biopharma cgmp technical overview 1.01...bio→pharma® steam sterilizer. cgmp technical overview....

BIO→PHARMA®

STEAM STERILIZER cGMP TECHNICAL OVERVIEW

PRIMUS Sterilizer Company, LLC 8719 South 135th Street, Suite 300 Omaha, NE 68137

TEL: (402) 344-4200; FAX: (402) 344-4242 [email protected] www.primus-sterilizer.com

mailto:[email protected]


http://www.primus-sterilizer.com/


PRIMUS Sterilizer Company. LLC BioPharma cGMP Technical Overview

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BioPharma cGMP Technical Overview 1.01/021417

1.0 Purpose This technical specification defines the standard features and documentation provided for a Bio → Pharma® sterilizer.

2.0 Scope

PRIMUS Bio → Pharma sterilizer’s are designed for a wide range of sterilizing applications suitable for the laboratory or pharmaceutical industry. Quality materials and workmanship have been incorporated into the chamber, piping and controls to provide a pharmaceutical sterilizer that exceeds industry standards. Bio → Pharma Sterilizer’s are designed for fully automatic, computer-controlled, operations with vacuum or gravity displacement cycles for processing of textiles, wrapped or unwrapped instruments, vented glassware and flasked liquids, culture media, laboratory supplies, pharmaceutical products and other temperature and moisture stable materials

3.0 Quality, cGMP and GAMP5

A. The Quality Policy of PRIMUS Sterilizer Company, LLC is to

improve our processes so we may meet delivery times of our customers, provide cost effective products and services that meet or exceed their expectations. The sterilizer is designed, manufactured and tested at the BIO → PHARMA® factory in Great Bend, Kansas USA with the features listed in Paragraph 4.0, according to Quality Management Systems, are in compliance with ISO 9001:2008, ISO 13485:2003, CMDCAS, and FDA’s Current Good Manufacturing Practice (cGMP). Nineteen standard sizes are available or PRIMUS can custom manufacture a sterilizer to meet end user/customer specifications.

B. PRIMUS BIO → PHARMA® Pharmaceutical cGMP Steam

Sterilizers comply with the cGMP regulations. Compliance is achieved by controlling the chamber using precise temperature control, not by pressure. Standard features such as the chamber trim and chamber boost valves, chamber bleed, chamber steam baffle, full jacket and quality temperature probes allow the temperature distribution within the chamber, to be verified to within ±0.5°C of the process sterilization temperature setpoint, including drain temperature.

C. The BIO → PHARMA® development follows PRIMUS’ ISO

13485:2016 based on the requirements and recommendations of


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the Good Automated Manufacturing Practice (GAMP5) procedures that exist to guide suppliers of automated systems to the pharmaceutical industry. The purpose of GAMP is to enable the validation of systems and equipment through their development, production and coding; thus reducing the cost to both customer and supplier of establishing compliance with specification.

4.0 Bio → Pharma® Sterilizer Standard Features

A. Frame - The vessel is secured to a welded structural frame. The frame

is constructed of 304L stainless steel. It is mounted on threaded leveling screws with supplemental stainless steel weight distribution footpads.

B. Chamber - The sterilizer features an SA240 TY316L stainless steel

(SS) rectangular, horizontal, fully jacketed chamber, with fully radiused longitudinal corners that are all fully welded and mirror polished to provide the most hygienic, long lasting appearance and durability available. All welds ground and polished and an interior surface finish to less than a 10 micro inch Ra finish. The chamber has a full-length steam baffle and one drain (50 cu ft and larger volume chambers feature two drains) positioned in the chamber to maximize steam distribution and cross flow within the chamber. The chamber is provided with a sanitary rupture disk safety device that is compliant with ASME Code. Chamber is designed for full vacuum to a maximum allowable working pressure 45 psig (3.1 bar).

C. Jacket - The jacket is constructed of SA240 TY316L SS and is

mounted to the chamber over channel supports designed to achieve uniform distribution of steam. The jacket enables the stabilization of temperature around the chamber thereby reducing the time required to bring the chamber up to sterilization temperatures, providing superior temperature distribution, and preventing the formation of condensation on the chamber walls. Jacket design pressure is rated at 45 psig (3.1 bar) internal pressure with full vacuum in the chamber.

D. Doors - Sterilizers are equipped with one or two manual vertical or

pneumatically powered horizontal sliding door(s). Horizontal door models are available with door(s) that slide from left-to-right, or right-to- left. Construction from mirror polished 316L stainless steel provides ease of cleaning and uniform quality for all chamber and door surfaces. Safety conscious engineering prevents the door from opening while the chamber is under pressure or vacuum. Double Door models, with BioSeal option, use door interlock software safeguards to prevent cross contamination through the chamber. All doors are sealed with a


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continuous silicone O-Ring gasket, recessed within the chamber head ring. The gasket is retracted before the door is opened.

E. Insulation – Vessel is insulated with one-inch semi-rigid high

temperature fiber glass board/blanket insulation overlaid with formed aluminum paneling. The aluminum wrapped insulation system eliminates wet, sagging insulation. (i.e., 4.1 KBTU/Hr at Fascia on a Double Door 26x26x39 and 7.8 KBTU/Hr in the service area) Optional two-inch insulation is available.

F. Piping, Fittings and Valves - All sterilant piping in the product contact circuit is composed of stainless steel with high quality Tri-clamped, flanged, sanitary fittings or orbital welded. Sanitary pipe clamps are located anywhere sanitary cGMP procedures require frequent maintenance access to process piping to allow ease of routine cleaning and maintenance. All sanitary valves are pneumatic.

Plumbing is sanitary from the inlet of the steam pressure regulator through the chamber to the first check valve below the drain.

After the chamber drain check valve, the plumbing is threaded stainless steel through the following check valves as applicable:

Heat exchanger check valve Heat exchanger condensate out check valve Special bleed check valve Chamber bleed check valve Chamber back flush check valve (optional)

The chamber exhaust line through the sterilizing air filter is sanitary plumbing and changes from sanitary to threaded stainless steel at that point.

G. Chamber Validation Ports - One sanitary type port (1 ½” on 26”, 2” on

larger units is standard) is provided for validation purposes sloped at 15° to prevent condensate build-up in the port. Additional validation ports are optional.

H. Load Probe Port - One sanitary type port is provided for load probe insertion sloped at 15° to prevent condensate build-up in the port.

I. Drain Line Design - The drain line is equipped with a non-clogging check valve to prevent back-flow of contaminates into the chamber. A critical (high-level) alarm is provided to monitor and prevent condensate from coming into contact with product(s) in the chamber.


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J. Air Filtration – The primary air inlet filter to the chamber is a 0.2 micron filter. A 316L stainless steel, sanitary, T-type filter housing is provided for this filter. It is rated for use in steam, water and air applications and is used to provide chamber air filtration. A 0.3-micron pre-filter is installed in line with the primary air inlet filter.

K. Steam Jacket Heating - House steam is used to heat the jacket and to

conserve the use of pure steam.

L. Vacuum System - Evacuation of chamber steam, condensate and air is achieved with a liquid ring vacuum pump, provided as standard equipment with the Bio → Pharma steam sterilizers. The vacuum pump is capable of air evacuation to a “deep” vacuum (approximately 1.0 PSIA). A dual pass, coil bundle, heat exchanger or plate heat exchanger, further reduces drain discharge temperature before entering the pump.

M. Standard Safety Systems - A door interlock system is provided to

ensure operator safety.

N. Drain Discharge Condensate Cooling - Drain discharge is cooled to < 140°F/60°C.

O. Control Systems: 21CFR Part 11 Compatible Platforms

1. PRI-Matic® 400 (PSS7) – Allen Bradley ControlLogix®

programmable logic controller (PLC) based control system with Ethernet connectivity utilizing a PanelView Plus 1000 and graphical color touch screen as the operator interface terminal (OIT). Offering a total of fifteen (15) cycles with thirteen (13) standard cycles available for product sterilization and two dedicated cycles for performing vacuum leak test and sterilizer filter.

2. PRI-Matic® 300 (PSS10) – Allen-Bradley CompactLogix™

PLC based control system utilizing a PanelView Plus 700 color touch- sensitive display as the OIT. Offering twenty-seven cycles, twenty-five (25) standard cycles for product sterilization and two dedicated cycles for performing vacuum leak test and sterilizer filter.

3. PRI-Matic® 200 (PSS9) – Allen-Bradley MicroLogix™ PLC based control system utilizing a PanelView Plus 700 color touch- sensitive display as the OIT. Offering twenty-seven cycles, twenty-five (25) standard cycles for product sterilization and two dedicated cycles for performing vacuum leak test and sterilizer filter.


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P. Alarms:

Deviations within the sterilization process are identified by alarms. All alarms are presented in a prioritized manner with the highest priority alarm presented on the OIT with the ability to silence the alarm. This alarm will remain active until the alarm occurrence has been resolved.

The following alarm conditions are indicated and recorded as listed below:

1. The Control System displays the highest priority active alarm

on the OIT. If multiple alarms are active, subsequent alarms report in order of priority after highest alarm has been resolved and this process continues until all alarms have been resolved.

2. Alarm occurrence, time and date are printed when the alarm

becomes active.

3. Advance to Exhaust and Dry from alarms is available to the operator.

4. Audible device is active until the Silence Alarm button is

pressed.

Cycle aborting alarms allow the user to initiate cycle abort by pressing the End Cycle function key on the alarm screen. If the alarm corrects itself, within the time specified by the Cycle Interrupt Timeout (see description below), the cycle continues and does not abort. If the user initiates End Cycle, the cycle will proceed to the Air Over phase, if available, or Exhaust and Dry ending the cycle in the controlled manner. Aborted alarms require that the loaded side of a double door sterilizer is opened and the cycle report prints, “Cycle May Be Compromised”. If the user decides to open the unload side, the maintenance key can be used to manually open the unload side and remove the product. The following cycle aborting alarms are provided:

1. Loss of Power - When electrical power is restored and after

the processor and PanelView “boots”, the cycle is automatically advances to the Exhaust and Dry phase.

2. Door Gasket Failure - Door Gasket A and/or B pressure is

low.

3. Under Temperature - Chamber Temperature is below the Low Temperature set point during the exposure (sterilization phase).


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4. Over Temperature - Chamber Temperature is above the Over Temperature set point during the exposure (sterilization phase).

5. Max Chamber Pressure - Chamber pressure exceeds the

Max Chamber Pressure set point.

6. Cycle Interrupt - This is a second stage alarm that occurs if the length of an alarm exceeds the Cycle Interrupt Timeout set in the cycle parameters.

Cycle non-aborting alarms will suspend the cycle and require maintenance personnel to resolve the condition. Except for Rupture Disc alarm, turning on the maintenance key during a cycle deactivates the alarm, allowing the user to finish the cycle. The following non-aborting alarms are provided:

1. Rupture Disc - Bursting of the Rupture Disc due to

exceeding the Rupture Disc pressure specification.

2. Water-In-Drain - Effluent build up in the chamber drain.

3. Sensor Failure - Failure of Chamber Drain RTD, Jacket RTD, Load Probe(s) RTD, Filter RTD or Pressure Transmitter will cause a Sensor Failure alarm.

4. Low Water Pressure - Loss of water pressure.

5. Low Air Pressure - Loss of process or instrument air pressure.

6. Low Steam Pressure - Loss of pure or building steam

Q. Emergency E-Stop:

E-Stop is available with a red mushroom push-button. Activating E- Stop removes electrical power from the output modules. Audible alarms will not sound during E-Stop since all outputs are removed. Gaskets will remain charged during E-Stop and pressure is maintained to gaskets by shuttle valves. E-Stop is disabled by deactiving the E-Stop button.

R. Printing:

The sterilizer may be equipped with an optional 32-column thermal printer or impact printer. Thermal printer offers cycle data to be stored in the printer memory until the next cycle has been initiated to


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allow for reprint of the last report. During a cycle both, cycle phase change and time and any alarm conditions are printed as they occur.

The following information is printed in the header of the cycle report:

1. Cycle Number

2. Date

3. Sterilizer Number

4. Daily Load Number

5. Charge Number

6. Sterilize Temperature (Deg C)

7. Load Temp (Deg C)

8. Sterilize Time or AF0 Setpoint

9. Dry Time

10. Cycle Start

The following process parameters are printed periodically (settable, but typically every minute) during the cycle:

1. Time

2. Chamber temperature

3. Chamber pressure

4. Product temperature

5. Instantaneous F0 value

f. Accumulated F0 value

The user can individually configure the batch number for each sterilization cycle prior to cycle initiation through the operator interface.


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5.0 Standard Sizes Available

Twenty-one (21) different standard size offerings. Both single door and double door configurations are offered in each size. Custom sizes are available as an option. The vessel and jacket is constructed in accordance with ASME Section VIII, Division 1 for unfired pressure vessels, and is so stamped. See standard sizes listed below:

Letter Designate B* C D E F G

WxHxL (in) 26x26x39 26x26x49 26x26x67 26x36x39 26x36x48 26x36x60

WxHxL (cm) 66x66x99 66x66x124 66x66x170 66x91x99 66x92x122 66x92x152

Capacity (ft3) 15.3 19.2 26.2 21.1 26.0 32.5

Capacity (l) 433.3 543.7 741.9 597.5 736.3 920.4

* Requires remote mounting of control enclosure for double door configurations

Letter Designate G.1 H I J K L M

WxHxL (in) 32x36x48 36x42x60 36x42x84 26x63x48 26x63x76 35x57x48 35x57x60

WxHxL (cm) 81x92x122 91x107x152 91x107x213 66x160x122 66x160x193 89x145x122 89x145x152

Capacity (ft3) 32.0 52.5 73.5 45.5 72.0 55.4 69.3

Capacity (l) 906.2 1486.8 2081.5 1288.6 2039.0 1568.9 1962.6

Letter Designate N O P Q R S T

WxHxL (in) 35x57x86 49x57x86 49x86x86 61x86x86 Custom 37x86x86 72x86x86

WxHxL (cm) 89x145x218 124x145x218 124x218x218 155x218x218 Custom 94x218x218 183x218x218

Capacity (ft3) 99.3 139.0 209.7 261.0 Custom 158.0 308.0

Capacity (l) 2812.3 3936.5 5938.7 7391.5 Custom 4474 8722


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6.0 Documents Option D1 All Operator Manuals contain the following sections: General Information, Installation, User, Maintenance and the Factory Acceptance Test (FAT) to include test runs, charts and graphs from Chamber Mapping.

All major components on the sterilizer listed on the Major Plumbing List (MPL) are tagged to identify the parts and cross-reference them to the part descriptions on the MPL.

Operator Manual Appendix A. Manufacturer’s / Sterilizer’s Records includes the following job specific items:

A. Drawings and Major Component Lists

1. General Arrangement Diagram 2. Major Plumbing List (MPL) 3. Piping and Instrument Diagram (P&ID) 4. Electrical Diagram 5. Major Electrical List 6. Minor Electrical List

B. Form U-1 Manufacturer’s Data Report for Pressure Vessels

C. Heat Numbers - All stainless steel sanitary components will have a

heat number engraved on the end of the component. The Assembly Production Supervisor or designee is responsible for recording these numbers on a list and provide the material certifications from the supplier for each component to be included in the Operator Manual.

D. cGMP ASME/Weld Documents (refer to the PRIMUS Code Quality

Manual - Exhibits)

1. In-Process Inspection Traveler 2. Weld Map 3. Weld Procedure Specifications (WPS) 4. Welder or Welding Operator Qualification Test (WPQ) 5. Material Heat Code List (Code components) 6. Material Certifications and Mill Test Reports

E. Keltron Printer Warranty Card, if applicable

F. If applicable Boiler User’s Manual and P2 Pressure Vessel Data

Report or Steam-to-Steam Generator User’s Manual

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Manufacturer’s Component Specification Manual is an additional manual consisting of the following:

A. Manufacturer’s Specification Datasheets and/or Instruction Manuals for

all components listed on the MPL and Major and Minor Electrical Lists. 6.1 GMP Documents Option D1.1

If the end user/customer selects only option D1.1, the documentation supplied with the sterilizer from Section 5.0 above is the Chamber Mapping charts and graphs. These documents are included in the Operator Manual in the FAT section.

6.2 GMP Documents Option D1.2

If the end user/customer selects only option D1.2, the documentation supplied with the sterilizer from Section 5.0 above is the tagging of the major and minor components listed on the MPL.

Component tags are stainless steel acid etched tags with a stainless steel beaded chain for attaching to the components. The following is an example of what must be etched on the tag. (e.g., AV-505, CV-01, PCV-01, etc.)

6.3 GMP Documents Option D1.3

If the end user/customer selects only option D1.3, all the GMP documents listed above in 5.0 under Appendix A only are being purchased. Chamber Mapping and tagging are not provided.

7.0 Additional GMP Options

The following are additional options available for Bio → Pharma® sterilizers:

A. Option D2-D5 Installation Qualification/Operational Qualification

(IQ/OQ) documentation based on the control system installed. Customized IQ/OQ package provided to be executed on-site by a qualified Validation Technician.

1. IQ verifies that the physical characteristics, including mechanical

and electrical components of the equipment, are to the manufacturer’s specification.

2. OQ verifies the operation of the equipment. All inputs and outputs; alarms, abort conditions and process operation are challenged. A final report containing a Certificate of Completion, IQ/OQ Protocol, Piping and Electrical Schematics and Spare Parts list is issued to the Customer at the completion of this Service.

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TABLE OF CONTENTS Page

1. INTRODUCTION................................................................................................................ 1 2. DESIGN DOCUMENTATION ............................................................................................ 5 3. TESTING SCOPE .............................................................................................................. 9 4. VERIFICATION ................................................................................................................ 14 5. MATERIALS OF CONSTRUCTION. ............................................................................... 16 6. INSTRUMENTATION ...................................................................................................... 18 7. SUPPORTING UTILITIES ............................................................................................... 20 8. CONSTRUCTION/INSTALLATION DOCUMENTATION ............................................... 29 9. PREVENTIVE MAINTENANCE ....................................................................................... 32

10. VERIFICATION OF HIGH & LOW LIMITS OF OPERATION ......................................... 34 11. NORMAL SEQUENCE OF OPERATION VERIFICATION ............................................. 40 12. VERIFICATION OF CLEANING, SANITIZATION/STERILIZATION PROCEDURES .... 45 13. VERIFICATION OF ADDITIONAL EQUIPMENT SPECIFIC OPERATIONS ................. 46 14. VERIFICATION OF SOFTWARE, CONTROLS, AND/OR SUB-SYSTEMS .................. 47 15. SOP VERIFICATION ....................................................................................................... 49 16. SUMMARY AND ACCEPTANCE .................................................................................... 50 17. FINAL APPROVAL .......................................................................................................... 51

Sample PSS9 IQ/OQ Table of Contents

B. Option D6 Software Source Code includes all the screens and ladder logic files for the software installed on the sterilizer.

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8.0 Typical Utility Connections and Requirements Operation of the sterilizer requires the following typical utility connections (pure steam, building steam, domestic water, compressed air, drain/atmosphere and electrical). For specific connection sizes, capacities and additional installation requirements, please reference the appropriate General Arrangement diagrams.

UTILITY CONNECTION PRESSURE

Pure steam Tri-clamp 60-80 psig (4-6 bar)

Building Steam NPT 50-80 psig (3.4 - 6 bar)

Domestic water1 NPT 50 - 70 psig (3.4 – 4.8 bar)

Instrument air NPT 60 - 80 psig (5 – 6 bar)

Process Air NPT 60 - 80 psig (5 – 6 bar)

Drain2

Open (Atmospheric

break)

Chamber discharge

Electricity

(Vacuum Pump)

Terminal

208, 240, 480, 3Ph, Range 3.4-32 Amps

Electricity

(Control System)

Terminal

Dedicated 110 VAC 60 Hz 1 Ph 10 Amps

Safety relief device for chamber Tri-clamp Discharge to open

air Safety relief device for

jacket NPT Discharge to open air

1. The recommended water temperature is 60°F (15.56 °CF). The efficiency and the depth of vacuum reached by the liquid ring vacuum pump are reduced 60°F (15.56 °C).

2. The discharge temperature is controlled down to 140 °F (60 °C).

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9.0 Control Systems Images

Steam Quality Test Kits for EN285 Compliance

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9.1 Authorized User Access

Unique user identification and password protection provides restricted access of unauthorized users to critical operational modes. Access levels are available for administrator, supervisor and operator level groups.

PSS7 Authorized User Access

LEVEL OF ACCESS USER IDENTIFICATION

ACCESS DESCRIPTION

Administrator 1 Access to all functions including Password Management

Service 2 – 4 Access to all functions except Password Management

Calibrator 5 – 7 Access to all Supervisor functions plus Calibrations

Supervisor 8 – 13 Access to all Operator functions plus Cycle Parameters

Operator 14 - 25 Access to operational functions including manual

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10.0 Piping Piping material is as follows:

A. Pure steam line, chamber pressure and drain line are 316L Stainless Steel

B. Domestic water line is Brass/Copper. Stainless Steel as an option.

C. Domestic water line is Brass/Copper. Stainless Steel as an option.

D. Compressed air line is Polyamide/Teflon, Brass/Copper, Stainless Steel.

E. Other piping is Polyamide/Teflon, Brass/Copper, Stainless Steel.

F. All pure steam piping is from quality manufacturers, with supplied

documentation.

G. All horizontal pipe runs are sloped to a minimum of 2° to promote drainage.

H All gaskets used are of pharmaceutical grade Viton, PTFE (Teflon) and

or EPDM.

I. Tri-clamps used are 13MHHM or equivalent.

J. Tubing wall thickness is nominally 0.0125-0.0500 IN (.03175-.127 CM).

K. Sanitary piping, valves, etc. have an ASME BPE surface finish designation of SF4 with electropolished ID 15 Ra. and mechanically polished OD 32 Ra, and Dixon Sanitary High Purity Code of PM.

L. Tubing and fittings are Finish number 7, polished 32Ra outside/inside

diameter (OD/ID) 11.0 Electrical – Wiring Methods

The electrical wiring is performed according to the following:

A. UL, NEMA, NEC and CSA standards.

B. Each wire end connected to a terminal strip or component is identified

with an individual wire or component tag.

C. No more than three wires are connected to a single terminal connection.

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D. A minimum of 20% spare terminal connections or additional are provided as required by the sterilizer configuration.

E. Low voltage wiring is routed separately from high voltage wiring, where

possible.

F. Low voltage control wiring and 4-20mA wiring is 18-24 AWG. High amperage 3 ph devices, such as motor starters, are 8-12 AWG. Control system for 120 Volt AC is 18 AWG with no splices.

G. Fuses or circuit breakers protect the electrical system.

H. Control Box wiring is installed in molded plastic raceways.

12.0 Sample Diagrams

Example PSS9-B-SPDD General Arrangement Diagram

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Example of a Process and Instrumentation Diagram for a Single Door Sterilizer

Sample Electrical Diagram

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Bio→Pharma® cGMP PSS7-B-SSSD

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PRIMUS and Bio→Pharma are registered trademarks.

We reserve the right to make changes to specifications and product information

This document and data contained within is intended for the exclusive use of PRIMUS customers, including architects or designers, engineers and general contractors. It shall not be reproduced in whole or part without permission of PRIMUS Sterilizer Company, LLC. Any authorized reproduction must bear the entire page to include headers and footers.

PRIMUS Sterilizer Company, LLC • 8719 South 135th Street Ste 300 • Omaha, NE 68138 Phone (402) 344-4200 • Fax (402) 344-4242 • [email protected] • www.primus-sterilizer.com



