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Arthur R. Mlodozeniec, PhD, is aprincipal of TechniPharm Consulting Group,652 Sand Hill Circle, Menlo Park, CA, 94025,tel. 650.854.1830, amlodozeniec@technipharm.com.

Challenging “The Process is theProduct”Clarifying the Role of Information Technology inBiopharmaceutical Process DevelopmentArthur R. Mlodozeniec

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The author argues that informationtechnology solutions will play a majorpart in confirming—by experimentaland statistical validation—thatbioprocesses may be interchangeableand therefore generic. Thebioprocessing ANDA will define bothin-house and contract manufacturing.

s the biotechnology industry approaches the dawn ofits generic era, much discussion has focused on whetherbiotech-product specifications alone are inadequate tomanage the ultimate quality of the medicinal drug pro-

duct. Some argue that not enough information is available inthese quality control specifications to ensure full safety and ther-apeutic response. Proponents emphasize the time-honored for-mula, “the process is the product” (1). This school relies onprocess control data that steers the biotech active pharmaceu-tical ingredient (API) through a well-managed, well-controlledcycle from raw material to finished goods. Bioprocessing, theyargue, is a very complex operation that demands many signif-icant information measurements (see Figure 1 for technologytransfer tasks [2]).

Indeed, many efforts to standardize the transfer of biotechoperations have addressed platforms for analytical method de-velopment and implementation. Information technology solu-tions such as laboratory information management systems(LIMS) programs (3), have been adapted to capture real timedata, as in process analytical technology (PAT) applications (4).We can thus assume that the future promises more, rather thanless, control of process variables than was possible at the time ofapproval of any given bioprocess. Complexity may not be thereal hurdle. The key may be timely data about critical variables,with closed-loop controls leading to interchangeable process-management techniques. This has suggested that compliant, val-idated process control may in fact be more readily achieved inthe current, biogeneric era than was possible 10–15 years ago.

It now appears that information technology solutions willplay a major part in confirming—by experimental and statis-tical validation—that bioprocesses may be interchangeable andtherefore generic. The bioprocessing abbreviated new drug ap-plication (ANDA) will define both in-house and contract manu-facturing. The Food and Drug Administration is working onthe guidelines, but they are not yet available.

Outsourcing bulk manufacture of the API is also a long-established pharmaceutical industry practice. More recently,outsourced biotechnological scale-up and manufacture haveprompted a global competitive surge. IT process-managementsolutions will punctuate the validation and compliance of theseoffshore operations.

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When biogenerics are manufactured, they must show inter-changeability with the reference product. Unlike small mole-cules, which are more easily controlled for chemistry, manu-facturing and control (CMC) criteria within the new drugapplication (NDA) registration process, the biotech productionprocesses—DNA cloning, protein expression, and hybridomatechnology—vary. Thus, the small-molecule generic is matchedvia analytical characterization and current good manufactur-ing practice (CGMP) controls of the innovator process andproduct specifications. The bioprocess requires cell culture, pro-tein harvesting, separating and purifying the protein product,and stabilizing the API. The biotech drug product’s fill–finishoperations require subtle handling to preserve the secondaryand tertiary structures, which are as important as the primarystructure.

Much bioprocessing takes place in a controlled environment,carefully protected against incidental contamination and processdisruption. In today’s technological environment, criticalprocess-control measurements and monitoring are required todrive the necessary information to a process control station orto the attention of a qualified operator (see Figure 2 for IT andPAT applications to bioprocessing).

Using electronic data capture in bioprocessing’s tight CGMP spacesThe burdens of paper-driven workflow have presented a for-midable hurdle for bioprocessing operations, which require iso-lated, almost sequestered personnel, dedicated to maintainingcontamination control of both product and worker. Pharma-ceutical process control requires remote sensing and monitor-

ing using electronic data capture(EDC) to gather more data, morequickly and more accurately (5).

Technologies for generatingand verifying the authenticity ofoperator control and observationhave been developed in recentyears to comply with 21 CFR Part11. Several electronic techniquesare used for developing and im-plementing a procedure for ver-ifying and documenting an indi-vidual’s identity before assigningan electronic signature. This ver-ification can be incorporated intothe system administrator’s stan-dard operating procedures. Bothbiometric and nonbiometrictechnologies have found useful-ness in the “smart room” conceptfor managing the bioprocessingsuite.

Using Bluetooth in sterile suitesSystem-integrated controllersconnected by robust, wireless net-

works are advancing rapidly into sterile product suite designs(6, 7). Such sterile suites are the focus of most biotechnologymanufacturing, demanding control of devices such as particlemonitoring systems, thermostats, and process-control mecha-nisms. Thus has the era of the “smart room” arrived.

The software for handling communications in a cleanroom—where workers wear clean suits and management requires freeaccess to voice and touch control—is commonly called a stackor Bluetooth protocol stack, because it refers to a collection ofsoftware partitioned in modules, or layers, using an open sourceinitiative network model.

The antenna efficiency and its pattern throughout the ster-ile suite will greatly affect the range and usability of the Blue-tooth installation. Specific portable devices may be validated ifthey are designed and set up for omnidirectional performance.

Using electronic logging devicesMost traditional sensing and critical-variable monitoring—automated by physical sensors in the pharmaceutical clean-room—have been converted to miniaturized electronic dataloggers. Total organic carbon (TOC) monitoring of water sys-tems, sampling of cleaning validation, and microbiological con-trol in a sterile suite can now be managed by data loggers.

Measuring disinfectant products for compliance monitor-ing, as well as the use of thermistor-style thermometers, per-mits calibration data retrieval in real time for accurate and re-sponsive management of a critical sterile condition. Data loggerspermit random sampling and testing by the operator, in addi-tion to required programmed-interval testing. Integrated in-formation analysis detects alarm conditions, and statistical

Facility assessment

Skill set analysis and training

Process development and approval

Analytical method transfer

Raw material component evaluation

Equipment qualification

Process transfer

Computer system validation

Technology transfer planning and success criteria.

Figure 1: Proper technology transfer is essential to produce quality biopharmaceutical products. Thechart lists key technology transfer tasks (adapted from reference 2).

Pharmaceutical Technology IT INNOVATIONS 2004 s15

process-control analysis determines the capability index of unitoperations such as filtration, chromatographic separation, andcell harvesting.

A hardware architecture that houses a central server in adedicated, secure off-site IT center fulfills the isolated-controlrequirements for fertile data mapping and strongroom management.

At-line, on-line, and in-line process monitoring devices—such as optical character recognition coupled with machine vi-sion detection—permit spectroscopic measurement for qual-ity control and assurance during the actual manufacturingoperations. The emerging acceptability of PAT allows assay con-trol during in-process management to align temperature andpressure controls, letting operators fine-tune product yield andquality (4). PAT-device detection of solvent-based operations,critical in making lyophilized solid protein, will help standard-ize the physical state of the API and drug product, which haveuntil now been subject to start-up and tailing fragmentationpatterns. Dryer shelves can be specifically monitored in realtime for validated investigatory as well as routine manufactur-ing operation for biotech products.

Computerized maintenance management systems (CMMS) integrate process management with equipment controlBioprocessing equipment is firmly managed for contaminationcontrol and product integrity, avoiding crosscontamination. Insuch situations, preventive maintenance is often a key. Newertechnology can monitor the reliability and readiness of criticalequipment. These systems use predictive maintenance ap-proaches, measuring properties such as temperature (which re-flects friction or misalignment), sound and vibration (whichcan signal that it is time to readjust a mixing or blending oper-ation), and other products of noninvasive tests.

Measurements made by comput-erized maintenance managementsystems show performance trends,which can guide product-improve-ment as well, indicating a spentprocess or a declining filter controlbefore a breakdown can interrupt acontinuous bioprocessing operation.

IT is critical to ensuring a genericproductProponents have recently used finalproduct specifications to demonstratethe interchangeability of several bio-generic products. Such generics al-ready have been marketed by severalnew manufacturers (especially in Eu-rope, where human growth hormonehas been distributed generically since2002). A major point of contentionin the United States has been the lackof suitable CGMP management ofthe process (8). Both statistical qual-ity control (SQC) of the drug prod-

uct and statistical process control (SPC) of the manufacturingoperation have been used to justify the specifications for the reg-istered product. IT management of the process database is citedas critical to process performance and compliance with the reg-istered methods. Indeed, the information is the platform for es-tablishing the confidence in maintaining control of operations.

The rising use of electronic sensors and digital data process-ing of key process variable measurements has opened up op-portunities for newer process-control management. This is justthe beginning of a new wave of emerging technologies that areshaping the follow-on biologics arguments, and changing thediscipline of bioprocess control.

References1. E. Polastro,“The Future of Biogenerics,” Contract Pharma 3 (5), 40–50

(2001).2. ISPE,“Analytical Methods, Active Pharmaceutical Ingredients, Dosage

Forms,” in ISPE Good Practice Guide: Technology Transfer (ISPE, Tampa,FL, 2003).

3. M. Venkatesan and Z. Grauer, “Leveraging Radio Frequency Identifi-cation (RFID) Technology to Improve Laboratory Information Man-agement,” Am. Lab. 36 (18), 11–14 (2004).

4. J.-M. Geoffroy,“Impact of PAT Implementation on Product and ProcessSpecifications,” Am. Pharm. Rev. 7 (3), 35–38 (2004).

5. J. Morrill,“The Future of EDC for the Life Sciences,” Biotech/Tech, 2(2), 20–26 (2003).

6. N. Baisa,“Taking the Bite Out of Bluetooth Technology,” National Edge,October 2004, www.national.com/nationaledge/.

7. N. Baisa, “Design Idea,” Electronic Design, 4 October, 44–45 (2004).8. “Consequences of Noncompliance,” The BioPharm Guide to GMP His-

tory, Supplement to BioPharm Int. 20–27 (2002).PT

Bioprocess

API sterile suite

Protein drug product form–fill–finishoperations

IT and process control technologies TPC, smart rooms, remote sensing, data loggers, PAT, CMMS, Bluetooth technologies, manufacturing controls (CMC), QA/QC/regulatory

Generic

Figure 2: Information technology and process analytical technology (PAT) applications tobioprocessing include total process control (TPC), smart rooms, remote sensing, data loggers,process analytical technology, computerized maintenance management systems (CMMS), and qualityassurance/quality control (QA/QC) and regulatory oversight.