A Case Study to Introduce ProcessAnalytical Technologies inPharmaceutical ManufacturingDr. Hubertus Rehbaum • Dr. Rehbaum Technology Consulting, Berlin

Correspondence: Dr. Hubertus Rehbaum, Dr. Rehbaum Technology Consulting, Friedrichstr. 68, D-10117 Berlin;e-mail: h.rehbaum@rehbaum.info

AbstractToday, Process Analytical Technologies (PAT) are well recognized as a set of tools withinthe pharmaceutical industry. However, the application for in-line or on-line measurementsdid not find the same response throughout the industry. Instead, the level of implementa-tion ranges from a few pharmaceutical manufacturers using PAT as a key tool in thequality control process to many companies not yet engaging in the use of PAT at all. Thisarticle provides an overview on PAT, followed by an analysis for the use case of upgrad-ing a container blending process with PAT. As such it is meant to be a guideline for man-agement, technical operation and quality assurance in the understanding and decision to-wards the introduction of PAT.

Introduction

The concept of the Process AnalyticalTechnologies (PAT) for the pharma-ceutical industry started more than15 years ago, although the technolo-gies such as Near-InfraRed (NIR)spectroscopy have been used formuch longer. One of the key driverswas the U.S. Food and Drug Admin-istration (FDA), which in 2004 re-leased a ‘Guidance for Industry’ [1]as part of their PAT initiative. It isimportant to emphasize that PATcannot be reduced to the use of an-alytical instruments such as NIRspectroscopy in a laboratory environ-ment. Instead, PAT must be under-stood as a holistic approach to de-sign, analyze and improve the pro-duction processes by monitoringCritical Process Parameters (CPPs)and Critical Quality Attributes(CQAs), to use the informationgained in controlling the processes.The PAT-based process control tar-gets improved drug quality and in-creased efficiency of the manufactur-

ing process while minimizing prod-uct loss. Obviously, PAT and Qualityby Design (QbD) complement eachother [1].

To exploit the full potential of aholistic PAT approach especially forcommercial manufacturing, thecomplexity increases significantly.That is, the analyzer equipment, theprocess machine with integrated rec-ipe management and control system,as well as the pharmaceutical prod-uct itself must be considered to-gether to design a new, PAT-enabledprocess.

The technical component furtherneeds to be augmented by knowledgeand experience on the use of equip-ment, data processing and interpre-tation. Only then, the benefits of PATand the return on investment can beachieved.

This obviously applies both forprimary and secondary manufactur-ing. For simplicity, this article willfocus on batch-oriented secondarymanufacturing of oral solid dosageforms and use blending as an exem-

plary unit operation to be equippedwith PAT.

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TechnoPharm 7, Nr. 3, 138–143 (2017)© ECV • Editio Cantor Verlag, Aulendorf (Germany)Rehbaum • Process Analytical Technologies138

Autor

Dr. Hubertus Rehbaum

Dr. Hubertus Rehbaum studierte Elektro- und In-formationstechnik (Dipl.-Ing.) sowie Betriebswirt-schaftslehre (Dipl.-Wirt.Ing.) an der RWTH Aachen.Während seiner Promotion in Angewandter Infor-matik an der Georg-August-Universität Göttingenentwickelte er Algorithmen für die Analyse vonBiosignalen zur Steuerung von Handprothesen. Mitder Stelle als Manager Scientific Operations bei L.B.Bohle wechselte er anschließend in die Pharma-industrie, um dort den Fokus auf Softwaresysteme,Automatisierung und PAT zu legen. Seit 2016 ar-beitet er als freiberuflicher Technologieberater fürdie Pharmaindustrie.

Key Words. OSD Secondary Manufacturing. PAT. Quality by Design. Spectroscopy. Data Processing. MVA

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PAT Applications in thePharmaceutical Industry

With the use of different analyticaltechnologies (such as NIR or Ramanspectroscopy) successful applica-tions have been implemented in sec-ondary manufacturing for all unit op-erations. A non-exhaustive overviewis provided in Fig. 1. Widely spreadPAT applications are in batch pro-cess equipment for blending andfluid bed processing, especially usingNIR for process end point detection.

After all, for all given applicationsthe potential is to improve the man-ufacturing process towards in-creased product quality and reducedcosts along the entire processingchain.

But, PAT by itself is a multidisci-plinary topic, requiring knowledgeand experience in the followingareas:. Process equipment and productionprocesses

. Analyzer equipment (e.g. NIR,Raman spectroscopy or specialimage processing)

. Data processing, Multivariate DataAnalysis (MVA) and quality datamanagement in regulated envi-ronments

. Process control design, softwareinterfaces and system integration

While selected vendors for process-ing equipment offer PAT-enabledsystems, these off-the-shelf solu-tions will only in few cases meetthe actual requirements of the phar-maceutical manufacturer. In the

end, PAT should also be able to beinstalled as an upgrade on existingprocess equipment. Consequently,in most cases the system ownerwill have to invest own knowledgeand resources to successfully intro-duce PAT.

For this reason, the questions andchallenges resulting from an upgradescenario for batch blending are out-lined in the following, but they alsoapply to any other unit operation.

PAT for Batch Blending

This example covers the case of anexisting or newly purchased con-tainer blender for a drug product,to be equipped with NIR for in-pro-cess monitoring. The pharmaceuti-cal manufacturer (further referredto as client) aims at stopping theblending process based on CQAsacquired.

Current Blending ProcessUntil now, all blending processes atthe client are performed using con-tainer blenders, like the equipmentshown in Fig. 2. The production rec-ipes are characterized by the givenrotational speed as well as the pro-cess time. At the end of the process,samples [2] are taken to be analyzedin the laboratory, e.g. using high-per-formance liquid chromatography(HPLC), and used to approve the in-termediate product.

The CQAs determined in the labo-ratory are the Active PharmaceuticalIngredient (API) content (%) in all

samples taken and thereby homoge-neity. As such, the client uses state ofthe art methods for pharmaceuticalproduction.

Motivation for PATExpectations towards a PAT-enabledblending process originate both froma quality and cost perspective. Con-sidering the quality, the samplingfrom the container has an inherentrisk for uncertainties. Moreover,manual processing and analysis inthe laboratory imply a risk for humanerrors.

Furthermore, laboratory work canrequire hours or even days, thus in-creasing the lead time significantly. If

TechnoPharm 7, Nr. 3, 138–143 (2017)© ECV • Editio Cantor Verlag, Aulendorf (Germany) Rehbaum • Process Analytical Technologies 139

Dispensing/Weighing

DryingRaw Material TabletCompression

Transport Transport Transport Transport TransportAPI

Excipient 1Excipient 2

Lubricant

Blending Film CoatingGranulation

▪ Identification ofraw materials

▪ Verification

▪ Homogeneity▪ Binder addition▪ Granule growth▪ Process end

point

▪ Moisturecontent

▪ Process endpoint

▪ Uniformity▪ Process end

point

▪ Homogeneity▪ Potency

▪ Process endpoint

▪ Homogeneity

Figure 1: Overview of PAT applications established in the pharmaceutical industry (source: Dr. Rehbaum Technology Consulting).

Figure 2: Exemplary container blender(source: L.B. Bohle).

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the laboratory results reveal insuffi-cient quality attributes, either theblending process must be repeatedor the product is discarded. In anycase, this causes increased costsand additional delays for manufac-turing.

Using PAT based on NIR spectro-scopy, an in-process assessment ofthe CQAs (API content or blend ho-mogeneity) replaces the manualsampling and laboratory analysis.Thus, not only the human error fac-tor is removed, but also the CQAs areacquired instantaneously during themanufacturing process.

But for successful implementa-tion, technical challenges need tobe resolved. Furthermore, process-specific knowledge and chemometricmodeling have to be established. Fi-nally, also the PAT approach requiresa validated process, as does the ex-isting approach.

Mechanical Integration ofNIR

NIR spectroscopy equipment can bepurchased off the shelf from variousvendors (e.g. Bruker, Brimrose, Sen-tronic, Viavi), featuring angle sen-sors, in-built PCs with battery andwireless connectivity. Ideally, noproduct contact is required, reducingalso the requirements for the NIRequipment. Instead, the mechanicalport to connect the probe to theblending container, ensuring a con-sistent and representative samplepresentation, should be resolvedwith the supplier of the container.Typically, a modified container lidwith a sapphire window and port(e.g. tri-clamp) to receive the NIRprobe head will be supplied by theequipment vendor. Therefore, when-ever the container is upside down,the window is covered by product,which is why a sample is taken auto-matically by the spectrometer andmade available for processing andanalysis.

With the mechanical connectionestablished, the NIR spectral datacan be acquired from the process.

Software Integration andData Processing

In contrast to the selection of theanalyzer hardware and mechanicalintegration, the data processing andsoftware integration implies a muchhigher customization and dependson expectations and knowledge levelof the client. But the raw data pro-cessing andMVA to extract the CQAscan be separated from the technicalsoftware integration.

Data Analysis and CQAExtractionThe multivariate NIR spectrum ac-quired by the analyzer does not pro-vide direct insight on the actual pro-cess or CQAs. Instead, the spectraldata needs to be processed and in-terpreted using multivariate dataanalysis based on chemometric mod-eling including data pre-processing.This is illustrated in Fig. 3 for theassessment of blend uniformity.

Thus, the client has to decide onthe MVA software product and de-velop the chemometric model. Still,chemometric model building re-quires training and sufficient experi-ence of the chemical properties to beanalyzed. If the necessary knowledgeis not available among staff, it musteither be acquired or external serviceproviders can be used for modelbuilding. It is important to stressthat very often the chemometricmodel is process-specific. A changeof the product or even the raw mate-rial supplier for an existing producttypically requires the chemometricmodel and parameters to be ad-justed. Furthermore, acquisition ofreference data for model buildingshould be planned and carried outbased on the targeted CQAs and ex-pected information content.

PAT ArchitectureWith the analyzer equipment inplace and the chemometric modeldeveloped, still the gap between theacquired CQA and the control systemof the process unit remains. There-fore, the second and often most com-

plex task is the design of the alloverdata infrastructure and modificationof the machine’s automation system.Three different scenarios can be con-sidered:. The simplest option is to not haveany integration between PAT dataacquisition with MVA and theprocess machine. That is, PAT dataacquisition and processing is op-erated as a standalone system,displaying the CQA on a computerscreen. If the CQA is used to ter-minate the process, it is within re-sponsibility of a human operator totransfer the result to the controlsystem of the process machine.This is illustrated in Fig. 4. Obvi-

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Acquire Spectral data(multivariate)

Inte

nsity

Wavelength

Apply MVA

Retrieve univariate CQA

signal processing, chemometric modeling

Time

BU

Figure 3: Extracting blend uniformity (BU)as CQA from multivariate spectral data(source: Dr. Rehbaum Technology Con-sulting).

Manual transferof CQAs

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Speed 8

Time elapsed 8:22

Process Control

StandalonePAT system

Figure 4: Basic PAT setup without anyintegration (source: Dr. Rehbaum Tech-nology Consulting).

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ously, this solution bears the samerisks for human errors as the stateof the art model. It should only beconsidered during an evaluationphase or during process develop-ment.

. A more advanced solution is toestablish a data connection be-tween the standalone PAT setupand the process control system asshown in Fig. 5. For this approach,often the proprietary software ofthe analyzer vendor can be used,implying a vendor-specific solu-tion. In this scenario, the CQA isprovided digitally to the controlsystem and used to end the processautomatically. Drawbacks of thissolution are dependency on thesoftware of the analyzer vendorand, in case of expanding PAT us-age, multiple isolated systems to bemaintained.

. Finally, a complete PAT datamanagement infrastructure can beestablished, serving multiple proc-ess machines and analyzers(Fig. 6).

This implies using a third-party sol-ution such as Optimal synTQ or Sie-mens SIMATIC SIPAT, providingvendor-independent PAT data ac-quisition, processing and storage.

Data acquisition is not limited tothe CQAs by the analyzer, but bi-di-rectional connections with the con-trol system of the unit operations canbe used to augment quality data byprocess information.

Especially for companies consid-ering using PAT in several unit oper-ations, this approach allows for cen-tralized management of data, pro-cessing and knowledge. The central-ized PAT data management can beused to generate comprehensive re-ports, track CQAs and CPPs along theprocessing chain and harmonize thetechnologies.

Obviously, the decision on thePAT data architecture depends onthe current and future strategy ofeach client.

Connectivity to Process ControlSystemFor both the vendor specific stand-alone integration and the centralizedPAT data architecture, a data con-nection must be established to thecontrol system of the unit operation.This includes the ProgrammableLogic Controller (PLC) and/or Hu-man Machine Interface (HMI), there-fore affecting also validation of the

equipment. In most cases, controlloops are added on unit operationlevel to receive and process the qual-ity information at hand, for instanceto compare them to threshold or tar-get values in the recipe. Conse-quently, this step implies to modifythe existing PLC code, HMI designand recipe management. Such soft-ware modification requires the orig-inal source code or support of thesystem manufacturer to be available.Obviously, modifications must alsobe specified, aligned with require-ments of the PAT analyzer equip-ment and communicated to the im-plementing entity.

Conclusion

As shown in this article, introductionof PAT requires a multidisciplinarytoolset, with thorough understand-ing of the topics process analyzers/spectroscopy, data management,process equipment and control sys-tems. Targeting a seamless integra-tion between PAT systems and thecontrol systems of various unit oper-ations, software modifications anddefining the interfaces become in-creasingly critical.

Although the example shownabove considers a very applied ap-proach, introduction of PAT shouldbe advanced strategically. That is, along-term PAT strategy including aroadmap has to be developed forthe client. This strategy has to con-sider factors such as existing knowl-edge, product portfolio, product in-novation and company size. Onlythen, a lasting PAT roadmap can bederived, avoiding disappointmentand overspending.

Critical decisions to be made inthis PAT strategy are:. Unit operations and viable productfor implementation roadmap

. Integration level for process con-trol

. PAT data architecture

. Chemometric modeling (make-or-buy decisions)

. Maintenance of PAT models

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Data exchangeprocess controland PAT

20 min0 min 10 min

Speed 8

Time elapsed 8:22

Process Control

StandalonePAT system

Figure 5: Standalone PAT system withvendor specific data integration (source:Dr. Rehbaum Technology Consulting).

20 min0 min 10 min

Speed 8

Time elapsed 8:22

20 min0 min 10 min

Speed 8

Time elapsed 8:22

Central PATdata management

PAT network

...

PAT

Clie

nt

PAT

Clie

nt

Figure 6: Centralized PAT data architecture with full integration into process control(source: Dr. Rehbaum Technology Consulting).

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. Reporting of CQAs and CPPs(centralized vs. local)

. Regulatory considerations andcurrent Good ManufacturingPractice (cGMP) or Good Auto-mated Manufacturing Practice(GAMP)

. ValidationIn conclusion, pharmaceutical com-panies are suggested to seek profes-sional advice on technologies and re-

quirements allowing them to suc-cessfully introduce PAT and eventu-ally build up internal working groupswhich suit their business cases andcapabilities best.

References[1] U.S. Department of Health and

Human Services, FDA: Guidance for

Industry; PAT – A Framework forInnovative Pharmaceutical Develop-ment, Manufacturing and QualityAssurance, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf(last access: 20/04/2017).

[2] Muzzio et al, Sampling and character-ization of pharmaceutical powders andgranular blends, Int. Journal of Pharma-ceutics 2003, http://doi.org/10.1016/S0378-5173(02)00481-7 (last access: 20/04/2017).

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