Quality of medicines questions and answers: Part 1

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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 for further information at qwp@ema.europa.eu.

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:

  • H: applicable to medicinal products for human use
  • V: applicable to veterinary medicinal products

Table of contents


Active Substance - Active-substance-master-file procedure

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1. Can a mixture of an active substance with an excipient be submitted through an active-substance-master-file (ASMF) procedure? H+V August 2007

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.

2. Quality Working Party questions and answers on API mix H+V April 216

Introductory note

These Q&A 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 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, unless the mixture is sterile (in which case GMP Part I 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 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 I (section 2.C.1.2) of Directive 2001/82/EC 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 3 (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:

  • The description of the manufacturing process for preparation of the mixture should be provided by the API manufacturer to the applicant - in addition to the CEP. This information should be part of section 3.2.S.2.2 in the MA application dossier for human products or section 2.C.1.1 for veterinary products;
  • Stability data of the mixture if not mentioned on the CEP;
  • Information on the packaging material if not mentioned on the 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, 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 and 2 under variation change code B.III.1). In this instance, as far as condition 2 is 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 1b).

3. The Active Substance Master File (ASMF) procedure guidance requires only one version of the ASMF (“most recent”) to be in use at any one time. What happens if product specific attributes are necessary in the active substance by only one applicant/MAH? H+V July 216

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.

Active substance - Declaration by the qualified person on the good-manufacturing-practice status of the active substance manufacturer

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1. The notice to applicants requires the submission of a declaration signed by the qualified person that the active substance used is manufactured in accordance with good manufacturing practice. The active substance in my product is widely used, but not normally as a pharmaceutical active substance, and I am having some difficulty in confirming compliance. What should I do to furnish the required declaration? H+V September 2008

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.

Active Substance - Good-manufacturing-practice compliance for sterilisation of an active substance

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1. What kind of good-manufacturing-practice documentation is needed for an active substance manufacturer who performs sterilisation of an active substance? H+V July 2010

The good-manufacturing-practice (GMP) basic requirements for active substances used as starting materials (European Union (EU) GMP guide part  II) 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 2003/94/EC; as interpreted in the basic requirements for medicinal products including annex 1 of the EU GMP Guide part I). 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.

Active Substance - Starting materials of herbal origin

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1. How should the quality of a starting material of herbal origin be controlled when it is used to manufacture a semi-synthetic active substance? H+V February 2012

There are several types of starting materials of herbal origin used to manufacture semi-synthetic active substances:

  • herbal drugs;
  • herbal preparations (typically extracts);
  • isolated plant constituents (no additional synthetic steps).

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) 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.

Change in the appearance of tablets during storage

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1. (When) is a change in the appearance of an oral medicinal product during its shelf life considered acceptable? H July 2013

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:

  • The root cause of the change is known and the change has no influence on other product characteristics (e.g. flavour);
  • The change in appearance does not pose a potential serious risk to public health;
  • The change in appearance does not occur due to uncontrolled or inadequately chosen packaging and/or storage conditions e.g. inaccurate handling by the manufacturer during packaging, an insufficiently protective packaging or too wide storage conditions;
  • The change in the appearance of the oral medicinal product during storage (e.g. color, speckling) is clearly stated in the shelf-life specification;
  • The appearance of the oral medicinal product and the change in appearance during storage are clearly and unambiguously stated and explained in the PIL and SPC.

In all other situations, a change in appearance should be assessed on a case-by-case basis.

Data submission

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1. Is the submission of data regarding manufacturing process validation, analytical validation, and stability studies, produced only by the developer of the product sufficient? Does it make any difference if the developer of the product is presented as one of the product manufacturers or not? H+V July 2008

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 guideline 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.

2. Who is responsible to verify the production scale validation data when this is available? H+V July 2008

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 guideline 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.

3. Can the test product of a bioequivalence study be produced by the developer, irrespective of whether that developer is one of the manufacturing sites of the new product? H+V July 2008

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:

  • The developer product and the new product must have identical formula, specifications, manufacturing process and equipment;
  • The active substance supplier is the same or it is ensured that characteristics of the active substance that may have an impact on the bioavailability are identical;
  • The excipients characteristics which may have an impact on the bioavailability of the active substance are identical;
  • The dissolution profiles of batches produced by the developer (including the biobatch) and the product from the new manufacturer (at least pilot batches) must be similar;

Comparative pilot batch analysis between the developer product (including the biobatch) and the new manufacturer product must be presented.

4. Is there any requirement for the marketing-authorisation holder to submit any kind of proof (e.g. statement or contract) that it has obtained the dossier from the developer legally? H+V July 2008

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.

European Pharmacopeia (Ph. Eur.) - Harmonised Ph. Eur. Chapters 2.6.12, 2.6.13 and 5.1.4

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1. 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? H+V February 2012

Any changes to implement the harmonised methods (2.6.12 and 2.6.13) should be submitted under change code B.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 – B.II.d.1.a (type IA), but only in the following situations:

  • The currently registered microbial control limits (present situation) are totally in line with the pre-January 2008 (non-harmonised) situation and did not include any additional specified controls over and above the Pharmacopoeia requirements for that particular dosage form. In addition, the proposed controls are totally in line with the harmonised monograph.

If for any reason these criteria are not met, a type IB variation (B.II.d.1.z) should be submitted.

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.

Please note that this advice supersedes the questions and answers dated August 2007, which are now out of date.

European Pharmacopeia - Monograph on tablets

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1. How should industry apply the revised test subdivision of tablets in the European Pharmacopeia monograph on tablets? H+V October 2006

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 2001/82/EC, 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.

European Pharmacopeia (Ph. Eur.) - Harmonised chapter uniformity of dosage units

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Background. H+V June 2012

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.

1. How should industry demonstrate compliance with the European Pharmacopoeia with regard to uniformity of dosage units? H+V June 2012

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.

2. How should the new text be interpreted, in particular in relation to testing frequency (routine test / skip test / test on validation batches only)? H+V March 2006

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.

3. How can the text be interpreted in light of the compliance objection made by the Food and Drug Administration to the United States Pharmacopeia on the 2% relative standard deviation clause? H+V March 2006

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.

4. 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.

5. What is meant by single component and multiple component in the harmonised chapter 2.9.40? H+V July 2008

'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.

Impurities - Calculation of thresholds for impurities

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1. What is the basis for the calculation of thresholds to set limits for impurities in the finished product specification? H March 2015

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 in those Member States where the medicinal product is to be licensed.

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.

Impurities - Harmonisation of policies on setting specifications for potentially genotoxic impurities, heavy-metal-catalyst residues and class-1 solvent residues

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1. What is a reasonable policy for setting specifications for potentially genotoxic impurities which are theoretical or actual impurities in a drug substance manufacturing process? H June 2012

Different possible scenarios can be identified and the applicable policies to be applied for each of them are described below:

Example 1 – A potential genotoxic impurity

The definition for a potential genotoxic impurity is derived from the definition for 'potential impurity': an impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the (new) drug substance (ICH Q3A, glossary).

If a potential genotoxic impurity is just a theoretical impurity i.e. based on theoretical considerations but not found in practice at any key stage in the manufacturing process as demonstrated by studies during development of the manufacture, the impurity does not need to be included in the drug substance specification or a specification of an intermediate.

Example 2 – A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesis

If a (potentially) genotoxic impurity is formed or introduced in a step before the final synthesis step, it is considered possible to not include this impurity in the drug substance specification if it is controlled by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated by analysis results (use of spiking experiments are encouraged) that presence of this impurity does not exceed 30 % of the limit, derived either from threshold of toxicological concern (TTC) or otherwise defined acceptable limit etc., in the drug substance.

It is considered possible to apply skip testing if the level of the impurity in a synthesis intermediate does not exceed 30% of the limit, derived from either TTC or otherwise defined acceptable limit etc, in the intermediate. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the intermediate is needed. If the impurity exceeds 30% of the limit, derived either from TTC or otherwise defined acceptable limit etc., in the drug substance the impurity has to be included in the drug substance specification and the test has to be carried out on a routine basis.

Should a genotoxic impurity not be controlled at the intermediate stage, then the scenario of example 3 applies.

Example 3 - A (potentially) genotoxic impurity is formed or introduced in the last synthesis step

If a (potentially) genotoxic impurity is formed or introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip testing if the level of the impurity does not exceed 30% of the limit, derived from either TTC or otherwise defined acceptable limit etc., in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug substance specification is needed.

Definitions:

For the purpose of these questions and answers, the following definitions apply:

  • Genotoxic impurity: an impurity that has been demonstrated to be genotoxic in an appropriate genotoxicity test model, e.g. bacterial gene mutation (Ames) test.
  • Potentially genotoxic impurity: an impurity that shows (a) structural alert(s) for genotoxicity but that has not been tested in an experimental test model. Here potentially relates to genotoxicity, not to the presence or absence of this impurity.

 

2. In order to harmonise the policies to be applied for setting specifications for genotoxic impurities and heavy-metal-catalyst residues, what are reasonable policies to be applied when setting specifications for heavy-metal-catalyst residues? H June 2012

In order to harmonise the policy for setting specifications for metal residues with that for setting specifications for genotoxic impurities, some clarifications of the interpretation of sections 4.5 and 4.6 of the heavy-metal-catalyst guideline (EMEA/CHMP/SWP/4446/2000) are given below. 

Since it is the class-1 metals that are the most toxic metals with permitted daily exposures (PDEs) that approach the level of the threshold of toxicological concern (TTC) applied for genotoxic impurities, it seems reasonable that class-1 metals are the prime focus for harmonisation with the policy for genotoxic impurities while class-2 and 3 metals could be treated similarly but somewhat less strictly.

Example 1 – A class-1 metal is not used or suspected to be present in a synthesis process

Metals are not expected to be formed in synthesis processes. Only if deliberately introduced or suspected to be present for other reasons, residues of metals can be expected. If not used or suspected to be present, the metal does not need to be included in the drug substance specification or a specification of an intermediate.

Example 2 – A class-1 metal is formed or introduced prior to the final step of the synthesis

If a class-1 metal is introduced in a step before the final synthesis step, it is considered possible to not include this metal in the drug substance specification if it is controlled by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated by analysis results that the presence of this metal does not exceed 30% of the guideline limit in the drug substance. 

It is considered possible to apply skip testing if the level of the class-1 metal in a synthesis intermediate does not exceed 30% of the guideline limit in the intermediate. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the intermediate is needed. If the class-1 metal exceeds 30% of the guideline limit in the drug substance the impurity has to be included in the drug substance specification and the test has to be carried out on a routine basis.

Should a class-1 metal not be controlled at the intermediate stage, then the scenario of example 3 applies.

Example 3 – A class-1 metal is introduced in the last synthesis step

If a class-1 metal is introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip testing if the level of the metal does not exceed 30% of the guideline limit in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug substance specification is needed.

3. In order to harmonise the policies to be applied for setting specifications for genotoxic impurities and class-1 solvent residues, what are reasonable policies to be applied when setting specifications for class-1 solvent residues? H June 2012

In order to harmonise the policy for setting specifications for class-1 solvents with that for setting specifications for genotoxic impurities, some clarifications of the interpretation of annex I to the residual solvents guideline (CPMP/ICH/283/96 / CVMP/VICH/502/99): Specifications for class 1 and class 2 residual solvents in active substances (CPMP/QWP/450/03 / EMEA/CVMP/511/03) are given below. 

Since it is the class-1 solvents that are most toxic solvents and have permitted daily exposures (PDEs) that approach the level of the threshold of toxicological concern (TTC) applied for genotoxic impurities, it seems reasonable that clas- 1 solvents are the focus for harmonisation with the policy for genotoxic impurities.

Example 1 – A class-1 solvent is not used or suspected to be present in a synthesis process

If a class-1 solvent is just a potential impurity, not used directly or found in practice as demonstrated by studies during development of the manufacture, the class-1 solvent does not need to be included in the drug substance specification or a specification of an intermediate.

Example 2 – A class-1 solvent is formed or introduced prior to the final step of the synthesis

If a class-1 solvent is formed or introduced in a step before the final synthesis step, it is considered possible to not include this solvent in the drug substance specification if it is controlled by a suitable limit in a starting material or synthesis intermediate and if it is unambiguously demonstrated by analysis results that the presence of this solvent does not exceed 30% of the guideline limit in the drug substance.

It is considered possible to apply skip testing if the level of the solvent in a synthesis intermediate does not exceed 30% of the guideline limit in the intermediate. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the intermediate is needed. If the solvent exceeds 30% of the guideline limit in the drug substance the solvent has to be included in the drug substance specification and the test has to be carried out on a routine basis.

Should a class-1 solvent not be controlled at the starting material or intermediate stage, then the scenario of example 3 applies. 

Example 3 – A class-1 solvent is formed or introduced in the last synthesis step

If a class-1 solvent is formed or introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip testing if the level of the solvent does not exceed 30% of the guideline limit in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches.

Impurities - Residual solvents

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1. Is there a need to take the actual batch results into consideration when specifying class-2 residual solvents for active substances or medicinal products? H+V August 2007

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.

Manufacture of the medicinal products - Process control

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1. When validating a manufacturing process, if a common bulk is used to manufacture a series of products, how should the pilot batch size be decided upon? H+V September 2007

It is the applicant’s responsibility to select and justify the pilot batch size.

The joint Committee for Medicinal Products for Human Use and Committee for Medicinal Products for Veterinary Use guideline on process validation (CPMP/QWP/848/96, CVMP/598/99) 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.

Variation

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What is understood by “manufactured by complex manufacturing processes” in change code B.II.b.4 (change in batch size of the finished product) or in change code B.II.b.1 (replacement or addition of a manufacturing site)? H+V October 2015

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.

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