An incredibly interesting session was one of the highlights of the recent IFPAC (International Forum and Exhibition Process Analytical Technology) meeting in Alexandria, VA that took place January 25-28, 2015. It was named Risk Management over Product Life Cycle, but unlike so many of the other meeting sessions, it was not aimed at initiator or proprietary manufacturers. Instead, it consisted of and was designed for generic companies and, by extension, contract facilities.

The meeting was chaired by G.K. Raju of MIT, whose work in the late 1990s helped lay the foundation for the USFDA’s PAT Guidance in 2002, and Daniel Peng of the FDA. The speakers were from either generic houses or the FDA, including a presentation from a speaker from Sandoz, Slovenia. Clearly, the session was not aimed at the Big Pharma houses. Before going into the details of the session, it would be good to discuss a number of developments in the industry. Some are occurring side-by-side and may not be causal, but all are contributing to the topic.

One major driving factor for outsourcing is economics. A combination of the high cost of performing a function in-house and the lure of lower overhead including wages and taxes of overseas corporations drove the move to outsource operations. However, the lower cost of these moves has recently been offset by a number of factors that may or may not have been foreseen.

1. Technical transfer of a validated method to a new plant takes time, causing a number of things to happen. The delays might allow a competitor (generic) to come to market more rapidly; differences in locally purchased raw materials including API might cause quality problems, leading to either rejected lots or recalls; and delays cause shortages, driving doctors to prescribe alternative suppliers.
2. Labor costs are rising as countries become industrialized and the competition for skilled labor raises salaries and benefit costs.
3. Initiator companies are moving to PAT/QbD principles as well as continuous manufacturing, often requiring equipment that generics or CMOs do not usually have on-hand. This makes out-sourcing less attractive and potentially more expensive.
4. Often, contract manufacturers and generic houses, especially at the smaller companies, don’t have a large number of formulators or experienced staff on hand to obviate or predict problems, so some of these changes may lead to production difficulties.
5. And, finally, and possibly the most important, Dr. Lawrence Yu, USFDA, OPQ, as head of the new Office of Product Quality, stated at IFPAC that he will hold generics and CMOs to the same inspection standards as the large pharmaceutical companies in the U.S.

The session in question had a series of interesting speakers. The first was Juandria Williams, CDER, Office of Compliance, who discussed the agency’s perspective on Quality Risk Management (QRM). She described that the keys to risk management, including moving the production of a product from the initiator site to a second site that is one of their own properties or a CMO, needs examination. It has been a common practice to assume that moving to a second site and using the same master manufacturing formula (MMF) with only minor changes will ensure that the product from site B is exactly the same as site A.

She explained that the time-honored method of hunt-and-peck, nicely known as making logical changes based on experience, does not quickly or easily shape a quality project. While a full-blown QRM program, needed for a new API, is not needed, the approach should be similar. A Sheward chart may be useful for evaluating an on-going process. Actually, a pair of charts is needed with one displaying individual values, the other, the difference from one point to the next, allowing in-process changes and upgrades. A Failure Mode Analysis, based on an Ichikawa fishbone chart, can give formulators ideas of which factors are most likely causing any difference or OOS problem. In short, using the tools that innovator companies used for initial R&D of new drugs can be helpful for generic and contract companies, as well.

Andre Raw, CDER, OPS, FDA, explained that the department was anticipating reviewing approximately 700 ANDAs, however, they received 968 in 2013 and over 1400 in 2014, with no decrease anticipated. As a consequence, he recommends performing a well-considered risk assessment for both the formulation of the submitted product and site transfer, as well. The office also performs risk assessment when deciding which application to address first. There is, he admitted, a large backlog; an immediate-release, low-toxicity drug will receive less scrutiny than a smaller dose level and/or higher toxicity API. These types of products are considered high risk by the group. However, he emphasized that high risk should not be seen as being deficient, but merely that risk mitigation needs to be documented and submitted.

He strongly suggested that all applications have, at very least, a brief risk assessment table and supporting comments or documentation. In short, the more time and effort spent preparing the dossier, the more quickly it will be addressed and if deserving approved. The more questions, the longer the process takes.

Some very good practical examples were given by Chetan Doshi, director of formulation development at Appotex, Inc. and Petra Brozic, pharm development, Sandoz, the generic division of Novartis. Dr. Doshi’s case study showed how they went step-by-step from R&D through final review of any change controls with the associated documents and tools for each step (See box below). While these guidelines currently only apply to solid dosage forms, he expects that they will, in a short time, be expanded to extended release, topical and oral solutions/suppositories.

Dr. Brozic admonished the attendees to maintain a QbD mindset throughout the lifecycle of any product. That is, never stop trying to improve both the process and final product from the time it is introduced until it is discontinued. The approach should include sound science and a QRM approach. For example, if a supplier of either API of an excipient is changed, merely using compendial tests—EP, USP, JP—is not good enough. Using a true QRM approach, a limited Design of Experiment (DoE) should be attempted to assure that the quality CQA or CPP, at least of the final product is not compromised. She exhorts producers to continuously improve product and process understanding and control. She recommends consulting the ICH Q9 Guideline for help.

There were scheduled talks from representatives from Prinston and Amneal Pharmaceutical companies, but the speakers were prevented from attending by the weather. In their place, Dr. Richard Friedman, assistant director, CDER, FDA filled in. His talk centered on how process controls are already a part of cGMPs, thus already law. He encouraged the companies to move from discreet sampling and off-line measurement and move to real-time monitoring. This is in keeping with PAT/QbD concepts. He suggested that real-time monitoring would help drive lifecycle improvements and bring the process into a state of control, another GMP requirement.

He also went over management responsibilities, including process performance under QRM programs, improving CApa to caPA where preventive actions including process understanding are emphasized over corrective actions, streamlining the change management system to include QRM analyses and an increased presence in management reviews.

The speakers kept insisting that these new concepts are far less expensive in the long run than “business-as-usual” or “the way we did it in the 1960s.” They all emphasized that QRM helped get a product approved and to market far faster, kept the product recalls and OOS to a minimum if not eliminated completely, and prevented both shortages, Agency warnings and 483s.

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Emil W. Ciurczak
DoraMaxx Consulting

Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.