FDA’s CDER director Janet Woodcock recently addressed a Congressional committee at a hearing on a potential new draft House bill on continuous processing. She was called on to award grants to institutions of higher education and nonprofit organizations for the purpose of studying and recommending improvements to the process of continuous manufacturing of drugs and biological products and similar innovative monitoring and control techniques.

Dr. Woodcock received a few questions asking to compare the differences between batch and continuous manufacturing and after explaining the fundamentals, said, “I don’t know why it’s not more widely used” as “this is the future.” She noted that what’s holding back innovation is that companies making the switch from older manufacturing processes will have to receive FDA approval. Continuous manufacturing also could be a way to bring manufacturing jobs back to the U.S. because it requires less space than batch and other manufacturing processes, she added.

Since she also mentioned CROs and CMOs in her appearance, I would like to pick up where she so eloquently began. This is the second time that an official of the agency has made some clear suggestions to reform the industry. Two years ago, Dr. Lawrence Yu in the generics division implied that QbD would “become law.” To clarify, QbD is not the law; what he was referring to was the requirements in the QbR (Question-Based Response) that was to become the template for ANDA’s initiated by generic houses wishing to do business in the U.S. However, upon close examination, QbR is a template for a company to eventually move to PAT controlled QbD.

The combination of the two concepts have a number of far-reaching implications for contract companies, both good and annoying.

The Good and Bad News
First, there is a growing trend for large companies to completely outsource clinical trials to CROs. This would include manufacturing, packaging, record-keeping, distributing, and documenting the clinical studies. This is outstanding news for the bottom line of CROs, but, like the Hope Diamond, it comes with a curse.

Under QbR requirements, the company submitting an ANDA now needs to expand its sphere of responsibilities. It needs to show that, as a surrogate drug producer, its raw material examinations are as rigorous as the initiator company: it can analyze API’s from various suppliers and their existing analytical method can show side products from differing synthesis routes—this will become even more critical for biosimilars—and its analytical methods can isolate and quantify break-down products in its stability samples.
It will also need to ascertain the bona fides of excipient suppliers via vendor validation visits. The purpose is to certify all suppliers as cGMP compliant. Not a difficult job, but it does take personnel, paperwork, etc. The burdens on both the lab and QA sections will be more than offset by the increased business.

Another benefit of including contract organizations earlier in the process is their performing the formulation of the clinical batches through to the final dosage forms. When continuous manufacturing is thrown into the mix, this allows the CRO/CMO to perform more pre-formulation and formulation studies utilizing design of experiments with far less API and excipients used, lowering costs greatly.

Add to that the use of a dosage form for clinical studies that will be, in practice, the formulation used for the commercial product. That means one or two years saved in both the scale-up and product transfer phases of a product’s life. If the product is patented, that is like adding one or two years to the patent life for both NCEs and orphan drugs; for a generic, attempting to be first to market is greatly aided by using the CRO facility to formulate, test, and produce the dosage form at a single location. And, needless to say, when the same facility is used to develop and produce a product, immediately, there are fewer issues and, consequently, far fewer OOS batches.

The savings include more than mere monetary considerations; if a new drug is being formulated, there is a possibility that there is not a large supply available, particularly if clinical efficacy has yet to be demonstrated. Making vast amounts of an API that may never see the pharmacy shelves is a waste of time and equipment. Thus, using far smaller volumes obviates massive synthesis time and expense. Of course, even the most common of excipients are hardly free, either, so the savings there are not negligible.
In addition, agency oversight, though seldom calculated into cost of goods sold (COGS), can be a major expense. The inspection, even when only of some specific paperwork, ties up mangers, lab personnel, QA, and others for up to weeks at a time. While this is merely an inconvenience at a large company, it can be quite disruptive to a smaller organization, running with many fewer bodies. Their absence/participation in meetings with FDA or EMA personnel can seriously delay projects, make the company miss deliveries, and delay development projects.

CDER personnel have stated, at any number of open meetings, that properly planned and executed PAT/QbD projects will result in “lower oversight.” Dr. Mohab Nasr, former assoc. director at CDER once explained to me that he envisioned an “ideal” inspection at a well-functioning facility would be to schedule a time, be given a password for a process, and observe the readouts from the validated sensors for a while, check against submitted NDA or ANDA parameters, and either approve the process or phone for a site visit to discuss the potential problem(s).

A corollary to this lessened oversight is submission of further ANDAs or NDAs; if the Agency has gained confidence in your company’s ability to properly design and control the production of your products, subsequent applications will be more readily and more quickly accepted, often with fewer questions. Of course, this doesn’t mean getting the first PAT/QbD submission right means you receive a “get out of jail free” card for subsequent submissions.

The Benefits off Wireless Technology
The suite of equipment used for a well-controlled PAT-based production line may also be used in a step-wise fashion, e.g., the wireless Raman or Near-Infrared unit used for blend uniformity of commercial products may also be used for development work. When checking out ideal blending times for new formulations, using a wireless monitor has a number of advantages.

A more accurate mixing time is achieved by not stopping the blender to take physical samples. Also, taking physical samples before an even mix is achieved can cause an imbalance in the ingredients and skew the final, homogeneous endpoint.
Homogeneous is used with trepidation, since powders are never truly a solution, the only homogeneous mixture
There also may be arguments that the NIR or Raman or LIF (light induced fluorescence) method you are using has not been validated. Considering that you are working with an unproven blend, there will seldom be a validated laboratory method in existence. In addition, most UV of HPLC methods are only used to assay the API, leaving no idea of how well the excipients are blended.

Every association and the FDA state that the “sample thief” approach to sampling a powder mix is possibly the worst manner. Since a powder blend, flowing at 450, will largely separate into its components; that means each cell of the thief must be remixed before an analysis is performed.

If scale-up is required, the monitored blend uniformity approach may be used for any sized batch. While merely one component of a PAT program, this tool can be integrated as a time-saver for traditional formulating. Also, since generic firms need, by law, to show blend uniformity for each batch, wireless monitors save sampling and lab time multiplied by the number of lots produced each year. The cost of HPLC solvents, both purchase price and disposal costs, in one year alone will pay for one or more blend uniformity monitors; after that, all you have is the maintenance costs and large savings.

Another “entrée” method, common to PAT programs, is qualifying incoming raw materials with NIR or Raman. The connection with PAT/QbD is to supply physical/chemical information to adjust the design space for producing dosage forms within quality specs. The benefit of using this PAT-tool is the major time and cost savings over performing conventional USP, EP, ASTM or other traditional methods.

These traditional methods, however, were only meant to test the purity, not their process-ability or ability to produce a good product. In addition, the time needed to test the excipients via GMP methods can take days or weeks for large numbers of samples, while a spectroscopic approach can give valuable process-related information as well as purity/ID in minutes instead of days. This is a huge time-saver and lab-time saver. Both translate into dollars saved.

The other side of the coin is safety. With the supply chain for APIs and excipients stretching around the world, embracing developing countries without strong EMA and FDA oversight, the safety of certificates of analyses can no longer be relied upon. With scant experience in GMP manufacturing, many new suppliers simply do not understand the possible consequences of no-sterile materials, for example.

So, there is a mixed message here. You have the opportunity to greatly increase business, but as with gaining a university education, you have to pay for the chance to earn more. If a CRO or CMO embraces the realities of the 21st century—PAT, QbD and continuous manufacturing—then their future is bright. If not, then these can be placed in the category of an insurmountable opportunity.

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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.