The answer seems obvious at first glance, chemical entities are produced by mixing two substances and obtain a third one, while biologics consists in taking it from a living thing, whether it is a plant, an animal or genetically modified CHO. It is the basis of their definition, as the FDA’s website shows us.
What is a biological product?
Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources – human, animal, or microorganism – and may be produced by biotechnology methods and other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.
But apart from that, are they really so different or is this just perception that they are different?
This is a fair question for a non-expert, as a biologic seems to have many drawbacks:
- It takes more staff to monitor and control the manufacturing processes;
- It requires a larger number of more expensive QC release and stability tests;
- It requires an extensive number of batches and testings records for QA to review, thus, taking QA longer to release each batch.
Let’s ask the regulators
It is always a good start to see what the US FDA and other state regulators say on a concept to have sound information in hands.
The FDA point of view
How is the manufacturing process for a biological product usually different from the process for drugs?
Because, in many cases, there is limited ability to identify the identity of the clinically active component(s) of a complex biological product, such products are often defined by their manufacturing processes. Changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the product’s safety, identity, purity and potency. Traditional drug products usually consist of pure chemical substances that are easily analyzed after manufacture. Since there is a significant difference in how biological products are made, the production is monitored by the agency from the early stages to make sure the final product turns out as expected.
From the US-FDA perspective, biologics are different from chemical drugs due to the use of living source material to produce the biologic, the increased complexity of the manufacturing process that comes along with the increased complexity of the product themselves.
The EMA point of view
It is no surprise that the EMA as a similar approach on the topic.
The manufacture of biological medicinal active substances and products involves certain specific considerations arising from the nature of the products and the processes. The ways in which biological medicinal products are manufactured, controlled and administered make some particular precautions necessary.
Unlike conventional medicinal products, which are manufactured using chemical and physical techniques capable of a high degree of consistency, the manufacture of biological active substances and medicinal products involves biological processes and materials, such as cultivation of cells or extraction from living organisms. These biological processes may display inherent variability, so that the range and nature of by-products may be variable. As a result, quality risk management (QRM) principles are particularly important for this class of materials and should be used to develop the control strategy across all stages of manufacture so as to minimise variability and to reduce the opportunity for contamination and crosscontamination.
Since materials and processing conditions used in cultivation processes are designed to provide conditions for the growth of specific cells and microorganisms, this provides extraneous microbial contaminants the opportunity to grow. In addition, some products may be limited in their ability to withstand a wide range of purification techniques particularly those designed to inactivate or remove adventitious viral contaminants. The design of the processes, equipment, facilities, utilities, the conditions of preparation and addition of buffers and reagents, sampling and training of the operators are key considerations to minimise such contamination events.
We have seen before that the difference between chemical drugs and biologics lies in three points, the use of living production systems, the impact of the manufacturing process on the product and, the complexity of the produced biologic.
Use of Living Production Systems
- First, living systems must be kept alive 24/7 during the whole fermentation process. This also means that the cells must be revived from the frozen state that they were in during their storage in the MCB. Then, during culture, an adequate number of living cells must be kept alive and is considered as a CQA that can affect not only the total amount of biologic produced but also the amount of process-related impurities.
- Second, they must be kept happy, so they do great work. This involves providing our living production system the adequate nutrients in the correct proportions and, a friendly environment of an appropriate oxygen and carbon dioxide gas concentration, pH, and temperature. There is a range of parameters where the living system will produce at a high rate a highly qualitative product, and we need to keep it during the whole manufacturing process.
- Third, they must be kept healthy. This means erecting multiple barriers around the manufacturing process to protect the living system from the attack by adventitious agents (bacteria, fungi, mycoplasma, spiroplasma, mycobacteria, rickettsia, viruses, protozoa, parasites, and TSE agent) during the production of the biologic. Chemical processes often prevent this kind of “infections” due to the unfriendly environment for bugs to develop. In the case of biomanufacturing, everything is done to make living production systems to grow fast and long. Adventitious agent can benefit fis environment too to grow.
It is also important to note that cells used as a production system, might have been infected in the past by a virus. The infection is latent and can be transmitted vertically from one cell generation to the next, since the viral genome persists. Upon stress, due to cell aging, or nutrient depletion, the latent viral contaminant can be shocked into activity and produce infection particles.
Impact of the manufacturing process on the product.
As said before, one of the major differences between chemical drugs and biologics is the complexity of the product. The molecular conformation, the 3D structure of the biologics, is then of main importance for the correct efficiency of the product. This results from complex interactions due to amide bonding, disulfure bonding, hydrogen bonding and nonbonded interactions.
The correct folding of the proteins can be impacted by minor changes in the manufacturing environment such as temperature increases, sheer forces or exposure to light. Even though some test methods are available to analyze molecular conformation, they are not applied routinely to biologics du to the size of the products.
Changes in the manufacturing process can also impair the biologic produced. For instance, although nutrient-deficient culture media in certain amino-acids are used as a selection mechanism in certain cases, it may cause substitutions in the protein produced. We can cite E.coli starving methionine and/or leucine will synthesize norleucine and incorporate it to replace methionine, yielding an analog of the wild-type protein, which can be difficult to separate chromatographically.
Complexity of the produced biologic
The complexity of a recombinant protein or monoclonal antibody is mainly due to 3 points:
- The possible modifications to amino acids on the intact proteins,
- DNA doesn’t translate straight into the final protein, modifications can occur both on the N-terminus and the C-terminus ends, the peptide bonds can undergo hydrolysis, the amino acids can undergo oxidation of methionine, disulfide scrambling of cysteine, deamination of glutamine or asparagine.
- The varying carbohydrate moieties attached to the product,
- Different types of monosaccharides present and linked in different sequences, length and branching of carbohydrate chains.
- The possible high-order molecular structure.
- It has been estimated that approximately 100 million possible molecular variants of a mAb can occur.
The complexity of the biological protein and the close similarity with similar proteins make the infrared (IR) identification test often used for chemical drugs not suitable for a monoclonal antibody. Instead of the half a day test, a peptide mapping fingerprint test is recommended, which under cGMP conditions, lasts from several days to a week. The challenges for QC due to the inherent complexity of a biological product if much higher than for a chemical entity.
We’ve seen that chemical drugs and biologics differ by 3 points:
- The use of a living system for the production,
- The impact of the manufacturing process on the product,
- The complexity of the biologic
That result in an incredible increase of the tests for QC release, in number, time and technicity, linked with the fact that the manufacturing process defines the final product more than the product itself.