The afternoon started out with a discussion of Biopharmaceutics Risk Assessment to Guide Dissolution Method Development for Solid Oral Dosage Forms.  The presentation provided an introduction to the understanding of the purpose of biopharmaceutics risk assessment and a discussion of how to perform the assessment which focused on understanding the role of in vitro dissolution testing for BA/BE risk mitigation.

The second presentation outlined the expectations of an integrated manufacturing assessment which also discussed the need to focus on responding to deficiencies and questions from the manufacturing review team. The primary objective was to let industry know that they need to understand the questions asked and provide relevant, complete, concise, and accurate responses that address the questions asked by FDA.

It is key to assure and understand that:

  • Common deficiencies are resolvable with due attention to detail and inclusion of information and justification supported by science and risk-based analysis.
  • Avenues for clarification and discussion with Agency are available. (e.g., mid-cycle telecons for complex ANDA review issues).
  • A submission that demonstrates thorough understanding of product, process and implementation risks allows for robust product quality management.

The Building a Better Sterility Assurance Application presentation focused on some of the common problems OGD finds in sterility assurance submissions.  Clarity and simplicity are key, along with making certain there are not discrepancies in different sections of the Sterility Assurance submission or DMF.  The common issues identified include:

  • Conflicting information – e.g., mentioning different pieces of equipment in differing modules or inconsistencies in narratives.
  • Absence of rationale or justification – e.g., validation should support commercial production runs
  • No information included about items received as sterile or depyrogenated
  • Sterilizing filter not identified in autoclave loads
  • Bioburden monitoring is not described
  • Bioburden monitoring location is not adequate – e.g., should be monitored prior to any filtration
  • No pressure and vacuum conditions used for container closure integrity testing
  • Unacceptable incubation conditions for Biological Indicators
  • Media fills are not representative of maximum production conditions
  • Incorrect use of pooling for endotoxins testing
  • Incorrect endotoxin limit for product release

Postmarketing safety issues with generics are usually not significant as they present a profile very similar to their brand name counterparts, but, as the Pharmacovigilance presentation noted, there may be differences seen in quality attributes when a new generic is first introduced, especially if there are any differences in drug-device combination products.  Some of the past experiences with quality issues include:

  • Tablets breaking apart
  • Scored tablets breaking unevenly or crumbling when split
  • Tablets sticking in the throat
  • Unusual odor, taste, smell, or texture
  • Precipitates in oral liquids and injectables
  • Patches not sticking
  • Container/closure issues
  • Eyedrop safety seals falling off
  • Large size tablet/capsule
  • Extended-release products not lasting through the day
  • Injector malfunctions/needle breaks

Proactive pharmacovigilance can detect if there are problems once a new generic is introduced into the market.  The presenter provided a few examples of where such activity can provide early notification of either the lack of a potential quality safety issue or identify a significant issue.  The Advair and generic Wixela Inhub that had minor differences in the dry-powder inhaler showed no quality or safety issues after initial monitoring. However, the allowed difference in the Copaxone and generic autoinjector showed that the generic autoinjector had a more frequent issue with bent or broken needles relative to brand. This issue is under investigation. The Proair HFA albuterol inhaler was the brand name product, the difference allowed and approved in the generic inhaler showed an unexpected safety signal after approval on February 24, 2020, when reports of inhaler clogging began to be reported.  In August 2020, the generic manufacturer and distributor discontinued manufacture and distribution, and recalled the product to the consumer level and is now investigating the clogging issue. The summary of the presentation emphasized:

  • Generic drugs are as safe and effective as brand drugs
  • Allowable differences on rare occasions may lead to unexpected or unanticipated

quality or safety issues

  • Complex generic drug-device combination products raise unique potential safety

concerns due to drug delivery, differences in device constituents, or unexpected quality

issues that may require immediate action

  • Anticipating concerns related to increasing generic drug market share helps to focus

generic drug pharmacovigilance efforts

  • Internal conversations across CDER help engage staff, support research, and develop

public communications

  • Outreach to generic drug stakeholders is key to refining OGD’s ongoing safety

surveillance processes and procedures

Additional presentations included Premarket Review of Expedited Serious Adverse Event Reports (SAERs) from BA/BE studies, REMS for Generic Drugs, and Post Approval Changes. Some takeaways are that expedited SAE reports are required only for BA/BE studies conducted in the US, and for foreign conducted studies it is voluntary, but all ADEs (both domestic and foreign) must be reported in the ANDA. The presentation also provided information on where to submit the SAEs and what FDA’s expectations are relative to the data submitted in the report.

The REMS presentation discusses that, if an RLD has a REMS, then all ANDAs must have a REMS in one of the following pathways – join an already existing Shared System (SS) REMS with ETASU – work with the RLD to develop a new Single, Shared System (SSS) REMS with ETASU – pursue a separate, comparable system from the Shared System ETASU REMS and work independently from the RLD (not a favorite of the FDA but it may be necessary if the RLD holder is not cooperating with establishing a shared system) – or, for a Medication Guide-only REMS – does not require the ANDA to interact with the RLD.  To correct a long-existing problem, the CREATES Act provides an avenue for ANDA sponsors to obtain samples of the RLD so that the ANDA applicant can conduct required BA/BE studies.

The post-approval changes presentation outlined the submission types, describes the supplement review process, resources for post-approval changes, and some of the most frequent supplement deficiencies, as well as tips for better supplement submission.

With the ever-changing nature of the review and approval process, the information obtained from these seminars provides a valuable learning experience.  It is strongly recommended that you take advantage of these free FDA offerings.