Drugmakers and industry groups are calling for changes to the US Food and Drug Administration’s (FDA) recently released draft guidance, Quality Considerations for Continuous Manufacturing
The 27-page draft guidance
was released for comment in February and is part of FDA’s effort to encourage the adoption of continuous manufacturing, which the agency believes can improve consistency and reduce the risk of drug shortages.
While there is great interest in continuous manufacturing at FDA, drugmakers have been slow to transition to continuous manufacturing processes. To date only a handful of drugs are manufactured using continuous manufacturing, though FDA noted in February that 20 companies “have engaged the FDA in their efforts to develop and implement [continuous manufacturing] processes.”
One impending issue brought up by drugmaker GlaxoSmithKline (GSK), as well as the Active Pharmaceutical Ingredients Committee (APIC) and the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), is how FDA’s guidance will relate to the upcoming International Council for Harmonization (ICH) Q13 guideline on continuous manufacturing.
Both GSK and APIC say they expect the ICH guideline to replace FDA’s own guidance to ensure standards for continuous manufacturing are harmonized.
Drugmakers, including GSK and Eli Lilly, also asked FDA to clarify the scope of the guideline as the agency states it supports continuous manufacturing for products submitted in new drug applications (NDAs), abbreviated new drug applications (ANDAs), drug master files (DMFs), biologics license applications (BLAs) and non-application over-the-counter (OTC) products.
However, the guidance only provides recommendations for small molecule, solid oral drug products and explicitly notes that the recommendations do not apply to biological products submitted under a BLA.
In its discussion of nonconforming materials, the draft guidance states that “manufacturing processes will include periods when nonconforming material is produced, such as during start-up, shutdown, or temporary process disturbances.”
Several drugmakers, including AstraZeneca, Bayer and Lilly ask that FDA revise the guidance to note that nonconforming material is not necessarily produced during those production steps depending on the manufacturer’s process design and controls, and ask that FDA change its wording to acknowledge that those production steps “may” result in nonconforming materials.
Lilly also asks FDA to clarify its position on how run time is considered as part of equipment qualification, suggesting that “duration of the continuous run during equipment qualification should be risk based.”
The draft guidance also suggests that continuous manufacturing could decrease the need for certain postapproval submissions such as manufacturing supplements by leveraging a robust pharmaceutical quality system (PQS).
In its comments, Janssen asks that FDA provide examples of the types of manufacturing changes that would or would not require postapproval submissions.
GSK also says it believes the guidance mixes regulatory and good manufacturing practice (GMP) topics and argues that the guidance “lacks clarity as to where the expectations are for submission versus GMP control. This may result in more rigidity and could be interpreted as pulling more from inspection activities into the regulatory domain.”
While the generic drug industry group Association for Accessible Medicines (AAM) acknowledges that continuous manufacturing can offer improvements and cost savings compared to batch manufacturing under certain circumstances, it warns that in other cases continuous manufacturing could have a negative impact on generic competition due to the costs associated with converting or acquiring facilities and hiring staff with continuous manufacturing expertise.
“There is a risk that these changes could exacerbate rather than alleviate concerns about availability and prices of prescription drugs, if these changes are not handled in a phased manner,” AAM writes, noting that the market for generic drugs is less predictable than for branded drugs during their period of market protection.
AAM also raises several questions for FDA, including whether the agency will differentiate between abbreviated new drug applications (ANDAs) using continuous manufacturing and batch processing and whether switching to continuous manufacturing for an existing application will require new bioavailability studies.
Additionally, AAM warns that branded drugmakers could use tighter specifications enabled by continuous manufacturing to block generic competition.
“FDA should be mindful of the possibility that [continuous manufacturing] could become a means for brands to block generic entry. This may come in the form of tightening specifications on impurities or other product characteristics to a level that cannot be met with a batch process and could block approval of a generic batch manufactured product, even though those tighter specifications have no clinical relevance,” AAM writes.