Well, there is a widely held belief that people in the sciences are more open to new ideas and technologies than the “common man.” The fact remains that children adopted Facebook, Netflix, and video games before “adult” scientists. However, when Max Planck stated, “Science advances one death at a time,” he was referring to the intransigence of scientists, overall. As one who has spent nearly a half-century in the industry, I can attest that we all tend to fix our views through the formal education and early experiences of our careers and are almost immune to change. I always refer to the technique HPLC as an example.
While it had been elucidated and terms formulated at the turn of the 20th century, in 1970, it was still not allowed as a release method by the FDA. Now, it is almost the only method allowed. Did they, the regulators, change their collective mind(s)? Hardly. I am fond of saying, “You can always tell a government agent; you just can’t tell him very much.” The anti-LC coterie either retired or died and were slowly replaced by scientists who had an education that included instruments beyond the burette and pipette. Sadly, these new people, having replaced their elders, have now become ossified in their views, so HPLC has become the only true religion.
However, as more scientists graduated from universities—pharmacists, chemists, and production engineers—and entered the workforce, there has been a “sea-change” in thinking, mostly. The vast majority of other industries have embraced, adopted, and implemented process controls, new analysis technologies, and computer controls. Hooray! The 21st century has arrived! Sadly, we in Pharma have been blessed with our own version of the Spanish Inquisition: namely, the Quality Assurance (and/or Compliance) departments to maintain the “purity of the beliefs.”
As a member of the FDA’s Advisory (sub) Committee on PAT, I observed the process quite carefully. I did warn the FDA personnel about how coolly it would be received, but they were confident that logic would rule (having been in a coma for four decades?). The “normal” six-month review/comment period before a Guidance moves from draft to final lasted almost two years. Why? Well, our watchdogs against heresy were aghast at phrases in the draft like “use your best scientific judgement” and “design space” to allow changes during a run. Perhaps, it isn’t entirely fair to complain against someone tasked with assuring we follow the cGMPs, avoiding warning letters and recalls. After all, we are accustomed to regarding the FDA as “the police” or “them,” while we were “we.”
That isn’t a stretch, since the FDA only came into existence because our industry was rife with snake-oil salesmen. A popular weight reduction product, pre-FDA, contained tapeworm eggs and, oddly, worked as advertised: you lost weight, magically. As with any government-sponsored bureaucracy, er, uh, I mean “Agency,” the FDA tended to be a “tiny bit” rigid. An adulterated product could be anything from a misspelled label to glass shards in tablets. And, the penalty for both was strangely similar. As a consequence, the entire industry became victim to Stockholm Syndrome. Simply stated, we would do nothing that could upset our abductors, including try a process or analytical procedure, not specifically required, or suggested, by the Agency.
The strength of this statement was brought home to me when I asked Dr. Ajaz Hussain, head of the PAT Guidance effort, why he had listed no specific examples in the PAT Guidance, while other Guidances were often very specific. I suggested NIR for raw materials as an example. At Sandoz, we had instituted NIR for RMID and qualification in 1985. “Surely,” I said, “a 2004 Guidance could, at least, refer to that obvious and well-documented technique as a possible cornerstone beginning point for a new company to try/adopt PAT, no?” His response gave me an immediate education on the mental state of the Pharma “minions” who run Pharma companies.
His answer was simply, “If we mention ANY technique, even as a suggestion, they will all rush out, purchase, and implement ONLY the technique mentioned in the Guidance, to the exclusion of any others, even if some of the others were better suited for that analysis.” He is too much of a gentleman to have used the word “lemmings,” but I received the message, loud and clear. The problem, as I saw, and still see it, was that pharmaceutical companies were and are so afraid of disappointing and being punished by the FDA, EMA, etc., that they have consciously or unconsciously chosen to do nothing, fearing doing something wrong and losing income.
Being a simple person, I like simple examples. Back in the days when AT&T (a.k.a., Ma Bell) was the only player in the telephone business, you paid per line and rented/leased the phone in your home. The fee was modest, less than $1/month, so most people didn’t bother switching to a store-bought unit when they became available. My mother continued to pay the modest fee until I did some simple math and showed her that her modest fees had added up to over $1000, since we were able to buy our own units at that time, for around $30. She switched the next day.
With the larger “branded” Pharma companies becoming serious about technologies like continuous manufacturing and 3-D printing of dosage forms and devices, generics and CMOs are beginning to remind me of a large number of soon-to-be wed-couples. My wife and I were regular ballroom dancers (met her there) for many years. Despite having a lot of experience in almost every dance, our wedding waltz took weeks of choreography and practice to make it look good. Yet, nearly weekly, a couple would come in and say, “We’re getting married in a week and want to learn how to dance.” Both instructors and regular students did their best not to laugh.
In a similar situation, Pharma companies are developing complex dosage forms, made with complex processes. When these are accepted (NDA, ANDA) and placed into production, there will come a time when either a generic or CMO will want to produce the product. It could be near patent expiry or as a hand-off from the branded company, wanting to not have to expand its production capacity. At this point, the initiator companies will look for a suitable CMO site for manufacture, or, a generic will want to introduce their version. That would be a really bad tome to try to “learn how to dance.”
You would be amazed, or not, at the number of spectacular failures I have witnessed for instruments/technologies that should have easily been put into practice, but were failures. Why? The lab director had the quaint idea that his/her analysts learned UV/Vis, titration, HPLC, GLC, and IR in school and never needed “extra” (read: “paid for”) training, so why spend good money training them on Raman, NIR, TeraHertz, etc. Of course, some, like NIR are never covered in college instrumentation courses, but that fact escapes them.
The three-four day basic training session, given by the instrument manufacturer, is considered just fine. Of course, the course mainly addresses setting up the instrument, how to press which buttons, and how to repair it, not method development of method validation for the Agencies. As I get older, I am less patient with clients. I now say, “Don’t waste your money and my time unless you are willing to follow my instructions.” When, not if, the project fails, they will not admit they messed up; invariably, they will blame the non-employee—the consultant.
In a similar manner, all too many CMOs and generics will scramble to find funds to buy, say, a continuous manufacturing set-up, be shocked to find it doesn’t come assembled—IKEA isn’t to blame, here—be even more shocked to find no one in their organization is familiar with the technology, be even more shocked to find that there isn’t a huge pool of talent for hire, and blame some subordinate for not telling him/her all this in the first place.
The time to prepare for the Olympics is planned years before they are held; the time to prepare for continuous manufacturing or 3-D printing is years before you actually expect to begin the production. You will need a place to set up your equipment. That means converting a building or facility, adding power, air handling, lighting, warehousing, etc. All that takes time.
Add to that, you will actually need to understand and have experience with PAT and QbD, because that is the heart of continuous manufacturing and 3-D production. So, as with the blissful couple, you need to begin dance lessons long before the wedding, um, I mean contract with Big Pharma.
Emil W. Ciurczak
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.