International Regulatory Audits for Pharma

Society is becoming global. It is reflected in our accelerating steps toward the harmonization of regulatory standards, and this has implications for regulatory audits. Two particular trends driven by this evolution have appeared over the last 12 months, and these have the potential to affect the way that we manage audits by regulatory agencies. First, and after a long period of confidence-building, the FDA and EMA have launched a trial period in which they are moving “to allow some inspections on each others’ territories to be deferred or waived completely based on a number of considerations”. Included in that list of considerations is compliance history. Thus, a good record of compliance rewards the manufacturer for its strong efforts to implement an effective quality system. Inspections are never fun; they are disruptive to operations and costly in terms of personnel time for preparation, site visit and audit responses. Wouldn’t it be nice to reduce this disruption through mutual recognition of audits by other reputable regulatory and third-party auditing organizations?

The second trend, however, may actually increase the numbers of inspections by regulatory agencies. As manufacturers position their products in foreign markets, they must remember that those countries will have their own regulations and can audit US manufacturers to those regulations. Unless mutual recognition agreements are in place between countries, manufacturers cannot neglect the differences between the regulatory standards of each country. China provides an excellent case in point. Effective March 1, 2011, new Good Manufacturing Practices have been issued by the China State Food and Drug Administration. This new set of regulations, including a significantly modified annex on sterile pharmaceutical products, is relevant for all pharmaceutical products destined for the Chinese market. This year, Chinese inspection teams have begun to audit US manufacturing operations for compliance with these new regulations. These teams expect that the US sites will have educated themselves on the new Chinese regulations, will have trained their personnel on the application of those regulations and will have incorporated the requirements of these regulations into the documentation that they inspect. Such requirements add a new level of attention to global quality expectations, particularly if the regulations are not harmonized. On the positive side, exposure of Chinese inspection teams to foreign companies and their other regulatory requirements and procedures may motivate and promote such harmonization. Emerging economies are generating double-digit growth in pharmaceutical sales but they are also relatively new to the science and policy of international regulation. Their first interactions will likely define policies, regulations and relationships for many years to come. Meanwhile, companies doing business internationally need immediately to implement procedures to prepare for and respond to inspections and audits that may be substantially different from their previous experience. They will aslo be watching carefully to undestand the consequences of an inspectional report with many findings of concern.

So how do we prepare for international regulatory audits? Here are 5 areas to consider, some that relate to the new challenges, some that have been areas of challenge for some time now.

1: Identify all relevant countries in which you are marketing and incorporate their quality regulations and standards into your quality system, from the quality manual down. In some cases, this may require the services of a competent technical translator. It is important that these regulations be referenced as benchmarks for exported product to that constituency. Careful examination of the requirements may reveal little need for real work with respect to quality system revision if your operations are already in good control. However, you may want to consider whether it makes sense for all products to be in compliance with all quality systems from various countries. If there are carve-outs, related for example to the need to satisfy country-specific pharmacopeial standards that would be onerous to apply across the board, it is important to define how such exceptional products are to be handled.

2: Educate your quality management regarding the requirements of emerging and changing national regulations. An endpoint for this ongoing education might include a matrix in which regulations are compared formally in order to identify areas where requirements are not harmonized. Since regulators are not always fluent in English, how are you going to communicate your system to the auditors when they are on site? When US inspectors conduct foreign inspections, some level of English-language translation is expected for high-level documents. It would not be unreasonable then for inspectors from other countries to query the fact that documentation is available only in English. A good first step might be to consider translation of high-level or critical documents when you prepare for a foreign inspection.

3: Use risk analysis extensively to determine where quality resource allocations should be made. Regulatory agencies are currently attempting to use a risk-based approach to determine where they put their inspectional energies, and so should you. If you use a formally documented, risk-based approach to identify areas where the largest safety or quality concerns might be centered, you stand a better chance of convincing the regulators that you have a responsive system in which critical processes and elements are controlled with heightened attention. Resources are not infinite, so directing those resources to the areas where problems are most likely to occur is a good business decision as well.

4: Put particular focus on corrective and preventive actions (CAPAs) that cut across several areas of concern in a manufacturing operation. Every year FDA speakers give talks on the failure of companies to perform effective and efficient CAPA. CAPA spreadsheets should not be the place that complaints and problems go for death and burial. If resources are limited, a risk-based approach to priority-setting is better than a first-in, first-out, or random selection of action items that can be seen in some organizations.

5: Become a proponent of harmonization activities, and encourage your company to get involved in harmonization efforts at the international and political level. If we must look to a future where every country has its own regulations and inspection schedules, we will be spending more time, not less, in inspectional activities that deflect energy from other tasks.