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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5737_Библиотеки_им_академика_М_И_Перельмана
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12
Technology Transfer
The term “Technology Transfer” refers to the chain of processes that are needed for
successful development of a drug product from discovery stage to full-scale com-
mercial batch manufacturing.
This could further be explained as the transfer of the product from one technol-
ogy company or site to another, to help make the product accessible to those area
people where it is not available. The transfer of a drug product from Research and
Development pilot batches to commercial production oor for a scale up batch is also
called as “Technology Transfer”.
A successful tech transfer not only requires knowledge about products and pro-
cesses but also knowledge about equipment, procedures, competencies, roles and
responsibilities, cultures, regulatory, and training requirements.
From a pharmaceutical manufacturer’s perspective, the focus is on how to deliver
better results to clients from a project management point of view.
There are key considerations to lead to a successful pharmaceutical tech transfer
and ultimately a product launch to market including a dedicated project management
program, standardized tech transfer procedures and robust quality systems.
HOW TO MANAGE TECHNOLOGY TRANSFER PROJECT
In order to carry out technology transfer effectively, there must be dedicated group
who could be assigned the responsibilities to identify and fulll the requirements
prior to execution.
• The project management needs to work out with the business development
team (BD) to understand the products/services or client needs.
• The team then assesses the technology package in collaboration with other
internal departments.
• To understand the client’s product manufacturing requirements, the project
management team has to rst understand the product and process require-
ments in detail and then evaluate its own capabilities to be able to success-
fully meet the needs.
• The next step is to generate a proposal and preliminary plan to successfully
complete a technology transfer for the client’s product and perform routine
commercial manufacturing at their site. In case the technology transfer is
being carried out in the same company from R&D to the production depart-
ment, then the client would be the company’s production department.
•
After the proposal is approved by the client (or the production department)
and the project is initiated, the project team will form a project management
program to start the overall and thorough project planning before execution.
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190 Basics of Pharmaceutical Manufacturing and Quality Operations
• Besides the project management team, a project manager could be the key
personnel to contact and coordinate with for a successful and smooth tech-
nology transfer. The project manager is required to monitor and look after
the transfer activities, track development, resolve issues, report milestones,
and communicate effectively with the top management and other stake
holders about the project.
• The Project Team should schedule periodic meetings to ensure proper com-
munications on project progress, key decision makings, issue discussion,
and risk management.
NECESSARY ACTIONS OF PROJECT TEAM
FOR TECHNOLOGY TRANSFER
Before going into the technology transfer, a responsible project manager has to look
into the following important points for completion:
1. The regulatory affairs department should rst submit a detailed assessment
package and got the submission le approved by the corresponding Health
regulatory body.
2. An approved change control discussing and outlining all necessary steps and
requirements is in place. The project manager must ensure that the documen-
tation of changes was approved by the client so that the interpretation of dis-
crepancies between expected and actual values could be possible. It is also
advisable to form a system to track these changes during the transfer process.
3. Availability of the Master manufacturing formula for the scaled up batch.
4. Availability of approved raw materials and products test methods and
specications.
5. Sufcient quantity of raw materials and APIs for three or more validation
batches. Sometimes unforeseen conditions or anomalies may lead a vali-
dation batch to failure and as a result the more quantity could be required
to complete the three consecutive successful validation batches.
6. Availability of successfully qualied and like-to-like equipment to accom-
modate the larger size batches.
7. Analytical methods are transferred to the site where the scale up batch
manufacturing will be carried out and are successfully validated.
Analytical methods are needed in the very initial stages of technology
transfer as all the studies require certain testing to provide data and dem-
onstrate the study results. Raw materials that meet the specications need
to be sourced, purchased, tested, and released to support study runs and
process qualications.
8. Analytical test equipment are successfully qualied and available for use.
9. All necessary reference standards and reagents are available.
10. The process validation protocol is approved with all sampling and testing
plans incorporated.
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191Technology Transfer
Besides all those above‑mentioned needs, the presence of experienced and techni‑
cally competent personnel is most important to accomplish the technology transfer
batches successfully.
Once the above‑mentioned requirements have been met, the site is considered
fully ready to carry out the technology transfer process.
CHALLENGES IN TECHNOLOGY TRANSFER
Most of the pharmaceutical industries have a very robust technology that works
smoothly to transfer the development batches to routine commercial scaled up
batches successfully. However, there are always new challenges that may come
across to surprise the personnel during the process. These challenges may be associ‑
ated with the different product processes, equipment design and scale, regulatory
needs, communication skills, and some other factors like geographic locations. Each
company should set up its standardized procedure to manage technology transfers in
a very structured and consistent way. A dedicated project management team is a plus
to work closely with the project team to communicate and to track progress along the
way to ensure timely and successful transfers.
QUESTIONS AND ANSWERS
1. What is technology transfer?
Answer: The term “Technology Transfer” refers to the chain of processes
that are needed for the transfer of the product from one technology company
or site to another to help make the product accessible to those areas people
where it is not available. The transfer of drug product from Research and
Development pilot batches to commercial production oor for a scale up
batch is also called as “Technology Transfer”.
2. What is the rst step in technology transfer?
Answer: The rst step in technology transfer is the submission of a detailed
assessment package to get the le approved by the corresponding Health
regulatory body.
3. What is the rationale behind having an approved change control prior
to commencement of technology transfer project?
Answer: An approved change control discussing and outlining all neces‑
sary steps and requirements is necessary prior to the start of the proj‑
ect so that the documentation of changes could be already approved and
understood by the client and the interpretation of discrepancies between
expected and actual values could be possible. The approved change
control also helps to identify all the needs in time before the project
commences.
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192 Basics of Pharmaceutical Manufacturing and Quality Operations
4. What is the strategy to be followed for the initial tech transfer batches
manufacturing?
Answer: The rst three batches in technology transfer are always made
as validation batches. These batches are manufactured under an approved
and agreed upon validation protocol with excessive sampling and testing
plans that could challenge the robustness of the processes and various other
factors involved in the tech transfer, for example, size of the batches, differ‑
ence in equipment type, and or change in location including environmental
conditions.
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13
Dispensing
The Good Manufacturing Practices are to be practiced everywhere in a pharmaceuti-
cal industry. There is no area or process which is free from GMP and this includes
even the dispensing process. The process of dispensing comprises of weighing and
dispensing of specic amounts of raw material in powder or liquid form from the
bulk container into smaller units that will be released and added in specic quantities
for batch manufacture.
STEPS INVOLVED IN RAW/PACKAGING MATERIAL DISPENSING
Dispensing is where the manufacturing process of a particular product starts. It is one
of the most critical steps as weighing and dispensing the correct amount of materials
are very important in drug manufacturing. The weighing and dispensing of active
pharmaceutical ingredient (API) is especially critical and any error in the weighing
machine or a human error could lead to a serious and major non-compliance issue
which could jeopardize the entire lot or could endanger patient’s life. The reason
being that the incorrect material by weight or selection of wrong material may not
be detected by quality control testing. Therefore, quality assurance has to establish
a system that could protect such mistakes and human errors right from the stage of
dispensing.
The dispensing process comprises the following steps:
1. According to the Batch manufacturing, a bill of material (BOM) is raised
by the production department and after necessary reviews and approval by
Quality Assurance department, the BOM is sent to the Material manage-
ment for dispensing the required amounts of material.
2. The responsible person in the store will review the material requisition sheet
or the BOM and ensure the availability of all of the materials in the list.
3. In case a material is not released yet or still under QC test, the QC manager
is communicated to expedite the release of the batch.
4. The Store person will check and release the containers of the required mate-
rial on the FIFO basis.
5. All the released material shall have a RELEASED tag on the containers
with all necessary information about the material name, code, batch num-
ber, release date, manufacturing and expiry dates, re-test date, etc. The label
must have an approval by QA, signed off by the responsible QA personnel.
6. The containers will be taken to the dispensing booth where a store person
will weigh and dispense the required quantity of the material in separate
bags.
7. Each person entering the dispensing booth will follow the secondary gown-
ing procedure.
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194 Basics of Pharmaceutical Manufacturing and Quality Operations
8. Use required personal protective equipment (PPE) such as hand gloves,
nose mask, Earmuff, Earplug, and safety goggle while working in dispens-
ing area.
9. The cleanliness of the dispensing booth will be checked by a store person to
ensure there is no container or material bags left from a previous dispensing.
10. Each and every weighing machine used in the dispensing booth shall have
a calibration sticker on them clearly showing the calibration status of the
balance, signed off by maintenance and checked and approved by QA
personnel.
11. Only one material will be taken to the dispensing booth at a time to avoid a
mixup.
12. Environmental conditions of the dispensing area will also be checked by
the store person so that any temperature, relative humidity, or light sensitive
material could be taken care off. To ensure the recommended environmen-
tal conditions, all the magnehelic gauges and instruments will be examined
for their current readings as well as their calibration status.
13. The store person shall also check and verify the cleanliness and dryness of
the scoops and other tools to avoid any cross contamination.
14. Once all these steps have been taken, the QA personnel will give clearance
to the store to start the dispensing process for the specic batch.
15. All the materials will be dispensed in clean and dry polybags, immediately
closed and tightened with a weighing slip.
16. The dispensing personnel will clearly indicate the name of the material, tare
weight, gross weight, and net weight on the weighing slip, sign, and tie it up
with the bag.
17. The QA personnel will check each and every material label for correctness
and verify the weight written on it with the actual weight on the BOM.
18. In case of a discrepancy found, it will be escalated and brought into the
notice of quality control, quality assurance, and store managers.
19. After the completion of dispensing process, the dispensed materials
enclosed in bags will be locked in a secured cage to be transferred to the
manufacturing oor.
20. The corresponding production supervisor or manager will receive the mate-
rials cage and will verify the materials weight and other details as peer the
BOM and will give his approval for receiving the materials.
This will complete the dispensing process and the responsibilities of the stores per-
sonnel after QA verication and approval with each step.
IMPORTANT POINTS TO CONSIDER
The stores personnel will ensure:
•
A separate scoop is used to dispense each material
• All scoops are cleaned and dried
• Material will be dispensed in double polybags
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195Dispensing
• Materials will be dispensed under a Laminar Flow hood
• Before dispensing active raw material, the potency will be re-checked and
veried
• The dispensed materials shall be sent to the production oor through the
passbox with the original and duplicate Bill of Materials
• The duplicate of BOM shall be used as receipt and will be signed off by the
production personnel to be sent back to the store manager
• The last container from where the material was used will be marked with a
label “In use” and the remaining quantity will also be put on the label
• After the dispensing is nished, stores person will clean the area to ensure
no remaining traces of the materials weighed remain there and the Laminar
Flow Hood will be switched off
DISPENSING OF PACKAGING MATERIALS
The primary and secondary packaging materials are also issued under the similar
kind of checks and verication by stores and QA persons except for weighing and
some other steps which may be required only for raw materials like usage of Laminar
Flow or scoops which are obviously not required for packaging materials. The pri-
mary packaging materials (PPMs) are dispensed under a reverse Laminar Flow to
clean any foreign particle lying on the body of the PPM.
The most important PPMs include:
• Vials.
• Bottles.
• Blister packs.
• Sachets.
• Syringes.
•
Ampoules.
The PPMs are more critical as they have a direct contact with the products. That is
why to check and verify the environmental conditions of dispensing booth is equally
critical for issuance of PPMs.
Since the releasing of PPMs follows a similar procedure like raw materials, the
necessary checks of the released lots and issuance of BOM for packaging materi-
als, dispensing, and verication by QA personnel are also very critical and impor-
tant to maintain the quality, efcacy, and safety of the product, the materials are
being used for.
The area clearance of dispense booth from any previous PPM is also important
here to ensure right materials with correct product’s name and strength is being
released for use and that no previous product documents or material is available in
the area.
Store person must also ensure that differential pressure reading on the magnehelic
gauge in the area and the HEPA lters is within the allowable limit for primary and
secondary packaging materials.
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196 Basics of Pharmaceutical Manufacturing and Quality Operations
Just like the raw materials, the PPMs shall also be dispensed in the cage/container
having lock and key arrangement.
Labels shall be issued by counting them in numbers. If the labels are available as
Roll labels, the entire Roll shall be given (if the Roll has a counter on the backside
of the label).
DISPENSING OF PACKAGING MATERIALS FOR STERILE PRODUCTS
There are some rules to dispense packaging materials for sterile products. However
these rules are just additional to the normal practice that we have seen earlier in the
chapter for dispensing of raw and other packaging materials.
These rules are as follows:
1. Vial and rubber stopper can be issued in full. If the full quantity differs
from the required quantity, a loose pack can be issued only if the material is
not pre-sterilized.
2. Pre-sterilized material shall be issued in the manufacturer’s original pack;
it cannot be issued in loose quantity. While dispensing such material, the
integrity of the pack needs to be ensured.
3. Flip of seals, needle guard, and plunger rod to be issued in full pack. If pack
quantity is differing from the required quantity, it can be issued by weight.
Standard average weight can be used to calculate the quantity.
4. After completing dispensing, the remaining material container shall be
transferred to the warehouse at a designated place.
After completion of dispensing activity, personnel working in the area shall
remove the hand gloves and cut them to prevent re-use of it. Discard the gloves in
the waste bin.
QUESTIONS AND ANSWERS
1. What is dispensing process in the pharmaceutical industry?
Answer: The process of dispensing comprises weighing and dispensing of
specic amounts of raw material in powder or liquid form from the bulk
container into smaller units that will be released and added in specic quan-
tities for batch manufacture.
The same approach is applied on dispensing of packaging materials
where the materials are dispensed in numbers instead of weighed amount.
2. Why is dispensing process considered critical?
Answer: Dispensing is one of the most critical steps as weighing and dis-
pensing the correct amount of materials is very important in drug manufac-
turing. The weighing and dispensing of active pharmaceutical ingredient
(API) is especially critical and any error in the weighing machine or a
human error could lead to a serious and major non-compliance issue which
could jeopardize the entire lot or could endanger patient’s life.
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197Dispensing
Similarly, in case of primary packaging material, packs with correct
information printed are critical while dispending as any incorrect informa-
tion printed on the PPM or a mixup in the packaging material with contra-
dictory information could be hazardous to the patient’s health.
3. Why the calibration status of the weighing machine in dispensing booth
must be cross‑checked by QA?
Answer: In case of a non-calibrated weighing machine, the amount of
material weighed could be incorrect which may lead to non-conformance
of the entire batch if noted during the QC tests. If not, then the efcacy,
quality and safety of the product will be jeopardized and a serious hazard
to patient’s health could happen. Therefore it is important that the weighing
machines should always stay in calibrated state.
4. Why primary packaging materials are considered more critical then
secondary?
Answer: The primary packaging materials (PPMs) are more critical as they
have a direct contact with the products. That is why to check and verify the
environmental conditions of dispensing booth is equally critical for the issu-
ance of PPMs.
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14
Production
The process of industrial-scale manufacturing of drug products in pharmaceutical
industries is known as production. The overall process of drug manufacture com-
prises of a series of unit operations.
Different dosage forms have different series of processes. Generally the dosage
forms are divided into the following main categories: Solid (tablets and capsules),
Liquid (also known as oral liquid), Semi-solid (creams, ointments suppositories), and
Parenteral (sterile solutions, injectable and infusion solution).
These processes are briey described as follows.
TABLETS
Tablet manufacturing is divided into the following steps or processes: milling, granu-
lation, mixing or blending, compression, and coating (if the nished tablet is required
with coating). Some tablets do not require to be coated and therefore the coating pro-
cess is not included in their manufacturing processes. The coating is often required
to cover the undesired taste of the active ingredient and excipients. However, another
type of coating called enteric coating is also employed in some products to protect
them from getting dissolved in small intestine.
CAPSULES
Capsule manufacturing processes are a little different than the tablets as some cap-
sules are found as granules encapsulated in the shells and therefore the manufactur-
ing processes do not have in them further mixing or blending and obviously the
product is not compressed. Instead the granules are put in the capsule shells with
a machine called encapsulator. The encapsulator has specially designed dosators
which facilitates the picking of a specic amount of granules to put inside one half
of the capsule shell and closing it using the other half. Once the shells are closed, the
product behaves almost like a tablet with the difference that the API is enclosed in
the form of small granules which are dissolved inside human body almost the same
manner as the tablets.
SOFT‑GEL CAPSULES
The soft-gel capsule manufacturing differs from that of regular capsules so that it is a
continuous method whereby two gelatin ribbons pass between twin rotating dies. As
the ribbons meet, the liquid, which is prepared according to the regular procedure, to
be encapsulated is precisely injected between them. The two ribbons are sealed like
an oval-shaped ball.
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