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LPPOM MUI

Getting to Know Vaccine Manufacturing and its Halal Critical Point

by: Prof. Dr. Ir. Sedarnawati Yasni, M.Agr

Lecturer of Food Science and Technology, Faculty of Agricultural Technology, IPB University 

Senior Halal Auditor LPPOM MUI  

Currently, the coronavirus disease 2019 (COVID-19) vaccine is in the center of public attention. In this case, The Assessment Institute for Foods, Drugs and Cosmetics Indonesian Council of Ulama (LPPOM MUI) has a role in overseeing the halallness of vaccines for the Indonesian people.

Halal inspection of products, including vaccines, starts from ups to downs. It starts from raw materials, manufacturing processes, packaging to vaccines until they are in the hands of consumers. Previously, LPPOM MUI had experience in certifying the halalness of several vaccines, such as the influenza vaccine and Bacillus Calmette–Guérin (BCG) vaccine.

Vaccines are compounds that are intentionally made to stimulate the formation of antibody compounds (anti-diseases) so that the body has immunity against disease or reduces the influence of infection from certain conditions. Although vaccines are considered the most effective against and destroying infectious diseases, each type of vaccine has limited effectiveness.

Often a person’s vaccination fails because the immune system does not give the desired response or even does not respond to antigens provided by the vaccine. This condition can occur due to clinical factors, such as diabetes, steroid use, infection HIV, or age. Genetic factors are also one of the factors that influence it. That is, if a person’s immune system does not have a B cell strain that can produce antibodies and react effectively in binding to antigens from the pathogen. 

Where is the Critical Point of Halal Vaccine?

The halalness of a product is generally known from the halal status of the raw materials used, the manufacturing process, and production facilities. In making vaccines that use tissue culture, recombinants or those that require the propagation of bacteria or viruses, of course, it is necessary to analyze the media materials used. 

Several types of vaccines in circulation can be known about their raw materials and manufacturing processes to analyze critical points.

The types of vaccines circulating in the world are classified according to the type of antigen present in them, so the vaccine formulation will affect how it is used, stored, and administered. In addition, vaccines are useful for preventing infectious diseases, such as polio, measles, hepatitis B; suppressing or reducing pathogens’ ability to spread (herd immunity); and protecting individuals who cannot be vaccinated. 

Summarized from various sources, it is known that vaccine types can be distinguished between monovalent or polyvalent and combinations. 

Monovalent vaccines contain a strain or antigen, such as the measles vaccine. A polyvalent vaccine includes two or more strains/serotypes of the same antigen, for example, the oral polio vaccine (OPV). While in combination vaccines, some of the antigens are combined into one injection preparation to prevent several different types of diseases.

For example, the DPT vaccine contains three types of antigens, namely diphtheria, pertussis, and tetanus. Combining various antigens is very useful for overcoming logistical problems if the vaccine is packaged in one package of only one type of antigen. In addition, this is also a solution to overcome children’s fear of pain due to repeated injections.

In general, the ingredients needed to manufacture a vaccine are antigens, stabilizers, adjuvants, antibiotics, and preservatives. 

To find out the critical point of halalness of a product, it can be observed from the halal status of raw materials, additives, and auxiliary materials used. 

1. Antigens that stimulate the formation of immunity are components produced from the structure of disease-causing organisms known as “foreign bodies” by the human immune system. 

2. The addition of a stabilizer is intended to ensure the stability of the vaccine during storage in an unstable cold chain system. Vaccine stability is mainly affected by temperature and pH. Stabilizers widely used in vaccines’ manufacture are MgCl2, MgSO4, lactose-sorbitol, and sorbitol – gelatin.

3. The addition of adjuvants into conventional vaccine formulations aims to stimulate, enhance and prolong the specific immune response to vaccine antigens. New vaccines made by subunit purification or synthetic vaccines caused using biosynthetic, recombinant, and modern technology will contain a small antigen, so it is essential to use adjuvants to obtain the desired immune response. 

In other words, adjuvants are a heterogeneous group of compounds with only one thing in common: their ability to stimulate an immune response. Adjuvants are intentionally added to vaccines to promote the formation of antibodies to the antigens in the vaccine more effectively. Examples of adjuvants that can be used include aluminum salts, potassium chloride, monobasic potassium phosphate, and sodium chloride. Even so, although currently being researched the types of adjuvants in vaccine technology.

4. The use of antibiotics (in small quantities) in the manufacture of vaccines aims to prevent bacterial contamination of virus-cell cultures cultured. This is indicated by the levels of antibiotics detected in the vaccine are very low, for example, in the MMR and IPV vaccines, there is only 25 g of neomycin for each dose of vaccine (< 0.000025 g). Therefore, someone allergic to neomycin should be monitored closely so that the onset of allergic reactions after vaccination can be treated quickly.

5. The addition of preservatives in the vaccine aims to prevent the growth of bacteria and fungi with multi-dose packaging. Several preservatives commonly used in multi-dose packaging include thiomersal, formaldehyde, and phenol derivatives. 

Thiomersal is a chemical compound containing ethyl mercury, although no one has reported any side effects at the doses used in the immunization program. Formaldehyde is used for virus inactivation (e.g. IPV) and to detoxify bacterial toxins in the manufacture of diphtheria and tetanus vaccines in deficient quantities so as not to harm human health. After that, a purification process was carried out to remove all formaldehyde in the vaccine. The method chosen in the purification process needs attention, too, regarding the material.

Example: Inactivated Vaccine (Killed Vaccine) 

Viruses are cultured by tissue culture (cell line or Vero cells derived from monkey kidneys). Virus splitting was done by trypsinization using trypsin enzyme, and virus inactivation using beta propiolactone which aims to inactivate RNA. Then purification was carried out using column chromatography with a stationary silica phase sucrose gradient so that the obtained whole virus was (as an active ingredient for vaccine manufacture). The active ingredient is dissolved in a solution buffer, a phosphate or buffer saline solution. Then, adjuvants are added to enhance the immune response (called immunogenic, and aluminum hydroxide is commonly used). The final stage is dispensing (bottling) and packaging.

From the above process, we can determine the critical point of the halalness of the resulting product:

1. The process of culturing the virus with tissue culture techniques must ensure the halal status of the materials used. 

2. The breakdown of virus cells with the trypsin enzyme must also be ensured from halal raw materials and processes. 

3. The process of inactivating the virus using beta propiolactone, this material must also be confirmed for its halal status. 

4. The purification process must be ensured using the proper technique.  

There is no problem with silica, but it is different when using a sucrose gradient.

Example: Vaccine Recombinant (RNA)

MRNA

Recombinant RNA vaccines consist of the essential genetic information of the virus in the form of messenger RNA, or mRNA, a type of molecule whose job is to transport copies of genetic instructions around cells to guide protein assembly. Think of an mRNA as a tape ticker long containing instructions. This raw is a reasonably sensitive material, and that’s why vaccines should be stored at about -100°F (-73°C) until use.

The vaccine, which is given as an injection into the muscle of the arm, contains an RNA sequence extracted from the virus itself, causing the cells to produce a large protein “surge” from the virus. By itself, without other viruses, the spike is harmless, but the body will react. This reaction makes the body immune and ready to repel the actual virus.

Lipid

This vaccine uses lipid nanoparticles to encapsulate RNA. Nanoparticles are tiny oily balls that protect the mRNA and help it slide through the cell. These particles may be about 100 nanometers in size.

There are four different lipids in the “defined ratio.” That’s because it can be ionized (can be given a positive charge), and because RNA has a negative charge, they stick together. Lipid ALC-0315 is the main ingredient in the formulation. It is also a component that can cause side effects or allergic reactions. 

Another lipid is the well-known cholesterol molecule, a “helper” that provides structural integrity to nanoparticles or stops their clumping. The RNA and lipids are stirred into a bubbly mixture during manufacture to form what the FDA describes as a “white to white” frozen liquid.

Salt

Generally, recombinant RNA vaccines contain phosphate-buffered saline (PBS). This material is very commonly used to maintain the pH or acidity so that the vaccine is close to the pH of a person’s body. Substances with the wrong acidity can injure cells or break down quickly.

Sugar

The vaccine includes plain old sugar, also called sucrose. It acts as a cryoprotectant to protect the nanoparticles as they freeze and stop them from sticking together. (*)

Sources: 

– www.who.int 

– www-prevention-com.cdn.ampproject.org  

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