ANG Report PDF

INDUSTRIAL TRAINING’S FINAL REPORT
PREPARED BY
ANG LI PEI
QIUP201609-000223
AT
AIN MEDICARE SDN. BHD. (Lot 4933 & 4934, Kawasan Perindustrian
Pengkalan Chepa 2, Jalan 6/44 Pengkalan Chepa, 16100 Kota Bharu, Kelantan
Darul Naim)
&
HOVID BERHAD (Lot 56442, 7 1/2 Miles Jalan Ipoh/Chemor, 31200 Chemor,
Perak Darul Ridzuan)
This report is submitted to
Faculty of Pharmacy
as partial fulfilment of the requirement for the
Bachelor of Pharmacy (Hons)
QUEST INTERNATIONAL UNIVERSITY PERAK
APRIL 2019
1
LIST OF CONTENTS
CHAPTER TOPIC PAGE

1 Introduction 6
1.1 Introduction 6-7
1.2 Objectives of Industrial training 8
1.3 Importance of Industrial Training 9
2 Company Background and Organization Structure 10
2.1 Ain Medicare Sdn. Bhd. 10-14
2.2 Hovid Berhad 15-21
3 Weekly Jobs Summary 22
3.1 Weekly Jobs Summary in Ain Medicare Sdn. Bhd. 22-24
3.2 Weekly Jobs Summary in Hovid Berhad 25-28
4 Technical Contents 29
4.1 Technical Contents for Ain Medicare 29
4.1.1 Research and Development (R&D) 29-31
4.1.2 Regulatory Affairs (RA) 32-37
4.1.3 Quality Affairs (QA) 38
4.1.4 Quality Control (QC) 39-41
4.1.5 Logistic, warehousing and distribution 42-46
4.1.6 Production 47-50
4.2 Technical Contents for Hovid Berhad 51
4.2.1 Research and Development (R&D) 51-58
4.2.2 Regulatory Affairs (RA) 59-65
4.2.3 Quality Affairs (QA) 66-74
4.2.4 Quality Control (QC) 75-80
4.2.5 Logistic, warehousing and distribution 81-87
4.2.6 Production 88-94
5.0 Findings and recommendations 95
6.0 Conclusion 96
2
FIGURE LIST
FIGURE ITEM PAGE

1. Logo of Ain Medicare Sdn Bhd 12
2. Map showing Ain Medicare Sdn. Bhd. 13
3. Entrance of Ain Medicare Sdn. Bhd. 13
4. Logo of Hovid Berhad 18
5. Map showing Hovid Berhad 18
6. Entrance of Hovid Berhad 19
7. Floor plan of Hovid Berhad 19
8. Product details of 0.75% Bupivacaine Hydrochloride 29
9. Patent data of 0.75% Bupivacaine Hydrochloride 30
10. Formulation sheet for Paracetamol 10mg/ml solution for 31
IV infusion
11. Raw material warehouse 44
12. Raw material warehouse 44
13. Finished goods warehouse 45
14. CRM usage records 56
15. Certificate of Analysis of IRM (Terbutaline Sulphate) 57
16. Result for precision for Rosuvid 20mg tablet 58
17. Manufacturing licence for Hovid Berhad 60
18. 5 tiered structure of document management system in 66
Hovid
19. “QUARANTINE” sticker for packaging and raw material 82
20. “PASSED” sticker for packaging and raw material 83
21. “REJECTED” sticker for rejected material 84
22. “ON-HOLD” sticker for pending write off material 84
3
CHART LIST
CHART ITEM PAGE
1. Organization Chart of Ain Medicare Sdn. Bhd. 12
2. Organization Chart of Hovid Berhad 17
3. Process of product registration 32
4. Process flowchart of INFUSOL® D10 48
5. Flowchart of handling of sample for post market 63

surveillance
6. Flowchart of procedure for handling of product 65

discontinuation in Malaysia
7. Manufacturing flow of solid dosage form products 88
4
TABLE LIST
TABLE ITEM PAGE

1. List of pharmaceutical products for human used and 14
veterinary used
2. List of medical device products 14
3. Product lists for Hovid Berhad 20
4. Job Summary for Week 1 22
12. Method of Evaluation According to Product Categories 33
13. Data to be submitted for different product category 34
14. Timeline for product registration 36
15. Recommended limits for microbial contamination 41
16. Batch manufacturing formula for INFUSOL® D10 49
17. Stability study perform in Hovid 54
18. Minimum requirement of approval for different types of 67
document in different levels
19. Degree of recall 71
20. USP limits for disintegration times of tablets 77
21. USP dissolution acceptance criteria 78
22. USP limits for weight variation test for uncoated tablets 79
23. Requirement of temperature and relative humidity control 85
for warehouse and container.
5
CHAPTER 1: INTRODUCTION
1.1 Introduction
The word ‘Pharmacy’ is derived from the Greek work ‘Pharmakon’, meaning
drug. Pharmacy is the art and science of preparing and dispensing medications and
the provision of drug and related information to the public or study of science of the
drugs. Pharmacists are members of pharmacy profession dealing with all aspects of
drugs, they also known as ‘experts of drugs’. There are wide field of career paths in
pharmacist profession which includes pharmaceutical industry, hospitals and clinics,
community pharmacy, wholesale pharmacy and government services (regulatory
affairs, drug testing laboratories, military services).
Industrial pharmacy is a discipline which includes manufacturing,
development, marketing and distribution of drug products including quality
assurance of these activities. There are various departments in industry which a
pharmacist can involve in such as marketing and provision of drug information,
research and development department, quality assurance department, quality control
department, production department and regulatory affairs department. The roles of
industrial pharmacists include conduct research, testing and analysis in the
development of medicines and production of pharmaceuticals and related supplies.
Industrial pharmacists use the latest methods, technologies and processes to develop
new medications, and may be involved in clinical drug trials.
According to the four years course plan for Bachelor of Pharmacy, each
student compulsory undergo 2 months training in industries. For instance, one month
is allocated to sterile industry and another month is allocated to non-sterile industry.
Ain Medicare Sdn. Bhd. that located in Kelantan was selected for my sterile industry
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training. The training started from 17th Feb 2019 to 14th Mar 2019 with duration of 4
weeks. I was given a chance for weekly rotation into different departments during
my training attachment including Research and Development (R&D) Department,
Quality Assurance (QA) Department and Production Department. In addition, Hovid
Berhad that located in Chemor, Perak was selected for my non-sterile industry
training. There were 4 weeks training started from 18th Mar 2019 to 12nd Apr 2019.
In Hovid, I was placed in R&D department for my whole 4 weeks industry training
without switching to other departments.
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1.2 Objectives of Industrial training
The objectives of the Industrial Training include:
• To gain experiences and knowledge throughout the period of training.
• To enhance the employability skills of the students.
• To apply learnt theoretical knowledge to practical work situations.
• To instil a sense of responsibility, build strength, teamwork spirit and self-
confidence.
• To expose students towards the real working environment as well as latest
technology and management utilized by the industry.
• To expose students to a work environment, common practices, employment
opportunities and work ethics in their relevant field.
• To provide opportunities for students to be offered jobs in the organizations
in which they undergo their Industrial Training.
8
1.3 Importance of Industrial Training
The industrial pharmacy is important to give an idea to students about the
roles and responsibilities of industrial pharmacists in different areas. It also gives a
real working situation on how to complete a task before deadline and how to solve
problems. Besides that, students can gain invaluable knowledge and experiences
from the workers. Students are able to strengthen skills such as communication skills
that could integrate into their future careers. With industry training, students are
preparing to be employed and expand student’s employment prospects. As students
are also given the opportunity to test their interest in the different areas of a career
before permanent commitments are made so they can assess themselves to prepare
for the working world after graduation. Furthermore, through the industrial training,
students are able to achieve key and functional competencies in various aspects of
industry pharmacy.
At the end of the training, the student will be able to achieve key and
functional competencies in various aspects of industrial pharmacy. As industrial
pharmacy is one of the main areas of practice for pharmacists, this training will
provide insight for students regarding a career in industrial pharmacy.
9
CHAPTER 2: COMPANY BACKGROUND & ORGANIZATION
STRUCTURE
2.1 Ain Medicare Sdn. Bhd.
2.1.1 Ain Medicare Organization Background
Ain Medicare Sdn. Bhd. is a trusted name and leading manufacturer of sterile
manufacturing pharmaceutical industry who produces pharmaceutical products and
medical device products. It started to establish in year 1993 in Malaysia. It is a
wholly-Malaysian owned company. For pharmaceutical products, it includes
intravenous solution, plasma expander, antiseptic solution, antimicrobial solution,
peritoneal dialysis solution, nebuliser solution, anticoagulant injection and other
small volume parenterals. Whereas for medical device products, it includes irrigation
solutions, continuous renal replacement therapy solution (CRRT) and haemodialysis
concentrates. In short, Ain Medicare manufactures about 67 registered products.
Ain Medicare Sdn. Bhd. located in Kelantan, on the East Coast of Peninsular
Malaysia. It operates from a multi-million dollar state-of-the-art pharmaceutical
complex. In 1997, the complex which fully equipped with production floor,
microbiological and chemical laboratories, warehouses and administrative centre was
inaugurated by former Prime Minister Tun Dr. Mahathir Mohamad.
The chairman of Ain Medicare Sdn. Bhd. is Dato' Wan Ariff Bin Wan
Hamzah whereas the Chief Executive Officer is Dr. Syed Ibrahim Bin Mohd. Ismail.
Over the years, AIN MEDICARE SDN BHD has successfully steered the company
towards numerous remarkable achievements through its far-sighted leadership and
strategic management system. Today, AIN MEDICARE's authorised share capital
stood at RM 20 million with paid up share capital of RM 20 million. Ain Medicare's
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products have gained international acceptance because they export their products to
other countries such as Singapore, Myanmar, Sri Lanka, Macau, Australia and etc.
Not only that, both private and public health care sectors as well as non-profit
healthcare providers in Malaysia also use their products too.
OUR MISSION
To further innovate superior quality healthcare products to the highest standard and
to provide outstanding customer services worldwide.
OUR VISION
AIN MEDICARE is committed to provide reliable and quality products and services
that consistently meet the satisfaction of health professionals and patients, in
compliance with regulatory requirements and best practices. We are continuously
committed to improving our operations to excel beyond the quality standard. AIN
MEDICARE strongly believes in providing excellent services that exceed customers'
expectations.
OUR ASPIRATION
Having carved a niche for itself in Malaysia and the region, AIN MEDICARE aims
to be a market leader in the international healthcare scene. To our customers, we
always position ourselves as a healthcare partner. With a wide marketing network
across the nation and key representatives abroad, we are confident of partnering with
our clients to achieve their ultimate goals.
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2.1.2 Company Organization Chart
Chart 1: Organization Chart of Ain Medicare Sdn. Bhd.
2.1.3 Company logo for Ain Medicare Sdn Bhd
Figure 1: Logo of Ain Medicare Sdn Bhd
12
2.1.4 Company Organization Address
The location of Ain Medicare Sdn Bhd is at Lot 4933 & 4934, Kawasan
Perindustrian Pengkalan Chepa 2, Jalan 6/44 Pengkalan Chepa, 16100 Kota Bharu,
Kelantan Darul Naim.
Figure 2: Map showing Ain Medicare Sdn. Bhd.
Figure 3: Entrance of Ain Medicare Sdn. Bhd.
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2.1.5 Product lists
i. Pharmaceutical products
Table 1: List of pharmaceutical products for human used and veterinary used
For human used For veterinary used

Intravenous solution Intravenous solution
Plasma expander
Antiseptic solution
Peritoneal dialysis
Antimicrobial solution
Nebuliser solution
Anticoagulant injection
Other small volume injection
ii. Medical device products
Table 2: List of medical device products
Irrigation solution
Continuous renal replacement therapy solution (CRRT)
Haemodialysis concentrates & powder
Table 2: List of medical device products
14
2.2 Hovid Berhad
2.2.1 Hovid Berhad Organization Background
Hovid Berhad is a local pharmaceutical company which started in the 1940s
as a Chinese Herbal Tea company with commercial and production operations. Mr
Ho Kai Cheong is the first founder of the company. The first product launched by
Hovid was Ho Yan Hor Herbal Tea, a Chinese herbal tea recipe made of 24 herbs.
Mr. Ho formulated the Ho Yan Hor Herbal Tea in the early 1940s, the name ‘Ho Yan
Hor’ indicate that ‘use for all people’. He started to sell boiled herbal teas in front of
his shop and residence. Herbal tea was a popular after World War II as it is
alternative to western medicine as people seek for traditional way for recovery.
In the 1970s, eldest son of Mr Ho, David Ho Sue San was sent to New
Zealand to pursue a pharmacy degree. After graduating, David Ho worked as a
research pharmacist for two years in the United Kingdom. In 1980, he returned to
Malaysia and took over his father's business. He started to transform the business
from a very traditional medicine focus to a more modern business model that
included the repackaging and remarketing of herbal teas. At that moment, he also
started expansion towards pharmaceutical solutions and especially OTC products. It
took around ten years for Hovid to develop their own formulations before starting its
manufacturing, marketing, sales and distribution in Malaysia. David then founded
Hovid Berhad and introduced the line of pharmaceuticals. Actually, each capital in
‘Hovid’ has its own meanings. For instance, H means for honour, O means for
optimise, V means for value, I means for innovation and D means for dedicate.
Hovid manufactures primarily generic drugs such as antihistamines,
antibiotics, tranquilizers, analgesics, antacids, and diuretics. Furthermore, it also
manufactures dietary supplements and disinfectant. Currently, there are nearly 400
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Hovid’s products in the market that available in different dose and dosage forms. The
products also marketed in more than 50 countries including Singapore, Vietnam,
Cambodia, Sri Lanka, African countries, Philippines and Hong Kong.
There are five core values in Hovid that are innovation, team work,
communication, respect and ethical. Innovation means improve lives through better
health solutions brought about by scientific excellence in R&D. Team work means to
enhance and integrate the capabilities and subject matter expertise of each employee
for a better outcome. Communication is hearing what isn’t said, Hovid ready to
listen, anticipate and interpret needs and requirements from patients. Next, foster a
culture which values the importance of respect and openness to different cultures,
views and opinions. They respect the efforts of our employees and the rights of
customer who use their products. Lastly, be ethical and honest to believe in
transparency in order to deliver trusted services to customers.
Mission
To improve lives through a culture of continuous innovation by providing high
quality pharmaceutical and healthcare products and services while achieving
customer satisfaction, enhancing employees and stakeholders’ returns. As a
responsible corporate citizen, we are also committed to adopt policies and activities
that protect the environment.
Vision
A culture of continuous innovation
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2.2.2 Company Organization Chart
Chart 2: Organization Chart of Hovid Berhad
17
2.2.3 Company logo for Hovid Berhad
Figure 4: Logo of Hovid Berhad
2.2.4 Company Organization Address
The location of Hovid Berhad is Lot 56442, 7 1/2 Miles Jalan Ipoh/Chemor, 31200
Chemor, Perak Darul Ridzuan.
Figure 5: Map showing Hovid Berhad
18
Figure 6: Entrance of Hovid Berhad
2.2.5 Company Floor plan
Figure 7: Floor plan of Hovid Berhad
19
2.2.6 Product Lists
Table 3: Product lists for Hovid Berhad
Anti-infective
• Penicillins • Antimalarials
• Cephalosporins • Antibacterial combination
• Macrolide • Antibiotics
• Quinolone • Antifungals
• Tetracycline • Antivirals
• Chloramphenicol
Gastrointestinal system
• Antacids & antiulcerants • Antispasmodics
• Antidiarrheal • Laxatives
• Antiemetics
Cardiovascular system
• Angiotensin receptor blockers • Calcium antagonists
• Anticoagulants • Dyslipidaemic agents
• Beta blocker • Other antihypertensive
Respiratory system
• Antiasthmatics • Cough & cold preparations
Endocrine & metabolic
• Antithyroid agents • Oral antidiabetic agents
Hormones
• Corticosteroid hormones • Progesterone
Central nervous system
• Analgesics & antipyretics • Anxiolytics
• Anticonvulsants • NSAIDs
• Antidepressants
Allergy & immune system
• Antihistamine • Antiallergics
Disinfectants
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Consumers products
Dietary supplements
• Anemia • Liver health
• Antioxidants • Vitamins and minerals
• Bone health • Brain health
• Eyecare • Nerve health
• Heart health • Neuroprotection
• Immune system • Pregnancy health
• Joint health • Women health
Herbal teas
Dermatological therapy
• Topical antibiotic • Topical antifungal
• Topical antibiotic with • Topical antiviral
corticosteroids
• Topical corticosteroids • Other dermatologicals
Muscolo-skeletal system
• Anti-inflammatory enzymes • Gout preparatios
• Anti-osteoporosis agents
Genito-urinary system
• Drug for erectile dysfunction & • Urinary alkalinizer
ejaculatory
Ophthalmic
Medical device
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CHAPTER 3: WEEKLY JOBS SUMMARY
3.1 Weekly Jobs Summary in Ain Medicare Sdn. Bhd.
Table 4: Job Summary for Week 1
Date Activities
• En. Hadi, from Human Resource brief us about company
17th Feb 2019 – profile of Ain Medicare.
• Each student has been assigned to different department

21st Feb 2019
such as QA and QC, R&D and production for each week
(Week 1)
and the last week all students stay in production site.
(R&D)
• En. Shahrizaila, Head of R&D brief me about the roles and
functions of R&D in pharmaceutical industry.
• Formulation of Paracetamol 10mg/ml solution for IV
infusion is calculated by using reference product.
• Key in the medical safety data sheet (MSDS) of newly
products such as Protamine Sulphate and Lignocaine
Hydrochlroide before submission for approval registered
products.
22
Date Activities
• En. Pazrul, from Revalidation section brief me about the
24th Feb 2019 – roles and functions of Validation department.
• Tour and briefing regarding SVP3 production line that

28th Feb 2019
manufacture small volume parenteral by using Blow Fill
(Week 2)
Seal (BFS) techniques.
(QA & QC)
• Tour and explanation about different autoclave machines
for revalidation purpose.
• Attend the briefing conducted by Regulatory affair
department.
• En. Megat, a pharmacist from Regulatory affair department
explains the job responsibilities and using guidelines for
new product registration and change notification.
23
Date Activities
• Explanations about Batch Manufacturing Formula (BMR),
3rd Mar 2019 – Standard Operating Procedure (SOP) and Product
7th Mar 2019 Manufacturing Instruction (PMI) for different products.
(Week 3) • Tour to production site at AIN Block 1 and AIN Block 2.
(Production) • Attend the briefing conducted by En. Zulkifli, Head of
Finish Good Warehouse.
• Attend the briefing conducted by Cik Azmahani, Head of
Raw Material Warehouse.
Date Activities
• Explanation about Good Documentation Practice (GDP) by
10th Mar 2019– En. Fikri, Head of Production Department.
14th Mar 2019 • Tour to AIN 5 that is more advanced compared to other
(Week 4) production line as it involves fully automated machines.
(Production) • Attend the briefing conducted by Pn. Zunaida in
Microbiological laboratory.
• Attend the briefing conducted by Pn. Zatil, Head of
Chemical laboratory.
24
3.2 Weekly Jobs Summary in Hovid Berhad
Date Activities
• Briefing by Ms. Lee Pei San, Human Resource from Ipoh
18th Mar 2019– branch regarding Hovid Berhad.
22nd Mar 2019 • Talk conducted by Ms. Nandini regarding the Good
(Week 1) Manufacturing Practice (GMP) policy in Hovid Berhad.
• Tour conducted by Ms. Lee Pei San to visit around Hovid
Berhad in Ipoh branch.
• A talk from Safety Officer, Mr Thiyagu on safety rules and
regulations in the industry as well as the requirements to
comply with OSHA in Chemor.
• Ms Ng Wei Yee, a section manager R&D, assigns me to
work under method analysis section under R&D.
• Ms. Ewa, supervisor of method analysis briefs me about
the jobs responsibilities and functions of method analysis.
• Learn about Certificate Of Analysis (COA) of different
products.
• Learn about certified reference material (CRM) and
internal reference material (IRM) to ensure that all IRM
comply the requirements of CRM.
• Documentation regarding Analysis Requirement Form
with code number (AS-F044) for new products.
25
Date Activities
• Check batch number and expiry date of CRM and IRM.
25th Mar 2019– • Check the validity of standard by using USP, BP and EP.
29th Mar 2019 • Perform dissolution test of Betahistine Dihychloride.
(Week 2) • Transfer IRM to small vials and record the transfer in IRM
Usage Record and CRM Usage Record.
• Documentation of Expired IRM Usage Record and Expired
CRM Usage Record.
• Learn the proper steps on disposal of IRM and CRM.
• Learn to operate different instruments such as HPLC and
UPLC.
• Learn to prepare buffer solution, standard and sample
solution.
26
Date Activities
• Perform accuracy test, precision test and specificity test on
1st Apr 2019 – different products such as Rosuvid and Butylated
5th Apr 2019 Hydroxytoleune.
(Week 3) • Prepare label for IRM.
• Perform Karl Fischer test to determine the water content of
the product.
• Check the method validation report.
• Perform disintegration test and friability test.
27
Date Activities
• Learn to operate Gas Chromatography (GC) for the sample
8th Apr 2019 – Stavid 40mg tablet to determine the residual solvent.
12nd Apr 2019 • Perform linearity test for sample Duloxetine
(Week 4) Hydrochloride.
• Transfer IRM such as Omega 3 and Griseofulvin into small
vials.
• Learn different type of columns such as C18, C8, column
Silica, column CN, column Hypersil Gold and arrange the
columns respectively.
• Ms Ewa, under method analysis gives a briefing on ICH
Harmonised Tripartite Guideline on validation of analytical
procedure.
• Ms Ooi under product development gives a briefing on
Bioequivalent Studies that conducted in Hovid Berhad.
28
CHAPTER 4: TECHNICAL CONTENTS
4.1 Technical Contents for Ain Medicare
4.1.1.Research and Development (R&D)
In Ain Medicare, the R&D department can further be divided into 3
subdivisions such as chemical, microbiology and technical. The roles and functions
of R&D are search for the patent of the reference products and try to find the drug
profile of the drug that wish to be manufactured so that the industry can come up
with new products or new formulation of the current products every year. When
handle a new product, it is necessary to check the patent expiration of the reference
product first. FDA Orange Book is use to check the patent expiration of the reference
product. Through this system, a lot of information can be obtained such as the
product number, application number, approval date, applicant holder, patent number
and patent expiration. The figure 8 and 9 indicate the steps on finding the patent of
reference product, 0.75% Bupivacaine Hydrochloride. Besides that, Quest 3+, an
official website of NPRA is used to check the registered products in Malaysia. A lot
of information can be obtained through the website such as the manufacturer,
distributor, different strength and dose of the products and MAL no. of the products.
This process can gain extra information whether the desired product has been
manufactured by local sterile company in Malaysia.
Figure 8: Product details of 0.75% Bupivacaine Hydrochloride

29
Figure 9: Patent data of 0.75% Bupivacaine Hydrochloride
If none of the local sterile company manufacture such product, it is best to
produce the generic product in local market which the product accessible to the
public with affordable price. Once the patent of reference product nearly expired, the
staffs involved in R&D department start to find the drug profile of the product such
as the formulation of the drug, manufacturing steps of drug, medical safety data sheet
(MSDS), pharmacodynamics and pharmacokinetic profile of drug, packaging of
drugs and etc. Then, starts to conduct chemical test or microbiological test to ensure
that the drug comply all the tests. For chemical division, the workers will conduct
chemical tests such as boiling point and melting point to ensure that the drug passed
all the specifications stated on the monograph. Besides, the chemical test also used to
test the raw materials from different suppliers. For the microbiological division,
sterility test, bacteria endotoxin test (BET) and assay are conducted. For technical
division, the workers in charge of the packaging of drugs such as choosing the best
type of container and cap to fill the drug, the types of material that used to make the
container and the size of cartoon box. Next, technical division also carry out different
tests such as leak test, integrity test, vacuum test, drop test, transport test, stability
test and dimension test to ensure that the manufactured products are safe, quality and
efficacy.
30
Figure 10: Formulation sheet for Paracetamol 10mg/ml solution for IV infusion
31
4.1.2. Regulatory Affairs (RA)
The roles and functions of RA personnel are to ensure good housekeeping
and maintained up-to-date regulatory documents in hardcopy and softcopy and
ensure content of packaging and other materials are compliant with local regulations.
Next, RA personnel maintain professional relationship with authorities and players of
similar industry and lastly support business development. In Ain Medicare, RA
personnel are responsible for registration of both pharmaceutical product and
medical devices. New product registration and renewal of product registration are
part of jobs for RA personnel. The registration for pharmaceutical product and
medical devices are totally two different processes.
Product registration process
Chart 3: Process of product registration
32
The process of product registration ensures that pharmaceutical products are
evaluated for its safety, efficacy and quality, whereas natural products are evaluated
for its safety and quality, prior to being registered by the Authority and finally
released into the market.
Prior to submission of an application for product registration, RA personnel
shall determine the category of the product, method of evaluation, general and
specific requirements, conditions applied, multiple applications, variants and
language. There are two types of method of evaluation for registration of a product
which are full evaluation and abridged evaluation.
Table 12: Method of Evaluation According to Product Categories
33
For full evaluation, the following data need to submit:
▪ Part I - Administrative data and product information
▪ Part II - Data to support product quality (Quality Document)
▪ Part III - Data to support product safety (Nonclinical Document)
▪ Part IV- Data to support product safety and efficacy (Clinical Document)
Table 13: Data to be submitted for different product category
34
RA personnel should separate apply for product registration if products come
from different manufacturer or products containing the same ingredients but made to
different specifications, in terms of strength/ content of ingredient, dosage form or
description.
Variants refer to products with differences in terms of fragrance/ flavour or
consequently colour. When variants are registered, the variants should only differ in
terms of fragrance/ flavour and colour. Product name of the variants shall remain the
same, with the addition of an identifying variant name and each variant shall be
registered as one product with a different registration number. Lastly, all data and
information including supporting documents for product registration such as
certificates, letters and product labels shall be in English or Bahasa Malaysia. RA
personnel should ensure all data requirements needed to support the application is
fulfilled before submission. Then, RA personnel submit the application of product
registration via the online QUEST system (QUEST 3+).
Secondly, screening process is done to ensure the required data or
information of the submitted application is complete. Further evaluation shall be
done after payment for the application has been made. Only a complete application
shall be accepted and approved for payment. RA personnel requested to make
payment within thirty (30) days from the date of approval for screening and
submission of hard copy documents. If the application is found incomplete during the
screening process, the application shall be rejected and the applicant shall be notified
via the system.
35
Upon confirmation of payment, the application with the submitted data shall
be evaluated. Review of applications follows a queue system. RA personnel are
required to respond to the correspondence from NPRA to submit the required
supplementary data/ information or documentation within six (6) months from the
first correspondence date.
Table 14: Timeline for product registration
36
Authority may approve or reject an application and the decision of Authority
will be sent via email/ official letter to the product registration holder. If application
is approved, product registration number (i.e. MAL number) and certificate of
registration will be sent via the system. Normally, the registration status of a product
is valid for five years. If application is rejected, RA personnel can made a written
appeal within fourteen days from the date of notification from the Authority. Then,
RA personnel should submit required additional information/ supplementary data/
documents within 60 days from the date of appeal confirmation.
Renewal of product registration
The registration of the product only valid for five years and RA personnel should
submit the renewal of product registration within six months prior to the expiry of
the validity period of a product registration, together with the appropriate fee.
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4.1.3. Quality Affairs (QA)
Quality Assurance (QA) department ensure that the product that are being
manufactured is up to the standard that had been set. Both QA and QC fall under
Quality Management and Compliance Department and both departments working
toward the same goal which ensure the quality of products are achieved. QA
department mainly have three session which are QA technical, QA operation and QA
release. QA technical personnel are responsible for product complaint and product
recall. Five reasons for product recall such as man, machine, material, method and
environment factor that cause products out of specifications. QA operation personnel
are responsible for testing sample, inspection, printed material, retained sample and
deviation. QA release personnel responsible for release the finished goods for sale
after passed the QC tests.
Validation department is part of QA department. Validation department can
further classify into qualification section, process validation section, revalidation
section and computerized system section. Qualification section personnel are
responsible for validation plan, user requirement specification (URS), functional
specification, design qualification (DQ), Installation Qualification (IQ), Operational
Qualification (OQ) and Performance Qualification (PQ). Process validation section
personnel responsible for mixing and filling validation, clean in place and standing
time whereas revalidation section personnel are responsible for sterilization in place
validation and media fill test.
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4.1.4. Quality Control (QC)
The main function of QC department is to assure the quality of all batches
manufactured, at every stage of manufacturing or processing pharmaceutical product.
This is achieved by sampling, inspection and testing on raw and packaging materials,
conduct in process quality control (IPQC) test sampling, inspection and testing on
finished products for release or rejection for further re-processing. QC department
are further divided into two sections which are microbiology testing and chemical
testing.
Microbiology testing
Microbiology personnel have 3 main responsibilities which are raw material
testing, cleanroom environment monitoring and In-process testing as well as finished
product testing for microbial contamination. For the raw material testing, active
pharmaceutical ingredients (API), water in the treatment facilities and packaging
materials are being tested. The water is tested for three times a week to ensure that
the contamination level is keep to minimum. For this kind of testing, Bioburden test
and Bacterial Endotoxin Test (BET) are carried out. Usually, the standard references
such as British Pharmacopeia (BP) and United State Pharmacopeia (USP) are used.
Each test has its own limit and the sample consider passed the test if the result is
within the limit range.
Secondly, cleanroom environment monitoring involves surface test on the
garment, finger dab test and surface test that was done on the floor, wall and
machine. The frequency of cleanroom testing is based on the products that are being
manufactured. For example, there are three types of products that are being
manufactured such as aseptic filling product, terminal sterilization product and non-
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sterile filling product. For aseptic filling product, perform testing for every batch due
to higher risk of contamination. For terminal sterilization product, it involves testing
for the BFS machine, IV bag filling machine and the filling of the syringe. The
testing interval is 2 times a week. Lastly, for filling process of non-sterile product,
the air sampling and swab test are done. The air sampling can classify into active air
sampling and passive air sampling. While passive air sampling is the “old way” and
taking a longer time (4 hour), while the active air sampling involve use of machine
that suck up the air which take shorter time about 10 minutes.
Thirdly, testing for in-process and finished product depend on the type of the
products such as non-sterile, terminally sterile and aseptic product. For the non-
sterile product, only bioburden test is performed. For the terminally sterilized and
aseptic product, it includes several steps followed by IPQC bioburden test,
sterilization process, sterility test and lastly bacterial endotoxin test.
Bioburden is the population of viable microorganism on a particular object,
formulation and/or finished product. It is the number of bacteria living on a surface
that has not been sterilized. Bioburden testing, also known as microbial limit testing
is performed on pharmaceutical products and medical products for quality control
purposes. Bioburden is generally expressed as CFU/mL (Colony Forming Units).
The purposes of bioburden testing are determine the total number of viable
microorganisms in or on a medical device, container or component after completion
of all in-process steps before sterilization and act as an early warning system for
possible production problems which could lead to inadequate sterilization or possible
product recall. Next, it tests the effectiveness of cleaning agent against bacteria and
act as an indicator of manufacturing condition. The purpose of environmental
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monitoring is to correct problems before product is placed at risk. All bioburden tests
must conform to the procedure outlines in ISO 11737. Tests must fit the basic FDA
criteria which include testing for yeast Candida albicans, bacteria such as
Escherichia coli, Pseudomonas aeroginosa, Staphylococcus aureus and fungus
Aspergillus niger.
Table 15: Recommended limits for microbial contamination
Bacteria Endotoxin Test (BET) is the test used to detect or quantify endotoxin
of gram negative bacteria origin using amoebocyte lysate from horseshoe crab
(Limulus polyphemus). There are three general techniques for this test such as gel
clot technique, turbidimetric method and chromogenic method. Gel clot technique is
based on gel formation whereas turbidimetric method is based on development of
turbidity after cleavage of an endogenous substrate. Chromogenic method is based
on development of colour after cleavage of a synthetic peptide-chromogen complex.
BET is important as it is an essential test for quality control of pharmaceutical
product and monitor product contamination during handling and processing.
Endotoxin can cause fatal if drug administered by human.
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4.1.5. Logistic, warehousing and distribution
In Ain Medicare, there are two warehouses which are raw material warehouse and
finished good warehouse. Both of the warehouses are located opposite of the
manufacturing building.
Raw material warehouse
There are total 10 workers in raw material warehouse where 8 store personnel
and 2 officers. Raw material warehouse is used for storage of raw materials and
packaging materials. But the storage of label and hologram are under responsible of
QA department. The storage of raw material and the packaging material are stored in
different places. Data loggers are used to monitor the temperature and relative
humidity for storage of raw material and packaging material. The raw material must
store at below 25℃, 60% RH. Whereas there is not strict control of temperature and
relative humidity for storage of packaging materials, store personnel still monitor
them.
There are two types of item that store in raw material warehouse, namely
direct item and indirect item. Direct item refers to the item for production uses. For
example direct items include packaging material, starting material and printed
material. Indirect item refers to items that are not directly related to the production
uses. For example indirect items include spare part for the machine and engineering
tool.
There are list of controlled raw materials that need the presence of pharmacist
when receiving them. The controlled raw materials are required to store in designated
area and only pharmacist is the key holder for them. Pharmacist need to lock and key
the controlled raw materials.
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The list of controlled raw materials:
1. Metronidazole
2. Sodium hydroxide (multi-compendiate)
3. Ciprofloxacin hydrochloride monohydrate
4. Salbutamol sulphate
5. Levofloxacin
6. Ciprofloxacin lactate
7. Fluconazole
8. Furosemide
9. Heparin sodium bovine
10. Dopamine hydrochloride
11. Lidocaine hydrochloride
12. Ipratropium bromide monohydrate
13. Ondansetron hydrochloride dehydrate
In-Coming Quality Control (ICQC) responsible for testing the samples for
approval. The testing samples further segregate parenteral items and non-parenteral
items (dialysis, irrigation solution) for testing. For parenteral items, it is compulsory
to take samples from every bag whereas samples are taken randomly from the bags
for testing non-parenteral items. ICQC take 14 days to release parenteral items and 4
days to release non-parenteral items. Hence, only raw materials that passed the ICQC
tests are allowed for manufacturing use. Raw material warehouse will supply the
requested raw materials for production site daily and dispense the raw materials
based on “First Expired First Out” basis.
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Besides that, the officers will create material pellet card via computer system
and generate the label. They also create item card before releasing raw materials for
production use.
Figure 11: Raw material warehouse
Figure 12: Raw material warehouse
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Finished goods warehouse
The finished goods warehouse is located in AIN Block 3. It is used to store
finished product, rejected product and returned product. There are total 35 workers in
finished goods warehouse and have 3 shifts (morning, afternoon and night) which
consists of 4 people in one shift. The warehouse has the capacity of holding 5000
pallets. The temperature in the warehouse is maintained at below 30℃. Data loggers
are used to monitor the temperature and they are place at 10 different places inside
the warehouse. Temperature mapping is done to determine the hot spot and cold spot.
Figure 13: Finished goods warehouse
Each pellet has different code number on it. The warehouse personnel will
pick up the selected finish goods based on the location of rack number and product
code. The finished goods warehouse in Kota Bharu, Kelantan will supply stocks for
East Malaysia including Sabah and Sarawak, Selangor, Negeri Sembilan, Melaka,
Johor, Terengganu, Kelantan and Pahang. Whereas the finished goods warehouse in
Kulim, Pulau Pinang will supply stocks to Northern region of Malaysia such as
Perlis, Kedah, Pulau Pinang and Perak.
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Besides that, the warehouse will perform pest control activity every one
month or two months. There are 5 mains pest need to be controlled such as termites,
rats, insects, flies and cockroaches. Storage of pesticide shall not be permitted in
manufacturing premises. There are procedures performing rodent and insect control.
Rodent control:
1. The “Glue Pad” shall be placed inside the Roda box for controlling the
rodents fortnightly and record shall be maintained.
2. Roda Boxes shall be inspected every week, unless a need for increased
inspections occurs.
3. In house inspection of Roda boxes shall be done by housekeeping personnel.
4. While doing the inspection, check to ensure the 18-inch border next to the
wall is clear of material. If not, remove material to maintain.
5. Rodent shall bury and records shall be maintained.
Insect control:
1. For controlling the insects, Insectocutor shall be placed at each entry point
and wherever necessary.
2. Insects controlled by electric flying insect eradicators. All lights shall be
remained on 24 hours a day.
3. Catch trays shall be emptied under electrostatic units weekly while sticky
pads should be monitored and replaced when needed.
4. The numbers of insect and their type shall be count daily and their record
shall be maintained.
5. Insectocutor try shall clean on daily basis and the killed insect shall bury &
record shall maintain accordingly.
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4.1.6. Production
Production department are responsible in manufacturing products of safety,
efficacy and quality. The manufacturing facility must follow Good Manufacturing
Practices (GMP). In Ain Medicare, majority of the sterile products being
manufactured are terminally sterilized and only a few products sterilized aseptically.
LDPE plastic is the most common plastic used in every product. Hence, recycle plant
is built in order to recycle the unwanted plastic during manufacturing process and
then reuse back the recycle plastic in the production.
The major concern in Ain Medicare is the quality of water, as water is a
vehicle that used in every product. The source of water in Kelantan is tap water
which full of minerals. Unfortunately, the water treatment water in Kelantan is a not
good compared in other states. Hence, Ain has two water treatment facilities which
locate at Ain 2 and Ain 5 and they are used to treat the tap water.
For the aseptically prepared product, the product did not go through any
terminal sterilization. This is due to the drug will degrade if it sterilize under high
temperature in autoclave. It is important to ensure no contamination during aseptic
preparation, several steps are done. Firstly, wash the vials with water for injection
(WFI) at 80℃. The inner part and outer part of the vials are spray with water when
the vials are turn upside down. Then, transfer the vial into a sterilizer. Several
processes are done in the sterilizer such as drying, heating and cooling. Secondly, it
proceeds to the filling process. The filling and the sealing are done in an isolator,
with a Grade A area and Grade B background. This process is complete
automatically. Thirdly, transfer the vials manually to the vacuum chamber to check
for any leakage after sealing. If no leakage is observed, the vials then go through
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auto-visual inspection. After that, start to pack the vials accordingly and quarantine
them until QC approved.
Manufacturing processes of INFUSOL® D10 (Dextrose 10% w/v Intravenous
Infusion BP)
Chart 4: Process flowchart of INFUSOL® D10
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It starts with calculation of batch manufacturing formula for INFUSOL® D10. To
produce 13,200 bottles of INFUSOL® D10, it needs 660.00kg of dextrose anhydrous
and 6600.00L of water for injections.
Table 16: Batch manufacturing formula for INFUSOL® D10
Section BFS 1
Tank Number 5, 6, 7 & 8
Packaging 500mL
Batch Size 6600L
Theoretical Quantity 13,200 Bottles

Grad Product Qty. per
Material Function
e Strength bottle
Dextrose Active
BP Ingredien 10% w/v 50g 660.00 kg
Anhydrous
t
Water for
Injections To
BP Solvent - To 6600.00L
(Quantity 500mL
Sufficient)
TOTAL VOLUME 500mL 6600L
Then, it proceeds to mixing process. Firstly, Water for Injections BP is filled
into the mixing tank (80% of batch size) at temperature 30 to 40°C. Then, switch
“ON” the stirrer and add material into the mixing tank and dissolve with stirring of
30 minutes at a fixed speed. Then, switch “OFF” the stirrer and add sufficient
quantity of Water for Injections BP up to the batch size. After that, switch “ON” the
stirrer and circulation pump to homogenize the solution for 30 minutes at a fixed
speed. Then, sample is collected for tank control chemical analysis.
Filter integrity test is done on the 0.22µm pore size filters using the calibrated
Filter Integrity Tester unit. For solution filtration, the solution is filtered first through
a pre-filter (0.5µm). A pair of filters 0.5µm and 0.22µm are located at mixing tank. A
final filter 0.22µm is located adjacent to the filling nozzle in filling area.
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For filling and capping process, it starts with filling into low density
polyethylene (LDPE) bottle is performed in an automatic Bottlepack machine
(Messrs Rommelag) which blows the moulding, fills and seals the low-density
polyethylene container in a single continuous operation in class 100 chamber (BFS
system) and cap is sealed immediately onto the bottle using mirror welding machine.
Sterilization is performed in a counter-pressure water cascade autoclave at 110°C ±
1℃ for holding time of 45 minutes.
After sterilization, the product is cooled to room temperature before visual
inspection is done. At the visual inspection stations/ booths, each product is
subjected to 100% visual checking for critical defects (e.g. volume inconsistency,
particle in solution, improper sealing), physical defects (e.g. damaged/folded hanger,
broken pull ring), cosmetic defects (e.g. dirty body, dented) and others defects.
After visually inspected, the containers are labeled using labeling machine.
The labeled products are packed into cartons and keep under quarantine until
released for sale by the Quality Control Department.
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4.2 Technical Contents for Hovid Berhad
4.2.1. Research and Development (R&D)
Research and Development in Hovid is known as Attest Research Sdn Bhd
which is ISO/IEC 17025:2005 certified. The establishment of a certified ISO/IEC
17025:2005 facility is important as it shows that the company`s laboratories are able
to meet all of the requirements and generate technically valid results. There are three
sub-sections which under R&D department, they are product development, stability
and method of analysis.
Product Development
The product development staffs are responsible to properly evaluated drug
and dosage form, established safety profile and assay methods of each drug, develop
quality products and elegant in design and packaging. Firstly, it starts with perform
pre-formulation studies by characterizing the physical, chemical and mechanical
properties of a new drug substance, in order to develop stable, safe and effective
dosage form. Then, it proceeds to conduct early laboratory scale batches to test the
formulation of the drugs. The laboratory scale batches maybe very small size which
is 100 or 1000 times less than production scale. These batches may find many uses,
for example to support formulation and packaging development, clinical or pre-
clinical studies. The data derived from these batches assist in the evaluation and
definition of critical product performance characteristics and thereby enables the
choice of the appropriate manufacturing process. Then, it will proceed to
optimisation stage to perform the pilot batches. Pilot batches may be used to support
formal stability studies and support pre-clinical and clinical evaluation. Its size
should correspond to at least 10% of the production scale batch that is the
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multiplication factor for the scale-up does not exceed 10. The purpose of the pilot
batch is to challenge the method purposed for routine production that is to analyse
and evaluate the difficulties and critical points of the manufacturing process and the
apparatus and methods most appropriate to large scale production.
Stability
The stability staffs mostly perform stability testing for different kind of drugs
with different dosage form such as tablets, capsule, solution and etc. In Hovid, they
follow Asean Guideline on Stability Study of Drug Product for stability study. The
objective of a stability study is to determine the shelf-life, namely the time period of
storage at a specified condition within which the drug product still meets its
established specifications. The general conditions for long term stability testing in the
ASEAN region are the Zone IVb conditions (30°C/75% RH). According to the
ASEAN guideline, for Generics and Variations the following will apply:
• For conventional dosage forms (e.g., immediate release solid dosage forms,
solutions) and when the drug substances are known to be stable, stability data
on at least two pilot scale batches are acceptable.
• For critical dosage forms (e.g., prolonged release forms) or when the drug
substances are known to be unstable, stability data on three primary batches
are to be provided. Two of the three batches should be at least of a pilot scale;
the third batch may be smaller, if justified.
Besides that, different test parameter are conducted that susceptible feature of
drugs to change during storage and likely to influence the quality, safety and efficacy
of the product. The test parameter includes physical properties of the product,
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organolepticproperties (taste, odour), active ingredient content and formation of toxic
degradation products and microbial properties. Different dosage forms have different
test parameter need to be conducted.
1. Tablets
It evaluated for appearance, odour, colour, assay, degradation products, dissolution
(or disintegration, if justified), water content, and hardness/friability.
2. Capsules
Hard gelatin capsules should be evaluated for appearance (including brittleness),
colour, and odour of content, assay, degradation products, dissolution, water content
and microbial limits.
Testing of soft gelatin capsules should include appearance, colour, and odour of
content, assay, degradation products, dissolution, microbial limits, pH, leakage, and
pellicle formation. In addition, the fill medium should be examined for precipitation
and cloudiness.
3. Emulsions
It evaluated for appearance (including phase separation), colour, odour, assay,
degradation products, pH, viscosity, microbial limits, preservative content, and mean
size and distribution of dispersed globules.
4. Oral Solutions and Suspensions
It evaluated for appearance (including formation of precipitate, clarity for solutions),
colour, odour, assay, degradation products, pH, viscosity, preservative content and
microbial limits.
Lastly, the staffs will include all the test parameter for different drugs inside
the stability data of each drug. For the duration of stability trials, Hovid required to
submit 3 months accelerated data (45-50°C/75% RH ±5% RH) or 6 months
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accelerated data (40°C/75% RH ±5% RH) and a commitment letter to submit real
time stability data once available is required to claim for 3 years shelf life.
Table 17: Stability study perform in Hovid
Study Storage condition Testing Frequency
Long term 30°C ± 2°C/75% RH ± 5% RH 0, 3, 6, 9, 12, 18, 24 months
and annually through the
proposed shelf-life
Accelerated 40°C ± 2°C/75% RH ± 5% RH 0, 3 and 6 months
Stress testing 40°C ± 2°C/75% RH ± 5% RH or at -
more stressful conditions
Method of analysis
The staffs will in charge of Analysis Requirement Form whenever develop a
new product or a new formulation. The internal code number for this form is AS-
F044. Inside the form, various tests are available such as hardness test, dissolution
tests, disintegration test, check physical appearance of the products and etc. Only
selected tests are performed based on nature of the product. The analysis requirement
form can further divide based into their dosage form such as tablet, liquid and others
(granules, dry powder, effervescent, capsules and external). There are three
departments who keep the Analysis Requirement Form for each product such as
Method of Analysis, Stability (R&D) and QA. Only Method of Analysis who keep
the real copy.
Analysis Requirement Form for new products include following records:
a. Name of product
b. Generic name
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c. Name and strength of active ingredient
d. Reference for specification
e. Proposed storage condition
f. Proposed pack size
g. Proposed shelf life
h. Parameter to be monitored
There are total 282 of in Hovid Berhad. It is advisable to check the expiry
date for each CRM through the website of BP, USP and EP every two months to
ensure the validity of CRM. It is important to check the validity of CRM so that the
expired CRM can be purchase soon without delaying the analytical works. The batch
number of each CRM in Hovid is according the batch number of USP, BP and EP.
The USP website shows the expiry date and the price of every batch of CRM
whereas BP website does not show the expiry date of the batch of CRM as it only
updates the current batch with new code. If new code of certain CRM is observed, it
indicates the previous batch of CRM has been expired.
Next, new CRM or Internal Reference Materials (IRM) is used to replace
expired CRM or IRM. There are few steps to follow when filling new CRM or IRM
into the separate small vials. First, search the old usage record for the expired IRM
and replace it with new IRM usage record. Then, fill in all the details and
information regarding the IRM. Start to transfer the new IRM into separate small
vials. Usually, the new IRM can transfers approximately 30 small vials and then
prepare the label for each vials. Lastly, dispose the expired CRM or IRM into the
solid waste container which will collect by Quality system. The usage records for
expired CRM or IRM need to be kept in the file of ‘Expired IRM or CRM’.
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Figure 14: CRM usage records
Next, it is compulsory to have Certificate of Analysis for all IRM used in
Hovid. The importance of Certificate of Analysis for each IRM is to ensure the IRM
follow the specification listed by BP standard or in-house standard. Certificate of
Analysis include the information such as drug name, batch number, certificate
number, date of standardization, expiry date, storage condition, tests, assay method
reference, specification reference and direction of use. Each IRM has its own date of
standardization and expiry date, it is necessary to restandardise the IRM once it
expired.
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Figure 15: Certificate of Analysis of IRM (Terbutaline Sulphate)
Moreover, staffs under method of analysis follow ICH Harmonised Tripartee
Guideline on Validation of Analytical Procedure: Text and Methodology Q2(R1) in
order to validate the analytical procedure that carried out. The objective of validation
of analytical procedure is to demonstrate that it is suitable for its intended purpose.
There are four common types of analytical procedures to be validated, for example
identification test, quantitative tests for impurities’ content, limit tests for the control
of impurities and quantitative tests of the active moiety in samples of drug substance
or drug product or other selected components in the drug product. Typical validation
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characteristics which Hovid are performed in R&D department are accuracy,
precision (repeatability, intermediate precision), specificity, detection limit,
quantitation limit, linearity and range.
Figure 16: Result for precision for Rosuvid 20mg tablet
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4.2.2. Regulatory Affairs (RA)
Application for renewal of manufacturer’s license (QUEST 3+ system)
For renewal application of manufacturer license, the regulatory affair (RA)
personnel will submit the form 4 months before the expiry date year. RA personnel
start to collect the required documents from relevant departments before submitting
to NPRA and monitor the progress until obtain the approval.
The documents required are:
1. Copy of company/business registration certificate
2. Copy of business license for premise and store
3. Applicant/license holder identity card
4. Copy of annual retention certificate and type a license for premise and store
address
5. Previous manufacturing license
Then, RA personnel complete all the documentation and submit the
application form on QUEST3+ system. All the documents are filed as reference in
the allocated file. RA personnel shall submit the correspondence reply before the
deadline given. Normally the application is estimated to be approved 21working days
from the date of complete submission and the result will be notified via QUEST3+
system. Once the result is released, RA personnel shall collect original License
Certificate from Centre of compliance counter and check the appropriateness of
information stated in the certificate within 7 working days. Any mistake in the
certificate cannot be amend or change after this period. RA personnel will request
and notify CCL officer to do amendment if any misplace and/or missing information.
59
If information stated in the certificate is correct, RA personnel will make photocopy
of license and submit certified true copy to CCL officer. CCL officer will frame the
original certificate of license for display. The final step is RA personnel will file the
copy of the license accordingly in Lesen Pengilangan folder and record in Senarai
Produk Pengilangan & Import Tracking File.
Figure 17: Manufacturing licence for Hovid Berhad
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Handling of sample for post market surveillance
Post marketing surveillance is the practice of monitoring the safety of a
pharmaceutical drug after it has been released. Therefore, RA personnel are
responsible to liaise with NPRA and submit necessary sample or documents such as
protocol of analysis (PoA) and certificate of analysis (CoA) to NPRA. There are two
methods for NPRA to request for post market surveillance sample:
1. Sampling of products by local enforcement officers
2. NPRA official letter requesting for samples
1. Sampling of products by local enforcement officers
The local enforcement officers will enter the premise to collect sample. RA
pharmacist should accompany and guide the local enforcement officers. If in case
absence of RA pharmacist, RA personnel with any pharmacist should assist the
officers. For the sample picking for export stock, RA pharmacist should guide officer
to take Malaysia stock. If not, RA pharmacist should write a letter of explanation to
inform NPRA. For the sample picking for Malaysia stock, the sample should be
sealed in box. RA personnel shall submit the samples and required documents to
NPRA within 5 working days from the date of sampling. Next, RA personnel will fill
up NPRA form and Hovid PMS sample form and file up all submitted documents.
They timely provide additional information or related documents or reference
standard to NPRA when requested. Lastly, RA personnel will check and update
packaging and PoA in NPRA Quest system within 3 working days of after
submission.
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2. NPRA official letter requesting for samples
Upon received official letter from NPRA to request for samples, RA personnel
should provide acknowledgement receipt to NPRA within 3 working days. Then, RA
personnel will check and request for the product samples requested from the logistic.
The RA personnel will request coa and poa from QC department for the batches of
samples available. If the sample is not available, RA personnel will submit a formal
letter to request extension from NPRA. All copies of poa and coa to be submitted
should be filed in PMS file for record. RA personnel must submit samples, poa and
coa to NPRA within 2 weeks upon receipt of letter. Next, RA personnel will fill up
NPRA form and Hovid PMS sample form and file up all submitted documents. They
timely provide additional information or related documents or reference standard to
NPRA when requested. Lastly, RA personnel will check and update packaging and
PoA in NPRA Quest system within 3 working days of after submission.
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Chart 5: Flowchart of handling of sample for post market surveillance
Handling of product discontinuation in Malaysia
Products may be discontinued due to marketing reason or regulatory reason.
It starts with RA personnel review the product list with RA manager two years
before the expiry date of the marketing authorization, the sales data or relevant
information such as stability, bioequivalence for particular product. RA personnel
will email to all relevant department of potential product discontinuation. Then, RA
personnel will highlight the products to be discontinued to management for decision.
There are three criteria to make decision which are sales history data, financial
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information and back order / pending order for the product. They are three types
product discontinuation:
1. Maintain in Malaysia
2. Discontinued in Malaysia but maintain for export
3. Discontinued in both Malaysia and overseas
If it is decided that marketing authorization for the product should be maintain in
Malaysia, RA personal will coordinate with all departments to fulfill the registration
requirements.
If it is decided that marketing authorization for the product should be
discontinued in Malaysia and maintain for export, RA personnel apply FEO license
for export and send official letter to NPRA to discontinue the product and request for
grace period to exhaust the stocks in market. Next, RA personnel issue a memo via
email to all relevant departments and raise change control. Each department shall
take all necessary actions.
If it is decided that marketing authorization for the product should be
discontinued in both Malaysia and overseas after license expiry date in Malaysia, RA
personnel shall send official letter to NPRA to discontinue the product or allow the
marketing authorization lapse on its own. Next, RA personnel issue a memo via
email to all relevant departments and raise change control. Each department shall
take all necessary actions.
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Chart 6: Flowchart of procedure for handling of product discontinuation in Malaysia
65
4.2.3. Quality Affairs (QA)
The roles of QA in Hovid Berhad is to ensure the quality system of company
in line with PIC/s GMP guideline. QA department also play a role in overseeing the
overall quality system of company and timely recommend ideas to improve the
current operating procedures. In fact, both Quality Assurance Department and
Quality Control Department are under Quality Department. The Quality Assurance is
headed by Quality Assurance manager whereas Quality Control Department is
headed by Senior Quality Manager; and both managers are directly reporting to
Operations Manager. The Quality Department is independent from production site so
that they can make decisions without influence or pressure from production site.
Document system
The documentation system in Hovid ensure that the documents’ format and practices
are complying with PIC/s GMP guidelines and Good Documentation Practice. QA
personnel responsible to review the documents regularly reviewed and kept them up-
to-date. In Hovid, they implement 5 tiered structure of document management
system.
Figure 18: 5 tiered structure of document management system in Hovid
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The highest level (eg Level 1) indicates that the documents are less accessible to user
and more controlled whereas the lowest level (eg Level 5) indicates that the
documents are more accessible to user and less controlled. The minimum
requirement of approval for different types of document is different for different
levels such as level 1 to 5.
Table 18: Minimum requirement of approval for different types of document in
different levels
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The documents are classified as:
1. Master copy
The original hard copy of the current version of document that shall be
approved and signed by authorized personnel.
2. Reference copy
Uncontrolled document that shall not be subjected for updating and
distribution when a new revision is released.
3. Controlled copy
Controlled document generated from Master Copy that shall be subjected to
automatically update when a new revision is released. It shall be tracked,
updated and destroyed to assure that it is current.
4. Obsolete copy
A document that has been superseded and will never be used again.
Once the document is approved, QA clerk will print the copy and stamp
“MASTER COPY” in red ink on every single page for first printed copy. Then, QA
clerk will enter document details into the relevant document register including title,
code and revision number, effective date and review date. If a document is changed
or revised each time, the details of changes must be recorded in the history of change
section of the document.
QA personnel will distribute copies of a document and stamp with
“CONTROLLED COPY” in red ink on every page of the document to all concern
person. Each controlled copy of SOP has dedicated number for stamp and it is based
on distribution location. All the distributed copies must record in Document
Distribution List in order to allow traceability for previous version of controlled
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copies from each department. Duplicate Document Request form is filled when
additional copies of documents are required.
For obsolete or discontinued document, QA personnel will stamp the
document as “OBSOLETE, REFER TO THE LASTEST VERSON” in red ink on the
title page to avoid confusion and to prevent unintended use. QA personnel withdraw
the controlled copies that issued to relevant departments.
QA personnel are responsible to keep and lock all master copy documents in
document room at Chemor Plant. All original copies of all controlled documents that
have been superseded are retaining in archive room for a retention period of 2 to 10
years according to the category of documents.
Handling of product complaint
It starts with customer lodges a complaint to Hovid representative
(sales/marketing/RA department). Then, the complaint form should submit to QA
department within 2 working days upon filling up the form. QA personnel will assign
a complaint number to the form once receive it. In Hovid, the complaints are
classified as:
1. Quality complaint: Includes all complaints pertaining to physical, chemical
or biological properties of the product or condition of its packaging.
2. Non-Quality complaint: Other than mentioned complaints such as slow
delivery.
3. Adverse Reaction complaint: Allergic or any other untoward reactions,
toxic reactions, fatal or nearly fatal reactions, nausea, dizziness or any other
disease due to the consumption of product.
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4. Counterfeit/Suspected counterfeit product complaint: A product which is
deliberately and fraudulently mislabeled with respect to identity and/or
source. Counterfeit product includes product with wrong ingredients, without
or insufficient quantity of active ingredients, and fake packaging.
5. Medically Related complaint: Lack of efficacy of clinical response.
After that, QA department will perform risk assessment as per clause where
the risk rating is categorized into critical, major and minor. QA personnel provide
interim reply within 5 days and done full investigation within 14 days and reply to
customer once completed the investigation. If the risk is critical, actions such as
product recall or field corrective action are taken. QA personnel performed follow up
on-site verification audit, data review and trending, validation to verify and monitor
the effectiveness of the correction, corrective action or preventive action. RA
department are responsible for adverse reaction and medicinal related complaint. QA
personnel reply to the respective customer in written notification to address the status
of the complaint accordingly. The complaint is “invalid” if the complaint description
is not matching with evaluation outcome or the complaint is due to improper
handling/storage by customer. The complaint is “valid” if the complaint description
is matching with the evaluation outcome or the non-conformance.
Handling of product recall
Product recall is a process taken by the manufacturer, importer, distributor
and wholesaler to remove or withdraw a particular product and/or cosmetic from all
links of distribution. The removal or withdrawal may be due to critical quality
defects discovered or serious adverse drug reactions reported or identity which might
cause health risks to users of the materials and/or products.
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Degree of recall is classified according to severity of quality defects or adverse
reactions.
Table 19: Degree of recall
Degree of Recall Description
Degree I Product are potentially life threatening or could cause a

serious risk to health upon consumption, it should be under
embargo within 24 hours.
Example : label and contents are different products
Degree II Product could cause illness or mistreatment upon

consumption, but are not degree 1 or are substandard. It
should be under an embargo within 72 hours.
Example: missing or wrong text figures in label
Degree II Product may not pose a significant health hazard to health

upon consumption, but withdrawal may be initiate for other
reasons. It should be under embargo within 30 days.
Example : faulty closure of the product
The level of recall depends on the nature of problem, extent of the material or
product distribution and degree of hazard involved.
• Level A: To all consumers
• Level B: To all points of sale
• Level C: To all sub-distributer
Hovid will conduct mock product recall once per year if no product recall
undertaken within the last one year. QA manager will select a particular batch of a
product for the initiation of the recall. Inventory record and stock statement are used
71
by logistic and Hovid Pharmacy branches to trace particular batch of the affected
product and locate the affected batch has been distributed to. QA department will
collect the stocks statement and perform reconciliation of the affected batch, finally
produce a summary report about it.
Procedure of handling product recall:
1. Customer complaint or internal or laboratory findings.
2. Initial risk assessment by QA within 3 days.
3. If no potential hazard exists and violate to marketing authorization, handle
internally according to respective SOP.
4. If potential hazard exists and violate to marketing authorization, pharmacist
should evaluate the health hazard within 3 days.
5. Escalate to senior management within 3 days and management will evaluate.
6. If no significant risk, handle internally according to respective SOP.
7. If presence of significant risk, management make a decision to recall and
determine degree and level of recall. At the same time, it is important to
determine degree and level of recall when handle government directive recall
from regulatory notification.
8. Notify relevant authority by sending interim report, recall notice and stock
statement.
9. Identify and locate products subject to recall.
10. Immediate detain or quarantine are done if stock within company control.
11. Implement strategy of recall if stocks are not within company control. Start to
prepare distribution list and issue recall notice and recall acknowledgement
form to sales representative.
72
12. Contact customer for removal of product from market back to ASRS
warehouse.
13. QA perform reconciliation, inspection and investigation.
14. Dispose products and submit report to authority.
Product release
QA department ensure the finished products fulfil required criteria before
releasing from inventory system. QA personnel will use the specific checklist to
assist the review process of batch manufacturing and batch packaging record and the
finished products in order to ensure fulfilment of criteria. QA manager has authority
to release or reject finished product. QA personnel should report to QA manager if
detect any non-conforming product.
Minimum criteria need to fulfil before releasing finished products:
• All records have been properly reviewed and approved by authorized
personnel.
• Every step for the manufacturing process has been carried out accordingly to
the procedures, specifications and working operations as stated in the BMR
and BPR
• All In-Process Quality Control (IPQC) results are within the set
specifications.
• Proper review of the out of specification data and justification has to be noted
by authorized personnel. All deviation records shall be properly recorded,
reviewed and approved by the Head of Department from Production or
Production Pharmacist, R&D (when necessary) and Quality Assurance
department.
73
• Yield of each stage of manufacturing process has been confirmed satisfactory
and in the event of any deviation from normal yield has been justified and
explained.
• Reconciliation of all packaging materials has been confirmed satisfactory and
in the event of any discrepancy has been justified ad explained.
• Quality control record of protocol of analysis has been reviewed and
conformed in compliance with specifications
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4.2.4 Quality Control (QC)
QC personnel responsible to conduct QC test for the finished products and IPQC test
for intermediate products. Besides that, QC personnel ensure that the incoming raw
materials pass the specifications before using for manufacturing process. The
laboratory set up in Hovid comply Good Laboratory Practice guideline. There are
SOP for operating equipment and SOP for cleaning equipment. QC personnel must
ensure the equipment such as weight balance should be calibrated. All tests
conducted should follow British Pharmacopoeia (BP) and United State
Pharmacopoeia (USP).
IPQC tests
IPQC tests are performed at regular intervals (generally each 1 hour later) during the
manufacturing process. The functions of IPQC are monitoring and adaption of the
manufacturing process in order to comply with the specifications as well as control
of equipment and environment. The identity, strength, quality and purity of in-
process materials should be tested. The QC unit should approve or reject in-process
materials during the production process. Identify rejected in-process materials and
control them under a quarantine system designed to prevent their use in
manufacturing. Standard operating procedures (SOPs) should be established in the
pharmaceutical industry and followed that describe the IPQCs and tests.
IPQC tests for tablets:
1. Hardness test
Hardness generally measures the tablet crushing strength. It determines the need for
pressure adjustments on the tableting machine. Disintegration is affected by
hardness. The tablet may not disintegrate in the required period of time if it is too
75
hard. Oppositely, the tablet will not withstand the handling during subsequent
processing such as coating or packaging if it is too soft. The limits for hardness test
are 5 kilograms minimum and 8 kilograms maximum.
2. Friability Test
Roche friabilator is used to determine friability of a tablet.
Procedure:
For this test, twenty tablets are weighed and placed in the friabilator and then
operated at 25 rpm for 4 minutes. The tablets are then dedusted and weighed. The
difference in the two weights is used to calculate friability. It is determined by the
following formula:
Friability = (Iw – Fw)/Iw × 100%
where, Iw = Total Initial weight of tablets; Fw = Total final weight of tablets.
As stated by USP if conventional compressed tablets that loss less than 0.5 % to 1 %
(after 100 revolutions) of their weight are generally considered acceptable.
3. Disintegration test
It is a measure only of the time required under a given set of conditions for a group
of tablets to disintegrate into particles. Controlled and sustained release tablets
cannot perform this test. The U.S.P device to test disintegration uses 6 glass tubes
that are 3 inches long, open at the top, and held against a 10 mesh screen at the
bottom end of the basket rack assembly.
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Procedure:
To test for disintegration time, one tablet is placed in each tube , and the basket rack
is positioned in a 1L beaker of water, simulated gastric fluid and at 37°±2°c ,such
that tablet remains 2.5cm below the surface of the liquid on their upward movement
and descend not closer than 2.5cm from the bottom of the beaker. A standard motor
driven device is used to move the basket assembly containing the tablets up and
down through distance of 5 to 6cm at a frequency of 28 to 32 cycles. The tablet
complies with the test, if the tablets disintegrate, and all particles pass through the
10-mesh screen in the time specified. If any residue remains, it must have a soft mass
with no palpably firm core. The tablet complies with the test according to USP, if all
of the tablets have disintegrated completely. If 1 or 2 tablets fail to disintegrate
completely, repeat the test on 12 additional tablets. The requirement is met if not less
than 16 of the total of 18 tablets tested are disintegrated.
Table 20: USP limits for disintegration times of tablets
4. Dissolution test
Dissolution is performed to check the percentage release from the dosage forms from
the tablet. When tablet disintegrate it breaks down into small particles which offers a
greater surface area to the dissolving media and drug will dissolve.
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USP Dissolution Apparatus I (Paddle method)
It consists of a cylindrical vessel with a hemispherical bottom, which may be
covered, made of glass or other inert, transparent material; a motor; a metallic drive
shaft; and a cylindrical basket. A single tablet is placed in a small wire mesh basket
attached to the bottom of the shaft connected to a variable speed motor. The basket is
immersed in a dissolution medium (as specified in monograph) contained in a 1L
flask. The flask is maintained at 37°±5°c by a constant temperature bath. The motor
is adjusted to turn at the specified speed and sample of the fluid are withdrawn at
intervals to determine the amount of drug in solutions.
Table 21: USP dissolution acceptance criteria
5. Weight Variation Test
According to the USP weight variation test, it is weighing 20 tablets individually
calculating the average weights and comparing the individual tablet weights to the
average. The value of weight variation test is expressed in percentage. The following
formula is used:
Weight Variation = (Iw – Aw)/Aw × 100%
where, Iw = Individual weight of tablet; Aw = Average weight of tablet.
78
As per USP the tablet complies with the test if not more than 2 of the individual
masses deviate from the average mass by more than the percentage deviation and
none deviates by more than twice that percentage.
Table 22: USP limits for weight variation test for uncoated tablets
6. Thickness
The thickness of a tablet is the only dimensional variable related to the process.
Thickness of individual tablets may be measured by a micrometre. Other techniques
involve placing 5 or 10 tablets in a holding tray, where their total thickness may be
measured by a sliding calliper scale. Tablet thickness should be controlled within a ±
5 % variation of a standard. Thickness must be controlled to facilitate packaging. It is
expressed in mm.
7. Uniformity of Content
A physically sound tablet may not produce the desired effects. To evaluate a tablet
potential for efficacy, the amount of drug per tablet needs to be monitored from
tablet to tablet and batch to batch.
Procedure:
According to BP, determine the individual contents of active substance(s) of 10
tablets taken at random. The tablet complies with the test if each individual content is
between 85% and 115% of the average content. The tablet fails to comply with the
test if more than one individual content is outside these limits or if one individual
content is outside the limits of 75% to 125% of the average content. If one individual
79
content is outside the limits of 85% to 115%, but within the limits of 75% to 125%,
determine the individual contents of another 20 tablets taken at random. The tablet
complies with the test if not more than one of the individual contents of the 30 tablets
is outside 85% to 115% of the average content and none is outside the limits of 75%
to 125% of the average content.
80
4.2.5. Logistic, warehousing and distribution
There are two warehouses in Hovid, one warehouse in Chemor that
implement ASRS (Automated storage retrieval system) and another warehouse in
Ipoh site where traditional warehouse is adopted.
Receipt and storage of raw materials and packaging materials
There are certain criteria need to be fulfilled for truck when receive packaging or raw
materials from the transporter.
• Truck is fully covered and closed.
• Truck is clean and ensures no dirt or debris.
• No evident of chemical spills, garbage, waste.
• No bad odor.
All raw materials and packaging materials should come from approved supplier,
otherwise quarantine the materials from unapproved supplier and inform warehouse
executive or warehouse pharmacist immediately. Reject the shipment on the spot if
posing high risk of contamination to the packaging or raw material and inform to
warehouse executive or warehouse pharmacist and QA personnel.
Next, the store assistant will conduct second checking and inspection as per
following criteria:
• Name and description of packaging or raw material
• Packaging or raw material is delivered from approved supplier
• Check against the P.O number in the delivery order
• Quantity received
• Supplier’s label on packaging, batch number and expiry
• Certificate of Analysis
81
• Overall condition of the material packaging
• No evidence of items that could contaminated the materials being received
Store assistant can reject any raw material on the spot if detect any damage
packaging, sign of contamination, broken seal, leaking, spillage, bag that is torn,
metal cover and closure ring rusty or damaged wet and dirty.
Next, store assistant starts to unload the packaging or raw material in
designated unloading area and then unload them onto clean pallet, lastly clean the
material container with 70% IPA. Store assistant will stamp, date and sign all copies
of the delivery order (DO) and return the duplicate copy to transporter. DO will
further submit to warehouse executive or warehouse pharmacist to maintain receipt
in stock control system. QC personnel are responsible to produce certificate of
analysis for the received raw material.
Besides that, the store assistant will re-palletize and segregate the packaging
or raw material received according to item codes onto the pallet. Maximum of four
item codes only can be place on a standalone pallet and segregate it by partition. The
store assistant transfer re-palletizing material to designated quarantine area and paste
the printed “Quarantine” sticker on the materials received on the same day.
Figure 19: “QUARANTINE” sticker for packaging and raw material
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Warehouse pharmacist should be presence when receiving and storage of
Kementerian Kesihatan Malaysia (KKM) controlled raw material. In the case where
warehouse pharmacist is not available, any pharmacist available in the Hovid can
accompany the receiving process. The examples of KKM controlled raw materials
are Dextromethorphan HBM, Pseudoephedrine HCL, Ephedrine HCL, and
Pholcodine. Warehouse pharmacist will check and verify the weight of controlled
raw material and paste “QUARANTINE” label onto it. Warehouse pharmacist will
store the controlled raw material in control cage and lock it securely.
Next, some sampling from quarantined materials will send to QC department
for testing purpose. The store assistant will store the raw material once it passed the
QC test. Store assistant will scan the storage location barcode followed by raw
material barcode and the information will store in computer inventory system
automatically. It is important to ensure the location scanned is tally with the physical
storage location. Lastly, paste “PASSED” label onto the pallet of passed raw material
before storing them.
Figure 20: “PASSED” sticker for packaging and raw material
83
QC personnel will send rejection memo to notify store assistant if the raw
material fail the QC testing and responsible to paste the “REJECTED” sticker onto it.
QA executive who is the key holder for rejection cage, allow transfer of rejected
material into the cage and lock it. QA executive will update the Reject Cage List to
notify the users from further using of rejected material.
Figure 21: “REJECTED” sticker for rejected material
When the material is expired and require being retest, it will be label with
“EXPIRED/RETEST MATERIAL". Then, wrap it securely with stretch film and
send to expire or retest cage. Warehouse executive or warehouse pharmacist will
update the expired or retest cage list later. Meanwhile, when materials are required to
write off, the store assistant retrieve “Pending Write Off Materials” from the storage
location and transferred the materials to the reject cage. If the reject cage is full,
cover the pending write off material with netting and label it as “ON-HOLD”.
Figure 22: “ON-HOLD” sticker for pending write off material
84
Relative humidity and room temperature monitoring in warehouses
All the raw material and finished products should be store in proper room
temperature and relative humidity to ensure the stability and quality of materials and
finished products. In hovid, Digital Thermo Hygrometer is used to monitor relative
humidity and temperature of warehouse and containers. Store assistant will check the
hygrometer twice per day for cold room and once per day for other warehouses and
controlled environment containers, and record all the readings into the logbook. Store
personnel also need to record readings into the logbook when load or unload stocks.
Table 23: Requirement of temperature and relative humidity control for warehouse
and container.
Store personnel shall notify QA department when temperature or relative
humidity is found to be out of specification so that immediate action can be taken to
correct the situation. Store personnel should check the setting of air-conditioner for
warehouse and adjust the setting accordingly, then submit the deviation or incident
report form to QA department for further action.
85
When there is power failure or the specifications are out of the limit during
weekend, an alarm system will trigger to Hovid’s security guard and they will
contact logistic manager, warehouse pharmacist or warehouse executive. In case of
power failure, warehouse executive should write deviation or incident report and
contact facility department for remedial actions to solve the problem.
Issue of raw material
Production clerk will key in the raw material required by production into the
computer system. Then, the store assistant will pick up the requested raw material
from the specific storage location and the material is dispensing based on “First
Expired First Out”. They will clean the outer surface of drums, carton, canister or
bag that filled with raw materials before sending it to staging area of production.
Store personnel will measure the gross weight of raw materials. The dispensing team
from the production will collect the raw material at staging area and transfer them
into dispensing area for dispensing. After dispensing, the balance of the raw material
in the container will be returned back to raw material store. Store assistant must
ensure that the remaining quantity in the container is properly packed and sealed with
cable tie to prevent from exposed to contamination. They also weigh the gross
weight of all returned raw material. The weight variation should not greater than 2%,
if not store assistant should further clarify from the production site.
Stock check and reconciliation
Store assistant will perform stock check and reconciliation for cyclical stocks
once a week. Only 10 cyclical stock items based on alphabetical order will be
selected. After completion of stock check, return stock check form to logistic office
and warehouse pharmacist or warehouse executive will verify, reconcile and adjust
86
the stock on the same day of stock count process. The logistic manager will call for
recount or investigation if variances are more than 2% and the stock reconciliation
and adjustment can be done after the investigation completed. The following results
are record in stock check form and adjust stock check differences in the stock ledger.
87
4.2.6. Production
Various products are produced In Hovid such as solution, emulsion,
suspension, tablets, capsules and herbal teas. The production team places utmost
priority and care on the medicines that are made to ensure all patient`s get best
possible care. This is possible by complying with international guidelines such as
ISO 9001, PIC/S, cGMP and GLP.
Chart 7: Manufacturing flow of solid dosage form products
88
Dispensing
It is important to dispense the right materials to the right batches prior to the
manufacturing process. The production personnel pre weigh materials to avoid
weighing errors and to assure rapid delivery at the critical stages of the drug
formulation process. Three basic principles for design of pharmaceutical weigh room
that are unidirectional flow of materials and personnel, segregation between
hazardous and non-hazardous materials and separation of storage and manufacturing
items and spaces.
Dispensing Process Flow
1. Create a batch.
2. Create detailed reservation for material that must be dispensed.
3. Acknowledge the defined instructions.
4. Weigh materials.
5. Perform dispensing.
6. Obtain electronic signatures.
7. Print labels.
Granulation
Granulation is the process in which primary powder particles are made to
adhere to form larger, multi- particle entities called granules, which is usually 0.2 -
4.0 mm in diameter. It is the process of collecting particles together by creating
bonds between them. Bonds are formed by compression or by using a binding agent.
Granulation is extensively used in the manufacturing of tablets and pellets. The
advantages of granulation are:
89
• It improves flow property and compression characteristics and increases
density of granules.
• Better distribution of colour and soluble drug if added in the binding solution.
• It reduces dust hazards.
• Prevents segregation of powders.
There are two granulation methods such as dry granulation and wet
granulation. Dry granulation methods mean that powder particles are aggregated
under high pressure. The dry granulation process is use to form granules without
using liquid solution because the product to be granulated may be sensitive to
moisture and heat.
Steps in dry granulation:
1. Mixing
2. Compaction of powder
3. Milling
4. Screening
Wet granulation involves the massing of a mix of dry primary powder particles using
a granulating fluid. The fluid contains a solvent which must be volatile so that it can
be removed by drying. Typically liquid used include water, ethanol or isopropanol
either alone or in combination.
Steps in wet granulation:
1. Mixing of the drug(s) and excipients
2. Mixing of binder solution with powder and form wet mass
3. Coarse screening of wet mass using a suitable sieve.
4. Drying of moist granules.
5. Screening of dry granules through a suitable sieve.
90
Mixing
Mixing is defined as shuffling type unit operation process involving both
large and small particle groups and even individual particles. The purpose of mixing
is to allow random distribution of particles. There are parameters that affect efficient
mixing are:
a) Particle parameters. (eg: particle size, particle shape, size distribution, particle
density, cohesivity, hygroscopicity and hardness)
b) Type of mixer: Speed, time, batch volume and movement
c) Segregation tendency of individual components based on density difference
Compression
Compression means that granules are being compressed into tablets and eject from
the die. Then, samples are collected and send for IPQC testing. The compressed
tablets should comply specifications in order to continue the compression process. In
Hovid, rotary type compression machine such as Fette, Narong and Manesty are used
for large scale tablet manufacturing. The main components of a tablet compression
machine are the dies which hold a measured volume of material to be compressed,
the upper punch which exerts pressure on the down stroke and the lower punch
which control the volume of die fill and tablet weight. Different tablets require
different punch size and the production personnel will change the pinch size
accordingly based on product specification.
91
Coating
There are various reasons of coating tablets such as protection of the
ingredients from air, moisture or light, protect the drug against decomposition and
mask the unpleasant taste of drug. Coating also enhances the appearance of tablets
and makes them more readily identifiable. Factors that affect tablet coating are such
as coating process, drying time, storage and environment monitoring. There are three
types of coating done in Hovid such as film coating, sugar coating and enteric
coating. The tablet coating equipment and machines used are coating pan, pan motor,
spray gun, blower with heater and exhaust pipe. At the end of coating process, some
samples are selected and send for IPQC testing. The results should follow the
specifications stated in order to continue the packaging process.
Tablet Coating Process:
1. Preparation of coating solution by mixing the coating ingredient in powdered
form in water or organic solvent depends on the nature of ingredient. The
solution is prepared in stainless steel drum in the coating solution preparation
room.
2. After preparation, the coating solution is transferred to a spray gun through a
pipe to apply on tablets in the pan.
3. The tablets to be coated are placed in coating pan and the rotation and
temperature of pan is adjusted as per specifications. Blower is provided to
blow compressed to blow compressed air so that the solution can be applied
easily and moisture is removed. Exhaust pipe helps to remove the compressed
air and to maintain the pan temperature.
92
4. Spraying of coating solution on the tablets in the pan through a spray gun
where the spray rate, pressure, temperature as well as the rotating speed is
controlled.
5. Drying is simply done in the same rotating pan by supplying compressed hot
air to the coated tablets which requires few hours.
6. Send the samples to Quality Control laboratory to check the proper coating
and amount of coating material is applied to the tablet. If Quality Control
department approves the batch of tablets then the process is continued for
packaging.
Encapsulation
Encapsulation is the process of closing the body and cap of the capsule together.
There are two types of capsules which are hard gelatine capsules and soft gelatine
capsules. In Hovid, both hard and soft gelatine capsules are used to fill medicine.
Capsule filling machines employed in Hovid are fully automated which are high
efficiency, easy maintenance and operation. Examples of fully automated capsule
filling machine are Bosch Capsylon, Ptam 40 and Ptam 90. These machines make
various sizes of capsules. Bosch Capsylon capsule filling machine can produce a
maximum of 42,000 capsules per hour.
Capsule filling process:
1. Empty capsules and powder to be filled are placed at respective feed
provided.
2. Capsule undergoes alignment and separation into a body part and cap part.
3. Separation of two segments whereby upward movement of cap segment and
forward movement of body segment to the dosing station.
93
4. In dosing station, powders are filled into the body part of capsule via a fixed
or height-adjustable dosing disk.
5. Body segment moving and alignment.
6. Extraction for non-open capsules which are automatically rejected and
extracted so that these faulty capsules are removed from the flow of good
capsules prior to the ejection station.
7. Uniting of the segments in which downward movement of cap segment and
backward movement of body segment.
8. Capsule closing station. The closing station is just after the filling station to
ensure minimal product loss from overfilled capsules.
9. Capsule ejection of filled capsules into a drum.
10. Segment cleaning station for next cycle of capsule filling process.
Packaging
In Hovid, tablets and capsules are packed in few ways such as blistering, stripping
and bottle filling. In blister packaging, unit dosage form is enclosed between
aluminum foils whereas in stripping, unit dosage form is sealed between strips of
aluminum foil and polyvinyl chloride (PVC).
Packaging is divided into three types:
1. Primary packaging: Tablets/ Capsules are packed in blisters or strips or bottle
filling as primary packaging which has direct contact with product.
2. Secondary packaging: Blisters, Strips and Bottles are packed in inner cartons
with circular by the packaging machine as secondary packaging.
3. Tertiary packaging: Inner cartons are packed in outer cartons and stored in
finished product storage room before transferring to warehouse.
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CHAPTER 5: FINDINGS AND RECOMMENDATIONS
Throughout the industrial training, it helps to sharpen my communication
skills and management skills. It also expands my knowledge beyond the theoretical
knowledge that we usually learn in classrooms. Good relationships are fostered
between students and the co-workers during training. Cooperation with co-workers
has provided a sense of tolerance and the importance of teamwork. However, most
of the staff has been very accommodating, friendly and patient with the students
when it comes to coaching them. They are also very knowledgeable and willing to
impart their wisdom generously to intern students. This will make students feel that
they are part of the team and made the learning experience beneficial and enjoyable.
However, there are some improvements can be made for the purpose of
improving the quality of this course in all aspects. For example, the industrial
training programme will be more efficient and meaningful if the students adhere to
one company for two months. As students have sufficient time to understand and
expose to every department in same company for 2 months. Furthermore, there
should be a meeting between the respective company preceptor and university
lecturers before the industrial training as this will give a clear picture for the
company preceptor for providing complete training courses to the internship
students.
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CHAPTER 6: CONCLUSION
In conclusion, I had gain valuable and beneficial experiences and knowledge
throughout this two-month of industrial training in both Ain Medicare and Hovid. I
have also acquired knowledge on the workings and systems of two pharmaceutical
industries. This industrial training gave me an opportunity to test my interest in the
different areas of a career before permanent commitments are made so I can assess
myself to prepare for the working world after graduation. Internships also helped to
instil a sense of responsibility, build strength, teamwork spirit and self-confidence.
However, some improvements can be made for the purpose of improving the
quality of this course in all aspects which mention in Chapter 5. Thankfully, most of
the challenges faced are minor inconveniencies and hopefully can be rectified in the
future. Lastly, I can conclude that I have received a lot of exposure in the sterile and
non-sterile pharmaceutical industries and I would like to thank Faculty of Pharmacy
of Quest International University Perak for giving me the golden opportunity to
experience this.
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INDUSTRIAL TRAINING’S FINAL REPORT

Perak Darul Ridzuan)

This report is submitted to

as partial fulfilment of the requirement for the

Bachelor of Pharmacy (Hons)

QUEST INTERNATIONAL UNIVERSITY PERAK

CHAPTER TOPIC PAGE

FIGURE ITEM PAGE

CHART ITEM PAGE

1. Organization Chart of Ain Medicare Sdn. Bhd. 12

2. Organization Chart of Hovid Berhad 17

3. Process of product registration 32

4. Process flowchart of INFUSOL® D10 48

5. Flowchart of handling of sample for post market 63

6. Flowchart of procedure for handling of product 65

7. Manufacturing flow of solid dosage form products 88

TABLE ITEM PAGE

pharmacist profession which includes pharmaceutical industry, hospitals and clinics,

community pharmacy, wholesale pharmacy and government services (regulatory

affairs, drug testing laboratories, military services).

Industrial pharmacy is a discipline which includes manufacturing,

development, marketing and distribution of drug products including quality

assurance of these activities. There are various departments in industry which a

pharmacist can involve in such as marketing and provision of drug information,

research and development department, quality assurance department, quality control

department, production department and regulatory affairs department. The roles of

industrial pharmacists include conduct research, testing and analysis in the

development of medicines and production of pharmaceuticals and related supplies.

new medications, and may be involved in clinical drug trials.

is allocated to sterile industry and another month is allocated to non-sterile industry.

my training attachment including Research and Development (R&D) Department,

Quality Assurance (QA) Department and Production Department. In addition, Hovid

without switching to other departments.

The objectives of the Industrial Training include:

• To gain experiences and knowledge throughout the period of training.

• To enhance the employability skills of the students.

• To apply learnt theoretical knowledge to practical work situations.

• To instil a sense of responsibility, build strength, teamwork spirit and self-

• To expose students towards the real working environment as well as latest

technology and management utilized by the industry.

• To expose students to a work environment, common practices, employment

opportunities and work ethics in their relevant field.

• To provide opportunities for students to be offered jobs in the organizations

in which they undergo their Industrial Training.

The industrial pharmacy is important to give an idea to students about the

roles and responsibilities of industrial pharmacists in different areas. It also gives a

preparing to be employed and expand student’s employment prospects. As students

functional competencies in various aspects of industrial pharmacy. As industrial

provide insight for students regarding a career in industrial pharmacy.

2.1 Ain Medicare Sdn. Bhd.

2.1.1 Ain Medicare Organization Background

manufacturing pharmaceutical industry who produces pharmaceutical products and

medical device products. It started to establish in year 1993 in Malaysia. It is a

wholly-Malaysian owned company. For pharmaceutical products, it includes

intravenous solution, plasma expander, antiseptic solution, antimicrobial solution,

peritoneal dialysis solution, nebuliser solution, anticoagulant injection and other

solutions, continuous renal replacement therapy solution (CRRT) and haemodialysis

concentrates. In short, Ain Medicare manufactures about 67 registered products.

Malaysia. It operates from a multi-million dollar state-of-the-art pharmaceutical

microbiological and chemical laboratories, warehouses and administrative centre was

inaugurated by former Prime Minister Tun Dr. Mahathir Mohamad.

towards numerous remarkable achievements through its far-sighted leadership and

strategic management system. Today, AIN MEDICARE's authorised share capital