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Switching grades of raw material late in the development cycle can be costly. Best practice says get it right at the beginning.
There are many factors to consider in developing new drugs and, in today’s competitive environment, less time to consider them. The choice of raw material grade used for excipients and reagents is often considered less in the early stages of development than other factors, leaving the evaluation of grades until later if priorities dictate.
In fact, defining what is meant by ‘grade’ is important and often not understood. Compendia grade, American Chemical Society grade, and GMP/non-GMP grade have differences that need to be appreciated.
This approach often has implications later on in the development process, as the drug gets closer to market approval. Switching grades later in the development cycle can be costly and may introduce risks that could have been avoided.
For scientists in the research laboratory, a typical way of selecting raw materials is to reach for the supplier’s standard R&D catalogue of materials. No second thought is given to where the material comes from because the suppliers are rightly trusted to have provided pure, chemically defined substances in line with industry specifications.
As the drug is tested in the clinic and later progresses to late-stage development, the material grade and specifications may be ‘baked’ in to relevant documentation such as investigational new drug (IND) submissions and example certificates of analysis (C of As). After this, change becomes more demanding particularly for non-compendial materials and will need to be studied properly. Impact on regulatory filings and necessary bridging tests or, in rare cases, possibly re-performance of clinical trials must then be considered to achieve regulatory approval. It’s here that the future practicalities of GMP status become relevant and potential changes to supply quality must be managed.
Most companies start to avoid change in raw materials between producing toxicology batches and Phase I trials. ‘No change’ is preferred but allowable with appropriate action. An example is stability testing and analytical characterization of minor adjustments to excipient concentration. At Phase III, full change control covering analytical comparability, impact evaluation on the process, and comparison of quality--all to be thoroughly documented--is essential. Further elements may include literature back up in support of the change, test plans for implementation, and follow up evaluation of the impact of changes. Change is not trivial when you get this far.
R&D grade versus GMP grade
Standard R&D catalogue materials may be sourced from vendors that may not have the required back up in terms of documentation, change control processes, supply chain transparency, and reliability required for commercial production of a drug. By contrast, GMP or pharmaceutical-grade materials are targeted to meet the different requirements of the commercial manufacturing situation. GMP-grade raw material supply chains are easier to map, have more robust specifications, reduced variability, and advanced change notification programs.
The other crucial issue is scale up. Commercial manufacturing uses much larger quantities compared to supply for the laboratory-scale experiments and, therefore, is a different ball game. Raw material batch-to-batch variability needs to be understood, process capabilities evaluated, and controls demonstrated by the vendor.
End users are waking up to the need to use appropriate grade materials as early as possible in the development cycle. This need doesn’t mean R&D-grade cannot be used if appropriate controls are in place. Good risk management analysis allows the vital materials to be identified. Then a conscious choice can be made to use more demanding grade at the best point in the product lifecycle if needed.
Tod Raeber from Sigma Aldrich Fine Chemicals (SAFC), an industry supply partner, explained in an interview that “growing numbers of customers are switching earlier to materials with the necessary controls that will support commercial supply. Our value management analysis shows significant economic benefit from using pharmaceutical grade materials for critical components at an early stage in development.”
Suppliers of raw materials, listening to the voice of their customers, are now performing the risk assessments of raw materials that they supply, which are typically used to support commercial production of a drug. The best suppliers are providing supporting documentation along with pharmaceutical-grade raw material, enabling end users the ability to rapidly assess raw material risk to drug safety, efficacy, and production continuity. In addition, and most importantly, the regulatory approval process is clearer due to the thorough documentation.
All of the above assumes a single material from a single supply source is used in early-stage development. However, the layers of added complexity may not be ending there. Increasingly, drug manufacturers ask for more than one supply source for a given material to mitigate supply continuity risk. The late-stage development team must evaluate comparability and effect of variability on the drug on top of everything else before commercial filing. In other words, the commercial manufacturing team can do their job better if their development colleagues do some extra work ahead of the game.
Carrying out additional development work is asking a lot from a scarce resource that has an increasingly wide range of demanding targets to meet. The cost-avoidance benefit seems far removed and distant. Moreover, there is, organizationally speaking, a functional gap between the development function and technical operations in the drug companies. In the future, the development teams should have a line of sight to commercial raw material supply as early as possible so there is less risk of switching later on. They should also make sure a second supply source is considered in Phase III. Whereas all this is changing because of the need to take an end-to-end view of drug lifecycles, getting the drug to the clinic remains the prime goal for the development part of the team. Nonetheless with the quality and consistency of chemical raw materials becoming a more important part of end-to-end perspective, it might be better to reach for the telephone to speak to the technically aware procurement experts rather than the catalogue to choose the best grade of material to support drug development.
Article DetailsBioPharm International
Vol. 28, No. 1
Citation: When referring to this article, please cite it as C. Chalk, “Raw Materials and the Development Cycle,” BioPharm International28 (1) 2015.