What is ICH Q11? Starting materials, control strategy and Q6A/Q6B specifications for peptide drug substances

ICH Q11 is where a peptide API’s regulatory story starts. It decides where the manufacturing process begins in the eyes of a regulator, which materials have to be justified and controlled, and how the control strategy is argued in CTD Module 3. ICH Q6A and Q6B then govern the specification, but neither was written with modern synthetic peptides in mind. This guide explains what ICH Q11 requires, how its starting material principles apply to solid phase peptide synthesis, how a peptide control strategy is built, where Q6A and Q6B fit, and how FDA’s 2021 synthetic peptide guidance and EMA’s 2025 peptide guideline change the picture.

What is ICH Q11?

ICH Q11, “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)”, was released for consultation on 19 May 2011 and adopted at Step 4 on 1 May 2012 [1]. It “is applicable to drug substances as defined in the Scope sections of ICH Guidelines Q6A and Q6B” and “is particularly relevant to the preparation and organisation of the contents of Sections 3.2.S.2.2 – 3.2.S.2.6 of Module 3 of the Common Technical Document” [1]. It “does not apply to contents of submissions during the clinical research stages of drug development”, although its development principles “are important to consider during the investigational stages” [1].

ICH Q11 allows a “traditional” or an “enhanced” approach to development, or a combination: “traditional and enhanced approaches are not mutually exclusive” [1]. At a minimum, process development should identify potential critical quality attributes (CQAs), define an appropriate manufacturing process and define a control strategy [1]. A CQA is “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality”, and “impurities are an important class of potential drug substance CQAs” [1].

How ICH Q11 is organised

Section	Topic	CTD location	Peptide relevance
3	Manufacturing process development	3.2.S.2.6	Prior knowledge on resins and coupling reagents may be referenced; substance-specific parameters must be shown [2]
4	Description of manufacturing process and process controls	3.2.S.2.2	Repeated SPPS cycles can be described once, with clear conditions [2]
5	Selection of starting materials and source materials	3.2.S.2.3	Protected amino acids, preloaded resin, fragments [2]
6	Control strategy	Summary in 3.2.S.4.5; detail in 3.2.S.2.2–3.2.S.2.4 and 3.2.S.4.1 [1]	In-process controls, pooling criteria, intermediates
7	Process validation/evaluation	3.2.S.2.5	EMA adds no peptide-specific requirement [2]
8	Submission in CTD format	3.2.S
9	Lifecycle management	Post-approval	Changes go through internal change management; changes to filed and approved information are reported under regional regulations [1]
10–11	Illustrative examples; glossary

Sources: [1], [3].

How are starting materials selected for a synthetic peptide?

The ICH Q11 general principles

ICH Q11 section 5.1.1 lists the principles for deciding where the drug substance manufacturing process begins [1]:

• Changes near the beginning of a process have lower potential to affect drug substance quality, because impurities introduced early have more chances to be purged. ICH Q11 then adds: “However, in some cases (e.g., when peptides or oligonucleotides are synthesised on a solid support), there is a more limited relationship between risk and number of steps from the end of the manufacturing process” [1].
• Enough of the process should be described for regulators “to understand how impurities are formed in the process, how changes in the process could affect the formation, fate, and purge of impurities” [1].
• Steps that impact the impurity profile should normally be included in 3.2.S.2.2 [1].
• ICH Q7 GMP “apply to each branch beginning with the first use of a starting material” [1].
• A starting material “should be a substance of defined chemical properties and structure”; “non-isolated intermediates are usually not considered appropriate starting materials” [1].
• It is “incorporated as a significant structural fragment into the structure of the drug substance”, a phrase intended “to distinguish starting materials from reagents, solvents, or other raw materials” [1].

The justification should cover the ability of analytical procedures to detect starting material impurities, “the fate and purge of those impurities and their derivatives in subsequent processing steps”, and how the starting material specification contributes to the control strategy [1]. “An applicant generally need not justify the use of a commercially available chemical as a starting material” [1].

What the 2017 Q11 Q&A clarified

The ICH Q11 Q&A, approved on 23 August 2017, focuses on chemical entity drug substances and addresses only section 5 [4]. Key clarifications:

• All principles, not a selection. “Applicants should consider all of the ICH Q11 general principles… rather than choosing just a few of the general principles” [4].
• Q7 and Q11 mean the same material. A Q11 “starting material” and a Q7 “API starting material” are “intended to refer to the same material” [4].
• “Significant structural fragment” is not a licence to start late. The principle “has frequently been misinterpreted as meaning that the proposed starting material should be structurally similar to the drug substance”, and starting materials justified solely on that basis “probably will not be accepted” [4].
• Commercially available versus custom synthesised. A commercially available chemical is one sold “in a pre-existing, non-pharmaceutical market”; availability from multiple suppliers “should not be the sole basis” for that designation [4].
• Previously accepted starting materials generally need not be re-justified unless the process changes significantly, but “a starting material accepted for one manufacturer’s process may not be considered acceptable for a different manufacturer’s process” [4].

EMA’s position for synthetic peptides

EMA’s synthetic peptide guideline states that “the requirements of ICH Q11 and its associated Q&A in relation to the selection of starting materials are relevant to synthetic peptides” and then applies them [2].

Candidate starting material	EMA position (2025 guideline)
Protected natural L-amino acid derivatives	”Generally acceptable as starting materials”
Short fragments, e.g. glycine dipeptides, Dmb-glycine, pseudoproline dipeptides	May be acceptable “in justified cases”, e.g. to reduce diketopiperazine formation or aggregation
Polypeptide fragments that undergo only limited further steps under GMP (e.g. cyclisation, conjugation to PEG)	“Generally not acceptable as starting materials but are considered intermediates”
Longer fragments in fragment condensation processes	Possibly acceptable “in duly justified cases”; scientific advice recommended
Resin preloaded with the first amino acid	Considered a starting material
Unloaded solid support resin	Not a starting material
Non-peptide structural moieties (e.g. PEG chains with or without linkers)	Case by case; Q11 compliance expected and selection justified

Source: [2].

EMA also lists typical quality attributes for amino acid derivatives (appearance, identification, related impurities, other impurities and assay) and typical related impurities: “enantiomeric and diastereomeric impurities, (partially) unprotected amino acids, dipeptides and β-alanyl impurities” [2]. Because such impurities “can react like the parent compound during coupling”, they should be “adequately controlled and limited in the starting material specifications”, supported by a fate and purge assessment [2]. The names and addresses of all starting material manufacturers must be given, and adding a manufacturer needs a variation [2].

This explains why peptide starting materials are defined so early. In SPPS, an impurity in a protected amino acid can be incorporated into the growing chain, producing a closely related peptide impurity that the final purification may not resolve.

What is a control strategy for a peptide API?

ICH Q11 takes its definition from ICH Q10: “a planned set of controls, derived from current product and process understanding, that assures process performance and product quality” [1], [5]. It “can include” controls on material attributes, controls implicit in process design, in-process controls, and controls on the drug substance such as release testing [1]. In a traditional approach, “more emphasis is placed on assessment of CQAs at the stage of the drug substance (i.e., end-product testing)”; an enhanced approach allows “more meaningful and efficient parametric, attribute, and procedural controls” [1].

EMA describes what this looks like for SPPS [2]:

Control layer	SPPS example from EMA	Ref
Material attributes	Specifications for protected amino acids and preloaded resin covering enantiomers, dipeptides, β-alanyl impurities	[2]
Process design	Repeated cycles of deprotection, washing, coupling and capping; defined cleavage cocktail and scavengers	[2]
In-process controls at critical steps	”Fmoc deprotection, control of washing steps, coupling or capping reaction monitoring, control of cleavage steps and drying steps”; Kaiser, chloranil or TNBS tests for coupling completeness	[2]
Purification controls	A “defined and justified” pooling strategy with purity criteria for fractions and the main pool; stated conditions for repurifying side fractions	[2]
Intermediate controls	The crude peptide after cleavage is “typically considered to be an intermediate” with justified specifications; the resin-bound peptide is normally not tested	[2]
Drug substance specification	Identity, purity, aggregates, assay, counter-ion, residual TFA, water, solvents, elemental impurities, endotoxins	[2]

Criticality “should be evaluated during development according to the principles described in ICH Q9–Q11” [2]. Splitting and pooling of sub-batches must be justified, and the commercial batch size (range) unambiguously defined in 3.2.S.2.2 [2].

ICH Q6A and Q6B: which applies to peptides?

Neither specification guideline covers modern synthetic peptides fully.

Guideline	What it covers	What it says about peptides	Ref
ICH Q6A (1999)	Specifications for new drug substances and products, chemical substances	”May be applicable to… synthetic peptides of low molecular weight; however, it is not sufficient to adequately describe specifications of higher molecular weight peptides and polypeptides”	[6]
ICH Q6B (1999)	Proteins and polypeptides from recombinant or non-recombinant cell-culture expression systems	”Does not cover antibiotics, synthetic peptides and polypeptides”	[7]
ICH Q3A(R2) (2006)	Impurities in new drug substances	Peptides are among the drug substances “not covered in this guideline”	[8]
EMA synthetic peptide guideline (2025)	Synthetic peptides, existing or new	Synthetic peptides are “fully or partially excluded from the scope of ICH Q3A/B… ICH Q6A/B… and ICH M7”	[2]

The general principles of ICH Q6A still frame the work. A specification is “a list of tests, references to analytical procedures, and appropriate acceptance criteria”, and specifications “are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval” [6]. Q6A’s universal tests for a new drug substance are description, identification, assay and impurities, and it warns that “identification solely by a single chromatographic retention time… is not regarded as being specific”, while combinations such as HPLC/MS are generally acceptable [6]. For a salt, identification “should be specific for the individual ions” [6], which is relevant to peptide acetates.

ICH Q6B matters for recombinant peptides. It describes characterisation as “the determination of physicochemical properties, biological activity, immunochemical properties, purity and impurities” and defines product-related impurities as molecular variants “which do not have properties comparable to those of the desired product” [7]. It also states that “specifications are one part of a total control strategy” [7].

Specifications for a synthetic peptide API

For synthetic peptides, EMA sets the expectations Q6A does not. Peptide-related impurities “should be reported above 0.1%, identified above 0.5% and qualified above 1.0%”, per the Ph. Eur. general monograph Substances for Pharmaceutical Use [2]. Acceptance criteria “should not only be based on the qualified limit but on data obtained from the batches”, and grouping of separable impurities “is not recommended” [2]. Characterisation should confirm primary and, where relevant, higher order structure; mass spectrometry, amino acid analysis (Ph. Eur. 2.2.56) and NMR are named tools [2]. Analytical procedures should be described so that an Official Medicines Control Laboratory can repeat them [2]; their development now sits under ICH Q14, adopted on 1 November 2023 [9].

Our peptide API impurities guide sets out the full specification table and the EU and US impurity thresholds side by side.

The FDA 2021 synthetic peptide ANDA guidance and its withdrawal

In May 2021 FDA issued “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin” [10]. It applied to synthetic generics referencing five peptides of rDNA origin: “glucagon, liraglutide, nesiritide, teriparatide, and teduglutide” [10]. FDA stated that it “considers any alpha amino acid polymer composed of 40 or fewer amino acids to be a peptide, not a protein” [10].

Its core criteria were that an ANDA would generally be appropriate if the applicant could show that each common peptide-related impurity was at or below the reference level, that there was no new specified peptide-related impurity above 0.5% of the drug substance, and that each new specified impurity at or below 0.5% was characterised and justified [10]. Applicants should “identify each peptide-related impurity that is 0.10 percent of the drug substance or greater”, using “sensitive and high resolution analytical procedures (e.g., UHPLC-HRMS)”, and justify that impurity differences do not change physicochemical properties, biological activity or immunogenicity risk, including T-cell epitope and aggregation assessments [10].

On 28 July 2026 FDA withdrew the guidance because it “no longer reflects FDA’s current scientific thinking” and published 17 revised draft product-specific guidances (PSGs) for calcitonin salmon, dasiglucagon, glucagon, liraglutide, pegcetacoplan, semaglutide, teriparatide, tirzepatide and vosoritide products [11]. The Federal Register notice (91 FR 47834, 29 July 2026) records the withdrawal and says FDA “plans to revise and reissue the guidance this year” [12]. With the guidance withdrawn, its text can still be read in the public docket, FDA-2017-D-5767 [10].

The revised semaglutide PSG shows the new direction. It recommends comparative characterisation on at least three batches each of the proposed product and the reference product, covering higher order structure, biological activity where appropriate, and active-ingredient-related impurities [13]. Impurities above 0.1% should be reported and those above 0.5% identified; common impurities should not exceed the reference level or 1.0%, whichever is greater [13]. It notes that such impurities may result from making the peptide “by recombinant, synthetic or semi-synthetic processes” [13]. The regulatory consequences for semaglutide generics are covered in our generic semaglutide pathways guide.

EMA’s guideline on the development and manufacture of synthetic peptides

The exact title is “Guideline on the Development and Manufacture of Synthetic Peptides”, reference EMA/CHMP/CVMP/QWP/367182/2025, dated 4 December 2025 [2]. Its history: draft agreed by the Quality Working Party on 6 September 2023; public consultation from 18 October 2023 to 30 April 2024; adopted by the CHMP on 1 December 2025 and the CVMP on 4 December 2025; in effect from 1 June 2026 [2], [14]. EMA’s guideline page lists the legal effective date as 1 June 2026 and first publication as 9 December 2025 [14].

Its scope is “the development, manufacture and control of synthetic peptides (existing or new chemical entities) used in a medicinal product”; it “is not applicable to biological and biotechnological products manufactured by recombinant technologies” [2]. It complements EMA’s Guideline on the Chemistry of Active Substances and covers conjugation, medicinal product development, synthetic peptides referencing biological reference products, and investigational medicinal products [2].

How Q11, Q6 and Q7 fit together in Module 3

CTD section	Content	Main guidance
3.2.S.1 General information	Nomenclature, structure, properties	M4Q [3]; EMA [2]
3.2.S.2.2 Process description	Flow diagram, narrative, IPCs	ICH Q11 section 4 [1]; EMA [2]
3.2.S.2.3 Control of materials	Starting material justification and specifications	ICH Q11 section 5 and Q&A [1], [4]; EMA [2]
3.2.S.2.4 Critical steps and intermediates	Coupling, cleavage, pooling, crude peptide	ICH Q11 section 6 [1]; EMA [2]
3.2.S.2.5–2.6 Validation and development	Process validation; development history	ICH Q11 sections 3 and 7 [1]
3.2.S.3 Characterisation	Structure, impurities	EMA [2]; Q6A/Q6B principles [6], [7]
3.2.S.4 Control of drug substance	Specification and justification	Q6A principles [6]; Ph. Eur. thresholds via EMA [2]; ICH Q14 [9]
All manufacturing steps from the starting material	GMP	ICH Q7 [15]

For a US Type II DMF, FDA’s draft DMF guidance points to ICH Q7, Q11 and their Q&As for “the definition and criteria for designating starting materials and intermediates” [16]. Our drug master file guide covers how this Module 3 content is filed, and the ICH Q7 guide covers the GMP side.

How Winhycare Pharma supports peptide API programmes

Winhycare Pharma supplies semaglutide, tirzepatide, retatrutide, cagrilintide and BPC-157 as APIs to licensed manufacturers; see peptide APIs. For semaglutide we support US-DMF Type II dossiers and CTD Module 3 CMC documentation for customers’ own filings. Our CRDMO services include analytical method development and impurity profiling for clients’ own programmes, and our research peptides are supplied for research use only at purity of ≥99% as stated in our product brochure, with custom peptide synthesis available. Enquire about semaglutide API or request research peptides.

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