The objective of Module 2 is to review the following:
- Manufacturing the API
- Manufacturing the excipient
PHARMACEUTICAL MANUFACTURING PROCESS
The process of converting a new molecular entity or NME to a viable drug is called as pharmaceutical development process. This process involves segregating and accumulation of the active component of the drug by using chemical and biochemical methods. The active ingredient is then incorporated along with stable compounds to convert it into a stable drug.
What constitutes a pharmaceutical product?
A pharmaceutical product is composed of two parts: active pharmaceutical ingredient (API) and a pharmaceutically inert carrier compound (excipient). The API is the actual drug or component that gives the desired pharmaceutical effect, while the excipient is the carrier material (chemical base of the tablet, emulsion, cream, capsules, etc.) in which the API is suspended in a biologically active concentration.
Figure 1: API
Steps in Pharmaceutical Manufacturing
Pharmaceutical product manufacturing is carried out in two phases. In the first phase, the API is manufactured from the bulk raw material. The nature of process depends on the source of the API. Currently chemical and biochemical methods are used for API production.
The second phase is incorporating the API into the excipient, which is either solid (tablet, capsule, chewable tablets) or liquid (injections) or semi solid (gels, creams) or aerosol (inhalers) in nature. The second phase is also called as formulation.
Manufacturing the API
API is the most important component of the entire medication and thus needs to be of best quality for human or animal use. API can be produced using chemical technology and biochemical technology. A good API production unit should run on a project plan that has the best strategy for logistics of the raw materials, can identify each batch of API correctly and has a flexible and well-protected production unit.
Chemical Process for API Synthesis
Chemical APIs represent 70-80% of the drugs in the market. Before the API is synthesized chemically, the process needs to be optimized and standardized for consistent API production. Thus, the raw materials, conditions and the equipments have to be coordinated for impurity-free and consistent outputs.
Common chemical APIs are hormones, peptides, sulphonamides and glycosides. There are innumerous chemical API production pathways. The exact method followed depends on the target API. Typically, chemical API production will involve transformations, catalysis reactions, isolations, filtration, extraction and purification.
The chemical API method requires large quantities of solvent. Apart from API production, recovery of solvent and reusing it is part of the chemical manufacturing. Chemical synthesis of API is a costly affair. To reduce the production cost, manufacturers focus on process reduction. By increasing a certain catalyst or reducing a certain element, a 5-step production could be reduced to 2 steps.
Whatever be the pathway, every chemical API synthesis facility needs to follow the following guidelines by the International Conference on Harmonization (ICH) Q7 (Compliance for APIs Manufactured by Chemical Synthesis):
- The equipment used for chemical API production should be properly calibrated for consistent results. The equipment should qualify for the API chemical production process in question.
- The equipment has to pass the validation criteria of Design qualification (DQ), Installation qualification (IQ), Operational qualification (OQ), Process performance qualification (PQ).
- The manufacturing facility should follow the exact same process for all batches of chemical API production through process validation.
- Each manufacturing unit (the machine) should be cleaned properly to remove contaminant trace elements. The acceptance levels of trace impurities should be clearly mentioned and verified by the operator.
Bio-Chemical Process for API Synthesis
Biochemical methods use cell lines, cell cultures, microorganism, biotechnology and fermentation technology to produce the biotech API or bio API. The process begins with identification of the biological source of the active ingredient.
For mass production, it is essential that the biological source used is identical (clone) and free of contaminants. Cell lines, cell cultures and microorganisms can get contaminated very quickly and need constant monitoring. The biological source usually has a tendency to mutate or morph under stress. For certain biological materials, the API could be an inhibitor. In such cases, the bio API should be removed quickly from the fermentation unit to avoid death of the inoculums/cell line/microorganism.
According to the ICH Q7 guidelines,
- The medium/media for the growth of the biological material needs to be standardized and validated for consistent results.
- Fermentation (continuous or batch) process should be performed in equipments that are fit for API production.
- The biological source should be checked constantly in the labs by the operator to identify contaminants, mutations, health, pH and viability.
- The manufacturing facility needs to be aseptic at all times.
Biological materials are very fragile. The initial cost of buying a certain kind of biological material for a large scale can be very huge. However, that cost can be recovered in a short time if the biological source is well maintained and monitored at regular intervals. Therefore, it is necessary to follow the proper maintenance guidelines in biological or biotech API production.
In both chemical and biochemical process technologies, the APIs need to be 100% pure. Aseptic API production is achieved by using closed systems that are sterile.
Manufacturing the excipient
As said earlier, a drug is combination of the drug itself and several other chemical components. The other components have to be studied intensively for their effects in combination with the API. If the excipient chemicals interfere with the functioning of the API, the purpose of developing that drug is defeated. Thus, formulation studies are a separate section of R&D that makes it possible to develop the correct delivery system for every pharmaceutical product.
In formulating a drug, its stability, bioavailability, particle size, pH, solubility, absorbance and allergic reactions are measured. Formulation also involves zeroing the correct inert packaging material in which the end pharmaceutical can be contained.
The second phase of the pharmaceutical manufacturing can take slightly longer time than the API production. It often happens that the API is ready, but the dosage form is not. And so, it isn’t uncommon that the dosage forms and delivery systems used for clinical trials are often not the final ones that are released in the market.
The pharmaceutical industry is a highly regulated industry and all production must be carried out in accordance with good manufacturing practice. Traditionally, virtually all manufacturing operations have been carried out batch wise in spite of cost disadvantages and the fact that in many cases continuous processing could lead to the manufacture of purer products. The regulatory environment tends to stiﬂe any attempts to change the process once the development stage is over and the product and process have been licensed. This has created a mind set amongst the industry’s professionals that batch processes are the only acceptable way forward. However; the regulatory authorities, particularly the Food and Drug Administration in America, have recognized that continuous processing has the potential to improve product quality and are encouraging the industry to reconsider their ideas.
This paper examines how chemical engineers can use the opportunity that arises from this changed regulatory environment to revisit their own ideas and drive a change of mind set within the industry.