Issue link: https://www.e-digitaleditions.com/i/1067339
44 January 2019 Tablets & Capsules make the application of appropriate GMP principles essential. Excipient cross contamination is controlled by applying appropriate GMP principles during manufactur- ing. The various excipient GMPs noted above discuss equipment cleaning and related requirements. Evidence of the effectiveness of cleaning procedures is based on studies showing that the procedures achieved predetermined acceptance criteria. Equipment and utensils must be cleaned at appropriate intervals to prevent cross-contami- nation of the excipient. In addition, excipient manufac- turers establish a composition pro- file [10] that identifies the main components of the excipient and determines their normal range of concentration. Acceptable limits are based on a risk assessment using sound science. Manufacturers of wheat-based excipients should con- duct product testing and process capability evaluations to certify that the excipient contains less than 20 ppm of gluten. Conclusion The position of IPEC-Americas i s t h a t F D A C D E R s h o u l d b e aligned with either the information on the CDER webpage (not more than 0.5 mg/unit dose) or CFSAN (<20 ppm) and define "gluten-free" for excipients. Not having estab- lished limits for the term "glu- ten-free" is confusing and does a disservice to consumers. The FDA should use consistent terminology and limits related to gluten content for both food and drugs. Further, IPEC-Americas does not support requiring that all drug products be "gluten-free" or labeled as such. IPEC-Americas recom- mends that an established gluten level should be defined in guidance and that, when applicable, manu- facturers use a labeling statement to reflect potential gluten concentra- tions above the established level. Patients with celiac disease need to know if a drug product contains a gluten risk so they know which products to avoid, but negative avoid confusion with the new prod- uct would also add costs. IPEC-Americas proposes that labeling only be based on the pres- ence, not the absence, of gluten at a threshold to be determined, and information is already available within CDER and CFSAN to estab- lish that threshold. IPEC-Americas recommends that the FDA replace the current suggested statement to require labeling a drug only when the presence of gluten is above a defined "gluten-free" threshold. IPEC-Ameri- cas recommends using the same limit as is used for foods considered to be gluten-free (<20 ppm). New IPEC industry guides improve excipient controls IPEC participated in the devel- opment of practical GMPs and good supply chain practices guides to mitigate excipient risks [7,8,9]. These industry guides can be used for managing and evaluating cross c o n t a m i n a t i o n f r o m a g l u t e n - containing ingredient. The various excipient GMPs were updated to bring them in line with the latest thinking on excipi- ent GMP requirements. The quality of excipients is critical to ensure the safety, quality, and efficacy of med- icines. Excipients have a wide range of applications and are essential components of the drug product formulation. Characteristics that excipients impart to drug products Shah et al. state in their article that: "In our opinion, the formulation of gluten-free drug products will not cause undue burdens or incur signifi- cantly higher manufacturing costs to pharmaceutical companies...Any impact of substituting one excipient by another on the cost of manufac- turing a drug product may also be very minor, if at all." IPEC-America's opinion is that the impact of substituting one s t a r c h - d e r i v e d e x c i p i e n t f o r another in an existing approved drug product is not minor and should be treated as a technical grade and specification change. This is a change in the qualitative or quantitative formulation of the drug product and, as such, accord- ing to the FDA's Scale-up and Post-Approval Changes Guidance for Immediate Release Products (SUPAC IR Guidance, 1995) [6] would require a PAS by all manu- facturers. This would require sup- porting details on chemistry, disso- lution, and stability along with either a biowaiver, if applicable, or an in vivo bioequivalence study. A s t a r c h - r e l a t e d e x c i p i e n t change may have a significant impact on formulation quality, manufacturing, and performance. The filing documentation required depends on the therapeutic range, and Biopharmaceutical Classifica- tion System (BCS) classification (solubility and permeability) of the drug substance molecule. Develop- ing the supporting data and docu- mentation requires extensive stud- i e s t a k i n g s e v e r a l m o n t h s t o complete, which would increase costs for drug product manufactur- ers and patients. In addition, the reformulated drug product manu- facturing process would require revalidation, which could further increase costs. Removing the older formulation from the market to IPEC-Americas recommends that the FDA replace the current suggested statement to require labeling a drug product only when the presence of gluten is above a defined "gluten- free" threshold.