RE: Docket No. FDA-2015-D-2537: Submission of Quality Metrics Data; Revised Draft Guidance for Industry; Extension of Comment Period
Dear Sir or Madam,
The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) is an industry association that develops, implements, and promotes global use of appropriate quality, safety, and functionality standards for pharmaceutical excipients and delivery systems.
IPEC-Americas provided verbal comments at the August 24th, 2015 Quality Metrics Guidance Public Meeting, regarding the agency questions included in the initial guidance “request for quality metrics” July 28, 2015. The Agency asked if metrics should be collected from high-risk excipient producers, and if so, which excipients should be considered high-risk and what metrics should apply.
IPEC-Americas responded to Docket FDA-2015-D-2537-0015 that there is currently no official U.S. FDA definition for “high-risk” excipients. The same excipients are often used in a variety of applications, where some may be considered “high-risk” and others may be considered “low-risk”. This makes it nearly impossible to assess whether an excipient should be considered high-risk or not as it relates to quality metrics for the manufacturing process. This determination can only be made by the drug product manufacturer and not the excipient supplier.
The FR Notice dated November 25, 2016, related to the voluntary phase of the quality metrics program suggests excipients and atypical API manufacturers may also submit quality metrics, yet there is no mention of either of these in the docket. The FDA has not provided the public with a definition of atypical actives in any official documentation. IPEC-Americas’ position remains that risk regarding the use of excipients, including those used as atypical actives, is predominately based on their use in high-risk drug products and applications (e.g. parenteral, ophthalmic, and inhalation), not in their manufacture. Quality Metrics, including those proposed by the FDA, are more focused on risk related to the drug product manufacturing process.
Manufacturing of excipients is very different from pharmaceutical manufacturing operations as discussed below. Excipients, including those used as atypical actives, are often produced in manufacturing plants utilizing continuous, large scale manufacturing processes. These manufacturing plants often produce high volumes of product annually (often thousands of tons) which are sold into numerous markets (e.g. industrial, personal care, food and pharmaceuticals). Excipients often represent only a small fraction of the annual production volume and an even smaller fraction (< 1 – 2%) ends up in atypical active applications. Since these manufacturing facilities were in place long before development and/or publishing of the GMP concepts found in ICH Q7 API GMPs, these facilities were not designed to meet this level of GMPs.
Therefore, IPEC-Americas does not support application of the Quality Metrics guidance to excipients whether used as excipients or atypical actives.
Applicability of Current Metrics to Excipient Manufacturing Facilities
The metrics that the Agency has suggested in the voluntary phase of the program would be difficult to apply to excipients or atypical actives because manufacturing processes are different for excipients than for drug product and APIs. The reasons for this are discussed in more detail below:
Quality Metric 1 from 2016 FDA draft Quality Metrics Guidance:
Lot Acceptance Rate (LAR) as an indicator of manufacturing process performance. LAR = the number of accepted lots in a timeframe divided by the number of lots started by the same covered establishment in the current reporting timeframe.
Excipients used in drug product manufacture will typically be within the specifications identified by the drug product manufacturer for their intended use, and therefore, the operational metrics for excipient production is not relevant. This is further explained below:
Excipient manufacturers typically manufacture multiple grades of the same product for sale into various markets (e.g. personal care, industrial, and food). It is common practice to downgrade an excipient product to another grade or intended use in one of these markets should a particular excipient specification not be met.
Oftentimes, in a continuous process, a certain portion of product may be dispositioned to another market or grade until such time that the process is equilibrated to within the excipient specification range.
Operational metrics for running a chemical manufacturing process that makes excipients as well as other grades is not relevant to operational metrics for a pharmaceutical drug product.
The LAR from one excipient manufacturer to another or to an API or pharmaceutical drug product manufacturer cannot be compared since downgrading does not exist for drug product or API processes.
Quality Metric 2 from 2016 FDA draft Quality Metrics Guidance:
Product Quality Complaint Rate (PQCR) as an indicator of patient or customer feedback. PQCR = the number of product quality complaints received for the product divided by the total number of dosage units distributed in the current reporting timeframe.
The quality complaint definition is different for an excipient versus a drug product. Pharmaceutical company customers (e.g., medical professionals, hospitals and patients) are significantly different from excipient manufacturer customers (distributors or pharmaceutical companies). There are defined regulatory requirements for complaints handling of drug products which are specific only to the manufacturers. Excipient complaints would be received from a pharmaceutical manufacturer or a distributor and NOT from a patient or a medical professional.
Excipient companies evaluate product complaints based on established procedures which would not necessarily equate to how complaints are handled for drug products and dosage units.
There are differences in how complaints are defined, investigated and reported for excipients as compared to drug products.
Quality Metric 3 from 2016 FDA draft Quality Metrics Guidance:
Invalidated Out-of-Specification (OOS) Rate (IOOSR) as an indicator of the operation of a laboratory. IOOSR = the number of OOS test results for lot release and long-term stability testing invalidated by the covered establishment due to an aberration of the measurement process divided by the total number of lot release and long-term stability OOS test results in the current reporting timeframe.
The excipient manufacturers are not part of the pharmaceutical manufacturing testing and decision making; therefore, they cannot provide the required indicators that the agency is seeking here.
Since the draft Guidance still has many unanswered questions for the finished drug product manufacturer, it is IPEC-Americas position that the Guidance should be devoted to pharmaceutical drug products and not expanded to include excipients and atypical actives.