The importance of the Regulatory Starting Material or RSM in regulatory strategy has gained significant attention over the past few years. Both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have weighed in on the topic, and have come to definitive conclusions concerning the manufacture and quality expectations of the RSM. Regulators have published guidances that underscore the importance of incorporating suppliers who possess strong analytical and quality infrastructure, and a more sophisticated supplier is needed to meet the new stringent requirements.
The FDA defines an RSM as follows: ‘A starting material is incorporated as a significant structural fragment into the structure of the drug substance.’ Significant structural fragment in this context is intended to distinguish starting materials from reagents, solvents or other raw materials. The applicant should provide a justification for how each proposed starting material is appropriate, based on:
- The ability of analytical procedures to detect impurities in the starting material;
- The fate and purge of those impurities and their derivatives in subsequent processing steps; and
- How the proposed specification for each starting material will contribute to the control strategy.
‘The relationship between risk and number of steps from the end of the manufacturing process is the result of two factors, one concerning the physical properties of the drug substance and the other concerning the formation, fate, and purge of impurities.’1
Meanwhile the EMA Committee for Medicinal Products for Human Use2 says: ‘The use of external sources for any steps in a manufacturing process may lead to a higher degree of risk to quality of the active substance than would be expected were the full manufacturing process to be carried out by the applicant or a single active substance manufacturer alone… Starting materials can only be justified once the criticality of all steps has been discussed. Often, starting materials are selected and then only subsequent steps are discussed. This is not sufficient.’
The natural inclination has been to source RSMs from companies possessing specific chemistry expertise, depending on the structural characteristics of the RSM
Some pharma companies and active pharmaceutical ingredient (API) manufacturers continue to pursue outsourcing strategies that utilise traditional low cost non-GMP fine or speciality chemical organisations with limited analytical, R&D and Q11 infrastructure. The natural inclination has been to source RSMs from companies possessing specific chemistry expertise (i.e. expertise in heterocycles, indoles, pyridines, etc.) depending on the structural characteristics of the RSM. However, while this is important, it is not the only factor to be considered to ensure the RSM is meeting all of the necessary criteria to reduce risk to the final API quality. Clearly, RSM suppliers will require a deep analytical and quality infrastructure.
EMA noted the following key point: ‘EU Authorities are concerned that introduction of impurities into the active substance from non-GMP manufacture, (e.g. from poor cleaning of vessels previously used for other purposes or inadequate control of processes), which would not necessarily be picked up by routine analytical testing, is a significant risk. The fewer synthetic steps carried out under GMP, the higher the risk to the quality of the active substance.’
Furthermore, due to pricing pressures, the notion that an RSM should be sourced principally from low cost suppliers/regions is also a flawed approach. The regulatory risk and potential impact of latent defects due to poorly characterised RSMs far outweigh the cost savings from a low cost supplier with minimal infrastructure.
Before even considering an RSM supplier, one needs to take into account all the risk factors associated with the RSM synthesis.
| Key RSM risks |
| What role do RSM impurities play in final API quality? |
| Are the structural characteristics of impurities in RSM understood? |
| Are the analytical methods used to release the RSM suitable for their intended use? |
| What impact do process changes in RSM synthesis pose to the API? |
| Does the RSM supplier have a Change Control system established? |
| Is the chain of custody of raw materials going into the RSM process well documented? |
| Is the RSM supplier willing to give process information to the client? |
| Is the RSM supplier able to source the right quality reagents? |
Considering which RSM supplier to use as part of the supply chain strategy can be complex and confusing. In addition to the risk factors, companies must keep in mind the increasing pressures by the pharmaceutical industry to reduce costs. It should be noted that issues with any one of the risk factors outlined above could add significant time and cost in the approval process. To address the key risk factors adequately, pharmaceutical companies need to consider carefully four key characteristics inherent to an RSM supplier that will ensure risk mitigation and sourcing success.
Must-haves in the ICH-Q11 era
No longer can RSM suppliers get away with a basic infrastructure. More is needed to ensure a complete understanding of the RSM chemistry and the consequences product purity and impurities have on API quality. This level of infrastructure closely mimics that of a fully cGMP compliant facility, and with this comes added cost. Hence, a supplier who has been vetted against the above four attributes will also need to supply the RSM at a competitive and acceptable price.
Furthermore, the RSM supplier now also has to take on the responsibility of managing the raw material, solvent and reagent supply chain and develop relationships that ensure at least a basic sharing of process detail to assess what other impurities are supplied along with the main product. Often, raw material Certificate of Analyses come in only a very basic form, stating only purity >97% and limited analytical method detail. This, therefore, will need to be developed at the RSM supplier side to better characterise the incoming quality aspects.
The following case studies, which SAI has experienced over the past 12 months, illustrate some of the points made above:
Case study 1: SAI was asked to supply an RSM for a high dose NCE in Phase III, which meant that the assay had to be >99.0% and unknown impurities <0.08%. Such tight RSM specs had not been seen before. Aside from having to implement very narrow operating parameters and develop highly accurate in-process control methods to execute the campaign, SAI still ended up finding unknown impurities in the 0.1% range. Finally the company was able to trace these back to the key raw material quality and found deviating amounts from batch to batch. An additional purification step had to be developed and added to the process to control this quality parameter and meet the final impurity specification.
Case Study 2: Increasingly SAI has received requests for relatively mundane building blocks, which the company had to pass on in the recent past. Recently, however, driven by the need to source very quality tight parameters, which the commodity industry is not able or willing to provide to the pharma industry, the company is now asked to develop novel routes to these building blocks, allowing for much tighter specifications to be achieved and controlled than available processes can achieve.
Suppliers who have demonstrated ability to deliver high quality RSMs at a reasonable price have a distinct advantage
Case Study 3: Finally SAI has seen an increasing number of companies asking for ‘GMP-like’ or GMP-light RSM development and supply as the companies are unsure whether the regulator will accept their RSM definition. The trend to expect a larger number of API stages to be made according to cGMP increases the risks of delayed approvals, which SAI has observed in several instances. In this case the RSM supply is set up at a cGMP supplier to provide a rapid addition to the filing. The cost of maintaining such a demanding RSM infrastructure and capability can be significant but pharma companies can no longer afford to gamble with RSMs from suppliers that do not understand Critical to Quality attributes.
This is where the ‘East versus West’ argument tips in favour of the lower cost regions, and suppliers who have demonstrated ability to deliver high quality RSMs at a reasonable price have a distinct advantage. The industry should be looking towards RSM suppliers that have a fundamental understanding of Q11 and cGMP, substantial analytical depth, chemistry R&D and trouble-shooting capability, and a high degree of business flexibility. Getting all this from a supplier in a lower cost region can be the right mix to ensure success in RSM supply and ultimately a successful API launch and commercial supply.
Cost savings can be achieved through simplified API Q11-compliance and a reduced quality risk profile.
SAI Life Sciences has gained significant experience in developing and supplying RSMs to many top 15 pharma companies, API CMOs and select biotech innovators from its location in Hyderabad, India.
References
1. FDA Q11 Document, November 2012.
2. EMA Committee for Medicinal Products for Human Use, September 16, 2014.