The FDA final guidance for combination product good manufacturing practices (GMPs) grew by 10 pages compared to the draft guidance, but the final product was hailed as "a good guidance document" by Bradley Merrill Thompson of Epstein Becker & Green, the law firm that has represented the Combination Products Coalition on combo product regulatory matters before the FDA.

The January 2015 draft guidance for combo product GMPs followed a similar document published in 2004, which the agency eventually withdrew. This was followed in 2013 by the final rule for combo product GMPs, an effort the agency undertook due to the concerns expressed regarding the 2004 draft guidance.

The 2015 draft guidance offered a more streamlined approach to compliance than was seen in the 2004 document, and it offered substantially more in the way of specifics. One consideration that emerged in connection with the 2015 draft was that design controls would take a more central place in the agency's expectations than was previously understood to be the case, and manufacturers were advised to take measures to ensure their processes and documentation were in compliance as the agency's previous forbearance on these issues was expected to end. (See Medical Device Daily, Feb. 4, 2015.)

The 2015 draft guidance, which was the subject of an extended comment period at the behest of several requestors, distinguishes the terms "constituent part" and "component" per the regulations for both drugs and devices. However, the final version explained that Part 4 of Title 21 of the Code of Federal Regulations does not stipulate that a facility that makes only device components to be used in a combination product is necessarily subject to the quality systems regulations (QSRs), and likewise that a facility making active pharmaceutical ingredients for use in a combination product is not automatically subject to compliance with Part 211 if that API is made for use in a combination product.

One of the interesting excisions of the draft was a paragraph discussing the meaning of the term "where appropriate" regarding a manufacturer's determination of the applicability of drug and device GMPs. The draft guidance pointed to the fact that the manufacturing practices seen in one regulation may be sufficiently similar "to demonstrate compliance in whole or in part" with the other. This paragraph, which made reference to 21 CFR 211.192 and 21 CFR 820.100, is entirely absent in the final guidance.

In its comments to the docket for the draft, the Advanced Medical Technology Association had requested that the FDA provide more details as to what the agency would expect regarding compliance with drug-related provisions in Part 4. The final guidance added details such as the types of containers and closures that would be subject to testing, and it noted that two ASTM standards for sampling can be used to test components, containers and closures.

The Pharmaceutical Research and Manufacturers of America had responded to the draft in part with the observation that drugmakers have experienced "varying expectations" in terms of compliance with Part 4 during inspections handled by FDA investigators from different product centers. PhRMA also said the agency should update its policies and procedures manuals so as to ensure that FDA staff are up to date on the streamlined GMP approach, but noted that some drugmakers have indicated that FDA staff from the Center for Drug Evaluation and Research will not routinely consult with their counterparts at the Center for Devices and Radiological Health when reviewing prefilled syringes and combination products for respiratory therapy.

PhRMA argued further that Part 4 is not exhaustive in its description of the features of the Quality Systems Regulations that agency staff would expect to see in a combination product GMP system. The final guidance offered additional details for Part 820's mandates for design controls, including a brief discussion of how a drugmaker might demonstrate compliance by extrapolating from a syringe maker's data to deal with most such issues, with the only exception being how the contact between the drug and the syringe might affect the combination's safety and effectiveness profiles.

Brad Thompson, who along with several other attorneys with Epstein Becker & Green had represented the Combination Products Coalition, told Medical Device Daily, "we are delighted to see this final guidance." He said the final is a solid guidance document thanks in part to the fact that the agency "has been incorporating into its guidance not only answers to questions, but case studies that illustrate how FDA approaches these issues."

Thompson said the final guidance clarified the circumstances in which the products in a kit cause that kit not to be considered a convenience kit. He explained that when a kit includes products "otherwise modified from the independently marketed product," the kit is no longer a convenience kit. "This slightly revised language seems to indicate that the act of kitting alone would not 'modify' the product," he said, adding "it appears the intention is that such modification pertains to changes to packaging or labeling of the independently marketed product."

The final guidance also clarified that manufacturers will not have to routinely submit GMP information prior to clearance of 510(k)s, Thompson said, and that the final version drops the use of the word "sponsor" so as to eliminate confusion as to the facilities that have to demonstrate compliance with GMPs.

"There are, of course, a few areas where we have lingering questions, and we look forward to exploring those issues with FDA," Thompson said, adding, "I think the agency is planning to do educational programs through some of the professional societies like RAPS, which will present an ideal opportunity for some dialogue and further understanding."

"On the whole, we are pleased" with the final guidance, Thompson said.