Active Pharmaceutical Ingredient Availability and Procurement

In a vast number of FIH studies it is this factor that regularly becomes the rate determining step. Initially you will calculate that you only require small quantities for you limited clinical dosing. The clinical requirements at this stage are often dwarfed by the amounts required for analytical method development and validation, stability testing, formulation development, reference and retains.

You need to be planning ahead to when the quantities required increase for the later phases of clinical manufacture. Any changes to the scale or route of manufacture could potentially influence or invalidate the previous trials; requiring bridging studies to be performed.

Analytical Methods

Transfer, development, and phase appropriate validation of all the necessary release test methods requires detailed planning. For early phase studies, developing an appropriate product specification and ensuring the methods where required are stability indicating, must be part of the project initiation at your CDMO. Analytical transfer and setup are usually one of the first major tasks on the project timeline as suitable analytical test methods must be in place to support the formulation development. Generally, the active pharmaceutical ingredient (API) supplier will have developed the analytical method for the API that can then be adapted for the product testing; promoting a good transfer by enabling communication between the API suppler and the CDMO is crucial.

Excipient Compatibility Studies

Depending on the complexity of your formulation and on the prior knowledge of the active compound the excipient compatibility study is a key task that should be risk assessed. Excipient compatibility studies are the mixing of the active drug substance and the likely excipients, which are tested after storage on accelerated conditions for a relatively short time (4 to 8 weeks).

If the FIH study is simply being conducted as powder-in-capsule (or a very simple formulation) and data already exists demonstrating that the active is stable and robust in all circumstances; the excipient compatibility study is sometimes omitted until a more definitive formulation is developed.

However, omission of the excipient study can on occasion backfire with unforeseen instability arising on the clinical batch; thus, reducing the product shelf life and availability of clinical supplies, potentially even requiring a recall. The time saved by omitting the excipient compatibility study at the start of the development campaign on a risk-based decision, can ultimately result in a serious loss of time and investment.

Formulation Development

For a CDMO to conduct the formulation development process efficiently and with appropriate scientific diligence, the project objectives are defined by the target product profile and the commercial objectives of the client.

When conducting the FIH clinical study, the formulation approach must be fit for purpose whilst not overly complicated. The drug properties should be reviewed and material characteristics (physico- chemical and pharmacological) established, so that the appropriate dosing strategy can be taken. For example, if the drug is known to be soluble and has no obvious bioavailability issues then a simple drug-in-capsule approach may be suitable to generate FIH clinical data; whereas drug substances that require bioavailability enhancement will need to undergo more extensive screening and the application of an enabling technology.

Even at this early stage, the CDMO formulator must work closely with the client to keep a clear line of sight to the formulation and manufacture of supplies for large scale clinical trials and the commercial viability of the processes being developed.

Parallel Screening and Development Protocols

Time rather than science is often the major factor challenging the early phase development of compounds. Strategies need to be employed to fast track the development while ensuring safety, quality and efficacy are maintained.

Assuming that a simple drug-in-capsule approach is not suitable, there are risk-based strategies that can be taken to minimise the timeline. If an enabling technology is required, a number of companies offer small scale screening protocols that establish and / or review physico-chemical and biological data. Developing a small-scale evaluation utilising a range of enabling approaches and perform parallel screening using both in vitro and in vivo models, in a relative short time and with limited drug substances. Upperton’s UpperSolv™ process typically requires less than 10 grams of API to produce and evaluate up to 6 proof-of-concept formulations, using an in vivo pharmacokinetic model and perform stressed stability study data in less than 2 months.

Parallel screening and evaluation strategies such as this are more time / budget efficient, over the usual trial and error approach. If planned with targeted and well considered methodologies, this can provide a high level of confidence for selection of the clinical formulation.

Engineering Batch

Once the clinical formulation(s) are selected, they should be tested for viability of the process at the required scale and more formal stability data generated at ICH conditions to support shelf-life assignment. Depending on the knowledge gained during formulation development, the extent to which the engineering batches are required and the amount of stability data that is generated before making a decision to proceed, is a regular subject of risk-based decision making.

Clinical Manufacture

After following all the steps prior to this, you will have garnered a lot of data on your formulation and API. Now you need to decide at what point you manufacture your clinical batch for FIH. This timeline has focused so far purely on the science lead up to clinical manufacture; there are other important trails of consideration that run in parallel to the science-based development. These include:

1. Difference in regulatory requirements (e.g. IND or IMPD)
2. Auditing and approval of the API supply.
3. Approval of excipients and excipient suppliers.
4. Establishing quality technology agreements.
5. Establishing Quality Person to Quality Person agreements.
6. Writing and submitting of regulatory documentation.

With these key considerations being decided upon in tandem with clinical product development, your business milestones and timelines should be within sight.

Packaging and Labelling

This stage can often be overlooked in a roadmap to clinic but can add a significant time onto your manufacturing timeline. You must ahead of clinical manufacture have defined a packaging, labelling and logistics strategy for your clinical supplies.