Prequalification of active pharmaceutical ingredients (APIs) is an independent procedure that identifies APIs that are of good quality and manufactured in compliance with WHO Good Manufacturing Practices (GMP).
API PREQUALIFICATION
History
The WHO Prequalification Team: medicines (PQTm) was first established as the then Prequalification of Medicines Programme in 2001, in response to the HIV/AIDS pandemic.
· Aim to guide UN agencies and other international organizations with respect to the quality of antiretroviral medicines, for supply to low-income countries.
Key outputs are the:
It benefits populations requiring treatment for priority diseases, and women and girls in need of medicines to ensure their reproductive health. But it also supports procurers, regulators, medicines quality control laboratories (QCLs), manufacturers and donors, in reaching their public health objectives.
APIs Eligible for Prequalification (EOIs)
The first step in the prequalification process of an active pharmaceutical ingredient (API) is its inclusion in an Invitation to Manufacturers to Submit an Expression of Interest for Product Evaluation (EOI).
EOIs are issued by WHO, by therapeutic area, following consultation with WHO disease Programmes and/or clinical specialists.
APIs used in the production of the FPPs included in the EOIs to FPP manufacturers are all eligible for prequalification, that is, selected APIs relating to the following therapeutic areas:
· Diarrhoeal disease
· Hepatitis B and C
· HIV/AIDS
· Influenza
· Malaria
· Neglected tropical diseases
· Reproductive health
· Tuberculosis
Benefits of WHO Prequalification
· Improved public health outcomes price competition and as a result enabled more medicines to be procured with the funds available so that millions more patients suffering from HIV/AIDS, tuberculosis or malaria can be treated. About 70% of WHO prequalified medicines are generic.
· Increased uptake of medicines designed specifically to meet low-income country needs including pediatric formulations for HIV/AIDS, TB and malaria, combination therapies to prevent HIV transmission from mothers to their new-born, affordable antimalarial, and second-line medicines for drug-resistant HIV and TB.
· Strengthened regulatory capacity in low-income countries (LIC) by providing professional development and training for their national medicines regulators, and opportunities to participate in innovative regulatory initiatives.
· Developed an effective mechanism that significantly reduces registration time for prequalified finished pharmaceutical products (FPPs) that helps minimize the time it takes to get medicines to those who need them. (A similar procedure is now being piloted for medicines with stringent regulatory authority approval.)
· Improved capacity to manufacture FPPs and active pharmaceutical ingredients to international standards by providing effective feedback and guidance during prequalification evaluation, and organizing training and technical assistance. The improved capacity is applicable not only to the FPP or API that has been submitted for evaluation but to any FPP or API that the manufacturer produces.
· Increased the availability of medicines testing services through prequalification of QCLs. Prequalified QCLs now exist in every WHO geographic region and are able to work together with their national medicines regulatory authority to monitor the quality of medicines on the national market, be these manufactured locally or imported.
PROCEDURE FOR WHO PREQUALIFICATION
Active Pharmaceutical Ingredient
Prequalification of active pharmaceutical ingredients (APIs) is an independent procedure that identifies APIs that are of good quality and manufactured in compliance with WHO Good Manufacturing Practices (GMP).
In order to become prequalified an active pharmaceutical ingredient (API) must be of good quality and manufactured in accordance with WHO Good Manufacturing Practices (GMP). Evaluation of an API for prequalification has two components: assessment of the API master file (APIMF) to verify compliance with WHO norms and standards, and verification that the site(s) of API manufacture comply with WHO GMP requirements.
Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment. A prequalified API is therefore clearly identifiable with a specific APIMF version. An APIMF version may be altered during prequalification assessment, or as a result of post-prequalification changes. Therefore, the version number of the current APIMF is included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference for the production and quality control of that API.
As well having their prequalified API(s) included in the WHO List of Prequalified Active Pharmaceutical Ingredients, successful applicants receive a WHO Confirmation of Active Pharmaceutical Ingredient Prequalification for each API for which they attain prequalification. This contains information regarding the accepted active ingredient specifications, and the assay and related substances test methods. It may be provided by the applicant to interested parties.
Routes to API prequalification
Manufacturing site requirements
All applicants must submit a site master file (SMF) for each manufacturing site of each API and intermediate involved in the preparation of the API for which prequalification is sought. An SMF is a document prepared by the manufacturer containing information with respect to the production and/or control of pharmaceutical manufacturing operations carried out at a named site, and to any closely integrated operations at adjacent and/or nearby buildings. If only part of the API production is carried out at a site such as analysis or packaging the SMF need describe only that operation.
Each API or intermediate manufacturing site must comply with WHO GMP. Manufacturers who submit an application for prequalification should therefore request inspection by WHO of the relevant manufacturing site(s) so that compliance with WHO GMP can be assessed. However, applicants whose manufacturing site(s) have already undergone a WHO GMP inspection, or inspection within the past two years by a member of the Pharmaceutical Inspection Co-operation Scheme (PICs) evidence of this inspection as part of their application for API prequalification, in lieu of a request for inspection by WHO.
Full API Assessment – APIMF Not Previously Assessed
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Components |
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APIMF |
The required technical content of the APIMF should follow the structure and format of the Common Technical Document (CTD).as per International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH. |
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Manufacturing Site |
The manufacturing site(s) of any API for which prequalification is sought must undergo inspection to verify compliance with WHO Good Manufacturing Practices (GMP). Irrespective of their GMP status, all applicants must submit a site master file (SMF) for each manufacturing site. |
Submission of an application for active pharmaceutical ingredient (API) prequalification involves preparation and submission of a number of documents in paper and/or electronic format, as follows:
· The covering letter (paper format).
· A labelled CD or DVD containing.
o The covering letter (in Word or text-selectable PDF (portable document) format)
o A completed API prequalification application form (in both Word and PDF format).
o The API master file (APIMF) correctly formatted.
o A site master file (SMF) for each manufacturing site (Word or text-selectable PDF).
o Evidence of compliance with WHO Good Manufacturing Practices (GMP), or a request for inspection by WHO for each manufacturing site (Word or text-selectable PDF).
Responses to requests from WHO for information should include:
· The covering letter (paper format).
· A labelled CD or DVD containing.
o An electronic version of the covering letter (in Word or text-selectable PDF format).
o The responses to the questions raised (in Word or text-selectable PDF format).
o If requested, an electronic version(s) of any APIMF subsections that have been amended or updated during the assessment process.
Since further questions may arise, APIMF holders should not submit a revised version of their APIMF when they submit their responses to questions, unless specifically requested to do so and/or any issues have been resolved.
An APIMF submitted as part of an application for full assessment should follow the format for module M4Q-R1 of the common technical document format of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (commonly known as ICH). This includes following the M4Q-R1 headings and sub-headings.
The APIMF should include a table of contents with headings listed in accordance with the 3.2.S.1 to 3.2.S.7 section levels of M4Q-R1.
If the APIMF is being used only for API prequalification, dividing it into an open (i.e. applicants) part and a restricted (i.e. confidential) part (as required under the APIMF amendment procedure) is not mandatory. Nevertheless, division of the document into an open
part and a restricted part is strongly encouraged. The document version number should appear on the cover page of each of the open and restricted parts, together with the name of the API and APIMF holder’s name.
If the APIMF is divided into two parts the recommended system of version numbering (see section below) should be adhered to.
Documents should be paginated throughout. Page numbers may be set at 1 at the start of each section or subsection.
The use of PDF bookmarks or hyperlinks is encouraged. Ideally, bookmarks will be inserted to at least the 3.2.S.X.X level. In very detailed sections, use of additional bookmarks is suggested.
Officially certified translations should be provided for any documents the originals of which are not in English.
Submitted documents should enable an assessor to navigate between sections easily and to copy critical information. Inclusion of summaries, conclusions, and most importantly analysis and discussion of raw data, will facilitate assessment of the API information provided.
The open and restricted parts of the document should each be assigned a unique document version number. This number should appear on the document cover page, together with the name of the API and the APIMF holder’s name, indicate whether it refers to the open or restricted part of the APIMF, and give the date of issue. For example:
Drugs Inc/Artemether/OP/01/Feb-2013.
If a replacement subsection of an APIMF is issued by the applicant, it is referred to as an amendment and should be assigned an amendment version number. The amendment version number should include reference to the “parent” open part document.
For example:
Drugs Inc/Artemether/OP/01/Feb-2013/Amend 01 – April-2013.
A change to the open-part version number, from OP/01 to OP/02 for example, would indicate the availability of a complete and revised version of the open part document. This new version (AP/02) would be assumed to incorporate all the accepted amendments made to the earlier version (AP/01), including all applicable CTD headings.
Applicants may choose to submit their APIMFs in accordance with non-eCTD (Common Technical Document) electronic submission (NeeS) requirements, or as two bookmarked text-selectable PDF documents (an open part and a restricted part). But whichever route is chosen, APIMF holders should refer to the NeeS guidance. It includes information specific to the submission of information within the European Union but it provides excellent technical guidance on electronic document formats.
· No single electronic file should exceed 50 MB in size.
· File or folder names should not exceed 64 characters in length.
· Path lengths should not exceed 180 characters, including the file name, and extension. Abbreviated file or folder names can be used.
· The use of special characters in folder or file names should to be avoided in order to prevent software conflicts.
These special characters include:
· Angle brackets (<>).
· Ampersand (&).
· Asterisk (*).
· Backslash (\.)
· Braces ({}).
· Colon (:).
· Forward slash (/).
· Number sign (#).
· Percent (%).
· Plus sign (+).
· Pipe (|).
· Question mark (?).
· Quotation mark (").
· Tilde (~).
A site master file (SMF) must be submitted ? as an electronic copy (i.e. on CD/DVD) for each manufacturing site of the API.
An SMF is a document prepared by the manufacturer containing information with respect to the production and/or control of pharmaceutical manufacturing operations carried out at a named site, and to any closely integrated operations at adjacent and/or nearby buildings. If only part of the API production is carried out at a site such as analysis or packaging the SMF need describe only that operation.
WHO assessment of GMP compliance at the site of API manufacture may take into consideration inspections performed previously at that site by WHO or by a stringent regulatory authority (SRA) or by a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S). In order to be taken into consideration any such inspection should have been performed within two years of submission of application and must be relevant to the specific API for which evaluation by WHO is now being requested. Any information available information that demonstrates WHO GMP compliance at the API manufacturing site should therefore be submitted. It may include, but is not limited to, GMP certificates, inspection reports, and corrective and preventive action reports, and the most recently completed product quality review report.
An application for the APIMF procedure and subsequent responses to questions raised by WHO assessors should be sent to:
World Health Organization
WHO Prequalification Team: medicines
HIS/EMP/RHT/PQT Room 613
20, Avenue Appia
1211 Geneva 27
Switzerland.
Abridged Assessment – APIMF Assessed Previously Using APIMF Procedure
If an active pharmaceutical master file (APIMF) was accepted previously by WHO during prequalification of a finished pharmaceutical product (FPP), an abridged rather than a full assessment of the APIMF will be carried out when the relevant API is submitted for prequalification.
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Components |
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APIMF |
APIMF is generally reviewed only with respect to key information and for conformity with administrative requirements. Before submitting an application for API prequalification, the applicant should ensure that the details of the APIMF held by WHO are up to date. This is likely to necessitate submission of an APIMF amendment. Once the APIMF has been completed, and a revised and updated APIMF accepted by WHO, an application for API prequalification can be submitted. Even if an APIMF undergoes abridged assessment, WHO may request further information to enable it to verify that the APIMF meets all WHO prequalification requirements. |
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Manufacturing Site |
The manufacturing site(s) of any API for which prequalification is sought must undergo inspection to verify compliance with WHO Good Manufacturing Practices (GMP). Irrespective of their GMP status, all applicants must submit a site master file (SMF) for each manufacturing site. |
Submission of an application for abbreviated assessment of an APIMF, previously submitted under the APIMF procedure, and now submitted for API prequalification, involves preparation and submission of a number of documents in paper and/or electronic format, as follows:
Submission of an APIMF is not required but the applicant should have already ensured that the APIMF held by WHO is fully up to date. If the APIMF is not up to date, an APIMF amendment should be submitted and accepted before the application for prequalification is made.
An application for the APIMF procedure and subsequent responses to questions raised by WHO assessors should be sent to:
World Health Organization
WHO Prequalification Team: medicines
HIS/EMP/RHT/PQT Room 613
20, Avenue Appia
1211 Geneva 27
Switzerland
Abridged Assessment – API Accepted Previously by an Authority applying stringent standards
If an active pharmaceutical master file (APIMF) had already been assessed and accepted by an Authority applying stringent standards, an abridged rather than a full assessment of the APIMF will be carried out when the relevant API is submitted for prequalification. This avoids duplication of regulatory work.
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APIMF |
The applicant should request that WHO conduct an abridged assessment, by reviewing the relevant authorities’ assessment report, rather than undertaking its own assessment of the APIMF.
This includes APIMFs previously assessed and accepted by the US Food and Drug Administration (US FDA), or the European Directorate for the Quality of Medicines (EDQM): i.e. applicants may request review of the relevant assessment report, in lieu of assessment by WHO.
The authority may have conducted multiple rounds of assessment, and/or multiple changes may have been made since approval was granted. The chronological summary of assessments should therefore be outlined clearly in the application, and any changes that have been made over time to the details of the APIMF should be described clearly.
If the details of the API submitted to WHO and of the API accepted by the SRA differ, these should be detailed in the submission. Only differences that are not significant are allowable.
After the application for prequalification has been received, WHO will contact the agency (e.g. US FDA or EDQM) and request access to the relevant assessment report. |
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Manufacturing Site |
If a Good Manufacturing Practices inspection of the API's sites or sites of manufacture has been carried out within the past two years by a member of the EDQM (PICs) the applicant may submit evidence of this inspection, with a request that inspection be waived, as part of its application for prequalification. If recent evidence of compliance with GMP cannot be provided, the applicant should request inspection of the manufacturing site(s) of the API. |
Submission of an application for abridged assessment of an active pharmaceutical ingredient master file (APIMF), previously approved by an Authority applying stringent standards for API prequalification, involves preparation and submission of a number of documents in paper and/or electronic format, as follows:
Please note that minor differences between the details currently held by the Agency and those that are being submitted to WHO are permissible.
Following receipt of the application, WHO will contact the Agency and request that it provide access to its assessment report.
The applicant may provide information additional to that outlined above, provided it is clear and well summarized.
World Health Organization
WHO Prequalification Team: medicines
HIS/EMP/RHT/PQT Room 613
20, Avenue Appia
1211 Geneva 27
Switzerland
GUIDELINES FOR ACTIVE PHARMACEUTICAL INGREDIENT MASTER FILE (APIMF)
INTRODUCTION
Information on the preparation control and stability of an active pharmaceutical ingredient (API) intended for use in a prequalified multisource (generic) finished pharmaceutical product (FPP) can be provided by the API master file (APIMF) procedure.
It is a scheme for manufacturers of APIs that are used in medicinal products for HIV, TB, Reproductive Health and Malaria.
Advantages of the APIMF Procedure
The main objective of the Active Pharmaceutical Ingredient Master File (APIMF) procedure is to allow valuable con?dential intellectual property or “know-how” of the manufacturer of the active pharmaceutical ingredient (API) to be protected, while at the same time allowing the applicant for prequali?cation or prequali?cation variation (from now on named in the text as the applicant) to take full responsibility for the ?nished pharmaceutical product (FPP) and the quality and quality control of the API.
The WHO Prequali?cation Programme thus has access to all the information necessary for an evaluation of the suitability of the use of the API in the FPP.
The APIMF procedure is a possibility offered to applicants for WHO prequali?cation of medicinal products and the manufacturers of their APIs.
Other means of submission of scienti?c data on the API include:
In addition, the WHO pharmaceutical starting materials certi?cation scheme (SMACS) can be used to attest the relevant data as covered in the scheme.
These guidelines are used to assist applicants in the compilation of the information on APIs in their dossiers for prequalification or when submitted during a variation on a prequalified product when the APIMF procedure is used.
Basic Structure of Prequalification Process.
Submission of dossier (AP) through FPP manufacturer or submission of the dossier (AP+RP) directly to WHO.
CONTENT OF APIMF
The information is organised and presented in the structure and format described in ICH guidelines which follows Common Technical Document (CTD) within the framework of International Conference on Harmonisation (ICH).
Common Technical Document:
The scienti?c information (CTD) in the APIMF should be physically divided into two separate parts:
The electronic version of the APIMF should also meet:
In addition to the OP and RP, the APIMF should contain a table of contents and a separate quality summary for the OP and the RP.
The OP and RP should each have a version number given by the APIMF holder.
The structure of the version numbers should be unique and the following structure is suggested:
Amendments should be numbered to reflect the “parent” APIMF version they below to. Whereas an updated APIMF should be given a new version number.
Open part (OP)
The Op contains the information that the APIMF holder regards as non-confidential to the applicant.
It is emphasized that the OP is still a con?dential document that cannot be submitted to third parties without the written consent of the APIMF holder. In all cases the OP should contain suf?cient information to enable the applicant to take full responsibility for an evaluation of the suitability of the speci?cations for the API to control the quality of this API for use in the manufacture of a speci?ed FPP.
Restricted part of APIMF
The RP should contain the remaining information, such as a detailed description of the individual steps of the manufacturing method (reaction operating conditions, data on validation and evaluation of critical steps) and the quality control during the manufacturing method of the API. Information relevant to the applicant such as that on impurities should be discussed in the RP, but it may be also submitted in the OP if considered necessary to enable the applicant to take full responsibility for its product.
USE OF THE APIMF PROCEDURE
The relationship between the quality of the API and its use in the FPP needs to be justi?ed in the relevant product dossier.
The APIMF procedure should be used for APIs where a professed standard is declared, i.e. where no monograph exists in The International Pharmacopoeia, European Pharmacopoeia, United States Pharmacopeia or Japanese Pharmacopoeia, or where a monograph exists but a manufacturer’s in-house standard is declared. The APIMF procedure can also be used when APIs are described in The International Pharmacopoeia, European Pharmacopoeia,
United States Pharmacopeia or Japanese Pharmacopoeia.
A Drug Master File (DMF) of an API (active substance) assessed by a drug regulatory authority in the International Conference on Harmonisation (ICH)-participating and associated countries can be accepted without further evaluation provided that:
The holder of the DMF should also declare in writing that there have been no changes to the manufacture of batches of API to be supplied for WHO prequali?cation and to the DMF content since its acceptance by the ICH participating or associated countries.
STEPS OF THE APIMF PROCEDURE
The APIMF holder should submit to WHO:
In addition, the APIMF holder should submit to the relevant FPP applicant (s):
It is the responsibility of the APIMF holder to notify the applicants and WHO about any changes to the OP and/or RP.
APIMF holder responsibilities
Benefits to API manufacturers
WHO requires that any APIMF updates made in relation to one prequalification dossier should apply to all other FPP dossiers referencing that specific APIMF It is the responsibility of the APIMF holder to notify the applicants and WHO about any changes to the OP and/or RP, so that the applicants can update all affected prequalification dossiers accordingly and file the appropriate variation(s) with WHO as necessary.
Prequalification process for APIMF
CONTENT OF THE PRODUCT DOSSIER WHEN THE APIMF PROCEDURE IS USED
The applicant for prequali?cation is responsible for ensuring that he or she has access to the relevant information concerning the current manufacture of the API.
The speci?cations used by the applicant to control the quality of the API should be unambiguously laid down in the product dossier. The applicant for prequali?cation should quote the OP version number. The version of the OP in the prequali?cation dossier should be the most recent and it should be identical to the OP as supplied by the APIMF holder to
WHO as part of the APIMF.
The applicant should include all relevant details from the OP in the Quality summary of the product dossier. Aspects of the APIMF that are speci?cally relevant to the FPP under consideration should be highlighted in this summary.
In the case of a single supplier/manufacturer of the API, and where the APIMF, a valid certi?cate of suitability of pharmacopoeial monographs or the WHO API prequali?cation procedure is used, the speci?cations of the applicant for the API in the product dossier should in principle be identical to those of the APIMF, the certi?cate of suitability or the prequali?ed API. The applicant does not, however, need to accept redundant speci?cations, unnecessarily tight speci?cation limits or outdated analytical methods. In cases where the applicant uses a different analytical method to the one described in the APIMF, both methods should be validated.
Technical speci?cations relevant to the FPP, which are normally not part of the speci?cations in the APIMF (e.g. particle size), should be part of the API speci?cations submitted by the applicant for prequali?cation in its product dossier.
In cases where there is more than one supplier/manufacturer of API using one of the APIMF, certi?cate of suitability or API prequali?cation procedures, there should be a core of one single set of speci?cations for 110the API presented by the applicant for prequali?cation that is identical for each supplier. It is acceptable to lay down in the speci?cation more than one acceptance criterion and/or analytical method for a specific single parameter with the statement “for API from supplier X” (e.g. in the case of residual solvents).
As for FPPs, APIMF holders should keep their APIMFs up to date on the actual synthesis or manufacturing process. The quality control methods should be kept in line with the current regulatory and scienti?c requirements. APIMF holders should not modify the contents of their APIMF (e.g. manufacturing process or speci?cations) without informing each applicant and WHO when a change introduced requires the ? ling of a variation to the product dossier. Changes in the RP of an APIMF not requiring ? ling of a variation, should, however, be noti?ed to WHO. Before implementation, any change to the APIMF should be reported to WHO by every applicant by means of an appropriate variation procedure.
A covering letter should be provided. In cases where the contents of the APIMF cannot be changed for a certain period of time, the APIMF holder should still provide the aforementioned data to the applicant and to WHO, making reference to this reason and requesting a later date of implementation. Before implementing any change to the APIMF WHO should be reported by means of appropriate variation procedure. Along with the covering letter.
The covering letter sent by the APIMF holder to WHO should contain the following information:
API-related changes
The fundamental responsibilities of API and FPP manufacturers remain the same, but the revised guidance documents
New APIMF Amendment Guidance
Four types of changes classes are envisaged
1. Annual Amendment Notifications (AAN)
2. Immediate Amendment Notifications (IAN)
3. Minor amendment (Amin)
4. Major Amendment (Amaj)
APIs for which the API master file and manufacturing site(s) meet prequalification requirements, are included on the WHO List of Prequalified Active Pharmaceutical Ingredients, together with the applicant’s name, and corresponding product and manufacturing site details.
API Prequalification
Application
An application should consist of:
Decision
WHO List of Prequalified APIs Includes
Confirmation of API PQ document issue date.
Intended for: UN agencies, National medicine authorities, FPP manufacturers, public
The above mentioned list is available in the site.
Common requirements
There are common issues that should be considered for all sections of your APIMF.
2. State the obvious
For every CTD subsection there are a number of issues addressed in guidance. Not all will be applicable. If they are not applicable, say so.
E.g. If the manufacturing process does not use recovered solvents, include a sentence saying:
"No recovered solvents are used in the manufacturing process."
3. Discussion
Whenever a section of the guideline uses words like discuss, compare, justify etc.it is expected that the limit, specifications, conclusion or decision are explained.
Frequent API Issues
1. Starting material quality
This means the API-SM cannot be assumed to be the molecule used in the first step at the API manufacturer's factory.
2. Polymorphism
Unexpected appearance or disappearance of a polymorphic form may lead to serious pharmaceutical consequences.
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Polymorphism Known |
Polymorphism not known |
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Highly soluble API |
The polymorphic form produced should be assigned. |
The crystalline form produced should be determined. |
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Non-highly soluble API |
The polymorphic form produced should be assigned. Stability of the form should be determined. |
The crystalline form produced should be assigned. Crystallinity under different crystallization condition should be investigated. Stability of the form should be determined. |
3. Specifications
4. Stability deficiencies
PQP has specific storage statements that should be adhered to:
Protect from moisture can be used when long-term trials at 30ºCwere performed at the lower humidity (65%RH), or where there are known concerns regarding the API.
Protect from light should be used when the API is known to be photosensitive, or where photo stability is unknown, i.e.no pharmacopoeial statement and no photo stability trials were submitted.
If there is no data available at 30ºC then the API manufacturer is requested to commit to initiating long-term stability trials at 30ºCand to change the recommended storage conditions to store below 30ºC once 24 months data has been accumulated.
If the API is known to be unstable at 30ºC then data is expected at 25ºC.
If there have been corrections or revision to the retest period and storage condition, this information must be incorporated in future revised APIMF versions.
5. Impurities
Impurities observed below the ICH identification threshold need not be individually specified in the specifications. They can be controlled under the limit for any unspecified impurity.
Impurities above the ICH identification threshold need to be identified and individually specified in the specifications.
Who site
