During its meeting on 13 December 2022, the SEARN Steering group requested that a capacity building program is set up on the issue of the integrity of starting materials and the supply chain, in the context of the persisting issues of substandard oral liquid medicines.

Since October 2022, the WHO has shared numerous Medical Product Alerts reporting contamination of liquid oral medicines with diethylene glycol (DEG) and /or ethylene glycol (EG), which are toxic to humans when consumed and can prove fatal. On 23 January 2023, WHO issued an urgent call to action to countries to prevent, detect and respond to incidents of substandard and falsified medical products.

This series of serious events has triggered considerable concerns in the region and at the global level. Further, although similar events contributed to laying down the basis of modern medical products regulation over one hundred years ago, the regular repetition of similar tragedies suggest that regulatory systems can be further strengthened to address this issue.

Considering the above, the Assembly created in January 2023 a dedicated action point (AP14) in the SEARN workplan, led by Working Group 1 (WG1) Quality.

The WHO Good Manufacturing Practices and the Good storage and distribution practices provides the following definitions:

• Active pharmaceutical ingredient (API) (TRS 986). Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
• Contamination (TRS 986). The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or intermediate during production, sampling, packaging or repackaging, storage or transport.
• Cross-contamination (TRS 986). Contamination of a starting material, intermediate product or finished product with another starting material or product during production.
• Falsified product (WHO Good storage and distribution practices for medical products). A product that has been deliberately and/or fraudulently misrepresented as to its identity, composition or source. Such deliberate/fraudulent misrepresentation refers to any substitution, adulteration or reproduction of an authorized product, or the manufacture of a product that is not an authorized product. “Identity” shall refer to the name, labelling or packaging or to documents that support the authenticity of an authorized product. “Composition” shall refer to any ingredient or component of the product in accordance with applicable specifications authorized/recognized by the national regulatory authority (NRA). “Source” shall refer to the identification, including name and address, of the marketing authorization holder, manufacturer, importer, exporter, distributor or retailer, as applicable
• Finished product (TRS 986). A finished dosage form that has undergone all stages of manufacture, including packaging in its final container and labelling.
• Good distribution practices (GDP) (WHO Good storage and distribution practices for medical products). That part of quality assurance that ensures that the quality of a medical product is maintained by means of adequate control of the numerous activities that occur during the trade and distribution process, as well as providing a tool to secure the distribution system from falsified, unapproved, illegally imported, stolen, substandard, adulterated and/ or misbranded medical products.
• Good manufacturing practices (GMP) (WHO Good storage and distribution practices for medical products). That part of quality assurance that ensures that pharmaceutical products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.
• Material (WHO Good storage and distribution practices for medical products). A general term used to denote starting materials (APIs and excipients), reagents, solvents, process aids, intermediates, packaging materials and labelling materials.
• Pharmaceutical excipients (TRS 885). Substances, other than the active ingredient, which have been appropriately evaluated for safety and are included in a drug delivery system to: aid in the processing of the drug delivery system during its manufacture; protect, support or enhance stability, bioavailability, or patient acceptability; assist in product identification; or enhance any other attribute of the overall safety and effectiveness of the drug during storage or use.
• Starting material (TRS 986). Any substance of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials.
• Substandard products (WHO Good storage and distribution practices for medical products). “Substandard” medical products (also called “out of specification”) are authorized by NRAs but fail to meet either national or international quality standards or specifications – or, in some cases, both.

Considering the issues which triggered this work, and the pre-existing regulatory mechanisms, it was agreed to focus this strategy on ensuring the integrity of excipients, with adequate consideration for substandard and falsified excipients. The strategy should in general look after all excipients, favoring effective implementation of what already exists. The strategy should also include a focus and recommend actions on excipients which may include impurities posing serious risks to public health. To date, only EG and DEG were identified for prioritization.

To ensure the integrity of excipients through a risk-based approach.

Excipients are an essential component of drug formulations, and any deviation or contamination in their quality or quantity can affect the drug's performance, stability, and safety.

The supply chain and life cycle

The supply chain for excipients is a complex network of activities that involves multiple players, including excipient manufacturers, distributors, brokers, re-packers and end-users such as pharmaceutical manufacturers.

The supply chain typically consists of the following stages:

Raw material sourcing: Excipients can be derived from various sources, including natural, synthetic, or semi-synthetic materials. Raw materials are sourced from suppliers and undergo quality control measures to ensure their suitability for excipient manufacturing.

Excipient manufacturing and quality control: Excipient manufacturers use various processing techniques to produce excipients in different forms, such as powders, liquids, and gels. The manufacturing process involves multiple steps, including mixing, granulation, drying, and milling, followed by quality control testing to ensure the excipients meet the required specifications.

Excipient distribution: Excipients are distributed to brokers, distributors, and end-users such as pharmaceutical manufacturers. Excipient distributors may be local or global, and they often maintain inventories of excipients to provide quick and reliable delivery to customers.

Storage and transportation: Excipients must be stored and transported under controlled conditions to prevent contamination or degradation. Excipient manufacturers and distributors use various techniques to maintain the stability and quality of excipients during storage and transportation, such as temperature control, moisture control, and packaging. Excipient manufacturers, distributors, traders, and end users should follow WHO guidelines for good storage and distribution practice (GSDP)

End-use manufacturing: Pharmaceutical manufacturers use excipients to formulate their products, such as tablets, capsules, creams, injectables and other dosage forms. The excipients must meet specific quality and safety standards to ensure the safety and efficacy of the final product.

Overall, the supply chain for excipients involves a complex multi-layer global network of activities that require coordination and collaboration between various players to ensure the quality, safety, and reliability of excipients. The increasing complexity of the global supply chain brings with it an increased risk in excipient security. This requires implementation of prevention, detection, and response strategies and actions, relying on coordination and collaboration between various players.

Formalised risk assessment for excipients

In March 2015 the European Commission published such Guidelines entitled “Guidelines on the formalized risk assessment for ascertaining the appropriate GMP for excipients of medicinal products for human use” according to which the manufacturing authorization holders have now to perform a formalized risk assessment of the excipients used in their drug products and of the excipients manufacturer where they purchase the excipients.

Based on this, a control strategy has to be established in order to manage and mitigate the risks of the use of the excipients Article 47 of Directive 2001 83 /EC provides that “The Commission shall adopt guidelines on the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients.

To perform the formalized risk assessment, the medical product manufacturer should refer to ICH Q9 especially tools (such as HACCP) as well as other QRM guidelines such as WHO TRS on QRM, PIC/S Annex 20.

Based on the determination of GMP requirement for an excipient manufacturer, a gap analysis should be performed by the FPP manufacturer and evidence should be maintained If excipient manufacturers are subjected to any GMP and quality system requirement in certain jurisdictions, it should be  considered.

Based on the formalized risk assessment, the medical product manufacturer establishes the risk profile of the excipient, accordingly, establishes GMP requirements for the pharmaceutical excipient manufacturers (e g GMP for APIs or GMP for FPPs or GMP for sterile FPPs).

PIC/S (PI 045 1 1 July 2018 also published Guidelines on the formalized risk assessment for ascertaining the appropriate GMP for excipients of Medical Products for human use.

Stakeholders may also refer to the US FDA Generally Recognized as Safe (GRAS) which lists substances that are generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use.

Further, It is a usual pharma industry practice to sample excipients using a statistical approach (such as under root n+1). A risk-based approach should be adopted by the FPP manufacturers to sample 100% (like for APIs) excipients where there is a potential risk of contamination, cross-contamination, and mix-up. This can be determined based on the manufacturing process of a certain excipient. In addition, based on the composition of the FPP, the FPP manufacturer should take more samples of those excipients whose % is higher than other excipients.

Similarly, it is a common industry practice to perform “paper assessment” of excipient manufacturers instead of performing “on-site” assessment to have more insight about the state of the excipient manufacturers.

Risk factors and risk mitigation measures to consider

Risk factors to consider include:

• Risk of the excipient/impurity, including route of synthesis (like for the APIs) from excipient manufacturers and assess potential risk of contamination, degradation or impurities during the manufacturing, storage and transportation of excipients.
• Excipients most at risk of falsification (also considering difficulties of detection)
• Manufacturing site producing various excipients with little or no cleaning validation
• Supply Chain – which parts are the most vulnerable
• Data integrity – valididy / traceability of the data
• Legality/history of compliance from the manufacturers
• The pharmaceutical dosage form and the function of the excipients
• shortage of excipients

Risk mitigations to consider include:

• vendor qualification and close attention to the procurement, handling (storage & usage), and distribution stages
• Effective testing of excipients for contaminants
• Periodic evaluation of high risk excipients suppliers trend analysis

It is critical for countries, regulators, and industry to implement pragmatic and evidence based policies and strategies for market control and surveillance of pharmaceutical excipients without affecting access and costs of pharmaceutical products.

The TRS 929 - Annex 4: WHO guidelines for sampling of pharmaceutical products and related materials, 2005 provides general guidance on surveying the national markets for the quality of drug products in accordance with national drug quality surveillance programmes for marketed products, whether registered for sale or compounded in pharmacies.

Critical measures for ensuring the quality, safety, and efficacy of pharmaceutical products through maintenance of robust market control and surveillance of pharmaceutical excipients, can reduce the risk of harm to patients and ensure the availability of safe and effective medicines. These may include;

• Quality standards: Countries and regulators should establish and enforce quality standards for excipients. This includes setting specifications for excipient quality, purity, and identity, and ensuring that these standards are met through testing and certification.
• Supplier qualification: Pharmaceutical manufacturers should ensure that their excipient suppliers are qualified and meet the necessary quality standards. This includes conducting supplier audits, evaluating supplier performance, and monitoring supplier compliance with quality standards.
• Traceability and documentation: Regulators and industry should require the implementation of robust traceability systems to track the movement of excipients throughout the supply chain. This includes maintaining accurate documentation of excipient origins, processing, testing, and distribution.
• Risk management: Countries, regulators, and industry should implement risk management strategies to identify and mitigate potential risks to excipient quality and safety. This includes conducting risk assessments, implementing risk mitigation measures, and monitoring for emerging risks.
• Surveillance and reporting: Regulators and industry should establish systems for surveillance and reporting of excipient quality issues. This includes monitoring adverse events associated with excipient use and conducting post-market surveillance to detect any issues with excipient quality or safety.

Further, excipient manufacturers should report excipients recalls to the appropriate authorities of applicable Member States, and FPP should immediately report excipients which may present a serious risk to public health (e.g. contamination with EG/DEG) to the NRAs.

During the Regional Workshop on Ensuring Quality of Medicines from Contaminated Substances Jakarta, Indonesia, 2–4 May 2023 (please see below), NRAs were invited to implement a risk-based sampling strategy to address the current situation, e.g. focusing on oral liquid medicines.

Each container of each lot of an incoming excipient at risk for EG/DEG contamination should be tested for identity and DEG/EG contamination before it is used in the manufacture of a finished product.

The importance of preparedness was also highlighted, and especially to ensure there is clarity in what should be done if a contaminated product was found. This exercise should consider all steps, from the reporting of the suspected product to the investigation, documentation of the destruction of the product, communication, recall, etc.) and all involved stakeholders. There may also be value in organizing a simulation exercise to ensure the robustness of the system.

Member States were requested to share any information related to contaminated medicines using the WHO Global Surveillance and Monitoring System and the South-East Asia Regulatory Network (SEARN) where a strategy on sharing information and guidelines are being discussed (Working group 4, Action point 3 of the workplan). The WHO can facilitate as required.

Considering that the supply chain is international, countries were also encouraged to directly liaise with each other (or facilitated by WHO) and arrange informal meetings between them as part of their investigations.

Since its establishment, WHO has prioritized ensuring the integrity of pharmaceutical products, introducing mechanisms such as the Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce (CPP scheme), a voluntary agreement operational since 1969. While the CPP scheme focuses on finished pharmaceutical products, the quality of starting materials, particularly active pharmaceutical ingredients (APIs) and excipients, demands urgent attention. Triggered by incidents of contamination leading to fatalities, the WHO Expert Committee on Specifications for Pharmaceutical Preparations proposed a new scheme in 1999. Consequently, the WHO Scheme for the Certification of Pharmaceutical Starting Materials Moving in International Commerce (SMACS) was endorsed by the World Health Assembly in 2003. Despite endorsement, SMACS implementation has been limited.

SEARN members considered that this scheme could be helpful to support reliance and ensure the integrity of excipients.

To test excipients for contaminations with ethylene glycol (EG), diethylene glycol (DEG), national and regional pharmacopoeias provide test methods and specifications. The International Pharmacopoeia, in addition, describes in the monograph on Paracetamol oral solution a procedure to determine these contaminates in a finished pharmaceutical product.

To enable national quality control laboratories and other stakeholders to test and evaluate suspicious samples, the World Health Organization is developing a test strategy for DEG and EG in liquid preparation of oral use for inclusion in The International Pharmacopoeia. It is intended to use thin-layer chromatography for the screening of suspicious samples and gas or liquid chromatography for the confirmation of non-compliances.

According to the WHO good practices for pharmaceutical quality control laboratories (WHO good practices for pharmaceutical quality control laboratories, World Health Organization, Technical Report Series, No. 957, 2010) equipment for thin-layer chromatography and high-performance liquid chromatograph is recommended for first-stage pharmaceutical quality control laboratories, while gas chromatographs (with flame ionization) are proposed for medium-sized laboratories.

Member States are also encouraged to liaise with each other to urgently establish multiple memorandums of understanding (MoU) between National Control Laboratories, and WHO may facilitate as required. Such MoU should consider specifically address the number of samples to be tested, the cost of testing per sample, target analysis timeframes and requirements for information sharing.

These tests are not intended for manufacturers which should test each contained of each lot of incoming excipient with risk of EG/DEG contamination for identify and purity according to the relevant compendium or alternative acceptable techniques such as FTIR (Fourier transform infrared).