K-Patents PR-23 User Manual

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Appendix to PR-23 Instruction Manual for K-Patents Products Intended for Use in Vaccine Production

K-Patents Pharma Refractometer PR-23-AC

Document/Revision No. IM-GB-PR23-AC-VACCINES: Rev. 1.01

Effective: November 1, 2013

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-GB-PR23-VACCINES: Rev. 1.01 Effective: November 1, 2013

Contents

Section 1	K-Patents Products for Vaccine Production and
	Sucrose Gradient Ultracentrifugation................................................................................			5
	1.1	Design Qualification.......................................................................................................		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 Miniflow 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
		2.5.1 Computer Communication Software CC-11.....................................................		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 Verification..........................................................................		21
Section 4	Electronic Data Capture and Storage...............................................................................			23
	4.1	Ethernet connection.....................................................................................................		23
	4.2	Computer Communication Software CC-11.................................................................		23
		4.2.1	Functionality and Main Menu...........................................................................	24
		4.2.2	Trend View Menu..............................................................................................	25
		4.2.3	Data Logging Menu..........................................................................................	26
Section 5	Complying with Documentation and Validation Regulations........................................			29
	5.1	Documentation.............................................................................................................		29
	5.2	Qualification..................................................................................................................		29
	5.3	Protocol Acceptance by Customer and List of Tests Performed.................................		29
	5.4	Electronic Data Management and Data Storage.........................................................		30
	5.5	Electronic Signatures/Audit Trail..................................................................................		30
	5.6	Record Keeping............................................................................................................		30
	5.7	Security.........................................................................................................................		30
	5.8	System Validation.........................................................................................................		30
	5.9	K-Patents Refractometer System Adherence to Part 11..............................................		31

Appendix to the Instructions Manual PR-23

Section 6	Onsite Qualification Protocols and Records: Installation Qualification......................			33
	6.1	Authorization and responsibilities................................................................................		33
		6.1.1	Documents and procedures.............................................................................	33
		6.1.2	Authorized officiator..........................................................................................	34
		6.1.3	Execution..........................................................................................................	34
	6.2	System..........................................................................................................................		34
		6.2.1	Qualifying the system.......................................................................................	34
		6.2.2	Manufacturers and suppliers............................................................................	34
	6.3	IQ Protocol....................................................................................................................		35
		6.3.1	Scope of delivery..............................................................................................	35
		6.3.2	Damage............................................................................................................	36
	6.4	Documentation.............................................................................................................		36
	6.5	Operating environment.................................................................................................		37
	6.6	Installation....................................................................................................................		37
	6.7	Setting up the system components and devices..........................................................		38
	6.8	Electrical connections and wiring.................................................................................		39
	6.9	Ethernet connection.....................................................................................................		40
	6.10	Computer communication software FC-11...................................................................		40
	6.11	Initial check and switching the device on ....................................................................		40
	6.12	Installation Qualification Summary Report..................................................................		42

Section 7	Onsite Qualification Protocols and Records: Operational Qualification.....................		43
	7.1	Individual module and system components check.......................................................	43
	7.2	Installation Qualification has been performed successfully.........................................	43
	7.3	Test procedure..............................................................................................................	44
	7.4	Authorized officiator.....................................................................................................	44
	7.5	System qualification.....................................................................................................	45
	7.6	Setting up the system components and devices..........................................................	45
	7.7	Instrument verification with Sample holder and Refractive Index Liquids...................	46
	7.8	Operational Qualification Summary Report.................................................................	47
Section 8	Routine Operation Phase...................................................................................................		49
Section 9	Preventive Maintenance.....................................................................................................		51
Section 10	Other Documentation.........................................................................................................		53

4	Document/Revision No. IM-GB-PR23-ACP: Rev. 1.01 Effective: November 1, 2013

K-Patents Products for Vaccine 1 Production and Sucrose Gradient

Ultracentrifugation

This Instruction Manual Appendix covers K-Patents Pharma Refractometer PR-23-AC when used in the production of viral vaccines. The vaccines are either produced by inoculating viruses into specific pathogen-free eggs or in animal cell culture based process. The allantoic fluid of these processes is harvested and purified by centrifugation and stabilised with buffer containing sucrose. The centrifugation process typically uses density gradient continuous flow ultracentrifuge for the purification 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. The K-Patents 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.).

The K-Patents 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	Sucrose gradient purification by zonal centrifugation
	Solution	Sucrose gradient purification by zonal centrifugation	Rotor unloading
• Inoculation egg
with virus	Inactivation
• Incubation	Inactivation
	of virus
• Inoculation
preparation	Low Density
• Cell expansion	Low Density	Fractionation and separation
• Cell expansion	Solution	Fractionation and separation
• Virus propagation	Solution
• Virus propagation		Chart Recorder
		Chart Recorder
		Filling

Low Density

High Density

Figure 1.1 Ultracentrifugation density gradient purification process steps.

Appendix to the Instructions Manual PR-23

1.1Design Qualification

Design Qualification (DQ) typically consists of manufacturer’s documentation to verify that the proposed design of the K-Patents Refractometer is suitable for the intended purpose.

K-Patents 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. K-Patents Pharma Refractometer PR-23-AC wetted parts materials comply with the contact-compatibility 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 3A Sanitary Standard and is tested for in-place-cleanability according to the Euopean Hygienic Engineering Design Group (EHEDG) test.

The K-Patents 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.

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 certificate comparing a set of standard liquids to the actual sensor output. K-Patents verifies 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 certified 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 K-Patents maintains a quality contracting and regular auditing system. The internal quality functions, from verification of incoming products to packing and delivery, are based on defined procedures. K-Patents provides full traceability of the wetted parts materials. Certificates of Origin, and any other required quality documentation is available upon request at time of order.

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 the branch in the U.S.

K-Patents warrants that all products made by K-Patents shall be free of defects in material and workmanship. K-Patents agrees either to replace or repair free of charge any such product or part thereof which shall be returned to the nearest authorized K-Patents repair facility within two (2) years from the date of delivery.

6	Document/Revision No. IM-GB-PR23-VACCINES: Rev. 1.01 Effective: November 1, 2013

2 The Pharma Refractometer

PR-23-AC

2.1System 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.

The optional Computer Communication software CC-11 provides further communication features such as drawing and monitoring of real-time trend chart on the computer screen, saving the measurement data in PDF format and saving and storing the batch data over a selected period of time.

Appendix to the Instructions Manual PR-23

2.2System components

2.2.1Checklist of components

11 12

14 15

Pharma Refractometer Sensor PR-23-AC-62-HSS-SC-EP calibrated with raw measurement data refractive index (nD) and temperature (T)

Indicating transmitter DTR-M/U-GP-SC that calculates and displays the process liquid concentration based on the refractive index and temperature, installed in a stainless steel enclosure that contains a key

Table top stand PR-7603-SS for Indicating transmitter, contains a set of two M5x10 A2 DIN 912 screws

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

Interconnecting cable between transmitter and sensor PR-8230

PR-8820 Crossover cable for Ethernet connection between Indicating transmitter and computer, length 5 m (16 inch), contains cable gland for enclosure connection

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

2.5” Sanitary Clamp for the Pharma Refractometer Sensor PR-23-AC-62-HSS contains a M5x16 A4 DIN 912 screw

Pharma Mini Flow Cell PMFC-HSS

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

two sets of PR-9235 0.5” Sanitary Clamp for the Pharma Mini Flow Cell connection two sets of PR-9236-USP Sanitary gasket EPDM for the 0.5” Sanitary Clamps

two sets of PR-9237 0.5” Sanitary ferrule (lenght 1.5 cm) for the inlet and outlet hose connections and Pharma Mini Flow Cell

Universal sample holder PR-1012

R.I. Liquid set PR-2300, consists of Cargille Certificate for the liquids

Memory stick with CC-11 Computer Communication software

8	Document/Revision No. IM-GB-PR23-VACCINES: Rev. 1.01 Effective: November 1, 2013

The Pharma Refractometer PR-23-AC

	7a
4	2
3a	2
	2
	7

15 6

		11
14	5	1
	5	1

Figure 2.1 System hardware and software components provided by K-Patents.

Appendix to the Instructions Manual PR-23

2.3Pharma 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 classification
-GP = General purpose	-GP
-AX = ATEX certified EX II 3 G Eex nA II T4 (up to Zone 2)	-AX
-IA = ATEX and IECEx certified 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 STRIndicating Transmitter and IS Isolator only

2.3.2Pharma Miniflow Cell Model code

The wetted parts materials for the Pharma Miniflow 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 Flowcell	PMFC
Sensor connection
-H = Sanitary 3A-clamp, 2 ½ inch	-H
Material of Construction
SS = AISI 316	SS
Process connection
-H = Sanitary mini fitting	-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

10	Document/Revision No. IM-GB-PR23-VACCINES: Rev. 1.01 Effective: November 1, 2013

The Pharma Refractometer PR-23-AC

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

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

Figure 2.3 Pharma Miniflow Cell PMFC-HSS-EP.

Appendix to the Instructions Manual PR-23

2.4Indicating Transmitter DTR-GP-SC

The Indicating transmitter DTR is a specialized computer designed to process data received from the refractometer sensor. The 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)	DTR
STR = Indicating Transmitter (connectivity for one –IA/-IE sensor)	STR
Cable connection
-U = ½ inch NPT-type conduit hubs	-U
-M = M20x1,5 metric cable glands	-M
Electrical classification
-GP = General purpose	-GP
Enclosure
-SC = Stainless Steel enclosure with window	-SC
Transmitter options (A) (leave this section blank, if AC supply is specified)
-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

12	Document/Revision No. IM-GB-PR23-VACCINES: Rev. 1.01 Effective: November 1, 2013

The Pharma Refractometer PR-23-AC

Front view Back view

153 mm	2
(6.04”)
	186 mm
	(7.32”)

304 mm (11.95”)

281 mm (11.06”)

45 mm (1.77”)

50 mm

(1.97”) 50 mm (1.97”)

254 mm (9.99”)

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

2.5Pharma Vaccines Accessories

K-Patents recommended accessories for the vaccines production application contain Ethernet crossover cable, CC-11 Computer Communication software, IQ and OQ documentation (this document) and parts for verification and usage of

K-Patents 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 fl.oz.; Including: 1.33; 1.37; 1.42; 1.47; 1.52

●● USB Memory stick with CC-11 Computer Communication software program PR-8893 (a standalone software that allows data logging via a cross-over Ethernet cable)

●● IM-EN-PR23-AC-VACCINES IQ and OQ Documentation for Equipment qualification

2.5.1Computer Communication Software CC-11

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, Mozilla, Firefox etc.). The Ethernet connection enables data download from an Indicating transmitter DTR to a computer. The connection works both directly

between a DTR and a computer, or via a hub or a switch, local area network (LAN),

Appendix to the Instructions Manual PR-23

wireless network (WLAN) or fiber Ethernet. Any type of computer (PC, Mac, PDA, mainframe...) with a compatible network connection can be configured to download data from the DTR. See PROCESS REFRACTOMETER INSTRUCTION MANUAL, Section 12 for detailed instructions.

The optional K-Patents Computer Communicaton software CC-11 allows improved communication features and makes it easy to draw and view real-time trend chart on the computer screen and save the measurement data in PDF format to store the batch data over a selected period of time. The operation is menu-guided.

14	Document/Revision No. IM-GB-PR23-VACCINES: Rev. 1.01 Effective: November 1, 2013

3 Installation of PR-23 Pharma

Refractometer

3.1Hardware 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 verification

●● The K-Patents Computer Communicaton software CC-11 is an optional communication product.

3.2Mechanical and Electrical Requirements

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

30VA.

3.3Sensor 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.

Appendix to the Instructions Manual PR-23

Attaching table top stand PR-7605-SS for Sensor and Miniflow 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 Miniflow cell first locate the PR-9244-USP O-ring 22.2x3.0 EPDM inside the Miniflow 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 flexible hoses and used as a free standing tabletop unit, see Figure 3.3.

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.

16	Document/Revision No. IM-GB-PR23-VACCINES: Rev. 1.01 Effective: November 1, 2013

Installation of PR-23 Pharma Refractometer

Figure 3.2 Sensor stand assembly: Installing the sensor and the miniflow cell to the stand.

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.

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