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Application of FDA Current Good
Manufacturing Practices (CGMPs) For
Drug/Drug Delivery "Combination Products”
Quality and Regulatory Compliance Solutions
Mark Iampietro
01-15-2017

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Application of FDA Current Good Manufacturing Practices (CGMPs) For
Drug/Drug Delivery "Combination Products"
Definition of "Combination Products"
The FDA views drug or biologic products that are intended for use only with a specified device
either physically combined as a “single entity”, e.g. prefilled syringe or auto-injector, or
packaged together in a single package, “co-packaged”, e.g. inhalers, auto-injectors, pumps, as
“combination products”. The drug and device are both constituent parts of the combination
product and as the drug provides the “primary mode of action”; the pharmaceutical manufacturer
is responsible for regulatory compliance of the product.
Daunting Task of Regulatory Compliance Can Be Simplified for "Combination Products"
As such, drug companies with "combination products" must comply with the FDA’s Quality
Systems Regulations, 21 CFR 820, in addition to the drug CGMPs.21 CFR 210/211.
This may seem a daunting task at first, but with the pragmatic approach suggested below, it may
be accomplished by simply augmenting the existing drug quality system, thereby significantly
minimizing resource allocation and training requirements.
Recommended Process to Narrow Potential Regulation Requirements
The first recommendation is to create a matrix or list referencing which of the medical device
Quality System Regulations are already addressed by the existing quality system’s drug based
standard operating procedures.
If the quality system in place is already fully compliant with the drug CGMPs, this matrix should
indicate that only a few incremental requirements exist that must be addressed with new
procedures for "combination products".
These requirements should be 820.20 Management Review, 820.30 Design Controls, 820.50
Purchasing Controls, 820.100 CAPA (Corrective and Preventive Actions), 820.170
Installation and 820.200 Servicing.
"Installation And Servicing" Regulations Compliance Typically Don't Apply.
For most companies, Installation and Servicing will not apply as these requirements are only
applicable when a device specifically requires installation or where servicing is a specific
requirement of the device.

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We are then left with the requirements for Management Review, Design Controls, Purchasing
and Corrective and Preventive Action (CAPA). As a "combination product" manufacturer these
processes must be embedded into your end to end regulatory compliance.
Management Review, Purchasing Controls, and Corrective and Preventive Action (CAPA),
although not requirements of the drug CGMPs, are typically addressed in some fashion
through Good Business Practices (GBPs).
The fundamental requirements for "Management Review" are that:
1) Management with executive responsibility must establish a quality policy and ensure that it is
understood, implemented and maintained throughout the organization;
2) An appropriate organizational structure to ensure product quality is established;
3) Quality Metrics must be established and monitored at defined intervals by senior management
with executive responsibility to review the suitability and effectiveness of the quality system.
The fundamental requirements for Purchasing Controls are:
1) Requirements for the product and quality must be established and met by all suppliers;
2) There must be a documented system to evaluate and select suppliers based on their ability to
meet the specified requirements;
3) The type and extent of supplier controls based on the above evaluation results shall be defined
and documented;
In addition there shall be a record of acceptable suppliers usually referred to as an Approved
Supplier List (ASL) and where possible supplier agreements shall be established to ensure the
manufacturer is notified of any changes to the product or service, Reference 820.40.
The fundamental requirements for CAPA (Corrective and Preventive Action) are that
there are established procedures for implementing corrective and preventive actions.
These procedures shall include the requirements for:
1) Analyzing quality data from such sources as work operations and processes, audit reports,
complaints, returned products, and other quality problems utilizing appropriate statistical
methods;
2) Investigating the root cause of nonconformities relating to product, processes and the quality
system;
3) Identifying the actions needed to correct and prevent recurrence of quality problems;

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4) Verifying the corrective and preventive actions to ensure they are effective;
5) Recording and disseminating this information to those responsible for assuring product quality
and Management Review.
The Major Gap Is "Design Controls".
Design Controls typically represent the largest gap in compliance for pharmaceutical companies
as they transition to be "combination product" manufacturers.
The fundamental requirement of Design Controls is that there are established procedures
defining the product development process. These procedures shall include:
1) The development of formal design plans describing the resource allocations and
responsibilities for design development;
2) A mechanism for addressing incomplete, ambiguous or conflicting design requirements;
3) Design input requirements shall be documented and approved;
4) Adequate evaluation of design output requirements in terms of conformance to design input
requirements;
5) Design output requirements shall be documented and approved.
In addition to these requirements, the manufacturer shall establish procedures that ensure:
1) The formal documented review of the design results are planned and conducted at appropriate
stages of the design’s development - these reviews shall ensure that participants at the review
include representatives from all functions concerned with the design stage being reviewed as
well as an independent reviewer;
2) Design verification shall confirm that the design outputs meet the design input requirements;
3) The results of design review, design verification and all pertinent development information to
demonstrate that the design was developed in accordance with the approved design plan and
regulatory requirements were met shall be documented in the design history file (DHF);
4) Design validation shall be performed under defined operating conditions to defined
specifications on initial production lots or their equivalents - design validation shall ensure that
devices conform to defined user needs and intended uses and may require Human Factors studies
in addition to the clinical studies required for drug development;
5) Formal design transfer of the design to the Device Master Record (DMR) and lastly;

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6) Design changes are identified and validated or as appropriate verified and approved before
their implementation.
Summary
The potential compliance gaps in a cGMP compliant drug quality system, when transitioning to a
cGMP compliant combination product quality system are: Management Review, Design
Controls, Purchasing Controls, Corrective and Preventive Action, Installation and Servicing.
Of these "combination product (single entity and co-packaged drug delivery devices plus a
drug)" requirements, Installation and Servicing will likely not be applicable in most cases and
given common Good Business Practices (GBPs) Management Review, Purchasing Controls and
Corrective and Preventive Action are typically already addressed in some fashion within the
existing quality system for drugs.
This leaves Design Controls as the area likely requiring the most work in bridging the gap to
fully compliant combination product quality system.