CMC For Long-Acting Injectables For TB
By Susan Ciotti, Ph.D., pharmaceutical drug product formulation/process development & manufacturing leader, Gates Medical Research Institute (Gates MRI)
Tuberculosis (TB) is one of the hardest to cure infections that we know. It kills more than 1.2 million around the world every year and threatens millions more. This disease is one of the primary global health threats the Gates Medical Research Institute is working diligently to address.
TB treatment is very problematic; eliminating the infection requires three to four or more strong antibiotics for at least six months, sometimes more. It’s a lot of pills every day, for a long period of time. It’s easy for patients to stop treatment once they feel better, usually after three months or so, but if they do that before becoming cured, the disease can become drug resistant and harder to completely cure.
In response to this problem of adherence, infectious disease experts have recommended directly observed therapy (DOT), having a health worker meet with patients every time medication should be consumed, to better ensure treatment adherence. This is not an effective strategy, however, as it requires a much larger healthcare workforce and also magnifies the stigma that can come with TB disease.
TB experts have long considered the concept of a long-acting injectable (LAI), something that can be administered with a minimum number of applications, as an attractive way to improve treatment adherence. LAIs have worked for a variety of health challenges, from HIV/AIDS to schizophrenia.
From a chemistry, manufacturing, and controls (CMC) perspective, we look at the concept of LAIs as a challenge to take an existing TB medicine and redesign the compound so it can be administered to the patient through this system. In doing so, there are five considerations that we take into account; they constitute the “Goldilocks” criteria.
1. ​Determining The Best Particle Size
There are many dosage forms of LAIs available, but the most practical and numerous on the market are micronized aqueous suspensions due to their capabilities of high-dosage drug loading, lower-cost manufacturing and suitability for both subcutaneous and intramuscular administration. When a compound is injected into a person, it is absorbed at a certain rate that depends on the size of each particle of compound. If the particle is too small, the absorption rate spikes, then drops off rapidly — and for LAIs, we are looking for a more even rate of absorption. If the particle is too large, it will take too long for the compound to be absorbed enough to reach a proper therapeutic level. The particle size therefore has to be large enough so it can’t be absorbed easily but not too large that the proper dose can’t be met initially.
2. Determining How To Best Manufacture The Particle Of The Selected Size
Once we have the right particle size and uniformity, we need to assess the best method of manufacturing the compound at that size. Given the complexities of manufacturing pharmaceutical products at scale, we have found that it can be more cost effective to take a quantity of the compound in its typical size and then use a jet mill to reduce the size to the desired level. Jet milling offers critical advantages for manufacturing LAI’s suspensions at scale by producing the consistent fine particle size needed for controlled drug release, stability, and administration. Unlike mechanical methods, jet milling is highly scalable and minimizes contamination and thermal degradation. Jet mills use compressed air to break apart materials without generating excess heat, which means they are best suited for work with temperature-sensitive materials like antibiotics.
3. Maintaining Sterility
Regardless of whether a compound is injected or ingested, as a pill or capsule, sterility is essential. Without it, the compound may cure TB but leave the patient — often in a weakened state — with another infection to cure. Typically, sterility can be maintained with sufficient heat to kill off bacterial viral contaminants, but as noted previously, many of the antibiotics used to treat TB are temperature sensitive and require alternate means of maintaining sterility. Common methods used for LAIs include gamma or e-beam irradiation. At a large scale, irradiation can be highly effective and is used widely for pharmaceutical products. It can penetrate the sealed final packaging, which simplifies the manufacturing process.
4. Selecting The Injection Site
Typically, with injections, the goal is for the compound to be injected so it is absorbed swiftly. LAIs instead aim to establish a reserve of the compound that gets absorbed steadily and at the most effective pace to maintain proper dosage. Thus, the development of the LAI involves examining the interaction of the compound at the injection site to determine absorption pace when injected below the skin (subcutaneous, or SC) or into the muscle (IM). LAI administered via SC or IM injection can provide sustained release of the drug over days, weeks, or months, reducing the frequency of dosing as compared to oral medication. The drug is formulated to create a depot at the site of injection, which slowly dissolves or releases the drug into the body.
IM injections can typically accommodate larger volumes, while SC injections may use shorter needles and be less uncomfortable for the patient. IM injections are given deep into the muscle where the medication can be absorbed by surrounding blood vessels as it is released from the depot.
SC injections are injected into the innermost layer of the skin called the hypodermis, which is made up of a network of fat and collagen cells. Medication given via SC injection is absorbed more slowly as compared to IM injections.
5. Incorporating Regulatory Considerations
As we design and evaluate the LAI, we take into consideration how the product must navigate the regulatory process. To do so easily, each injectable should contain only one medicine, otherwise each medicine would need to be evaluated for safety and effectiveness, and then the entire multiple-medicine injection would need evaluation through clinical trials. While the first process — using only one medicine — would lead to requiring multiple injections for each part of the TB regimen, with injection sites varying (utilizing both arms, for example), the LAIs could work through the regulatory processes and reach patients much faster.
Currently, our models project one to two months of a lead-in process with oral antibiotics and then a combination of LAIs afterward. This regimen pacing best matches the current first-line treatment regimen for drug-sensitive TB, with an intensive first two months followed by less rigorous dosing. It is the potential to lose patients due to lack of adherence during the less rigorous stages that LAIs specifically address.
LAIs Could Be The Breakthrough Needed For TB
Many in the field see the progress LAIs have made in the fight against HIV/AIDS, and they see the potential to similarly impact TB incidence and mortality. LAIs can also greatly improve treatment adherence, thus reducing the risk of drug resistance developing. The expertise of the CMC sector is perfect for solving this problem, and we have already made great strides.
In conclusion, it’s important to note that developing an LAI combination for TB treatment is both exceptionally difficult and increasingly important. It has been a grave disease throughout human history, but the concept of LAIs presents an opportunity worth pursuing — and the lessons generated in the process are helpful to keep in mind when tackling other intractable diseases as well.
About The Author
Susan Ciotti, Ph.D., is the pharmaceutical process development and manufacturing leader for the Gates Medical Research Institute. She has extensive CMC experience in the optimization and manufacturing of conventional and novel formulations, such as lipid nanoparticles, nano emulsions, and long-acting injectables.