CRED Getting the CMC Dossier Right 2024

28/08/2024

3.2.P.5 Control of Drug Product

Specification

● Should contain all test relevant for the respective pharmaceutical form – refer to Ph. Eur. 07 Dosage forms

● General requirement – ICH guideline Q6A Specification ● Should be “self - explanatory“ ● Release / shelf-life / in-use shelf-life specification ● Include references to in-house/compendial test methods ● Limits should be justified

● In line with other parts of the dossier and SmPC (e.g. appearance, pH) ● If the product is diluted/reconstituted before administration: in-use spec

Alejandro Montón Silva

The Organisation for Professionals in Regulatory Affairs

27

3.2.P.5 Control of Drug Product

Powder for solution for infusion → Ph.Eur. 0520 Parenteral preparations

In-use specification

Test

P.1 & SmPC-paragraph 3

Acceptance criteria

Analytical method /Ref.

Release

Shelf life

Appearance

White to off-white lyophilized powder

Visual examination

2 different (chromatographic) techniques ICH (Q6A)

Identification of DS by UV 1

Complies with the reference substance spectrum

In-house

Complies with the reference substance chromatogram (Rt)

by HPLC

In-house

Justified with data (release and stability)

Water content (KF)

NMT 2.0%

NMT 3.5%

In-house

Uniformity of dosage units, by mass variation Uniformity of content of single-dose preparations 1

AV ≤ L 1 (L 1 =15.0)

-

Ph.Eur. 2.9.40

Genotoxic impurities? → ICH M7 Solvents? → ICH Q3C

Average content 85%-115% and individual content 85-115% (10 units) or Average content 85%-115% and not more than one individual content 75-125% (30 units)

Ph.Eur. No. 0520

Ph.Eur. 2.9.6; In-house

Assay of DS (HPLC) % of labelled amount Degradation impurities (HPLC)

Justified with data (in this case only stability) EDQM Technical Guide for the elaboration of monographs on medicinal products containing chemically defined active substances

95. 0 -105. 0 %

90. 0 -105. 0 %

In-house

Impurity A Impurity B

NMT 0.3% NMT 0.2% NMT 0.2% NMT 0.2% NMT 0.3% NMT 2.0%

NMT 1.5% NMT 1.0% NMT 1.0% NMT 0.5% NMT 0.5% NMT 3.5%

maximum daily dose: 2.7 mg

Impurity RRT=0.15 Impurity RRT=0.45 Any unspecified impurity Total impurities

In-house

ICH Q3B

Reporting 0.1% - Identification 0.5% - Qualification 1.0%.

Justified with data (release and stability)

Bacterial endotoxins

Ph.Eur. 2.6.14, chromogenic method D Ph.Eur. 2.6.1, membrane filtration method

NMT 1.59 EU/mg

Ph.Eur. 5.1.10 → K/M

Sterility

Sterile

1 Test only performed at release

Ph.Eur. 5.1.4; for non-sterile DP TAMC/TYMC/specified m.o.

Alejandro Montón Silva

The Organisation for Professionals in Regulatory Affairs

28