What is a drug master file? DMF, ASMF and CEP for a peptide API, with the CTD Module 3 sections

A peptide API manufacturer rarely hands its synthesis route, purification conditions and process validation to customers. Regulators still need to see them. The drug master file solves that problem in the US, the active substance master file does it in the EU, and the Certificate of Suitability offers a third route where a pharmacopoeial monograph exists. This guide explains what each is, what a peptide API’s CTD Module 3 drug substance section contains, how letters of authorisation and GDUFA completeness assessments work, and what a buyer should ask for.

What does DMF stand for?

DMF stands for drug master file. Under 21 CFR 314.420, “a drug master file is a submission of information to the Food and Drug Administration by a person (the drug master file holder)” who intends it either to be incorporated by reference in their own applications, or “to permit the holder to authorize other persons to rely on the information to support a submission to FDA without the holder having to disclose the information to the person” [1].

Four points define how DMFs work:

• Not required. DMFs “are not required by statute or regulation” [2]. An applicant can include API information in its own application instead.
• Not approved. DMFs “are neither approved nor disapproved” [2]. “FDA ordinarily neither independently reviews drug master files nor approves or disapproves submissions to a drug master file” [1].
• Reviewed in context. FDA “customarily reviews the information only in the context of an application” [1].
• Confidential. FDA’s draft guidance describes DMFs as submissions “that may be used to provide confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of human drug products” [3].

So “we have a DMF” means a file exists and has a number. It does not mean FDA has accepted the content. What matters is whether the DMF has been reviewed in support of an application, and for generics whether it has passed the GDUFA completeness assessment (see below).

What are the types of DMF?

Type	Subject	Peptide API relevance	Ref
Type I	Discontinued	Discontinued in 2000; the numbering of the other types did not change	[3]
Type II	Drug substance, drug substance intermediate and materials used in their preparation, or drug product	The DMF type for a peptide API	[1], [4]
Type III	Packaging material	API container closure, if the supplier keeps it proprietary	[4]
Type IV	Excipient, colorant, flavour, essence or material used in their preparation	Not for the API itself	[4]
Type V	FDA-accepted reference information	Uncommon for APIs	[1], [4]

21 CFR 314.420(a) lists the subjects for Types II to V; paragraph (1) is “[Reserved]” [1].

What goes into a Type II DMF for a peptide API?

FDA’s draft guidance (November 2019) sets out the expectations [3]:

• One API, one process. A Type II DMF “should be limited to a single drug substance”, and “separate DMFs should be submitted for drug substances manufactured using different processes” [3]. For a peptide, an SPPS route and a hybrid SPPS/solution route would normally be separate DMFs.
• A CGMP statement. DMFs for drug substances “should state that the material covered by the DMF is manufactured under current good manufacturing practices (eCTD sections 3.2.S.2 or 3.2.P.3)” [3].
• Starting materials per ICH Q7 and Q11. “The definition and criteria for designating starting materials and intermediates are discussed in” ICH Q7 and Q11 and their Q&As [3], [5], [6].
• Ongoing stability. Drug substance manufacturers “should collect stability data according to their stability protocol and should continue to submit data from ongoing studies” [3].
• Electronic format. DMF submissions “must be submitted in the electronic format specified” in FDA’s eCTD guidance; “the standard electronic format for DMFs is electronic common technical document (eCTD) format”, and an original DMF in eCTD needs a pre-assigned number [3].
• An agent for foreign holders. “FDA strongly encourages foreign DMF holders to appoint an agent”, but “DMF holders, not their agents, are responsible for the contents of their DMFs” [3].

The technical content sits in Module 3, with a Module 2 summary of it [3].

CTD Module 3 section 3.2.S for a peptide API

The drug substance section of the CTD quality module is defined in ICH M4Q(R1) [7]. EMA’s peptide guideline follows the same numbering and adds peptide-specific expectations [8]. For an EU ASMF, the guideline on the ASMF procedure assigns each section to the Applicant’s Part (AP) or the Restricted Part (RP) [9].

Section	M4Q content	Peptide-specific expectations	ASMF part
3.2.S.1.1 Nomenclature	INN, compendial name, chemical names, codes, CAS number [7]		AP [9]
3.2.S.1.2 Structure	Structural formula, molecular formula, relative molecular mass; for biotech, amino acid sequence [7]	Three-letter codes acceptable for the primary structure, with a legend for unnatural residues and termini shown; D-residues need a formula with stereocentres [8]	AP
3.2.S.1.3 General properties	Physicochemical and other relevant properties [7]	Water content, isoelectric point, solution pH, optical rotation, solubility across the physiological pH range, hygroscopicity [8]	AP
3.2.S.2.1 Manufacturer(s)	Name, address and responsibility of each site, including contractors [7]		AP
3.2.S.2.2 Process and process controls	Flow diagram and sequential narrative; reprocessing justified [7]	Repeated SPPS cycles described once with conditions; full detail of cleavage; pooling and repurification criteria; batch size range [8]	Flow chart and short description in AP; detail in RP [9]
3.2.S.2.3 Control of materials	Raw materials, starting materials, solvents, reagents, with quality and controls [7]	Justified starting materials; protected amino acid specifications; names and addresses of starting material manufacturers [8]	RP
3.2.S.2.4 Critical steps and intermediates	Tests and acceptance criteria at critical steps; intermediate quality [7]	Fmoc deprotection, coupling and capping monitoring, cleavage, drying; crude peptide specification [8]	AP where relevant to the applicant; otherwise RP [9]
3.2.S.2.5 Process validation	Validation and/or evaluation studies [7]	No additional peptide requirement [8]	RP
3.2.S.2.6 Process development	Development history [7]	Prior knowledge allowed for general aspects; substance-specific parameters expected [8]	RP
3.2.S.3.1 Structure elucidation	Evidence of structure [7]	MS with fragmentation, amino acid analysis, NMR; higher order structure where relevant [8]	AP
3.2.S.3.2 Impurities	Impurity information [7]	Peptide-related impurities from starting materials, process and degradation; aggregates [8]	AP; process-related detail may be RP if justified [9]
3.2.S.4.1–4.4 Specification, methods, validation, batch analyses	[7]	Purity, named HMW impurities, assay, counter-ion, residual TFA, water, solvents, endotoxins; Ph. Eur. thresholds 0.1/0.5/1.0% [8]	AP
3.2.S.4.5 Justification of specification	[7]	Limits based on batch data, not only the qualified limit [8]	AP; process detail in RP [9]
3.2.S.5 Reference standards	[7]	Qualification approach that prevents drift in assigned peptide content [8]	AP
3.2.S.6 Container closure	[7]	Desiccant or inert atmosphere may be considered for hygroscopic powders [8]	AP
3.2.S.7 Stability	Summary, post-approval protocol and commitment, data [7]	Water content in stability protocols for hygroscopic powders [8]	AP

The ASMF table shows a useful principle: the customer sees enough to take responsibility for the specification, and the regulator alone sees how the peptide is made.

What is a letter of authorisation?

“FDA will not review a DMF until the DMF holder submits a letter of authorization (LOA) to the DMF regarding a specific application or other DMF” [3]. The LOA “permits FDA to review the DMF and permits the authorized party… to incorporate information into an application or another DMF by reference” [3]. Points that are often missed:

• An LOA should be submitted “even if the authorized party and the DMF holder are the same company” [3].
• The holder sends a copy to the authorised party, which “must include a copy of the LOA in its application (§ 314.50(a)(1))” [3]; the NDA form must identify the drug master files referenced [10].
• “An LOA does not give an authorized party permission to view or access a DMF” [3].
• “An LOA should not have multiple authorized parties”; a separate LOA is needed for each party [3].
• Under the regulation, the DMF must contain “a complete list of each person currently authorized to incorporate by reference any information in the file” [1], and the holder must notify each authorised person in writing of any addition, change or deletion [1].

The EU equivalent is a letter of access, by which the ASMF holder gives “permission to the National Competent Authorities/EMA to assess the data in the ASMF in relation to a specific MAA/MAV” [9].

What is a GDUFA completeness assessment?

For generics, the Generic Drug User Fee Amendments add a gate. Since 1 October 2012, “DMF holders are required to pay a DMF fee when first authorizing the reference of their DMF in a generic application” and “Type II API DMFs must undergo an FDA completeness assessment (CA)” [11]. The fee is one-time, and only Type II API DMFs used in generic drug submissions incur it; the guidance does not apply to DMFs used only for NDAs, BLAs or other non-generic submissions [11].

In the CA, FDA asks whether the DMF is active, whether the fee has been paid, whether it has been previously reviewed, whether it pertains to a single API, whether it contains the required administrative information and “all the information necessary to enable a scientific review”, and whether it is in English [11]. “The CA does not replace the full scientific review” [11].

Step	What happens	Ref
Timing	FDA “strongly encourages” a complete DMF and fee payment “at least 6 months prior to the submission of an ANDA”	[11]
Review time	Under the GDUFA II commitment letter, FDA committed to complete the initial CA for 90% of Type II API DMFs within 60 days of the later of submission or fee payment	[11]
Prior review	A DMF reviewed for CMC after 30 November 2007 passes the CA without further analysis	[11]
One API, one process	A DMF covering more than one API or process “will be deemed incomplete”	[11]
Unpaid fee	If not paid within 20 days of notification, FDA will refuse to receive the ANDA	[11]
Complete	DMF number posted on FDA’s public list of DMFs available for reference	[11]
Incomplete	GDUFA DMF Incomplete Letter; the holder amends and FDA reassesses	[11]

For complex APIs, “DMF holders should ensure the DMF provides the data necessary for the Agency to review the DMF with respect to active ingredient sameness”, as described in the product-specific guidance [11]. For peptides this is now substantial: FDA’s revised semaglutide PSG recommends comparative characterisation of higher order structure, biological activity where appropriate, and active-ingredient-related impurities against the reference product [12].

FDA’s public list of DMFs is updated quarterly; the 3rd quarter 2026 file covers DMFs received by 30 September 2026 and shows each DMF’s activity status (A, active; I, inactive) [13].

Annual reports, amendments and closure

Changes are reported as amendments; “annual reports should not be used to report changes in the DMF” [3]. The annual report should include a signed statement of commitment that the DMF is current, the dates of amendments since the last report, the list of authorised parties and any withdrawn authorisations [3]. DMFs may be closed at the holder’s request or “because FDA cannot be assured that the DMF is current”; if the holder does not respond with an annual report, “FDA could close the DMF” [3]. For a peptide buyer, an inactive or closed DMF is a red flag, because a GDUFA CA treats a primary DMF as incomplete if it, or any subject DMF it references, is inactive [11].

What is an ASMF in the EU?

The EU active substance master file is governed by the Guideline on Active Substance Master File Procedure (CHMP/QWP/227/02 Rev 4/Corr), in effect from 17 June 2019 [9], [14]. Its legal basis is Annex I to Directive 2001/83/EC, Part I, section 3.2(8) [9].

• Format. ASMFs for human medicines “should be presented in the format of the Common Technical Document (CTD)” [9].
• Two parts. The scientific information “should be physically divided into two separate parts, namely the Applicant’s Part (AP) and the Restricted Part (RP)”; the AP “is still a confidential document” that cannot be passed to third parties without the holder’s consent [9].
• Responsibility. The AP “should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specification” [9].
• Scope. The procedure applies to new active substances and existing ones with or without a pharmacopoeial monograph, but “cannot be used for biological active substances” [9]. Synthetic peptides are in scope; EMA’s peptide guideline excludes recombinant peptides from its own scope [8].
• Changes. ASMF holders “shall not modify the contents of their ASMF… without informing each Applicant/MA holder and each National Competent Authority/EMA”, and each MA holder reports the change by variation [9].
• ASMF and CEP together. Referring to both an ASMF and a CEP for one active substance in one application is “generally… not acceptable”, except where the CEP contains too little information [9].

What is a CEP?

A Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) is issued by EDQM. According to Resolution AP-CSP (07) 1, the procedure “is intended for substances for which a monograph, either general or specific, has been adopted by the European Pharmacopoeia Commission”, and “does not apply for direct gene products (i.e. proteins), products obtained from human tissues, vaccines and blood products” [15].

For peptides the first question is therefore whether a Ph. Eur. monograph exists. A search of the EDQM certification database for semaglutide returned “No record found” on 26 October 2026, meaning no semaglutide CEP was listed [16]. Without a CEP, a semaglutide API manufacturer supplying the EU with a confidential process uses the ASMF route [9].

DMF vs ASMF vs CEP

	US DMF (Type II)	EU ASMF	CEP
Authority	FDA	National competent authorities or EMA	EDQM
Legal basis	21 CFR 314.420 [1]	Annex I to Directive 2001/83/EC [9]	Resolution AP-CSP (07) 1 [15]
Requires a monograph	No	No	Yes [15]
Format	eCTD [3]	CTD, split into AP and RP [9]	Application to EDQM against the monograph
Customer access	None; LOA only [3]	Applicant’s Part only [9]	The certificate
Authorisation letter	Letter of authorisation [3]	Letter of access [9]	Not applicable
Assessed when	With each referencing application; GDUFA CA for generics [1], [11]	With each MAA or variation [9]	By EDQM, against the monograph [15]
Approval status	Neither approved nor disapproved [2]	Assessed as part of the MA [9]	Certificate granted by EDQM

What a peptide API buyer should ask for

1. The DMF number, type and status, and whether it has passed the GDUFA completeness assessment if you are filing an ANDA [11], [13].
2. A letter of authorisation naming your company and application, filed to the DMF [3].
3. The open part: for an ASMF, the current Applicant’s Part and its summary; for a DMF, the information the holder shares directly, typically the specification, methods and batch data [9].
4. Confirmation of one API and one process per DMF, and which process your batches come from [3].
5. Starting material justification consistent with ICH Q11 and EMA’s peptide guideline [8], [6].
6. Sameness and impurity data where your product is a generic of a peptide reference product [12].
7. A change notification commitment, since DMF and ASMF holders must notify authorised customers of changes [1], [9].

Our supplier qualification checklist covers the audit and quality agreement side.

How Winhycare Pharma supports semaglutide filings

Winhycare Pharma supplies semaglutide API to licensed pharmaceutical manufacturers. For semaglutide we support US-DMF Type II dossiers and CTD Module 3 CMC documentation for customers’ own filings. Tirzepatide, retatrutide, cagrilintide and BPC-157 are also supplied as APIs; ask us about the documentation available for each through peptide APIs. Our research peptides are a separate, research-use-only range at purity of ≥99% as stated in our product brochure, and custom peptide synthesis is available. Enquire about semaglutide API or request research peptides.

For laboratory research use only. Not for human or veterinary use.