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QUALITY & COMPLIANCE I

Combination Product Quality Systems

By Michael Gross, PhD, RAC

This article, the fifth in a series on the regulationof combination products in the US, considers thestate of the quality system regulatory frameworkfor combination products. This article is not a com-mentary on the recently published proposed rule1 or the previously published draft guidance2 onquality systems for combination products. Rather, itdescribes approaches based on existing regulationsthat may be taken now to establish a compliant

quality system for the manufacture of a combina-tion product in anticipation of the final rule.

Manufacturers should prepare for the daywhen the quality system regulation for com- bination products is final. Six months after thefinal rule is issued it will become an enforceablerequirement. By then, FDA is also expected tohave issued additional guidance explaining howmanufacturers of single-entity or kit combinationproducts may implement a quality system thatcombines elements from more than one qualitystandard (i.e., a streamlined quality system).

Currently, there is no final regulation orguidance describing requirements for a combi-nation product quality system. The principlesdescribed in the proposed rule and the draftguidance are similar. They are not final but theyreflect FDA’s current thinking.

Combination Products Quality

System Principles

When the constituent parts of a combinationproduct are manufactured separately and remainseparate, each is subject only to the qualitysystem regulation that pertains to that type ofconstituent part (drug, biologic, medical device).The quality system regulation that normallyapplies to a drug, biologic or medical devicestill applies when these are part of a combina-tion product formed through final productor investigational labeling (i.e., combinationproducts that fit the definition of a cross-labeledcombination product3 or a combination productformed through investigational labeling4). Note,however, that an investigational constituent partis normally not held to the full scope of qualitysystem requirements.

When the constituent parts of a combinationproduct are brought together to form a single-

entity or kit combination product, the constituentparts retain their regulatory status before andafter they are combined. They do not lose theirdiscrete regulatory identity as a drug, device,or biological product when they are constitu-ent parts of a combination product. The qualitysystem requirements that apply to each constitu-ent part also apply to the entire combinationproduct.

Many manufacturing facilities operateunder only one type of quality system. Drug

and biologic manufacturers generally follow thecurrent Good Manufacturing Practice regula-tion (CGMP)5 and medical device manufacturersusually follow the Quality System Regulation(QSR).6 Both regulations state that should amanufacturer engage in only certain opera-tions that are subject to the requirements of theregulation, and not in others, the manufacturerneed only comply with those requirements thatare applicable to the operations in which it isengaged. FDA considers the two regulations to be similar, with considerable overlap betweenthem, and both allow flexibility in their applica-tion. Because each regulation is tailored to thecharacteristics of the types of products for whichit was intended, it contains specific requirementsthat may be addressed more generally in thecounterpart regulation. However, there are gapswhere the regulations do not overlap.

For single-entity and kit combinationproducts that contain both drug and deviceconstituent parts, rather than implementingmultiple (and potentially redundant) qualitysystems, compliance with either CGMP or theQSR, under certain conditions, will satisfy mostrequirements. To ensure full compliance withquality system requirements for a single-entityor kit combination product that contains drugand device constituent parts, elements of theCGMP regulation may be added to an existingQSR-based quality system, and vice versa. FDArefers to this kind of quality system as a “stream-lined” system. Specifically, for a single-entity orkit combination product manufactured under aCGMP-based quality system, the additional ele-ments from the QSR regulation that may need to be complied with are:

820.20 Management responsibility•

820.30 Design controls•

820.50 Purchasing controls•

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820.100 Corrective and preventive•

action820.170 Installation•

820.200 Servicing•

Similarly, for a single-entity or kit combinationproduct that contains drug and device constituentparts and is manufactured under a QSR-basedquality system, certain elements of the CGMPregulation may need to be complied with:

211.84 Testing and approval or rejection•

of components, drug product containersand closures211.103 Calculation of yield•

211.132 Tamper-evident packaging for•

over-the-counter (OTC) human drugproducts211.137 Expiration dating•

211.165 Testing and release for•

distribution211.166 Stability testing•

211.167 Special testing requirements•

211.170 Reserve samples•

The need to fill the gaps between the CGMP andQSR will vary depending upon the manufactur-ing activity being performed and the nature ofthe combination product being manufactured.

Requirements for firms that perform operationssuch as repackaging articles into conveniencekits will generally be less demanding thanrequirements associated with the manufactureof complex devices such as drug-coated cardiacstents.

The QSR and CGMP require that writtenprocedures be established and maintained toensure that regulated products that are manufac-tured, processed and held meet the requirementsof the applicable quality system. Accordingly, thewritten procedures for a streamlined quality sys-tem must ensure that the firm can demonstratecompliance with all applicable quality system

requirements. FDA will consider a demonstra-tion of compliance with the requirements of oneset of regulations (e.g., CGMP), and compliancewith the requirements of the specified provisionsfrom the other quality system regulation (e.g.,QSR), to be a demonstration of compliance withall requirements of the counterpart regulation.

If a constituent part of a combinationproduct contains blood or blood components,allergenic products or other biological productsregulated under the Public Health Act, its manu-facturer will need to comply with additionalquality system requirements.7 When a human

cellular or tissue product (HCT/P) is a constitu-ent part of a combination product, it will be

regulated as a drug, device and/or biologicalproduct but additional requirements (i.e., GoodTissue Practices)8 also apply.

When a constituent part is not manufacturedin the same facility as another constituent part,the quality system under which it is manufac-tured must be shown to comply with all of thequality system regulations that are applicableto that constituent part. For example, a drugproduct manufactured in one facility would besubject to CGMP while a device manufacturedin another facility would be subject to the QSR.When two or more types of constituent partsare manufactured in the same facility, a stream-

lined quality system approach may be taken.However, when a constituent part is produced ata facility that is separate from the manufactureof other constituent parts, manufacturing musttake place in accordance with the quality systemrequirements that are directly applicable to thatconstituent part. When two or more types ofconstituent parts that are to be incorporated ina single entity or kit combination product arriveat the same facility, or when the manufacture ofthese constituent parts is proceeding at the samefacility, a streamlined quality system may be uti-lized, except with respect to any constituent partwhose manufacture does not occur in the same

facility. Under these circumstances the qualitysystem for the manufacture of that constituentpart must be shown to comply with all of thequality system regulations which are applicableto that constituent part.

Discussion

There are a few differences in the principlesdescribed in the 2004 draft guidance and the2009 proposed rule. The proposed rule expandsthe list of gaps between the CGMP and QSR reg-ulations. It instructs manufacturers how to apply

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the quality system requirements to combinationproduct constituent parts when separate facilitiesare involved. The proposed rule also suggeststhat manufacturers must establish and maintaindocumentation demonstrating that the qualitysystem under which combination product manu-facture occurs addresses all applicable qualityregulations that pertain to a particular combina-tion product.

Conclusion

It will likely take a year or more until thecombination product quality system rule isfinalized and issued. Then manufacturers ofcombination products and combination productconstituent parts will have about six monthsto implement changes to their quality systemsin order to be fully compliant with the newregulation. Manufacturers that are developingor marketing combination products shouldprepare for this eventuality. First, they should become familiar with the proposed rule, assessits potential impact on their operations andidentify questions that it raises or clarificationsthat may be needed. FDA has extended thedeadline for public comments on the proposedrule from 22 December 2009 to 5 February2010. Comments should be sent to FDA docketnumber 2009–N–0435.

Based on the proposed rule, manufactur-ers of combination products should assess

the potential impact of a final rule on theirmanufacturing and quality systems and thoseof their vendors and contractors. Vendors andcontractors should do the same. Risk-based gapassessments should include review of purchas-ing agreements and SOPs, and on-site audits.Depending upon the nature of the manufactur-ing operations, implementing a streamlinedquality system may be appropriate. Additional

SOPs and training programs may need to beestablished and strategies developed to demon-strate compliance with non-core quality systemprovisions. This will likely take a considerableamount of planning and time.

ReferencesCurrent Good Manufacturing Practice Requirements for1.Combination Products (74 FR 48423)Draft Guidance for Industry: Current Good Manufacturing2.Practice for Combination Products (69 FR 59239)21 CFR 3.2(3)3.21 CFR 3.2(4)4.21 CFR 210, 2115.21 CFR 8206.21 CFR 606-6087.21 CFR 12718.

AuthorMichael Gross, PhD, RAC, is a senior consultant with theBiologics Consulting Group specializing in quality, regulatoryand technical issues for combination products. Over his 30-yearcareer, he has worked for FDA and drug, biological productand medical device manufacturers. Gross has spent more than20 years working on combination product problems. He can bereached at mgross@bcg-usa.com.

The Food and Drug Administration is looking for individuals to serve

as Outside Experts with experience in FDA Quality Systems Regulations

in relation to medical devices in the following areas:

Cardiology, General Surgical and Hospital, Dental, ENT and Ophthalmic

OB/GYN, Gasteroenterology and Urology Products, Cardiac Rhythm

and Electrophysiology, Vascular Circulatory Support, Orthopedics,

Physical Medicine, Radiology as well as Anesthesiology and Neurology.

Interested applicants should be registered in the Central Contractors

Registry located at www.bpn.gov/ccr in order to be hired by our office.

To apply, email/send resume to:Collin L. Figueroa, Program Management Officer, OC

10903 New Hampshire Avenue, White Oak Bldg. 66, Room 3438

Silver Spring, Maryland 20903-0002

Email: collin.figueroa@fda.hhs.gov