Comparative post-approval regulatory requirements for specification changes and

Container closure system in the USA and EU, below is a table showing the type of
change and how it's classified in both regulatory regions:

Sr.
Changes
No. USA EU
1 Relaxing an acceptance criterion PAS Type II
2 Deleting any part of a specification
PAS Type II
3 Change outside the approved specification limits range
PAS Type II
4 Tightening of acceptance criteria Annual Report Type IA
5 Addition of new test and limits CBE-30 Type IA
Addition or replacement of a specification parameter as a
6
result of a safety or quality issue
CBE-30 Type IB
7 Deletion of a non-significant specification parameter
CBE-30 Type IA

A change in an analytical procedure that does not provide the

8 same or increased assurance of the identity, strength, quality, CBE-30 Type IB
purity, or potency

Container closure system

Sr.
Changes USA EU
No.
For liquid and semisolid dosage forms, a change to or in
1 PAS Type IB
polymeric materials of primary packaging components

For liquid and semisolid dosage forms in permeable or

semipermeable container closure systems, a change from an
ink and/or adhesive used on the permeable or semipermeable
2 packaging component to an ink or adhesive that has never PAS Type IB
been used in an approved drug product of the same dosage
form and same route of administration and with the same
type of permeable or semipermeable packaging component

A change in the primary packaging components for any drug

3 product when the primary packaging components control the PAS Type II
dose delivered to the patient

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 Sr.
Changes USA EU
No.
For sterile drug products, any change that may affect drug
product sterility assurance (e.g., change from a glass ampule
4 PAS Type II
to a glass vial with an elastomeric closure, change to a
flexible container system, etc.)

Deletion of a secondary packaging component intended to

provide additional protection to the drug product or a change
5 in the composition of, or the addition of, a secondary PAS Type II
packaging component that may affect the impurity profile of
the drug product
A change to a new container closure system if the new
container closure system does not provide the same or better
6 PAS Type II
protective properties than the approved container closure
system
A change in a container closure system that does not affect
7 CBE-30 Type IB
the quality of the drug product
Changes in the size or shape of a container for a sterile drug
8 CBE-30 Type IB
substance
Type IAIN
A change in the number of units (e.g., tablets, capsules) or
(within range),
9 labeled amount (e.g., grams, milliliters) of a nonsterile drug CBE-30
Type IB (outside
product in a unit-of-use container
the range)
A change in the size and/or shape of a container for a
10 nonsterile drug product, without a change from one container CBE-0 Type IA
closure system to another

A change in the labeled amount (e.g., grams, milliliters) of

11 drug product for a nonsterile drug product in a multiple-unit CBE-0 Type IB
container, except for solid dosage forms

12 A change in or addition or deletion of a desiccant CBE-0 Type IA

A change in the container closure system for a nonsterile
13 Annual Report Type IA
drug product
A change in the size and/or shape of a container for a
14 Annual Report Type IA
nonsterile solid dosage form
Type IAIN
A change in the number of units (e.g., tablets, capsules) or
(within range),
15 labeled amount (e.g., grams) of nonsterile solid dosage form Annual Report
Type IB (outside
in a multiple-unit container
range)
Changes in the container closure system of drug products as
long as the new package provides the same or better
16 protective properties (e.g., adding or changing a child- Annual Report Type IA
resistant closure, changes in packaging materials used to
control odor, etc.)

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 Sr.
Changes USA EU
No.
Type IAIN (if
A change in the flip seal cap colour as long as the cap colour affects product
17 is consistent with any established colour coding system for Annual Report info.), Type IA
that class of drug products (if not affect
product info.)

Key:

• PAS (Prior Approval Supplement) in the USA requires the submission of additional
information to the FDA for approval before making any changes that might affect the
product's identity, strength, quality, purity, or potency as these characteristics may relate to
the safety or effectiveness of the drug product.

• CBE-30 (Changes Being Effected in 30 Days) in the USA allows for the implementation of
certain changes before the FDA's approval, but the agency must be notified within 30 days.

• CBE-0: Changes Being Effected in 0 Days (FDA)

• Annual Report in the USA is a notification method where certain changes are made to the
product and reported to the FDA as part of the annual reporting process.

• Type IA, Type IB, Type II in the EU represent different levels of variation applications
according to the European Medicines Agency (EMA), with Type IA being minor changes not
likely to have a significant impact on the quality, safety, or efficacy of the drug. Type IB are
changes that require more regulatory scrutiny than Type IA, but less than Type II, which
represents significant changes likely to have a major impact on the product's quality, safety,
or efficacy.

Guidance Links:

For detailed guidance on these regulatory requirements, the following resources are useful:

• FDA Guidance for Industry: GFI #216 - Chemistry, Manufacturing, and Controls (CMC)
Information — Fermentation-Derived Intermediates, Drug Substances, and Related Drug
Products for Veterinary Medicinal Use (fda.gov)

Immediate-release solid oral dosing forms Scale and post-approval changes: chemical,
manufacturing and controls, in vitro dissolution testing, and in vivo bioequivalence
documentation. | FDA

• EMA Variation Guidelines: Guideline on the details of the various categories of variations

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These links provide comprehensive insights into the regulatory frameworks for post-approval
changes in the USA and EU, respectively.

Type of Submission and Relevant CFR Sections

1. Annual Report
• 21 CFR 314.70(d): Pertains to postmarketing reporting of minor changes in human
drug products.
• 21 CFR 314.81(b)(2): Details requirements for periodic reporting on the safety,
efficacy, and labeling of drugs.
2. CBE-0 (Changes Being Effected - 0 days)
• 21 CFR 314.70(c)(6): Covers changes to an approved application without prior
approval of the FDA for certain specified changes.
• 21 CFR 601.12(c)(5): Relates to biological products and specifies the conditions
under which certain changes can be made with immediate implementation.
3. CBE-30 (Changes Being Effected in 30 days)
• 21 CFR 314.70(c): Addresses changes to an approved application that require FDA
notification at least 30 days prior to distribution of the product.
• 21 CFR 601.12(c): Similar to the above but specific to biological products, requiring
notification to the FDA 30 days in advance.
4. PAS (Prior Approval Supplement)
• 21 CFR 314.70(b): Requires submission and approval of a supplement to an
approved application before making a change affecting the strength, quality, purity,
or potency of a drug.
• 21 CFR 601.12(b): The counterpart for biological products, requiring prior approval
for changes that might affect the safety, purity, or potency.

Direct Links to the CFR

Go to eCFR (Electronic Code of Federal Regulations) or GPO’s govinfo.

Use their search feature to look up the specific CFR sections (e.g., "21 CFR 314.70(d)").

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