As expected, moderate changes carry “a moderate potential to have an adverse effect” on the product. One type of moderate change requires submission 30 days before distribution and is called a “Changes Being Effected in 30 Days” submission, by which FDA has 30 days to decide. If the Agency decides information is missing (the most common reason for denial), the subsequent corrections are identified as Changes Being Effected (CBE). Minor changes, which are expected to have little impact on the product, are handled through the Annual Report submission.
The official book on manufacturing changes is embodied in CFR 314.70(a)(1)(i), which states that “the applicant must notify FDA about each change in each condition established in an approved application…” and 314.70(a)(2): “The holder of an approved application … must assess the effects of the change before distributing a drug product made with a manufacturing change.”
The most common reasons for CMC change submissions are facility (34%), control (34%) and actual manufacturing alterations (16%). Thus, fewer than one-sixth of applications involve what a chemist or chemical engineer would call chemical process changes. Historically, the fraction of these falling into the PAS (riskiest) category has been less than 5%. Perhaps reflecting sponsors’ reliance on risk-based strategies, PAS filings rose to about 10% between 2010 and 2012. Still, significant chemical process changes represent only 1% of all post-approval submissions under the larger umbrella of “CMC changes.”
From filing data alone, it is clear that companies rarely consider significant CMC changes — even when economically justified. But submission data tells only part of the story. Companies appear to be taking more liberties with assessments of CMC change riskiness.
Geoffrey Wu, Ph.D., from FDA’s Office of Generic Drugs, has spoken and written on post-approval CMC changes. In a 2014 study, Wu noted that the total number of supplements for generic drugs, CBE 30 submissions, and CBEs, remained approximately equal between 2005 and 2012. These figures are approximately 3600 for total submissions, 2700 for CBE 30s, and 575 for CBEs. At the same time, PAS submissions rose six-fold, from fewer than 100 in 2005 to approximately 600 in 2012. The rise in PAS applications most likely reflect industry’s embrace of risk management, albeit more in facility, control and packaging than in chemical processing.
At the same time, FDA has subjected medium-risk submissions to greater scrutiny. FDA upgraded 55 CBE/CBE 30 applications, 1.6%, to PAS in 2005. By 2012, 150 such applications, 4%, were upgraded into the higher risk category.
Determining causal factors for the 150% increase in upgrades is not easy, but the consequences are obvious for an industry that lives and dies by market exposure. According to guidances, getting bumped into a higher risk category delays the point at which companies may distribute post-change drug products — a fact that Wu acknowledges.
He disagrees, however, that risk upgrades are a natural result of any new thinking regarding risk-based compliance. “Risk is solely decided by the nature of the proposed change,” he explains. “Any reasonable applicant should conduct risk assessment on proposed changes prior to regulatory submission and implementation. FDA’s risk-based approach is to further assure product quality and safety.”
The most common reasons for upgrading a risk category are lack of scientific or product information, failure to cite appropriate guidances, insufficient investigation of out-of-specification product, lack of supporting information for CMC changes, and paradoxically, too much unnecessary information.
How to explain, then, given the resources devoted to regulatory compliance, the rise in misunderstanding risk levels for relatively straightforward CMC changes? Wu has no explanation. “Industry folks may give you further insights to this question,” he says.
BECAUSE THEY CAN
Companies purposely underestimate risk in regulatory filings because they can, says Susan Bain. “They’re looking to shortcut testing time and the amount of data they need to supply to justify the CMC change.” She says the practice is “huge” at top companies. “It’s a matter of resource allocation,” she says. Companies obviously benefit from expending less time, money and product than they normally would to achieve a risky CMC change.
Some companies (particularly startups) are so time-crunched that they may institute changes based solely on a letter-to-file — basically putting a letter into a file that states they observed no risk to products from process changes. Then they play catch-up when regulators ask about the letter. Bain believes that companies consciously weigh the cost of rejection against that of completing studies. “It sometimes comes down to how long it takes to validate a new process before getting caught,” she says. Some tactics resemble grade school strategies. “They will submit a CB30 without the validation data, hoping to have completed the studies before regulators reach that part of the submission. When confronted, they say, ‘Oh yeah, here it is.’”
The submissions that FDA cites are often those that fail to complete validation before time is up due to unsuccessful studies. For these firms the clock starts all over again, often with product sales put on hold, and inventories recalled. “It’s horrible publicity and very expensive, particularly for temperature-sensitive products or those with short shelf-lives,” Bain says.
Incomplete data is a problem that goes beyond post-approval CMC changes, according to Bain. “Forty percent of NDAs are sent back because of incomplete data.” Again, the problem lies mostly with sponsors who believe they will be able to play catch up between submission and FDA action. “The market is so competitive, and with generics knocking at the door, companies are taking more risks to streamline the approval process in any way they can.” She stresses that this activity is limited to regulatory submission risk, not patient safety. “Sponsors are not cutting corners with quality.”
Bain recalls one firm, seeking approval for a new filling line lacked critical validation data. “They didn’t get the work done in time and had to start over. In the long run that didn’t save them any time.” Such companies, she adds, often develop bad reputations with regulators who feel they are wasting Agency time.
Regardless of how the uptick in original and re-designated PAS submissions originates, the risk-based approach to development and regulatory review are here to stay. “Most companies understand and accept this reality,” says Luba Skibo.
FDA has already adopted risk assessment for inspections, as sponsors implement similar practices for auditing suppliers and service providers. How risk plays into post-approval CMC changes is a complex question.
In its landmark 2004 cGMP revision guidance, FDA enunciated its cooperative, risk-based vision to exploit advances in quality management and to allocate limited regulatory resources more effectively. CMC regulatory review, according to the guidance, “should be based on an understanding of product risk and how best to manage this risk.” CDER’s follow up guidance, CMC Post-approval Manufacturing Changes to Be Documented in Annual Reports, extended the risk-based approach to CMC review, and recognized that many post-approval CMC supplements posed low risk.
This extensive list included relaxation of blend uniformity testing, changes in coatings and mixing times for immediate-release drugs, and alterations in filtration parameters excluding pore size. Subsequent guidances outlined how, and to what extent, companies needed to document low-risk changes through the Annual Report. Without going into details, it was obvious that FDA’s goal was to streamline submissions while simultaneously sparing the Agency’s need to review vast volumes of irrelevant data. “While not directly linked to cGMPs for the 21st Century, this certainly seems like an application of risk management,” Skibo says.