Stability Program Management: Clinical Trial Materials - Points to consider when using a contract stability lab
How many times have you read a stability article and all it provided was the information specified in the ICH guideline? It’s enough to make you pull your hair out before you have turned the first page.
But we promise this article is different. We will focus on the start-up and set-up of a stability program when it must be outsourced to a third-party laboratory. Our discussion will center on the following key issues:
• Initial communications with your contract stability organization
• The transfer of your methods
• Required product knowledge and program management
• Data presentation for important decision making on label claims
This document will review the development of a parenteral stability program from the standpoint of effective program management — not from the regulatory or scientific requirements approach covered extensively by most other stability white papers.
COMMUNICATIONS — THE FIRST STEP
So you need a stability program, but don’t have the facilities to handle it. Welcome to the world of outsourcing. You have joined the ranks of most virtual clinical manufacturers (and some non-virtual companies as well). These organization’s lack the “bricks and mortar” facilities for a fully compliant and capable stability laboratory. So they must outsource the work.
When using a contract stability laboratory, up-front discussions must occur and a comprehensive statement of work must be formalized (including a CDA and service agreement). It is imperative that these discussions include any nuance or variation in your product that may be ultimately affected by the increase in temperature for an accelerated track. You should also inform the lab about how your product should be handled during analysis in their facility (i.e. sensitivity to light, oxygen, etc.) to avoid costly testing errors. Remember, the contract lab will not have experience working with your product in the earlier stages of its development. You are the product expert and will likely be aware of the challenges that can be expected through your molecule’s lifecycle. Sharing this knowledge early in the relationship will help your lab overcome the learning curve inherent to working with a new product.
Some specific items for discussion include (not in any defined order):
Facility – Does the facility have enough space and lab capacity for your product? Will their lab and storage facility have enough capacity to support your growing needs and potential new products — in other words, adequate space for expansion? While you may be looking at this partnership today for one product, it’s likely you don’t have just one. And if the partnership does indeed work out, you’ll want to continue it with additional products.
Regulatory – Is the lab registered and audited by the FDA? Were the audits successful? Are they GMP-compliant? Do their chambers meet cGMP validation requirements? Are they ICH compliant?
Personnel – Are the stability/analytical personnel of sufficient education, experience, and training to perform the required testing and to manage the program? The keyword here, of course, is “sufficient.” Typically it’s the four-year degree in a science area along with any experience and training to the relevant GMPs. But the exact specs vary, company to company and project to project. It’s up to you to determine the specifics, and then for the lab to prove that they can meet them — and how well.
Internal program manager – Personalities are important. The length of a stability study means you must work with the lab’s point of contact for many years. Are you comfortable with this person? Can you partner with them for the successful implementation of your program? And while the internal program manager doesn’t necessarily need a scientific education, his or her lab and project management experience — and orientation to detail — is critical. A litmus test: would you hire this person for your own staff with similar responsibilities?
Laboratory expertise – What lab facilities and equipment are available? Do they have what you need for the stability assessment? Some possible red flags: lack of analytical equipment such as HPLC, liquid particle counter and an osmometer — on the small molecule side. On the large molecule side, the capacity for electrophoretic methods. Additionally, does the laboratory have experience working with similar methods and products (small molecule/large molecule, etc.)? Will it need to send out some of your work? And to where? Are the sub-contracted labs qualified? Is “subbing out” — with its added layer of process and additional time — something that you want to take on?
Reputation — a softer issue for sure, but it can be telling. What’s the word of mouth around the industry on the lab? Whom have your colleagues worked with and whom do they recommend and why? Additionally, can the lab provide relevant references? If the lab has strong relationships and a history of quality work with its clients, it should. Don’t expect details of course, but the fact that a company would stand up and recommend its lab in response to an inquiry from a prospective client should speak volumes.
Once these discussions are complete, specifics requirements discussed, and the service agreement and Statement of Work (SOW) drafted, then the process will begin.
Begin your stability program by scheduling a quality audit of the facility to ensure GMP compliance and confirm the lab is aligned with your internal procedures and requirements. The quality audit can be performed in two ways. Typically, it is conducted by your company’s internal quality assurance group and includes a person educated in stability programs. Now, you’ve got a specialist in quality plus someone who can ask the tough questions on the manufacturing and laboratory sides. Moreover, the audit should take place onsite. Onsite, you can go beyond the specs and checkboxes to get a better feel of where you are on the “mutual understanding” you’re attempting to reach. This approach is the most beneficial because product-specific questions can be asked and answered.
The other approach uses an outside consultant to perform the audit. This auditing method has limitations since it will focus on only GMPs and not the specifics of the product(s) transferred in. However, each approach is acceptable and will give the program manager the “warm and fuzzy” feelings necessary to begin the project.
In addition, a quality agreement should be signed by both parties to ensure alignment and agreement on the quality of the stability documentation and program. The quality agreement should state that you will be notified in a prescribed amount of time about any issues, deviations, or out of tolerance issues concerning your product.
When implementing a stability program with a contract laboratory/manufacturer, you probably will become your organization’s point of contact for the project. It is essential that you become intimate with the management of your program at the contract facility. You should work closely with the laboratory’s stability department project manager and develop a mutual understanding of your respective roles and responsibilities. Remember that program management is the most important ingredient in the success of a stability program. Poor management can impact the determination of expiry dating, parameters of specification, and the ultimate life of a pharmaceutical article. It also can hinder the timely submission of regulatory documentation and affect the development of further stability programs.
Armed with executed service and quality agreements, plus a successful quality audit, the transfer of stability-indicating assays, identification of materials to be used, and the protocol must be completed.
The first item is the transfer of the stability-indicating assays to determine if there is failed stability. Technical transfer of the analytical test methods, including all of the testing, documentation, and reporting, typically requires 4 to 6 weeks. So this process becomes the time-limiting step in most programs. If no stability-indicating assay exists, then one must be qualified to correctly assess the quality of the product. Determination of an assay to be stability indicating is a process that is well-defined and is not covered in this article.
Ask your contract laboratory to provide a protocol with the specific parameters listed in the executed service agreement. Once the protocol is implemented, then the material can be added to the specific temperature-controlled chambers. An inventory list should be utilized to track the number of units you have in stability, including all retains. The stability lab will have a schedule of pull, based on the protocol. This schedule acts as a roadmap that indicates when material becomes available for associated quality control (QC) testing.
To keep up to date on stability program testing, the lab will send you interim reports, upon request. These reports contain a table of the QC testing done with results compared to the T=0 testing. The reports should be reviewed to determine if there are any out of specifications or trends that the product is exhibiting. As your company’s program manager, you also should request the raw data and review this against the interim reports. There may be some trending that you observed in early stage development work that may be transparent to the stability lab. If this is the case, notify the stability lab to determine the best course of action. A footnote: does the lab provide these reports consistently on a timely basis? Though the reports are only interim, the lab should. Again, attention to details.
OUT OF SPECIFICATIONS (OOSs)
Any OOSs must be investigated to determine the root cause of the failure. In a case of a true OOS and a failure of the quality specifications, one may choose to test an alternate temperature (as in the case of an accelerated temperature). You must determine if this is a failure due to lab error or a need for a revision to the methodology, product, or formulation quality. Or perhaps because accelerated temperature is excessive for the product compared to what it will typically experience in its lifetime. The outcome of an OOS investigation may compel you to consider a shorter expiration period than desired or alternative storage conditions. You also may need to explore the impact of short-term excursions at the temperature for which an OOS result was observed, alternative packaging options, or even reformulation.
Any successful stability program will include trending as part of the review process. Make sure that either you or the stability lab has a program for trend analysis. This procedure is useful for many reasons, but the most important is the predictability and determination of potential expiry dating issues.
It’s ironic. While many often approach stability as a second thought, it’s been said that the most-cited regulatory issue for parenteral drug products is, in fact, stability. In these cases, it was found that the program did not properly address the expiration dating and determination of future product quality. When you choose a stability testing house, be sure to perform the highest level of due diligence when auditing its capabilities (from technical to facility to quality). This will ensure a successful stability program and certainly serve you well in your regulatory filings.
ABOUT THE AUTHORS
Alex Mello is Director of Project Management, Manufacturing, for Microtest Laboratories. Mr. Mello’s 15 years of experience span Aseptic Fill/Finish, Microbiology, Method Transfer, Stability of Drug Product, Medical Devices/Combo Devices, and Sterilization Sciences. He holds a graduate degree in Biological Sciences and is a Specialist Microbiologist (NRM). Contact Alex at 800-631-1680 ext. 121 or email@example.com.
Jessica Labrie is Project Manager/Stability Coordinator for Microtest Laboratories. Ms. Labrie’s experience includes ICH Stability of Drug Product, stability programs for medical devices/combo devices, accelerated aging of medical devices, and cGMP aseptic fill/finish. She holds her B.A. from the University of Massachusetts and M.S. from Springfield College. Contact Jessica at e-mail firstname.lastname@example.org.