UNIVERSITY OF SANTO TOMAS

ELECTRICAL ENGINEERING DEPARTMENT

1st Term, AY 2018 - 2019

PRODUCTION AND ACTIVE PHARMACEUTICAL INGREDIENTS

EE524
Engr. Erica M. Ocampo

By

Dimaliwat, Edelaine

Infante, Richard Bryan

Lucinario,Mel

Ramos, Derrick

Ubaldo, Godwin
 I. MANUFACTURING EXECUTION SYSTEM

MES is a manufacturing system that connects, monitors and controls complex manufacturing
systems and data flows. Its main goal is to ensure effective execution of the manufacturing
operation and improve production output.
Benefits of using MES are:
● Improved regulatory compliance
● Reduced manufacturing cycle time and order lead time
● Elimination of paperwork and manual data- entry processes
● Lower labor costs
● Reduced WIP inventory
● Increased machine utilization

Active Pharmaceutical Ingredient Industry

The Active Pharmaceutical Ingredient Industry is where active pharmaceutical

ingredients are manufactured from raw materials through both chemical and physical means.
Active pharmaceutical ingredients or APIs are the chemicals used to manufacture
pharmaceutical drugs. The active ingredient (AI) is the substance or substances that are
biologically active within the drug and is the ingredient responsible for the desired effect of the
medicine.
APIs are generally manufactured through a variety of processes that include:

· Chemical synthesis
· Fermentation processes
· Recombinant DNA
· Isolation and recovery from natural sources
· A combination of these processes

Active ingredients are produced by chemical or biotechnical processes (plant extracts, chemical
synthesis, or biotechnological fermentation).
The purpose of APIs according to the FDA is to cause ‘pharmacological activity or other direct
effects in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the
structure and function of the human body.

Pharmaceutical Products

1. Solid Medicines e.g. tablets, capsules, granules, powders, sachets, reconstitutable powders, dry
powder inhalers and chewables.

2. Liquid Medicines e.g. medicine includes liquids, solutions, syrups and mixtures.
3. Aerosol Medicines Several classes of drugs with different properties and indications may be
given by inhalation

II. PHARMACEUTICAL COMPANIES

The world’s biggest pharmaceutical companies in 2018

Johnson & Johnson

J&J announced the approval of its HIV type-1 infection treatment JULUCA® and the acquisition
of biopharmaceutical company Actelion. Actelion added pulmonary arterial hypertension as a
sixth therapeutic area to J&J’s Pharmaceutical division.

Pfizer

Pfizer announced the approval of BESPONSA® for the treatment of relapsed or refractory B-cell
precursor acute lymphoblastic leukaemia in 2017.

Novartis

Significant developments in 2017 included the approval of Rydapt® for the treatment of acute
myeloid leukaemia, Kisqali® for the treatment of advanced or metastatic breast cancer and
Zykadia® for the treatment of anaplastic lymphoma kinase (ALK) positive advanced non-small
cell lung cancer (SCLC).

Sinopharm Group

Based in China, Sinopharm is a subsidiary of China National Pharmaceutical Group (CNPG). It

is engaged in the wholesale and retail of pharmaceutical and healthcare products. The company’s
main business divisions include pharmaceutical distribution and retail pharmacy.

Hoffmann-La Roche

Roche received approvals for several key products in 2017, including Perjeta for the treatment of
early breast cancer, haemophilia A therapy Hemlibra, Gazyva for the treatment of advanced
follicular lymphoma, and therapy for Erdheim-Chester disease, Zelboraf.

Sanofi

Based in France, Sanofi is a pharmaceutical company that develops, manufactures and markets
medicines and vaccines. The company’s business units include diabetes and cardiovascular,
Sanofi genzyme (speciality care), Sanofi pasteur (vaccines), consumer healthcare, and general
medicines and emerging markets.

GlaxoSmithKline
The approval of Trelegy Ellipta for chronic obstructive pulmonary disease and JULUCA ® for the
treatment of HIV-1 infection helped increase the company’s revenues.

GSK is a UK-based pharmaceutical company that develops medicines, vaccines and consumer
healthcare products.

Merck & Co

Merck also reported the approval of STEGLATRO™ for the treatment of Type 2 diabetes
mellitus, the ISENTRESS® therapy for HIV-1 infection, and PREVYMIS™ for the prevention of
cytomegalovirus (CMV) infection during Q4 2017.

Merck invested $7.3bn in R&D during the year to investigate the additional indications and
combination therapies of its key drug KEYTRUDA®. The combination of Eisai’s LENVIMA®
and KEYTRUDA®

Based in the US, Merck & Co provides innovative prescription medicines, vaccines, biologics
and animal health products. Its business is organised under pharmaceutical, animal health,
healthcare services and alliances divisions.

III. PHARMACEUTICAL RAW MATERIALS

Pharmaceutical crude materials for the involves components which are utilized for
assembling diverse kinds of medications.

3 Major Categories of Raw Materials:

Raw Material of API

API (Active Pharmaceutical Ingredient) means the active ingredient which is contained in
medicine. A small amount of the active ingredient has an effect, so only a tiny part of the active
ingredient is contained in medicine. You will find the name and amount of the active ingredient
contained in the medicine on the package of OTC (over-the-counter) drugs.

It is considered as one of the principle part of the medication which is in charge of the
medication activity. Primary concern is that Accuracy and Precision are must for the crude
materials which is utilized for making the API.

Raw Material of Excipients

Inactive ingredients or also called as Excipients. Excipients are pharmacologically

inactive substances that are generally used as a carrier of the API in the drug.

Excipients provide bulkiness to formulations, facilitate absorption of the drug, provide

stability and prevent denaturation of drugs. Pharmaceutical excipients are cost effective, stable,
feasible for handling, and inert in nature. Excipients are used in a variety of medicinal products
such as capsules, tablets, oral liquids, inhalers, implants and injections among others.

Pharmaceutical Raw Materials utilized for excipients, it generally concerns solvents and
different carriers which are equipped for transporting the genuine medication.

Raw Material of Packaging

Raw material which is used in making most of the packaging involve plastic & polymers,
glass, paper, aluminum foil and paper boards. Crude material which are exploited in making the
majority of the bundling and packaging including plastic and polymers, glass, paper, aluminum
foil and paper sheets and sheets.

IV. PRODUCTION OF ACTIVE SUBSTANCE

In manufacturing API, it is started with a chemical reaction by simply putting solvents and
chemicals into large container which is called a reactor. The Reactor blends them for the
chemicals to start reacting to each other. When the process of reaction is finished, It would then
boil the solvent that is no longer needed. The next step then is to cool the remains to form a
crystallized sediment called a slurry. The slurry is then filtered to get rid of excess liquid into
forming a crumbly dough, Finally the dough is dried into a powder. The powder is then sent on
to the next step of the production process called formulation. In the formulation process the API
powder is mixed with solvents usually contains water and ethanol as binding agents and
pharmaceutical excipients in a large mixing machine. The moist powder mix is then dried in a
fluid bed dryer until it forms a tiny dry grain into a few millimeters in diameter only, in this
process it would take up to 3-6 hours finish. When the drying process is complete more
pharmaceutical excipients are added before the grains are brought to the tablet compression
machine in order to shape the desired pill, Lastly, the final process is that the tablets are coated to
disguise flavors which would make them cosmetically pleasing as well as easier to swallow.

V. ACTIVITIES INVOLVED IN PHARMACEUTICAL PLANT

There are eight activities involved in the production of active pharmaceutical ingredients.
These activities are: resource management, definition management, detailed scheduling,
dispatching, execution management, data collection, tracking, and analysis. Each of these
activities ensures that the production, quality, maintenance and inventory of the plants in in the
good state.

For the resource management, this involves the employees and the process equipment in
the plant. This manages the training of the employees and the planning of their shifts and
holidays. The definition management deals with the controlling of the equipment and the
employees by implementing work instructions and safety instructions. For the detailed
scheduling, this determines the resources and time for carrying out operations. This interfaces to
enterprise resource planning system, which is a software that allows an organization to use a
system of integrated applications to manage the business and automate many back offices
functions related to technology, services and human resources. This also includes the unit
assignment proposal, connection proposal and selection based on the recipe needed and the
availability of the unit at the expected time it will run. This compare the target production to the
actual production of the plant. In dispatching, this controls the flow of production by scheduling
the batches in a batch control system. This includes the order assignment for campaign setup,
weighing of ingredient containers, processing of the individual batches, test orders for the
laboratories, immediate cleaning and for the final cleanup. In execution management, it includes
the management of the products in line with the schedules and in comply with the standards for
the products. It also includes the recipe control for the medicine production. This also manages
the transfer of one process to another process in the production of the medicine. For the data
collection, this concerns the data which are used in the production of the medicine like the data
inputted on the sensors for the processes. This also includes the storage of data according to US
legal requirements: 21 Code of Federal Regulation Part 11: Electronic Records; Electronic
Signatures. For tracking, this includes the evaluation of data related to the resources utilized in
the production of medicines. It includes automatic tracking of changes in state of campaigns,
batches, work and transport orders. It also tracks the feedback of material consumption and
manufactured products to enterprise resource planning. And lastly for the analysis, this includes
activities which are related to the evaluation and reporting of data to business systems. This also
generate electronic batch records of the time progress, quality-relevant discrepancies, and
historic trend plots of quality-relevant measurements. It also overviews which ingredients were
used in a batch of medicines and which batch these ingredients were used. It also has statistical
analyses for the key performance indicator.

How Is Medicine Quality Assured?

To ensure quality product, employees were properly trained and these employees are
qualified to do the right job. The equipment is maintained properly and are always available
when it is needed to be used. Current good manufacturing practice are required to conform to the
guidelines recommended by agencies that control the authorization and licensing of the
manufacture and sale of pharmaceutical products. Tests are required for good receipt, in-process
control and product releases. The target production is compared to the actual production. Test
orders and test procedures are available online. The test results are also documented. Tracking of
completed test orders and warning if analysis values outside tolerance is automated.

Maintenance Involved in Pharmaceutical Plant

The maintenance of the process involves:

- Training of the personnel

- Maintenance and calibration of the equipment used

- Availability of spare parts and operating materials

- Creation, quantification, release and control of maintenance plans, test procedures,
and calibration cycles

- Planning of status inspection and maintenance

- Assigning of the maintenance orders

- Control and monitoring of maintenance orders

- Electronic data recording of failure time, damage, necessary working times, spare
parts needed, maintenance order costs, and resulting costs of production losses

- Collection of completed maintenance orders

- Statistical analysis of the technical plant availability, reliability of parts and

optimization of maintenance plans

Inventory

Inventory for each activity:

1. Resource management

a. Personnel training and availability

b. Types, quantity and status of material

c. Capacity and allocation of storage

d. Packaging of material

2. Definition management

a. Handling of dangerous materials

b. Specification of permitted packaging

3. Planning

a. The material stock level

b. Weighing of the necessary containers

c. Required transport operations

 4. Dispatching

a. Sampling of received goods

5. Execution management

a. Checking of the correct weight of material

b. Checking of the transportation of materials

c. Checking of the quarantine of materials and products

6. Data Collection

a. Material Data

b. Data recording of stock levels and location

c. Data of the use and status of mobile containers

d. Data of the execution of transport orders

7. Tracking

a. Collection of completed goods received

b. Collection of completed shipped goods

c. Collection of completed weighing of materials

d. Collection of completed transport orders

8. Analysis

a. Supplier Evaluations

VI. INDUSTRY 4.0 FOR PHARMACEUTICAL MANUFACTURING PLANTS

Industry 4.0 as the convergence of individuals, physical systems, and data information
inside a industrial procedure to expand quality, profitability and benefit by utilizing the intensity
of cutting edge information analysis, Pharma 4.0 can be characterized similarly. Pharma 4.0
innovation considers persistent, continuous checking of real-time monitoring of manufacturing
processes so any drift away from indicated parameters can be anticipated and redressed before it
transforms into a deviation, maintaining a strategic position from the related downtime and loss
of item.
 A pharmaceutical manufacturing plant set up as indicated by Pharma 4.0 standards is
comprised of machines, gear and PCs, but instead than the ordinary automated process control
(APC) components that have been standard since the late nineties, every one of the machines and
hardware – even individual components inside them – are fitted with numerous sensors that are
continually monitoring each part of the procedure and even their very own wear and tear. These
'self-aware' components can give their very own account condition, display how much valuable
life they have left, and speculate when it is on the verge of probability to fail.

There are fewer operators needed on a Pharma 4.0 production line and the jobs are highly
skilled. Some commentators are calling for ‘Data Scientists’ to staff these operations. In a
Pharma 4.0 environment, a Data Scientist is not an individual person, it has to be a team or a
consultant, as there are so many different skills required. In addition to their technical skills, staff
need industry knowledge and an in-depth understanding of their facility and the production
processes. Data quality will improve with increasing automation, but it will be some time yet
before all the data needed is delivered in a clean, ready-to-use format, so staff will spend time
preparing data for analysis.

Technologies That Can Improve the Pharmaceutical Process

Robotics

-making use of robotics to automate specific processes in drug development, including

drug screening, anti-counterfeiting and manufacturing tasks

Internet of Things

- facilitate connectivity and easy exchange of data in real-time in the factory

Big Data Analytics

- useful in predictive manufacturing to provide early warning for anomalies and system
failures and to predict product quality

AI Technology

- analyze patient data to identify treatment options predicting a patient’s response

to possible drug treatments

-machines which are like humans which can come up of a solution given a
situation
 How do these technologies relate to each other?

AI Technology

Big Data Internet of Robotics

Analytics Things

Some of the new technologies that can be implemented in the Industry 4.0 of a
pharmaceutical manufacturing process are the AI technology, big data analytics, internet of
things and robotics. The big data analytics are used to gather data from the internet. These data
are used to predict early warnings of anomalies and system failures. The warnings are analyzed
by the AI technology and it can create solutions based on those warnings. The AI technology
will then control the robotics on the system. The internet of things is basically the
interconnection of all the technologies.

REFERENCES:
1. https://searcherp.techtarget.com/definition/manufacturing-execution-system-MES
2. https://www.newcastlesys.com/blog/what-is-mes-manufacturing-execution-systems
3. http://www.mdtvalliance.org/
4. https://www.quora.com/What-are-pharmaceutical-raw-materials
5. https://www.pfizer.com
6. https://www.novartis.com.ph/
7. https://www.sanofi.ph/
8. https://www.katsura-chemical.co.jp/en/drugs/
9. https://www.proleit.co.uk/fileadmin/user_upload/Englisch/Content/04_Solutions/MES/Z
VEI_MES_Brochure_EN.pdf
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he_pharma_industry?fbclid=IwAR21yUImChinofj_m7zFMZReHvrkPNVxBkVWfxbtBy
vN5j4hVY0fs_u6ylM