challenges of biological drug registrationinvietnam and suggesting for improving registration process in a local pharmaceutical company

HO CHI MINH CITY OPEN UNIVERSITY UNIVERSITÉ LIBRE DE BRUXELLES SOLVAY BRUSSELS SCHOOL OF ECONOMICS & MANAGEMENT MBQPM5 “NGUYEN NHU TRANG” “CHALLENGES OF BIOLOGICAL DRUG REGISTRATION

HO CHI MINH CITY OPEN UNIVERSITY UNIVERSITÉ LIBRE DE BRUXELLES

SOLVAY BRUSSELS SCHOOL OF ECONOMICS & MANAGEMENT

MBQPM5

“NGUYEN NHU TRANG”

“CHALLENGES OF BIOLOGICAL DRUG

REGISTRATION IN VIETNAM AND SUGGESTING

FOR IMPROVING REGISTRATION PROCESS IN A

LOCAL PHARMACEUTICAL COMPANY”

MASTER FINAL PROJECT

MASTER IN BUSINESS QUALITY AND PERFORMANCE MANAGEMENT

Ho Chi Minh City (2016)

HO CHI MINH CITY OPEN UNIVERSITY UNIVERSITÉ LIBRE DE BRUXELLES

SOLVAY BRUSSELS SCHOOL OF ECONOMICS & MANAGEMENT

MBQPM5

“NGUYEN NHU TRANG”

“CHALLENGES OF BIOLOGICAL DRUG

REGISTRATION IN VIETNAM AND SUGGESTING

FOR IMPROVING REGISTRATION PROCESS IN A

LOCAL PHARMACEUTICAL COMPANY”

MASTER FINAL PROJECT

MASTER IN BUSINESS QUALITY AND PERFORMANCE MANAGEMENT

Tutor: Jacques Martin

Ho Chi Minh City

HO CHI MINH CITY OPEN UNIVERSITY UNIVERSITÉ LIBRE DE

BRUXELLES SOLVAY BRUSSELS SCHOOL OF ECONOMICS & MANAGEMENT

MBQPM5

“NGUYEN NHU TRANG”

“CHALLENGES OF BIOLOGICAL DRUG

REGISTRATION IN VIETNAM AND SUGGESTING

FOR IMPROVING REGISTRATION PROCESS IN A

LOCAL PHARMACEUTICAL COMPANY”

MASTER FINAL PROJECT

MASTER IN BUSINESS QUALITY AND PERFORMANCE MANAGEMENT

Tutor: Jacques Martin

Ho Chi Minh City (2016)

ACKNOWLEDGEMENTS

Firstly, I would like to acknowledge the support of Prof Jacques Martin who gave me

strength, encouragement and his kind input and re-sharpening of my ideas

Special appreciation is also expressed to all Drs and Professors from the Master In Business Quality And Performance Management 5 program, for their professional advice

on data collection, review and methodology that truly supporting for final report writing

I also extend my gratitude to DAV Officers, specifically the Director of the Drug registration Department, Mr Chu Dang Trung, for approving for me to purse the data collection and follow – up interview, and the whole Department of Medicines Registration for their material support during data collection

I extend my gratitude to pharmacist in-charge and evaluators for devoting their time cooperation given during data collection

I specially acknowledge the HL Pharma company, the Executive Management team, and Head of R&D department, for accepting this work to be done supported me academically and materially during this final report preparation

I also extend my gratitude for the moral support and assistance from my colleagues in the MBQPM5 class during times academically

Finally, I would like to send my deep gratitude to my family for all of their supports and encouragements

ACCEPTANCE OF FINAL PROJECT REPORT FOR DEFENSE

Mr/Ms NGUYEN NHU TRANG’s final project report for the degree of Master in

Business Quality and Performance Management is officially accepted for defense

On 14 April 2016

Dr Jacques M.A Martin

Academic Director

Master in Business Quality and Performance Management

Solvay Brussels School of Economics and Management – Ho Chi Minh City Open University

5

TABLE OF CONTENT

1 INTRODUCTION 11

1.1 BACKGROUND 11

1.2 PHARMACEUTICAL MANAGEMENT SYSTEM 12

1.3 HL PHARMA 12

1.4 HISTORY OF REGISTRATION IN VIETNAM 13

1.5 GENERAL DESCRIPTION OF REGISTRATION PROCESSES 14

1.5.1 Drug regulation process 14

1.5.2 Key players and tasks in drug registration 15

1.5.3 Regulatory affairs department 15

1.6 Drug registration process in HL Pharma 16

PART 1: METHODOLOGY 18

Chapter 1 REGULATORY FRAMEWORK 18

2.1 Legislative in harmonization trends 18

2.1.1 ICH hamonization 18

2.1.2 ASEAN Harmonization strategy 19

2.1.3 ASEAN Harmonization in Vietnam 20

Chapter 2 METHODS AND MATERIALS 21

3.1 Study Design 21

3.2 Study participants 21

3.3 Study Period 21

3.4 Sampling technique 21

3.4.1 For identification the challenges of medicines registration process in Vietnam 21

3.4.2 To determine the need of good registration process in HL Pharma 22

3.5 Data Collection 22

PART 2: ANALYSIS AND REVIEW 23

Chapter 1 RESULTS 23

4 1 Socio-demographic information of participants 23

4.2 Companies represented, and their number of biological products registered 24

4.2.1 Companies represented 24

4.2.2 Time taken for dossier registration approval 25

4.2.3 Time taken for dossier registration preparation 25

4.3 Assessment of knowledge with regards to medicines registration 26

4.4 Practice among DAV evaluators on medicines registration 27

Chapter 2: ASSESSMENT OF CHALLENGES IN DRUG REGISTRATION PROCESSAND REVIEW 29

5.1 Challenges encountered by evaluators (21) 29

5.2 Challenges encountered by representatives of manufacturer (40) 31

6 REVIEW CURRENT QUALITY MANAGEMENT IN HL PHARMA 32

6.1 GDP system in HL Pharma 32

6.2 Registration system in HL Pharma 33

6.2.1 The current role of regulatory activities within HL Pharma 33

6.2.2 Improve the registration process 34

7 CONCLUSION AND RECOMMENDATIONS 38

7.1 CONCLUSION 38

7.2 RECOMMENDATIONS 38

REFERENCES 42

LIST OF ABRIVIATIONS AND/OR SYMBOLS

ASEAN Common technical dossier ACTD

Balance scorecard BSC

Drug administration of Vietnam DAV

Africa countries

on Harmonisation

LIST OF FIGURES, TABLES AND ANNEXES

Figure:

Figure 1: Pharmaceutical Management system 12

Figure 2: Reason of delay in DAV registration process 30

Figure 3 Reason of delay in registration process (encountered by Pharmacist-in-charge) 31

Figure 4: The plan–do–check–act cycle……… ……… ……… 34

Table Table 1: ACTD harmonization in drug registration guidelines from 2009-2015 20

Table 2: Socio-demographic characteristics of medicine evaluators (n=21) 23

Table 3: Socio-demographic characteristics of pharmacists’ in-charge of pharmacies (n=45) 24

Table 4: Local companies distribution in relation to companies represented, and dossiers applications registered (n=25) 24

Table 5: Time taken for dossier registration preparation in HL Pharma 26

Table 6: Proportion of evaluators’ knowledge assessment in relationship to the correct responses 26

Table 7: Summary of responses to practice on medicines registration among evaluators 28

Table 8: Challenges encountered by evaluators (n=21) 29

Table 9: Challenges encountered by representatives of manufacturer (n=40) 31

Table 10: Assessment and overview of the current drug regulatory situation in the company 35

Annex

Annex 1_Questionaires to Evaluators_Pharmacist

Annex 2_DAV Regulatory_Process_VIETNAM

Annex 3_2016-02 BSC_RA HL Pharma

Annex 4_Estimated registration time

Annex 5_Regulatory Roadmap 2016_Template

Annex 6_Proposed drug registration Procedure

Abstract

Total quality management is considered important in the competitive industry strategies at the level of organizations on one hand, including Pharmaceutical industry Quality represents specific behavior for a group of consumers It is becoming imperative for businesses to supply goods and services of high quality to achieve a competitive advantage

in their markets (Amalia Venera, Todorut, 2012)

Dugs (Pharmaceutical finished products) are only authorized to circulate in the market after being registered The Drug administration of Vietnam (DAV) has been mandated by the Vietnam Ministry of Health to ensure quality, safety and efficacy of medicines Since about 70% of medicines are imported from abroad, registration process contributes to the availability of quality, safe and efficacious medicinal products in the country (Assembly, 2005) In this regard the registration process needs to be effective and should avoid unnecessary delays in order to increase the variety of medicines registered in the country

In order to distribute in Vietnam market, once approval granted, the imported medicines must be also complied with some requirements in labeling, distribution legislation, and the local pharmaceutical companies must also meet the required qualifications approved the DAV (GDP – Good Distribution Practice; GSP – Good Storage Practice)

Study objective:

- The aim of this study is to identify challenges of biological drug registration process in Vietnam and the impact of registration processes as independent variables on the development of registration policies used in HL Pharma to identify the chance developing appropriate registration system elements followed by these facilities

-The final report also attempted to identify the realities and readiness of GDP/GSP management in HL Pharmaceutical Trading Company (HL Pharma) These findings are closely linked to the capacity of product supply and quality of product control to meet customer requirements on product supply continuity

1 INTRODUCTION

1.1 BACKGROUND

The first purpose of this study was to determine challenges faced by both DAV and local pharmaceutical companies in biological drug registration In Vietnam, medicine registration is an official authorization or registration of a product by DAV for the purpose

of marketing or free distribution in the country after evaluation for safety, efficacy and quality(Drug Administration of Vietnam, 2015). Hence, the objective of evaluation is to ensure that before a medicine is placed on the market there is enough evidence that it has been properly formulated, manufactured and adequately tested and meets the criteria of safety, efficacy and quality

A drug product registration dossier is a set of document that consists of data on administrative, pharmaceutical, clinical and labeling of the product The administrative part gives preliminary information of that medicine, applicant and its manufacturer The quality part contains detailed information of the active pharmaceutical ingredient(s) (APIs) used and finished pharmaceutical product whereas in ensuring medicines safety and efficacy, these data are provided in the clinical part of the dossier 3

Quality has been recognized broadly as one of the key factors to success in the global market for all kind of business Quality is describe as products’ or services’ totality of features and characteristics while quality system is "a set of interdependent processes that function harmoniously, using various resources, to achieve the objectives related to

quality” (Juran, 1951) In pharmaceutical industry, the QMS lives in a dynamic business

environment characterized by acquisitions, portfolio changes, operational realignment, manufacturing relocation, facility repurposing, restructuring, and workforce right-sizing The QMS also lives in a dynamic regulatory environment of the registration and compliance requirements of global markets as well as inspections Present day the biggest challenge faced by the pharmaceutical organizations is to build up a quality system that could focus on sustainability issues and assume that quality problems and regulatory non-compliances will be reduced as a result of the organized way of thinking, transparency, documentation and continuous evaluation of Quality Management System (QMS) QMS starts with recognizing that customers play a significant role in defining requirements as inputs and monitoring of customer satisfaction is necessary to evaluate and validate whether customer requirements have been met As QMS is related to regulatory compliance and continuous inspection readiness, it shall maximize benefit to the organization by improving quality, increasing the yield, cutting costs due to quality failure, and import alerts

And as an effect, in drug registration process, the quality of registration dossier is key factor for a successful registration

From the applicant or manufacturer’ representative in Vietnam, not only the quality of their registration dossiers but also the implementations of quality management system to ensure product quality after registered become very important Quality management is generally referred to the identification and administration process of the activities in order to achieve the quality objectives of the organization The main purpose of the quality management is

to get competitiveness by improving quality performance (Deming, 1982; Garvin, 1988;

Steeples, 1992)

In order to improving quality performance constantly, quality system of HL Pharma must properly maintain whereas the company has to develop, be self-motivated and develop for better internal and external quality services persistently While following consistently with GDP/GSP guidelines issued by DAV, the company needs to ensure the compliance with Manufacturer’ quality requirements applied for their registered products in Vietnam

1.2 PHARMACEUTICAL MANAGEMENT SYSTEM

Managing medicines supply is basically organised into four functions which include selection, procurement, distribution and use In order to achieve its function there is a need

to have efficient management support The entire cycle rests on policy and legal framework that establishes and supports the public commitment to essential medicines

supply (MSH and WHO, 1997)

Figure 1: Pharmaceutical Management system

Source: Managing Drug Supply, 2nd Edition of 1997

1.3 HL PHARMA

HL Pharma is a diversified local healthcare company that specializes in imported medical devices, pharmaceuticals They also have imported food supplements and tent to reach to cosmetic portfolio

HL Pharma operates main business activities on doing marketing, trading for pharmaceutical products in Vietnam All importation activities are done by their third-parties, a local Government’ company, this local company also does the service of registrations of medical devices, import license for food supplements HL Therefore, HL Pharma plays only the key role as distributor for all of their devices and food supplement products in Vietnam market For pharmaceutical products, HL Pharma does the registration and doing distribution in Vietnam They also store products in their warehouses, control the tender listing and selling to hospitals/pharmacies

HL Pharma’ business segments are differentiated into 3 categories:

- The pharmaceutical products which is biological products, this segment consists of recombinant and plasma based proteins to treat hemophilia and other bleeding disorders, plasma based therapies to treat immune deficiencies This segment comprised 68.4% of total revenues

- The food supplements segment consists of: nutrition products, infusion pumps, and inhalation anesthetics, as well as products and services related to pharmacy compounding, drug formulation and packaging technologies This segment comprised 22.7% of total revenues

- The medical devices which has just been started from early 2015, consists of devices to treat sore throat, asthma, This segment, together with some registration services to their foreign’ partners, comprised ~ 8.1% of total revenues

The company has a simply quality system which based on the requirements of their foreign’ partners (the Manufacturers) and DAV GDP standards Due to the different of quality management for each type of products, they follow several sets of quality requirements by each Manufacturer They also have some basic processes that required by local regulations in Good practice distribution, which will be studied and enhanced during this final report

1.4 HISTORY OF REGISTRATION IN VIETNAM

In Vietnam, drug registration is also known as marketing approval, marketing authorization or product licensing

In the last two decades, medicinal regulation had become more organized at international and regional level for instance International Conference on Harmonization, ICH, EUROPEAN, and ASEAN Agencies respectively Since 1998, about fourteen guidelines have been harmonized in the European Union, Japan and USA through the ICH and in July

2003 a Common Technical Document (CTD) that assists in medicine application among

the three regions was finally implemented (ICH, 2008) Nowadays, many medicines

regulatory authorities structure their dossier requirements along with WHO guidelines

which are very close to the CTD format in respect to their national settings as part of the ASEAN harmonization initiative

In 1990, the DAV embarked on a drug registration exercise Before then, all drugs imported into the country had not been subjected to a drug registration process The process has been a control measure to ensure that only drugs of proven quality, safety and efficacy are licensed for importation into Vietnam

The registration of drug was made under the Pharmaceutical Law, 2005 The Act provides conditions under which a medicinal product may be registered in Vietnam that include the availability of medicine to be of the public interest, safe, efficacious and of acceptable quality, the premises and manufacturing operations should comply with the current GMP requirements or any other requirements as may be prescribed by the authority The Registration guidelines were introduced specific requirements for each product category such as chemical medicines, biological products, herbal medicines, food supplements and medical devices

In 2009, Vietnam was the 2nd authority in ASEAN region to partly require registration dossier in ASEAN Common technical dossier (ACTD) which was still new and country-specific requirements to EU countries In early of 2015, DAV has changed the Drug regulation guideline to fully allow ACTD template only, and to require the registration companies to follow ASEAN Stability condition Including in the 2015 Drug registration guidelines(Drug Administration of Vietnam, 2015), DAV also sets a number of variations

required approval before implementation, this increase a significant number of registration dossiers in maintaining a product license

Currently, DAV has gained expertise and more knowledge of medicine evaluation These has led to changes in medicines registration requirements which has resulted in most of dossiers submitted ending up in non-conformance, rejection or queried hence prolonged registration time The evaluation timeline can last from 14-18 months for chemical products, and 18-24 months for biological products, while the Guideline saying that drug licenses will be granted 6 months after submission of qualified and sufficient registration dossier The delay in registration has created more customer complaints and unavailability

of medicines within the medicines supply chain

1.5 GENERAL DESCRIPTION OF REGISTRATION PROCESSES

1.5.1 Drug regulation process

A drug registration process generally covers the following areas:

• Pre-marketing assessment and evaluation of the quality, safety and efficacy of

a medicine, including compliance of manufacturing sites and processes with Good Manufacturing Practice (GMP) standards

• Assessment and inspection of all components of the pharmaceutical supply chain

• Maintenance of a register of available products, and post-marketing surveillance activities, including random sampling of registered medicines for quality control and pharmacovigilance

• Promotion, advertising and provision of medicines information

All of these activities require an appropriate legislative framework The precise nature and scope of legislation, as well as models for drug regulatory frameworks, varies from setting

to setting

1.5.2 Key players and tasks in drug registration

Drug regulation is an interplay between law and sciences, as well as between regulators and the pharmaceutical manufacturers, with input and influences from patients and medical/health professions In addition, Drug regulatory authority of Vietnam (DAV) interrelates with many other authorities active in the health sector, such as the Ministry of Health and other health protection agencies

DAV also needs to interact with politicians; apart from anything else, politicians need to be persuaded of the importance of effective regulation in order to ensure that it is paid for at

an appropriate level In general, effective drug regulation requires effective legislation and administration, as well as a mechanism for control of the market and enforcement of penalties for breaches of legislation that applies equally to both the public and private sectors

1.5.3 Regulatory affairs department

At the organization level, Regulatory affairs (RA) professionals play critical roles throughout the healthcare product lifecycle, from concept through product obsolescence They provide strategic, tactical and operational direction and support for working within regulations to expedite the development and delivery of safe and effective healthcare products to individuals around the world The Regulatory Affairs departments of pharmaceutical companies ensure that their companies comply with all of the regulations and laws concerning their business

The Regulatory Affairs department is an important part of the organizational structure of pharmaceutical companies Internally it liaises at the interphase of drug development, manufacturing, marketing and clinical research Externally it is the key interface between

the company and the regulatory authorities (Bevan, 2009)

Regulatory Affairs department contributes essentially to the overall success of drug development, both at early pre-marketing stages and at all times post-marketing

At the late stage of product development regulatory professionals are responsible for the submission of the registration dossier It is their responsibility to provide the strategic regulatory framework for the submission, to advise on procedures and formats, to collect, evaluate and compile the scientific data and information on the product They manage the communication and negotiations with the authorities They are accountable for maintenance of marketing authorizations and are involved in the life-cycle management of

a product In addition to handling regulatory submission, Regulatory Affairs leads labeling compliance, and DAV listings and registrations, and acts as the official DAV correspondent

1.6 Drug registration process in HL Pharma

In both GDP / GSP guidelines, DAV has not identified any requirement on registration process

In all regulations related to the drug registration in Vietnam, no specific requirements have been set for a Regulatory department, or a registration process in practical operation Based

on current practice, the registration processes includes all sub-processes that ensure the compliance in term of product specification in product registration, product quality control and product information As a result, HL Pharma has only a simple registration process as

a part of R&D processes The main tasks of their regulatory activities related is to ensure product licenses on time for drug supply continuity, and only 1 Pharmacist is assigned as R&D Head who takes care for all related activities in registration management These tasks are not documented clearly and reviewed to see whether any risk to new drug registration regulation

Due to constantly increasing regulatory obligations and new DAV requirements as well as the globalization of the pharmaceutical market, the demands and responsibilities of regulatory departments for HL Pharma is becoming more and more compulsory and complex

Furthermore, starting from 1 Jan 2015, DAV issued a guideline to accept ACTD dossier format only This applies for both new drug registration and renewal registrations, effective from 1 Jan 2015 and 1 Jan 2016 respectively All of key existing biological products of HL Pharma will be required renewal submission in 2017-2018 That’s the reason HL Pharma needs to be ready for the country specific requirements and work with their manufacturers

to fulfill these changes in regulation while taking into account the continuity supply for their medicines

An example of this stringent requirement by local Health Authority is the normal storage condition followed ASEAN region Since Jan 2015, new applications for marketing authorization are only accepted if they include either the results of stability studies at

ASEAN condition or an EMEA decision on a waiver by good justification and rational for the different condition during registration evaluation The specific storage condition strategy must therefore be considered early on and built into the overall development plan

to avoid any delays in view of market access of the product The EU manufacturers mostly

have their products stored at below 25 o C while ASEAN countries require normal storage

conditions at not above 30 o C For biological products, DAV now accepts only a good

justification and rational for the different condition during registration evaluation Without rational in writing at timeline of submission, the dossier will be rejected by DAV after first evaluation Therefore, in addition, a close storage and delivery system to ensure manufacturer’ storage condition to prove how HL controls the quality of their products, their drug registrations can be results in withdrawal or pending approval of their registered products in Vietnam market This is also the critical need to re-assess and improve their GDP compliance

PART 1: METHODOLOGY

Chapter 1 REGULATORY FRAMEWORK

2.1 Legislative in harmonization trends

2.1.1 ICH hamonization

Harmonization of regulatory requirements was initiated by the European Community (EC),

in the 1980s, the EC moved towards the development of a single market for pharmaceuticals At the same time there were discussions between Europe, Japan and the

US on possibilities for harmonization ICH is a unique undertaking that brings together the drug regulatory authorities and the pharmaceutical industry of Europe, Japan and the

United States (K.Sparrow, 2000)

ICH provides various guidelines which are categorized into four category, Quality guidelines, safety guidelines, efficacy guidelines and multidisciplinary guidelines These guideline give special concern for the patient population, large-scale human clinical trials lasting up to one year can begin in the absence of completed carcinogenicity studies in rodents The major aim of ICH is to achieve greater harmonization in the interpretation and application of technical guidelines for the registration of new active substances or products obtained by biotechnology by its members; to improve the efficiency of global drug development; to reduce redundant studies; and to improve pharmacovigilance activities and quality assurance

As of today, ICH has completed an important phase Key guidelines are now being implemented in the areas of Efficacy, Quality and Safety in the three ICH regions The organization has established a maintenance procedure to ensure that the guidelines continue to reflect the latest scientific developments and best practice These maintenance activities are essential to the future of ICH, and to ensure that harmonization continues Several more ambitious guidelines are under development, such as Good Manufacturing Practice (GMP) for Active Pharmaceutical Ingredients (APIs), Pharmacopoeias Harmonization The Common Technical Document and its electronic counterpart will be available in less than two years, both set to change procedures for regulatory dossier submission significantly The organization has recognized the importance of making available information on the ICH process and guidelines to non-ICH regions with the establishment of the Global Cooperation Group As well as making information available, the group will act as a resource in the understanding, and even acceptance, of many of the guidelines

Drug Registration harmonization provide benefit for better health:

• Regulatory harmonization offers many benefits to both regulatory authorities and the pharmaceutical industry, and has a positive impact for the protection of public health

• Through the development of harmonized guideline: streamline the regulatory assessment process for new drug applications; reduce the development times and resources needed for drug development; prevent duplication of clinical trials in humans; and minimize the use of animal testing without compromising safety and effectiveness

• To harmonize requirements in the drug registration process promotes quicker access to medicines for patients

2.1.2 ASEAN Harmonization strategy

ASEAN member countries have established the framework on economic cooperation for a long time already Since the 9th ASEAN Summit on 7th October 2004, the members have agreed to integrate ASEAN countries to become ASEAN Economic Community (AEC) with in 2020 The goals are to become single market and production base, and to promote convenience and liberalization in the goods, services, investments and funds movement Because pharmaceutical product is among the healthcare sector, it is necessary to accelerate the harmonization by assigning appropriate measures and definite time lines for every procedure Hence, for these matters, the roadmap of healthcare integration was set up:

1 Study the feasibility of ASEAN Mutual Recognition Arrangement (MRA) in Pharmaceuticals by 30th September 2005

2 Establish alert systems for under-standard and unsafe products by 31stDecember 2005

3 Establish labeling standards by 31st December 2006

4 Implement ASEAN Common Technical Dossier (ACTD) by 31st December

2.1.3 ASEAN Harmonization in Vietnam

The initiation of ASEAN Pharmaceutical Harmonization have affected directly to the drug

registration system The harmonization program focuses in 2 principles that are to promote

and support drug registration system, trade and cooperation in the region, and to eliminate

technical barrier to trade among ASEAN countries

Vietnam Ministry of Health, by DAV, had decided to fully implement ACTD by 31st

December 2016 in response to ASEAN goal and government strategy to be actively

involved in the region Below are summarized changes and implementation phrase for

adopting ACTD harmonization in drug registration guidelines from 2009-2015

Table 1: ACTD harmonization in drug registration guidelines from 2009-2015

Technical regulations in excess of what is necessary may become a technical barrier to

trade In applying technical regulations, DAV has adopted an approach of using

international standards and practices and alignment with the WTO/TBT obligations, where

possible Furthermore, DAV need to provide a Regulatory Practice Guide for regulators

and Applicants to assist in the preparation and adoption of efficient regulatory

arrangements that would improve the consistency and transparency of technical

regulations, thereby reducing barriers to trade

As a result of this harmonization approach, the involvement of local business sectors,

especially small pharmaceutical companies would take into consideration A significant

Administrative documents Drug substance and drug product section

Dossier format: either ICH CTD or ACTD format

Administrative documents Quality and Clinical/Non-clinical section

Dossier format: ACTD format only

Scope Both renewal and

new registration

No differences between

Chemical and biological

products

From 1.1.2010 for new registration, and 1.1.2012 for renewal registration Applicable for chemical medicines only

From 1.1.2017 for biological

ICH CTD is acceptable only

in case of new drug substance entity

applicable This enhance chance to accept evaluation per quality risk management based Applicants are required to provide strong rational/justification

step up needs to be taken at particularly the national level but also regional level It is required small and medium-sized enterprises to get involved when it is not too late, i.e before the implementation phase of regulations is already impacting them Pharmaceutical companies need to look specifically all potential impact across, and to actively go out and evaluate what this might be This task may even be outsourced as interim option, and the critical need to redesign the Registration management activities at HL Pharma

Chapter 2 METHODS AND MATERIALS

Drug registration evaluators within DAV (25)

RA representatives of foreigner manufacturers (25): All of their imported products are biological products

And 45 pharmacists in-charge related to R&D including registration activities in above local representatives

3.3 Study Period

The study took about five months for its completion

The study period includes proposal development in September 2015, data collection in September to Dec 2015 and final report submission in Apr 2016

3.4 Sampling technique

A convenient sampling technique was used to get the sample size due to the small number

of evaluators and pharmacies involved in medicines registration in the country Study participants who were willing and available during the survey at the study sites were included

3.4.1 For identification the challenges of medicines registration process in Vietnam

A convenient sampling was used to get the sample size due to the small number of evaluators and pharmacies involved in biological medicine registration in the country Study participants who were willing and available during the survey at the study sites were included Retrospective data of all applications received in the past two years was collected (2014 and 2015).

3.4.2 To determine the need of good registration process in HL Pharma

Retrospective data of all applications prepared and submitted in the past 5 years was collected (2009- 2014) The rationale for selecting this period was based on the fact that the current Drug registration guidelines were reviewed in 2009, and in Jan 2015 respectively

Factors that hinder smooth registration process were evaluated based on the number of dossiers registered, queried or rejected

3.5 Data Collection

- Using a questionnaire (Annex 1)

- Questionnaires were distributed and the information was required to set the date for collection

- Survey questions focused on the demographic data, training, work experience, knowledge

on medicines registration, views (challenges) and experiences in dealing with regulatory requirements The survey also included registration document template classification, storage condition type

- Face-to-face interview with responsible pharmacists in HL Pharma during warehouse visiting

PART 2: ANALYSIS AND REVIEW

Chapter 1 RESULTS

4 1 Socio-demographic information of participants

Out of 25 targeted medicines evaluators, 24 of them filled the questionnaires which made response rate of 96% Among these 25 targeted pharmacies, only 21 could be enrolled in the study (ensuring further follow-up after finalizing questionnaires) which made a response rate of 84% Respondents included medicines evaluators, representatives of manufacturers and pharmacists‟ in-charge of the premises The results for socio-demographic characteristics of medicines evaluators are summarized in Table 2 below

Table 2: Socio-demographic characteristics of medicine evaluators (n=21)

Officer Medicines Inspector

Clinical Trial Officer

*includes lecturers, researchers and administrative employed evaluators

Out of 21 respondents, 15 (71.42%) were females while 6 (28.5%) were males with majority (47.62%) of respondents being pharmacists, medical doctors (33.33%) and other qualifications (19.05%) The high number of pharmaceutical – medicinal professional related here reflects the essential competency for pharmaceutical industry, that a Pharmacy

or doctor degree is required

Most evaluators 12 (57.14%) had experience of ≤ 1 year and 7 (33.33%) had worked for more 2-5 years while only 2 evaluators (~8.5%) had experience of between 6 to 10 years

Taking into account the retrospective study period (about 5 years from starting 1st Drug registration guideline per ACTD format and recent revised Guideline), it shows few number of evaluators could experience the changes and challenges for new Drug registration guideline Among the 21 respondents, only 12 of them (57.14%) could be categorized as medicine evaluators based on their main daily activity at DAV and job description Six (28.58%) respondents had attended training on dossier evaluation abroad

Table 3: Socio-demographic characteristics of pharmacists’ in-charge of pharmacies

Attended training in medicines Registration

Guidelines for Biological products

4.2 Companies represented, and their number of biological products registered

Majority of local biological companies (80%) are representing ≤ 5 foreigner manufacturers Among the companies, 18 (56%) of them were representatives of China and/or Indian companies Only three (12%) pharmacies were representing European and USA companies where ICH dossier format is available HL Pharma is the only company that is representing for European companies (Germany and Belgium)

Out of these 25 local companies, 12 (48%) had registered 11-20 products, 9 (36%) had registered less than 10 products while 4 (16%) had registered 21-30 products since registration came into effect No company had more than 30 registered biological products This also reflected the more stringent quality management required for from registration and distribution for this type of products in pharmaceutical industry

4.2.2 Time taken for dossier registration approval

None (0) of representatives of the manufacturers agreed with the current time taken of

20-24 months for registration approval of a new biological product, and 14-16 months for renewal per 2009 Guideline Among the respondents, 13 (54%) disagreed and 12 (48%) strongly disagree with time taken for dossier registration This indicates that the time taken for dossier is much longer than that stipulated in the Drug registration guidelines; which was 6 months

During interview, all representatives have requested for shorter evaluation time and insisted asking for interim solutions for in-valid license validity during evaluation process for existing products Especially based on the new Guidelines in 2015, DAV now requires full ACTD format of technical sections (for both Drug substance and Drug products for Biologicals) which is effective from 1.12017, representatives worry a lot for potential longer delay in getting license approval This needs to take into consideration the nature of biological products in supply The biological drugs are produced and isolated from living cells, cannot be fully characterized, and are relatively sensitive to storage and handling conditions Production of biologicals requires specialized manufacturing facilities with precisely designed equipment for producing the desired product critical quality attributes under aseptic conditions to prevent microbial contamination Manufacturers also have to distribute and store their products under controlled conditions to prevent loss of quality Strategic safety stock levels are applied after consideration of factors such as availability of multiple sources of raw materials and location of manufacturing facilities as well as historical experience with supply disruptions Management of operational and strategic safety stock levels is applied at all stages of manufacturing in an effort to mitigate the risk

of any single disruption in the supply chain However, in certain instances such as for awaiting license approval in imported countries, manufacturer will need to consider holding such stock to mitigate interruptions in supply This requires a lot of resources and cost impact indeed

4.2.3 Time taken for dossier registration preparation

None (0) of representatives of the manufacturers have recorded this data before replying the questionnaire This is also the difficult question as it would be various by many factors such as the availability of registration data, the level of readiness compared to Vietnam

requirements, as well as the priority and workload based on each organization’ regulatory strategy

After receiving the response, only 02 pharmacists in HL Pharma were asked for follow-up interview Reason for this selection is to focus on the second objective of this final report

of development a better registration practice in HL Pharma

Table 5: Time taken for dossier registration preparation in HL Pharma

Dossier preparation time (2009-2015)

Germany manufacturers (non-ICH dossier)

Belgium manufacturers (ICH dossier)

8-9 4-6

4-6 1-3

Dossier preparation time before 2009

Germany manufacturers (non-ICH dossier)

Belgium manufacturers (ICH dossier)

4-6 2-3

2-3

1

4.3 Assessment of knowledge with regards to medicines registration

Table 6: Proportion of evaluators’ knowledge assessment in relationship to the correct responses

DAV medicines evaluators(n = 21)

Representative charge pharmacists (n=45)

Know core activity of DAV

Correctly described core activity

Know medicine registration process

Correctly explained registration process

Know information to be submitted

Correctly explained information to be

submitted

Know importance of SOP for evaluation

Able to mention when was last SOP

Mention four categories of information

on dossier for generic medicines

Dully filled application form

Data for Active Pharmaceutical Ingredient

Data for finished pharmaceutical ingredient

Data for safety and efficacy

Among 21 evaluator pharmacists who indicated to know the importance of medicines evaluation, all (100%) could explain correctly the importance of medicines evaluation “that

is to ensure quality, safety and efficacy of medicines in the country” Out of 21evaluators who were questioned, only 18 of them knew the information to be submitted before a dossier can be evaluated, and all of them (85.71%) mentioned correctly the information that are required to be submitted 18 ‟in-charge” evaluators mentioned that they knew the process of medicines registration; only 15 of them could explain correctly the process involved “that is assessment of quality, safety and efficacy of medicinal product dossier and analysis of sample eventually granting of market authorization”

Regarding the detailed requirements of drug registration dossier, out of 21 evaluators, most

of them (95.24%) knew well the information required for preparation of a dossier for generic medicines and were able to respond correctly questions assessing the knowledge level This shown the overall knowledge of evaluators with regard to medicines registration process was found to be high Only 15 respondents mentioned the active pharmaceutical ingredients (API), 18 mentioned finished pharmaceutical products (FPP),

20 mentioned dully filled application form in Administrative part and only 6 mentioned data for safety and efficacy as the requirements for preparation of a dossier for generic medicines This could explain by the recent requirement on API and FPP section, and small number of new chemical/drug substance registration in Vietnam

Also, medicine registration evaluators knew well the important of using standard operating procedure (SOP) for evaluation of medicinal product dossier (18 of them)

Out of 45 respondents, more than half of them (55.55%) could correctly described DAV as

“to regulate products such as drugs, food, cosmetics, and medical devices in order to protect and promote public health” Among 25 respondents who knew the meaning of medicine registration, nearly one three quarter (33.33%) were able to properly define medicines registration as “that process of assessing quality, safety and efficacy of medicinal product and granting marketing authorization”

The overall knowledge of ‟in-charge” pharmacists in local representatives with regard to medicines registration process was found to be quite low Out of 45 respondents, only 15 (33.33%) were able to respond correctly questions assessing the knowledge level (up to 8 questions).Among them, more than half (55.55%) had low knowledge on medicines registration process

Among 30 respondents who knew the information that are required to be submitted in order for the dossier to be evaluated, only 23 (51.11%) were able to mention such requirements Few respondents (26.67%) who knew the importance of using standard operating procedure (SOP) for evaluation of medicinal product dossier, only 3 were able to mention the year when that SOP was last reviewed in their companies

4.4 Practice among DAV evaluators on medicines registration

Practice among evaluators during medicines registration are summarized in Table 7 below

Table 7: Summary of responses to practice on medicines registration among evaluators

Questions

Number of Respondents (n=21)

Percentage (%)

Follow SOP for

Dossiers that are

Often (1-2 official comments) 12 57.14

Very often (3-4 official

Introduction section for new Guideline before implementation in Jan 2015

The majority of evaluators mentioned inadequate number of evaluators as one of the factors hindering timely assessment of medicines dossier Lack of regular and expertise training 19 (90.48%) was also mentioned as the factor that affects medicines registration Also, twenty one (100%) evaluators indicated poor dossier arrangement; quality and authenticity of information as the causes of delay in registration process No submission in study period was recorded as approval right after 1st evaluation From Dec 2014, DAV had

to issue a list of insufficient criteria that would classify for an official rejection after 1stevaluation This is part of Good regulatory practice provided to control the quality of registration dossier Lack of updated reference materials during evaluation was also

mentioned as one of the challenges in drug registration process (DAV registration process – Annex 2)

Chapter 2: ASSESSMENT OF CHALLENGES IN DRUG REGISTRATION PROCESS AND REVIEW

Challenges that hinder smooth drug registration process were investigated in two ways; first to the evaluators who are dealing with assessment of medicines dossier and on the

other part to the representatives of manufacturers (Bevan, 2009)

5 CHALLENGES IN DRUG REGISTRATION PROCESS

5.1 Challenges encountered by evaluators (21)

The challenges faced by evaluators during medicines registration are summarized in table 8 below

Table 8: Challenges encountered by evaluators (n=21)

Inadequate number of evaluators 18 22,22

Lack of regular and expertise training 8 9,87

Lack of updated reference materials 9 11,11

Lack of clear communications 12 14,81

The majority 18 (23,45%) of evaluators mentioned inadequate number of evaluators as one

of the factors hindering timely assessment of medicines dossier The other findings show that 8 (9.87%) of evaluators mentioned insufficient evaluation time as a challenge encountered in medicines registration Lack of regular and expertise training 8 (9.87%) was also mentioned as the factor that affects medicines registration Insufficient evaluation time were also reported Evaluators also indicated poor dossier arrangement; quality and authenticity of information as the causes of delay in registration process Lack of updated reference materials during evaluation was also mentioned as one of the challenges in medicines registration process

Follow further analyzing by using Pareto chart, the study found cause of delay in registration process, with the length of the bars represents quantity (number) of causes, expressed in %: The Pareto principal is applicable, major challenges found by regulators are from lack of essential training, or lack of updating materials, and not clear enough in commucations

Figure 2: Reason of delay in DAV registration process

After in-depth interview with regulators regarding the views of the key informants on challenges encountered in medicines registration process, the top key challenges were identified into 4 themes as provided by the interviewees:

(i) Long registration time/meeting timelines

(ii) Communication gap between DAV and customers

(iv) Lack of expertise in some areas

(v) Lack of updated medicines register

This study, through questionnaires and in-depth interview, had intention of assessing the knowledge of DAV evaluators and pharmacist in-charge who are involved in medicines registration Many issues regarding registration of medicines have been revealed through this study Effective medicines registration requires the medicines regulatory authority to have adequate number of qualified staff to perform medicines evaluation and registration The staff, specifically evaluators, should be knowledgeable enough to provide the required technical assistance, which DAV needs to improve It was revealed that most of the evaluators had received training on dossier evaluation

However, no workshops or face-to-face training forum from evaluators specialized in vaccine and biological drug registration to Applicants have been conducted till end of Q1

2016 This is an indication that majority of staff involved in medicines evaluation do not have the sufficient required expertise for evaluation of medicines, as said by WHO (2010) reported, that authorization of medicines for sale in a country should be based on a scientific assessment of their safety, efficacy and quality, and must be able to communicate

0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00

Poor dossier arrangement

Lack of clear communications

Lack of updated reference materials

Lack of regular and expertise training

No (%)

and educate Applicants on evaluation process This is considered the core function of the regulatory authority in an effective registration process

5.2 Challenges encountered by representatives of manufacturer

The challenges faced by representatives of manufacturer are summarized in table 9 below

Table 9: Challenges encountered by representatives of manufacturer (n=40)

Number of managing factor No Cumulative %

Inadequate number of evaluators 31 14.35

Inefficient registration database 29 20.37

Delay of queries submission 27 25.99

Majority of representatives of manufacturers complained that registration process takes long time 38 (95.0%),and 31(77.5%) representatives mentioned inadequate number of DAV evaluators was the cause of delay in approval process

Also, the third issue identified as challenge factor in registration process was inefficient registration database 29 (72.5%)

Figure 3 Reason of delay in registration process (encountered by Pharmacist-in-charge)

These findings help to figure out the most significant problem causing delay in registration processes facing by DAV This also brings chance and potential solutions for Applicants when they want to improve their timely registration process In order to determine what the quality improvement solutions will be, based on the above determined significant problem

38

0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00

in registration process, the Pareto was valuable tool to identify the most common cause of customer dissatisfaction in registration in Vietnam, was long wait times for approval Regarding the views of the key informants on challenges encountered in medicines registration process in Vietnam, representatives of manufacturers also agreed that medicines registration process is facing challenges The top 3 key challenges were identified as (1) Inefficient registration database; (2) Delay of queries submission; and (3) communication gaps between DAV and customers

By finding that the most common cause of problems was training and communication (human factors), a change management approach for both DAV and Applicants should be focusing on improving employee training, core competencies and registration skills

6 REVIEW CURRENT QUALITY MANAGEMENT IN HL PHARMA

a close storage and delivery system to ensure manufacturer’ storage condition to prove how HL Pharma controls the quality of their products, this is the critical need to re-assess and improve their GDP/GSP compliance

An independent assessment of compliance against international GDP requirements is the most effective way to establish that HL Pharma quality management system aligns with GDP guidance, and how they are ready to new Drug regulation HL Pharma obtained their first GDP certificate by DAV in 2010, in 2013 and they need to review the GDP certificate

by September 2016 This proves that HL Pharma quality system is complied with basic quality standards per local regulation However, during the visiting warehouse, we found some definiteness in their documentation management, while this aspect is mainly significant link to the registration strategy to adapt for new Drug registration regulation

At the visiting, it took time for any case we asked for retrospective records of an event Sometime it was unable to identify whether a non-conformity occurred and managed, or proved for the trustworthy evidence of their quality activities Although small businesses

like HL Pharma don't have as many files as large corporations, it doesn't mean these smaller companies can't benefit from having all of their documents properly organized and easily accessible In order to improve the inefficient registration database, HL Pharma needs to manage their organizations’ records so they can comply with an rapidly increase

of the registration data required per New Drug registration, and to achieve better business outcomes However, in both Drug registration guideline, and GDP guideline, DAV has not specific required any document management requirements, just generally states that“3 An applicant has obligations to: Provide sufficient and accurate data, reports and information about drugs during the period in which the application for drug registration is submitted or processed, the drugs are permitted for sale, or at the request of the competent agency”;

(Article 3 Item b- Requirements, rights and obligations of the applicants) (Drug Administration of Vietnam, 2015), and “To archive sufficient application and provide

application for competent agencies upon request;” (Article 3, Item g) For long term

development of the quality system as a whole, and registration management itself, HL Pharma should improve their record management, adopting a systematic approach to creating and maintaining records allow them to:

• make the records they really need

• realise the true value of their records as information assets

• find and access all of the right records at the right time and use them with confidence

• preserve records for as long as required and then dispose of them appropriately

• assess the relative importance of different kinds of records

• identify and protect records containing sensitive, confidential or private information, and

• control costs associated with finding, accessing and preserving records

This is for future development in HL Pharma quality system As a finding from the warehouse visiting and BSC actions, the short-term action required is to build up a record management process in distribution storage management of biological products in HL Pharma, which can be used as key rational supporting for new/renewal registration in 2017-2018

6.2 Registration system in HL Pharma

6.2.1 The current role of regulatory activities within HL Pharma

A process may be described as a transformation of inputs (resources) into output (goods or services), a group of activities that convert inputs to outputs by using organizational resources Process management, therefore is the set of technical and behavioral practices emphasizing the management of processes, or means of actions, rather than results15 It requires knowledgeable individuals who are able to manage in the increasingly complex process oriented environment However, the current registration process in HL Pharma (Annex 2) seems to include all RA activities in a product lifecycle, from pre-launch till

marketing It does not define clear responsibilities, no specific criteria in term of time required while this is key important for business planning

The current product development process also showed lack of standard processes to address business requirements and/or process improvements with new Guideline From the survey results, it also revealed that there is lack of training and communication in the use

of the current process, and inappropriate allocation of resources for RA activities Based on the current RA activities in HL Pharma, it appears highly reactive organizations creating business processes due to issues at hand instead of creating proactive processes to eliminate potential issues

Indeed, the number and complexity of processes required within a registration means that a regulatory professional is more than likely to be working in a component part of the regulatory process rather than having a focus on the end to end process Never the less, a regulatory or R&D department must have a good appreciation of why and how their component part fits within the regulatory process, and retain a focus on how all of the component parts of the regulatory process contribute to the attainment of the policy goals

So the registration strategy needs to be developed in holistic manner

By using Balance scorecard, the study has proposed an RA strategy to develop Regulatory activities in HL Pharma to respond for 2017 registration requirements The purpose of BSC strategy is also to improve registration framework in e HL Pharma in effective way to meet company mission till 2025 (Annex 3)

6.2.2 Improve the registration process

Furthermore, the study aimed to improve the current registration process at HL Pharma in order to meet good regulatory practice The process management in this study refers to planning, implementing, controlling and continuously improving the processes, producing

a qualified registration dossier

Figure 4: The plan–do–check–act cycle

The plan–do–check–act cycle Figure is a four–step model for carrying out change The solution is to have a process that solves current registration management problem in HL Pharma; An effective process will ensure our strategy to be reviewed, tested and incorporated with feedback before you commit to implementation

Planning and redesign the process

The planning process should begin with an assessment and overview of the current drug regulatory situation in the company, and an inventory of the market

Regulatory department has usable data if its files physically contain all the pieces of information that are required due to the new Guideline, and these data are accurate and reflect the current need of the marketed drugs

The appropriate registration timeline required for each drug registration application

In preparation for the drug registration management in 2017, it is essential to review and update the regulatory registration procedures

At first, we need to have a well-developed understanding of the operating environment, challenges and risks to HL Pharma business being addressed Regulation is not a one-size-fits-all approach, and different strategies and approaches are required to address different risks It is also the case that the operating environment and risks may change over time and regulators need to have a flexible and ongoing ability to assess such changes

A Assessment and overview of the current drug regulatory situation in the company

Table 10: Assessment and overview of the current drug regulatory situation in the company

Presence of requirements to submit

HL Pharma, resulting in business lost

How many applications are

received/expected every year for

of the drug registration system in place

Presence of an efficient inspection system

covering manufacturing and distribution

channels

The absence of regular inspections of the distribution channels poses a serious challenge to the credibility of the information

on marketed drugs available

The lack of documentation management in product distribution and storage requires a new standard procedures

Presence of written procedures and

compliance with them

This element is important when assessing the possibility of using existing information in order to CTD dossier If there is no assurance that standard procedures (especially regarding completeness of information) have been followed in the past, it is very likely that the existing information is incomplete or inconsistent and, therefore, unsuitable for direct transfer into the new requirements

By Q1 of each year, the R&D department must provide registration plan in next 2 years to ensure no supply issue due to license change and validity This target of timeline is based

on retrospective timeline data from registration preparation, submissions and approvals, taking into consideration for tender supply, shipment and stock schedule in order to plan for temporary licenses in some situations A clear registration plan must be communicated, reviewed and well-documented After this study, we proposed a record template for these communications, the RA Roadmap, to manage registration changes and impact assessments from various functions

B Estimate time required to enter registration information into the new requirements

The amount of time required to prepare data will vary from type of applications, the nature

of manufacturer country (Non EU or EU products, which related to the availability of CTD dossier), before HL Pharma has not count these different factors to their registration process Also, the speed of response by Manufacturer RA will need to take into consideration; this will differ depending on whether Manufacturer supporters have knowledge and experiences with country specific requirements in Vietnam The assessment described above should enable HL Pharma to determine which situation is most like its own And by calculating preparation time into drug registration process, taking into account the registration evaluation timeline from DAV, the company will be able to plan for a more accurate and measureable launching plan (see Annex 4)

C Review and Update Procedures

In preparation for the new drug registration guideline, it is essential to review and update the company regulatory procedures The key thing of this stage is to define sufficient time required for processing steps to prepare for new drug product registrations (both containing new chemical entities (NCE) or generic), renewal of existing licenses, variations,

temporary certificates, etc

This is a crucial decision for most regulator department The purpose of registration process is ensuring to keep track of all applications, identify those that have been awaiting assessment decisions for a long time, and describe their status at any given time More importantly, to achieve necessary information into registration database while different types of applications require different types of assessment, time for preparation, it is necessary to carry out some preliminary work so that the types of assessment procedures and the steps each entails can be entered in the setup of the computer system

Procedures must also be defined for archiving and access to hard copies of submitted documentation after the licenses granted Good records management may dictate how long the documentation must be kept, or establish how and when it can be destroyed

Last but not least, procedures must clear responsibilities of relevant functions in drug registration preparation

There are some procedures in RA activities, such as registration for promotion and materials, tender document managements, and also the Record management for Distribution and storage procedure to prepare for 2017 new regulation, focusing on stability study requirements However, within this study, we focused only on improving the Product registration procedure

D Review and Update Forms and Certificates

In addition to updating procedures, it is also very useful to review the forms and certificates used for drug registration, organizing information should be prepared as a common technical template, and update them as needed The first step is to define the types of forms required, based on legislation and regulation required by both DAV and Health Authority in the country of manufacturer, and the common technical dossier template must be specified per type of applications

E Training staffs

The introduction of new drug registration process is a major undertaking and due for improvement The investment also involves training and retaining of staff As the drug registration process takes time (in 18-24 months at least), if staff leave the company, most

of the effort put into their training is lost Therefore, HL Pharma should try to ensure that critical R&D staff are not lost to other organization Some ways to retain staff may include opportunities for training, fair salaries, and establishing an appropriate level of status for the positions

7 CONCLUSION AND RECOMMENDATIONS

7.1 CONCLUSION

This study has found that biological drugs registration process in Vietnam is faced with a number of challenges which are multifaceted from evaluators, knowledge management, manufacturers and their representatives

The study has revealed that registration takes longer time than what has been stipulated in the Circular on registration of drug The prolonged registration is contributed by human factors (resources, knowledge management, and training) In the case of Vietnam Health Authority, inadequate number of evaluators was observed as one of the main factor that could be contributed by limited capacity of the Authority to hire adequate number of evaluators This shortcoming causes delay in evaluation of applications received resulting

in prolonged registration time

Meanwhile limited knowledge, as well as lack of registration management system observed among the pharmacist in-charge working in the pharmacies dealing with medicines registration contributes to their delay due to submission of poorly prepared medicine dossiers If this problem is identified earlier it would certainly reduce the number

of queries and rejection, thereby shortening registration process

7.2 RECOMMENDATIONS

Because resources are usually limited, it is important to take steps that will make the most

of them Several options are listed below, and a regulatory authority could benefit from some or all of the educational approach suggestions

For DAV to enhance vaccine and biological registration process in Vietnam

 From the overall DAV registration process (Annex 2), it shows close collaboration with many stakeholders such as Specialists and professors in the University of Pharmacy in the country All of these stakeholders should review pharmacy training curriculum for undergraduate course to include regulatory issues particularly in the area of medicines registration DAV in collaboration with other stakeholders particularly the manufacturers, representatives of manufacturers should conduct continuing education for pharmacist-in charge in order to impart them with updated knowledge and technological advancement in the field of medicines registration for the purpose of expediting registration process

 In several countries, one or more technical advisory groups or committees are established to provide technical advice to the DRA Such advisory groups may consist

of national experts in clinical pharmacology, pharmacology, pharmaceutical sciences, clinical medicine, and other areas The group or theme-specific subgroups could meet once or twice a month to provide advice on specific issues This is great approach to get regularly technical support to improve registration process at DAV

 DAV should establish effective and meaningful communications with other regulatory authorities When facilities or resources do not allow for analyzing a large amount of technical documentation or for conducting appropriate studies (e.g., sufficiently large clinical trials, laboratory analysis, and post-marketing surveillance), ad hoc connections with more advanced regulatory authorities in other countries could be established This would allow the DRAs to learn from each other’s experience and to have a reasonably solid basis for a decision about licensing active ingredients

 Also, DAV should improve close communications with local Applicants, through more training sections, face-to-face meetings to guide on the regulations They should promote regular activities such as running conferences and training courses in different fields of pharmaceutical manufacturing, case-studies, training on registration guidelines and can also refer to other regulated markets DAV should take the leading responsibility in improving knowledge on pharmaceutical technology among pharmaceutical companies and linking with other international conferences on medicines and related issues This in turn will help shorten registration timeline, improve the quality of registration dossiers and reduce workload at DAV

Invest more on quality by design approach in order to facilitate the registration process

is also recommended This may significantly contribute to the efficiency and the reliability of the evaluation of applications In all cases where the safety and efficacy profile of the product for which registration is sought is well established, and the licensing authority is satisfied with the available information showing that this item meets recognized therapeutic needs, quality becomes the most important concern in evaluating an application If regulatory authorities with limited human and material resources limit most of their licensing activities to well-established drugs, they will be better able to evaluate the manufacturing process and its controls, the specifications of the medicinal product and its regulatory status in other countries, and the GMP profile

of the manufacturer

For long term development, DAV should follow a regulatory approach by designing

a system to automatically identify products registered and used in countries with stringent regulatory authority in order to assign a minimal evaluation time.DAV should