Working with contract development and manufacturing organizations (CDMOs) in Asia has become a popular strategy for European and U.S.-based sponsors because of the associated lower costs to manufacture complex active pharmaceutical ingredients (APIs). Given the high costs and resources required to produce these advanced chemicals—combined with the need to rein in rising drug costs—it’s no wonder Chinese CDMOs have seen heightened business demand.

Yet, events such as the recall of heart drug, valsartan or widespread contamination discovered in a Chinese-manufactured vaccine have also put quality concerns in the spotlight. The big question remains: how can companies manufacture life-saving drugs and other treatments more cost effectively while making quality paramount? There is another alternative, and that is leveraging a mix of GMP and pre-GMP facilities.

Facilities that operate in accordance with current Good Manufacturing Practices (cGMP) adhere to regulations enforced by the U.S. FDA and the European Medicines Agency (EMA). They ensure the proper design, monitoring, and control of manufacturing processes and facilities. Adherence to these regulations requires that API manufacturers adequately control manufacturing operations in order to ensure the identity, strict observance of the registered process, quality, and purity of drug substances. This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories.

The Four Stages of Drug Manufacturing 
The pharmaceutical manufacturing process is comprised of four key stages of development:  the Regulatory Starting Material (RSM), the drug substance, the formulated drug, and finally the packaged and labeled finished product. All stages have very different requirements. The development of the RSM is the first compound to be described in a marketing authorization dossier for the API synthesis, essentially the last chemical in the API value chain to not require full cGMP inspection by the FDA or EMA. A starting material is also typically the point at which the sponsor commits to GMP manufacture of a drug substance.

RSM: The Frontier Between GMP and PreGMP
Following strict Standard Operating Procedures (SOPs) for quality control, yet avoiding the costly and unnecessary infrastructure required for GMP, the ability to produce APIs in FDA inspected facilities in a strict cGMP environment and the RSMs in a pre-GMP facility brings a lot of value to pharmaceutical customers. Consider the following benefits:

• Control of impurities. CDMOs that provide a blend of cGMP and pre-GMP facilities not only offer greater value in the manufacture of APIs and other New Chemical Entities (NCEs) without compromising quality, but they also can ensure better control of the carry-over of impurities that could come from another CDMO. This is especially true with the increasing complexity of the new API chemical structure. 
• Speed in development. When an API is developed under compressed timelines, for example on a fast-track status NCE program, two process development teams can work in parallel within the same CDMO to ensure faster completion, as well as greater collaboration to ensure improvements in the GMP synthesis. When hybrid environments are available on the same manufacturing site, the costs of operating two different systems can generate complexity and sub-optimal operations.
• Cost control. It can be difficult to have a reliable long-term commitment from Asia in terms of pricing, but by keeping production of critical RSMs in-house, CDMOs can have better control of cost evolution. They also can avoid the costs associated with delays, drug denials or penalties associated with chemical impurities or other issues.
• Oversight of environmental and safety conditions. For the production of pre-GMP Intermediates, even with very long synthesis, the owner of a new drug should be responsible for the level of environmental protection or working conditions required to produce early intermediates which are specific to their compound. Having a pre-GMP intermediate custom produced in a country where the Environmental Health & Safety (EHS) regulations are strict is a better guarantee for long term supply security and compliance.

Another issue to consider is that the quality environment required for the production of RSMs or pre-GMP intermediates for APIs has always been in a certain “grey area” without clear guidance, which left most of the large pharma companies to audit the CDMO operations and chemicals produced using their own internally developed guidelines. While the manufacture of the RSM is not in the scope of the ICH Q7 guidelines on GMPs for APIs, some of the principles for control can be applied to RSMs.

Yet, the situation is beginning to change and RSMs are now gaining more attention from a quality perspective, thanks to new guidelines and documents providing better guidance about the quality control system required for RSMs. One of the more recent publications helping to set quality standards is the European APIC Guide (Active Pharmaceutical Ingredient Committee) on auditing Registered Starting Materials for Manufacturers, released in February 2018. According to the guide, quality risk management processes as described in the ICH Q9 Guideline on quality risk management should be applied to the RSM. Following the release of this guide, I suspect that additional guidance will be delivered globally.

Following newly released guidelines, pre-GMP sites will continue to conduct their own internally developed audits, as well as regular evaluations of its RSM suppliers to ensure ongoing quality oversight. The quality of the RSM is intrinsically linked to the quality of the final API, so key aspects of the RSM quality management system such as change control and production controls are essential parameters that are evaluated in these audits.

Pre-GMP facilities should never be confused with lower quality, given the high standards for product commercialization. A combination of Pre-GMP and cGMP environments, however, can provide the perfect balance, given the rising costs and complexity in bringing sophisticated molecules to market. Sometimes keeping manufacturing closer to home and seamlessly enabling collaboration between the two types of facilities can enable the safe, yet value-driven delivery of critical molecules without sacrificing quality. 

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Didier Combis is the commercial director of Seqens CDMO, an integrated global leader in pharmaceutical synthesis. Previously for 18 years, he served as Global Head of Business Development of PCAS, an internationally recognized developer of fine chemicals, until it was acquired in 2018 by Seqens CDMO. Didier has extensive experience in API development with deep understanding of regulatory affairs and CMC requirements to help sponsors successfully meet their chemical manufacturing needs.