Draft Guidance on Good Manufacturing Practices for Combination Products – FDA Delivers on Promises

Are you familiar with the draft guidance 
on GMPs for combination products?
Two years ago, in January 2013, FDA published the final regulations on Good Manufacturing Practices for Combination Products.[1]  These regulations are built on the concept that the constituent parts of a combination product retain their regulatory identity as a drug, device, or biological product, even after they are physically, chemically, or otherwise combined into a single-entity combination product (i.e., prefilled injector or drug eluting stent) or co-packaged together.[2]  Therefore, all the good manufacturing requirements associated with each constituent part must be complied with in the manufacture of single-entity and co-packaged combination products. 
The regulations recognize that compliance with the full set of drug current Good Manufacturing Practices (cGMPs – 21 CFR Parts 210 and 211) and device Quality System Regulations (QSR – 21 CFR Part 820) could be quite burdensome.  Therefore, FDA created the “streamlined” approach to good manufacturing practices for combination products.  The streamlined approach is based on FDA’s observation that cGMPs and QSRs contain many similar requirements and that compliance with one system will come close to complying with the other.  For both cGMPs and QSRs, FDA identified the provisions that do not have comparable provisions in the other system.  Under the streamlined approach, when the constituent parts are brought together within the same manufacturing facility, the manufacturer may identify one of the systems (either cGMPs or QSRs) as the base system, and add in the additional provisions from the other system.  The specific additional requirements that must be complied with are listed in 21 CFR 4.4(b)(1) and (2). 

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In response to the proposed rule on good manufacturing practices for combination products,[3] many commenters requested additional information on how the streamlined approach should be implemented.  In the preamble to the final regulations, FDA said it intended to issue additional guidance on numerous issues.  FDA issued the Draft Guidance on January 27, 2015,[4] and has been true to its word – the draft guidance addresses all the issues identified in the preamble to the final rule – and more.  In addition to helpful information on many topics, the Draft Guidance includes three detailed illustrations of the application the streamlined approach using a drug cGMP-based approach, and a device QSR-based approach.  This Draft Guidance should serve as a valuable resource to combination product manufacturers.
Comments on the Draft Guidance must be submitted by April 29, 2015 in order to ensure that they are considered in the Final Guidance.  This is not much time to digest the information in the Draft Guidance and prepare thoughtful comments.  However, the Draft Guidance repeatedly states persons with questions or desiring further information should contact the lead agency center or the Office of Combination Products. 
A few of the highlights of the Draft Guidance are described below. 

               The meaning of “where appropriate.”  The drug cGMPs, device QSRs, and human tissue Good Tissue Practices (GTPs)[1] use the term “where appropriate” to acknowledge that certain measures may not be necessary under certain circumstances.  This language indicates that manufacturers have the opportunity to document justifications for determining that requirement with such a proviso is not appropriate for a particular product or manufacturing step.  Manufacturers of combination products have this same opportunity to carefully consider the applicability of good manufacturing requirements and to document their justification for not complying with certain requirements that would be otherwise applicable. 
               “Constituent part” and “component.”  The original combination product regulations referred to a combination product as a product comprised of “two or more regulated components.”[2]  It later became clear that this use of the term “component” might be confusing because manufacturers of components of devices are not directly subject to QSRs.  For this reason, FDA now refers to combination products as comprised of two or more regulated constituent parts.  In preamble to the final regulations, FDA clarified that the rule describing GMP requirements for combination products is not intended to change underlying GMP requirements for drugs and devices.  The Draft Guidance reiterates that FDA uses the term “constituent part” as a succinct way to identify a drug, device, or biological product included in a combination product, and that the term “component” in the drug and device GMP requirements serves a different regulatory purpose. 
              Drug containers and closures versus delivery devices.  Drug product container / closures are subject to specific drug cGMP requirements.[3]  There has frequently been confusion as to whether a container is a container / closure subject to drug cGMPs, or a device subject to QSRs.  According to the Draft Guidance, the essential distinction between a drug container / closure and a drug delivery device is whether the article is intended to deliver the drug it contains or merely to hold it.  If the article only holds the drug, and does not deliver it, it is only subject to drug cGMPs as a container or closure.  (The preamble to the final regulations clarified that drug container / closures are not “components” of drug products, but are covered by specific provisions of the drug cGMPs.)  A packaging system may be considered a container / closure system – examples of packaging components include ampules, vials, screw caps, stoppers, and stopper overseals.
An article that holds or contains, and delivers the drug is a delivery device, and may be subject to QSRs.  A piston syringe, for example, is a device and is subject to QSRs.  
            Class I, QSR exempt drug delivery devices.  The Draft Guidance discusses Class I delivery devices that may be exempt from most QSR provisions, such as a simple liquid medication dispenser,[4] including a dropper.  By virtue of being a constituent part of a combination product, certain additional requirements may apply, which would not be applicable to the dropper as a stand-alone device.  For example, if the dropper is incorporated into the cap of the drug container closure, it would need to be included as part of the drug container because it would be in direct contact with the drug product. 

Similarly, design controls to assure that the dropper maintains its integrity when in contact with the drug product may be needed.  
               Design controls.  Devices are subject to design controls,[1] and design controls are among the QSR requirements that must be incorporated into a drug cGMP-based streamlined system.  Many questions have been raised about how to implement design controls for combination products.  The Draft Guidance contains a fairly detailed discussion of design controls in general, explaining concepts that may be less familiar to manufacturers of drug products, such as device verification and validation, and design history file.  Design control procedures apply to product development and premarket assessment activities, as well as to post market changes.  The Draft Guidance does not go into specific design control requirements, probably because the wide variety of combination products makes such a discussion very difficult.  The Draft Guidance refers the reader to the preamble to the final QSR regulations,[2] the lead agency center, or the Office of Combination Products for assistance with their specific product. 
               Calculation of yield.  Drug cGMPs require actual yield and percentage of theoretical yield.[3]  Excess or low yields suggest errors in the product process.  Under a device QSR-based streamlined approach, this provision applies to combination products as well.  The Draft Guidance states that yield determinations should be made at each phase at which loss may occur, during the formulation of the drug prior to incorporation into the combination product, during incorporation (e.g. filling or coating), and during the packaging process.    
               Testing and release.  Drug cGMPs require an appropriate laboratory determination of conformance to final specifications (including the identity, strength, and freedom from objectionable microorganisms) for each batch of drug product prior to release. [4]  Under a device QSR-based streamlined approach, this provision applies to combination products as well.  The Draft Guidance states that manufacturers must test each batch of single-entity combination products, and the drug constituent part of each batch of co-packaged combination products, to assure conformance with the specifications for the drug constituent part. 
               Reserve samples.  Drug cGMPs require that representative samples of each lot of active ingredient and each lot or batch of finished product be retained under certain conditions until one year after the expiration date of the drug product. [5]  Under a device QSR-based streamlined approach, this provision applies to combination products as well.  The Draft Guidance states that for single entity combination products, such as a drug eluting stent, reserve samples of the entire combination product should be kept for the appropriate time period.  For a co-packaged combination product, reserve samples of the drug constituent part would likely suffice.
            Combination products with a biological product or human cell, tissue, or cellular or tissue based product (HCT/P) as a constituent part.  The preamble to the final regulations provided little information on how to determine the applicable good manufacturing practices applicable to combination products with a biological product or HCT/P as a constituent part.  Specifically, the final rule contains no analysis of the similarities and differences between biological product good manufacturing practices and HCT/P GTPs on one hand, and drug cGMPs and device QSRs on the other.  
The Draft Guidance provides very helpful additional information on how to determine the applicable good manufacturing requirements for combination products with a biological product or HCT/P constituent part.  The critical point is that by definition, biological products and HCT/Ps that are constituent parts of combination products also meet the definition of a drug or device.  Therefore, these constituent parts are required to meet the drug cGMPs or the device QSRs, as appropriate.  The streamlined approach is available for these combination products. 
In addition, 21 CFR Parts 600 through 680 address particular challenges posed by biological products, and all HCT/Ps are subject donor screening requirements and GTPs.[1]  Because the good manufacturing provisions applicable to biological products and HCT/Ps are supplemental to the drug cGMPs and device QSRs, these provisions will always apply to a combination product with a biological product or HCT/P constituent part.  The Draft Guidance states that in the event of a conflict between GTPs and a requirement in drug cGMPs or device QSRs, the regulations more specifically applicable to the product in question will supersede the more general requirement. 

Submitting Comments
If you want to submit comments electronically, go to www.regulations.gov, and enter the docket number: FDA-2015-D-0198 in the search box, and click on “Search.”  This will bring up the docket for this guidance document.  On the right hand side there are buttons that say “Comment Now!”  Click on one of the buttons, and the comment page comes up.  Enter comments directly or upload a document with comments.  All comments are posted on www.regulations.gov for public review. 
Submit written comments to:
Division of Dockets Management (HFA–305)
Food and Drug Administration
5630 Fishers Lane
Rm. 1061
Rockville, MD 20852
Identify comments with the Docket Number: FDA-2015-D-0198. 
Written comments will also be publicly available.  


[1] See the Federal Register of January 22, 2013, 78 FR 4307.  The final regulations are contained in 21 CFR part 4.
[2] The regulations also address cross-labeled combination products under 21 CFR 3.2(e)(3).  However, because these products are not physically, chemically or otherwise combined, or co-packaged, the cGMP requirements are fairly straightforward.  The usual GMP requirements for each type of product apply to each constituent part.
[3] The proposed rule published in the Federal Register of September 23, 2009, 74 FR 48423
[4] See the Federal Register of January 27, 2013, 80 FR 4280.  The actual guidance is available is available here.
[5] 21 CFR 1271, Subpart D 
[6] For example, see 21 CFR 3.2(e)(1). 
[7] 21 CFR 211, Subpart E  
[8] See 21 CFR 880.6430
[9] 21 CFR 820.30
[10]  See the Federal Register of October 7, 1996, 61 FR 52602. 
[11] 21 CFR 211.103
[12] 21 CFR 211. 165
[13] 21 CFR 211.170.  Different time periods apply to over the counter drug products. 
[14] See 21 CFR 1271, Subparts C and D.  The Draft Guidance recognizes that some sections of part 1271 overlap with requirements of drug cGMPs and device QSRs.  The agency has addressed these overlaps in part 1271 and in the Guidance for Industry on Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)

Suzanne M. O’Shea has a unique ability to conceptualize complex issues, helping her clients find a path forward through the maze of vague, confusing, and sometimes contradictory laws, regulations and guidance issued by the Food and Drug Administration. 
She has extensive knowledge and experience in the drug, device, biological product, combination product, and human cells and tissues product life cycles.  Before joining Faegre Baker Daniels in 2007, Suzanne served for 21 years as Regulatory Counsel for Food and Drug Administration headquarters in Rockville, Maryland. Her last position at FDA was Product Classification Officer in the Office of Combination Products. In that capacity, she was responsible for classifying products as drugs, devices, biologics, human tissue, or combination products. She worked with many innovative, cutting-edge products while at the agency and was also a member of FDA's Tissue Reference Group. She may be reached at suzanne.oshea@FaegreBD.com.