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Because a phase 1 clinical trial initially introduces an investigational new drug into human subjects for the first time, the FDA’s primary concern is ensuring subject safety. This is how the agency introduces its guidance – with potential problems:
Section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351 (a)(2)(B)) requires drugs, which include IND products, to comply with current good manufacturing practice as follows:
A drug…shall be deemed adulterated…if…the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.
Industry research shows that an astounding 90 percent of drugs that reach clinical stage development do not get approved by the FDA. Further, only half of drugs the FDA rejects fail due to a lack of efficacy. Reasons often include a failure to maintain proper manufacturing protocols and errors in form submissions1.
To have the best chance of being in the 10 percent that does receive approval, it is imperative to find a CMO with deep experience and expertise in navigating the regulatory minefield. This article provides some insights on how to gain confidence in your CMO partner, and five tips for assuring a successful phase 1 clinical supply.
NCE manufacturing can make or break a project
Most NCE development and manufacturing is outsourced to CMOs. Since successfully navigating FDA regulations can be challenging, it’s advisable to carefully scrutinize the CMO’s track record of adherence to the highest cGMP standards. Contaminants, hazards and quality control in manufacturing are key issues that could result in the FDA’s delaying the trial. With time pressures always paramount, any setbacks cause headaches – many of which could have been avoided.
In applying appropriate cGMP, we [the FDA] recommend that manufacturers consider carefully the hazards and associated risks from the manufacturing environment that might adversely affect the quality of a phase 1 investigational drug, especially when the phase 1 investigational drug is manufactured in laboratory facilities that are not expressly or solely designed for their manufacture. For example, of particular importance is the susceptibility of a phase 1 investigational drug to contamination or cross contamination with other substances (e.g. chemicals, biologicals, adventitious agents) that may be present from previous or concurrent research or manufacturing activities.
How to gain confidence in your CMO – what to look for
According to the agency, sponsors and manufacturers are jointly responsible for assuring a product’s safety. In vetting a CMO, sponsors should evaluate the manufacturing setting as follows in order to identify potential hazards:
- Product environment and facilities: Are work areas properly equipped and controlled for the specific operation(s)? Not all environments are suitable for the manufacture of specific phase 1 investigational drugs.
- Equipment: Are they adequate for scaleup? For example, PCI Synthesis’ production capabilities range broadly from grams to multiple kilograms.
- Processes:Are they designed to minimize any potential manufacturing problems during repeated kilo scaleup?
- Personnel: Are the scientists and project managers experienced and do they continuously focus on improving efficiencies? Can they solve the inevitable problems that arise, and do their best to meet timelines?
- Materials: Do they have supply chains capable of delivering a consistent supply of quality raw materials?
- Quality control functions: Do they eliminate or mitigate potential hazards to safeguard the quality of the phase 1 product?
- Regulatory documentation prowess: Do they know what the agency is looking for and how to document accordingly, helping keep the project’s timeline on track?
Once a sponsor has complete confidence in the CMO’s manufacturing environment, a deeper in the weeds assessment is in order. Ask about the CMO’s technologies and resources that could streamline product development. Ask questions such as:
- Do you use disposable equipment and process aids to reduce cleaning burden and chances of contamination?
- Do you use commercial or prepackaged materials such as Water For Injection (WFI), pre-sterilized containers and closures to eliminate the need for additional equipment or for demonstrating cGMP control of existing equipment?
- Do you use closed process equipment so that the phase 1 investigational drug is not exposed to the environment during processing, in order to alleviate the need for stricter room classification for air quality?
Top 5 Practical Tips for Assuring Successful Phase I cGMP Supply
- It’s always better to have too much product than too little. Accidents happen. We had a situation where the product was shipped to the formulator and formulating inadvertently left a valve open, dumping the entire formulated batch onto the floor. The project timeline was thrown off as the sponsor had to get back into line for a new manufacturing slot. We always recommend making 50 percent more product for phase 1. If you need a kilo, order 1.5 kilos.
- Use an integrated CRO/CMO. Everyone wants to keep costs down. It’s a no brainer. What we’ve found in our decades of experience is that sure, there are certainly opportunities to offshore development of APIs at lower cost. However, what sponsors sometimes don’t anticipate is the additional transition costs when manufacturing is to be done elsewhere. When a sponsor comes to a reputable CMO like PCI Synthesis for cGMP manufacturing, we need to repeat all the other lab’s processes to make sure the product can be efficiently manufactured and provide the documentation the FDA will want.
- Choose a CMO focused on speed to market but who doesn’t cut corners. The more experience the CMO has, and the busier, the more likely the manufacturer will want to get your product out the door on time and on budget. To that end, the CMO will continuously focus on process improvements, tweaking the manufacturing process to streamline production and improve yield while assuring pharmaceutical grade quality. The more efficient the process becomes, the lower the cost.
- Meet the project manager. Trust between the CMO and sponsor is based on a relationship built on open and frequent communication between the sponsor’s team and a project manager who skillfully manages risk, timeline and budget. As we previously reported in our blog article, “Pharmaceutical Toll Manufacturing: Cost is Not the Only Consideration” ¬(insert link or hyperlink), law firms caution that manufacturing also represents unique risks for the potential loss of trade secrets. Trust is essential.
- Beware of low cost estimates followed by multiple change orders. Every NCE is different, and unforeseen technical challenges are bound to come up. Anticipating and fixing problems is usually built into process research. Some CMOs estimate a shorter development time than needed to keep costs down, then issue change orders when technical challenges arise. Rolling the dice and hoping for the best can cost more than money – and it can cost the project valuable time in starting the phase 1
Developing an API or NCE is not a commodity so it’s important to make sure you’re asking the right questions of prospective CMOs to make sure the team is one you can trust, collaborate with, and get the kind of support you need. This is an area where a low-cost provider may end up costing you more and taking more time to deliver the final product. For insight into working with offshore CMOs, check out “Outsourcing API Manufacturing to Asia: Good Opportunities But Buyer Beware: Four key questions to ask to get the most out of a CMO relationship.”.
- Plaford, Why Do Most Clinical Trials Fail? Clinical Leader July 8, 2015
About the Author
Ed is the President and CEO of PCI Synthesis (PCI), he serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA).
Do you have questions? Talk to Ed.