Taking (Better) Control Of Your Outsourced Analytical Activities
By Sue Wollowitz, Ph.D., president, Wollowitz Associates LLC
When a sponsor signs a contract with a CDMO, the analytical chemistry to-do list may look like the easiest part of the agreement. However, it can be the most challenging to manage in a total outsourcing model of drug development.
Selecting processes and formulations, appropriate containers and storage conditions, and manufacturing parameters and controls — as well as the interpretation of in-process controls (IPCs) and the resolution of out of specification (OOS) situations and investigations — all depend on having meaningful data available. If data comes from methods that, for example, are irreproducible, have poor specificity or lack sensitivity, or if data is simply unavailable, the reliability of the decisions are at risk. At best, the program has missed opportunities for development efficiency; at worst, products need to be rejected or recalled due to problems that could have been identified earlier.
For meaningful data to be available, scientifically valid and consistent methods across the development program are important. In addition, the ability to sample and test at will and in real time for standard and sometimes one-off parameters, analytical experts actively engaged in the development process, and access to all data to detect trends and inconsistencies are invaluable. It is easy to assume that validating methods and QA oversight of procedures and results ensures quality results. But that might not be possible in a “phase-appropriate” development scenario, where methods are being selected and optimized in parallel with other development activities and data collection.
These are all potential problems regardless of who is carrying out the development. But, it is particularly of concern in the small pharma outsourcing model where CDMOs have most of the responsibility for analytical development and the sponsor may have limited internal expertise to best monitor analytical issues.
An Outsourced Model Challenges Optimal Analytical Engagement
Most projects involve more than one CMO and/or CDMO. Even with the creation of vertically integrated CDMOs, the project will involve more than one analytical laboratory with different expertise, standard procedures, methods, equipment, personnel, training, and agreed-upon responsibilities. This can confound data collection and interpretation and increases the responsibility of the sponsor to coordinate and communicate across facilities. Additionally, for many small pharma companies, a regulatory strategy to aid in phase-appropriate development decisions may be vague or undefined, and the CMOs may apply their own strategy in the absence of guidance.
In addition, the CMO’s analytical chemists are typically involved in a number of projects and may interact with the sponsor on an “as-needed” basis. Unless they are actively involved, analysts are less aware of evolving project understanding; they cannot be proactive in problem solving. In addition, analytical labs can have a bottleneck due to activity with competing programs. Prioritization and scheduling may be an opaque process for the sponsor, and slow turnaround on testing means delaying decisions or moving ahead with less data.
Development contracts are most often written with a fixed fee for method development validation/qualification. Additional time in the analytical lab may involve a change in scope, and there may be less flexibility to make spontaneous decisions to add samples or tests to better understand development issues.
Finally, there is the challenge to fully use the expertise of all the outsourced providers together to the benefit of the program. Analytical labs at CMOs are there to support the process activities at those facilities. Asking CMOs for activities that don’t directly relate to the process activities or are outside the main expertise of the facilities can be distracting and does not always benefit the project.
How Do We Take On The Challenge?
First, the sponsor must appreciate that analytical development cannot be “thrown over the wall” even when working with highly experienced CDMOs. Frank and timely communication between the sponsor and the CMO is essential. How to build extra testing into a contract, when and how to qualify and validate methods, when testing might get backed up, and what alternatives are available all need to be addressed.
All data should be critically reviewed for inconsistencies or trends and to identify if these are analytical issues. Once methods are moved into validation, QA’s input and standard procedures are invaluable, but much data is collected outside of the GMP envelope. In addition, each time a method changes ownership, either between CMOs or just from a method development group to a QC lab, incomplete knowledge is transferred and often there is less connection to the project science. These are weak points and merit extra oversight until it is clear the new labs are fully on top of the project. Some CMOs have highly engaged analytical team members or others who carry out such review, but the sponsor must participate. Responsibility for errors may lie with the CMO, but it is the sponsor’s project that is at risk.
Identify potentially risky data and decide how to manage it. Examples include data from different facilities using unspecified or just different methods and data collected with methods that are subsequently recognized as nonspecific or irreproducible. Samples may require immediate retesting or storage for possible future testing with validated methods or just recognition of the risk point if issues arise in the future.
Documentation of test results needs to be available for retrospective analysis at the sponsor regardless of whether it was of concern when the data is collected. Method descriptions and raw data (especially spectral and multipoint data where limited information appears on a certificate of analysis or in a report) should be in the hands of the sponsor. Trends in data or method performance may only be seen when looking back over a number of testing events.
Consider the whole spectrum of analytical activities and potential issues and understand options for managing them. Not all testing needs to be done at the main CDMO.
Outsourcing Options For Analytical Activities
Outsourcing options offer trade-offs. The simplest plan is to have all the analytical activities managed by the API and drug product CDMOs. They know the products best and may detect nuances and trends more quickly than if the work is divided among other labs. But again, asking CDMOs for activities that don’t directly relate to the main development, that are outside the main expertise of the facilities, or that overload the facility can be distracting, can cause delays, and do not always benefit the project.
Some activities such as raw material testing, stability storage, and testing of packaged material or comparators may be most easily done by focused analytical organizations. They generally have state-of-the art equipment, have a wide variety of standard methods in-house, and bring knowledge and experience from a wider variety of products. They may provide more cost-effective services; however, they will not have the same attention to detail on custom products, and transferring immature methods to such a lab is risky. The sponsor takes on additional responsibility to monitor and integrate these third-party results.
Smaller development or testing facilities (not manufacturing facilities) can be useful to fill in gaps between the CMOs. Such labs may be able to front-run new methodology; carry out initial evaluation of new configurations, packaging stability, or other issues without distracting the main labs; identify impurities observed at the drug product manufacturer; and offer specialized nonstandard analytical capabilities. Finally, in small pharma companies, CMC (chemistry, manufacturing, and controls) leads or consultants are frequently generalists. Bringing in experienced analytical chemistry hires or consultants can greatly increase oversight and improve decision making.
Analytical testing and data collection is a large, critical, and sometimes unpredictable piece of the overall development effort. It requires equal technical, business, and strategic attention to ensure it can be the major asset it should be.
About The Author:
Sue Wollowitz, Ph.D., is a pharmaceutical development consultant and educator. She is interested in CMC tactics and strategies in small companies that increase operational quality and best support project goals. Wollowitz has led pharmaceutical operations at Medivation, Inc. and held various positions at Cerus Corp. and Dow Chemical Corp. She is the holder of 32 patents and the author of over 20 publications. Wollowitz has a Ph.D. in organic chemistry from the University of Wisconsin-Madison and further training at CNRS in France and at the University of Chicago. She can be contacted at suewollowitz@gmail.com or on LinkedIn.