Today’s pharmaceutical manufacturing facilities bear little resemblance to those of even a decade ago. More modular construction platforms are available, each with its own distinct identity and strengths. In addition, new single-use process equipment and contained process equipment and cleanrooms enable dramatic increases in flexibility and reductions in capital costs. Vaccine manufacturing facilities also have been transformed by new production platforms and better plant design.
Some biopharma facilities, especially those where single-use process equipment is being used extensively, are even starting to resemble discrete manufacturing plants.
There is a much greater emphasis on the bottom line, and reducing both capital and operating costs than there was 10-15 years ago, says Timothy McNeill, Director, Business Development Manufacturing and Life Sciences with Fluor Corp. (Irving, Texas). “Our pharma clients are much more interested in being competitive regarding cost of goods sold (COGS) and quality. Overall equipment effectiveness (OEE), equipment utilization, utility savings, HVAC, water and labor costs are being considered more closely today,” he adds.
Chris Miles, bioprocess specialist with Foster Wheeler Biokinetics (Walnut Creek, Calif.), says his clients are analyzing input and waste streams more closely, evaluating process scheduling improvement opportunities and working to better understand the advantages of incorporating single-use systems. “In each case, the goal is to use the latest technology to drive down costs at the level of the facility, the process and the components.”
Most facilities of the future are now, or will soon be, under construction in emerging markets such as China. There, the emphasis is on speed, yet there is often little understanding, at least not initially, of what the product’s final price will be. This is very different from the approach taken in the United States and Europe, explains Bikash Chatterjeee, President and CTO of Pharmatech Associates (Hayward, Calif.), which is now working on a large biosimilars facility in China for a client that plans to make its own products, and also offer contract manufacturing capacity.
“If a U.S. pharmaceutical company is going to build a manufacturing facility, they already know where they need to be in terms of final product pricing and, thus, what they can tolerate for the project. In Asia, they don’t think about that until well after the fact. Consequently, you don’t want to sink a lot of money into a facility design only to have to change it a few years down the line.”
In addition to differences between FDA, EMA, WHO, Japanese and China’s SFDA regulations, there are other uncertainties when building abroad. For instance, Chatterjee says, if you file an IND in China it takes a year or two before you get approval to move to clinical trials. The IND submission triggers an immediate inspection by the regional SFDA, which will assess your ability to support clinical activities and send recommendations to the central office in Beijing. “You have to anticipate where the concerns are going to be for that facility in the future.”
The best approach, Chatterjee says, is to consider global and local regulatory requirements carefully, and recognize that the trend is for tougher, more conservative regulations. “What you consider to be conservative today will more than likely become baseline five years from now,” says Chatterjee.
Consider the auditing of final fill-finish operations. Currently, Chatterjee says, EMA is extremely concerned about the ability of quality control professionals to audit final fill-finish operations without having to enter the area. FDA wants them to be able to audit entire operation without having to gown up and enter the area.
Regulators are concerned that if QC professionals have to gown up to enter Grade C class 10,000 areas, they might be less likely to audit them, and that, as a result, the proper degree of oversight and control won’t be there. While cameras and centralized control rooms, popular in both China and Japan, do provide some visibility into the process, they still can’t give QC the ability to intervene immediately if they see something wrong, Chatterjee explains.
“When you consider FDA’s broader requirements, and the fact they want to be able to see everything from cell banking to final fill-finish, that changes design parameters significantly,” says Chatterjee. “But that consideration needs to be there at the outset of the plant’s design.” He points to other examples, such as waste treatment for both solid and liquid plant waste. Chatterjee says the biosimilars plant in China has two halves: one, based on single-use technology, for small scale manufacturing; and the other, hard-piped, for large scale manufacturing. Both are being built in phases and are being designed to be completely autonomous as far as utilities are concerned. However, there are points where decontaminated solid waste streams do cross. “Even though one could argue that everything is contained, labeled and isolated,” he says, “regulators from MHRA commented that it would be optimal if there were no way for waste streams to cross.”
He also points to a client’s original wish to run its sterile core at a wide temperature range, to save energy and reduce costs. Without the right risk analysis, he says, one might make this change without realizing that it could require new gowning policies or a narrowing of the temperature range to ensure sterility.
“These are the little considerations that can cause you to stumble on your pre-approval inspection (PAI), says Chatterjee. Putting together a risk management framework up front that talks about the compliance, operational, design, business component, is really important.” The Chinese biosimilars plant currently has more than 40 different risk management plans for compliance alone, he says.