Discuss key regulatory compliance concerns in the API arena.
ML: Active Pharmaceutical Ingredient manufacturers have faced their share of regulatory concerns over the years. In fact, the adoption of the ICH Q7A API GMP Guidance would have never occurred if not for the absence of an accepted API GMP globally. In my opinion, the following example was one of the most serious regulatory issues that U.S. firms had to address with their customers in the European Union (EU).
Recently, the EU established an importation requirement: in order for an API to be imported, the API would need certification by the exporting country’s regulatory authority clearly stating that the API was manufactured under GMPs equivalent to that of the E.U. This requirement could have created a serious trade issue for US manufacturers, as the USA had no universal exemption from the EU prerequisite. This also would have required an incredible amount of paperwork for every USA exporter.
Both the US and the EU use ICH Q7 as their API GMP standard. However, under the mentioned requirement, firms would still need to provide the required certification. The only way to avoid a large amount of paperwork for each API being shipped to the EU from the US was to get advanced approval by the EU stating that the US FDA GMP requirements were indeed equivalent to the EU requirements.
The US FDA petitioned the EU for an equivalency determination effective before the new requirement was operational. The FDA, which uses the same API GMP as does the EU, had to show the EU authorities that the FDA's inspections matched those of the EU. This was accomplished, and the United States API industry avoided what could have been a significant trade obstacle with the European Union. If the US FDA were unsuccessful in petitioning the EU to grant the US FDA regulatory equivalence with the EU, US manufacturers would have faced an increased documentation burden to ship their API products into the European Union.
How has the growing trend to manufacture highly potent APIs affected the market?
ML: From my regulatory compliance perspective, high potency (HP) APIs pose a special risk to buyers of any API produced within the same API facility. Cross-contamination of APIs has long been a concern of the drug industry and its regulators. This issue dates back to the days when antibiotic allergies created very strict requirements for contamination prevention at very low levels. HP APIs carry similar concerns with their potential of being sources of contamination. Manufacturers of High Potency drugs must take extra care when designing and operating any facility that processes HP API substances.
BS: The need for highly potent APIs has defi nitely driven capital projects at CMOs as they work to accommodate the increasing demand. Expectations of workplace exposure levels and cleaning residue carryover continue to drop, but I believe the containment equipment vendors have responded nicely with practical and cost-effective, retrofi t designs. Compared with 5 years ago, we are much more aware of the handling issues involved with higher potency compounds and are asking the right questions at the beginning of a project. Even in the clinical supply area, where PharmaCore predominantly operates, customers are asking containment capabilities questions before any work begins. I think this trend will only continue, and the CMOs that keep up will be rewarded.
In what ways has the API landscape evolved over the last few years with regard to the development of new technologies?
BS: In many ways, small molecule API manufacturing has remained unchanged over the past 10 years. Process bottlenecks related to reaction work-ups (solvent exchanges, extractions, fi ltrations and drying) still consume most of the time and costs of manufacturing. I believe we are nearing some breakthroughs as concepts of continuous manufacturing steadily gain foothold, but we are not there yet. However, we have seen some nice improvements in process monitoring instrumentation. Software and hardware design improvements will continue to move PAT to the mainstream. The lower barriers to implementation, such as smaller fl exible devices, simpler software interfaces, and easier process changeovers are all allowing broader use in the multipurpose, frequently-changing world of clinical contract manufacturing. This PAT trend will allow process development chemists the luxury of faster in-line or at-line control of reactions and product isolations. For example, PharmaCore has several early clinical phase customers asking for real-time morphology control. Ten years ago, the cost and timing of XRPD analyses would have made this much more diffi cult.
Briefl y describe how green chemistry initiatives can be applied to the API manufacturing process.
BS: The end goal of a greener manufacturing process is well understood; the broader chemical industry provides good examples. However, the unique product development lifecycle in the pharmaceutical industry poses a challenge. It is absolutely critical that greener chemistry techniques be applied in late stage tox or very early phase clinical API production. There is a host of real and potential hurdles to changing synthetic routes during drug development: timelines, new impurities, unrecoverable cost and even unknown risks to a program. So, unless there is another driver such as basic manufacturability, these hurdles are usually enough to prevent signifi cant green-driven process improvement. The application of green chemistry initiatives in early drug development requires a change in mindset. Selecting better reaction types, greener solvents and minimized work-up conditions during early drug synthesis will be the most infl uential to changing large-scale manufacturing techniques.
Any closing thoughts?
ML: Active Pharmaceutical Ingredients are being manufactured and consumed in almost every part of the world. Most are likely produced by legitimate, legal entities that are registered and reviewed by regulatory authorities. However, there are fi rms that produce APIs or other materials in unregistered, uninspected facilities. It is for this reason that fi rms purchasing APIs must have a program to assure that the sources of APIs are meeting the appropriate standards of quality and regulatory registration and reviews. Knowing your suppliers, their reliability as a source of API, and one that meets Quality Supply standards are all a necessary part of purchasing and using reliable API in today’s world.
BS: I believe this is a good time to be in the CMO business. Small and virtual pharma companies seem to be increasing in their share of the drug discovery pie, and larger companies are trimming their clinical manufacturing capacity. However, along with this increased business and a broader customer base, CMOs need to rise to the challenge of these partnerships. Being the best drug development partner means something very different to large pharma than it does to small or virtual pharma. Successful CMOs need to have the business and project management models that can accommodate that diversity.