Testing of High-Risk Drug

Components for Diethylene

Glycol and Ethylene Glycol
CAPT Matthew R. Dionne
Compliance Officer, Div II GCB6
Office of Manufacturing Quality
Center for Drug Evaluation and Research
Office of Compliance

November 1, 2023
Pharmaceutical Quality Symposium: Quality, Supply Chain & Advanced
Manufacturing 2023
 CDER Office of Manufacturing Quality
• We evaluate compliance with Current Good
Manufacturing Practice (CGMP) for drugs based
on inspection reports and evidence gathered by
FDA investigators.
• We develop and
implement
compliance policy
and take regulatory
actions to protect
the public from
adulterated drugs in Source: FDA

the U.S. market.

www.fda.gov 2
Enforcement and Advisory Tools
FY2023 Regulatory Actions
Untitled Consent
Regulatory Injunctions
Letter, 3 Decree, 1

Meetings

Consent Import Regulatory

Discretions,
Warning
Letters, 94
Decrees Alerts 91

Warning
Seizures Import Alert Regulatory
Letters Cases, 91 Meetings, 69
55-05: 1
66-40: 40
66-78: 1
Untitled Administrative
66-79: 49

Letters Detention

Excludes compounding-related actions

*Actions Taken October 1, 2022 to September 30, 2023

3
 Shift in Basis of Action for
non-compounding CGMP Warning Letters FY18-23

4
Data as of 9/30/2023
How FDA Looks at
Excipients

5
 What is an Excipient?
• In FDA nomenclature, an excipient
is also known as an “inactive
ingredient”
– 21 CFR 210.3(a)(8):
“Inactive ingredient means any component
other than an active ingredient.”

• But more importantly, FDA

considers both active ingredients
and excipients/inactive ingredients
to be drug “components”:
– 21 CFR 210.3 (a)(3):
“Component means any ingredient intended
for use in the manufacture of a drug product,
including those that may not appear in such drug
product.”

www.fda.gov 6
 Drug Components are Also Drugs
• Under the FD&C Act, a drug is defined per Sec 201 (USC 321)

– “(g)(1) The term "drug" means (A) articles recognized in the official
United States Pharmacopoeia,….; and (B) articles intended for use in the
diagnosis, cure, mitigation, treatment, or prevention of disease in man or
other animals; and (C) articles (other than food) intended to affect the
structure or any function of the body of man or other animals; and (D)
articles intended for use as a component of any article specified in
clause (A), (B), or (C).”

• Long story short: excipients (or inactive ingredients) are themselves

considered drugs when they are intended for use, or used as, a
component of a drug product.

• And all the drug adulteration provisions of the Act apply to them as
well.

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 Who in the Supply Chain Does FDA
Inspect?
• Drug manufacturers are subject to inspection (section 704 of the
FD&C Act)
• FDA conducts several types of inspections to help provide access to
needed medical products and to protect consumers and patients
from unsafe products, such as routine CGMP surveillance inspections
and for-cause inspections
• FDA implemented a risk-based approach to prioritizing human drug
manufacturing facilities for routine CGMP surveillance inspections
– FDA’s site selection model prioritizes certain types of manufacturers, such
as finished dosage form (FDF) manufacturers and active pharmaceutical
ingredient (API) manufacturers
• Some types of manufacturers are not prioritized for routine CGMP
surveillance inspections such as excipient manufacturers
– These drug manufacturers may be inspected for-cause

www.fda.gov 8
Diethylene
Glycol/Ethylene Glycol
(DEG/EG)

9
 Background on DEG/EG
• Diethylene glycol (DEG) is an industrial
chemical, used as an antifreeze, and is
poisonous.
• In 1937 a DEG poisoning outbreak
occurred when DEG was used as a
solvent in Sulfanilamide:
• Led to 107 deaths, many of them
children
• This led to the enactment of the
FD&C Act in 1938
www.fda.gov 10
 Background on DEG/EG
• Unscrupulous manufacturers/suppliers have
used DEG/EG in excipients, or as an excipient,
in lieu of costlier ingredients (for economic
gain).
• Typically in the excipient
distribution/repacking supply chain
• Lack of CGMP controls at finished dosage form
sites allowed for the contamination to enter
drug products.

www.fda.gov 11
 Background on DEG/EG

• Periodic DEG/EG events have occurred:

• DEG substitution for glycerin in Central
America in the late 2000s,
• FDA took actions against Chinese
toothpastes containing DEG in 2007
• History repeats itself:
• 2022/2023 outbreaks in children's drug
products overseas

www.fda.gov 12
 Recent DEG/EG Outbreaks Overseas

www.fda.gov 13
 FDA’s Role
• Following the 2022/2023 reports of overseas deaths,
FDA extensively interacted with WHO, other regulators,
and industry.

• Unlike the 2006 incidents resulting from DEG/EG

substitution in glycerin, the 2022/23 incidents appear
related to substitution of DEG/EG in propylene glycol.

• While FDA has ramped up monitoring, FDA has not seen

data indicating the contamination has affected the US
drug supply.

www.fda.gov 14
 DEG/EG Guidance Published
In 2023, FDA published a final guidance (replacing a 2007 guidance) that provides updated
recommendations on testing and other activities that will help pharmaceutical manufacturers,
repackers, other suppliers, and compounders prevent the use of high-risk components that are
contaminated with DEG and EG.

www.fda.gov 15
 CGMP Identity Requirements
• 211.84 Testing and approval or rejection of components,
drug product containers, and closures.

– “(a) Each lot of components, drug product containers, and

closures shall be withheld from use until the lot has been
sampled, tested, or examined, as appropriate, and released for
use by the quality control unit.

– (b) Representative samples of each shipment of each lot shall be

collected for testing or examination….

– (d) Samples shall be examined and tested as follows:

• (1) At least one test shall be conducted to verify the identity of
each component of a drug product. Specific identity tests, if
they exist, shall be used.”

www.fda.gov 16
 CGMP Identity Requirements
• Question: Can a drug product manufacturer rely on a supplier Certificate
of Analysis (COA) and not conduct raw material testing?

• Answer: Potentially for some attributes, but never for identity.

• 211.84 Testing and approval or rejection of components, drug product containers,

and closures.
– “(d) Samples shall be examined and tested as follows:
– (1) At least one test shall be conducted to verify the identity of each
component of a drug product. Specific identity tests, if they exist, shall be
used.
– (2) Each component shall be tested for conformity with all appropriate
written specifications for purity, strength, and quality. In lieu of such testing
by the manufacturer, a report of analysis may be accepted from the supplier
of a component, provided that at least one specific identity test is conducted
on such component by the manufacturer, and provided that the
manufacturer establishes the reliability of the supplier's analyses through
appropriate validation of the supplier's test results at appropriate intervals.”

www.fda.gov 17
 CGMP Identity Requirements
• 211.84 states “Specific identity tests, if they exist, shall be used”

• If a USP monograph includes testing for DEG/EG in the identity section, it is required of
the drug product manufacturer under CGMP.

• This includes DEG/EG identity testing in the following excipients:

– Glycerin,
– Propylene Glycol,
– Maltitol Solution,
– Hydrogenated Starch Hydrolysate,
– Sorbitol Solution,
– and other High-Risk Drug Components

• Also, other drugs with history of similar contaminant specific identity testing
requirements:
– Over-sulfated Chondroitin Sulfate (OSCS) in Heparin:
• https://www.fda.gov/media/82924/download
– Methanol in Alcohol:
• https://www.fda.gov/media/145262/download

www.fda.gov 18
Recent DEG/EG
Compliance Actions

19
Heightened Supply Chain Monitoring
• As FDA evaluated the recent outbreaks, we
are closely scrutinizing multiple liquid
formulations of FDA-regulated drug products
• FDA sent a reminder of CGMP requirements
to registered manufacturers using high risk
components.
• FDA reviewed the drug manufacturing
inventory, and sent 704(a)(4) Records
Requests to:
– Drug product manufacturers in
geographies of concern,
– Who use excipients of concern,
– Asking for information on their CGMP
controls for DEG/EG
• FDA has also sent records requests and been
in contact with excipient manufacturers and
distributors of note.
• And FDA has increased sampling, inspections,
and other activities in this space.
www.fda.gov 20
 Resulting Compliance Actions

www.fda.gov 21
Increased Number of DEG/EG-Related
Import Alerts Issued

22
FY23 Data: 10/1/22-9/30/23
Increasing Reference to DEG/EG Testing in
CGMP Warning Letters FY21-23

Non-Compounding CGMP Warning Letters

Does Not Reference DEG/EG testing
References DEG/EG Testing

23
Warning Letters Issued 10/1/2020 to 9/30/2023
 Case Examples: Lack of Controls for
Components at Risk of DEG/EG Contamination
Excerpts from Warning Letters:

“you did not demonstrate that you adequately tested each shipment of each lot of incoming
components at high-risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. These
include, but are not limited to, testing of glycerin, propylene glycol, and sorbitol solution you
used in manufacturing drug products to determine their appropriate identity…”
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/lcc-ltd-657336-08032023

“in response to our record request, you tested retain samples of some finished product batches
that had been shipped to or distributed in the United States for the presence of DEG and EG
impurities using the 2018 Indian Pharmacopeia (IP) monograph for glycerin. However, you did not
demonstrate that the 2018 IP method used for glycerin testing is suitable to identify the levels of
DEG or EG in the finished drug product. Furthermore, you did not test every lot of drug product
shipped to or distributed nor provide any evidence that would substantiate the results of the
analytical testing (e.g., quantitative worksheets and chromatograms for impurities for each batch
that was tested)….”
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/champaklal-maganlal-homeo-pharmacy-private-
limited-652319-04102023

In each case FDA placed all drugs and drug products manufactured by the firms on Import Alert
66-40.

www.fda.gov 24
 In Summary
• OMQ works to minimize consumer exposure
to unsafe, ineffective, and poor-quality
drugs.
• Excipients are drugs, and we have seen
recent quality issues with certain excipients.
• We take actions to protect the public from
adulterated drugs in the US market.

www.fda.gov 25