Import Alerts And Your Supply Chain
By David Upchurch
Last month, FDA issued a Warning Letter to Polydrug Laboratories of Maharashtra, India, stemming from an inspection in March 2015. Certainly, Polydrug has conducted extensive negotiation with the agency since the inspection, and is now feeling the impact of the unresolved deficiencies. However, closer review of the text of the Warning Letter reveals Polydrug was placed on Import Alert in September, 2015, inflicting immediate restrictions on Polydrug’s US revenue.
Most pharmaceutical innovator firms, and manufacturing or supply companies, are familiar with the regulations and procedures regarding FDA Warning Letters. The Warning Letter and other procedures available to FDA help protect US drug supplies from the risks associated with improper manufacturing procedures.
Import Alert or Warning Letter – the procedures
FDA displays here another option in its quiver when the drug supply involves international manufacturing – the Import Alert (or Detention Without Physical Examination, DWPE; occasionally referred to as the Import Ban). The Import Alert enhances FDA’s ability to protect US drug supplies by placing responsibility for ensuring compliance upon the importer. However, many firms may not be familiar with the procedures for initiating an Import Alert, nor the procedures to remediate such action.
The Warning Letter is in fact not an enforcement action, but is one of the final tools to encourage voluntary compliance and may be used to establish prior notice before enforcement actions are undertaken. As such, the issuance of a warning letter follows multiple steps outlined in the FDA Regulatory Procedures Manual, particularly chapter 4-1. Issuance of a Warning Letter typically follows an unacceptable inspection or sample analysis, and follows specific procedures as described in the Regulatory Procedures Manual section 4-1-7 and 4-1-8.
Most Warning Letters involving the supply chain for pharmaceuticals, including cGMP compliance issues for API or drug product, require concurrence with the center (CDER, CBER, CDRH, or others). Further, if the Warning Letter is to be issued to a foreign firm, the issue “should be discussed with the Office of the Chief Counsel.”
By contrast, Import Alerts or DWPE recommendations are progressed from any FDA unit to the Office of Enforcement and Import Operations (OEIO), Division of Import Operations (DIO). The recommendation may be based on a variety of data, including FDA Establishment Inspection Reports (EIR), or similar reports from other US or foreign government agencies with a Memorandum of Understanding in place with FDA. Most importantly, District Directors may detain materials from a specific importer even while the recommendation for action is under review by DIO. The DWPE may be issued against the manufacturers name, the importers name, or specific compounds.
The impact of the Import Alert
While both Warning Letters and Import Alerts are designed to protect the US drug supply from harm, they also present risk to your supply chain. If your supply chain includes international components being imported to the US for further elaboration or marketing, risk exists for disruption of that supply with immediate effect. Whereas the Warning Letter is typically presaged by an FDA inspection, form “483” issuance, and written communications regarding the observations, the Import Alert can occur suddenly. Negative review of a foreign supply node by an entity outside the US FDA, or potentially review of a separate related (through ownership or importer) location could result in a ban on importation from your supply node. The nature of the DWPE that allows for swift action by FDA can cause immediate, and unintended, interruption of supply chains. The DWPE resolution pathway is less clear than that for Warning Letters, and may require reinspection prior to full resolution.
The Polydrug Warning Letter includes some notable elements indicating the relationship between the inspection, the Import Alert, and the Warning Letter. In one observation, the agency recognizes the elements of the deficiency related to non-US customers, and therefore potentially outside their jurisdiction. While Import Alerts can be targeted for specific products, in this instance a broad import alert would be appropriate due to systems concern. The Warning Letter proceeds to advise the firm that failure to adequately address the deficiencies may prevent approval of new applications and may further prevent relief of the Import Alert.
Is it really your business?
Protection against risk of an Import Alert is not just consistent with normal measures to build a robust supply chain, but requires suppliers and sponsors to consider practices and systems throughout the supplier’s business. One sponsor’s business regarding an intermediate for the US market can be impacted by severe deviations found for an API in another region. Indications of systems gaps, particularly in known areas of concern such as data integrity, should be further pursued by both the supplier’s internal quality structure and sponsor’s management system, regardless of the functional or business area in which the gap occurs. In the event a gap is revealed during inspection, prompt action and proper handling of responses is critical.
Could a Warning Letter be a good sign?
To return to the Polydrug story, the timeline is interesting. In March 2015, US FDA conducted an inspection and provided the firm with observations. The firm responded in April, 2015, within the standard expected timeline. In the Warning Letter, FDA notes Polydrug issued additional responses, which indicates the original response was incomplete. In June 2015, citing also a March 2015 inspection, Europe’s EDQM rejected multiple CEPs, effectively an import ban for Europe. Later in June 2015, Health Canada quarantined imports from the firm.
Consistent with the steps required for FDA to issue a Warning Letter as compared to the relative ease of the Import Alert, in this case the Warning Letter arrived fully seven months after the Import Alert was in place. For the firm already under an Import Alert, the arrival of the Warning Letter may be greeted as a renewed option for normal communications, which can hopefully lead to resolution of all actions.
Good supply chain management in the pharmaceutical industry requires effort in strategy, tactics, and remediation. The supply chain needs to be constructed with an understanding and mediation of primary risks, through both selection of the supply relationships and systems improvement. Both parties need to remain aware of, and prepare properly for all inspections. Finally, as inspections generally result in observations, responses need to be constructed to convey the full intent and skill of the team.
David Upchurch is an independent consultant to the pharmaceutical industry with over 20 years experience in project management, CMC, and API manufacturing.