Originally Published MDDI June 2005
Device and pharmaceutical manufacturers must understand the differences in scientific expectations and cultural environments between CDRH and CDER to obtain FDA approval of drug-device combination products.
Stuart Portnoy and Steven Koepke
FDA requirements for drug testing of combination products are rigorous. To avoid costly and time-consuming missteps, companies seeking marketing approval of such products need to fully understand the requirements for FDA approval.
This article discusses preclinical testing requirements for drug-device combination productions and focuses on chemistry, manufacturing, and controls (CMC). Specifically, it explores several critical drug-testing requirements that are routine for pharmaceutical manufacturers but may be unfamiliar to medical device manufacturers. A previous article discussed the preclinical testing requirements for such products.
Combination products offer unique challenges to FDA. Problems can arise from unfamiliar timelines, center-specific policies, and development cycles; multiplicity of combination-product configurations; and expenses associated with single-unit production and packaging. It is essential for device manufacturers to understand that FDA centers often differ in their regulatory approaches.
Both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) carefully assess any changes that may affect product strength, quality, purity, or potency before granting market approval. That approach is data-driven. It typically requires any potentially significant drug or biologic formulation change to be supported by appropriate and adequate levels of product testing. From a time and planning perspective, one of the most
important considerations for testing is collecting product stability data. Most other data requirements can be obtained through testing fairly rapidly, but collecting product stability data, by definition, takes time. Consider a product with a relatively short life cycle in the marketplace, such as a drug-eluting stent (typically 1–2 years). For such a product, the requirement for adequate time to collect stability testing results becomes a critical issue for ensuring timely availability and distribution of a finished product.
By contrast, CDRH is typically more concerned with risk assessment. CDRH focuses on administrating design controls and ensuring that manufacturers properly document quality in all aspects of product development and manufacturing. Its approach often simplifies design and manufacturing changes by permitting less in-depth testing than the other centers prior to product approval. It also shifts some of the product performance liability to the manufacturer.
However, some areas of concern are common to both CDER and CDRH. Such areas typically include laboratory testing, stability testing, animal studies, clinical trial design, long-term follow-up, and postapproval data collection requirements. But the views of each center can vary widely and often need to be negotiated, sometimes on an ongoing basis concurrent with product development.
Complicating these fundamental concerns, combination products frequently incorporate relatively small doses of a drug, compared with conventional pharmaceuticals. As a result, sensitive analytical methods (e.g., micrograms versus milligrams) must be used. It is often difficult or even impossible to measure these very small circulating drug levels using an in vivo model. CDRH would likely view minor variations in such small drug doses as being well within an acceptable level of risk. CDER, however, would likely be concerned that such a variation might alter the product's efficacy and challenge the manufacturer to address this as a potentially significant problem. From CDER's point of view, any variability of the delivered drug dose should be controlled by the manufacturer to ensure the reproducible efficacy of each individual product. A device manufacturer pursuing market approval of a combination product may not understand that CDER has higher expectations and different testing-performance standards for the drug component of the product compared with CDRH's requirements for the
FDA Review of CMC
|Table I. FDA's CMC definitions and parameters (click to enlarge).|
Pharmaceutical manufacturers devote significant resources to providing FDA the required laboratory results and documentation from CMC drug testing. However, these critical concepts are often unfamiliar to a device manufacturer.
As shown in Table I, chemistry refers to the underlying physical science of the drug. Manufacturing refers to the specified production methods. Controls refers to the combination of in-process controls and analytical characterization of the final drug product. Drug evaluation is almost always much more data intensive, and more time consuming, than device evaluation. It is critical for manufacturers to obtain early feedback from CDER regarding the center's expectations for CMC and other drug-related testing requirements.
It is important to CDER that the drug product's future performance remains comparable to the originally marketed product within the parameters for which it was initially evaluated and approved. A typical CMC review by FDA defines the parameters that must be tested and controlled to ensure that this happens. These parameters become regulatory specifications—future deviations from them are subject to prior FDA approval and require adequate justification by the manufacturer. The CMC review also gives CDER the opportunity to develop knowledge and understanding about the manufacturing and control processes. The knowledge gained in FDA's review also allows the manufacturer to pursue future changes in specifications and product performance based on negotiated and well-characterized evaluation parameters, rather than requiring additional clinical trials.
CDER chemistry reviewers typically expect the manufacturer to provide a full characterization of the following:
• Drug substance, or the active ingredients that provide the clinical benefit.
• Excipients, or any substances other than the active ingredients used in the drug product.
• Final drug product, or the finished dosage form that contains the active ingredients and excipients.
One of CDER's concerns is the potential for reactivity between the drug and the excipients. The center requires a manufacturer to provide quality control data on any interactions between the drug and excipients. The level of testing and data needed to support using any specific excipient depends on how it is being used in the drug product.
|Table II. CMC testing components (click to enlarge).|
For some excipients, the manufacturer is expected to provide the same level of quality and quantity of testing data as the drug substance itself. In those cases, the quality control data must be provided to FDA in the same reporting format as for the drug substance. Excipients that require the more-substantive quality control testing include the following:
• The excipient is being used for the first time in a human drug product in the United States.
• There is a new route of drug administration (e.g., was previously given via an IV and is now part of a drug-eluting stent).
• The excipient is critical to the release rate of the drug (e.g., a polymer that controls the drug release rate from the stent).
Finally, CDER chemists often expect the manufacturer to provide valid scientific evidence that all CMC testing results are reproducible. These parameters must be adequately defined in the marketing submission to enable reproducibility of CMC testing. Table II provides a list of the components of CMC testing for the drug substance and the final product.
CDER is typically focused on the full characterization and adequate validation of drug stability throughout the specified shelf life of a combination product. Usually, applicants must obtain data on drug release rates when the investigational product is being tested under accelerated (forced) stability conditions. Results from these initial stability studies performed under stressed conditions provide a baseline for future product performance.
Once a drug is approved, FDA can typically rely on parallel performance profiles under accelerated conditions to approve future incremental manufacturing and product changes without requiring the sponsor to perform full-term stability testing. If a submission provides FDA with the appropriate data, CDER typically accepts accelerated stability-testing results as a surrogate for long-term product performance. When a process change is made, CDER expects the manufacturer to provide data showing the comparability of the accelerated performance data for the revised drug product and the originally approved product.
For drug-eluting stents, the ability to matrix and bracket product samples based on a range of drug-dose and device configurations reflects an important testing consideration. The sample matrix and bracket in Table III shows a possible stability evaluation of a drug-eluting stent manufactured in various lengths and diameters. The testing plan includes intermediate samples as well as the outer corners of the matrix. Utilizing bracketing or matrixing stability studies requires prior FDA approval with adequate justification provided by the sponsor.
A potentially serious problem with matrixing arises when a particular sample fails stability testing. Under these circumstances, FDA may mandate a recall of all unsupported product included in that matrix, even from the untested cells. Although such an event is unlikely, its potential harm to a company can be significant. To manage critical aspects of this risk, sponsors should prospectively develop a recovery plan intended to identify the cause of the failure in a definitive and timely manner. Manufacturers usually store representative samples of finished product for each cell in the matrix to enable them to perform comprehensive failure analysis. Doing so is prudent and likely worth the extra effort, especially if an investigation becomes necessary to identify the cause of the problem.
Some companies accumulate man-ufactured portions of a device long before final product assembly. Under these circumstances, a sponsor might assume that drug product expiry period begins when the final product is assembled. However, CDER considers the expiry period to start as soon as the drug has been manipulated.
Another important consideration is how a product's life cycle can affect planning for current and future combination-product release. Many drugs have an expected life cycle of 30 years or longer. A typical device may have a life cycle of as few as two years. By the time CDER obtains two-year stability data for a combination product, the device manufacturer is likely well into development of the product's next generation.
To avoid potential regulatory problems, the sponsor should plan for rapid, multiple changes of the commercial product. One way to do so is to initiate new batches of product for performance and stability testing according to a predetermined schedule. Batches will typically overlap with prior versions of the product whose testing results are not yet complete for market release. This enables an un-interrupted flow of fully tested and validated product.
Drug Product Characterization
Applicants should provide sufficient drug product characterization so CDER can form a baseline understanding of the drug. This characterization will enable evaluation of future changes in product performance. The more thorough the original characterization, the less likely CDER will be to require results from a new clinical study to support future changes.
CDER is also concerned with drug product consistency. Testing should demonstrate that product performance remains unchanged over time and through iterations of the product or manufacturing process. If a sponsor is unable to provide sufficient data to support such proposed changes, the expiry date is typically shortened. A shortened expiry could result in a distribution bottleneck with significant financial consequences.
It is critical that combination product manufacturers understand CDER's stringent requirements for drug quality. It is usually necessary for a manufacturer to test multiple lots and analyze cumulative drug product stability data to demonstrate drug quality. Analytical and stability testing can account for a significant share of the cost of drug development.
FDA requires that each drug lot undergo individual quality-release testing of a representative sample of finished product prior to commercial distribution. The production scale thus plays an important role in the economics of drug development—usually, it is unfavorable for combination products. Lot sizes for drug products typically number in the millions of units for tablets and capsules, and in the hundreds of thousands for more-complicated and capital-intensive drug-delivery configurations. This is different from lot sizes for combination products, in which lot sizes typically number in the tens to hundreds.
Given the relative volumes, the marginal production cost of an individual drug-device unit is much higher than for a single pill or capsule. Consequently, manufacturers should carefully review FDA's release-testing expectations early in the product development process. That way, the manufacturer can establish acceptable parameters and sample sizes and avoid any surprises prior to FDA approval that could result in a delay in product availability.
Kinetic Drug Release
Most testing submitted to FDA should be performed on the finished product intended to be released on the market. This is especially true for testing used to characterize quantitative aspects of drug release. CDER typically requires that a release-rate assay in real or simulated deployment conditions demonstrate an overall in vitro release of at least 80% of the drug. This is true even if this amount is never intended to be released from the product under normal clinical use conditions. The distribution of drug within a unit and across units should be uniform. For example, a stent's coating should be uniform and contain the same dose density of drug throughout its length.
CDER also expects the sponsor to establish an in vivo–in vitro correlation of the total amount of drug released from the finished product, under real or simulated deployed conditions. This testing provides local and systemic drug safety results at intended doses of drug release. It can be important in supporting approval of future change to the combination product.
One often-unexpected issue that complicates the development and final approval of a combination product is the method of sterilization. For example, ethylene oxide (EtO) is widely used to sterilize devices. However, EtO is a reactive agent that can chemically interact with the drug substance, resulting in reduced efficacy and potentially toxic by-products.
Another important consideration is the potential for cross-contamination, since EtO sterilization can be a batch process. Any batch process creates the potential for cross-contamination with other residual material, either from a previous sterilization cycle or a product that may be concurrently in the chamber.
The sterilization method is an important factor that contributes to establishing lot size. The entire lot should be sterilized for the same time in the same chamber to avoid concerns of differences within a lot. Preparing a lot size large enough to support product release from an economic perspective while meeting CDER's requirements typically requires applicants to adjust their manufacturing processes and lot sizes accordingly.
CDER is also concerned about the presence of drug impurities, both before and after manufacture. CDER expects a manufacturer to be able to demonstrate that the drug substance is unchanged throughout the drug product manufacturing process. Otherwise, the applicant should be able to fully characterize the change that occurs during the manufacturing process and provide testing data demonstrating that the safety and efficacy of the finished product has not been affected.
Lessons to Be Learned
To facilitate FDA approval of combination products, device manufacturers need to appreciate the substantial differences in scientific expectations and cultural environments between CDRH and CDER. FDA's testing requirements for drugs are much more complex than its requirements for devices, especially from a stability standpoint. Failure to address quality and process issues early during product development and validation testing will likely result in some combination-product approval delays, shortened expiry periods, and restrictive storage conditions. These regulatory setbacks can ultimately interfere with successful marketing of a newly approved combination product. Given the high financial stakes of these products, it is critical that the applicant be sensitive to all CMC considerations.
Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products [on-line]. Rockville, MD: FDA, CDER, 2003; available from Internet: www.fda.gov/cber/gdlns/ichq1d.htm.
Swain, Erik. “Extra Effort: Packaging for Combination Products.” Medical Device & Diagnostic Industry 27, no. 1 (2005): 98–106.
Stuart Portnoy, MD, is senior director of medical device consulting at PharmaNet Inc. (Washington, DC). Steven Koepke, PhD, is president and founder of SRK Consulting LLC (Walkersville, MD).
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