Risk & Regulations of TSE/BSE in pharmaceuticals are of great importance because of its irreversible fatal effects on human health. Before knowing the risk and regulations of TSE/BSE in pharmaceuticals, it is very much necessary to know what TSE/BSE is, how it affects human, sources of TSE/BSE, the history/discovery and the modus operandi.
Raw material of Pharmaceutical products which derived from the animal source have risk of Transmissible Spongiform Encephalopathy ﴾TSE﴿. This disease can transmit in human through pharmaceutical dosage forms from the cattle infected with the Bovine Spongiform Encephalopathy ﴾Full Form of BSE﴿.
TSE – Transmissible Spongiform Encephalopathy
In general, TSE is a human disorder. A group of rare degenerative brain disorders characterized by tiny holes that give the brain a “spongy” appearance. It is a rare disease occurs in Humans and Vertebrate animals (Vertebrate = Animals having backbone)
TSE = A disease capable of being transmitted by infection and gives the appearance of sponge like tiny holes in the brain. There are many types of Human TSEs. This disorder makes the brain porous ﴾spongy﴿ that can be easily seen under the microscope.
The literal meaning of TSE is as below
Transmissible = Capable of being transmitted by infection Spongiform = Sponge like Encephalopathy = Brain Disease [encephalon + pathy = the technical name of brain + Pathy = disease]
Prions are self replicating proteins but some scientists say that those are having genetic information in their nucleic acids and categorize them as viruses. These are highly stable forms of proteins and have resistance against drying, freezing and cooking temperature.
BSE – Bovine Spongiform Encephalopathy
It is a brain disease that occurs in bovines; generally known as “Mad Cow Disease”. It is a rare disease occurs in Vertebrate animals; for example, cow/cattle.
The disease has a long incubation period of four to five years, but ultimately fatal to cattles within weeks to months of its onset. BSE affects the brain and spinal cord of the cattle. The lesions are characterised by a sponge like appearence which is vissible under ordinary microscope. Cow, sheep and goats are the most susceptible animals for this disease.
BSE = A disease capable of transmitted by infection and gives a appearance of sponge like tiny holes in the brain of bovines.
The literal meaning of BSE is as below
Bovine = Characteristic of or resembling cows or cattle. Spongiform = Sponge like Encephalopathy = Brain Disease [encephalon + pathy = the technical name of brain + Pathy = disease]
The known cause of BSE in cattle is protein cattle feed ﴾meat and bone meal﴿. That was banned by FDA in 1997. Most of the cases of this disease are found in European countries like United Kingdom, France, Ireland and Italy. By the end of 2002, over 182,000 confirmed cases of BSE had been reported in the UK. One case was also reported from United States and Canada.
The Causative agent
The causative agent is NOT a bacterium or a virus or a fungus or any plant(s). It is a protein called as Prion, usually present in the body cells of Human and Animals . The structure of the prion protein is given below.
Prion have two forms as said below.
Prion = proteinaceous infectious particle, named as Prion Proteins [PrP] Normal Form A harmless protein found in the body’s cells which is unfolded in structure which does not cause TSE Abnormal Form The protein which is in folded structure and can cause TSE.
Both normal and abnormal prion are identical except the folding in the structure of abnormal proteins. The accumulation of an abnormal isoform of the prion protein in the Central Nervous System causes the diseases.
TSE diseases of humans include Creutzfeldt–Jakob disease, new variant Creutzfeldt–Jakob disease (nvCJD, a human disorder related to madcow disease), Kuru,Gerstmann–Sträussler–Scheinker syndrome (GSS) & Fatal familial insomnia (FFI).
Bovine Spongiform Encephalopathy ﴾BSE﴿ transmits from cattle to humans in the form of Creutzfeldt–JakobDisease ﴾CJD﴿ known as variant Creutzfeldt–Jakob Disease ﴾vCJD﴿, a commonly known TSE in human.
Human TSE’s can occur in three ways
2.As heriditary diseases
3.Through transmission from infected individuals.
TSE’s cannot be transmitted through the air or through touching or most other forms of casual contact. However they may transmitted through contact with infectious tssue, body fluids or contaminated medical instruments. Normal sterilization procedure such as boiling or irradiating materials do not prevent transmission of TSE’s. Presently this disease has no effective treatment.
Symptoms of TSE’svaries but commonly includes personality changes, psychiatric problems such as depression, lack of coordination etc. Patients may also experience involentry jerking movements, unusual sensations, insomnia and memmory problems. In latter stage of the disease, patients have severe mental impairment and lose the ability to move or speak.
CJD is transmitted through the medical, vaccine and pharmaceutical products, especially in the countries where CJD is not detected yet. Blood and plasma could be the great vehicle for the transmission of this disease.
In India these are rare diseases in animals but if you are importing products derived from animal sources you should ask for TSE/BSE certificate and the source of the product. Gelatin and other products used in pharmaceutical dosage forms may carry the TSE infection.
Risk of TSE/BSE in Pharmaceuticals
There is a possible risk of contamination of infected animal derived products in the pharmaceutical finished dosage form for human consumption leads to transmission of TSE/BSE to human beings.
In some cases, the Pharmaceutical preparations like Finished Dosage Forms, Active Pharmaceutical Ingredients and their Starting Materials, and Primary Packaging Materials involves the use of products/materials derived from animals. For example, use of proteins, enzymes, amino acids from animals used in the manufacturing of API and API starting materials.
The primary packaging materials like gelatins capsules derived from the fat of animals also increases the possibilities of transmission of TSE/BSE.
There is a high risk in the case of biotechnological products like serums, blood products and vaccines where the source material is derived from animals and animal derived products.
There is also a possible risk of TSE/BSE through the equipments/utilities where in biologically-derived products and/or products of animal origin is handled. For example, Culture media used in reactors for media fill studies.
Ideally, the use of such animal derived product/material should be avoided in the pharmaceutical preparation. However, during unavoidable circumstances, the use of such animal derived products is accepted, provided that the manufacturing process and procedures complies to the applicable regulations set by WHO, European Commission and USFDA.
Regulations to minimize the TSE/BSE risks
Since the use of animal-derived materials is unavoidable for the production of some medicinal products and that complete elimination of risk at source is rarely possible, the measures taken to manage the risk of transmitting animal TSEs via medicinal products represent risk minimization rather than risk elimination.
TSE-relevant animal species
Cattle, sheep, goats and animals that are naturally susceptible to infection with transmissible spongiform encephalopathy agents or susceptible to infection through the oral route other than humans and non-human primates are defined as ‘TSE-relevant animal species’
When manufacturers have a choice the use of materials from ‘non TSE-relevant animal species’ or non-animal origin is preferred. The rationale for using materials derived from ‘TSE- relevant animal species’ instead of materials from ‘non-TSE- relevant species’ or of non-animal origin should be given. If materials from ‘TSE-relevant animal species’ have to be used, consideration should be given to all the necessary measures to minimise the risk of transmission of TSE.
Minimising the risks of transmission of TSE is based upon three complementary parameters:
— the source animals and their geographical origin,
— nature of animal material used in manufacture and any procedures in place to avoid cross-contamination with higher risk materials.
— production process(es) including the quality assurance system in place to ensure product consistency and traceability.
Ministry of Health, Government of India has also published guidelines on TSE and BSE requirements.
Other sources of TSE/BSE
Culture Media (used in reactors for process simulation studies like media fill)
Any equipment that comes in contact with TSE-RAS
Milk and Milk derivatives
Bovine blood derivatives (serums for vaccines)