INTRODUCTION:

Vaccines are a novel category of Pharmaceutical products that meet the definition of a drug and biological product. Pharmaceutical products that meet the definition of a drug and biological product. They are the foremost significant contributions to public health. No alternative medical countermeasures are as effective in reducing or eliminating the incidence of infectious diseases. A Vaccine is a biological preparation that improves immunity to a selected disease.

A Vaccine generally contains associate agent that resembles a disease-causing micro-organism, and is commonly made up of weakened or killed varieties of the microbes, its toxins or its surface proteins.

Vaccination is one of the best public health achievements, reducing morbidity and mortality from a broad vary of vaccine-preventable diseases. A vaccine may be a substance that is introduced into the body to stop infection or to control disease to a definite infectious agent that may be a disease-causing organism. The Vaccine teaches the body a way to defend itself against the infectious agent by making associate immune reaction. The Vaccine industry is highly regulated. Vaccine development is an advanced and long method. Before a new vaccine is approved for release into the market, a rigorous regulative procedure to assess quality, effectiveness and safety should be undertaken. The regulative system features a responsibility to guard and promote the general public health, to make sure the protection and effectiveness of vaccines as a result of the injection of ineffective and poor quality of product typically will cause terribly serious issues even death and undermine the confidence within the health system, health professionals, pharmaceutical manufacturers and distributors.¹

Vaccines Related to Regulatory Oversight:

All vaccines under development follow a predefined pathway that begins with nonclinical testing (in suitable animal models and in vitro testing), followed by a stepwise evaluation in human clinical trials to demonstrate safety and efficacy. After clinical results are carefully reviewed and deemed satisfactory, a candidate vaccine can be registered and granted marketing authorization. Vaccine clinical trials are carefully designed human studies aimed at systematically assessing safety and efficacy. Regulatory oversight of clinical trials is critical to ensure that vaccines under development meet the required quality, safety, and efficacy standards. Data from the trials are submitted to national regulatory agencies (NRAs) for registration of the vaccine before the vaccine can be used.

There have been numerous attempts to align regulatory requirements between countries and regions, as well as attempts encouraging mutual recognition practices between regulators of different countries in order to save both resources and time, avoiding redundancy. One such international initiative is represented by the International Council for Harmonisation (ICH) of technical requirements for pharmaceuticals for human use, originally established by the European Union, Japan and the United States of America in 1990 and expanded to other member and observer countries. The ICH developed and promoted the use of a Common Technical Document (CTD) which represents a common dossier for regulatory submissions for use in the ICH countries. The CTD has subsequently been adopted by additional countries globally, which should have led to a harmonisation of requirements. Countries adopting the CTD have however made local individual adaptations of the ICH CTD template, thus defeating the original intention of harmonisation. Hence, the divergence of requirements between countries remains high and evident in two-areas: (a) dossier numbering structure and contents and (b) the registration application/evaluation procedure.

International guidelines define the criteria and review processes that are used to register vaccines. In general, clinical trial applications for new vaccines must be submitted to the NRA of the country where the trials are to be conducted for their review and approval. At the end of the clinical trials, provided the results are satisfactory, an application for marketing authorization can be submitted to the NRA. The most accepted format for the licensing application is the Common Technical Document (CTD), which comprises 5 modules (administrative and legal information; summaries; quality; and nonclinical and clinical information about the product). New products can be registered first in the country of origin and later in other target countries. However, manufacturers may elect to register a new vaccine in user countries if the product is of little interest or applicability in the country of origin.

According to the ICH, the CTD includes 5 modules. Module 1 is not harmonised and contains regional/country information. Each country or region has its own numbering system and requirements. Modules 2–5 are harmonised modules, and include information regarding quality, safety and efficacy.²

In the late 1980s and early 1990s the country produced some of its own vaccines. But this capacity disappeared in the mid-1990s; the State Vaccine Institute and the South African Vaccine Producer, both run by the national health department, closed down because they weren’t operating at the required levels of manufacturing practice. So that South Africa has a very much demand for vaccines import and most of the Indian vaccine manufacturers are concentrating towards South African market.

General Description of Registration Processes:

Drug regulation 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.

Health Authorities of many countries insist on company registration, which may also include plant inspection prior to product registration. Only after the company is registered, the Health Authorities consider products for registration. For instance, in Vietnam and Bahrain for company registration, only submission of documents is essential whereas in some countries like Saudi Arabia, South Africa and Ukriane for company registration, submission of documents as well as inspection is essential.

For Company registration following documents need to be submitted:

1. Name and address of the manufacturer along with telephone no., fax no.; email address.

2. Person responsible for the quality of the products of the manufacturer.

3. Manufacturing licence of the manufacturer.

4. Plant GMP certificate i.e. COPP (Certificate of Pharmaceutical Product).

5. Statement of capital assets (i.e. Annual report of the company).

6. Number of employees in detail department wise (e.g. No. of employees in Quality control, Production, Stores, Administrative, R&D, etc.).

7. List of products manufactured by the company.

8. List of equipment’s/instruments in manufacturing, quality control and Research and development.

9. Research and development activities.

10. Prescription of Quality Control & Manufacturing areas, Production capacity.

11. List of company patented products

12. Status of registration in other countries (List of countries where company/products are registered)

13. International approvals if any

14. Plant layouts

General Requirements:

Common Technical Document:

A process by which an organization/ sponsor/ innovator gets authorization to introduce a drug in the market is known as drug approval process. Drug approval is the long process of drug development. A drug approval process undergoes various stages: conducting clinical trials, filing of NDA and post marketing studies. Every country has its own regulatory authority which is responsible to enforce the rules and regulations and issue the guidelines to regulate the marketing of drugs.

Common technical document (CTD) is having 5 modules:

1) Administrative and Prescribing information

2) Overview and summary of module 3 to 5

3) Quality (Pharmaceutical documentation)

4) Safety (toxicology studies)

5) Efficacy (clinical studies)

Module 1 is region specific and modules 2, 3, 4 and 5 are intended to be common for all regions.

Module 1: Administrative Information & Prescribing Information

Module 2: Common Technical Document Summaries

Module 3: Quality

Module 4: Nonclinical Study Reports

Module 5: Clinical Study Reports

I. Saudi Arabia:

The SFDA currently requires full pharmaceutical, chemistry, manufacturing, and controls (CMC), non-clinical, and clinical data with submissions. The agency conducts a detailed assessment of the pharmaceutical/CMC and clinical data, whereas the non-clinical data are only reviewed if a query has been raised. In addition, Saudi Arabia requires information relating to pricing as part of their review process.

WHO guidelines no longer require a CPP for regulatory submission; however, the SFDA currently conducts a full review of dossiers with the requirement of a CPP at the time of submission, which can cause delays in submission and consequent delays in patients’ access to medicines. The SFDA currently maintains a submission pathway that allows the CPP to be submitted at the time of authorisation for certain products, and consideration should be given to expanding these criteria for use of this pathway. In addition, the utilisation of other tools such as reference agency websites to confirm marketing authorisation could expedite patients’ access to medicines.

Registration Rules and Requirements:

Drug sector at SFDA sets the rules for registering different types of drugs. Such rules are developed by examining the current and future competencies of its evaluators. These rules will help the applicants to decide whether to submit their drug applications or not.

The following rules/conditions if met, the submitted drug application will be accepted:

1. New Drug and Biological (either registered in an SRA or not).

2. Generic Drug that is equivalent to the registered innovator in an SRA (the drug shall be registered as “New Drug” because the API is not registered in KSA).

3. Bio similar drug only if it is manufactured locally.

4. Bio similar drug if registered in an SRA.

Registration Process of vaccines in Saudi Arabia:-

To Register and Get approval for Vaccines there are Mainly Three Process that we need to Understand and process,

1. Drug Establishment National Registry (DENR)³:

For Establishment Registration (Registration in Saudi Arabia).

Drug Establishments National Registry (DENR) is an electronic system aims to build-up a national database for all drug establishments including companies, manufacturers, agents and wholesale distributor in Saudi Arabia.

Apply in DENR Process:-

Go to the link: http://denr.sfda.gov.sa/

Press the button “Create a New Account”.

Create a user ID and password.

Choose the type of your establishment.

Complete the form and submit it.

A code will be sent to your email to activate your account.

After activation, complete the full information.

Submit the form.

Figure 01: DENR Registration Process in Saudiarabai³

DENR Registration Requirements by the Companies:

1. Manufacturer registration certification.

2. A copy of technical contract with the agent which represent the company.

3. Manufacturer License from SFDA.

II. SDR (Saudi Drug Registration)⁴:

The Saudi Drug Registration (SDR) System is an electronic system which aims to facilitate the registration of medicinal, herbal and health products for both Human & Veterinary use. The SDR will allow the registered establishments in Drug Establishment National Registry (DENR) to use the system in new application, renewal and variation of their products.

Select the type of Application:-

1. MAA fro Human Use.

2. MAA for Vetrinary Use.

3. MAA for Herbals and Health Product

MAA for Human Use

1.New Drug 2.Generic 3.Biologicals 4.Radiopharmaceuticals

Enter Product Information in the Application .

Enter Contact Information of Agent in KSA.

Enter Manufacturer Information

Fee Payment details

Select the Appointment Schedule of Which Date and Time.

Figure 02: Vaccine Registration Process in Saudi Arabia through SDR system⁴

Submission of Dossier:

The process of submitting a New Drug Application to the SFDA consists of three major steps:

1 Online submission of the APPLICATION FORM,

2 The PRODUCT FILE

3 DRUG SAMPLES

Applicant shall go to the Saudi Drug Resgistration system (SDR) website (http://sdr.sfda.gov.sa/)

Choose and complete the appropriate application form and applicant has to pay the submission fee (Through SADAD payment system) in order to submit the application form.

At the appointment, applicant will deliver the product file along with the samples.

Phase 1:Validate the application form, Product file(hard and soft copy) and samples.

Phase 2: Completed file assessment,testing and inspection.

Marketing Authorisation

Step by step Procedure:-

Figure 03: Marketing Authorisation for vaccines in Saudi Arabia⁵

Step by step procedure:

1. Applicant shall go to the Saudi Drug Registration system (SDR) website (http://sdr.sfda.gov.sa/)

2. Login to apply (each applicant should have a user ID and a password)

3. Choose and complete the appropriate application form:

· The application form can be saved partially as the applicant may complete it in several steps.

4. Then, the applicant has to pay the submission fee (through SADAD Payment System) in order to submit the application form and schedule an appointment to deliver the hard and soft copy of the product file:

· Submission fees are mandatory in order to proceed to the next step.

· The applicant can reschedule 3 weeks before the appointment. An automatic reminder will be sent 3 days before the appointment.

· A reference number will be generated, and this number should always be used with regard to any communication with the SFDA.

5. At the appointment, the applicant will deliver the product file along with the samples.

6. The Regulatory Affairs Pharmacist will validate (Phase I) the following:

a. The application form

b. The product file (hard and soft copy)

c. The samples

· If the above are valid, an acknowledgment letter will be generated and given to the applicant. The drug application will enter the queue.

· If some of the above are missing or not satisfactory, an acknowledgment letter will be generated and given to the applicant stating the deficiencies. The applicant will have a period of 90 days to complete the requirements and the drug application will not be queued. When the required information is met, an appointment (completion appointment) is requested by email (sdr.drug@sfda.gov.sa), and the step no 6 will be repeated again.

III. Marketing Authorization Application (MAA):

A. Validation (Phase II):

1. The product file will be validated to ensure that all information provided are according to the requirements and/or guidelines:

a. The completed file will proceed to the next steps in parallel – assessment, testing and inspection.

b. If any information is missing or incorrect, the applicant will be notified electronically. The applicant will be given an opportunity to complete the file within 90 days. Otherwise, the file will be rejected.

2. Performance target: 10 days for all drug submission type.

B. Assessment:

1. The product file will be distributed by the product manager to THREE groups: Quality, Safety and Efficacy.

2. Quality assessment will be performed by a quality group. Once completed, a report will be forwarded to the product manager.

3. Safety assessment will be performed by a safety group. Once completed, a report will be forwarded to the product manager.

4. Efficacy assessment will be performed by an efficacy group. Once completed, a report will be forwarded to the product manager.

5. If a clarification is required, an electronic “Inquiry Form” will be forwarded to the applicant through the product manager. The response should be received within 90 days. Otherwise, the application will be rejected.

6. The reports (i.e. recommendation for approval or rejection) will be forwarded to the secretary of the Registration Committee.

Performance target:

Biologicals:

i. Registered in SRA: 245 days

ii. Not registered in SRA: 370 days

C. Testing:-

1. Samples received by SFDA headquarters will be sent to the laboratory.

2. If more information, clarification or additional samples are needed, an electronic “Inquiry Form” will be forwarded to the applicant through the product manager. A response should be received within 90 days.

3. The results will be written in a report and forwarded to the product manager.

4. Performance target: 90 days for all drug submission types

Note:

· Testing will not delay the registration of a product

· The 1st batch imported after approval will be tested and the company will be notified of the results within 35 days. However, the company should not distribute the product during this period. After 35days, the company may distribute the product under their own liability.

IV. SFDA Submission of Dossier⁶

On the Appointment date Applicant should submit the Product file (Dossier) to the SFDA (Hard copy & Soft Copy) & Vaccine sample.

Some of the documents that need to be given only in Hard copy (Some of Module1 documents) & Soft Copy (Module2-5 in Pdf format).

i. Structure and Content of Submission for Vaccine Dossier

· The SFDA will require all applicants to submit their applications in accordance to the ICH Common Technical Document (CTD) format. For more information on the CTD, please refer to above listed CTD structure of vaccine.

· It is important to remember that the CTD provides a format for an MAA and does not indicate the content of a dossier and which studies should be performed. Regional and national requirements may affect the content of the dossier; therefore the dossier will not necessarily be identical for all regions.

ii. Presentation of the Product File (Dossier)

A Softcopy (electronic-based) of the product file shall be submitted by the applicant along with a hardcopy (paper-based) of selected documents of Module 1 ONLY.

The softcopy shall be either:

a. eCTD2, or

b. An electronic version of the product file in NeeS format

Hardcopy and Softcopy Requirements

For the hardcopy (selected documents of Module 1), it should be bound into one volume (flat file). The flat file specifications:

· A4 lightweight flat file

· Clear front and opaque back cover with removable title strip, and with a two hole flat bar filing mechanism

· Label: should contain the following information:

1 Reference number (generated from SDR system)

2 Company name

3 Product trade name

4 Product Generic name

5 Date of submission (DD/MM/YYYY)

6 Type of submission (e.g. initial, renew or variation)

For the softcopy (electronic-based), each CD or DVD and its hard plastic cover submitted should include the following label information, clearly presented and printed on the media with the font of 12 Times New Roman (or equivalent):

1. The reference number

2. The company name

3. The product Trade name

4. The Generic name

5. The submission type of each submission(s) contained on the CD/DVD (e.g. initial)

6. The sequence number(s) of the submissions contained on the CD/DVD (e.g. 0002)

iii. Number of copies:

Applicants should submit:

a) THREE (3) softcopies (full submission).

b) ONE hardcopy of selected documents of Module 1 for all drug submission types. The submitted copies should be identical. The submission shall be in ONE media only (CD or DVD) i.e. if the submission size was above 750MB then the applicant has to use a DVD.

The submitted copies should be identical. The submission shall be in ONE media only (CD or DVD) i.e. if the submission size was above 750MB then the applicant has to use a DVD.

iv. Language:

Information and documents supporting a drug application – such as certificates and approval letters– must be either in Arabic or English. If documents are neither in Arabic nor English, a translation to English (from an authorized translation office) and authentication from the Saudi Embassy in the COO are required.¹⁸

Required Number of Vaccine Sample submit to SFDA

Table 01: Number of Vaccine Samples required to SFDA

Sl.No	Sample Type	Volume	Quantity
1	Ampoules, Vials & PFS	<0.5mL	50 sample
2	Ampoules, Vials & PFS	0.5-1.0mL	25 sample
3	Ampoules, Vials & PFS	1-2mL	20 sample
4	Ampoules, Vials & PFS	2-5mL	15 sample

Some of the Documents in Module Should be submitted in the Hardcopy and Original Document (Not Photocopy):-

Table 02: List of Documents that has to provide Hard and Soft copy to SFDA

Hardcopy	Original Document (Not Photocopy)
Cover Letter	Cover Letter
Application Form	Number of samples
Number of samples	Pharmacovigilance System
COPP	Risk Management Plan
Free Sales Certificate	COA of Drug substance & FP
Price List	Alcohol content declaration
Acknowledgement of DMF	Pork Declaration certificate
	Price list

CONCLUSION:

The main idea of this is to give clear information regarding the registration requirement and approval procedures for vaccines in Saudi Arabia. Stringent regulatory requirements must be achieved throughout development for a vaccine to be considered for licensure because Vaccines are important for safeguarding individuals and communities from the mortality and morbidity associated with many infectious diseases. . The vaccine must meet the standards established by Saudi Arabia Food and Drug Administration (SFDA) to be approved for marketing in Saudi Arabia, so it is necessary to know the clear registration requirement and approval procedure for vaccines.

REFERENCE:

1. Vaccine Basics [Internet] Available at: http://www.vaccineinformation.org/how-vaccines-work/.

2. Baylor NW* the Regulatory Evaluation of Vaccines for Human Use. 2016; 1404:773-87.Available at: https://www.ncbi.nlm.nih.gov/pubmed/27076337.

3. DENR-How to use [cited 2018 26]. Available at: https://denr.sfda.gov.sa/public/Howto.aspx

4. Saudi drug registration system. [Online] Available at: file:///C:/Users/HP/Desktop/PROJECT/Major%20Thesis/Saudiarabaia/Saudi%20drug%20Registration%20system.pdf

5. Regulatory framework for drug approvals. Available at: chrome-extension://oemmndcbldboiebfnladdacbdfmadadm/https://www.sfda.gov.sa/en/drug/drug_reg/Regulations/Regulatory_Framework_for_Drug_Approvals_v_5%200.pdf

6. GCC Data Requirement’s for registration of Human Pharmaceutical products Available at: chrome-extension://oemmndcbldboiebfnladdacbdfmadadm/https://www.sfda.gov.sa/en/drug/drug_reg/Regulations/The-GCC-Human-Drugs%20Submission-v2.1.pdf

Received on 04.04.2019 Modified on 27.04.2019

Research J. Pharm. and Tech 2019; 12(9):4531-4538.

DOI: 10.5958/0974-360X.2019.00780.7