Complying with FDA Quality Regulations for Development and

Quality &
Compliance
By Michael Gross,
PhD, RAC
Complying with FDA Quality Regulations
for Development and Manufacture of
Prefilled Drug Delivery Devices
W
hen developing and manufacturing a prefilled drug delivery device, does a pharmaceutical manufacturer need to comply with
two quality system regulations—current Good Manufacturing Practices (CGMP) for drugs and biologics
and the Quality Systems Regulation (QSR) for medical devices? Should a device vendor or contract
manufacturer’s quality systems be linked to the quality system of the pharmaceutical company engaged
in developing and manufacturing a drug-device
combination product? When developing a drugdevice combination product, should a pharmaceutical company supplement its quality system by
incorporating device quality system elements into a
GMP-based quality system to create a hybrid quality
system? Uncertainty exists over FDA’s expectations
for quality systems that control combination product
design, development and manufacture. Still, companies developing and marketing combination products
must ensure product quality and comply with existing quality regulations. This article raises questions
and provides suggestions that manufacturers may
take to comply with CGMP regulations and the QSR
in the absence of regulations and final guidance on
how to apply existing quality regulations to drugdevice combinations.
CGMP and QSR Regulations and
Guidance on Combination Products
CGMPs (21 CFR 210, 211) and the QSR (21 CFR
820) are well-established. FDA is drafting a proposal
for a quality system regulation specific to combination products.1 Publication of the Proposed Rule is
expected later this year; publication of a Final Rule
will take several years. The Draft Guidance for Industry and FDA: Current Good Manufacturing Practice
for Combination Products (September 2004) is the
only published source that provides insight into
FDA’s expectations for combination product
quality systems.
A “single-entity” combination product
(21 CFR 3.2(e)(1)) is produced when different medical product types (e.g., drug
and device) are physically combined (e.g.,
a prefilled drug delivery device). From a
quality system design standpoint, this type
of combination product suggests a quality
system that combines elements of
42 October 2007
CGMP regulations and the QSR. When the constituent
parts of a combination product are separate, as in the
case of cross-labeled combination products (21 CFR
3.2 (e)(3)), (e.g., photodynamic therapy where a photosensitizing drug is combined with a label-specified
laser), the quality systems for the drug and device
constituents can be separate, and compliance with
quality system regulations is more straightforward.
The draft FDA guidance states that the CGMP
regulations and the QSR are intended to achieve similar goals. They overlap yet differ in many details. Each
regulation addresses unique quality characteristics of
the products it is intended to regulate. Each contains
specific requirements, which are often more generally
described in the counterpart regulation. Most pharmaceutical manufacturing facilities operate under a
single quality system intended to comply with CGMP
requirements (i.e., a CGMP-based quality system).
According to the draft guidance, when manufactured
separately as constituent parts to be combined later,
each constituent part of a combination product is
subject only to its governing quality regulations. Both
quality regulations, however, apply during and after
the constituent parts are joined. FDA notes that compliance with both CGMPs and the QSR during and
after joining the constituent components of singleentity combination products can generally be achieved
through compliance with one regulation, recommending that under a general requirement of one regulation,
practices can be developed that comply with a more
specific requirement of the other. Thus, it is not necessary for manufacturers of single-entity combination
products to fully implement two separate quality systems. But to ensure combination product quality, it
may be necessary to supplement a CGMP-based
quality system with certain elements of the QSR.
For CGMP-based quality systems, FDA’s draft
guidance identifies three gaps where pharmaceutical
manufacturers need to consider supplementing an
existing quality system with QSR elements. These are
Design Controls, Purchasing Controls and Corrective
and Preventive Actions (CAPA).
Design Controls
for CGMP-based Quality Systems
Design Controls (21 CFR 820.30) are a set of interrelated practices and procedures that control medical
device design and process development throughout
the product lifecycle. The process is iterative. Originally termed preproduction quality assurance in an
early QSR draft, they are first applied in product
development when the initial device design specifications are established. The initiation of Design
Controls early in the development process may be
foreign to pharmaceutical product developers, both
in the nature of the process and its timing.
Design Controls apply to all medical devices not
specifically exempted by FDA from compliance with
the QSR. Reason dictates that they also apply to
combination products that incorporate such devices.
Even where the device constituent part of a combination product is exempt, if its intended use is
changed by incorporating it into a combination
product, the combination product may be subject to
Design Controls. The QSR requires that procedures
be established and maintained to define design
planning process activities and responsibilities.
Formal procedures are required throughout development to ensure design inputs appropriately
address patient needs and design outputs allow an
adequate evaluation of their conformance to design
inputs. Formal design reviews must be conducted
by multidisciplinary teams at appropriate times
throughout the design development lifecycle. Design
verification procedures must be established and
maintained to confirm that the design output meets
design input requirements. Procedures must be
established and maintained for validating production units under use conditions to demonstrate that
the intended use and user needs are satisfied.
Design changes and manufacturing transfer from
prototypes to production are also controlled through
Design Control procedures. Finally, all records
needed to demonstrate that the product was developed in accordance with the design plan are
archived as a Design History File. The Design History File is somewhat analogous to the Pharmaceutical Development Report. However, there is no
counterpart to the overall Design Control process in
the pharmaceutical development and manufacturing process. Pharmaceutical companies engaged in
the development of prefilled drug or biologic medical devices should become familiar with and utilize
this useful quality tool.
Purchasing Controls
for CGMP-based Quality Systems
The QSR also requires procedures for establishing
and maintaining Purchasing Controls (21 CFR
820.50). They ensure that purchased products,
components and services conform to specifications;
that suppliers, contractors and consultants are
qualified and their performance is regularly
assessed; and that appropriate quality controls are
established and maintained based upon this performance. Vendors must be selected based upon an
evaluation of their ability to meet specified requirements, and appropriate controls must be established
on the basis of this evaluation. Records of acceptable suppliers must be established and maintained.
Communication of requirements, including quality
requirements, must be documented. Purchasing
documents should include—where possible—agreement that the vendor will notify the device manufacturer of changes to product, processes or services
to enable an evaluation of the impact of the change
on overall product quality.
QSR-based Corrective
and Preventive Actions
for CGMP-based Quality Systems
The QSR requires that procedures for Corrective and
Preventive Actions (CAPA) be established and maintained (21 CFR 820.100). CAPA must be based
upon timely statistical analyses of data from variety
of sources, including production and postmarket
quality data and trends (e.g., failure investigations,
non-conformances, Medical Device Reports) to
detect, identify and appropriately correct existing
and potential causes of nonconforming product and
other quality problems. The sources of these nonconformities must be investigated to determine the
need for action to correct and prevent recurrence of
these and other quality problems. CAPA effectiveness must be determined through verification or
validation testing of the finished device. Changes to
methods and procedures needed to correct and
prevent quality problems must be documented.
Management must review corrective actions and
information related to quality problems or nonconforming product, which then must be disseminated
to those directly responsible for assuring product
quality or preventing quality problems.
RA focus 43
Hybrid GMP-QSR Quality Systems
Quality &
Compliance
A hybrid* (or umbrella) quality system incorporates
elements from the counterpart quality regulation. For
example, to implement a hybrid quality system, a
pharmaceutical manufacturer does not need to
implement all provisions of the QSR. Rather, if a
hybrid quality system is needed, the manufacturer
should include those additional controls needed to
ensure the combination product’s overall quality.
When a manufacturer joins, merges or combines two
or more constituent parts into a single combination
product, the company needs to determine through
risk assessment whether the existing quality system
is adequate to ensure the finished combination product’s overall quality. Parallel quality systems are
unnecessary unless a company designs and/or
manufactures both the drug and device constituent
parts or components of constituent parts, since they
are subject to different quality regulations before they
are combined, merged or joined.
Partner, Vendor
and Contractor Compliance
A combination product manufacturer has the overarching responsibility for complying with relevant
quality regulations. Those regulations may also
apply to partners, vendors and/or contract manufacturers of constituent combination product parts.
If a partner, vendor or contract manufacturer joins
drug and device constituent parts, it should be in
compliance more than one quality regulation. The
combination product manufacturer must ensure
overall compliance with the Design Control elements of the QSR. The exception might be when a
pharmaceutical company is not involved in establishing or changing design specifications for an
existing drug delivery device. If a pharmaceutical
company chooses to either outsource device development or allow a vendor to modify an existing
device to meet drug delivery requirements, as long
as the company is involved with establishing design
requirements, it needs to be involved effectively in
the Design Control process. Its quality system
SOPs should reflect this. A Design Control process
shared between a pharmaceutical manufacturer
and a device vendor or contract manufacturer can
serve as a useful link between CGMP- and QSRbased quality systems. Linkage between the two
constituent part developers serves in part to control
and communicate design evolution and design and
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44 October 2007
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manufacturing changes. Each company’s quality
system SOPs should reflect this linkage.
Conclusion
Proper compliance with quality system regulations
is an important combination product “downstream
issue.”* Of equal importance, the overarching quality system must be robust enough to ensure that
drug-device combination products are not adulterated, misbranded or improperly designed. FDA’s
regulatory approach to a number of combination
product downstream issues is taking form. Quality
system regulations and guidance for combination
products are anticipated in the medium-term.
Meanwhile, developers and manufacturers of combination products and their constituent parts and
components must be prudent in designing and
assessing their own quality systems and those of
their partners, vendors and contractors. There are
important differences between CGMP regulations
and the QSR. For compliance and robust quality of
single-entity combination products, quality system
manufacturers must identify gaps in existing systems and fill them by adding elements from the
counterpart regulation.
*These are the author’s terms. Downstream issues
are downstream of a determination of product jurisdiction and refer to both pre- and postmarketing
regulatory complexities and ambiguities.
REFERENCES
1.FR71, 22565 (2006)]: Current Good Manufacturing Practice for Combination Products, Proposed Rulemaking on
Good Manufacturing Practice
AUTHOR
Michael Gross, PhD, RAC, is a consultant specializing in
quality, regulatory affairs and development strategy for drugs,
biologics, medical devices and combination products. He has
worked in senior quality and regulatory roles in the medical
products industry for more than 30 years. Gross has worked for
a number of large and small pharmaceutical and biotech companies, a large medical device manufacturer and FDA. He can
be reached via email at [email protected].
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