UNIT OPERATION / PRODUCTION PROCESS


Potent Formulation

The term potent describes the required amount of drug to achieve the desired therapeutic effect. Exposure to highly potent drugs during manufacturing can pose significant health risks. Thus, the design of the manufacturing facility must be planned and be restricted only to trained personnel. Though safe handling protocols of potent compounds are common, it is not product specific. Therefore, it is agreeable to apply engineering controls to achieve maximum containment in minimizing risks and hazards and in promoting the safety of the product, the working personnel, and the environment.

Facility Design

The facility for potent formulation must be designed to promote sterility, safety, and continuity of workflow process. The most common facility design requirement for drug manufacturers is known as process isolation. In this process, enclosed equipment such as sealed reactors and dryers are utilized for product transfer systems. This is mainly use for moving materials through a process train. A facility should also be designed with equipment such as isolators, laminar flow hoods, and local exhaust ventilation appropriate for potent compound handling.

Aside from the design, the airflow inside the facility should be single-pass to prevent cross contamination or concentration of chemicals in the area. It is important to make sure that the exhausted air to the external environment must be filtered. Areas handling potent compounds must be negatively pressurized to prevent it from contaminating adjacent process rooms. Engineering controls and facility design is also applicable to process development and quality control laboratories.

Proper training on procedures for operation and maintenance of containment and isolation equipment is critical. Staff members must understand why the use of engineering controls is crucial for a manufacturing process. The staff handling potent formulation must wear proper Personnel Protective equipment (PPE) and respiration equipment (if necessary) at all times.

Open Active Restricted Access Barrier System (oRABS) and closed Restricted Access Barrier System (cRABS) can both be integrated with filling line machine, electronic sievers and millers for better containment of potent and hazardous products. The rigid walls and the panels provide physical separation during aseptic processing operations.

Product Categories

All drug products must be evaluated and characterized according to its potential hazards hence, correct handling procedures can be established beforehand. The performance – based exposure control limits (PBECL) categorization system links compound toxicity and potency to procedures for safe handling practices. The most common system has four categories, listed as follows.

Category 1 compounds have low potency with higher dosage levels. These products have minimal acute or chronic health effects and will have no genetic effects. Its absorption is slow, therefore requiring no medical intervention during exposure to it.

Category 2 compounds have moderate acute or chronic toxicity, but their effects are reversible. They may be weak sensitizers. Most have fair warning properties, a moderate absorption rate, and no genetic effects, but medical intervention may be required after exposure to them.

Category 3 compounds have elevated potency, with high acute or chronic toxicity. These effects may be irreversible. The products may be moderate sensitizers, and their warning properties are likely to be poor or absent. Their absorption rates may be rapid, they may have suspected or known genic effects, and moderate to immediate medical intervention will be required.

Category 4 compounds have high potency and extreme acute and chronic toxicity. They cause irreversible effects and are likely to be strong sensitizers, with poor or no warning properties and a rapid absorption rate. These products will have known genetic effects and require a higher degree of medical intervention. They may also affect sensitive subpopulations to a greater extent than the public overall.

All potent products that fall into category 3 and 4, both requires containment and protection but varies on the precise ways they are put into practice. The details depend on whether a product is an infectious biologic such as virus or vaccine, a highly potent small molecule, or an antibody drug conjugate that links a biologic to a potent small molecule.

Containment of Hazards

Current good manufacturing practice (cGMP) is the guideline that governs manufacturing practice. cGMP requires facilities processing highly potent active pharmaceutical ingredients (API) to comply in installing containment equipment such as isolators, downflow booths, and single air pass systems. Every step of the manufacturing process must be sealed from raw material in addition to the packaging of the final products. This is to prevent exposure of operators from harmful chemicals that may pose irreversible health damage during the manufacturing process. Only nonhazardous chemicals can be added freely without stringent restrictions.

For a category 1 molecule — which offers little risk during manufacturing — generally safe laboratory practices and gowning are sufficient. Open handling may be acceptable for small quantities of product, but local ventilation is advisable for handling larger quantities. However, no containment is needed. Standard laboratory practices and gowning are enough for category 2 as well, but the cut-off point for local ventilation is lower, and containment is needed for high-energy, dust-generating operations such as milling.

Category 3 molecules handling requires containment room controls, process isolation equipment, and operators wearing PPE with respiration equipment (if necessary) at all times. Preventing the operators and the environment from exposure of potent chemicals is the main goal of containment. Thus it is vital to follow these requirements.

Category 4 products as the most hazardous require full PPE with respiratory protection in a specialized facility in addition to all the requirements in category 3. The area is restricted to few trained personnel only. All solutions and powders have restrictions against open handling.

Requirements for Different Product Types

Many general requirements for chemical API plants are the same for facilities manufacturing highly potent biologics, but there are some important differences. Viral vectors and vaccines are manufactured in sealed bioreactors, and because they are infectious, these products must be carefully contained. Operators and the public must be protected in the event of an escape. As with chemical facilities, air should be single-pass and HEPA-filtered, with each manufacturing suite exhausting separately through further HEPA filters to prevent cross-contamination. People, equipment, and raw materials should all flow from clean to dirty areas, with exit vestibules providing the final line of containment.

TideCell® High Density bioreactor system is the extended large scale system of the lab scale CelCradle® bioreactor system. In this system, a matrix vessel is packed with porous BioNoc™ II carriers and functions as an artificial lung with huge contact surface for nutrition and aeration.

Cross – contamination is an even greater issue with virus-based products. One means of prevention is the use of disposable bioreactors. Though single-use technology is a bit more costly, but it reduces the need for cleaning and validation which allows much faster changeover between different products. This is more applicable in facilities that produce numerous batches of different viruses and vaccines.

CelCradle™ is a disposable bioreactor capable of high-density cell culture for protein expression, virus, and monoclonal antibody production. It is designed based on the concept of bellow-induced intermittent flow of media and air through porous matrices, where cells reside. This provides a low shear, high aeration, and foam-free culture environment.

An antibody–drug conjugate combines an antibody that targets a specific site in a patient’s body with a small-molecule payload that provides a therapeutic effect. As high-potency small molecules become more frequent in bioconjugates, containment issues become crucial. Not only do the chemical issues have to be considered, but manufacturing the antibodies also requires a biologic facility — and biologic and chemical facilities have very different requirements. Facilities designed for conjugating antibodies to small-molecule potent compounds must combine the two facility types to ensure that containment, cleaning, and proper aseptic handling techniques are incorporated.

It makes more sense when designing a facility for manufacture of antibody–drug conjugates to introduce chemical handling capabilities into a facility designed for biological manufacturing rather than vice versa. This can be done by installing a containment isolator (complete with airlock, rapid transfer port, and utility connection plate) into an aseptic environment that also contains a biological safety cabinet and other equipment necessary for biologics. Essentially, introducing all the equipment for high-potency API manufacture within a biologics facility adds greatly to its complexity.

Secondary metabolites involve compliance in current good manufacturing practice (cGMP) during manufacturing of these highly potent small molecule drugs which uses biologic systems, and organisms such as yeast or fungi. Handling these products will concern containment, so a full assessment of the chemical’s nature must be evaluated first.

Containment Barrier Isolator (CBI) integrated with a Biological Safety Cabinet (BSC) made out of full stainless steel

If a secondary metabolite product is highly potent, then a combination of biological-and chemical-enhanced containment will be necessary, with level 2 large-scale biological safety alongside the ability to isolate highly potent compounds up to category 4. Each separate manufacturing suite will require single-pass HEPA air supply and separate exhaust complete with room pressure differentials and full airlocks and vestibules around each manufacturing suite as well as directional flow (from clean to dirty) of personnel, materials, and waste. For multipurpose facilities of this type, strict changeover procedures must be observed using automated steam-and clean-in-place (SIP and CIP).