Challenges Involved in Scaling up Drug Substance Development

1. Challenges Involved in Scaling up Drug Substance Development Preserving a drug’s integrity during pharmaceutical manufacturing scale-up is a challenging task, but it is important for developers who wish to expand their operation to guarantee legal compliance and high standards. Pharmaceutical firms globally are under immense pressure today to speed up drug substance process development while making it more cost-effective. They are trying their best to ensure that all their drug candidates showing promise hit the market. Bringing drugs to the market as fast as possible is the key to success, but it is also important to address the challenges concerning process development, formulation, stability challenges and scalability. To avoid any late-stage failure, drug companies must follow smart and systematic scientific solutions to eliminate all threats with respect to the drug development process. As new drugs move from the initial preclinical stages through subsequent phases, the demand for clinical substances is likely to grow enormously. Scaling production is hardly ever uncomplicated, as there are several difficulties such as cost incurred, unforeseen challenges and a lot of time consumption. When drug development is at its early stages, the drug substance is formed through a synthetic route which may not even be finalized. The drug substance’s physicochemical properties may alter with

2. enhanced synthetic routes or a superior crystallization process, leading to an enhanced impurity profile. However, this is likely to considerably change the behaviour and physicochemical properties of the Active Pharmaceutical Ingredient (API). The problem is quite acute when it comes to products with a higher drug loading and higher dose in formulations. Processing and formulation experts face several processing and scalability challenges. These challenges can be addressed with no major impact to in vitro release profiles and smart solutions. Any significant change to the drug product process or formulation may necessitate rework. Early clinical-stage drugs are made on a small scale enough only for a small clinical study and proof-of- concept. Because of the small prerequisite, drugs are produced on semi-automated manual equipment. They are produced on slow-speed gear to have better control over critical process parameters and to preserve materials. Here’s a look at some of the challenges facing drug firms during scaling up for drug substances and the various factors that are key to the success of a project: 1.Contamination The biggest worry for drug firms is the danger of product contamination at the time of moving from a small-scale to a large-scale operation. The challenge is quite acute especially when it comes to getting to grips with new processes. To reduce the risk of contamination, the whole pharmaceutical processing system sometimes has to be shutdown. 2.Moving from the milligram method to multi-kilogram process As contract drug substance development evolves from candidate drug selection to the clinical stages, more drug substance is needed. Therefore, a drug which was earlier produced in milligrams must develop into a multi kg process. This transformation must happen without having any impact on the performance or quality of the API. In other words, there is an escalating demand for larger quality, quantity, and documentation when moving towards market authorization. Major expertise is needed to flawlessly move products from pre-clinical stage to industrial scale. The synthesis paths used by the chemists are often designed for speed and diversity and to make variants from a known hit substance. In this stage, the primary goal is to optimize and enhance the lead substance for its key activity and the physicochemical properties needed only for dispensing the substance to patients. 3.Cohesivity & Static Charges New small molecular units in large volumes show high cohesivity and hydrophobicity to the contact surfaces of processing equipment. To boost the surface area of drug substances, active substances are frequently micronized to enhance the solubilization rate. A micronized API frequently show static charges and sticks to container walls and the processing equipment. Adhesion or cohesion to surface parts can lead to unpredictable funnel flow, content uniformity issues and rat holing.

3. 4.Regulatory considerations: It is important to be mindful of regulatory considerations. For instance, prior to scaling up of any US-based production unit, it must adhere to the Scale-up and Post-Approval Changes (SUPAC) sanctioned by the Food and Drug Administration (FDA). Before scaling up, it is imperative to make sure that all essential steps are performed to reduce timelines and handle any complexities.