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tech transfer

Tips for transferring legacy products and processes

Anthony Grenier

The many mergers and acquisitions of the last 5 years ofteninvolved moving legacy products from sites where they weremanufactured for decades. Perhaps they were even developedthere. Here are some tips on making it a smooth transition.

t’s always a little heart-breaking to learn that a manu-facturing facility will shut down because the people run-ning it couldn’t achieve compliance or because a BigPharma company is “rationalizing” its manufacturing net-work. In many such cases, the products must be trans-ferred to a new site, and the destination could be anotherplant the company owns, a different company’s manufac-turing site, or a plant run by a contract manufacturingorganization.

Operators. Even if it’s not recorded, the informationthat long-term employees can provide is nearly unlimitedand is crucial for understanding how legacy products aremade. These people could be the only ones who remem-ber how things were done before the facility wasextended or reorganized. Some might even recall the ini-tial product and process transfer from R&D.Sugar coating is a good example. It was once preva-

lent, and required operators to master the art of a confec-tionery process instead of how to click through drop-down menus on a human-machine interface of a filmcoater as they do today. In North America, sugar coatinghas all but disappeared, but in Europe it and other oldtechniques are still used. They’re difficult to validate butthese practices continue nonetheless thanks to the exper-tise of the operators. Ask them how they make theseprocesses successful.The tooling room is one of my favorite places to

explore, and if you’re involved in technology transfer,take the time to speak to the employee in charge of thepunches, dies, and other change parts. This person caninform you how frequently tooling is ordered and tellyou about the specific features of the tooling design,including the addition of special treatments, such as achrome coating. Whoever is in charge of the toolingroom will also know about the tablet presses and thechange parts they use, including the force feeders andturrets, and how to set up the press. Ask how the staffconducted troubleshooting of the tablet presses and cap-sule fillers. What worked? What didn’t?

I’ve helped transfer multiple products from maturefacilities, and in this article I share some of what I’velearned. The focus is on how to collect the informationyou need to gain enough process and product under-standing to facilitate a successful site change without dis-rupting supply. The article doesn’t discuss how to handleshutdowns of new facilities when volume falls short ofexpectations or corporate strategy changes.

Old facilitiesOne cause of obsolete production environments is a

management decision to save money by not investing innew equipment, even though it would increase efficiencyand improve operator safety. Of course, that decisiononly hardens once managers learn that a divestiture islooming, and instead of being upgraded, such facilitiesmay become donor sites.These facilities—working time capsules many of

them—often use manufacturing processes that wereadapted to suit the site’s physical limitations. At somefacilities, for example, the clearance between the ports ofthe V-type blenders and the ceiling is so tight that theymust be loaded by an operator with acrobatic skill. Inother cases, workers must scoop the compression blendsinto the tablet press hopper because it’s impossible to dis-charge them from a lifted container or from an upperfloor. I’ve seen a few cases where workers were allowed tocharge the V-type blenders indiscriminately via the twoports. In short, there are almost as many different setupsas there are companies when it comes to loading mixersand blenders, holding or storing powders, and feedingtablet presses and capsule fillers.Today, companies transfer products into manufactur-

ing environments that have a smaller process footprintand require fewer workers. And the high ceilings popularin facilities built after World War II, which allowed pow-der blends to free-fall into the press hopper, are disap-pearing because process engineers recognize that longchutes can cause powders to segregate. Bin blenders arethe modern approach.

How and where to recover informationThe black notebook. FDA-approved processes must

be run by the book, but if you want to know how thingsreally work at legacy sites, ask long-term employeesabout their “black notebook.” It’s usually concealed intheir back pocket or locker. While the practices itdescribes may not meet GMP, the notebook is a valuablesource of information because it reveals key process para-meters and/or specific product handling methods that aresometimes decisive in whether a legacy product passes orfails. I remember asking one senior operator whether hehad kept notes or drawings from the time when the prod-uct ran well. He had indeed, and that information helpedme set up a roller compactor properly. I also recall a note-book that reported that the operators intentionally leftcompressed cores to “relax” for a few minutes before theywere measured for hardness. Good to know!

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Manesty’s DryCota tablet press, a machine used to developand manufacture many tablet-in-tablet products. Most are nowmanufactured on more modern equipment.

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Beware of recycling old equipmentIt’s an understatement to say that the pharmaceutical

industry is conservative: Some facilities still use equip-ment and processes from the 1970s and 1980s. In fact, it’snot unusual. The industry abounds with painted-frametablet presses that require operators to turn hand wheelsto adjust performance. At some facilities, nothing haschanged since the process was conceived and the equip-ment installed.Perhaps that’s OK if the

process works, but when newequipment eventually replacesthe old, beware of repurposingthe old machines in-house. I’veseen equipment that shouldhave been sold or scrapped butwas instead transferred to the product development section.That seems like an economical and sound decision, but itoften isn’t. After all, your colleagues would inherit amachine that has no equivalent elsewhere and/or uses a dif-ferent principle of operation than the modern productionequipment. Examples include planetary mixers and oldtablet presses with worn turrets. I understand it may be dif-ficult for the R&D people to refuse no-cost equipment, butthat’s what they should do in most cases. In fact, it’s coun-terproductive to accept the outdated equipment because itsperformance will never be representative of the process at alarger scale. In addition, because of wear and tear, oldmachines will likely generate unreliable data.Installing donated equipment at another production

facility isn’t usually a good idea either. It can take a longtime to fit the outdated equipment in with more recentequipment and connect it to process controls.Consider Manesty’s DryCota tablet press, which was

used to develop many tablet-in-tablet products duringthe 1970s, 80s, and 90s (photo). Those products wereeventually transferred to a facility equipped with 21st-century tablet presses like IMA’s S-250 and Kikusui’s Libra2 DC. The switch to modern machinery, though chal-lenging, enables operators to confirm online that thecores are present, which the original equipment didn’t.I can’t stress enough the importance of making time to

monitor—in depth—the donor sites to understand howthe equipment there is installed, how it operates, and howit fits in the process. Ideally, come with an experiencedoperator from the receiving site and take photos or videos.Survey different operators to find out how they have triedto change the process, how different setups/adjustmentsaffect results, and what they have observed behaving dif-ferently under certain circumstances. These could includeseasonal changes, changes in flow behavior, and day versusnight shift. Operator seniority could also have an impactbecause sometimes only senior operators know how to runhard-to-handle products, an ability they mastered fromyears of experience. The most interesting observations arethose not documented in the batch record. Be sure toinclude them in your unofficial product history.

Case study: Hiccups after upgradeYears ago, I was asked to help transfer an old product

that had run on the same press for 15 years. The productwas running well at an output of 1,300 to 1,500 tabletsper minute (tpm), and there were no problems with flowor content uniformity during the initial process valida-tion. The product was then moved to a new facilitywhere the press typically produced in the range of 3,500tpm. During the trial batches at the receiving site, the

product wouldn’t flow at all.A long investigation androot-cause analysis revealedthat at the previous site, theold, mobile press had beenbrought to the productionarea at the start of each cam-paign. It was also standard

practice not to level the press, which caused it to vibrate.That helped the powder to flow. Of course, operating thepress at a lower speed also helped with weight unifor-mity, but the vibrations were the main reason because theblend at both sites had the same particle size distribution.With no slower press available at the receiving site, thesolution was to reformulate the blend to improve itsflowability and content uniformity so it would run on thehigh-speed press.

Validation and process understandingIn some cases, the processes used to make legacy

products were never validated or validated retrospec-tively based on the history of the process and product.That works well if it’s done properly using, for example,statistical tools such as control cards or a process-capabil-ity index—often denoted Cpk—on relevant process para-meters and/or controls. If no validation was done, yourcompany’s specialist in technology transfer or a consul-tant will have to pull executed batch records from a rep-resentative number of lots and analyze the data. That willgive you an unbiased picture of process behavior at thedonor site. It will also help you design the technology-transfer plan and help you draft a comparability protocol.

Other important documentsData from the site to be closed usually includes master

batch records and product and raw materials specifica-tions. Within the master batch records, there is typicallya section that lists the history of changes and the corre-sponding change-control numbers. With that informationyou can find reports and/or justification of the changes inthe process, materials, and equipment.Several other documents can provide more details that

will help you continue manufacturing within-spec legacyproducts. They include:• A certificate of analysis (CoA) for each active ingredient,excipient, and primary packaging component. The CoAwill list a specific grade of material and the manufacturer’scode for it, enabling you to order the exact same material.Use the most recent CoA to procure the material. Onecaveat: The specifications of some lots of excipients

Installing donated equipment atanother production facility isn’t

usually a good idea.

within the same technical grade could fall in a narrowerrange when tested a certain way, but that information isunlikely to appear anywhere.Additionally, the last three CoAs will indicate whetherthe lots were trending in terms of some physical charac-teristic, such as particle size distribution, density, or spe-cific surface area. If you change any of your sources,compare the new supplier’s data to those of the previoussupplier and be sure you can demonstrate that the newmaterial meets the critical material attributes.• Executed batch records. These contain data for actualprocess parameters and in-process results. For legacyproducts, the actual operating values tend to be close tothe upper or lower limits of the in-process specification.Sometimes, that’s the only way the product can be man-ufactured and still meet other parameters. A classicexample is setting a broad tablet hardness specificationand then keeping hardness in a narrow upper range sothat the tablets withstand subsequent handling andcoating.• Annual product report. This key document lists thenumber of rejected batches and, more rarely, the num-ber of reworked batches, if any. It will also cite anymajor deviations. From this information, you’ll knowfairly quickly whether you need to dig into the archivesto find out what could go wrong with the product andprocess when you transfer them to a new site. T&C

Anthony Grenier is an independent technology transfer andoutsourcing consultant. A chemical engineer by training, Gre-nier has conducted more than 50 technology transfers for largemultinational corporations and specialty and virtual pharma-ceutical manufacturers. His work spans all major segments ofthe life science industry. E-mail: agrenier.ag@gmail.com. Web-site: www.anthonygrenier.com

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