# ![](media/image1.jpeg){width="6.497916666666667in" height="2.560416666666667in"}

December 3, 2004

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061

Rockville, MD 20852

> **[RE: Comments on Draft Guidance for Industry and FDA: Current Good
> Manufacturing Practice for Combination Products, Food and Drug
> Administration Docket No. 2004D-0431]{.underline}**

Dear Sir or Madam:

The Combination Products Coalition ("CPC") respectfully submits for
consideration these comments on the Food and Drug Administration's
("FDA") Draft Guidance on Current Good Manufacturing Practice for
Combination Products (the "Draft Guidance"). The CPC is a group of
leading pharmaceutical, biologics, and medical device manufacturers with
substantial experience in the combination products arena, as well as in
each of the constituent technologies. Because of its diverse membership,
the CPC brings a uniquely broad and experienced perspective to the
problems of regulating combination products. With that background in
mind, we offer the following comments.

**I.** **General Comments**

The CPC applauds the FDA's effort in crafting this Draft Guidance, which
provides a good start to tackling the difficult problems that arise with
application of Current Good Manufacturing Practices (\"CGMP\") and
Quality System (\"QS\") regulations to combination products. We believe
the Draft Guidance, which approaches the issues from the
\"hundred-thousand foot\" level, is the right place to begin the complex
task of working through the plethora of issues raised by applying two or
more distinct sets of regulations to one product. It is the beginning,
however, not the end. With the diverse array of combination products
that fall within the agency\'s scope, the only way for FDA to achieve
consistency in application of CGMP and QS regulations is to develop a
number of specific guidances to address the variety of issues raised.
With that in mind, we urge FDA to continue its efforts, and to develop
more specific guidance on application of CGMP and QS regulations to
combination products.

That said, the purpose of these comments is to identify specific areas
in which FDA\'s approach needs further clarification or revision. Our
goal is to ensure predictable, transparent, and consistent application
of the guidances that ultimately apply to the manufacturing of
combination products. To that end, we offer the following specific
comments.

**II**. **Specific Comments**

> **A**. **FDA needs to clarify impact of assignment on application of
> CGMP and QS regulations**

One of the most critical issues impacting application of CGMPs and QS
regulations to combination products is whether, and to what extent, FDA
will allow assignment of a lead center to drive the determination of
what CGMPs and QS regulations should apply to a particular combination
product. As discussed in the CPC\'s *Response to Request for Comment on
Primary Mode of Action* filed with the FDA on August 18, 2004,[^1] and
raised again in the CPC's comments on the *Draft Guidance for Industry
and FDA Staff: Application User Fees for Combination Products*, filed
with the agency on November 24, 2004, we believe that FDA needs to
clarify its view of what assignment to a particular agency component
means before FDA proceeds with issuing further regulations or guidance.
If FDA adopts the view that assignment determines not only who will take
the lead, but also which authorities and obligations will apply, that
has tremendous implications on downstream regulation. The application of
good manufacturing and quality systems regulations are just the start --
albeit an important one.

The Draft Guidance provides a good example of the impact that the
assignment issue can have in practice. Although it is not clear from the
Draft Guidance what role the FDA intends the lead center to play in
determining which regulations will apply to a given combination product,
the Draft Guidance seems to suggest that FDA intends for the lead center
to oversee regulation of a combination product. Presumably, that could
include determination of which manufacturing and quality system
regulations apply. However, the Draft Guidance also allows that
compliance with CGMPs and QS regulations can generally be achieved \"by
using the current good manufacturing practice system already operating
at a manufacturing facility."[^2] Indeed, under the Draft Guidance, the
manufacturer's pre-existing current good manufacturing practice system
(referred to in the Draft Guidance as the "Operating Manufacturing
Control System") would be a major factor in deciding which regulation
sets the overall, general quality system for a particular combination
product. The other regulations would be incorporated in a subordinate
capacity to address specific issues that may be pertinent to one of the
product's components.[^3] Giving the lead center ultimate authority over
regulations applicable to the manufacturing of a combination product
very well could negate this provision -- which is the foundation of the
guidance\'s approach. Instead, the lead center for each combination
product would control. Consider the potential inconsistencies:

-   For a device manufacturer that manufacturers a drug/device
    combination product, the Operating Manufacturing Control System in
    place likely would be based on QS regulations applicable to medical
    devices. Scale up of those manufacturing facilities, therefore,
    would likely be handled under the device regulations, and no filing
    may be required.

-   If however, CDER is assigned as lead center for the drug/device
    combination and given ultimate control over regulation, CDER might
    require that scale-up of the manufacturing facilities be handled
    under the drug authorities. If so, CDER could require the
    manufacturer to file a supplemental NDA to accommodate the change.

This need not be the case, though. FDA has made very clear that,
although the statute provides a mechanism for determining which agency
component will take the lead on review of a particular combination
product, it did not provide a similar mechanism for determining which
regulatory authorities will apply. Instead, Congress chose to rely on
FDA\'s expertise to determine which regulatory authorities should apply
to a given combination product.[^4] We urge FDA not to take that
responsibility lightly.

With that in mind, the CPC disagrees strongly with allowing assignment
to a lead center to control the complex question of which regulations
apply downstream, and believes that such a determination would lead to
inconsistent and unintended outcomes. For this reason, we exhort FDA to
make a clear and unambiguous statement of its intent.

> **B. FDA should reconsider its case-by-case approach to regulation of
> specific combination products**

Generally, we believe that FDA\'s case-by-case approach to regulation of
specific combination products outlined in the Draft Guidance misses the
mark. FDA has stated time and again that it intends to develop
regulations and guidance that ensure consistency, predictability and
transparency of combination product regulation. The outlined approach
cannot achieve that goal. With the wide variety of combination products
to be covered by the Draft Guidance, and thousands of custom-tailored
systems likely to result, there is an incredible potential for disparity
in regulatory treatment among similar combination products. In addition,
without more direct and specific guidance, word of mouth among reviewers
and investigators may lead to misapplication of similar, generalized
principles to very different combination products.

We understand and appreciate that, in the world of combination products,
one size does not fit all. In fact, in our white paper submitted to FDA
in April 2004,[^5] the CPC commented on the need for flexibility in
defining quality systems and good manufacturing practice requirements
for various types of combination products, since each combination is
different and may involve widely different development and production
processes. However, the current approach goes too far, exchanging
flexibility for customization. Instead, we recommend that FDA develop
specific guidance to address the particular manufacturing and quality
systems issues that arise with different types of combination products.
The only way to ensure consistency, predictability and transparency is
to specify the rules. Only then can manufacturers be assured that: (1)
They know and are complying with the rules; and (2) they are complying
with the same rules as their competitors.

> [1. At the very least, FDA should consider putting procedural
> safeguards in place]{.underline}

Although we strongly believe that FDA\'s current approach fails to meet
FDA\'s goals, we understand that FDA may disagree with our assessment.
For that reason, should FDA continue down the path described in the
Draft Guidance, we offer the following suggestions.

If FDA follows the case-by-case approach enumerated in the Draft
Guidance, the agency needs to elaborate a set of basic procedural norms
that will be followed in all such discussions. This will provide at
least some level of assurance to manufacturers that they are on a level
playing field and promote public confidence in the integrity of
combination-products regulation.

To that end, we believe that, at a bare minimum, the Draft Guidance
needs to provide additional procedural detail to clarify how this
process might work for various types of combination products. For
instance: What are the specific pathways for initiating and conducting
these discussions? How can sponsors ensure they are involved in all
relevant discussions with FDA staff? What data and submissions may be
required for different products that involve different combinations of
the regulations? What information will FDA require a manufacturer to
submit in support of its proposed CGMP/QS plan? What are the standards
for determining the adequacy of manufacturers' proposals? Are there
indicative time lines for processing manufacturers' requests? What are
the end-points of these discussions, e.g., will the results of these
discussions be memorialized in a letter of agreement or other record on
which manufacturers can rely in planning their ongoing operations? FDA
should include guidance to address all of these questions.

> We recognize that the diversity of combination products makes it very
> hard to outline a single procedural pathway that will be appropriate
> in every instance. With that in mind, to clarify the appropriate
> procedures for conducting discussions between FDA and manufacturers,
> it may be necessary for the Draft Guidance to elaborate multiple
> pathways and criteria for determining which combination products
> appropriately belong on which procedural pathway. The Draft Guidance
> should consider a number of indicative example products, clarify how
> these procedures might actually work for each of them, and enunciate
> the key factors FDA will consider in determining what process is
> appropriate for a given combination product.
>
> In addition, to ensure at least some level of transparency in the
> process, we encourage FDA to publish its CGMP/QS decisions, with as
> much supporting documentation as possible. While we understand that
> confidentiality concerns may prevent sharing of all of the information
> exchanged between manufacturers and FDA, it is critical that FDA
> provide easy access to at least basic information to give the industry
> a sense of how FDA might apply the rules in a given circumstance.
> Along these same lines, we suggest that FDA provide an interactive
> webpage for manufacturers, with a feature that enables manufacturers
> to ask FDA questions, and receive answers. Posting of questions and
> answers on the webpage would provide an additional opportunity for
> bringing transparency to the process.
>
> **C. FDA should specify which regulations will apply to different
> types of combination products**

We believe that FDA\'s simultaneous application of CGMPs and QS
regulations to combination products is unnecessary and impractical to
achieve. Instead, we believe that FDA should: (1) Apply appropriate
regulations to *each constituent component* of the combination product
as long as the manufacturer can distinguish between the components of
the product; and (2) if constituent components become indistinguishable
(which may happen with respect to some integral combination products
that are formed into a unit), specify which of the CGMP regulations and
which of the QS regulations will apply to that type of combination
product. We discuss this approach in greater detail below.

> [1. FDA should apply the appropriate regulations to each constituent
> component as long as they are distinguishable]{.underline}

We believe that FDA should apply the appropriate regulations to each
constituent component of a combination product -- even if the products
are joined together -- as long as the constituent components remain
distinguishable. As currently written, the Draft Guidance applies device
QS regulations to device components and drug CGMPs to drug components,
until the components become one. The Draft Guidance provides that, for
integral and kit combination products, "both sets of current good
manufacturing practice regulations are applicable during and after
joining the constituent parts together."[^6]

The concept of "during and after joining," while simple on its face,
assumes too much. It assumes that there is some clear point at which the
constituents of a combination product merge, and that only at that point
do both regulatory schemes become relevant. In practice, however, there
may not be a finite point in time at which the constituents join as a
product. Instead, they may retain their individual constituent character
throughout the manufacturing process (as in the case of virtual
combination products and some kits).

-   For example, the constituent components of a drug and delivery
    system -- such as an IV pump \-- can maintain their individual
    constituent character, even after being combined.

Conversely, the nature of the constituent parts may trigger
consideration of *both* regulatory schemes even *prior to joinder*.
Consider how this example from FDA\'s archives might be handled:

-   FDA determined that, although a catheter flush solution containing a
    blood-thinning drug and an antibiotic combined with a catheter had a
    primary mode of action that was \"physical in nature,\" and
    typically would be subject to review by CDRH, the innovative aspects
    of the solutions raised important scientific and regulatory
    questions that were more appropriately reviewed by CDER.[^7] FDA had
    clinical investigations of the product proceed under the
    investigational drug provisions of the statute. Since the
    combination product was being treated as a drug -- would drug CGMPs
    control, or would QS regulations (including design controls) apply
    to the catheter component?

As this example illustrates, if it is known that a given constituent is
destined to be "joined" into a particular combination product, it may be
necessary to take certain steps even before any such joinder, to lay the
groundwork for compliance with regulatory requirements that will later
come into force. Given these practicalities, the concept of \"during and
after joinder\" may be too simple to work in practice.

As an alternative, we believe that FDA should provide for appropriate
regulation of each of the constituent components, as long as they are
distinguishable. What is *appropriate*, however, should depend on the
type of combination product involved. In many (likely most) cases, a
device component should be subject only to device QS regulation until
such time as the device is no longer distinguishable from the other
constituent components of a combination product. Depending on the nature
of the combination product, *appropriate* regulation may require the
incorporation of certain regulations from the drug CGMP scheme to ensure
patient safety of the ultimate combination product. We do not advocate
duplicative or parallel regulation; rather, we encourage FDA to choose
appropriate regulations depending on the type of combination product
involved.

As discussed in our April 2004 White Paper, a case-study approach may be
the best way to identify and address these subtleties. This would
involve looking at development and production processes for various
example products, considering the CGMP/QS issues that may arise at
various points in these processes, and specifying the appropriate
combination of regulations that apply at various stages. Again, this
requires much more specific guidance than FDA has provided in the DRAFT
Guidance

> [2. If constituent components become indistinguishable, specify which
> of the CGMP regulations and which of the QS regulations will
> apply]{.underline}

Even when there may be a temptation to apply dual CGMP and QS
requirements to a particular combination product -- as when the
components become indistinguishable \-- we believe FDA must make choices
among which regulations should apply. Attempting to mesh the CGMP
regulations and QSR requirements into one common regulatory scheme is
tantamount to fitting a square peg into a round hole. It ignores the
purpose and shape of the underlying regulations. For instance, the
device QS regulations reach farther "upstream" into the design process
than the drug CGMP regulations reach. As a result, manufacturers
otherwise subject to CGMP regulation may find that their existing
Operating Manufacturing Control Systems do not have appropriate upstream
"slots" into which the device requirements can be fit. Blanket
application of both sets of regulations may provide a simple answer, but
it falls short in implementation. FDA needs to choose which regulations
will apply, under what circumstances.

Once again, we believe that the answer is to provide specific guidance
on which QS and which CGMP regulations apply to particular types of
combination products. Using case studies and examples, FDA could go a
long way toward simplifying the process for the agency and industry
alike.

D. **Training and Personnel Development**

As discussed in our April 2004 White Paper, because of the complexity of
the different CGMP and QSR systems for biologics, drugs and devices,
appropriate regulation and enforcement of combination products will
require cross-training of inspectors, or in some instances, inspection
by a team of two or more inspectors with complementary skills and
experience. The Draft Guidance does not yet address the important
question of how compliance inspections may differ for different types of
combination products: *e.g.*, What are likely to be the criteria for
determining whether a given CGMP/QSR system can be adequately inspected
by a single inspector with cross-training, as opposed to needing
separate inspections of its CGMP and QSR components? Will the "lead"
inspection personnel vary, depending on the assignment of the lead
center for regulating a particular combination product? How will the FDA
ensure consistent treatment of similar products? What role can
manufacturers usefully play in developing appropriate solutions and in
exchanging ideas related to training and development of personnel? These
questions should be addressed in, or in parallel with, the Draft
Guidance.

III\. **Conclusion**

We appreciate FDA\'s efforts in preparing this Draft Guidance, and
believe it is the right place to start. The next step, however, is
critical. We firmly feel that FDA needs to provide more specific
guidance on how CGMP and QS regulations will be applied to particular
types of combination products, using case studies and examples to
illustrate the agency\'s thinking. FDA has a tremendous opportunity to
use its scientific expertise and experience to craft thoughtful and
practical guidelines that will ensure consistent and predictable
application of the regulations. This should be familiar ground for FDA,
and we urge the agency to take this step. We stand ready to assist in
any way we can.

We appreciate this opportunity to present our comments on the Draft
Guidance, and look forward to working with FDA as the agency moves
forward.

Respectfully Submitted,

![](media/image2.png){width="1.9152777777777779in"
height="0.7916666666666666in"}

Bradley Merrill Thompson

For the Combination Products Coalition

[^1]: (Letter from Bradley Merrill Thompson, Combination Products
    Coalition, to FDA of August 18, 2004, regarding Response to Request
    for Comment on Primary Mode of Action, Food and Drug Administration
    Docket Number 2004N-0194).

[^2]: FDA, *Guidance for Industry and FDA, Current Good Manufacturing
    Practice for Combination Products,* at 5 (September 2004).

[^3]: *See* Draft Guidance at 6, Table 1.

[^4]: *See* *Final Rule, Regulations Restricting the Sale and
    Distribution of Cigarettes and Smokeless Tobacco to Protect Children
    and Adolescents*, 61 Fed. Reg. 44396, 44400 (August 28, 1996)
    (Discussing in general FDA\'s discretion to determine which
    regulatory authorities apply to combination products).

[^5]: Combination Products Coalition, *Combination Products: Proposed
    Policies to Enhance the FDA Regulatory Process* (Submitted to the
    FDA in April, 2004).

[^6]: Draft Guidance at 5.

[^7]: Final Tobacco Rule, 61 Fed. Reg. at 44403.