Approach 3: Hybrid method combining elements of approaches 1 and 2.
The use of a full design of experiments approach can result in a significant amount of batches being manufactured to cover
the design space. As the number of batches required to describe the design space increases, the development time and cost
increases. A third method combining elements from approaches 1 and 2 optimizes the balance between development time and cost
and maintains a good understanding of the manufacturing process. This hybrid approach can be achieved by breaking the manufacturing
process into defined sections. The initial blending step can be performed using Approach 1. The blend could be manufactured
to specification, and end-product testing will show the quality (e.g. blend uniformity/assay). Parameters such as blending
time and blending speed can be determined by intensive blend uniformity and bulk-assay analysis allowing blending windows
to be established. A second confirmatory batch could be manufactured using the parameters obtained from the initial batch
that could provide additional confidence in the manufacturing process.
The blend will have been shown to meet specification and can then be progressed to the next processing steps. An experimental
design approach can then be performed. For example, the next steps could involve dry granulation followed by compression into
tablets. As described in approach 2, following completion of a full risk assessment and subsequent cause and effect diagram
detailing the potential process parameters, a structured design of experiments plan can be devised. Rather than completing
each experiment at the full scale, the experiment can be performed using a suitably sized aliquot of the blend manufactured
already. As both dry granulation and compression are a continuous throughput process, the parameters investigated are mainly
independent of batch size used. Using this approach, a 60-kg blend could be divided into 3-kg sublots, allowing up to 20 experiments
to be run.
Following completion of the experiments and analysis of the data, a confirmatory batch could be manufactured using the optimized
parameters determined from statistical analysis and preparation of a design space. The resulting batch or tablet cores could
be progressed to coating if required. Again, the coating process can be investigated using method 1 or 2.
Strategies for product development can vary from company to company and from product to product, and as such, a contract development
and manufacturing organization (CDMO) must be able to provide a service that can suit the requirements of any customer. For
a variety of reasons, a company might choose either an empirical approach or a more systematic approach to product development.
The approaches described can aid in the provision of a high-quality development offering from the outset while striving to
control timelines and costs, which are commonly seen as opposing forces in the pharmaceutical industry.
Conor P. Long* is a senior formulation development scientist and John Mc Quaid is a technical development manager, both at Almac Pharma Services, 22 Seagoe Industrial Estate, Craigavon, BT63 5QD, UK, tel:
+44 (0) 2838 363363, fax +44 (0) 2838 363300, firstname.lastname@example.org
*To whom all correspondence should be addressed.
1. ICH, Q1A (R2) Stability Testing of New Drug Substances and Products, (ICH, Geneva, Feb. 2003).
2. EMA, Note for guidance, Process Validation, CPMP/QWP/848/96, (EMA, London, Sept. 2001).
3. ICH, Q8 (R2) Pharmaceutical Development, (ICH, Geneva, Aug, 2009).