Ignacuinos v. Boehringer Ingelheim Pharms.

20-3643-cv
Ignacuinos v. Boehringer Ingelheim Pharms.
UNITED STATES COURT OF APPEALS 1
FOR THE SECOND CIRCUIT 2
3
August Term, 2020 4
5
(Submitted: April 30, 2021 Decided: August 6, 2021) 6
7
Docket No. 20-3643 8
9
_____________________________________ 10
11
CARL IGNACUINOS, ON BEHALF OF HIMSELF AND OTHERS 12
SIMILARLY SITUATED, PAMELA DAVIS, ON BEHALF OF 13
HERSELF AND OTHERS SIMILARLY SITUATED, 14
15
Plaintiffs-Appellants, 16
17
v. 18
19
BOEHRINGER INGELHEIM PHARMACEUTICALS INC, 20
21
Defendant-Appellee.* 22
_____________________________________ 23
24
Before: 25
26
LOHIER and BIANCO, Circuit Judges, and ABRAMS, District Judge.** 27
28
The Plaintiffs-Appellants were prescribed a metered-dose inhaler 29
manufactured by the Defendant-Appellee and approved by the Food and Drug 30
Administration (FDA) to alleviate symptoms of chronic obstructive pulmonary 31
disease. The Plaintiffs-Appellants filed this action claiming violations of state 32
law premised on the Defendant-Appellee’s allegedly deceptive labeling or 33
* The Clerk of Court is directed to amend the caption as set forth above.
** Judge Ronnie Abrams, of the United States District Court for the Southern District
of New York, sitting by designation.

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defective design and manufacture of the metered-dose inhaler. Relying largely 1
on the language of the relevant FDA regulation, 21 C.F.R. § 314.70(b), the 2
United States District Court for the District of Connecticut (Underhill, J.) 3
dismissed the claims as preempted by federal law. We AFFIRM. 4
5
C.K. Lee, Lee Litigation Group, PLLC, New York, 6
NY, for Plaintiffs-Appellants Carl Ignacuinos and 7
Pamela Davis. 8
9
James T. Shearin, Pullman & Comley, LLC, 10
Bridgeport, CT; Shankar Duraiswamy, Emily S. 11
Ullman, Covington & Burling LLP, Washington, DC, 12
for Defendant-Appellee Boehringer Ingelheim 13
Pharmaceuticals, Inc. 14
15
L OHIER , Circuit Judge: 16
Plaintiffs-Appellants Carl Ignacuinos and Pamela Davis appeal from a 17
September 25, 2020 judgment of the United States District Court for the 18
District of Connecticut (Underhill, J.), which dismissed their putative class 19
action claims contained in a third amended complaint against Defendant- 20
Appellee Boehringer Ingelheim Pharmaceuticals, Inc. The plaintiffs asserted 21
various state law claims for injuries caused by the alleged deceptive 22
marketing or defective design and manufacture of Boehringer Ingelheim’s 23
metered-dose inhaler. The District Court dismissed the complaint in its 24
entirety, holding that the plaintiffs’ claims were preempted by federal law. 25
On appeal, the plaintiffs challenge only the dismissal of their design and 26

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manufacturing-related claims. For the reasons set forth below, we AFFIRM 1
the judgment of the District Court. 2
BACKGROUND 3
For the purpose of resolving this appeal, we accept as true the 4
following allegations in the third amended complaint. See Mirabilio v. Reg’l 5
Sch. Dist. 16, 761 F.3d 212, 213 (2d Cir. 2014). 6
Boehringer Ingelheim manufactures Combivent Respimat, a metered- 7
dose inhaler that is prescribed to alleviate symptoms of chronic obstructive 8
pulmonary disease (COPD). The Combivent Respimat inhaler, which the 9
Food and Drug Administration (FDA) approved in 2011, consists of an 10
inhaler equipped with a mouthpiece (Respimat) and a cartridge, which 11
contains the medication itself (Combivent). The product’s label recommends 12
a dose of “one inhalation four times a day, not to exceed six inhalations in 24 13
hours,” and it represents that the product will deliver 120 metered doses (i.e., 14
120 “puffs”). App’x 12–13. The inhaler locks and will not spray any more 15
medication after 120 doses have been dispensed. In 2016 the FDA approved 16
an updated version of the labeling of the product, including “Instructions for 17
Use” that noted the possibility that “[t]he dose indicator on the [inhaler] 18

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4
[may] reach[] zero too soon” under certain circumstances involving user 1
error. App’x 80. 2
The plaintiffs were prescribed Combivent to alleviate their COPD 3
symptoms. They allege, however, that the Combivent inhalers deliver 4
significantly fewer than the labeled 120 doses, and that they were physically 5
and economically injured as a result. The plaintiffs therefore seek to hold 6
Boehringer Ingelheim liable under Connecticut, Florida, and Indiana state law 7
for alleged design or manufacturing defects that caused the failure to deliver 8
the labeled number of doses.1 9
The District Court dismissed both sets of claims as preempted by 10
federal law. This appeal followed. 11
DISCUSSION 12
We review the District Court’s dismissal of the plaintiffs’ claims de 13
novo. See Dolan v. Connolly, 794 F.3d 290, 293 (2d Cir. 2015). To determine 14
whether the claims are preempted, “we start with the basic principle that 15
under the Supremacy Clause of the Constitution, state and local laws that 16
1 The plaintiffs also brought claims premised on Boehringer Ingelheim’s alleged
misrepresentation of the number of doses on the inhaler’s label, but they have
abandoned their labeling-related claims on appeal. See Appellants’ Br. 7.

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conflict with federal law are without effect.” UnitedHealthcare of N.Y., Inc. v. 1
Lacewell, 967 F.3d 82, 91 (2d Cir. 2020) (cleaned up); see Gibbons v. Bristol- 2
Myers Squibb Co., 919 F.3d 699, 708 (2d Cir. 2019). The Food, Drug, and 3
Cosmetics Act (FDCA) authorizes the federal Government to regulate the 4
manufacture, labeling, and sale of pharmaceuticals. 21 U.S.C. § 301 et seq.; 5
see Gibbons, 919 F.3d at 707. Design and manufacturing defect claims that a 6
drug manufacturer has breached its duties under state law are preempted by 7
federal law if the manufacturer would require prior FDA approval to comply 8
with those duties. See Gibbons, 919 F.3d at 708. Conversely, the same state 9
claims may proceed if the manufacturer could have acted unilaterally without 10
prior FDA approval. See id.; PLIVA, Inc. v. Mensing, 564 U.S. 604, 620 (2011) 11
(citing Wyeth v. Levine, 555 U.S. 555, 573 (2009)) (explaining that 12
“impossibility” preemption applies when a private party cannot 13
“independently do under federal law what state law requires of it”). 14
When does a drug manufacturer need FDA approval, and when can it 15
act unilaterally without approval? The relevant FDA regulation, 21 C.F.R. 16
§ 314.70, makes clear that a manufacturer must obtain prior FDA approval for 17
any “major” changes to the design and manufacturing of already-approved 18

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drug products, but not for “moderate” or “minor” changes. See 21 C.F.R. 1
§ 314.70(b)–(d); see also Mut. Pharm. Co. v. Bartlett, 570 U.S. 472, 477 (2013) 2
(“Once a drug—whether generic or brand-name—is approved, the 3
manufacturer is prohibited from making any major changes[.]” (citing 4
21 C.F.R. § 314.70(b)(2))). The question presented on appeal is whether the 5
changes necessary to cure the Combivent inhaler’s alleged defects qualify as 6
“major” under § 314.70(b). 7
We start with “major” changes, which § 314.70(b) defines as follows: 8
(b) Changes requiring supplement submission and approval 9
prior to distribution of the product made using the change (major 10
changes). 11
(1) A supplement must be submitted for any change in the 12
drug substance, drug product, production process, quality 13
controls, equipment, or facilities that has a substantial 14
potential to have an adverse effect on the identity, strength, 15
quality, purity, or potency of the drug product as these 16
factors may relate to the safety or effectiveness of the drug 17
product. 18
(2) These changes include, but are not limited to: 19
(i) Except those described in paragraphs (c) and (d) 20
of this section, changes in the qualitative or 21
quantitative formulation of the drug product, 22
including inactive ingredients, or in the 23
specifications provided in the approved [drug 24
application]; . . . 25

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(vi) Changes in a drug product container closure 1
system that controls the drug product delivered to a 2
patient . . . .” 3
21 C.F.R. § 314.70(b). Section 314.70(b)(1) thus tells us how to identify 4
changes that require FDA pre-approval: A change in drug design or 5
manufacturing requires pre-approval if it has a “substantial potential to have 6
an adverse effect.” And § 314.70(b)(2) provides a specific but non-exhaustive 7
list of “[t]hese changes.” 8
The provisions that define “moderate” and “minor” changes have a 9
similar structure. They first broadly define a category of changes with 10
“moderate” or “minimal” potential to have an adverse effect. Id. 11
§ 314.70(c)(1), (d)(1). They then list specific categories of qualifying changes. 12
Id. § 314.70(c)(2), (d)(2). 13
On appeal, the plaintiffs argue that a manufacturer must show that a 14
change has a “substantial potential to have an adverse effect” under 15
§ 314.70(b)(1) to qualify as “major,” even if the change is specifically listed in 16
§ 314.70(b)(2). Here, the plaintiffs submit, Boehringer Ingelheim failed to 17
show that the proposed modifications to the inhaler’s design or manufacture 18
would have a substantial adverse effect. 19

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We have not previously addressed the argument that a change listed in 1
§ 314.70(b)(2) must also separately be proven to have a “substantial potential 2
to have an adverse effect” to qualify as a “major” change. But we agree with 3
the First Circuit in holding that “if a change fits under any of the categories 4
listed in section (b)(2), that change necessarily constitutes a ‘major’ change 5
requiring FDA pre-approval,” regardless of whether the defendant has shown 6
a substantial potential for an adverse effect. Gustavsen v. Alcon Lab’ys, Inc., 7
903 F.3d 1, 11 (1st Cir. 2018). 8
As the First Circuit explained, there are three principal reasons for this 9
interpretation and for rejecting the plaintiffs’ proposed reading of the 10
regulation. First, section (b)(2)’s non-exhaustive list of qualifying changes is 11
provided “in a heading of the same level as the broad definition in section 12
(b)(1) (rather than in section (b)(1) itself, or as perhaps in a hypothetical 13
section (b)(1)(i)).” Id. at 10–11. That (b)(2) is not a subpart of (b)(1) “makes it 14
unlikely that the ‘changes’ in (b)(2) are a subcategory of the changes in (b)(1).” 15
Id. at 11. Second, under the plaintiffs’ reading, “whether a change is major or 16
moderate would depend in every case on a separate determination of the 17
qualitative magnitude of the change,” which the Supreme Court has never 18

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“previously read these regulations to . . . require[.]” Id. at 11 (citing Wyeth, 1
555 U.S. at 568); see Bartlett, 570 U.S. at 477. And third, “the categories later 2
defined in section (b)(2) do not map easily onto the types of changes 3
identified in (b)(1),” such that much of the regulatory language in section 4
(b)(2) would not “have any meaning under [the plaintiffs’] reading.” 5
Gustavsen, 903 F.3d at 11. 6
We would add to the First Circuit’s compelling analysis only that the 7
authorizing statutory language of 21 U.S.C. § 356a(c)(2) provides that “a 8
major manufacturing change is a manufacturing change that is determined by 9
the [FDA] to have substantial potential to adversely affect the . . . safety or 10
effectiveness of a drug.” The FDA’s decision to refer to a particular product 11
modification in 21 C.F.R. § 314.70(b)(2)’s list of major changes tells us that it 12
considers the modification’s potential to have an adverse effect to be 13
substantial per se. See Supplements and Other Changes to an Approved 14
Application, 69 Fed. Reg. 18,728, 18,736 (Apr. 8, 2004) (“FDA has used this 15
provision of the act [(21 U.S.C. § 356a(c)(2))] to identify a limited number of 16
changes that it considers to have a substantial potential to adversely affect the 17
. . . the safety or effectiveness of a drug.”). 18

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For these reasons, we conclude that the plaintiffs’ state law design and 1
manufacturing defect claims are preempted to the extent that they would 2
require any change listed in § 314.70(b)(2). 3
Do the plaintiffs’ claims require such a change? Although the 4
complaint broadly alleges that the Combivent inhaler suffered from design 5
and manufacturing defects in violation of various state laws, it proposes no 6
specific changes that might have remedied the defect other than to suggest “a 7
change in the design of the Product so that it actually delivers 120 metered 8
doses,” or, “to the extent that the Product’s design is sound, but the 9
manufacturing process is compromised, improvements in the manufacturing 10
process.” App’x 21–22.2 Nevertheless, the District Court recognized that an 11
increase in the number of doses delivered would necessarily require either an 12
increase in the amount of Combivent per cartridge or a change in the design 13
of the inhaler to release more doses from the same amount of medication. 14
With that in mind, we consider whether Boehringer Ingelheim could 15
have unilaterally changed the design of the inhaler to release a different 16
2 We assume without deciding that the plaintiffs correctly describe the requirements
of state law.

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amount of medication per puff. Our answer is no. Section 314.70(b)(2)(vi) 1
provides that any modification to “a drug product container closure system 2
that controls the drug product delivered to a patient” qualifies as a major 3
change. According to the FDA, the paradigmatic product in this category is 4
“a metered dose inhalation product.” Supplements and Other Changes to an 5
Approved Application, 69 Fed. Reg. at 18,739 (emphasis added). A patient 6
using a metered-dose inhaler “cannot control the amount of drug product the 7
container closure system delivers or verify that the appropriate amount has 8
been administered.” Id. Because the “design and operation of these container 9
closure systems is critical to ensure that the patient receives the correct dose,” 10
the FDA “requires information to be submitted to support that the container 11
closure system can accurately and repeatedly deliver the required amount of 12
drug product.” Id. So changes to a drug-product-delivering container- 13
closure system such as a metered-dose inhaler are categorically “considered 14
to have a substantial potential to adversely affect . . . the safety or 15
effectiveness of a drug product,” and they therefore qualify as major changes. 16
Id.; see also FDA Guidance for Industry: Changes to an Approved NDA or 17
ANDA, 2004 WL 3199016, at *16 (Apr. 1, 2004) (stating that any change to “the 18

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valve or actuator of a metered-dose inhaler” constitutes a “[m]ajor [c]hange[ ]”); 1
Gustavsen, 903 F.3d at 11–12 (changing a prescription eye solution’s 2
dispensing bottle to adjust “the size of the drops dispensed” is a “major” 3
change under § 314.70(b)(2)(vi)). Any state law claim premised on a duty to 4
make such a change to the design of the Combivent inhaler is therefore 5
preempted by federal law. 6
Nor could Boehringer Ingelheim have unilaterally increased the 7
amount of liquid Combivent medication in each cartridge (that is, a change in 8
the product’s “fill volume” or “fill weight”). Section 314.70(b)(2)(i)’s list of 9
“major changes” includes “changes in the qualitative or quantitative 10
formulation of the drug product, including active ingredients, or in the 11
specifications provided in the approved [drug application],” unless those 12
changes are otherwise “described” in the paragraphs defining “moderate” 13
and “minor” changes. 21 C.F.R. § 314.70(b)(2)(i). The statute from which the 14
regulation derives itself says that any change “made in the qualitative or 15
quantitative formulation of the drug involved or in the specifications in the 16
approved [drug] application” qualifies as a major change “unless exempted 17
by the Secretary [of Health and Human Services] by regulation or guidance 18

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from the requirements of this subsection.” 21 U.S.C. § 356a(c)(2)(A); see also 1
Supplements and Other Changes to an Approved Application, 69 Fed. Reg. 2
at 18,737 (explaining that the “[e]xemptions by regulation are provided in 3
§ 314.70(c) or (d)”). A change in specification or quantitative formulation thus 4
qualifies as a major change unless otherwise provided by the FDA. 5
The plaintiffs do not dispute that increasing the amount of medication 6
in each Combivent cartridge would change either its “quantitative 7
formulation” or its “specifications.” But they argue that increasing the 8
cartridge’s fill volume must be a “moderate” or “minor” change because it 9
would not have a substantial potential to have an adverse effect on the safety 10
and effectiveness of the drug product. For the reasons explained above, their 11
argument rests on a misreading of § 314.70(b). We need not independently 12
consider the potential adverse effect of increasing the volume of liquid 13
medication in each cartridge. But even if we did consider it, the FDA’s 14
guidance for industry explains that “[a] change in the fill volume of a drug 15
product” involves a change under § 314.70(b)(2)(i) for which “[t]here is no 16
exemption.” FDA Guidance for Industry: Changes to an Approved NDA or 17

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ANDA Questions and Answers, 2001 WL 34768253, at *7 (Jan. 1, 2001).3 1
Although the FDA’s guidance is not binding on this Court, it fully comports 2
with the plain meaning of the regulation, and we find it persuasive. See 3
21 C.F.R. § 10.115(d)(1) (“[FDA] [g]uidance documents do not establish legally 4
enforceable rights or responsibilities. They do not legally bind the public or 5
FDA.”). The plaintiffs, furthermore, have not made us aware of another 6
regulation or guidance that would exempt from the requirement of FDA pre- 7
approval the change in fill volume that they propose here. Their proposed 8
change in fill volume therefore “must be submitted in a prior approval 9
supplement.” FDA Guidance for Industry: Changes to an Approved NDA or 10
ANDA Questions and Answers, 2001 WL 34768253, at *7; see 21 C.F.R. 11
§ 314.70(b) (defining “major changes” as those “requiring supplement 12
submission and approval prior to distribution of the product”). 13
3 The FDA Guidance more specifically states that a change in fill volume is a change
in “specification.” FDA Guidance for Industry: Changes to an Approved NDA or
ANDA Questions and Answers, 2001 WL 34768253, at *7. FDA regulations
elsewhere define “[s]pecification” to mean “the quality standard . . . provided in an
approved [new drug application] to confirm the quality of” a drug product.
21 C.F.R. § 314.3(b). Consistent with the FDA’s guidance, we agree that a change in
fill volume meets the criteria of § 314.70(b)(2)(i), regardless of whether it does so as a
“specification” or a “quantitative formulation” of the drug product.

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Setting aside for a moment that the plaintiffs themselves have failed on 1
appeal to point us to any specific regulation that would render an increase in 2
fill volume a “moderate” or “minor” change, we note that the District Court 3
considered whether a particular regulation, § 314.70(c)(6)(ii), applied. We 4
agree with the District Court that that provision does not. Indeed, it helps 5
illustrate why the desired change here is “major.” Section 314.70(c)(6)(ii) 6
provides that “[a] change in the size and/or shape of a container for a 7
nonsterile drug product, except for solid dosage forms, without a change in 8
the labeled amount of drug product” qualifies as a “moderate” change. “The 9
phrase ‘labeled amount of [drug] product’ refers to the total quantity of drug 10
product (e.g., milliliters, grams).” Supplements and Other Changes to an 11
Approved Application, 69 Fed. Reg. at 18,745. Because a change in the 12
quantity of Combivent per cartridge represents a change in the labeled 13
amount of drug product, it cannot qualify as a moderate change under 14
§ 314.70(c)(6)(ii). 15
There is yet another reason such a change does not qualify as anything 16
less than major. Combivent is a sterile liquid drug product, and the FDA 17
specifically declined to include changes to sterile drug products in 18

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§ 314.70(c)(6)(ii)’s exemption from prior approval. See Supplements and 1
Other Changes to an Approved Application, 69 Fed. Reg. at 18,745. The risk 2
associated with a change in the size or shape of a sterile drug container, the 3
agency explained, is categorically “higher than for nonsterile products.” Id. 4
Because even a “minimal” modification “may affect the sterility assurance” of 5
a sterile drug product, such a modification constitutes a “major change.” Id. 6
By contrast, “changes in the labeled amount of a nonsterile drug product in a 7
unit-of-use container” have only “moderate potential to adversely affect the 8
safety and efficacy of the drug product,” and are appropriately classified as 9
“moderate change[s]” under § 314.70(c). Id. at 18,746 (emphasis added). 10
Because the modifications that the plaintiffs’ claims would require 11
under state law constitute “major” changes, we conclude that those claims are 12
preempted by federal law. The complaint failed to plausibly state any non- 13
preempted claim and was properly dismissed. 14
CONCLUSION 15
We have considered the plaintiffs’ remaining arguments and conclude 16
that they are without merit. For the foregoing reasons, the judgment of the 17
District Court is AFFIRMED. 18

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