During the 2022-2023 work plan, SEARN also reflected on strategies and good practices to reduce the use of reference standards.

Indeed, procuring reference standards may be difficult in certain areas of the world due to delays in their delivery and the cost of purchase. The number of reference substances prescribed in authoritative analytical procedures shall therefore be reduced, if possible.

Acknowledging this situation, The International Pharmacopoeia applies, for example, the following strategies and practices when elaborating monographs:

• in situ preparation of impurities for identification of related substances/impurities;
• establishment of compounded reference substances that contain several potential impurities for identification;
• quantification of impurities by comparing their detector responses with the response of the parent compound in a diluted sample solution along with the establishment of correction factors to compensate for differences in the responses of the impurity and the parent compound;
• provision of International Infrared Reference Spectra (IIRS) for use in identification tests;
• provision of assay methods not requiring reference substances, like titrations and ultraviolet spectrophotometry using absorptivity values. These methods shall be provided as alternatives in particular to chromatographic assays in monographs for pharmaceutical substances.

These strategies are only be applied when, during the elaboration of the methods, evidence has been obtained demonstrating that the intended measures do not compromise the quality of the analytical results or the ability of the tests to conclusively demonstrate conformance to the applicable standards.

A regional list of suppliers of reference standards to support reliance was developed, and will be kept up to date if any supplier was assessed:

SEARN Regional list of suppliers of reference standards

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The possibility of sharing samples between NQCLs is a tool to strengthen the individual capacity for testing in each of the member states, as well as to strengthen the network in terms of a consolidated approach to testing.

Assessment of needs for testing samples outside the NQCL

Due to numerous reasons, such as lack of access to a certain analytical technique and unavailability of reference standards and/or materials, a NQCL may need to have access to another laboratory in which it can rely on for testing.

Also, as part of the market surveillance plan of each of the SEARN members, an exchange programme for planned samples between NQCLs could address the issue of lack of availability of some reference standards and enable a better use and distribution of resources.

The NQCL , herein designated as “interested NQCL”, should clearly define priorities for testing samples in other NQCL, herein designated as “testing NQCL”, such as:

• Samples for routine testing (for instance, for market surveillance purpose), for which there is currently no testing capacity at the NQCL:
• Samples for non-routine testing (for instance, for investigating quality defects or possible substandard and falsified medicines), for which there is currently no testing capacity at the NQCL.

These should be considered as non-exhaustive examples.

SEARN NQCL Capacities database

To support the identification of NQCLs which could provide support for a certain tests, SEARN developed a simple database using an excel spreadsheet, which is shared between all the members of SEARN.

Please refer to AP9 for more information.

Guidance for selecting a testing NQCL and practical aspects to consider

General requirements

Please refer to SEARN AP5 Strategy to facilitate reliance.

Specific requirements

Prior experience with a specific analytical technique, such as gas chromatography coupled with mass spectrometry, dissolution testing or any other analytical technique should be available, if needed.

The testing NQCL should be able to:

• demonstrate prior experience with the product to be tested, or be able to prepare the testing prior to receiving the sample,
• perform the method verification, or if applicable, the method validation;
• inform about the minimum amount of sample required for the testing requested.

The testing NQCL should be able to provide a date for issuance of the final test report / certificate of analysis.

Ad hoc testing

Based on the priorities established, the NQCL should prepare a call for Expression of Interest (EoI) to any potential testing laboratory, preferably another NQCL, clarifying which are the testing requirements, such as:

• which are the tests to be performed,
• which is the testing method to be used – if applicable,
• number of samples to be tested,
• transport and storage requirements for the samples,
• timelines for the delivery of results,
• and any other testing requirements.

The bidding process should also be detailed and clarified in the EoI, as well as specific financial details and timelines for submission of proposals.

Information about specific custom requirements to be expected for the shipping of samples and entry should also be requested to the bidder(s).

Systematic testing

In order to facilitate a request for testing, interested NQCLs can also establish MoU or contracts with another NQCL , the testing NQCL”), to perform specific testing on their behalf.

The requirements of this agreement may include the information detailed in sections “Specific requirements” and “Ad-hoc testing”, but should address specifically the needs of the interested NQCL. Information on who is responsible for certain aspects, such as acquiring reagents, materials, reference standards, costs for shipping the samples and customs fees as well as maximum number of samples to be tested per period of time, should also be addressed, for transparency purposes.

NQCLs are encouraged to address this possibility with their top management, to determine feasibility and acceptability, as well as to establish the maximum capacity that the NQCL is able to provide to other NQCLs in general terms and for a specific period of time.

Financial aspects

Ideally, an exchange programme between NQCLs, with a very limited number of samples to be tested, for instance, under the testing NQCL national market surveillance programme, would be cost free, with the exception of the shipping and customs fees. However, this situation will configure more the exception than the rule.

Hence, the interested NQCL should ensure that funding is available to support testing, if this is required in any MoU or contract. When national funding is not available, support from development partners or WHO could be explored.

Provisions should be in place to ensure that the interested NQCL is able to perform the payment in the currency required by the testing NQCL, as described in the terms of the signed MoU or contract. However, challenges are expected to arise at this level, as national requirements for currencies used for this purpose may not be acceptable both for the interested parties, and this should be clearly discussed.

Engagement with the International Meetings of World Pharmacopoeias

In order to optimize the use of reference standards and facilitate access for SEARN members, SEARN engaged the main pharmacopoeias by participating in the 15^th International Meetings of World Pharmacopoeias, New Delhi, India, 6- 7 February 2025.

During the meeting, the Chair of WG1 Quality highlighted that countries without pharmacopoeias often have less resources but require to spend much more on reference standards as manufacturers refer to different pharmacopoeias.

He advocated for:

1. reduced use of RS in monographs
2. enabling use of RS from different pharmacopoeias
3. Develop / communicate access schemes for NQCLs

During IMWP, the participants representing world pharmacopoeias ‘noted the importance of finding a mechanism to hear and consider the perspectives of pharmacopoeias not participating in IMWP as well as those of countries without a pharmacopoeia’.

SEARN agreed to continue engaging with IMWP in the future.

Engagement with producers of reference standards

In order to support its engagement with producers of reference standards and identify and advocate for access programmes for NRAs, SEARN decided to conduct a series of interviews.

In order to support this plan of actions, a discussion guide was developed.

SEARN identified and prioritized the main needs for which there is a need for developing risk-based approaches through identifying minimum standards for screening strategies as follows:

1. Sterility
2. Identification of sildenafil citrate
3. Identification of dexamethasone
4. Identification of amoxicillin
5. Identification of ciprofloxacin
6. Identification of clonazepam

In general, with respect to active substances, a general high-level strategy was proposed, which would require support from a laboratory willing to support the development of these methods:

1. TLC method for identification
2. HPLC to quantify if suspicion

A survey was conducted to identify the needs for biological reference standards in SEARN countries.

Highlights:

• About half of SEARN members indicated that their laboratory has the capacity to conduct tests requiring biological reference standards. When it was not the case, several members indicated intentions to develop this capacity.
• SEARN members indicated that:
  • they mostly require biological reference standards for vaccines/biological medicines/IVDs for screening and confirmatory tests for market control and surveillance, and marketing authorization, which would require further discussion.
  • A few members also indicated needs related to lot release and export.
• Members were also requested to rank the top 5 biological reference standards they required for testing biological medicines, vaccines, and IVDs. While rabies vaccines and anti-rabies immunoglobulin slightly stood out, this part of the survey could not elicit clear shared needs.
• Challenges related to accessing biological reference standards also appeared diverse:
  • Only a minority of respondents selected each proposed challenge.
  • Costs was the most identified challenge (3 responses), followed equally (2 responses) by the absence of supplier, custom clearance and delays in receiving the reference standards.

Based on these results, SEARN considered that further in-depth discussion on the need for biological reference standards and their use was required. These discussions will also provide an opportunity to better consider biological reference standards in the strategy on access to reference standards, which was mostly developed considering chemical reference standards.