A Lean Development Approach to Microsphere Formulation Development
Syed Reza, MD PhD, May 7 2015
Lean is in.
From Lean Manufacturing to Lean Startup, the business world is ablaze with examples of organizations seeking to improve operational efficiency through a disciplined, systemic approach that eliminates waste and reduces cycle times.
In the pharmaceutical industry these initiatives focused at first on product manufacturing with an emphasis on shortening launch times and increasing process quality, and most importantly to minimize batch failures and lot recalls. Within pharmaceutical research and development the application of lean principles is not always intuitive. It is well accepted that in research many projects will fail, therefore it is not reasonable to define metrics based on research outcomes alone. Yet, product development costs continue to weigh on the success of many pharmaceutical companies. A recent study by the Tufts center for Drug Development estimates lifetime R&D costs exceed $1.4B for the average innovator compound to reach the market and the development time is more than a decade. There is therefore great interest in applying lean approaches to drug development.
At Octoplus we began by applying Lean Product Development concepts within our microsphere development team. The development of controlled release formulations is particularly challenging as typically each iteration requires the in vitro release kinetics to be reassessed. For a controlled release target of three months a conventional, serial iterative approach may take more than a year.
We set out to address the challenge for a faster product development cycle by building a development strategy incorporating lean development principles. As originally, conceived at Toyota Corporation, the three core principles of lean product development are
- Develop the product to meet the expectations of the customer
- Aggressively remove waste by eliminating non-value creating activities
- Tightly integrate upstream and downstream development
Let’s see how each of these principles can be applied to pharmaceutical development.
- Develop the product to meet the expectations of the customer
The starting point for a microsphere project is to first determine the desired Therapeutic Product Profile (TPP). What is the desired length of release? What is the daily desired dose? Route of Administration? These and other parameters are described in Table 1.
Table 1: Typical Target product profile (TPP) of protein API loaded Polyctive microspheres
Octoplus scientists have a wealth of experience in microsphere formulation with a track record of almost 10 years on a variety of formulations. We draw on our experience to work with clients to preselect projects with the right fit starting with an assessment of whether the client’s desired therapeutic performance goals fit within the broad capabilities of the technology (summarized in Table 1). Preferably, the PK profile of the therapeutic agent should already be known which will be used to set the upper limit for the daily dose and the burst release. Subsequently the other parameters of desired needle gauge, route of administration, and release duration are guided by market and clinical application considerations.
Establishment of the Therapeutic Product Profile thus permits the design of a targeted development program to meet the desired criteria guided by the magnitude of the gap between the desired outcome and known performance of the technology.
Once the TPP is obtained from the client, Octoplus formulation scientists then evaluate the probability of success of achieving each criteria. Development tasks are prioritized to address the critical, high-risk objectives. A Go/No-Go decision point may be offered immediately after the first key development priorities are addressed in line with the inflection point of the risk-value ratio of the project. For example, a client requested a 3 month duration formulation of a protein therapeutic. The daily dose was about 0.8 ug or 2ug. This was well within the known loading rates for Polyactive. However the stability of the protein for 3 months was unknown. Octoplus therefore began with a stability study of the protein in a standard formulation of Polyactive. It was determined the protein retained 60% of activity after 3 months, therefore the target loading was increased by 40%. A full development program then started with the new dose. This approach increased the probability of success while conserving the resources required to demonstrate a Proof-of-Concept.
Waste in operations can be classified as waste of time or waste of resources. If activities have to be repeated then time is wasted as the project timeline is unnecessarily extended. If activities are conducted which do not produce results of sufficient quality to build knowledge or support decision making then the activity is wasted as it clearly adds no measurable value to the project. Therefore tasks plans are constructed using good experimental practices including matched controls, duplicate samples, and analysis with verified methods. This ensures data generated is of sufficient rigor and can guide the development pathway.
Integration of Upstream and Downstream Activities
Within the context of microsphere formulations, upstream activities include the creation of several prototypes and downstream activities encompass the remaining phases such as process development and scale-up to clinical and commercial batch sizes. The release kinetics of the microspheres and other characteristics can change during scale-up, sometimes in an unpredictable manner.
Minimizing the range of these variances in the formulation can be frustratingly time consuming. A proactive strategy to manage scale-up risk includes sophisticated process development with elements of Quality by Design and Design of Experiment approaches. Process development prior to initiating scale up is time consuming and can be expensive yet offers a significant reduction in downstream risk and batch failure rate.
With these concepts it is possible to develop most technically complex microsphere products in a accelerated manner while minimize re-do loops and lost time and productivity.