Aseptic Processes

Terms about aseptic manufacturing

Aseptic processing

Is the process by which a sterile (aseptic) product (typically food or pharmaceutical) is packaged in a sterile container in a way that maintains sterility.

Antiseptics

Are used to prevent infection by killing or inhibiting the growth of microorganisms. Because these products are used in or on humans or animals, they are considered drugs and are approved and regulated by FDA.

Bioburden

Is normally defined as the number of bacteria living on a surface that has not been sterilized. The term is most often used in the context of bioburden testing, also known as microbial limit testing, which is performed on pharmaceutical products and medical products for quality control purposes.

Cytotoxic

Cytotoxicity is the quality of being toxic to cells and cell-killing. Chemotherapy and radiotherapy are forms of cytotoxic therapy.Cytotoxic drugs (sometimes known as antineoplastics) describe a group of medicines that contain chemicals which are toxic to cells, preventing their replication or growth, and so are used to treat cancer. They can also be used to treat a number of other disorders such as rheumatoid arthritis and multiple sclerosis

Endotoxins

Is a heat-stable toxin associated with the outer membranes of certain gram-negative bacteria, including Brucella, Neisseria, and Vibrio species. Endotoxins are not secreted but are released only when the cells are disrupted; they are less potent and less specific than the exotoxins; and they do not form toxoids. In large quantities they produce hemorrhagic shock and severe diarrhea; smaller amounts cause fever, altered resistance to bacterial infection, leukopenia followed by leukocytosis, and numerous other biologic effects.

Exotoxins

Is a potent toxin formed and excreted by the bacterial cell and found free in the surrounding medium; exotoxins are the most poisonous substances known. They are protein in nature and heat labile, and are detoxified with retention of antigenicity by treatment with formaldehyde. Bacteria of the genus Clostridium are the most frequent producers of exotoxins; diphtheria, botulism, and tetanus are all caused by such toxins.

Pyrogens

Is a polypeptide injected into humans - in sufficient amount - that produces fever by causing metabolic changes in the hypothalamus. Pyrogens are either exogenous (produced by infectious agents) or endogenous (produced by cells in the body such as macrophages).

Terms about drugs

Media Fill

(sometimes known as a "process simulation") is the performance of an aseptic manufacturing procedure using a sterile microbiological growth medium in place of the drug solution. Microbiological growth medium is used in place of the drug solution during media fills to test whether the aseptic procedures are adequate to prevent contamination during actual drug production. A media fill is one part of the validation of an aseptic manufacturing process.

Biosimilar

(products are designed to be similar to an already approved biologic product)

FDA says, a biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.

Bioequivalent

(products are pharmaceutically equivalent to and have bioavailability identical to that of an already approved drug)

FDA has defined bioequivalence as, the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

Branded Drug

is a drug with a valid patent (hold by the originator).

Blockbuster Drug

is an extremely popular drug that generates annual sales of at least $1 billion for the company that creates it. Examples of blockbuster drugs include Vioxx, Lipitor and Zoloft.

Ethical Drug

is a drug that is available only with written instructions (prescription) from a doctor or dentist to a pharmacist.

Generics

or generic drug is a pharmaceutical drug that is equivalent to a brand-name product in dosage, strength, route of administration, quality, performance, and intended use. It is usually intended to be interchangeable with the originator brand product, manufactured without a license from the originator manufacturer and marketed after the expiry of patent or other exclusivity rights. It should be Bioequivalent to the originator.

Originator

is the brand-name product where the company holds the patent for.

OTC (Over The Counter) Drug

are drugs that have been found to be safe and appropriate for use without the supervision of a health care professional such as a physician, and they can be purchased by consumers without a prescription.

Definitions about surface disinfection in pharmaceutical production

Cleaning agent

chemical used in combination with water to clean a surface or product. As side effect also microbes are reduced: ideally removal of 90-99 %.

Disinfectant

chemicals used to inhibit or prevent the growth of microbes on inanimate objects: ideally killing of 99,999 %.

Bactericide

kills bacteria

Fungicide

kills fungi

Virucide

kills virus (enveloped / lipophilic are typically easier to kill than nonenveloped viruses)

Sporicide

kill spores (fungi and bacteria)

Biocide

kills living organisms

Bacteriostat

inhibits the growth of bacteria

Detergent

contains free ions (leaves film on surface)

Anionic Detergent

(soaps) have free negative ions that produce curd when combined with calcium and magnesium in hard water

Cationic Detergent

Quaternary ammonium contains positively charged ions which remain suspended in solution

Disinfectant effectiveness depends on many factors

Type of contaminating microorganism. Each disinfectant has unique antimicrobial attributes.

• Degree of contamination. This affects the time required for disinfection and the amount of chemical required.
• Amount of protein-containing material present. Protein based materials absorb and inactivate some chemical disinfectants ("protein error").
• Activity in organic matter and other compounds such as soaps. Soaps can react with chemical disinfectants and inactivate them ("soap error").
• Type of chemical. It is important to understand the mode of action in order to select the appropriate disinfectant.
• It is important to choose the proper concentration and quantity of chemical that are best used for the disinfection of each situation.
• Sufficient contact time and appropriate temperature, which is proportional to the degree of contamination, must be allowed for action of the disinfectant.
• Residual activity and effects on fabric and metal.
• Application temperature, pH and interactions with other compounds must be considered.
• Toxicity to the environment and relative safety to humans that may be exposed.
• Materials and surfaces are used in aseptic manufacturing area and the influence of the depending detergent on it (material studies).
• Cost

Types of disinfectants considered

• Chlorine
• Iodophors
• Chlorhexidine
• Alcohols [e.g. Isopropyl Alcohol (IPA)]
• Peroxide
• Phenols
• Quaternary ammonia
• Aldehydes

A selection of microorganisms

• A microorganism or microbe is a microscopic organism, which may be single-celled or multicellular.

Bacteria

Bacteria constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a number of shapes, ranging from spheres to rods and spirals. Bacteria were among the first life forms to appear on Earth, and are present in most of its habitats. Bacteria inhabit soil, water, acidic hot springs, radioactive waste, and the deep portions of Earth's crust. Bacteria also live in symbiotic and parasitic relationships with plants and animals. Most bacteria have not been characterised, and only about half of the bacterial phyla have species that can be grown in the laboratory. The study of bacteria is known as bacteriology, a branch of microbiology. There are typically 40 million bacterial cells in a gram of soil and a million bacterial cells in a millilitre of fresh water. There are approximately 5×1030 bacteria on Earth, forming a biomass which exceeds that of all plants and animals.

Spore

A bacterial spore is a structure produced by bacteria that is resistant to many environmental or induced factors that the bacteria may be subjected to. Spores help bacteria survive by being resistant to extreme changes in the bacteria's habitat including extreme temperatures, lack of moisture/drought, or being exposed to chemicals and radiation, but it is still not clear where they get nutrition from in these conditions. Bacterial spores can also survive at low nutrient levels, as well as being resistant to antibiotics and disinfectants. These factors make it nearly impossible to eliminate bacterial spores, as they are found in many places, especially in food products.

Most bacterial spores are not toxic and cause little harm, but some bacteria that produce spores can be pathogenic. Most spore-forming bacteria are contained in the bacillus and clostridium species but can be found in other species of bacteria as well.There are different types of spores including endospores, exospores, and spore-like structures called microbial cysts. Each of these aid the bacteria in survival and serve as protection for the cell.

Bacterial spores are extremely resistant. Spores of tetanus and anthrax, for example, can survive in the soil for many years. The origin of these spores was discovered in the 19th century, when a biologist noticed, under the microscope, a small, round, bright body inside bacterial cells. This survived even when the bacteria were boiled for five minutes. This killed the bacteria, but not the spores. They germinated when conditions were right. Because spores are so resistant, they are highly transmissible. This makes them a very problematic aspect of spore-forming pathogens such as Clostridium difficile .

Fungus

Describes any of a group of unicellular, multicellular, or syncytial spore-producing organisms feeding on organic matter.

Virus

A virus is a small infectious agent that replicates only inside the living cells of other organisms. Viruses can infect all types of life forms, from animals and plants to microorganisms, including bacteria and archaea.

Comparison of decontamination principles: Vaporized H2O2 in an isolator (biodecontamination cycle) and autoclaving

• First of all the difference between disinfection (e.g. Isopropyl Alcohol Wipes) and sterilization:

Disinfection and sterilization are both decontamination processes . While disinfection is the process of eliminating or reducing harmful microorganisms from inanimate objects and surfaces, sterilization is the process of killing all microorganisms. That is the main difference between sterilizing and disinfecting . Sterilization also destroys the spores of various organisms present on surfaces, in liquids, in medication, or in compounds such as biological culture media. Such "extreme" forms of decontamination are needed during critical times like surgery, or in environments like industrial, laboratory or hospital. It is more practical to use disinfection in everyday life.

• H2O2 Biodecontamination in an Isolator is a surface sterilization .
• Autoclaving has a deeper impact and leads to a complete sterilization (by influence of temperature and pressure).

Sterility Assurance Level (SAL) and Log Reduction (D Value) in Sterilization

Sterilization of pharmaceutical articles is affected by a lot of factors as temperature, population of microbes, quantity of material, sterilization exposure time etc. Log reduction plays important role in the sterilization process. It shows the potential of the sterilization process. One log reduction shows the decrease in microbial population by 10 times. It means if a solution has 100 cfu (colony forming unit), after 1 log reduction it will have 10 cfu and 1 cfu after 2 log reduction. It is 90% reduction in a specified microbial population. The time (in minutes) required to achieve 1 log reduction (at specified temperature) is called D-value. Generally in sterilization it is required to achieve a SAL (sterility assurance level) of 106 and an additional 6 log reduction. It means all 106 (one million) organisms present in the material are killed effectively and assured by extra 6 log reduction. In 6 log reduction the microbial population shall be reduced from 106 to 1 and in other 6 log reduction population shall be reduced to 0.000001 that assures the sterility of the sterilized material. For example, if a material has a bioburden of 540 cfu then to reduce the microbial population from 540 to 1 = log (540) = 2.73. It shows that only 2.73 log reduction is required to decrease the microbial population from 540 to 1. Total log reduction required for sterilization of the material with SAL value of 106 2.73+6 = 8.73. Total sterilization time at 121°C with D- value of 2.5 min/log shall be 2.5x8.73 = 21.82 minutes. Most of the biological indicators have a population of 106 spores and 6 log reduction is required to reduce the population to 1. Another 6 log reduction is required for SAL value of 106.