Securing Pharmaceutical Supply Chains in Emerging Markets

With the 2008 Olympics in Beijing upon us, Chinese officials are going out of their way to improve the quality of exported products. According to Xinhua News Agency, product safety is also now a top priority. Chinese Premier Wen Jiabao announced at the opening meeting of the National People's Congress in March this year that, “it is imperative that the people feel confident about the safety of food and other consumer goods, and that our exports have a good reputation.” Premier Wen added that the country is planning to create and update a total of 7,700 national standards to ensure that product safety testing is meets international standards.

These initiatives, also known as the National Special Rectification Program for Product Quality and Food Safety, are coming at a time when China is exporting $10.6 billion worth of active pharmaceutical ingredients (APIs) for the preparation of drugs in North America and the European Union (EU) (2006 figures).

The program Chinese officials are deploying coincides with growing concern in western consumer markets of tainted goods sourced from suppliers in Asia. Several incidents over the past few years have been reported, most recently a worldwide recall of batches of heparin in January this year that caused serious adverse effects and even death after patients were administered with the contaminated product.

Two Approaches

With concerns over drug safety on the rise, a growing number of regulatory and industry actions to ensure drug safety are underway. Regulators in North America and Europe are taking slightly different approaches to address the issue.

Under the United States Food and Drug Administration’s (FDA) “Beyond our Borders” initiative, which began this year, the agency is establishing offices in regions of interest to enhance their inspection capability of local manufacturing facilities exporting their products to US markets. In March, the agency announced the establishment of FDA affiliates at the US Embassy in Beijing and at the US Consulates General in Shanghai and Guangzhou. This initiative also facilitates stronger cooperation with FDA counterpart agencies around the world.

The EU is adopting a risk assessment-based approach putting primary responsibility on drug product manufacturers to ensure quality compliance among their suppliers. In the EU, the European Medicines Agency (EMEA), in a 2005 directive, changed its guidance to incorporate drug companies’ responsibility to use active substances that have been manufactured in accordance with the detailed guidelines on Good Manufacturing Practice (GMP) for starting materials (Basic Requirements for Medicinal Products, part I, sections 5.25 and 5.26).

Under this guidance, all aspects of production and control of starting materials are considered. This includes receipt and handling of raw materials, manufacturing processes, labeling and packaging of the active substance, complaints and rejection procedures, quality testing, and the drugs’ release. EMEA has indicated that, typically, it does not consider so-called paper audits - a review of documents, questionnaires, and historical experience of a supplier - as sufficient evidence of quality. As indicated by EMEA, regular on-site audits are the only way to deliver evidence as to quality compliance in relation to GMP, and some additional guidance is provided in relation to the optimal organization of supplier audits:

 The audit should be conducted by properly qualified and trained staff. As procedures are generally written in the local language, local staffing is to be preferred over foreigners.

 The audit should be properly documented in accordance with approved procedures. Parties should be aware that audit reports and other documentation relating to the audit have to be made available to government officials during formal inspections of the drug company holding the marketing authorization (MA).

 It should be satisfactorily demonstrated that there is no conflict of interest, and that the auditor is acting completely independently from the audited party. Objectivity and independence are of extreme importance, and it should be noted that trading companies, agents, or brokers advertising their auditing services, cannot be involved if they are affiliated with specific factories that are paying them a commission.

Self-regulation the best alternative

The concept of self-regulation is a better alternative than enhanced inspections by government officials as, for example, the cost of drugs would rise and ultimately harm the very end-users that the increased inspections and regulations seek to protect. Under the circumstances, there are several options for drug manufacturers to follow once they start organizing their GMP quality management audits:

 Supplier audits to be performed by quality unit personnel of the drug company (the MA holder), of each actives and non-actives intermediate producer, in so-called second party audits.

 Third party audits to be performed on behalf of the quality unit of the drug company by a contractor ensuring an objective assessment of the intermediate manufacturer.

 Shared third party audits, where one active pharmaceutical ingredient or non-active substance (excipient) is used by several MA holders. This option is typically of interest as audits are time consuming and expensive for both the intermediate and drug product manufacturer.

When looking at the the entire field of those manufacturing intermediates as well as service providers liaising with western pharmaceutical firms, it is important to keep these parties in mind:

 Active pharmaceutical ingredient manufacturers,

 Non-active substance manufacturers,

 Raw material manufacturers,

 Manufacturers of supplies, like glass ware, filters, etc.,

 Storage and distribution providers (third party warehousing), and

 Quality control and other testing laboratory facilities.

Existing Good Manufacturing Practice Resources

It is evident that all these services, substances, supplemental materials and components of drugs be delivered from and manufactured in hygienic and state-of-the-art facilities according to the standards set in the country where the finished product is to be marketed. Although there is an overwhelming amount of regulations that companies have to comply with, some common features exist and are readily available to the intermediates and services industry sector, such as:

 Active pharmaceutical ingredient guidance as set out by the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use in their Quality Guideline #7 (ICH 7). It is this document, which for several years now has been formalized into the GMP regulations by the US, the EU and Japan. Several other countries are also adopting this guidance.

 Excipients GMP guidance as set out by the International Pharmaceutical Excipients Council and the Pharmaceutical Quality Group, in their (IPEC/PQG) 2006 ed. document.

 Guidance on Good Distribution Practice (GDP) for warehouses, distributors, and wholesalers for drug intermediates as set out by guidance published by the World Health Organization (WHO) and also by the IPEC/PQG.

Cause for Concern

A review of EMEA’s Inspections Sector records published in 2007 shows that inspections of API manufacturing plants in the European Economic Area and third countries against the formal guidance for GMP on active substances, show that the most common deficiencies are found in the areas of process validation, risk of (cross) contamination, documentation control, and design and maintenance of premises. These areas formed the top four deficiencies as assessed by the EMEA Inspections Sector during a 10-year period between 1995 and 2005. In total, these four areas amounted to over 50% of the overall number of 9,500 deficiencies identified by the Inspections Sector in API production plants. Three out of these four areas form critical aspects of GMP of API manufacturing.

The control of (cross) contamination, appropriate design and maintenance of premises, and proper validation of manufacturing processes are typically regarded as the “backbone” of drug manufacturing. Problems with these aspects generally give rise to major and even sometimes critical concerns about the GMP status of the manufacturer, potentially leading to warning letters and seizures. More importantly it clearly demonstrates that patients are at risk if a manufacturer fails to ensure consistent state-of-control of their API manufacturing plants in relation to these and other areas.

This clearly demonstrates the need for good quality operations in API and excipient manufacturing, and also during the storage and transportation of high quality medicinal products. As US and EU companies continue to source their intermediates from third party manufacturers in Asia, self-regulation based on western current GMP is the safest and most cost effective way to deliver good quality drugs to consumers. Hiring qualified and experienced local experts can help to bridge the language and cultural gaps during the sourcing of state-of-the-art GMP compliant suppliers in Asia.