Guidance for Industry
Current Good Manufacturing Practice for Combination
Products
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This draft guidance, when
finalized, will represent the Food and Drug Administration's (FDA's) current
thinking on this topic. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. You can use an
alternative approach if the approach satisfies the requirements of the
applicable statutes and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing this guidance. If
you cannot identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
This document provides
guidance to industry and FDA staff on the applicability of current good
manufacturing practice
provisions to combination products as defined under 21 CFR 3.2(e). Such
provisions apply to the manufacture
of combination products to ensure that (1) the product is not adulterated; (2)
the product possesses adequate strength, quality, identity, and purity; and (3)
the product complies with performance standards as appropriate for the marketed combination product.
This guidance does not address technical manufacturing
methods or make recommendations for manufacturers'
selection of facilities to manufacture products.
FDA's guidance documents, including this guidance, do not
establish legally enforceable responsibilities. Instead, guidances describe
the Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that
something is suggested or recommended, but not required.
A combination product is a product composed of any
combination of a drug and a device; a biological product and a device; a drug
and a biological product; or a drug, device, and a biological product. Under
21 CFR 3.2 (e), a combination product is defined to include:
1. A
product comprising two or more regulated components (i.e., drug/device,
biologic/device, drug/biologic, or drug/device/biologic) that are physically,
chemically, or otherwise combined or mixed and produced as a single entity;
2. Two or more
separate products packaged together in a single package or as a unit comprising
drug and device products, device and biological products, or biological and
drug products;
- A drug, device, or biological product packaged separately
that according to its investigational plan or proposed labeling is
intended for use only with an approved individually specified drug,
device, or biological product where both are required to achieve the
intended use, indication, or effect and where, upon approval of the
proposed product, the labeling of the approved product would need to be
changed (e.g., to reflect a change in intended use, dosage form, strength,
route of administration, or significant change in dose); or
4. Any
investigational drug, device, or biological product packaged separately that
according to its proposed labeling is for use only with another
individually specified investigational drug, device, or biological product
where both are required to achieve the intended use, indication, or effect.
For the purposes of this
guidance document, a constituent part of a combination product is an
article in a combination product that can be distinguished by its regulatory
identity as a drug, device, or biological product, as defined in section 201 of
the Federal Food, Drug, and Cosmetic Act (the Act) or 351(i) of the Public
Health Service Act. For example, a device coated or impregnated with a drug
has two constituent parts, the device and the drug. For simplicity, the
concepts in this guidance are described in the context of a combination product
composed of two constituent parts. These concepts are also relevant for
combination products with more than two constituent parts.
A combination product is assigned to an Agency center or
alternative organizational component that will have primary jurisdiction for
its premarket review and regulation. Under section 503(g)(1) of the Act,
assignment to a center with primary jurisdiction, or a lead center, is
based on a determination of the primary mode of action (PMOA) of the
combination product. For example, if the PMOA of a device-biological combination
product is attributable to the biological product, the Agency component
responsible for premarket review of that biological product would have primary
jurisdiction for the combination product. The lead center generally has
responsibility for oversight of the regulation of the combination product,
including the evaluation of current good manufacturing practice.
Section
503(g)(4)(D) of the Act requires FDA to "ensure the consistency and
appropriateness of postmarket regulation of like [combination] products."
To achieve consistency, FDA will treat like combination products similarly. To
ensure appropriateness, FDA plans to require that manufacturers use the
applicable current good manufacturing practice regulations for their
combination products. In the regulation of a combination product, the
application of consistent and appropriate current good manufacturing practice
should help to ensure that the combination product is not adulterated
under section 501 of the Act and is manufactured in accordance with appropriate
regulatory provisions for the combination product and its constituent parts.
Section 501 of the Act
states the circumstances under which a drug or device is deemed adulterated and
authorizes FDA to establish current good manufacturing practice to avoid
adulteration. Adulteration
includes a failure of the drug, biological product, or device to be
manufactured in accordance with current good manufacturing practice, regardless
of whether the product is actually deficient in some respect.
Current good manufacturing practice regulatory provisions are intended to
ensure that the drug, biological product, or device is not adulterated; to ensure
the product possesses adequate strength, quality, identity, and purity of a
drug or biological product; and to ensure compliance with performance standards
for a device. The following current good manufacturing practice regulations and
other applicable standards are codified for products that may be constituent
parts of a combination product:
§ Current
good manufacturing practice (CGMP) regulations for finished pharmaceuticals, or
drug products (21 CFR Parts 210 and 211). Drug
products not subject to these regulations (e.g., bulk drugs or active
pharmaceutical ingredients) must still meet the current good manufacturing
practice general standard required by the statute.
§ Quality
system (QS) regulation for devices (21 CFR Part 820).
The biological product regulations,
21 CFR Parts 600-680, may also apply to the manufacture of drugs that are also
biological products along with the drug CGMP provisions.
They also may apply along with the QS regulations to the manufacture of devices
that are also biological products.
There is considerable
overlap in the CGMP and QS regulations, and for the most part the overlap is
apparent. For example, both establish requirements for management,
organization, and personnel; both require documentation and record keeping; and
both allow flexibility in application to the manufacture of particular
products. FDA
considers the CGMP and the QS
regulations to be similar, and they are meant to achieve the same goals.
Nonetheless, FDA recognizes
that each set of regulations is somewhat different because each is tailored to
the characteristics of the types of products for which they were designed
(i.e., CGMP for drugs or biological products, QS regulation for devices). Each
set of regulations contains certain express/specific requirements that may be
only more generally described in the other regulation. Typically, these
express/specific requirements are related to the unique characteristics of a
drug, device, or biological product. For example:
·
Calculating the yield and stability of a drug constituent part:
The CGMP regulation has specific requirements for the calculation of yield (21
CFR 211.103) and for ensuring stability of the drug product (21 CFR 211.166).
Under the QS regulation, for a combination product with a drug constituent
part, yield and stability requirements would be incorporated more generally as
part of the design validation provisions (21 CFR 820.30(g)).
·
Corrective and preventive action (CAPA): The QS regulation has
detailed CAPA requirements (21 CFR 820.100), while CAPA principles are more
generally identified in the CGMP regulation as part of Production Record Review
(21 CFR 211.192).
FDA has not promulgated
current good manufacturing practice regulations specifically for combination
products. Until it does so, each constituent part (i.e., the drug, device, or
biological product) remains subject only to its governing current good
manufacturing practice regulations when marketed separately, see 21 CFR
3.2(e)(3) and (4), and when manufactured separately as constituent parts of a
combination that will later be combined, see 21 CFR 3.2(e)(1) and (2). For
example, if a drug is marketed that is intended for use only with an approved
individually specified device that is also marketed separately, the drug
constituent must comply only with 21 CFR Parts 210 and 211, and the device
constituent must comply only with 21 CFR Part 820. Similarly, during the time
of separate manufacture (i.e., before drug and device combination products are
produced as a single entity or are co-packaged) 21 CFR Parts 210 and 211 apply
only to the drug constituent, and 21 CFR Part 820 applies only to the device
constituent.
However, for combination
products that are produced as a single-entity or are co-packaged, see 21 CFR
3.2(e)(1) and (2), both sets of current good manufacturing practice regulations
are applicable during and after joining the constituent parts together. The
rest of this section refers only to situations when combination products that
are produced as a single entity or are co-packaged as defined in 21 CFR
3.2(e)(1) and (2) are joined together.
FDA recognizes that many
manufacturing facilities operate under one type of current good manufacturing
practice system (i.e., either that described by the QS or CGMP regulation). As
noted above, FDA recognizes that there is considerable overlap between the QS
and CGMP regulations. It should generally not be necessary for manufacturers
who make combination products that are produced as a single entity or are
co-packaged to maintain two separate manufacturing systems to ensure compliance
with both sets of regulations during and after joining the constituents
together. FDA believes that compliance with both sets of regulations during
and after joining these types of combination products can generally be achieved
by using either the CGMP or QS regulations, e.g., by using the current good
manufacturing practice system already operating at a manufacturing facility, as
described below.
During and after joining
these types of combination products together, FDA believes that compliance with
both sets of regulations can generally be achieved by following one set because
under a more general requirement in one set of regulations, it will be possible
to develop and implement a practice that complies with a more specific
requirement in the other set of regulations. To ensure consistent and
appropriate current good manufacturing practice, FDA recommends that manufacturers
of these types of combination products assess how best to comply with both sets
of regulations, during and after joining the constituent parts together, by
carefully considering the requirements of the CGMP and QS regulations in
relation to the constituent parts, and the combination product(s) they
manufacture.
Table 1 identifies key
provisions of the CGMP and QS regulations that differ in their specificity.
FDA recommends manufacturers of combination products that are co-packaged or
produced as a single entity carefully consider these provisions during and
after joining the constituent parts, to ensure compliance with both the CGMP
and QS regulations.
Table 1: Key Current Good Manufacturing Practice Provisions to
Consider During and After Joining Together Co-packaged and Single-Entity
Combination Products
If the Operating Manufacturing Control System is Part
820 (QS Regulation)
|
If the
Operating Manufacturing Control System is Part 210/211 (CGMP Regulation)
|
Carefully Consider These Specific CGMP Requirements
|
Title
|
Carefully Consider These Specific QS Requirements
|
Title
|
§ 211.84
|
Testing and approval or rejection of components, drug
product containers, and closures
|
§ 820.30
|
Design controls
|
§ 211.103
|
Calculation of yield
|
§ 820.50
|
Purchasing controls
|
§ 211.137
|
Expiration dating
|
§ 820.100
|
Corrective and preventative actions
|
§ 211.165
|
Testing and release for distribution
|
|
|
§ 211.166
|
Stability testing
|
|
|
§ 211.167
|
Special testing requirements
|
|
|
§ 211.170
|
Reserve samples
|
|
|
* Including
all subsections, as appropriate.
|
In addition, depending on
the particular combination product, it may be important to consider other
specific requirements to ensure compliance with both the CGMP and QS
regulations. Examples include aseptic control assurance for drug and
biological product constituent parts unable to withstand terminal sterilization
(21 CFR 211.113(b) and § 211.42)); 21 CFR 606 for blood and blood component
constituent parts; 21 CFR 211.132 for combination products incorporating drug
constituent parts that are sold over-the-counter; and any good tissue practice
regulations that may be promulgated.
FDA recommends that
manufacturers of these types of combination products present information to the
Agency when the product is being developed (e.g., during Agency meetings or
during inspections) about how they intend to achieve compliance with each set
of regulations during and after joining the products together, in particular by
showing how they achieve compliance with the provisions identified in Table 1
above, as well as any other provisions applicable to the combination product
being manufactured.
If a manufacturer of these types of combination products is
concerned about whether application of one set of current good manufacturing
practice regulations satisfies the requirements of the other set(s), FDA
encourages the manufacturer to discuss with the appropriate Agency personnel
when the product is being developed how best to achieve current good
manufacturing practice compliance. Further, FDA expects that this guidance
will be revised as FDA modifies the existing CGMP/QS regulations.
As described under section
I.A, there are four types of combination products. To summarize, the following
are considerations by type of combination product:
- Combination products with constituent parts that are
physically, chemically or otherwise combined or mixed and produced as a
single entity (21 CFR 3.2(e)(1)), and combination products with
constituent parts that are packaged together (21 CFR 3.2(e)(2)):
Before combination or co-packaging, the manufacture
of each constituent part is subject only to the current good manufacturing
practice regulations associated with each constituent part. For example, for a
drug-coated device, the drug constituent part would be subject only to the CGMP
regulation (or to Section 501(a)(2)(B) of the Act for a bulk drug substance or
active pharmaceutical ingredient), while the device constituent part would be
subject only to the QS regulation.
Once the product is combined into a
single entity or co-packaged, both sets of regulations apply to the
combination. FDA recommends manufacturers follow the guidance described in
section III.B above to achieve compliance with all applicable current good
manufacturing practice regulations.
- Combination products with constituent parts that are
separately marketed but intended to be used together (21 CFR 3.2(e)(3) and
(e)(4)):
The manufacture of each constituent part is subject
to the current good manufacturing practice regulations associated with each
constituent part, and is not subject to both sets of regulations. For example,
for a photodynamic therapy system consisting of a laser and a photosensitizing
drug that are marketed separately, the laser would be subject to the QS
regulation while the photosensitizing drug would be subject to the CGMP
regulation.
FDA recommends that manufacturers
of combination products discuss with the Agency how current good manufacturing
practice regulations apply to their products. Manufacturers are encouraged to
seek FDA comment on their implementation of current good manufacturing practice
during pre-investigational (pre-IND/IDE) meetings and throughout combination
product development. FDA recommends that
these discussions include consideration of the risks of the combination
product, its technology, and any anticipated postmarket development and post
approval changes. FDA recommends that the applicant(s) include all critical
manufacturers in these discussions and include information on critical steps
that may be conducted at source/contract firms and any special testing.
FDA staff involved in the
discussions about the application of current good manufacturing practice
regulations to a combination product may include, but are not limited to,
reviewers in the lead and consulting product review divisions (CBER, CDER, and
CDRH); the current good manufacturing practice experts in the Offices of
Compliance in the lead and consulting centers and the district office; Office
of Regulatory Affairs national expert advisors, as appropriate; and the Office
of Combination Products.
[16] FDA will document its
recommendations concerning the manufacturer’s proposal in FDA meeting minutes,
letters, or other permanent communication records, as appropriate. Also, FDA
staff should communicate this information to the appropriate District Office.