This article appeared in the March 2010 issue of Drug Delivery Technology magazine.
The U.S. Food & Drug Administration (“FDA”) recently announced the long-anticipated new proposed rule for combination product Good Manufacturing Practices (“GMPs”).[i] Published on September 23, 2009, the proposed rule may well substantially change the way companies develop and commercialize combination products, clarifying many of the issues that manufacturers have struggled with over the years, but also injecting some new ambiguities. Comments on the proposed rule are due February 5, 2010.[ii] (Shortly after publishing the GMP proposed rule, the agency issued a proposed rule on post-market safety reporting for combination products. The next issue of Drug Delivery Technology will explore this equally important rule.)
After summarizing the GMP proposed rule and the issues it clarifies, we’ll highlight a few new concerns that might impact the drug delivery industry and discuss how FDA might implement the rule.
Until now, the primary pronouncement on combination product GMPs was a draft guidance document issued in September 2004. After this draft guidance, the agency announced its intent to publish a proposed rule in Spring 2006 and issued at least one Warning Letter citing a company for violations of combination product GMPs in June 2006.[iii] The practical effect of announcing its plan to publish the rule turned out to be a quiet period on the topic of combination product GMPs in which the agency felt constrained not to discuss the topic while it formulated its proposal. That left many companies with unanswered questions over the last 5 years, as they struggled to figure out how to develop new facilities and manufacture combination products.
Scope of the cGMP Proposed Rule
The basic content of the proposed rule is similar to the framework under the September 2004 draft guidance. In a nutshell, constituent parts (that is, the drug, biological product, and device parts) of a combination product retain their unique regulatory status throughout the combination product’s lifecycle. As a result, all constituent parts must meet the requirements for their respective GMPs, even after those parts are combined or joined together. In particular:
- A drug constituent part must comply with the GMPs in 21 CFR Parts 210 and 211;
- A device constituent part must comply with quality system regulation (“QSR”) requirements in 21 CFR Part 820;
- A biological product must comply with drug GMPs and, as applicable, GMP requirements in 21 CFR Part 606 for blood and blood components and other sections of 21 CFR Parts 600-680; and
- A human cell, tissue, and cellular and tissue-based product (“HCT/P”) must comply with the current good tissue practice and donor eligibility requirements for HCT/Ps in 21 CFR Part 1271.
Although these requirements apply to a constituent part even after it’s joined, combined or packaged with another part, the proposed rule allows for a “streamlined” approach for combination products made at one facility. More specifically, the proposed rule says that a streamlined GMP system may be used when two or more constituent parts “have arrived at the same facility” or when “manufacture ?… is proceeding at the same facility.” In using the streamlined approach, the facility may adopt a primary GMP system (presumably the system under which the facility already operates), and then add on elements of the other applicable sets of GMP requirements. The rule lists the elements of other GMP requirements that must be added.
If the facility makes drug/device combination products, and operates under a device quality system, the facility must also observe the following elements of the drug GMPs :
- Testing and approval or rejection of components, drug product containers, and closures. (21 CFR 211.84)
- Calculation of yield. (21 CFR 211.103)
- Tamper-evident packaging requirements for over-the-counter (OTC) human drug products. (21 CFR 132)
- Expiration dating. (21 CFR 211.137)
- Testing and release for distribution. (21 CFR 211.165)
- Stability testing. (21 CFR 211.166)
- Special testing requirements. (21 CFR 211.167)
- Reserve samples. (21 CFR 211.170)
In converse, if the combination product manufacturer operates under drug GMPs, it must apply the following elements of the device QSR:
- Management responsibility. (21 CFR 820.20)
- Design controls. (21 CFR 820.30)
- Purchasing controls. (21 CFR 820.50)
- Corrective and preventive action. (21 CFR 820.100)
- Installation. (21 CFR 820.170)
- Servicing. (21 CFR 820.200)
These specific lists represent an important clarification over the 2004 guidance –although the guidance lists elements of the drug and device GMP systems that should be followed, it leaves room for confusion on what specifically applies, saying that “depending on the particular combination product, it may be important to consider other specific requirements to ensure compliance with both the CGMP and QS regulations.”
Although fundamentally the proposed rule is similar to the 2004 draft guidance and thus may be familiar to combination product manufacturers, a number of questions about the proposed rule need answered.
Definition of Constituent Part to Include Components and Ingredients
The proposed rule defines a constituent part to include any drug or any device that is part of a combination product. Under existing combination product regulations, a device constituent part is considered a finished device, and a drug constituent part is considered a drug product. However, because the statutory definition of a device also includes components— which include any raw material, substance, piece, part, software, firmware, labeling, or assembly for medical devices — a component that is part of a combination product is defined as a constituent part and therefore in effect considered a finished device or drug product.
But under existing GMPs, device and drug components are not treated as finished products and are only covered by GMPs when they are received by the final manufacturing facility. In this way, components are not directly subject to GMPs, although the final manufacturer has responsibility for ensuring appropriate quality requirements and in the case of devices are encouraged to use the GMPs as guidance.
However, because the application of GMPs is tied to a constituent part, the proposed rule raises questions about applying GMPs to components and ingredients even before their arrival at a combination product manufacturing facility. Similarly, confusion may also result with regard to drug container closures (i.e., drug components) and when these components constitute a device constituent part subject to the QSR.
There are also a number of issues concerning how the new rules would be implemented at a practical level. For instance, the rules do not address how manufacturers should implement combination product GMPs for products currently under development or on the market. Do these manufacturers have to implement the rules retroactively? For example, if these manufacturers are incorporating elements of the QSR, might they have to retroactively create a Design History File where one did not previously exist?
In terms of timing, the proposed rule recommends that a final rule would be effective 180 days after final publication. Manufacturers should consider whether this timeframe is enough for their operations. The implementation of device management controls and design controls, for example, may require a significant ramp up for firms that are not experienced with these requirements. Back in the 1990s, when the agency originally instituted device design controls, FDA gave device firms an additional year (beyond the eight months applicable to other provisions of the QSR) to comply with those controls. For drug and biologic companies not already experienced in design controls, a similar timeframe might be needed.
Importantly, the proposed rule acknowledges that FDA will need to produce guidance upon implementation of the final rule. Unfortunately, the proposed rule doesn’t specify when we should expect the guidance. This guidance is critical to a full understanding and implementation of the rule, so the sooner the better.
The good news is that the publication of the proposed rule has opened up important dialogue on GMPs. The not-so-good news is that any final rule and implementing guidance will take a while, and in the meantime, combination product manufacturers will be left in a state of limbo on a clear path forward for GMP implementation. At least one thing is clear, though — the agency believes that GMPs apply to the various constituent parts throughout that product’s lifecycle, and combination product manufacturers as a result are likely to be subject to requirements of multiple GMP systems.
Combination product companies should take a close look at the proposed rule and how it may impact their operations. To help with that, on January 12, 2010, the Regulatory Affairs Professionals Society (“RAPS”) and the Combination Products Coalition (“CPC”) are offering a workshop on the proposed rule that will offer attendees a unique opportunity to examine the contents of the rule and the agency’s implementation plan. In addition to hearing from FDA’s Office of Combination Products and industry experts, attendees will apply the proposed rule to case studies to analyze the rule’s strengths, weaknesses, ambiguities, unintended consequences and more. RAPS and the CPC plan to synthesize the major themes that emerge from the workshop and submit them as comments to the proposed rule.
Finally, although the precise content of the final rule remains to be seen, the fundamental content will most likely be similar to the proposed rule. Thus, for planning purposes, companies engaged in the development or commercialization of combination products should consider conducting a preliminary gap analysis of current operations under the fundamental principles of the rule. To the extent there are major gaps, companies should consider factoring the implementation of combination product GMPs into upcoming plans and budgets.