WHITE PAPER

Automating Biopharma Quality Control to Reduce Costs
and Improve Data Integrity
Tony Harrison, Applications Specialist | Beckman Coulter, Inc.

Abstract
One report suggests that an average pharmaceutical manufacturing factory spends around $40M per year on quality
control1. At the same time another report states that 79% of all 483 Warning Letters issued by the FDA in 2016 cited
21CFR part 11 data integrity issues2. Whilst re-training is a common response to an FDA 483 Warning Letter, thismay be only part of the solution: was the problem simply that the worker(s) didn’t follow the SOP correctly, or was
it really that manual SOPs are simply not robust enough to prevent future recurrences of the problem? Any processthat automates the quality control SOP can potentially both reduce the impact of human error on data integrity
issues and also bring welcome savings by reducing the time technicians need to devote to carrying out the SOP.
This paper takes a look at four common quality control procedures and how automation can help improve data
integrity by reducing opportunities for human error, whilst also saving time and reducing operating costs. The four
quality control procedures discussed in this paper form a common thread in the biopharmaceutical manufacturingindustry and are water quality testing, cleanroom routine environmental monitoring, biological cell counting andviability testing and final injectable drug particulate testing.

Introduction
Despite encouragement from the FDA in their 2004 PAT initiative3, many routine quality control (QC) test
procedures in the pharmaceutical industry remain intensely manual and time consuming. A study by the Industrial
BioDevelopment Laboratory showed >20% variability in test results between 16 experienced QC technicians
performing the same manual SOP4. Clearly the manual SOP could be improved and the technicians re-trained, butsuch variability in results suggests that the manual process itself is not robust enough to deliver the required levelsof quality control.
Whilst the technical specifications of similar instrumentation may appear equivalent, when looking to improve
quality control QC teams should be looking at the level of automation in the instrument to make QC testing morerobust and repeatable. For example a common source of errors in QC testing is sample preparation. An instrumentthat automates the sample preparation process can bring enhanced reproducibility and robustness to a QC test4.
Additionally, following the FDA PAT initiative, users could consider moving from sole reliance on laboratory-based
QC testing, to using the on-line QC instrumentation instead. For example, many companies have validated on-line
water quality testing instrumentation on their Purified Water (PW) and Water for Injection (WFI) loops, but they
continue to rely on time-consuming laboratory water testing for product release testing. As long as the on-line
instruments can be validated and meet the requirements of the pharmacopoeias, it makes sense to at least reduce
the amount of laboratory testing and to rely on data from the on-line instruments instead. As the on-line instruments
are automated, their use makes the testing more robust by avoiding human error, thus improving data integrity and,at the same time, reducing QC costs.

Purified Water and Water for Injection QC Testing
TOC and conductivity are two of the four critical quality attributes defined for WFI and PW in the United States
Pharmacopoeia11. On-line analysers such as the ANATEL PAT700 from Beckman Coulter can be validated to comply
fully for both of these key quality attributes according to the pharmacopoeial requirements.
The FDA Process Analytical Technologies (PAT) initiative4 encouraged the pharmaceutical industry to invest in
on-line process control instrumentation to ensure in-process quality control rather than relying so heavily on final
product quality testing. Right first time quality for batch manufacturing is encouraged because final product testingon pharmaceutical products is a destructive test and, for this reason, 100% batch testing cannot be performed –one slip during sampling and testing and the whole batch may face destruction. To this aim, many pharmaceuticalmanufacturers are connecting their on-line TOC analysers to their factory control systems so that any potential
TOC or conductivity excursions detected can be used to halt production and prevent the chance of potentiallycontaminated water being mixed with valuable active pharmaceutical ingredients.
With the revision to the European Pharmacopoeia (EP) chapter on WFI now permitting the production of WFI fromdouble pass reverse osmosis (RO) and ultra-filtration12, TOC and conductivity monitoring of pharmaceutical water
systems takes on an increasing significance due to the perceived risk of potential contamination break-through in
the RO system compared to the secure barrier afforded by a water still.

The four FDA water quality attributes

Cl Na +

Inorganic

H

CH2OH
C

HO

H

H
HOCH2

O

C

C

C

O

C
OH

H

CH2OH

C

O

H
C

HO

Endotoxins

C
C

OH
H

HO

H

H

Organic

Microbial

Figure 1. The four critical quality attributes for PW and WFIIn their guidance, the FDA are keen to emphasise that the 21CFR part 11 ruling applies only to the data historian
where electronic records are kept10. The danger with on-line instruments with their own local data historian built inis that they could attract the full requirements of the 21CFR part 11 ruling. Analysers such as the PAT700 avoid thisissue by allowing the local data historian to be disabled, thus ensuring that it does not attract the full 21CFR part 11
requirement as a data archive for electronic records.

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Traditionally, data from on-line TOC analysers was stored in validated Supervisory Control And Data Acquisition(SCADA) or Distributed Control Systems (DCS) systems, making process control improvements challenging andadding a further significant amount of change control. More modern approaches keep quality critical data records
in a separate secure archive, leaving SCADA and DCS systems dedicated to process control only and more agile.
In support of this the PAT700 can be configured to automatically send PDF electronic records via secure FTP over
Ethernet for review and batch release, thus satisfying the ALCOA requirements for electronic records to be legible,
contemporaneous, original and attributable.

Figure 2. Beckman Coulter PAT700 exports PDF data straight to data archive via Ethernet

Unlike laboratory water quality testing instrumentation which utilise reagents and require manual configuration foreach sample and frequent, often daily, calibration, the on-line PAT700 from Beckman Coulter requires no reagents,
automates the test protocol and only requires calibration once every 12 months. Calibration and System Suitability
Testing SOPs are automated, requiring no manual data entry and pass/fail reports are automatically generated
eliminating manual calculations.

Figure 3. Beckman Coulter PAT700 calibration standards export certified value via RFID

Cleanroom Routine Environmental Monitoring
Of course GMP mandates the air quality conditions for biopharmaceutical production in cleanrooms. In fact thereal danger is the microbes on the human body. Humans shed around 30,000 skin cells per hour5, all of which arepotential carriers of microbes. Unfortunately we do not currently have technology to detect airborne microbes
real-time, so air particle counters are used as a surrogate.

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30 to 50 trillion microbes on
and inside the human body.
Humans shed 30,000 skin cells
per hour, approximately
3.6kilos/year.

Figure 4. Humans and microbial contamination

Discussions between the author and Environmental Monitoring Managers at facilities across the world highlights
an increasing trend where the burden of carrying out environmental monitoring is moving away from the QC
microbiology team over to the production staff, for two reasons: a) microbiology staff are relatively expensive toemploy to carry out such routine tasks and b) it reduces the number of people inside the cleanrooms, thus reducing
the potential for product contamination. However, the production team do not have the same level of knowledge
about routine environmental monitoring and this is creating challenges itself.

Increasing regulatory
expectations.
Responsibility passing
from QC microbiology
team to production team.

Figure 5. Risks to cleanroom routine environmental monitoring data integrity

In larger biopharmaceutical manufacturing plants, there can be teams 10 technicians or more whose job it is every
month to take thousands of routine environmental monitoring samples. At each sampling location, they haveto manually type the location name into the counter before they start sampling. Counters have to be manuallyconfigured following written SOPs. At the end of each day, the paper print outs from each sample location have tobe photocopied because the printers in the particle counters are thermal and the print-outs fade over time. Then the
results from every location have to be manually transferred into electronic format one by one.

Figure 6. Manual Cleanroom routine environmental monitoring SOPs

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In larger biopharmaceutical manufacturing plants, there can be teams 10 technicians or more whose job it is every
month to take thousands of routine environmental monitoring samples. At each sampling location, they haveto manually type the location name into the counter before they start sampling. Counters have to be manuallyconfigured following written SOPs. At the end of each day, the paper print outs from each sample location have tobe photocopied because the printers in the particle counters are thermal and the print-outs fade over time. Then the
results from every location have to be manually transferred into electronic format one by one.
In an effort to improve data integrity, some manufacturers have optimised their particle counting instrumentation
specifically for pharmaceutical QC use, building into the instrument design the capability for pre-configured
electronic SOPs including:•A

Instrument set-up and configuration•B

Automatic pass-fail reports to GMP criteria•C

Generation of 21CFR part 11 electronic records straight from the instrument

The user simply selects the electronic SOP that has been pre-configured in the instrument and hits the ‘Start’ button
and the instrument configures itself correctly according to the SOP, carries out the correct test and produces anelectronic test result record, all automatically. This not only improves data integrity, but also can reduce costs
as technicians no-longer have to take time collating the paper records and manually transferring the data into
electronic records. Additionally, by de-skilling the use of air particle counters through automated SOPs, this processfacilitates moving the responsibility for cleanroom routine environmental monitoring from qualified microbiologists
over to production staff, further reducing costs.

Figure 7. Collapsing the routine environmental monitoring workflow with electronic SOPs

Characterized by Ingenuity | 5

Viable Cell Counting
Cell therapy products in the form of homogeneous cell populations
are typically enumerated for concentration and viability basedon the cells ability to exclude a supravital dye, such as trypan
blue. Traditionally this is done manually using a microscope andhaemocytometer, but this method can be both time consuming
and error prone. Originally designed for counting blood cells, thesample volume used in the haemocytometer method is typicallyjust 100nanolitres and small errors using this method caused
during sample dilution, mixing, pipetting and visual enumerationby the technician can lead to large errors in results as the final
count result is multiplied up to report cell concentration in
viable counts/mL. One study revealed variances in the reported
cell concentration results between each member of a teamof 16 experienced and knowledgeable technicians using the
haemocytometer method of up to +/-20% 4.

Figure 8. Cell counting using the haemocytometer andmicroscope method

The USP chapter <1046>9 indicates that automated cell counting and viability instruments can provide a higher
degree of precision and a more reproducible enumeration. These improvements are optimal if the sample
preparation stage is automated, thus reducing the opportunity for technician errors. Additionally, if the automatedcell counter can use electronic, pre-programmed cell-counting SOP libraries that match the manual SOPs for cellcounting designed by the user, then results are more likely to be accurate and reproducible. As well as improving the
precision and reproducibility, automated cell counters can reduce the cost of this QC test by allowing the technicians
to carry out other tasks while the counter automates the preparation and counting stages for each sample. Countersthat can count from 96-well plates can save significant technician time, hence reducing QC costs. At the sametime, by automating the cell counting SOPs making the method more robust and creating the electronic record
contemporaneously, data integrity is improved as the results are attributable, legible, contemporaneously created,
original and accurate as per the FDA ALCOA guidance in their 21CFR part 11 guidance document6.

Figure 9. Beckman Coulter automated Vi-CELL cell counting SOP library

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Injectable Drug Final Product Particulate Testing
Although largely harmonized, the requirements for parenteral drug particulate testing do vary from country tocountry and from product to product. The volume of the sample to be analysed and the format that the results
are reported varies from product to product, e.g. the sampling requirements for small volume therapeutic protein
product, such as vaccines7, is different for that of a large volume parenteral such as an intravenous drip bag8 .
Results must be calculated and expressed in the correct format, e.g. counts per container, or counts per mL,
depending on the product under test.

Particles/container

Particles/mL

Figure 10. Particulate contamination reporting requirements are product-dependant

Whilst general-purpose liquid particle counting instrumentation can be used for the testing of particles in parenteral
products, counters that have been optimized for the application are preferable due to the wide range of complexity
in the testing. Particle counters that have been optimized for this testing will have the various compendial tests
built-in and will calculate a pass/fail result automatically. As QC teams tend to use their product brand name todescribe the product sample under test, optimized particle counters will allow the user to select the required test foreach sample by selecting the product by name from a drop-down menu.

Figure 11. Electronic SOP functionality in Beckman Coulter HIAC PharmSpec software allows automated SOP test routines to be named
according to the brand name of the product under test and selected by the technician via drop-down box

Characterized by Ingenuity | 7

Conclusion
Whilst the industry focusses on errors and omissions in 21CFR part 11 electronic records, the underlying issue is that
re-training may be only part of the solution. Manual SOPs are not robust enough to prevent future recurrences ofdata errors and omissions. QC instrumentation that automate the quality control SOP can potentially both reducethe impact of human error on data integrity issues and also bring welcome cost savings by reducing the time
technicians need to devote to carrying out the SOP.

References:
1.

Managing the Cost of Compliance in Pharmaceutical Operations, Frances Bruttin and Dr. Doug Dean, IBM
Business Consulting Services, Pharmaceutical Sector, Aeschenplatz 2, CH-4002 Basel, Switzerland, April 2004

2.

An Analysis of FDA Warning Letters, Barbara Unger, Unger Consulting Inc., Pharmaceutical Online Guest
Column, July 14, 2017

3.

Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, andQuality Assurance, U.S. Department of Health and Human Services Food and Drug Administration Center for
Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory
affairs (ORA) Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug
Administration 5600 Fishers Lane, Rockville, MD 20857 USA, September 2004

4.

Comparison of Manual versus Automated Trypan Blue Dye Exclusion Method for Cell Counting, Kristine S. Louis,
Andre C. Siegel, Gary A. Levy, Industrial BioDevelopment Laboratory, www.ibdl.ca.

5.

Health How Stuff Works, How many skin cells do you shed every day?, by Ed Grabianowski.
http://health.howstuffworks.com/skin-care/information/anatomy/shed-skin-cells.htm, published July 6, 2010

6.

Data Integrity and Compliance With CGMP, Guidance for Industry, April 2016, U.S. Department of Health andHuman Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for
Biologics Evaluation and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information,
HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane, Rockville,
MD 20857 USA.

7.

USP<787> Subvisible Particulate Matter In Therapeutic Proteins, Department of Health and Human Services
Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation
and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information, HFD-240 Center for Drug
Evaluation and Research Food and Drug Administration 5600 Fishers Lane, Rockville, MD 20857 USA

8.

USP<788> Particulate Matter in Injections, Department of Health and Human Services Food and Drug
Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research(CBER) Office of Regulatory affairs (ORA) Division of Drug Information, HFD-240 Center for Drug Evaluation
and Research Food and Drug Administration 5600 Fishers Lane, Rockville, MD 20857 USA

9.

USP<1046> Cell and Gene Therapy Products – Analytical Methodologies, Department of Health and Human
Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics
Evaluation and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information, HFD-240
Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane, Rockville, MD
20857 USA

10. Guidance for Industry, Part 11, Electronic Records; Electronic Signatures — Scope and Application August 2003
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation
and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory affairs (ORA)
Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857 USA

Characterized by Ingenuity | 8

11.

United States Pharmacopoeia U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Officeof Regulatory affairs (ORA) Division of Drug Information, HFD-240 Center for Drug Evaluation and Research
Food and Drug Administration 5600 Fishers Lane, Rockville, MD 20857 USA

12.

European Pharmacopeia (Ph. Eur.) Commission press release 18th March 2016 https://www.edqm.eu/sites/
default/files/press_release_water_for_injections_march_2016_0.pdf EDQM Expert Workshop, 24 March2011 European Directorate for the Quality of Medicines & Healthcare (EDQM) 7 allée Kastner, CS 30026
F -67081, Strasbourg

About the author: Tony Harrison
Tony held the Convenorship of the ISO Working Group revising ISO 14698-1 & -2 for microbial control in cleanrooms
and was the UK subject matter expert to the ISO Working Group who created the 2015 versions of ISO 14644-1 & -2
for cleanroom monitoring and classification at the heart of the aseptic manufacturing chapters of both the European
GMP and the USA cGMP documents.
Tony holds a Bachelor’s Degree in Electrical & Electronic Engineering and is employed by Beckman Coulter Life
Sciences as a Senior Marketing Manager.
Experienced in water system TOC, conductivity and ozone analysis and cleanroom monitoring systems as well as
particulate characterisation and viable cell counting, Tony has spent the last eighteen years in applied metrology
for the pharmaceutical and healthcare manufacturing industries. Prior to that, he worked for companies providing
process control automation solutions for manufacturing industries.
Tony was joint-editor on the ISPE Guide to Ozone Sanitization of Pharmaceutical Water Systems and was also chief
editor of the PHSS Best Practice Guide for Cleanroom Monitoring.
Tony is a well-known international speaker and has provided educational seminars on TOC, liquid particle counting,ozone sanitization for water systems and cleanroom monitoring in UK, France, Italy, India, Malaysia, China, USA,
Scandinavia, Ireland, Hungary, Switzerland, Indonesia, Belgium, Greece, Switzerland, Turkey, Egypt, Denmark andmost recently Poland and Italy.

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