Complete Response Letters Due to Failed PAIs – More to Come?

Over the course of the past two months, FDA issued a complete response letter (CRL) relative to the applications for two potential blockbuster drugs.  Receiving a CRL is almost the worst FDA correspondence for an applicant as it anxiously awaits the fate of its application. Since the rule was made final in 2008 (Federal Register /Vol. 73, No. 133 /Thursday, July 10, 2008 /Rules and Regulations, Application for Approval to Market a New Drug: Complete Response Letter; Amendments to Unapproved Applications), FDA has sent an applicant a CRL if FDA, upon the completion of its review, does not deem the NDA or ANDA is ready for approval in its present form.  CRLs have mostly been issued based on safety and efficacy concerns or chemistry and manufacturing control (CMC) or bioequivalence deficiencies. However, it is noteworthy that the two recently issued CRLs were issued due to manufacturing observations from the pre-approval inspection (PAI). Will there be more CRLs to come inspectional and manufacturing deficiencies based on the new integrated review process within the Office of Pharmaceutical Quality?  Will FDA truly speak with one quality voice by integrating review and inspection across product review disciplines?

The PAI is usually one of the last reviews completed during the drug approval process, which, if found deficient, may affect the availability of the product to the patient. Three main goals of a PAI are: site’s state of readiness for commercial manufacturing, conformance with the commitments in the application and data integrity; i.e. authenticity, reliability and accuracy of data submitted in the application.

With the globalization of the supply chain and more dependence on contract manufacturers, the application holder should not lose sight of the myriad of quality systems in support of the manufacture of drug product regardless where the new drug product is made. The key to a successful PAI is truly understanding the purpose of such a critical inspection and subsequently methodically plan for it.

The following is a quick refresher on PAIs.

Key items that are typically reviewed to demonstrate a firm is ready for commercial manufacturing include but are not limited to the following:

  • Overall site GMP compliance as it relates to the new drug dosage form
  • Adequacy of facility, equipment, critical utilities – how does the facility present itself? Is it well maintained?
  • Batch records for submission batches (including raw data)
  • Product development report
  • Change control, deviations initiated during process development
  • Sampling plans – are they statistical and representative?
  • Quality systems – management of deviations, laboratory investigations, product disposition, complaints, adverse events
  • Stability program
  • Supplier qualification program; Quality Agreements
  • Cross contamination controls
  • Training
  • Analytical methods

Conformance with the commitments in the application require that the formulation, manufacturing records and analytical methods are in accordance with what was filed in the CMC section of the application. This means that FDA will review equipment, procedures and supporting records submitted in the application and verify that such equipment exist and was used for the batches listed in the application.  Additionally, FDA will verify that the manufacturing process is the same that was used for the bioequivalence or clinical batches submitted in the application, the method filed in the application is validated for its intended use, and that stability batches are stored appropriately per the application.

Data integrity (or lack thereof) has been given a lot of press in the last couple of years and has been uncovered during routine GMP inspections.  It could also happen during a PAI.  FDA will review raw data (hard copy and electronic) to verify accuracy and authenticity of data and look for unexplained discrepancies between data (manufacturing and laboratory) submitted in the application versus data reviewed during the inspection. Furthermore, firm’s controls for management of electronic raw data that reside in chromatographic and/or stand-alone systems as well as manufacturing computerized systems will be evaluated to assure data cannot be altered, deleted or manipulated. Other questionable practices that can lead to data integrity include non-contemporaneous recording, discarding data, no raw data, document back dating and re-running samples to obtain better (or passing) results.

In addition to setting the logistics for a PAI, having documents readily available for the investigator(s) and beefing up housekeeping, the firm should have site personnel ready for interacting with the investigator(s). Has the firm assigned roles and responsibilities for those participating during the inspection and more importantly, have they been trained to respond to the investigator’s questions?

Lastly, it is a management responsibility to be always inspection ready! Don’t let your PAI derail a potential approval. Be ready, be smart and be prepared.