Stating the obvious here, but drug development is a protracted, expensive and risky process. From the lab bench to pharmacy shelves, bringing a new drug to market often stretches 10+ years and costs in excess of $1 billion.
Costs certainly rise as production scales ramp up and compounds enter clinical trials, but much of the drug development work – the honest-to-goodness benchtop scientific research – happens at the earlier discovery & process development stages.
At least, it should.
In many cases, API manufacturers like Neuland are contracted at later stages when companies are ready to scale-up compounds. Late-phase development, which generally refers to the period of Phase II clinical studies and beyond, tends to involve much greater regulatory scrutiny. Challenges with later stages often arise when the early-stage benchwork was limited in scope and focused on creating a viable process rather than the most efficient – and scalable – process.
Perfecting Processes for Scale
Earlier this month, we published a post on route scouting INSERT LINK WHEN LIVE – a key practice for optimizing and scaling a process. It’s a timely topic, given that the bulk of late phase CMS work aims to develop practical, scalable and sustainable drug manufacturing processes which minimize environmental, health and safety liabilities by selecting the right method of synthesis.
Early & Late Phase Development – Delivery Versus Data
Early phase drug development is driven by delivery, whereas later phase work (notably Phase 2 and beyond) is guided by data. In the early phases, the focus is on ‘delivery on time in quality’ – even if this means using a tedious, inefficient, or labor-intensive technology. The precedence is that the product meets the requirement of that particular phase, which is typically a one-time small-scale delivery rather than recurring deliveries in larger quantities.
[In fairness to earlier stage development efforts, it should be noted that ‘driven by delivery’ is not exempt from process R&D. A good amount of work is performed in the earlier stages, but late phase programs tend to embrace more tools and assess more process options during optimization.]
As products continue through clinical trials with increasingly larger patient populations, delivery dates take on secondary importance and data becomes the key driver of additional development work. However, this does not mean that time is no longer a factor. Clinical materials still must be delivered for late phase programs. But at this stage strong emphasis is placed on ensuring the robustness of the manufacturing process – regardless of the scale of operation. The idea is to develop a process that consistently generates the same quality of product, whether it is the first batch or the hundredth batch.
Improving COGS During Late-Phase Development
During late-phase development, the overarching objective shifts to identifying a process which lowers cost of goods while delivering consistency in quality and yield.
What are some of the measures pharma companies (or their manufacturing partners) can take to lower COGS during late-phase development?
- Identify lower cost vendors based on their expertise, experience, geography.
- Increase yields or purity by reducing cycle times, processing times or reaction times.
- Enhance capacity or ‘de-bottleneck’ capacity constraints.
- Add equipment to speed up operations.
- Reduce the solvent volumes needed to process and deliver more material.
- Develop technology that will reduce overall cycle times. For example, using an asymmetric induction to generate a stereoselective process with minimal purification – rather than resolving racemic material multiple times.
- Eliminate safety liabilities by developing safe-by-design processes, so that potential risks to business continuity or product capacity are averted.
The Late-Phase CMS Toolkit
Regulatory authorities worldwide, driven largely by the U.S. FDA and its European counterpart, are making increasing demands in the interest of patient safety. Pharma companies and organizations in the health sector must apply more complete and complex techniques – mainly for process validation but also for the monitoring and the evaluation of the performance of production processes (traditionally called SPC – Statistical Process Control).
As projects progress through scale-up and into later stage clinical trials, there are a range of tools used to ensure an optimized, safe, reproducible process is in place. Approaches such as Quality by Design and Design of Experiment alongside data analysis tools are used to ascertain that all impurities are well below the thresholds of risk to human health, and that the drug manufacturing process is performing as intended.
These and other techniques generate quantifiable data using precise engineering controls and analytical checks. During late-phase development, the data generated can include an understanding of the design space of operations during manufacturing through QbD and DoE, the identification of Normal Operating Range (NOR), Proven Acceptable Ranges (PAR) and Critical Quality Attributes (CQA), and an understanding of impurity profiles and their limits to meet the specifications.
There are also greater regulatory demands for the use of statistical procedures for method or measurement validation, notably to check for measurement imprecision and bias. To meet these demands, it is good practice to follow these three ‘critical checks.’
Quality by Design (QbD)
Using the risk-based Quality by Design approach, late-phase pharmaceutical projects should focus on building a comprehensive understanding of both the end product and process used to deliver it. QbD allows companies to fully understand any potential risks, and control strategies to mitigate those risks. The QbD approach is typically applied during the lab optimization stage at Neuland, after feasibility lab work has been concluded.
Design of Experiment (DoE)
Design of Experiment focuses on selecting independent, dependent, and control variables in order to understand and predict variations in a process. The emphasis is on establishing the validity and reliability of the drug’s chemistry, and ensuring the method is appropriately documented. Along with QbD, DoE helps identify the final optimized ranges in the desired chemistry for both early- and late-phase drug development projects. In the past, DOE studies were typically performed at the request of a client. It has since become a key tool for all large-scale projects – both early- and late-phase.
There are a broad range of data tools used by the pharma industry to characterize, analyze, secure and otherwise ensure the optimal use and storage of relevant process data. In the realm of QbD and DoE, for example, Minitab statistical software is used to increase performance and improve quality & reliability of a process by reducing the uncertainty of measurement systems. The rationale behind statistical analysis software in drug manufacturing is to look at current and past data to discover trends, find and predict patterns and uncover hidden relationships between variables to develop thorough process understanding.
What to Consider in a Late-Phase Manufacturing Partner
What important factors should pharma companies consider when choosing a CMO/partner for late phase development? Here are the top four:
Does the manufacturer have the capability to handle your process? You require specific skills to handle a variety of chemistries – particularly hazardous or sensitive chemistries or more complex techniques. Your partner’s experience, professionalism and track record of projects will be a key decisive attribute in selecting a late-phase manufacturing partner.
Capacity refers to the presence of adequate infrastructure for the process. Infrastructure should be sufficient to allow for identically reproducible processes, with appropriate automation to ensure the precision of each processing step.
The importance of strong communication skills should be evaluated. At its core, your CMS partner should be sharing both good and bad news in a timely fashion with equal candor. It’s understandable that in some cases manufacturers don’t like to deliver bad news. But delays can have wide-ranging impacts, whether connected to go/no-go decision-making on the clinical/drugmaker front or process safety issues on the manufacturing front. The rapid, clear dissemination of relevant information is critical to success.
At the heart of a successful late-phase CMS project is regulatory approval. While a compound may fail in clinical trials for a number of reasons, your drug candidate should not be held up or derailed due to facility compliance issues. Ensure that your potential partner has a strong regulatory track record, including Documentation, Integrity, Quality, Safety and Environment.
Late-phase CMS projects tend to have a lot of moving parts. Processes must be optimized for production scales, product quality – especially as regards mutagenic and genotoxic impurities – becomes critical, regulatory oversight grows more meticulous, and any delays will likely have a significant bottom-line impact. Selecting a manufacturing partner with a strong reputation in your space and the capabilities to deliver per your project timeline is mission critical.