In this installment of Ophthalmic Product Development Insights, we’ll review considerations for early-stage development of a new product as the entrepreneur charts his path to the first clinical trial. Most of the prior columns have emphasized that having the target-product profile drafted and defined early is critical to understanding key elements that contribute to designing a proper clinical development strategy. In this article, we’ll specifically look at issues around CMC (Chemistry, Manufacturing and Controls), an area that’s often outside the expertise and experience of the entrepreneur ophthalmologist. Proper CMC planning requires a basic understanding of the various interdependent steps of development: the design of the first clinical trial and of the toxicology studies; a preliminary idea of the commercial container closure; formulations; clinical dosing; pharmacokinetic considerations; and other components. All of these factors influence the CMC strategy.
We aren’t able to exhaustively review all of the critical requirements for CMC here, but we can offer a few pearls we’ve picked up after taking part in many development projects. We hope these pearls are useful, and pertinent to the issues the entrepreneur/first time startup company will encounter.
Container Closure
Locally administered ophthalmic products are required to be sterile and in a container closure system that prevents contamination. This alone can cause unique issues, but also presents multiple options for proceeding in some cases.
The closure system you use in your early trials may not be the one you ultimately settle on for commercial use. It helps, however, to understand your end goal so that you can understand the overall strategy as you progress from early to later stages of development, and set expectations about requirements that may be involved at each step. This includes anticipating technology transfer, or shifting from one source or manufacturer to another, that may be required between Phases II and III. In ophthalmology, there are a few standard approaches to container closure: multidose, three-part systems (bottle, tip, cap); blow-fill seal (BFS; typically unit dose and preservative-free); and tubes, which are generally used for ointments. Other novel systems like multidose, preservative-free bottles; or dual-chamber containers that allow drug components to be separate until mixing before use, are available for consideration but are more complex solutions that often aren’t used in early trials due to their time and cost requirements, which can be prohibitive for startup companies. In those cases, alternatives for use in the early trials should be considered. In some situations in which a unit-dose blow-fill seal doesn’t fit the timeframe/cost of the early program, small multidose containers can be used as single-dose units in initial studies. But we’ve also learned that headspace inside the bottle (the empty space inside the bottle between the top of the bottle and the drug inside) may be critical for a specific drug, and that scaling up the process to BFS later may highlight new issues when you’re trying to start Phase III (e.g., problems with the heat involved in the BFS processing). Therefore, one needs to keep in mind the potential risks associated with any anticipated changes to container closure down the road. Ultimately, it’s a business decision that balances time, cost and risk.
Formulations and Stability
As you plan your toxicology studies (per Good Laboratory Practices standards), it can be useful to know that the laboratory can take aliquots from bulk drug containers.(There’s no specific requirement to use your intended clinical container closure system at this stage.) However, it’s important to use a formulation for GLP ocular toxicology that’s similar to—or, optimally, the same as—that used in your intended clinical study. In many cases, formulation and scale-up are the rate-limiting factors in ophthalmic product development, so setting your formulation early and then locking it in for the trials is important.
If changes to the formulation are necessary as you proceed through your nonclinical program, you need to consider whether you can demonstrate to the FDA that those changes don’t impact safety or penetration of the drug into the ocular tissues. Adding a demulcent, for example, while a seemingly benign addition, can increase dwell time of the drug on the surface of the eye and thus, theoretically, drug penetration. Don’t underestimate the implications of formulation changes as you near investigational new drug status with the FDA. It goes without saying that you want to avoid having to repeat GLP ocular toxicology.
Another aspect of formulation you don’t want to underestimate is the addition of the preservative, which is usually required for multidose containers. While, again, simply adding a preservative may be considered a benign change, it’s the type of change that requires a confirmation of stability as an early part of your plan, since there have been cases in which a preservative ends up compromising a drug’s stability. Also, excipients have been shown to interact with preservatives. Therefore it’s a good idea to perform a standard preservative effectiveness test (PET) early on as you work through formulation development, to avoid surprises that require you to make adjustments. If adjustments are required after learning that an excipient impacts preservative activity, as mentioned earlier, there’s a risk that you’ll need to repeat at least some bridging toxicology. These cases may not require a full toxicology study, but only a streamlined study that bridges to earlier toxicology studies. Properly sequencing these steps is paramount. Even if supplies don’t use the final manufacturing process, as long as toxicology is conducted with a formulation that doesn’t have a cleaner impurity profile than the intended clinical formulation, you’ll have appropriate toxicology coverage.
GLP requirements state that the trial investigator needs to confirm activity and stability during the course of the study. This of course relates to the timing of when stability-indicating assays are available for the active drug in your specific formulation. This all relates to the duration of the planned clinical trial. As a side note specific to biologicals, as part of the release testing of clinical supplies prior to the study, the FDA likes to see that drug activity is also measured in an assay that is pertinent to the mechanism of action of the drug. The release of clinical supplies refers to the testing that measures the amount of the active drug, and also includes tests of pH and osmolarity, all of which have to meet predefined specifications prior to using a drug product in a trial. Therefore, setting up the appropriate assays early in the process is important. Lastly, as another side note, remember that the toxicology for a biological agent needs to be done in a species in which activity is also confirmed.
Another pearl on the sequencing of CMC centers on how to best leverage the engineering batch. This is usually a batch manufactured using the same intended process and formulation as the clinical batch, but at smaller batch size. While not a regulatory requirement per se, this batch can be used to supply the GLP toxicology study and also to show stability for the intended clinical batches. We have seen clients who, as they scale up from, for example, early lab-pharmacy-compounded drugs to full GMP manufacturing of drugs, find unexpected issues that take more time to solve. While engineering batches are standard and may seem an obvious step, make sure the timing is built in up front not only for the engineering batches themselves but for timing and work involved in developing the process.
Demonstration of stability of the intended concentrations of the drug is required for the entire length of the clinical trial. (Note that this, of course, includes the start-up time of the trial and full time that drug will be at sites, not just how long a single patient is enrolled). Your early engineering batches can serve as support for this, so that once clinical batches are manufactured and labeled they can be used in the trial.
Another point in manufacturing and testing: If you expect that your drug product will have a drop in stability during processing (e.g., down to 80 percent), you might wonder if you can just plan to manufacture at 120 percent so as it degrades it winds up at 100. This is not acceptable, because it implies that you don’t have full control of your process, setting aside other concerns around what dose is being delivered to different patients. For drugs, don’t simply plan that overages can solve stability issues.
There are nuances that are indication-specific, e.g., such as those for dry eye. Excipients that are already approved as monograph demulcents (see 21 C.F.R. 349), may lead to issues in the clinical/regulatory path with FDA, because those excipients in effect are already accepted to be used in dry eye as tear substitutes. This may lead to the FDA considering your drug a combination product. Therefore, if you’re going after dry eye as an indication, your best bet is to make sure you don’t have HPMC, CMC, PVA, etc., in monograph-level ranges early on in your formulation unless they’re needed and you anticipate having a proper clinical-regulatory strategy accounting for this. This has been an issue in some projects that were thought to need a surfactant or demulcent for stability or comfort, or one of these agents was part of a product profile early on, and led to delays in reformulation or unexpectedly increased the complexity of a clinical program.
Sterilization’s Impact
Ophthalmic products need to be sterile, and indeed most ophthalmic products are sterile-filtered. This highlights the importance of ensuring that the drug product can be filtered with filter validation studies early in the process. While an option, it’s best not to have to resort to other methods like heat, e-beam or ethylene oxide for early work. Thicker products may have issues with standard filtering. Generally, these issues can be solved by methodically working through them, but don’t underestimate the potential for filtration problems. Ointments can create cost and time delays because many manufacturers that make ointments, such as those made for dermatological applications, aren’t necessarily set up to be sterile. Keep in mind the time it takes to define manufacturing site options if you’re going after approval for an ophthalmic ointment.
Quality Systems
One final note: As the sponsor, the ultimate responsibility for the project and for your vendors lies with you. In order to properly demonstrate sponsor oversight, even if you’re a virtual company and plan to outsource all the work, you need to establish a basic system of standard operating procedures to ensure quality. It also helps to be able to demonstrate competence in these SOPs when you attempt to find a partner to help develop the product, since it shows that you’ve maintained the proper level of oversight and controls. As a sponsor, for example, vendor qualifications (before any work is done) and audits should be part of your plan. Don’t ignore the quality oversight required for complying with GLP (Good Laboratory Practices) and GMP (Good Manufacturing Practices) regulations.
In Conclusion
The path for CMC leading to IND and starting the first trial requires knowledge and expertise (or access to it) in the areas of formulations, GMP, sterile manufacturing, microbiology and others. It’s critical to understand how the CMC components tie into toxicology, regulatory and clinical concerns, and shouldn’t be viewed in isolation. A cross-disciplinary approach is needed to avoid delays or repeating activities later. This holistic view also feeds into formulating proper questions for pre-IND meetings and anticipating any specific issues your program might run into early on, so you can avoid multiple meetings with the FDA, if possible (though multiple meetings are acceptable and a separate CMC meeting with the FDA isn’t uncommon).
We’ll conclude with the theme that runs through all of these columns: Always keep the end goal in mind, and develop a properly defined target product profile early on. When you begin, it’s critical to focus on building a multidisciplinary strategy and timeline of all activity in order to identify interdependent and/or rate-limiting steps and to effectively conduct the product-development orchestra.
Mr. Chapin is senior vice president of corporate development at the ophthalmic consulting and development firm Ora, and Mr. Patterson is vice president of quality. Ora provides development, clinical-regulatory and consulting services for developers, investors and pharmaceutical companies. The authors welcome your comments or questions regarding product development. Please send correspondence to mchapin@oraclinical.com or hpatterson@oraclinical.com, or visit oraclinical.com.
