifying the performance
of equipment, calibrating instruments, running control samples, and participating in
prociency testing programs to validate the lab’s competency.
resuLts revieW
Once the assigned work is completed, lab analysts submit their ndings and data to
the appropriate authority, such as a senior scientist, quality manager, or quality assur-
ance team. These individuals review the results, verify compliance with specica-
tions and protocols, and approve the data before it can be used for decision-making
or further processes.
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