Vaisala PR-23 Instructions Manual

IM-EN-PR23AC-VACC-A

Appendix

to PR-23 Instruction Manual for Vaisala K-PATENTS®

Products Intended for Use in Vaccine Production

Vaisala K-PATENTS® Pharma Refractometer PR-23-AC

Appendix to the Instructions Manual PR-23

Do not underestimate or neglect the laboratory and factory safety rules:

●

Before you start, assess the workplace to determine if hazards are present, or are
likely to be present, which necessitate the use of personal protective equipment, e.g.:

●

protective clothing and shoes

●

safety goggles

●

protective gloves

●

respiratory shields and devices

●

Locate the nearest safety equipment, extinguishers, eyewash, and emergency shower

2

Document/Revision No. IM-EN-PR23AC-VACC/A Effective: March 1, 2020

Contents

Section 1 Vaisala K-PATENTS® products for vaccine production and sucrose gradient

ultracentrifugation ............................................................................................................... 5

1.1 Designqualication........................................................................................................ 6

Section 2 The Pharma Refractometer PR-23-AC ................................................................................ 7

2.1 System description ........................................................................................................ 7

2.2 System components ...................................................................................................... 8

2.2.1 Checklist of components .................................................................................... 8

2.3 Pharma Refractometer Sensor PR-23-AC- 62-HSS-SC ............................................. 10

2.3.1 Sensor model code .......................................................................................... 10

2.3.2 Pharma Mini Flow Cell model code ................................................................. 10

2.4 Indicating Transmitter DTR-GP-SC ............................................................................. 12

2.4.1 Indicating Transmitter model code ................................................................... 12

2.5 Pharma vaccines accessories ..................................................................................... 13

Section 3 Installation of PR-23 Pharma Refractometer ................................................................... 15

3.1 Hardware and software requirements ......................................................................... 15

3.2 Mechanical and electrical requirements ...................................................................... 15

3.3 Sensor installation for use in pharmaceutical batch manufacturing ............................ 15

3.4 Indicating Transmitter installation for use in table top ................................................. 19

3.5 Wiring transmitter connections to sensor, power cable and computer ....................... 20

3.6 Refractometerinstrumentverication .......................................................................... 21

Section 4 Electronic data capture and storage ................................................................................ 23

4.1 Ethernet connection ..................................................................................................... 23

Section 5 Complying with documentation and validation regulations ......................................... 25

5.1 Documentation ............................................................................................................. 25

5.2 Qualication ................................................................................................................. 25

5.3 Protocol acceptance by customer and list of tests performed .................................... 25

5.4 Electronic data management and data storage ........................................................... 26

5.5 Electronic signatures/audit trail .................................................................................... 26

5.6 Record keeping ............................................................................................................ 26

5.7 Security ........................................................................................................................ 26

5.8 System validation ......................................................................................................... 26

5.9 Vaisala K-PATENTS

Section 6 Onsitequalicationprotocolsandrecords:InstallationQualication ....................... 29

6.1 Authorization and responsibilities ................................................................................ 29

6.1.1 Documents and procedures ............................................................................ 29

6.1.2 Authorizedofciator ......................................................................................... 30

6.1.3 Execution ......................................................................................................... 30

6.2 System ......................................................................................................................... 30

®

refractometer system adherence to Part 11 ............................. 27

© Copyright Vaisala 2020. All rights reserved.

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Appendix to the Instructions Manual PR-23

6.2.1 Qualifying the system ...................................................................................... 30

6.2.2 Manufacturers and suppliers ........................................................................... 31

6.3 IQ protocol ................................................................................................................... 31

6.3.1 Scope of delivery ............................................................................................. 31

6.3.2 Damage ............................................................................................................ 32

6.4 Documentation ............................................................................................................. 32

6.5 Operating environment ................................................................................................ 33

6.6 Installation .................................................................................................................... 33

6.7 Setting up the system components and devices ......................................................... 34

6.8 Electrical connections and wiring ................................................................................ 35

6.9 Ethernet connection ..................................................................................................... 36

6.10 Initial check and switching the device on ................................................................... 36

6.11 InstallationQualicationsummaryreport .................................................................... 37

Section 7 Onsitequalicationprotocolsandrecords:OperationalQualication ...................... 39

7.1 Individual module and system components check ...................................................... 39

7.2 InstallationQualicationhasbeenperformedsuccessfully ........................................ 39

7.3 Test procedure ............................................................................................................. 40

7.4 Authorizedofciator ..................................................................................................... 40

7.5 Systemqualication ..................................................................................................... 41

7.6 Setting up the system components and devices ......................................................... 41

7.7 Instrumentvericationwithsampleholderandrefractiveindexliquids ...................... 42

7.8 OperationalQualicationsummaryreport .................................................................. 43

Section 8 Routine operation phase ................................................................................................... 45

Section 9 Preventive maintenance .................................................................................................... 47

Section 10 Other documentation ......................................................................................................... 49

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Vaisala K-PATENTS® products for

1

vaccine production and sucrose
gradient ultracentrifugation

This instruction manual appendix covers Vaisala K-PATENTS® Pharma Refractometer
PR-23-AC when used in the production of viral vaccines. The vaccines are either produced

by inoculating viruses into specic pathogen-free eggs or in animal cell culture based
process. The allantoic uid of these processes is harvested and puried by centrifugation

and stabilised with buffer containing sucrose. The centrifugation process typically uses

density gradient continuous ow ultracentrifuge for the purication of the virus particles.

The internal subviral core of the virus is separated and fractionated on the basis of its’
sedimentation rate, and the buoyant sucrose density. Pharma Refractometer PR-23-AC is
used for accurate measurement of these sucrose densities. The measurement signal is used
for reliable and timely determination of the product peak in the density gradient (0 to 60%
w/w sucrose), and the subsequent collection of the virus rich fraction (Figure 1.1.).

Pharma Refractometer PR-23-AC can be installed in the vaccines fractionation unit for
in-line process control. The output of the transmitter is a 4 to 20mA DC output signal
proportional to sucrose solution density or Brix. Process data can also be downloaded to a
computer via an Ethernet cable.

High Density
Solution

• Inoculation egg
with virus

• Incubation

• Inoculation
preparation

• Cell expansion

• Virus propagation

Figure 1.1 Ultracentrifugation density gradient purication process steps.

© Copyright Vaisala 2020. All rights reserved.

Inactivation
of virus

Low Density
Solution

Sucrose gradient purication by zonal centrifugation

Fractionation and separation

Chart Recorder

Filling

Low Density High Density

Rotor unloading

5

Appendix to the Instructions Manual PR-23

1.1 Design qualication

Design Qualication (DQ) typically consists of manufacturer’s documentation to verify

that the proposed design of the Vaisala K-PATENTS
intended purpose.

Pharma Refractometer PR-23-AC is an in-line real-time instrument that is designed to meet
the pharmaceutical industry standards and guidelines including PAT, GMP, CIP/SIP and
validation. Pharma Refractometer PR-23-AC wetted parts materials comply with the contact­compatibility of a substance with pharmaceutical materials. Gasket materials conform to the
FDA requirements 21 CFR 177.2600 and to biocompatibility standards according to USP
Class VI. Meeting the FDA and USP criteria guarantees that the seal material is acceptable
for sanitary process applications and the material, or extracts from the material will not
be harmful to human health. No animal derived ingredients (ADI) have been used in the
machining and polishing processes. The PR-23-AC also meets the 3-A Sanitary Standard
and is tested for in-place-cleanability according to the Euopean Hygienic Engineering Design
Group (EHEDG) test.

The refractometer has an Ethernet communications solution. The transmitter uses the
IP protocol to communicate over the Ethernet to any type of computer. This eliminates
human error and allows for easy capture of the refractometer generated measurement
and diagnostic data for storage, analysis and reporting. Access to the refractometer

and the generated data can be restricted to authorized personnel using password and

padlock protection.

®

Refractometer is suitable for the

Vaisala K-PATENTS refractometers are designed, manufactured and serviced under
ISO 9001 quality system and procedures that guarantee the accuracy and repeatability
of the measurement results. Each refractometer sensor is provided with a calibration

certicate comparing a set of standard liquids to the actual sensor output. Vaisala veries

the calibration of all delivered instruments according to the procedure similar to the
one described in the PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL,
Section 13.

The quality system is ISO 9001 certied by Det Norske Veritas. The quality performance

is improved by critical self-assessment, internal auditing and feedback system. The chain
of quality starts from the subcontractors with whom Vaisala maintains a quality contracting

and regular auditing system. The internal quality functions, from verication of incoming
products to packing and delivery, are based on dened procedures. Vaisala provides full
traceability of the wetted parts materials. Certicates of Origin, and any other required

quality documentation is available upon request at time of order.

Vaisala K-PATENTS process refractometers and support services are available to customers
anywhere in the world. Application, installation and technical assistance are provided both
locally by the representatives and by the headquarters in Finland and a branch in the U.S.

Vaisala warrants that all products made by Vaisala shall be free of defects in material and
workmanship. Vaisala agrees either to replace or repair free of charge any such product or

part thereof which shall be returned to the nearest authorized Vaisala K-PATENTS repair

facility within two (2) years from the date of delivery.

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2

The Pharma Refractometer
PR-23-AC

2.1 System description

The recommended system for the vaccines production process comprises of a
Pharma Refractometer PR-23-AC unit and a Pharma Mini Flow Cell PMFC-HSS
that allows the sensor connection to the zonal ultracentrifuge rotor unloading and
fractionation phase.

The standard Ethernet communication solution allows for simultaneous data
logging and continuous monitoring of the measurement values and diagnostic
data from the Indicating Transmitter DTR to a computer via an Ethernet connection.

© Copyright Vaisala 2020. All rights reserved.

7

Appendix to the Instructions Manual PR-23

2.2 System components

2.2.1 Checklist of components

Pharma Refractometer Sensor PR-23-AC-62-HSS-SC- EP calibrated with raw

1

measurement data refractive index (n

Indicating Transmitter DTR-M/U-GP-SC that calculates and displays the process liquid

2

concentration based on the refractive index and temperature, installed in a stainless steel

2a

enclosure that contains a key

Table top stand PR-7603-SS for Indicating Transmitter,

3

contains a set of two M5x10 A2 DIN 912 screws

3a

Wall mounting screws kit for mounting the Indicating Transmitter DTR on the wall

4

Interconnecting cable between transmitter and sensor PR-8230

5

PR-8820 Crossover cable for Ethernet connection between Indicating Transmitter and

6

computer, length 5 m (16 inch), contains cable gland for enclosure connection

Table top stand PR-7605 -SS with an integral support rod and

7

2.5” Sanitary Clamp for the Pharma Refractometer Sensor PR-23-AC-62-HSS

7a

contains a M5x16 A4 DIN 912 screw

7b

Pharma Mini Flow Cell PMFC-HSS

8

PR-9244-USP O-ring for the Pharma Mini Flow Cell, 22.2x3.0 EPDM

9

Two sets of PR-9235 0.5” Sanitary Clamp for the Pharma Mini Flow Cell connection

10

Two sets of PR-9236 -USP Sanitary gasket EPDM for the 0.5” Sanitary Clamps

11

Two sets of PR-9237 0.5” Sanitary ferrule (lenght 1.5 cm) for the inlet and outlet hose

12

connections and Pharma Mini Flow Cell

Universal sample holder PR-1012

13

R.I. Liquid set PR-2300, consists of Cargille Cer ticate for the liquids

14

) and temperature (T)

D

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The Pharma Refractometer PR-23-AC

1

13

2

11

8

9

10

7b

7a

5

3

3a

14

2a

7

12

6

4

2

Figure 2.1 System components provided by Vaisala.

© Copyright Vaisala 2020. All rights reserved.

9

Appendix to the Instructions Manual PR-23

2.3 Pharma Refractometer Sensor PR-23-AC-62-HSS-SC

2.3.1 Sensor model code

Model and Description Model

PR-23 = Sensor PR-23

Sensor model

-A = 3A approved -A

Sensor type

C = Compact type for pipe line installation C

Refractive Index range limits

-62 = R.I. 1.320....1.530 ( 0-100 Brix ) -62

Process connection -SC

-H = Sanitary 3A-clamp, 2 ½ inch -H

Sensor wetted parts material

SS = AISI 316 L SS

Electrical classication

-GP = General purpose -GP

-AX = ATEX certied EX II 3 G Eex nA II T4 (up to Zone 2) -AX

-IA = ATEX and IECEx certied EX II 1 G Ex ia II C T4 Ga (up to Zone 0) (A) -IA

Sensor housing

-SC = Stainless steel -SC

Sensor wetted parts surface treatment option

-EP = Electropolished process wetted parts (Ra 0.4µm, 15 µ inch ) -EP

(A) Available with STR- Indicating Transmitter and IS Isolator only

10

2.3.2 Pharma Mini Flow Cell model code

The wetted parts materials for the Pharma Mini Flow Cell are AISI 316 stainless
steel standard Ra 0.4µm, 15 µ inch and EPDM (ethylene propylene diene
monomer) for the O-ring sealing.

Model and Description Model

PMFC = Pharma Mini Flow Cell PMFC

Sensor connection

-H = Sanitary 3A-clamp, 2 ½ inch -H

Material of Construction

SS = AISI 316 SS

Process connection

-H = Sanitary mini tting -H

Pipe section diameter

04 = 4 mm 04

05 = 5 mm 05

06 = 6 mm 06

Options

-EP = Electropolished process wetted parts (Ra 0.4µm, 15 µ inch ) -EP

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The Pharma Refractometer PR-23-AC

2

Figure 2.2 Pharma Refractometer PR-23-AC-62-HSS-EP sensor and Pharma Mini Flow Cell

Figure 2.3 Pharma Mini Flow Cell PMFC-HSS-EP.

PMFC-HSS-EP with PR-7605 -SS table top stand.

© Copyright Vaisala 2020. All rights reserved.

11

Appendix to the Instructions Manual PR-23

2.4 Indicating Transmitter DTR-GP-SC

Indicating Transmitter DTR is a specialized computer designed to process data
received from the refractometer sensor. Indicating Transmitter (Figure 2.4) contains
a front panel with a backlit Liquid Crystal Display (LCD) and a keyboard. A lock and
a key are included in the enclosure’s door to prevent unauthorized access. Please
note that neither any power cables nor any external power switches are included in
the standard delivery.

Materials for the Pharma Indicating Transmitter Enclosure DTR-M/U-GP-SC are:
Stainless steel enclosure and polycarbonate window.

2.4.1 Indicating Transmitter model code

Model and Description Model

DTR = Indicating Transmitter (connectivity for two sensors)
STR = Indicating Transmitter (connectivity for one –IA/-IE sensor)

Cable connection

-U = ½ inch NPT-type conduit hubs -U

-M = M20x1,5 metric cable glands -M

Electrical classication

-GP = General purpose -GP

Enclosure

-SC = Stainless Steel enclosure with window -SC

Transmitter options (A) (leave this section blank, if AC supply is specied)

-AC = Power supply 100-240 VAC 50/60 Hz -AC

-DC = Power supply 24 V DC -DC

(A) Note standard power supply is 100-240 VAC 50/60 Hz

DTR
STR

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The Pharma Refractometer PR-23-AC

Front view Back view

186 mm

(7.32”)

281 mm
(11.06”)

153 mm

(6.04”)

304 mm
(11.95”)

254 mm

(9.99”)

50 mm
(1.97”)

50 mm
(1.97”)

45 mm

(1.77”)

2

Figure 2.4 Indicating Transmitter DTR-GP-SC with Stainless steel enclosure; dimensions (mm/in).

2.5 Pharma vaccines accessories

Vaisala recommended accessories for the vaccines production application contain
Ethernet crossover cable, IQ and OQ documentation (this document) and parts for

verication and usage of Pharma Refractometer sensor and Indicating Transmitter

mounted on a table top or a trolley via metal support stands. The recommended
accessories and corresponding part numbers are:

●

PR-7603-SS Table top stand for Indicating Transmitter (contains a set of two M5x10
A2 DIN screws)

●

PR-7605-SS Table top stand with the intregral support rod and 2.5” Sanitary Clamp
for the Pharma Refractometer Sensor PR-23-AC (contains a screw)

●

PR-8820 Crossover cable for Ethernet connection between Indicating Transmitter
and computer, length 5 m (16 feet)

●

Parts for off-line instrument verification:
PR-1012 Sample holder
PR-2300 R.I. liquid set 5 x ¼ .oz.; Including: 1.33; 1.37; 1.42; 1.47; 1.52

●

IM-EN-PR23AC-VACC IQ and OQ Documentation for Equipment qualification

© Copyright Vaisala 2020. All rights reserved.

13

Appendix to the Instructions Manual PR-23

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3

Installation of PR-23 Pharma
Refractometer

3.1 Hardware and software requirements

PR-23 software is included in the Indicating Transmitter DTR and it comprises the
following functions:

●

Automatic temperature compensation

●

Ethernet connection for data download

●

Sensor diagnostics and verication

3.2 Mechanical and electrical requirements

Power supply for the refractometer is AC input 100-240 VAC/50-60 Hz, optional 24 VDC,
30 VA.

3.3 Sensor installation for use in pharmaceutical batch
manufacturing

Laboratory table top or trolley installation and key considerations for the site
preparation

1. Physical dimensions of the instrument and accessories: make sure there is enough
space to accommodate them.

2. Suitable recommended operational environment for the instrument and for the Cargille
Refractive Index Liquids should be maintained between 20 – 30 °C (68 – 86°F).

3. Utilities: 100-240 VAC/50-60 Hz (optional 24 VDC, 30 VA) electrical power supply and
computer network connection.

© Copyright Vaisala 2020. All rights reserved.

15

Appendix to the Instructions Manual PR-23

Attaching table top stand PR-7605-SS for Sensor and Mini Flow cell

Attach the 2.5” Sanitary clamp and the support rod to the base plate. The supplied screw
(M5x16 A4 DIN 912) for attaching the stand is inserted from the bottom of the base plate

through the bottom hole (Figure 3.1). To assemble the Pharma Mini Flow Cell rst locate the

PR-9244-USP O-ring 22.2x3.0 EPDM inside the Mini Flow Cell (Figure 3.2). Then insert the

2.5” Sanitary clamp for the sensor and Mini Flow Cell.

Finally insert the two PR-9236-USP Sanitary EPDM gaskets and the two PR-9237

0.5” Sanitary ferrules for the inlet and outlet connectios using the two PR-9235 0.5”
Sanitary Clamps.

Sensor can now be connected to exible hoses and used as a free standing tabletop unit,

see Figure 3.3.

1

Sanitary clamp
and support

Base plate

Retaining screw

Sensor stand assembly

Figure 3.1 Sensor stand assembly: Attaching the clamp and support rod to the base plate.

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Installation of PR-23 Pharma Refractometer

2

3

Figure 3.2 Sensor stand assembly: Installing the sensor and Mini Flow Cell to the stand.

3

PR-9236-USP Sanitary gasket
EPDM for the 0.5”

PR-9237-USP

0.5” Sanitary ferrule

PR-9235 0.5” Sanitary Clamp

Figure 3.3 Sensor assembly: Attaching the ferrules for the feed pipes.

© Copyright Vaisala 2020. All rights reserved.

17

Appendix to the Instructions Manual PR-23

Figure 3.4 Sensor stand assembled.

4

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Installation of PR-23 Pharma Refractometer

3.4 Indicating Transmitter installation for use
in table top

Attaching table top stand PR-7603- SS for Indicating Transmitter

Unlock and open the transmitter cabinet door, then unscrew the retaining screw for the keypad
panel and open the panel. The supplied screws (M5x10 A2 DIN 912) for attaching the stand
are inserted from the inside through the top two holes located at the back of the cabinet. These
are aligned and screwed into the threaded attachment points located at the top of the stand.
The enclosure can now be used as a free standing tabletop unit, see Figure 3.2.

3

1

Figure 3.5 Attaching the laboratory table top stand to the Transmitter for use in the laboratory.

© Copyright Vaisala 2020. All rights reserved.

19

Appendix to the Instructions Manual PR-23

3.5 Wiring transmitter connections to sensor,
power cable and computer

For Indicating Transmitter DTR wiring and Ethernet connections instructions see PROCESS
REFRACTOMETER PR-23 INSTRUCTION MANUAL, Section 3 and Section 12. When the
wiring connections have been made sensor calibration and verication can commence.

Indicating Transmitter
DTR-M-GP-SC

Pharma Mini Flow Cell
PMFC-HSS-EP

Pharma Refractometer
PR-23-AC-62-HSS-EP

Interconnecting cable
PR-8230

PC -Windows
(not supplied by Vaisala)

Figure 3.6 Connection diagram

Power Supply
Cable (not supplied
by Vaisala)

Crossover Cable

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Installation of PR-23 Pharma Refractometer

3.6 Refractometer instrument verication

The operational procedure checking the refractometer calibration accuracy, linearity and

short-term repeatability and reproducibility consists of verication tests using Cargille

standard refractive index n

The verication of the refractometer calibration is performed whenever a new Vaisala
laboratory refractometer is qualied as a part of the validation process, and also if any of the

following occurs:

●

There is a replacement of optical parts (prism and prism gasket).

●

Refractometer readings reect an unusual shift, or are outside of the acceptable limits,

and other means of assessing and correcting unacceptable control values fail to
identify and correct the problem.

Verication is recommended to be performed once every 12 months (or more frequently if
specied in the client’s own quality system) as a routine quality control check. Verication

is carried out using the Sample Holder PR-1012 and the set of Cargille standard refractive
index n
PR-1012 consists of a sample receptacle with O-ring seal around the bottom aperture.

Before commencing the verication process make sure that your refractometer and sample

holder are at normal room temperature. Preferably take all components to the laboratory

already one day prior to the verication. Check the condition and expiry date of your

standard refractive index liquids and that you also have the required cleaning solution
(e.g. Isopropyl alcohol) and cleaning tissue to clean the sensor wetted surfaces and the
sample holder.

liquids. A set (R.I. Liquid Set PR-2300) is supplied by Vaisala. The Sample Holder

D

liquids.

D

3

For full Sensor verication instructions see PROCESS REFRACTOMETER PR-23,
INSTRUCTION MANUAL Section 13.

After verication of the PR-23 sensor, further verication of the Laboratory Test Cuvette and
Sensor combination can be carried out.

© Copyright Vaisala 2020. All rights reserved.

21

Appendix to the Instructions Manual PR-23

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4

Electronic data capture and storage

4.1 Ethernet connection

In addition to software operation via the hardware, the DTR can be considered as a web
server and is accessible via a web-browser (e.g. Internet Explorer, Firefox, Chrome etc.).
The Ethernet connection enables data download from an Indicating Transmitter DTR to a
computer and replaces the traditional paper-based data collection methods and streamlines
data collection. The connection works both directly between the DTR and a computer, or via
a hub or a switch, local area network (LAN), wireless network (WLAN) or ber Ethernet.
Any type of computer (PC, Mac, PDA, mainframe…) with a compatible network connection
can be congured to download data from the DTR.

For connecting and operating instructions of the Ethernet connection see PROCESS
REFRACTOMETER PR-23 INSTRUCTION MANUAL Section 12.

© Copyright Vaisala 2020. All rights reserved.

23

Appendix to the Instructions Manual PR-23

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5

Complying with documentation
and validation regulations

5.1 Documentation

When a pharmaceutical company purchases new measuring instruments, they must take
into account the documentation requirements covered by national and international laws
and directives, for example, the US Food and Drug Authority’s Code of Federal Regulations
(CFR). FDA’s validation requirements leave it up to the manufacturer to determine what
data is essential to prove control over their processes. Therefore, the requirements vary

from company to company, and each pharmaceutical company is responsible for dening

and maintaining its own documentation requirements list. Some areas to consider and their
Vaisala K-PATENTS solutions are presented in the sections below.

5.2 Qualication

The qualication action consists of proving and documenting that the equipment and
ancillary systems are properly installed, operating correctly, and producing veried results.
Qualication is a part of the validation process, but the individual qualication stages alone

do not constitute process validation.

Installation Qualication, Operational Qualication and Performance Qualication protocols

are normally required to document that the correct refractometer model and parts have been
ordered, delivered and installed according to Vaisala’s recommendations, and also to check

that the refractometer meets its performance specication and is able to reliably measure

typical samples using the selected measurement method. Users are able to create their
own protocols using the relevant information from this manual appendix and the product

manual, and/or using their own templates. The complete qualication process must be

fully documented.

5.3 Protocol acceptance by customer and list of
tests performed

A qualication protocol which provides details about the system, the scope and constraints
of the qualication, the qualication tests, test procedures and acceptance criteria should
be available for review and approval before the qualication begins. The protocol should
also contain an exception log to record any out of the specication results, investigation and
problem resolution. After the qualication, the test results must be reviewed and approved

before the instrument can be put into routine use.

© Copyright Vaisala 2020. All rights reserved.

25

Appendix to the Instructions Manual PR-23

5.4 Electronic data management and data storage

The Code of Federal Regulations (CFR) FDA 21, Part 11 requires that pharmaceutical
companies use electronic (i.e. software-maintained) data recording and storage, rather
than paperwork. In case of instrument measurements, the code requires that every reading
taken with the instrument must be logged and permanently stored electronically, and the
data is password-protected ensuring alteration accountability (i.e. which operator makes
an alteration) and tracking.

Part 11 describes four basic system elements that must be addressed. They are:

●

Electronic signatures and tracking

●

Data storage and logs

●

Security

●

System validation.

5.5 Electronic signatures/audit trail

Data records must be linked to the relevant electronic signatures so that when accessed,
either electronically or through printout, the signatures will be openly displayed along with
the date and time of execution.

5.6 Record keeping

Data records must be stored in a format that the FDA can reasonably expect to be able to
read. These records must be retained for the length of time required by the predicate rule.

5.7 Security

System access can be restricted to authorized individuals using the lock on the Indicating
Transmitter door and password protected access to the transmitter and to the computer.
There are also four input switches behind the front panel of Indicating Transmitter. An input

switch can be congured to seal the calibration and to prevent access to the calibration
and to conguration, see PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL,

Section 6.4.

The actions of these authorized individuals in relation to the data must be openly accounted
for throughout the audit trail.

5.8 System validation

The system must be validated to prove that it complies with the technical requirements of

Part 11. The Installation Qualication, Operation Qualication, and Performance Qualication
(IQ/OQ/PQ) should also be performed.

26

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Complying with documentation and validation regulations

5.9 Vaisala K-PATENTS® refractometer system
adherence to Part 11

It is not possible to supply a system readily in compliance with Part 11. This is because the
requirements of Part 11 fall into two categories: those that are handled technically (through
software features), and those that are handled procedurally (such as through system
validation, SOPs, policies, etc.).

Part 11 applies to all computerized systems that create, modify, maintain, archive, or
retrieve records required by the FDA. Pharma Refractometer generates electronic records

via Ethernet connection. These records can be stored as digital les and printed out for
signature or led and maintained as hard copies. The computer les are subject to Part 11
regulation. The instrument parameter and conguration changes also fall into this category.

These computer les may be used in either of the two ways:

1. as a non-subject system by printing results, signing by hand, and maintaining
hard copies

2. as an electronic record-keeping system subject to Part 11 regulation.

Systems described by number 1 would be subject only to predicate rules, not Part 11.

Systems described by number 2 must comply with Part 11.

Please note: While Vaisala has taken account of the FDA Part 11 rules during development of
the Pharma Refractometer package and in the compilation of the instructions and guidelines
contained in this Instruction manual appendix, the system described has not been approved
or mandated by the FDA or any other government agencies. So all compliance responsibility
lies with the end user and Vaisala makes no claims that the completion of all the procedures
described here will exempt these companies or individuals from FDA sanctions.

5

© Copyright Vaisala 2020. All rights reserved.

27

Appendix to the Instructions Manual PR-23

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6

Onsite qualication protocols and
records: Installation Qualication

This Installation Qualication (IQ) involves documented verication of the complete
system: Pharma Refractometer PR-23-AC and Pharma Mini Flow Cell PMFC-HSS with
Ethernet connection, as installed and connected to a fractionation unit and a computer,
and in compliance with the approved design, the manufacturer’s recommendations and
user requirements.

6.1 Authorization and responsibilities

6.1.1 Documents and procedures

The following documents and procedures are inspected:

●

Scope and Procedure for Qualication

●

Report on Installation Qualication

●

Protocol for Installation Qualification

The authorized ofcial (client) hereby declares that the execution of the Installation
Qualication (IQ) for the Pharma Refractometer and Pharma Mini Flow Cell have been
approved in accordance with this document/log. The authorized ofcial is responsible for all
relevant matters in regard to the installation qualification.

Release by superior department:

Name:

Function:

Date:

Signature:

Initials:

Authorization by a higher-level authority is a prerequisite for carrying out the
qualication procedure. If no valid written authorization is available, terminate the

Installation Qualification.

© Copyright Vaisala 2020. All rights reserved.

29

Appendix to the Instructions Manual PR-23

6.1.2 Authorized ofciator

Selection of the individual authorized to carry out the Installation Qualication of the Pharma
Refractometer system should be in accordance to their relevant ability to undertake the
procedure. The authorized ofciator’s signature is required for the next stage to validate
Date/Initials in the Installation Qualication log and reports.

Name:

Function:

Date:

Signature:

Initials:

6.1.3 Execution

As it is executed, each described step of the Installation Qualication requires initialing
and dating. If any deviations occur, the qualication must either be aborted or a detailed
explanation of the deviations must be entered in the subsequent “Deviation, evaluation,
corrective actions” logs and must be documented appropriately.

6.2 System

6.2.1 Qualifying the system

Location of the Pharma Refractometer Sensor and Pharma Mini Flow Cell:

Location of the Indicating Transmitter:

Device Serial Number Supplier Manufacturer

Pharma Refractometer:
Sensor PR-23-AC-62-HSS

Pharma Refractometer: Indicating
Transmitter DTR-M/U-GP-SC

Computer

Vaisala Oyj

Vaisala Oyj

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Onsite qualication protocols and records: Installation Qualication

6.2.2 Manufacturers and suppliers

Full address of the manufacturers and suppliers:

Manufacturer: Supplier:

Vaisala Oyj

Postal address: P.O. Box 26,
FI-00421 Helsinki, Finland

Street address:
Vanha Nurmijärventie 21,
FI-01670 Vantaa, Finland

Tel. Int.+358 9 89491
Fax Int.+358 9 8949 2227

www.vaisala.com

6.3 IQ protocol

6.3.1 Scope of delivery

Description of requirements

Check that the delivery is complete and that all the listed instrument components and
accessories are included in the delivery.

6

Requirement acceptance values

Compliance with the component checklist “System components provided by Vaisala”,
included in the Manual Appendix (this document) Section 2.2.

Failure to meet delivery values

If any essential component is missing terminate the installation qualication and call your
support, otherwise check conditional pass and move with the IQ, inform your support.
Terminate the IQ.

*

Date Signature Pass

*Conditional pass:

Conditional Pass Fail

© Copyright Vaisala 2020. All rights reserved.

31

Appendix to the Instructions Manual PR-23

6.3.2 Damage

Description of requirements

Inspection of all components and devices to check they are undamaged and functional.

Damage or malfunction detected

Terminate the IQ.

Report to:

*

Date Signature Pass

*Conditional pass:

6.4 Documentation

Description of requirements

Make sure that the Operating Instructions and all other required documentation are complete
and accessible.

Type of document Document/Revision No.

Instruction Manual for Inline
Refractometer
PR-23(-...-AX/FM/CS/IA/IF)

Appendix to Instruction
Manual

Operating Manual for:

Material Safety Data Sheet
for Cargille Refractive Index

Liquids

Conditional Pass Fail

Requested

Present Missing Not requested

IM-EN-PR23

IM- EN- PR23AC-VACC- A

32

Date Signature Pass

*Conditional pass:

Document/Revision No. IM-EN-PR23AC-VACC/A Effective: March 1, 2020

*

Conditional Pass Fail

Onsite qualication protocols and records: Installation Qualication

6.5 Operating environment

Description of requirements

Ensuring that the appropriate power supply and power switch are available.

Requirement acceptance values

An electrical power supply with a voltage and frequency of 100-230 VAC/50-60 Hz (Optional
24 VDC). A computer (PC, Mac, PDA or mainframe).

Failure to meet any of the acceptance values
A new environment must be established and the qualication performed again from Section

6.3.1 (of this document) onwards.

Date Signature Pass

*Conditional pass:

6.6 Installation

Requirement description

The authorized operator who in accordance with Section 6.2 (of this document), must read
the installation instructions in Section 3 (of this document).

6

*

Conditional Pass Fail

Requirement acceptance values

The relevant sections have been read.

Date Signature Pass

*Conditional pass:

*

Conditional Pass Fail

© Copyright Vaisala 2020. All rights reserved.

33

Appendix to the Instructions Manual PR-23

6.7 Setting up the system components and devices

Description of requirements

The Pharma Refractometer system with Refractometer sensor, Pharma Mini Flow Cell and
Indicating Transmitter, are assembled and mounted correctly as described in the Section

3 (this document). Also the ancillary sample system is connected in accordance with the
Section 3 (this document). The ancillary equipment is switched on in accordance with the

corresponding operating manuals.

Requirement acceptance values

The system and devices are complete and have been set up in compliance with
the instructions.

Failure to meet the acceptance values

Terminate the IQ.

*

Date Signature Pass

*Conditional pass:

Conditional Pass Fail

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Onsite qualication protocols and records: Installation Qualication

6.8 Electrical connections and wiring

Description of requirements

The frequency of the power supply must match the frequency indicated on the instrument’s
rating plate. The electrical wiring connections have been connected in accordance with
the instructions laid down in the PROCESS REFRACTOMETER PR-23 INSTRUCTION
MANUAL Section 12.

Requirement acceptance values

All electrical wiring connections have been connected in compliance with the instructions laid
down in the PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL Section 12.

*

Date Signature Pass

*Conditional pass:

Description of requirements

Ethernet connections and wiring have been connected and set up in accordance with the
PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL Section 12.

Conditional Pass Fail

6

Requirement acceptance values

The Ethernet connections comply with the PROCESS REFRACTOMETER PR-23
INSTRUCTION MANUAL Section 12.

*

Date Signature Pass

*Conditional pass:

Conditional Pass Fail

© Copyright Vaisala 2020. All rights reserved.

35

Appendix to the Instructions Manual PR-23

6.9 Ethernet connection

Description of requirements

Ethernet connections and wiring have been connected and set up in accordance with the
PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL Section 12.

Requirement acceptance values

The Ethernet connections comply with the PROCESS REFRACTOMETER PR-23
INSTRUCTION MANUAL Section 12.

*

Date Signature Pass

*Conditional pass:

Conditional Pass Fail

6.10 Initial check and switching the device on

Description of requirements

The initial check has been performed and the electrical power has been connected in
accordance with the PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL

Section 5.1.1.

Requirement values

The corresponding screen displays occur in accordance with the PROCESS
REFRACTOMETER PR-23 INSTRUCTION MANUAL Section 5.1.1.

Failure to meet acceptance values

Terminate the IQ.

*

36

Date Signature Pass

*Conditional pass:

Document/Revision No. IM-EN-PR23AC-VACC/A Effective: March 1, 2020

Conditional Pass

Fail

Onsite qualication protocols and records: Installation Qualication

6.11 Installation Qualication summary report

Successful completion of the preceding activities and checks indicates that this instrument
has been satisfactorily delivered and installed. This instrument has passed the Installation
Qualication and may now be submitted for Operational Qualification.

IQ completed by

Name:

Function:

Date:

Signature:

Signature:

IQ deviations approved by

Name:

Function:

Date:

Signature:

Signature:

6

IQ approved by

Name:

Function:

Date:

Signature:

Signature:

© Copyright Vaisala 2020. All rights reserved.

37

Appendix to the Instructions Manual PR-23

Comments (including discrepancies)

38

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7

Onsite qualication protocols and
records: Operational Qualication

Operational Qualication (OQ) is documented verication stating that the equipment and
systems, as installed for the rst time or after repairs and major incidents, perform as
intended throughout the required operating ranges. The OQ is to ensure that the Pharma
Refractometer meets predened specications, and all system components function
correctly and according to specications within a specic environment.

7.1 Individual module and system components check

Checking the operation of the refractometer as an individual module, and as a system that
comprises also of the Pharma Mini Flow Cell, the computer, the Ethernet connection and
Ancillary equipment such as fractionation unit.

●

Operational check on the refractometer consists of refractive index n
linearity and short-term repeatability and reproducibility verication tests with Cargille
standard refractive index n

●

In addition to the system components, testing functional challenge, testing the system
software operation, should be conducted.

●

Stage by stage operational procedure checking. A pre-determined set of instructions
can be input stage by stage into the system. The system responses are then
compared to the expected outcome of the instructions to determine any problems in

their fulfillment.

●

Sign off when successfully completed.

liquids.

D

accuracy,

D

7.2 Installation Qualication has been performed

successfully

Description of Requirement

An Installation Qualication has been performed for the system.

Requirement Acceptance values

The Installation Qualication has been carried out successfully with the required approval.

Date of Installation Qualification:

Performed by:

Do not proceed with the Operational Qualication until a valid Installation Qualication has
been successfully completed and signed off.

© Copyright Vaisala 2020. All rights reserved.

39

Appendix to the Instructions Manual PR-23

7.3 Test procedure

The Operational Qualication of the system is performed in accordance with a set plan in
which the following points are tested and documented sequentially:

●

The required documents, measuring instruments, refractive index liquids, and required
cleaning materials are available

●

Functional checks and verication of the refractometer performance

●

Functional checks have been made for the ancillary equipment.

The authorized ofcial (client) hereby declares that the performance of the Operational
Qualication (OQ) for the Pharma Refractometer and Pharma Mini Flow Cell has been
approved in accordance with this document/protocol. The authorized ofcial is responsible
for all relevant matters in regard to the operational qualification.

Release by superior department:

Name:

Function:

Date:

Signature:

Initials:

Authorization by a higher-level authority is a prerequisite for carrying out the
qualication procedure. If no valid written authorization is available, terminate the
Operational Qualification.

7.4 Authorized ofciator

Selection of the individuals authorized to carry out the Operational Qualication of the
Pharma Refractometer system should be in accordance with their relevant ability to
undertake the procedure. The authorized ofciator’s signature is required for the next stage
to validate Date/Initials in the Operational Qualication log and reports.

Name:

Function:

40

Date:

Signature:

Initials:

Document/Revision No. IM-EN-PR23AC-VACC/A Effective: March 1, 2020

7.5 System qualication

Onsite qualication protocols and records: Operational Qualication

Check that the system is the same as dened in the IQ, with no changes.

Denition of requirements

All system equipment remains the same as for the IQ and the ancillary equipment IQ is valid.

Date Signature Pass Conditional Pass Fail

Conditional pass:

7.6 Setting up the system components and devices

Description of requirements

The Pharma Refractometer system comprised of refractometer sensor, Pharma Mini Flow
Cell and Indicating Transmitter, is assembled and mounted correctly as described in the
Section 3 (this document). Initial startup checks for the Refractometer have been made
according to PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL, Section 5.
Also the ancillary fractionation unit and the sample delivery system (if required) are
connected and the ancillary equipment is switched on and functional checks are made in
accordance with the corresponding operating manuals.

7

Requirement acceptance values

The system and devices are complete and have been set up in compliance with
the instructions.

Failure to meet any of the acceptance values

Terminate the OQ.

Date Signature Pass Conditional Pass Fail

Conditional pass:

© Copyright Vaisala 2020. All rights reserved.

41

Appendix to the Instructions Manual PR-23

7.7 Instrument verication with sample holder and

refractive index liquids

Description of requirements

Refractometer, Sample Holder PR-1012 and a set of ve standard refractive index
liquids PR-2300 with Cargille Certication are allowed to be settled to laboratory
ambient temperature (between 20-30 °C, 77-86°F) 24 hours prior to commencement of
the qualification.

Requirement acceptance values

Refractometer, sample holder and Refractive index liquids positioned in the laboratory 24
hours prior to verication with the ambient temperature at between 20-30 °C (77-86°F).

Date Signature Pass Conditional Pass Fail

Conditional pass:

Description of requirements

The procedure is done with all ve liquids using a sample holder and verication instructions
at PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL, Section 13.

Nominal R.I. values:

●

1.330

●

1.370

●

1.42 0

●

1.470

●

1.520

Requirement values

The verication results are OK for all samples and acceptance / deviation values (not
more than + 0.0004 of the nominal values) are received for each sample. The Instrument
Verication page in the browser for the complete verication test procedure shows

Verication result: pass.

Failure to meet acceptance values

Terminate the OQ.

Date Signature Pass Conditional Pass Fail

42

Conditional pass:

Document/Revision No. IM-EN-PR23AC-VACC/A Effective: March 1, 2020

Onsite qualication protocols and records: Operational Qualication

7.8 Operational Qualication summary report

Successful completion of the preceding activities and checks indicates that this instrument
performs satisfactorily. The Operational Qualication has been accepted.

OQ completed by

Name:

Function:

Date:

Signature:

Signature:

OQ deviations approved by

Name:

Function:

Date:

Signature:

Signature:

7

OQ approved by

Name:

Function:

Date:

Signature:

Signature:

© Copyright Vaisala 2020. All rights reserved.

43

Appendix to the Instructions Manual PR-23

Comments (including discrepancies)

44

Document/Revision No. IM-EN-PR23AC-VACC/A Effective: March 1, 2020

8

Routine operation phase

After the instrument is qualied, it can be used to measure analytical data. A Standard
Operating Procedure (SOP) has to be written for the new instrument. Operational
instructions, maintenance and calibration should be included in the SOP. It is unnecessary
to copy the complete operation manual into the SOP. Writing down simple instructions
referencing the related manual sections is more effective. The particular tasks and the
frequency they should be performed during maintenance should be clearly stated in the
maintenance section. Tests required to verify the instrument, the acceptance criteria and the
frequency for each test should be covered in the calibration section of the SOP.

Denitions of major and minor repairs, which necessitate partial or full system re-qualication,
should be included as well. For example, the replacement of a Teon pad in the sample mixer
does not require a full re-qualication. Replacement of optical parts (prism) will warrant full
re-qualication.

Good system maintenance starts with the users. Proper care, which can be as simple as
a good system rinsing and clean up after use, will reduce the possibility of system failure
during runs and will extend the useful life of the instrument.

Maintain good usage and service records for the instrument for Good Manufacturing
Practice (GMP) purposes. Records of usage allow the users to be alerted to any system or
instrument calibration failure. The user may have to do an impact assessment to determine
whether the failure would have affected the reliability of the results generated by the system.
The service records will also provide useful information about the system, which may
simplify trouble shooting in some cases.

The GMP requirements dictate that the refractometer calibration verication (see Section

3.1) should be performed at suitable intervals in accordance with an established schedule.
Any instrument failing to meet established specications shall not be used. Each Pharma
Refractometer is recommended to have a calibration verication label applied with the
relevant status information on the system, date of the last calibration verication, who carried
out the verication and the scheduled date for the next verification.

© Copyright Vaisala 2020. All rights reserved.

45

Appendix to the Instructions Manual PR-23

46

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9

Preventive maintenance

The need for Pharma Refractometer regular maintenance is minimal, due to the construction
with no moving parts, no mechanical adjustments, no trimpots and with a solid-state light
source, see Section 7, PROCESS REFRACTOMETER PR-23 INSTRUCTION MANUAL.

The following checks should be performed for Mini Flow Cell at suitable intervals in
accordance with an established schedule:

●

Check the condition of the O-ring (PR-9244-USP O-ring 22.2x3.0 EPDM) of the
Pharma Mini Flow Cell

●

Check the condition of the two sanitary gaskets (PR-9236-USP EPDM) of the 0.5”
sanitary clamps

© Copyright Vaisala 2020. All rights reserved.

47

Appendix to the Instructions Manual PR-23

48

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10

Other documentation

You may want to include the following documents in your les concerning this Vaisala

K-PATENTS

●

●

●

●

®

instrument:
Delivery Data Sheet (supplied with the instrument)
Certicate of Traceability for Standard Refractive Index liquids
(supplied with the liquids PR-230 0)

Material Traceability Certicate of Compliance in accordance with EN 1024-3.1b.
Note: This document is delivered on request and it must be specied when ordering.
Vaisala ISO 9001 certificate

© Copyright Vaisala 2020. All rights reserved.

49

Appendix to the Instructions Manual PR-23

Notes

50

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www.vaisala.com