Updated on 28 January 2026
Administrative changes implemented to ensure alignment with the revised variations classification framework
These questions and answers address a number of questions that have been brought to the attention of the Joint Committee for Medicinal Products for Human Use / Committee for Medicinal Products for Veterinary Use Quality Working Party (QWP) by marketing-authorisation holders (MAHs) or European Economic Area (EEA) competent authorities, on matters related to the quality of medicines. They have been developed and are maintained by the QWP.
They provide the EEA's harmonised position on issues that can be subject to different interpretation or require clarification, typically arising from discussions or correspondence during assessment procedures.
If a question is not addressed, marketing-authorisation holders are encouraged to contact the European Medicines Agency (EMA) for further information.
These questions have been produced to provide clarification or additional information, and should be read in conjunction with the European Pharmacopoeia, quality guidelines and other guidance documents.
Key:
No. A mixture of an active substance with an excipient cannot be submitted through an ASMF procedure.
The blending of an active substance and an excipient is considered as the first step in the manufacture of the medicinal product, and therefore does not fall under the definition of an active substance.
The only exceptions can be made where the active substance cannot exist on its own, for example, due to insufficient stability without a stabilising agent, or in the case of herbal dry extracts if it is not possible to produce a solid extract without excipients.
The Active Substance Master File (ASMF) procedure guidance already allows for technical tests in the specification of the active substance that are relevant for the medicinal product, and which are not normally part of the specification in the ASMF (e.g. particle size), but which should be part of the active substance specification of a particular Applicant/MA holder. It is also common practice where a CEP is used that additional information can be provided in the marketing authorisation application dossier (e.g. concerning particle size, microbial quality or bacterial endotoxins).
Therefore, in situations where an Applicant/MAH requires product-specific attributes to the active substance then these may be included in the relevant section of the MA dossier/Module 3 (or Part 2 for veterinary medicinal products) rather than the ASMF dossier to maintain the “one version” philosophy for the ASMF.
Introductory note
These Q have been developed to provide information on how to deal with mixtures of API and excipients (called API mix), and to identify situations where it will be acceptable to use the ASMF/CEP procedure and perform manufacture under EU GMP Part II (for human medicinal products) or Commission Implementing Regulation (EU) 2025/2154 (for veterinary medicinal products) for the API mix.
1. What is the definition of an API mix?
An `API mix’ is defined as a mixture of an API (active pharmaceutical ingredient) with one or more excipients. Typical examples are the addition of an antioxidant to an API, or the introduction of an API into a matrix.
The manufacture of an API mix is considered to be the first step of the manufacture of a finished product.
a) Under which circumstances can an API Mix be submitted as part of 3.2.S (or 2.C.1) or via an ASMF resp. a CEP?
In certain circumstances, i.e. stability or safety reasons, the applicant can submit data on such a mixture under part 3.2.S (or part 2.C.1 for products for veterinary use) or in the form of an ASMF or via a CEP. The API mix should comply with the same requirements as for an API with regard to GMP Part II (for human medicinal products) or Commission Implementing Regulation (EU) 2025/2154 (for veterinary medicinal products), unless the mixture is sterile (in which case GMP Part I (for human medicinal products) or Commission Implementing Regulation (EU) 2025/2091 (for veterinary medicinal products) is mandatory for the sterilisation activities and steps after sterilisation). A re-test period for the API mix can in such cases be accepted, if justified.
In case of an API mix prepared due to workability purposes or reasons other than safety and stability, the manufacturing steps from the addition of the excipient to the API should be described in (the appropriate part of CTD 3.2P....). In addition, the steps following addition of the excipient must be conducted in accordance with GMP Part I (for human medicinal products) or Commission Implementing Regulation (EU) 2025/2091 (for veterinary medicinal products) and an appropriate manufacturing authorisation.
b) Is an API mix acceptable when it is stated in a pharmacopoeial monograph “A suitable antioxidant may be added” (under ’Definition’)?
A statement in a pharmacopoeial monograph, such as “A suitable antioxidant may be added” is considered sufficient and acceptable per se as a justification for the use of an API mix.
However, additional justification on the choice and level of antioxidant needs to be provided, and a control test is required for the antioxidant in the API mix.
Particular care should be given regarding API mix acceptability in cases where different sources of API are used in the same medicinal product to avoid a medicinal product with alternative compositions.
c) Are APIs in solutions (e.g. Benzalkonium chloride solution) considered as an API mix, and are ASMFs or CEP applications for solutions of APIs acceptable?
APIs in solutions are considered as API mixes. ASMFs for solutions are acceptable in certain circumstances as explained under question 1.b.
d) Is there a difference if there is a Ph. Eur. monograph that permits an API mix or not?
For an existing Ph. Eur. monograph for an API mix, an ASMF can be accepted or CEP can be granted, with the assumption that new monographs for mixtures would normally not be introduced into the Ph. Eur. if not justified by the safety or stability of the API.
If there is no Ph. Eur. monograph for an API mix then an ASMF can be accepted only for safety or stability reasons on a case by case basis.
2. An API mix is acceptable when there are safety or stability issues: What data should be submitted to justify the acceptability of an API mix for which there is no Ph. Eur. monograph?
In all cases the choice and level of excipient should be justified.
In case the originator uses no stabiliser, it is expected that the same approach as the originator is taken by any subsequent new product.
Acceptable stability reasons include both chemical and physical stability.
Documentation to be provided: A comparison of the stability data of both the stabilised and non-stabilised API under (V)ICH long term conditions for up to 6 months (in a refrigerator/freezer/inert atmosphere where relevant). Results with a stabiliser should demonstrate a relevant stability improvement.
For APIs of an explosive nature the use of an API mix may be justified, and an appropriate explanation is considered sufficient.
A justification based only on workability reasons, e.g. to ease handling when processed into final dosage form, is not acceptable.
Toxicological considerations (e.g. very potent drugs) fall under workability reasons and are not accepted as justifications.
3. If an ASMF/CEP for an API mix is accepted:
a. What data are required and how should the data be organised in the dossier/ASMF?
If an ASMF for an API mix is accepted, the open part of the ASMF/dossier should contain all relevant information on the mixing process, qualitative and quantitative composition of the mixture and control strategy. Data supporting the choice and the amount of the excipient should also be provided.
Information requested for the excipient(s) – Ref. Annex I (section 3.2.2.4) of Directive 2001/83/EC for products for human use and Annex II (section II.2C2.) of Regulation (EU) 2019/6 for products for veterinary use.
b. Where should the excipient be stated?
Excipients should be stated in the composition of the drug product (Module 3.2.P.1 for products for human use or Part 2.A for products for veterinary use); in the SmPC – 6.1, 2 (in the case of antioxidants and/or preservatives or if required according to the CxMP excipients guidelines); in the PL – 6 and in the labelling (if required according to the CxMP excipients guidelines).For the PL for products for veterinary use: section 2 (i.e. composition, only antioxidants and/or preservatives). See also QRD templates.
c) What should be required as additional information in the case of a CEP?
The same principles apply as for ASMFs. The following information should be required as additional information in the case of a CEP:
If a new CEP is presented as a variation then these above mentioned elements should also be included as part of that submission.
In addition, for human medicinal products, as far as the variation submission category is concerned and whether or not a Type IA or even a variation will be possible at all, particular consideration should be given to the potential impact of the change on the currently registered specifications of both the API and the finished product (conditions 1, 2 and 3 under variation change code Q.III.1). In this instance, as far as condition 2 and 3 are concerned, it is important to note that product specific requirements also include the qualitative, and where relevant, quantitative composition of the API mix, as indicated in the CEP, which may impact the currently registered composition of the finished product (see question 1.b.).
For veterinary medicinal products, the same principles as mentioned for human medicinal products apply for deciding on which type of variation (VNRA or VRA) should be submitted.
Full compliance with good manufacturing practice (GMP) for finished products and active substances is a legal obligation for manufacturing-authorisation holders. It is recognised that for a small number of medicinal products the primary use of the active substance is not in a medicinal product and the producer may therefore not be aiming to meet the specific requirements of pharmaceutical customers that represent an insignificant volume of business. Alternative sources should normally be sought but in exceptional circumstances the manufacturing-authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation. The declaration provided by the qualified person should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. The European Medicines Agency will collect experience with this approach which can be used as a basis for discussion on related amendments to guidelines in the future.
The good-manufacturing-practice (GMP) basic requirements for active substances used as starting materials (European Union (EU) GMP guide part II (for human medicinal products) or Commission Implementing Regulation (EU) 2025/2154 (for veterinary medicinal products)) only applies to the manufacture of sterile active substances up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing of sterile active substances are not covered by this guideline and shall be performed in accordance with GMP for medicinal products (Commission Directive (EU) 2017/1572; as interpreted in the basic requirements for medicinal products including annex 1 of the EU GMP Guide part I (for human medicinal products) and Commission Implementing Regulation (EU) 2025/2091 (for veterinary medicinal products)). This implies that for any active-substance manufacturer who performs sterilisation and subsequent aseptic handling of the active substance, a valid manufacturing authorisation or GMP certificate from an EEA authority or from an authority of countries where mutual recognition or other Community arrangements apply has to be submitted.
Also, the active substance manufacturer has to submit data on the sterilisation process of the active substance (including validation data) to the marketing-authorisation applicant or holder for inclusion in the dossier submitted for the finished product and approval by the licensing authority or authorities.
There are several types of starting materials of herbal origin used to manufacture semi-synthetic active substances:
Starting materials of herbal origin should be characterised to ascertain their suitability and a contaminant profile should be established and submitted, taking into consideration the number of chemical steps between the starting material and the semi-synthetic active substance.
In all cases, the scientific name (genus, species, variety and author) of the plant and plant part used should be specified. If the starting material is an extract or an isolated constituent, the extraction solvent and strength (e.g. ethanol 50% v/v) used for the first extraction from the herbal drug should be specified as well.
The quality of the starting material of herbal origin should follow the principles set out in the European Pharmacopoeia monographs on herbal drugs, herbal drug preparations, extracts and essential oils, as applicable: the potential presence of foreign matter, pesticides, microbiological contamination, total ash, heavy metals, aflatoxins, ochratoxin A, radioactive contamination, residual solvents, and other relevant impurities should be discussed.
Potential contaminants that may be carried through the extraction and purification processes should be fully addressed taking into account the production of the herbal drug, and the subsequent extraction and purification processes.
The specification for the starting material of herbal origin should be fully justified by the applicant and should include suitable tests for identity, assay, impurities and potential contaminants.
Compliance with the Guideline on good agricultural and collection practice (GACP) for starting materials of herbal origin - Superseded is not mandatory in the steps prior to the starting material of a semi-synthetic active substance, since it applies to herbal medicinal products and traditional herbal medicinal products. However, information on the geographical origin, collection or cultivation, harvesting, and post-harvest treatments (possible pesticides and fumigants used and possible radioactive contamination) could justify limited testing for (possible) contaminants.
Introductory note:
This Q&A provides information on how Ph. Eur. general chapter 2.2.46 Chromatographic separation techniques (in particular with respect to the adjustment of chromatographic conditions) can be used for non-compendial (in house) analytical procedures and when the conditions described in the pharmacopoeia text apply.
Background information:
When a pharmacopoeial test procedure is used as intended, the test procedure is not required to be described in the dossier. Instead a cross-reference to the current respective Ph. Eur. monograph is considered sufficient.
A pharmacopeial test procedure adjusted within the limits prescribed in Ph. Eur. general chapter 2.2.46 Chromatographic separation techniques is considered to be the pharmacopoeial test procedure.
In all other cases, the test procedure is considered to be an in-house test procedure. This means that the full description of the test procedure and validation data should be provided in the dossier.
a) If the applicant is using the pharmacopoeial test procedure as described in the respective monograph
No, a variation application is not necessary.
b) If the applicant is using an in-house test procedure for the finished product, that is based on the one described in the respective monograph of the active substance
Yes, a variation must be submitted according to the relevant variation guidance and the relevant documentation should be provided.
c) If the applicant is using an in-house test procedure for the active substance/finished product/excipient (regardless of whether reference to the corresponding Ph. Eur. general chapter(s) is made)
Yes, a variation must be submitted according to the relevant variation guidance and the relevant documentation should be provided.
Where an adjustment of chromatographic test parameter(s) is made to a non-compendial (in-house) test procedure, within the limits and conditions defined in Ph. Eur. general chapter 2.2.46, it is considered that the method of analysis remains the same. The analytical procedure description in the dossier should be updated accordingly. The change can be notified to the competent authority as a minor Type IA variation (for veterinary medicines: variation not requiring assessment (VNRA)) under the relevant classification category.
Where an adjustment of chromatographic test parameter(s) is made to a non-compendial (in-house) test procedure outside the limits and conditions defined in Ph. Eur. general chapter 2.2.46, it is considered that the method of analysis has changed. The analytical procedure description in the dossier should be updated accordingly. The change can be submitted to the competent authority as a minor Type IB variation (for veterinary medicines: variation requiring assessment) under the relevant classification category.
General chapter 2.2.46 describes the extent to which various parameters of a chromatographic test procedure, as described in an individual monograph, may be adjusted without fundamentally modifying the pharmacopoeial analytical procedure.
The same principles as those described in Ph. Eur. 2.2.46 may also be applied in case of adjustments to chromatographic parameters of non-compendial (in-house) analytical procedures.
Adjustments other than those indicated in Ph. Eur. 2.2.46 require revalidation of the test procedure.
If the adjustment has been performed within the limits and conditions described in Ph. Eur. general chapter 2.2.46, compliance with system suitability test (SST) criteria and other conditions described in the chapter (e.g. selectivity and elution order of any specified impurities should be equivalent) is considered sufficient to show that the updated test procedure is at least equivalent to the former test procedure. In this case, further validation of the test procedure is not deemed necessary.
An SST covering the relevant critical analytical procedure attributes should be described in the dossier. After adjustment of an analytical procedure, it should be considered whether the SST requirements are still adequate and sufficient for the adjusted analytical procedure.
A change in the appearance of an oral medicinal product during its shelf-life is considered acceptable when all of the following conditions are met:
In all other situations, a change in appearance should be assessed on a case-by-case basis.
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
Provided that the formula, manufacturing process, analytical methods and packaging materials are the same, data originating from the developer of the product is normally sufficient. As regards manufacturing process validation, the marketing authorisation holder, according to the Note for guidance on process validation, must submit with the new application the process validation scheme and the commitment to carry out process validation and initiate stability studies along with the batch analysis for production scale batches for the new manufacturing site. This is irrespective of whether the product developer is one of the manufacturing sites of the new product or not.
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
According to the Note for guidance on process validation, "the results can be subsequently verified by supervising authority according to national procedure.” Depending on the product and the concerns that may arise, in some countries this may be dealt with as a post-authorisation commitment or it may be brought to the attention of good-manufacturing-practice inspectors to be checked during their next inspection.
The marketing-authorisation holder is usually not expected to present these data with the new application, unless it is requested by the licensing authorities.
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
The product used in the bioequivalence study must be representative of the industrial scale product to be marketed.
A bioequivalence study conducted using a test product produced by the developer is acceptable if the developer is also one of the manufacturers of the new product.
If the developer is not one of the manufacturers of the new product, it has to be demonstrated that the bioequivalence batch is representative of the industrial scale product to be marketed.
For this the following applies:
Comparative pilot batch analysis between the developer product (including the biobatch) and the new manufacturer product must be presented.
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
No such proof is necessary to be presented in the application dossier.
How should any update to the microbial quality control of a finished product, specifically linked to the update to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) harmonised Ph. Eur. methods (2.6.12 and 2.6.13) and limits (5.1.4) be achieved?
For human medicinal products
Any changes to implement the harmonised methods (2.6.12 and 2.6.13) should be submitted under change code Q.II.d.2.a (type IA).
Any changes to implement the harmonised limits (5.1.4) should be submitted as follows:
Changes to the limits – Q.II.d.1.a (type IA), but only in the following situations:
If for any reason these criteria are not met, a type IB variation (Q.II.d.1.z) should be submitted.
For veterinary medicinal products
Any changes to implement the harmonised methods (2.6.12 and 2.6.13) should be submitted under change code B33 (VNRA); if conditions are not fulfilled, a VRA under category F.II.d.2.z should be provided.
Any changes to implement the harmonised limits (5.1.4) should be submitted as a VNRA under category B30d; if conditions are not fulfilled, a VRA under change code F.II.d.1.z should be provided.
In accordance with current requirements, any changes should be clearly identified (present / proposed) in the variation submission and the affected parts of the marketing-authorisation dossier should be appropriately updated, including a description of how the method is applied to the specific product.
The requirements of the European Pharmacopoeia (Ph. Eur.) general monograph on tablets for tablets with one or more breaklines have been revised as of 1 July 2006. The previous version of the monograph, which has been in force since April 2002, requested compliance with either test A (uniformity of content of single-dose preparations) or the test for uniformity of mass of single-dose preparations. It did not, however, give any information on how to select the parts to be tested. Supplement 5.5 now provides background information on the use of breakmarks and describes the sampling procedure and the number of tablet parts to be tested in detail. As a test procedure, it prescribes determining uniformity of mass, while setting the somewhat wider acceptance criteria of the test of content uniformity, namely 85 - 115% (in this case of the average mass).
According to Directives 2001/83/EC and Regulation (EU) 2019/6, the monographs of the Ph. Eur. are the official standards of appropriate quality in the marketing authorisation procedures. In the pharmacopoeia it is also stated that a preparation must comply with the monograph throughout its period of validity.
As the revised text defines lesser requirements with wider acceptance criteria than the previous version (see above), a decision has been taken by the regulatory authorities of the European Union (EU) that the revised test on subdivision of tablets is to be applied to all new applications for marketing authorisations as well as all existing products. It is acknowledged, however, that the new test will not have been applied to products which are in the final stages of their development. In order not to delay any immediate applications and in line with the period of time defined in the variations regulation, a transitional period of 6 months following the coming into force of Ph. Eur. 5.5 has been defined, in which the EU regulatory authorities will accept submission of results which have been generated using the previous version of the monograph.
As the requirements on subdivision of tablets are listed in the production section of the general monograph on tablets, it will normally be sufficient to perform the test only in the framework of pharmaceutical development. There is no need to include the test in the release specification. However, in situations where there is a significant change in tablet hardness during storage, it may be necessary to repeat the test at the end of shelf-life in order to ensure that the scorability has not changed as a function of hardness.
Between 2004 and 2008, various questions and answers have been published on this website to clarify how the harmonised European Pharmacopoeia (Ph. Eur.) chapter on uniformity of dosage units (2.9.40) and the general chapters on uniformity of mass of single-dose preparations (2.9.5) and uniformity of content of single-dose preparations (2.9.6) should be applied in the European Union (EU), also in view of the compliance objection made by the United States Food and Drug Administration to the USP on the 2% relative-standard-deviation clause in general chapter 2.9.40. This matter has been recently reviewed by EU regulators and the resulting agreed position is presented in the following questions and answers, which replace the previous questions and answers 1 and 4 published on the same subject in 2004 and 2006, which have now been deleted from the website.
Medicinal products marketed in the European Union need to be in compliance with the relevant requirements in the European Pharmacopoeia (Ph. Eur.).
From a pharmaceutical quality point of view, the approach taken in the harmonised general chapter on uniformity of dosage units (2.9.40) is considered equivalent to what was previously required in the Ph. Eur. through the general chapters on uniformity of mass of single-dose preparations (2.9.5) and uniformity of content of single-dose preparations (2.9.6). These general chapters, 2.9.5 and 2.9.6, are still included in the current version of the Ph. Eur.
Taking this into account, the decision on what approach to take is left to the applicant. Application of either the Ph. Eur. harmonised general chapter on uniformity of dosage units (2.9.40) or the Ph. Eur. general chapters on uniformity of mass of single-dose preparations (2.9.5) and uniformity of content of single-dose preparations (2.9.6) are both considered acceptable options to demonstrate compliance with the Ph. Eur. with regard to uniformity of dosage units.
Please note that this advice supersedes the previous questions and answers 1 and 4 published on the same subject in 2004 and 2006. The remaining previously published questions and answers on the use of the general chapter 2.9.40 (former questions and answers 2, 3, 5 and 6) are still valid and remain published as questions and answers 2 to 5.
Where a dosage form monograph in the European Pharmacopoeia refers to this general chapter, the product should comply. This is normally verified by routine testing unless otherwise justified and authorised.
The harmonised text is included in the European Pharmacopoeia and the 2% clause will thus be valid in the European Union. This will not be dependent on the final outcome of the discussion between the Food and Drug Administration and the United States Pharmacopeia.
When can the requirements in the harmonised European Pharmacopoiea general chapter on uniformity of dosage units (2.9.40) for mass variation, rather than content uniformity, be applied with reference to a relative standard deviation (RSD) of not more than 2%? Is it sufficient to determine the RSD on for example 3 validation batches? H+V July 2008
It is the opinion of the Quality Working Party that the requirement in the harmonised chapter 2.9.40 regarding the 2% relative-standard-deviation clause represents minimum requirements. The use of this clause should be based on sufficient experience. Normally, results from 3 validation batches are not sufficient. It is rather to be used post-approval when more extensive production experience is gained.
'Single component' means one active substance with no excipient. 'Multiple component' could mean 'at least 2 active substances' or 'at least 1 active substance and at least one excipient'; both cases are valid.
Directive 2010/63/EU establishes measures for the protection of animals used for scientific and educational purposes, with the final aim of replacing all animal research with non-animal methods. To that end, the Directive lays down principles of replacement, reduction and refinement (3Rs). When choosing methods, these principles should be implemented through a hierarchy, with the ultimate goal of replacing animal testing by alternative methods. The principle of replacement ensures that a procedure using live animals is not carried out, if another method or testing strategy is recognised under the legislation of the Union that does not entail the use of live animals.
EMA supports the implementation of this Directive and the 3Rs principles in the EU, by, among other initiatives, helping marketing authorisation holders to comply with new or revised measures. The 3Rs Working Party acts as a focal hub for EMA 3Rs activities and has recently published a Reflection Paper on the current regulatory testing requirements for human medicinal products and opportunities for implementation of the 3Rs.
In this context, EMA is publishing guidance for phasing out the Rabbit Pyrogen Test, following the revision of the European Pharmacopoeia. This revision includes the introduction of a new general chapter, 5.1.13 Pyrogenicity and the removal of references to the Rabbit Pyrogen Test from 57 existing monographs. The new and revised texts will be published in Supplement 11.8 of the Ph. Eur., with an implementation date of 1 July 2025. As a result, the use of the Rabbit Pyrogen Test will no longer be required in any text of the European Pharmacopoeia and it will be the responsibility of medicine developers to select a suitable in vitro test to control the pyrogenicity of their product, based on a risk assessment as described in the new general chapter 5.1.13.
Applicants/Marketing Authorisation Holders are reminded that EU law makes specific reference to the mandatory character of the European Pharmacopoeia’s monographs in Directive 2001/83/EC on medicines for human use. Therefore, to comply with these changes, Applicants/Marketing Authorisation Holders should remove the Rabbit Pyrogen Test from their Marketing Authorisation dossiers and assess the need for a method replacement.
Following a revision of the European Pharmacopoeia (Ph. Eur.), the Rabbit Pyrogen Test is being deleted from Ph.Eur. texts. The revised texts omitting references to chapter 2.6.8 Pyrogens are published in Supplement 11.8 of the Ph. Eur., with an implementation date of 1 July 2025. Chapter 2.6.8 will be permanently deleted from the Ph. Eur. in January 2026.
Applicants/Marketing Authorisation Holders (MAHs) are reminded that EU law makes specific reference to the mandatory character of the Ph. Eur. monographs in Directive 2001/83/EC.
Therefore, to comply with the changes to the Ph. Eur., MAHs should remove the Rabbit Pyrogen Test from their Marketing Authorisation dossiers and assess the need for a method replacement.
In accordance with the new general chapter 5.1.13 Pyrogenicity, Applicants/MAHs should perform a risk analysis and assess the potential presence of pyrogens. It is the Applicant’s/MAH’s responsibility to decide on a testing strategy and limits.
In case the risk assessment shows that a new method needs to be added, the Applicant/MAH should consider that the general chapter 5.1.13 Pyrogenicity makes reference to 2.6.14. Bacterial endotoxins, 2.6.32. Test for bacterial endotoxins using recombinant factor C, and 2.6.30. Monocyte-activation test.
However, if the risk assessment shows that a suitable method is already being applied in the existing controls of the product, the addition of a replacement method may not be required.
An update of the Marketing Authorisation dossier to remove or replace the Rabbit Pyrogen Test will always require the submission of a variation for assessment. The type of variation to be submitted will depend on whether or not a replacement method is proposed and on the type of replacement method.
In case the risk assessment concludes that a suitable method is already being approved in the dossier and allows appropriate control in the absence of the Rabbit Pyrogen Test, a type IB variation should be submitted for the removal of the Rabbit Pyrogen Test. The risk assessment should be included in the submission.
In case a replacement method is proposed, the type of variation would depend on the type of method. In case of a pharmacopoeial bacterial endotoxins method (2.6.14 or 2.6.32), a type IB variation should be submitted. In case of the pharmacopoeial monocyte activation test (2.6.30 MAT) or a non-pharmacopoeial in vitro method, a type II variation should be submitted.
The different scenarios are summarised in the decision tree below.
With regard to the specific scope of the variation, this will depend on the situation and on where the Rabbit Pyrogen Test is applied (this may include the finished product, active substance, starting/raw materials, reagents, intermediates or excipients). The revised Variations Classification Guideline, which enters into application on 15 January 2026, introduces specific indents for the submission of changes involving the replacement of a specification attribute with its corresponding analytical procedure. Note that “z” scopes may be used in case of a deletion without replacement (reliance on a suitable approved method).
Some examples are provided below, but the list is not exhaustive.
This guidance has been agreed by the Biological Working Party (BWP) and the Quality Working Party (QWP) and applies to human centrally and nationally authorised products (CAPs and NAPs). In case of questions, the MAH should contact the responsible Authority (EMA for CAPs; National Competent Authorities for NAPs).
Mono-component products
For medicinal products containing only one active substance, the calculated thresholds should be based on the highest maximum daily dose of the respective active substance in authorised medicinal products and the limits in the specification set accordingly. The threshold for impurities should be the same for all strengths. The applicant is responsible to consider the maximum daily dose (MDD) that is approved for a given active substance. Since the MDD may differ between pharmaceutical forms, the MDD of the active substance in authorised medicinal products having the same pharmaceutical form should be considered.
Fixed Dose Combination products (FDC)
For medicinal products containing more than one active substance, the calculated threshold should be based on the maximum daily dose (MDD) described in the SPC of the FDC(s) under evaluation. The FDC(s) are indeed developed in a specific ratio of active substances composing the medicinal product and therefore considering the MDD of an active substance in mono-component medicinal products would not be appropriate.
If an unidentified impurity cannot be assigned to one of the active substances in the FDC it has to be compared to the signals of all active substances in order to verify whether the respective ICH identification threshold is exceeded or not. If exceeded, the impurity should be identified and assigned to the signal of the respective active substance. If not exceeded, the specification limit should be set with reference to the active substance that would ensure the lowest amount/exposure to the patient.
Yes. In accordance with Annex I of Directive 2001/82/EC, all relevant European Pharmacopoeia (Ph. Eur.) monographs, including general monographs and general chapters, are applicable with respect to the quality (pharmaceutical) part of dossiers for non-immunological veterinary medicinal products.
The Ph. Eur. General Monograph Substances for Pharmaceutical Use* requires that elemental impurities are considered in a risk assessment and the Ph. Eur. General Monograph Pharmaceutical Preparations* requires elemental impurities to be controlled based on a risk assessment for products outside the scope of Ph. Eur. Chapter 5.20 on Elemental Impurities*.
Whilst specific guidance for veterinary medicinal products is currently not available with respect to application of these principles to elemental impurities, the principles elaborated in the ICH guideline Q3D can be adapted and applied to veterinary medicinal products, or other justified approaches used.
* Note: Published in revised form in Ph. Eur. 9.3 in July 2017
This Q&A is specific to nitrosamine impurities in veterinary medicinal products only and must not be extrapolated to other situations.
Some CEPs include limits for nitrosamine impurities. It is acknowledged that the requirements for risk evaluation of nitrosamines formation in the Ph. Eur. General Monographs 2034 Substances for pharmaceutical use and 2619 Pharmaceutical preparations are specific to human medicinal products. Nevertheless, the presence of nitrosamines in a veterinary medicinal product (VMP) should be controlled. Taking into consideration the detailed substance specific acceptable intake information available in Appendix 1 to the Q&A for human medicines (EMA/409815/2020).
Therefore, when a limit for a nitrosamine impurity is included on a CEP, it must be controlled in the active substance used in the VMP1. When the CEP is being added to an existing MAA or updated following a revision of the CEP, this may be done by way of VRA or VNRA, depending on an adjusted limit for the nitrosamine for the specific veterinary medicinal product.
1This applies even in the rare situations where a statement such as ‘Applicable only for human products. Not applicable for veterinary medicinal products.’ is included on the CEP annexes.
Calculation of adjusted nitrosamine limit for veterinary medicinal product:
Using the acceptable intake (AI) for human medicines, an adjustment for veterinary medicines should be made as follows:
AIvet (ng/kg bw/day) = AIhuman (ng/pers/day) /50 (kg)
The acceptable limit for the nitrosamine is then calculated as follows:
Limit (ppm) = AIvet (ng/kg) /max daily dose of active substance (mg/kg bw)
If the limit for the veterinary medicinal product, as calculated above, is equal to or above the limit specified on the CEP, the nitrosamine limit specified on it, may be included in the MAA via a VNRA. However, if the limit for the veterinary medicinal product, as calculated above, is below the limit specified on the CEP, the CEP must be included via a VRA-R F.III.1.a.z and the safety of the limit will be evaluated within the assessment of that VRA. For both VNRAs and VRAs, the calculations made by the MAH to decide whether a VRA or VRNA applies should be included in the variation documentation submitted to the Competent Authority.
In the event that an MAH wants to justify a higher limit than that specified on the CEP for the nitrosamine(s), this can only be reviewed in the context of a VRA application. In the absence of a limit for the nitrosamine in Appendix 1 to the Q&A for human medicines (EMA/409815/2020), or in cases where more than one nitrosamine is included on the CEP, a VRA submission is required.
When the CEP is included in an initial MAA this will be dealt with during the initial assessment using the same principles described above for variation applications.
For example:
CEP states a limit for nitrosamine of 1 ppm:
Situation 1
The calculated limit for the VMP is below this e.g. 0.5 ppm. In this case, the CEP limit is above the limit for the VMP and therefore assessment is needed for the VMP application and submission of the CEP as a VRA is needed;
Situation 2
The calculated limit for the VMP is the same as or above this e.g. 1 ppm or 2 ppm. In this case the CEP limit is equal to or stricter than needed for the VMP and no assessment is needed. The CEP limit can be applied, and submission of the CEP as a VNRA is acceptable.
For class-2 residual solvents in active substances or medicinal products, it is sufficient to restrict the specification to the concentration limit (parts per million) as defined in the notes for guidance on impurities: residual solvents (CPMP/ICH/283/95 EMEA/CVMP/511/03) and related maintenance guidelines or to calculate it based on the respective permitted daily exposure (mg/day) outlined in the guidelines.
It has been agreed by the QWP that there is no need for further tightening of the specification in line with batch results, as the limits in the guideline are based on safety assessment.
It is the applicant’s responsibility to select and justify the pilot batch size.
The Note for guidance on process validation states that, “pilot-batch size should correspond to at least 10% of the future industrial scale batch i.e. such that the multiplication factor for scale-up does not exceed 10. For oral solid dosage forms this size should be at least 10% or 100,000 units whichever is greater* unless otherwise justified”.
The guideline does not dictate that the 10% figure should always be linked to the scale of manufacture of individual product presentations. In addition, it allows for departures from the guidance where this is justified. Furthermore, the guideline does not preclude the use of bracketing.
Certain bulk products are used to produce a series of presentations, for example a bulk powder blend may be used to produce 50-mg, 100-mg and 200-mg direct compression tablets with the same percentage composition. In such instances, as long as the applicant can demonstrate a satisfactory link between the pilot batch size used for validation and the routine production batch size, it will usually be acceptable to define the pilot batch size as 10% of the planned production scale for the bulk product. During the process validation study, the complete pilot scale bulk batch should be used to manufacture the individual presentations. The division of the bulk batch between the different presentations should also be justified.
*In the case of veterinary medicinal products, the minimum pilot size may be smaller than 100,000 units where justified.
By convention, the strength of vancomycin products is stated on labels and prescribed in terms of mass (that is in milligram [mg]) e.g. 500 mg and 1000 mg for IV administration; 125 mg and 250 mg for oral capsules. The product information also includes the quantitative amount of active substance, expressed in international units (IU), i.e. the potency, as determined by microbiological assay.
Historically, the manufacturing formulae and expressions of declared strength have been based on a nominal potency of 1,000 IU/mg. For example, when a dose of 500 mg vancomycin for IV administration was prescribed, then not less than 500,000 IU of vancomycin would be administered.
The potency specified by the European Pharmacopoeia (Ph. Eur.) monograph for vancomycin hydrochloride has changed since the first publication and currently specifies a minimum potency of 1,050 IU/mg. This change has led to discrepancies in the manufacturing formulae and expression of potency in the product information.
To avoid confusion in clinical practice it is essential that the convention of labelling vancomycin products by mass, i.e. mg, is retained. However, to ensure that the established therapeutic dose in terms of IU, e.g. 500,000 IU or 1,000,000 IU, is maintained, the amount (mg) of active substance in the drug product should be adjusted to achieve the declared product strength in terms of IU.
The manufacturing process and batch formulae should be revised where necessary, to achieve the declared content e.g. 500,000 IU or 1,000,000 IU.
To take account of the convention used for vancomycin products, the product information should be expressed as follows:
Vancomycin 500mg powder for concentrate for solution for infusion:
Each vial contains 500mg vancomycin hydrochloride equivalent to 500,000 IU vancomycin.
Vancomycin 1000mg powder for concentrate for solution for infusion:
Each vial contains 1000mg vancomycin hydrochloride equivalent to 1,000,000 IU vancomycin.
Vancomycin 125mg capsule:
Each capsule contains 125mg vancomycin hydrochloride equivalent to 125,000IU vancomycin.
Vancomycin 250mg capsule:
Each capsule contains 250mg vancomycin hydrochloride equivalent to 250,000IU vancomycin.
The product name should remain consistent with prescribing convention as follows:
Vancomycin 500mg powder for concentrate for solution for infusion.
Vancomycin 1000mg powder for concentrate for solution for infusion.
Vancomycin 125mg capsule.
Vancomycin 250mg capsule.
Yes. The deletion of a general Heavy metals test from the specification of an ingredient is accepted as a Variation Type IA. The change does not have to be justified.
No. Reference to the general Heavy metals test (2.4.8) has been deleted in the Ph. Eur. 9.0 from all individual monographs for substances for pharmaceutical use (except those for veterinary use only). Instead the Ph. Eur. General Monograph Substances for Pharmaceutical Use will require that elemental impurities are considered in a risk assessment and the Ph. Eur. General Monograph Pharmaceutical Preparations will make ICH Q3D mandatory for all medicines within the scope of the guideline. Compliance with the revised monographs is an expectation and therefore the deletion of the general Heavy metals test from the specification would not require a variation.
No. Reference to the Heavy metals test (2.4.8) has been deleted in Ph. Eur. 9.0 from all individual monographs for substances for pharmaceutical use (except those for veterinary use only). Instead the Ph. Eur. General Monograph Substances for Pharmaceutical Use will require that elemental impurities are considered in a risk assessment and the Ph. Eur. General Monograph Pharmaceutical Preparations will require elemental impurities to be controlled based on a risk assessment for products outside the scope of Ph. Eur. Chapter 5.20. Compliance with the revised monographs is an expectation and therefore the deletion of the Heavy metals test from the specification would not require a variation.
A series of questions and answers relating to the guideline on ICH guideline Q11 on the development and manufacture of drug substances became effective in February 2018 (EMA/CHMP/ICH/809509/2016). In order to avoid any potential confusion arising from differences in wording between these questions and answers and the previously existing document 'Requirements for selection and justification of starting materials for the manufacture of chemical active substances' - EMA/CHMP/CVMP/QWP/826771/2016 Corr. 1 , it was agreed that EMA/CHMP/CVMP/QWP/826771/2016 should be replaced by the ICH Q11 questions and answers and EMA/CHMP/CVMP/QWP/826771/2016 is therefore no longer valid. For veterinary medicinal products, the same principles apply and the ICH Q11 questions and answers document EMA/CHMP/ICH/809509/2016 should be consulted for guidance on this topic. Application of this document does not introduce any new requirements but ensures harmonisation and avoids potential confusion.
These standard terms should be used for capsule formulations where only the capsule contents and not the whole capsule should be ingested. The entire contents need to be removed from the capsule before administration, and subsequently administered according to the PI instructions. The administration of only a part of the capsule contents is not allowed. This dosage form is generally intended for those patients unable to swallow the whole capsule, e.g. paediatric and geriatric populations.
The choice of these dosage forms and the administration instructions should be justified by pharmaceutical development data.
For capsules that may be swallowed whole or opened (based on experimental data provided by the applicant) these terms should not be used.
Clear administration instructions should be included in the SmPC and in the package leaflet, including pictures. The capsules should be imprinted so that it is obvious to patients and caregivers that capsules need to be opened rather than swallowed whole. A warning should be present on the primary and secondary packaging to inform the patient and caregiver that the capsule should be opened and should not be swallowed.
The ease of opening and emptying the capsules should be demonstrated throughout the proposed shelf life.
For safety reasons (if accidentally swallowed), the capsule should be made from readily digestible materials. Monitoring the safe use of these capsules should form part of the risk management plan.
Yes. Peptone is considered to be a critical raw material, whose origin (animal or vegetable) and source (supplier name and address) should be specified in any Active Substance Master File (ASMF), Certificate of Suitability (CEP) and where relevant Marketing Authorisation (MA) dossiers. Consequently, if there is any change to the registered information, the change should be sought by appropriate variation (CEP or MA) and for transparency and to ensure relevant responsibilities are adhered to, the change should be immediately communicated to any finished product manufacturer who uses the material.
Yes. If fish peptone or fish meal is used in the fermentation process there is a potential serious risk to public health if it is contaminated with high levels of histamine. In order to reduce the risk to public health it is important that the finished product manufacturer is aware that fish peptone or fish meal has been used in the manufacturing process and that histamine is also a specified impurity in the active substance which is controlled to an acceptable limit.
Histamine in gentamicin active substance has been identified as the root cause of allergic reactions to parenteral solutions administered to horses. In line with the scientific opinion adopted in 2018 by the CVMP under Article 30(3) of Regulation (EC) No. 726/2004, a limit of 8 ppm should be applied to histamine in the gentamicin active substance specification of parenteral solutions for horses.
In change code B.II.b.4
Complex manufacturing processes is intended to cover situations where the actual manufacture of the finished product involves a process which includes one or more processing steps that may give rise to scale-up difficulties.
In change code B.II.b.1
Complex manufacturing processes is, amongst others, intended to cover situations where the link between quality characteristics and in-vivo performance is not fully understood (e.g. nanomedicines).
In both cases these will be considered on a case by case basis.
Where relevant, if a change is submitted as a type IB variation, it is up to the applicant to provide adequate justification for not considering a manufacturing process as a 'complex' one. However, under the safeguard clause, it should be noted that if the supplied justification is not accepted, it is possible for the competent authority to upgrade the submission to a type II variation during the validation phase. If unsure, applicants should consult the relevant competent authority before submitting the variation.
In categories Q.II.b.1 and Q.II.b.4, a "novel or complex manufacturing process" refers to situations where the manufacturing process involves novel or complex technology that may present challenges during site transfer and/or scale-up activities that could impact the quality of the finished product and therefore require submission of type II variations.
It should be noted that not all non-standard processes (as defined in Annex II of the Guideline on process validation for finished products - information and data to be provided in regulatory submissions) are considered complex in this context.
For example, ‘aseptic processing’ is not a complex manufacturing process for the purpose of classifications of changes in categories Q.II.b.1 and Q.II.b.4, but as it is a non-standard manufacturing process, production scale process validation data is required.
Therefore, to help the interpretation of the term "complex manufacturing process" in the categories Q.II.b.1 and Q.II.b.4, some examples of products manufactured by processes that could be considered complex are provided below (but are not limited to):
In addition, examples of "novel or innovative manufacturing processes" include (but are not limited to):
If a change is submitted as a Type IB variation, applicants must provide a justification if they consider that the manufacturing process is not "novel or complex”, as per the above interpretation. If the justification is not accepted, the competent authority may ask the applicant to withdraw and resubmit as Type II variation. Appropriate variation categorisation can also be anticipated using Post Approval Change Management Protocols. If there is any uncertainty, applicants may consult the relevant authority before submitting the variation.