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Tips for Working with CMOs: Preparing for Phase 1 Clinical Trials Edward S Price, President of PCI Synthesis, advises companies to invest in their new chemical entity (NCE) assets to assure quality and avoid regulatory delays. 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% of drugs that reach clinical stage development do not get approved by the FDA. Further, only half of drugs rejected by the FDA fail due to a lack of efficacy. In fact, reasons for rejection most often include a failure to maintain proper manufacturing protocols and errors in form submissions.1 To have the best chance of being in the 10% that does receive approval, it is imperative to find a contract manufacturing organization (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 delaying the trial. With time pressures always paramount, any setbacks cause headaches – many of which could have been avoided.

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Invest in your NCE asset to assure quality and avoid regulatory delays. Section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351 (a)(2)(B)) 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. 1. 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. 2. Equipment: Are they adequate for scale-up? Can their production capabilities range broadly from grams to multiple kilograms? 3. Processes: Are they designed to minimize any potential manufacturing problems during repeated kilo scale-up? 4. 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? 5. Materials: Do they have supply chains capable of delivering a consistent supply of quality raw materials? 6. Quality control functions: Do they eliminate or mitigate potential hazards to safeguard the quality of the phase 1 product? 7. 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: 1. Do you use disposable equipment and process aids to reduce cleaning burden and chances of contamination? 2. 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?

Speciality Chemicals Magazine April 2017  

Volume 37 Issue 02