WELCOME TO OUR NEW SINGAPORE FACILITY...•Blister manufacture •Packing of tablets or capsules...

WELCOME TO OUR NEWSINGAPORE FACILITY

CUSTOMER AUDIT GUIDEAlmac Pharmaceutical Services Pte. Ltd. 9 Changi South Street 3 Unit 01-01 Singapore 486361

OVERVIEW 03 – 06

SITE AND FACILITY 07 – 11

MATERIAL MANAGEMENT 12 – 17

MATERIAL STORAGE 18 – 19

MANUFACTURING & PACKAGING 20 – 31

DISTRIBUTION 32 – 33

FACILITIES MANAGEMENT 34 – 35

CERTIFICATION AND LICENSING 36

VALIDATION 37

INTRODUCING A NEW ALMAC FACILITY 38 – 39

CONTENTS

ALMAC - A BRIEF HISTORY

Almac Clinical Services began operating in 1988 in Northern Ireland, whilst Almac Clinical Technologies commenced operations in 1995 in Princeton, NJ. Since then, the business units have grown and evolved with the market, expanding rapidly to become global leaders within their sphere.

Almac recognise the benefits ofcombining the strengths of both clinical supply and technology services.

With our unique structure, only Almac can give a complete view of the entire clinical supply chain, managing the technology and logistics holistically for maximum speed, productivity, and cost effectivness.

From our European, North American and now Asia Pacific Headquarters in Singapore, we provide the most complete clinical development service offering for our customers across the globe.

ALMAC SINGAPORE - ALMAC PHARMACEUTICAL SERVICES PTE. LTD.With over 15 years of supporting clinical trials within the Asia PacificRegion, the Almac Group has a vast amount of experience in this area. The creation of Almac Pharmaceutical Services Pte. Ltd. in Singapore is an exciting new opportunity to better serve our customers. From our new facility, Almac offers a range of services to further optimize the supply chain, minimise wastage and reduce cost of clinical trials throughout the region.

THE ALMAC GROUP ENCOMPASSES INTERRELATED SERVICE OFFERINGS THAT ENABLE OUR CUSTOMERS TO OPTIMIZE THEIR DRUG DEVELOPMENT PROGRAMMES THROUGH EACH STAGE OF THE PRODUCT DEVELOPMENT LIFECYCLE

THE ALMAC GROUP WAS FOUNDED IN 2002 BY SIR ALLEN MC CLAY, ALTHOUGH THE HISTORY OF THE ORGANISATION DATES BACK TO 1968 WHEN SIR ALLEN FOUNDED HIS ORIGINAL PHARMACEUTICAL COMPANY GALEN LTD IN NORTHERN IRELAND.

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ABOUT THIS DOCUMENTThis guide has been prepared to communicate to Almac customers the key design, build, and operational elements of the new Singapore facility.

CONTACT INFORMATIONIf you have any specific questionsregarding operations at Almac's Singapore facility or if you wish to schedule an audit or a general visit, please contact:

Lo Suk SzeQuality ManagerTel: +65 6309 [email protected]

ARCHITECTArchitects Team 3 was established in 1967 and has continued to develop and expand providing architecture, interior design and planning services both in Singapore and internationally. The practice has expertise in a wide range of building sectors including healthcare, research, logistics and institutional.

MEP / FIRE PROTECTION ENGINEERSSquire Mech is an international MEP engineering practice established in 1979. Since then they have grown from strength to strength and have become a major force in the industry providing MEP design services in healthcare, commercial, residential and institutional sectors.

PROJECT MANAGERS / COST CONSULTANTSStevenson Munn is a project management and cost consultancy practice established in 1921. The core strength of the practice is to deliver high quality buildings on time and on budget. It has a wealth of experience in all building sectors including Pharmaceutical, healthcare, commercial and institutional.

CONSTRUCTION MANAGERSSato Kogyo is a building and civil engineering company established in Japan in 1862. The Singapore office was opened in 1972 and became a regional headquarters in 2002, providing construction skills and expertise to many different countries in the region. They are revered as one of Asia’s leading building and civil engineering construction companies with substantial experience and expertise in all building sectors.

CLIENTAlmac Group has provided extensive ongoing project and quality management oversight in regards to all aspects of the Singapore project. A dedicated build team, comprised of key Almac Group personnel from facilities, operations, engineering, projects, validation and quality management have remained involved with the project since its original inception.

Upon completion of the build, Almac personnel will also be responsible for qualifying all facilities, equipment, systems, and processes at the facility in order to ensure they meet all user requirements prior to their use in performing GMP activities.

PROJECT PRINCIPALS

MILESTONE PROJECTED DATE ACTUAL DATE

Project kick-off – 13 Feb 2014

Principal contractor selection – 30 May 2014

Design review – 31 Jul 2014

Occupation of office block – 08 Sep 2014

Start of GxP area fit-out – 01 Sep 2014

Completion of commissioning & handover from principal contractor

– 30 Jan 2015

Validation release 30 Jun 2015 –

KEY PROJECT MILESTONES


DESCRIPTION OF SERVICES

SERVICES TO BE INITIALLY PROVIDED BY ALMAC AT THE SINGAPORE FACILITY INCLUDE:• Manufacture of placebo capsules

• Over encapsulation of tablets /capsules

• Bottling of tablets and capsules

• Blister manufacture

• Packing of tablets or capsules intotamper evident containers

• Assembly of patient wallet packs

• Assembly of randomized and doubleblind clinical trial packs

• Global distribution of clinical supplies

• Supply chain management

• Project management

• Consultancy services

• Accountability and destructionof returned clinical supplies

• Reconciliation and destructionof unused end-of-trial material

MANUFACTURING• Hard shell capsules

PRIMARY PACKAGING• Hard shell capsules• Soft shell capsules• Tablets• Other solid dosage forms

SECONDARY PACKAGING• Most solid, semi-solid, and

sterile dosage forms

DISTRIBUTION• Most solid, semi-solid, and

sterile dosage forms

Specifically toxic and hazardous substances, as well as sensitising antibiotics such as penicillins and cephalosporins, will not be handled at the Singapore facility.

A variety of investigational medicinal products can be handled by Almac in Singapore including:

A variety of Clinical Trial project management services can be handled by Almac in Singapore including:

SUPPLY CHAIN MANAGEMENTAlmac’s Supply Chain Manager can support a wide range of activities:

• Full Management• Creating an initial forecast• On-going forecast and demand planning• Regional Demand• IRT Specifications review

and approval

• Temperature Excursion reviewand management

• Master Label Text generationand translation

• Kit Design• Drug Returns and Accountability• Expiry Date Management• Inventory Management• Management and tracking

of Import Licenses• Management of Investigator Initiated

Study (IIS or IIT) Programs• Expanded Access Programs

(Compassionate Use)

DESIGN MANAGERS: Almac Clinical Technology Design Managers work with clients to elicit requirements for the development and deployment of Almac’s IXRS IRT solution. Almac Design Managers are not just simple order takers; they seek to understand the ultimate need of the client in supporting a clinical trial and look to offer the most effective solution, based upon Almac’s long experience as an IRT provider. This partnership is a key driver of the successful implementation of an IRT product.

SOLUTIONS MANAGER: Almac Clinical Technology Solutions Managers oversee the day-to-day support and systems operations of an IXRS system once implementation is complete. They support the Design Manager in ensuring the consistent execution of support-related tasks according to Almac standards and with quality.

TECHNICAL SUPPORTCOORDINATOR: These Level I support resources are the first point of contact for technical support requests and other queries. They are part of Almac Clinical Technologies 24/7 support structure.

SITE DESCRIPTION

ADJACENCIESThere are no heavy industrial production units within the immediate locality of the Singapore facility.

FIRE PROTECTION• Changi Fire Station - 2.5km

from the facility

• Fire Extinguishers - hand heldportable units throughout the facility

• Fire Hose Reels - fire hose reelsthroughout the facility

• Comms Room - automatic FM-200 drychemical fire protection system

• Fire Alarm - fire alarm system

SECURITY AND ACCESS CONTROL• Changi Neighbourhood Police

Centre - 3.9km from the facility

• Burglar Alarm - door contacts,glass breaks and motion detection

• CCTV Surveillance - CCTV camerasand HD hard drive video recorder

• Card Access - card accesscontrol system

SITE SPECIFICATIONS


Almac’s new Singapore facility is situated conveniently within the Changi area, just a five minute drive from both Singapore’s Changi Airport and the Tanah Merah train station.

Utility services are provided to the facility by the following organizations:

• Water Supply - Public Utilities Board(Singapore’s National Water Agency)

• Sanitary Sewer - Public UtilitiesBoard (Singapore’s NationalWater Agency)

• Electric - SP Powergrid (a memberof Singapore Power (SP) Group,a leading energy utility companyin the Asia Pacific

• Natural Gas - City Gas Pte. Ltd.

Almac Pharmaceutical Services Pte. Ltd. 9 Changi South Street 3 Unit 01-01 Singapore 486361

FIRST FLOOR - ADMINISTRATIVE AREAS

In addition to offices and work spaces for staff, the administrative floor also provides key functional areas designed to enhance employee performance and help Almac meet customers’ needs, including:

• Comms room

• Staff and customer meeting rooms

• Customer audit rooms

• GxP document archive

• IVRS Technical Support Centre

• Staff break room

AREAS OF GMP/ CUSTOMER RELEVANCE Administrative spaces will reside primarily on the first floor. There are a number of meeting and work areas designed to facilitate customer visits to the Singapore facility.

• 12-person Board Room

• Three smaller, 4-person meetingrooms ideal for customer visitsor breakout sessions

THE FIRST FLOOR OF THE FACILITY PROVIDES APPROXIMATELY 418M² OF OFFICE AND ADMINISTRATIVE WORK SPACES FOR ALMAC PERSONNEL.

NETWORKS, COMPUTING AND TELECOMMUNICATIONSThe Singapore facility includes two communications rooms supporting both the office and GxP processing floors. All local se ver infrastructure is virtualised and redundant. User Application payload is delivered from Data Centres in Europe and North America which provide full redundancy. The facility also has primary and backup network links to these data Centres.

Emergency power is provided via a back-up generator.

Temperature and humidity within the communications rooms are controlled and monitored.

The network infrastructure has been qualified prior to use and provides complete wired and wireless connectivity.

Office area Boardroom

First Floor Reception Area

ADMINISTRATIVE AND OFFICE AREAS


Office

Office

Open Plan office Area

Office

Meeting Rooms and Boardroom

GMP Document Store

Boardroom

Meeting Room

Meeting Room

Meeting Room

OfficeOffice

General StoreLift DB Room

Staircase E

Office

Tech Support

Reception

Canteen

Staircase D

Women's Toilet

Men's Toilet

GMP Document

Store

Shower

TAS Riser

Telecom Room

FIRST FLOOR PLAN FLOOR AREA 418M²

THIRD FLOOR - GxP AREA

LEVEL 3 OF THE FACILITY IS DEDICATED TO MANUFACTURING, PACKAGING, DISTRIBUTION AND RETURN AND ACCOUNTABILITY ACTIVITIES; AN AREA OF APPROXIMATELY 1700M².

The floors are concrete slabs. The exterior walls are metal cladding with a masonry internal skin. The interior walls are generally steel stud with gypsum board lining.

THE MAIN OPERATIONAL AREAS INCLUDE:

• Goods Receiving

• QC Inspection and Approval

• Materials Management, including the storage of raw materialsand finished goods- Controlled room temperature

(18 to 25°C ≤65%RH)

- Refrigeration (2 to 8°C)

- Frozen (-25 to -15° )

• Primary Manufacturing and Packaging

• Secondary Packaging (18 to 25°C and 2 to 8°C)

• Clinical Label Storage

• Finished Goods Distribution

• Returns and Accountability

Primary Production corridor

Inspection of Capsules

GxP FLOOR - MATERIAL AND PERSONNEL FLOW


Store 3009

Warehouse 3005

3009A

Distribution 3007

office 3013

Comms 3028

Dispatch Area 3030

Cold Storage 3031

Frozen Storage 3033

Primary Prod. Changing Area

3016

Airlock 3018

Clean Store 3029

Fire Access Corridor

Goods In Lobby 3001

Receiving & Quarantine

3002

QC Approval Area3004

QC Inspection3003

Goods Out Lobby 3034

2-8˚C Secondary Production

3032

Corridor

Corridor 3006

office3020

Secondary 3012A

Primary 3021

Airlock 3021A

Airlock 3022A

Primary 3022

Airlock 3035

Lobby 3025

ReturnsWarehouse

3026

Plant Room 3027

Corridor 3019

Store3023

Wash Room 3024

Secondary 3012B

Store 30143017

Label Control 3008

Secondary 3011 Corridor

3010

Corridor

Logistics: Goods Receiving / Warehousing / Distribution

Primary Production

Secondary Production Changing Area

Label ControlSecondary Production

Primary Production Changing Area and Airlock

THIRD FLOOR PLAN FLOOR AREA 1700M²

Returns Warehouse

Personnel Flow

Material Flow

MATERIALS MANAGEMENT

Figure 1: Flow of materials through the facility

RECEIVING

WAREHOUSE

DISTRIBUTION

Refrigerated

Drug / Components

Expedited Material

Controlled Room

Temperature

Components

Drug

Finished Goods

Bulk Returns

Finished Goods

Finished Goods

Frozen

QC Approval Area

Distribution Suites

Courier Staging

Distribution Processing

Distribution Bulk Order Processing

Distribution Staging

Long Term Quarantine Production

Production Staged

Released Staging

QC Release Area

Receiving Quarantine

Warehouse Goods in Lobby

Material Delivered from Truck

Material Inspection and / or Sampling

Sample Storage

QC Retain Storage

Reject Cage

Production returned

ALMAC’S ENTERPRISE RESOURCE AND PLANNING SYSTEM

COSMOS, OR THE CLINICAL SERVICES ORDERING AND SUPPLY MANAGEMENT OPERATING SYSTEM, IS AN ENTERPRISE RESOURCE AND PLANNING (ERP) SYSTEM DESIGNED TO HELP SUPPORT AND ENHANCE ALMAC’S POSITION AS THE PREMIUM SUPPLIER OF GLOBAL CLINICAL SUPPLY CHAIN SOLUTIONS.

BUSINESS PROCESSESSUPPORTEDBY COSMOS

The COSMOS platform is based on Oracle’s eBusiness R12 and Clinical platforms and has been heavily configured by Almac to meet the evolving needs of the clinical trial supplies industry.


As a global ERP, COSMOS allows for the complete globalisation of Almac, minimizing site-to-site variation in processes, systems, and documentation.

Figure 2: Business process flow diagram showing the core clinical processes supported by COSMOS.

Global Processes

Integrated Billing Solution Improved Cost Visability

BILLING DATA

SOURCE

Enhanced SCM Tools

Customer Invoice

Site and PatientManagement

Create Quote

Create Items

Cost & Price Rollup

Raise PO

No Yes

Almac Manufacturing

Work Order Completion

Material Receipt of Customer Supplied FG

Planning

Material Receipt

Work Order Generation

Quality Country Release

Distribution

COSMOS SUPPORTS ALMAC’S CORE CLINICAL SUPPLY AREAS INCLUDING:

QUOTINGQuote creation and maintenance, determination of services required, price list creation, maintenance, and linking to a quote.

PROJECTSProject creation and maintenance, inventory set-up, medication number management, assembly set-up, site management set-up, distribution set-up, patient management set-up, accountability set-up and project close out.

OPERATIONS Development of timeline information for quotes, work order creation, operations scheduling, and work order release.

SITE AND PATIENT MANAGEMENTSite re-supply, site correspondence, site detail management, patient listing, treatment schedule set-up, and forecasting simulation.

DISTRIBUTIONDistribution order picking, order processing, shipment fulfilment,quality release for lot to country, Just-In-Time Labelling, POD Management, POR Management, Air Way Bill number generation, and Depot Management.

PURCHASE ORDER TO INVENTORYItem creation, inventory planning, lot management, requisition creation and approval, supplier entry and approval, PO creation and approval, receiving, and inspection.

DRUG ACCOUNTABILITY Receiving of returned drug, labelling of returned drug, storing of returned drug, re-use of returned material, and disposal of returned drug.

LABELLINGClinical label design and approval, label printing, label inspection, quality control processes, and label re-prints.

FINANCE Sales order billing, monthly project billing, invoice matching and payments, recurring billing, and inter-company billing.

CLINICAL FORECASTINGEnables the production of a forecast quantity for medication type items and the corresponding detailed assembly items over a given period of time. The total calculated quantity per month per item will be used to create a forecast per COSMOS protocol for the purpose of capacity and materials planning.

SUPPLY CHAIN PLANNING AND MANAGEMENT Enables enhanced clinical supply data management, manufacturing planning and scheduling.

For further information in relation to COSMOS, please request a COSMOS information pack from the Quality Manager:


Drug Accountability

StudyStart-Up

StudyManagement

Global Distribution

Labelling &Randomization

Blinding &Packaging

Release of Product

Supply Chain

Management

INCOMING GOODS

RECEIVING Materials are received to the facility at the receiving dock. The outside receiving interface is covered by a cantilever roof which affords protection from the weather during unloading activities. Materials are transported into the facility from the receiving dock to the Goods In Lobby (3001) via a materials elevator.

The materials elevator area is separated from the inner staging area (3002) through the use of two fast-action shutter doors which help to mitigate the impact of external temperature and humidity on conditions within the warehouse.

Once offloaded, ma erials are checked by Warehouse personnel in the Goods In Lobby (3001) before being transferred into the inner Receiving and Quarantine area (3002).

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Dispatch Area

Goods In Lobby

www.almacgroup.com

QUALITY CONTROL

QC APPROVAL The area (3004) adjacent to the Receiving area (3002) is dedicated to the purpose of approving incoming drug product and components by Quality personnel and the storage of QC samples.

Materials released in this area are moved to inventory locations under the appropriate storage conditions for use in clinical manufacturing, packaging, and / or distribution.

MATERIAL SAMPLING Sampling and inspection of primary manufacturing and packaging components by Quality personnel is performed within the Primary Production Rooms (3021 and 3022).

Each room is accessible via dedicated interlocking airlocks which provide positive pressure differentials (≥15 Pascal) relative to both the room and the outside corridor.

Each room is designed to and will be monitored against PIC/S GMP PE 009-11 Annex 1 Grade D, EU GMP Annex 1 Grade D and EN ISO 14644-1 Class 8 cleanroom standard.

SAMPLE RETENTION A dedicated sample retention location within the QC Approval / Inspection area (3004) is used for the storage of master blindness samples and other QC retention samples.

QC Receiving Area

MATERIALS STORAGE

THE GxP FLOOR PROVIDES A NUMBER OF LOCATIONS FOR THE STORAGE OF PHARMACEUTICAL MATERIALS, INCLUDING RAW MATERIALS, IN-PROCESS MATERIALS, AND FINISHED GOODS.

Access to all material management areas is restricted and controlled. Environmental conditions in all material storage areas, including all cold stores, are continuously monitored and alarmed via a

LOCATION SPECIFICATIONS AREA / CAPACITYTemperature RH (%)

Warehouse Controlled Room Temperature

18 to 25ºC ≤65% 215 m² (72 Pallets)

Controlled Refrigerated 2 to 8ºC ≤65% 72 m² (12 Pallets)

Controlled Freezer -25 to -15ºC Not Controlled 24m²

Distribution 18 to 25ºC ≤65% 185 m² (61 Pallets)

validated SmartStruxture Building Management System (BMS). Local audio and visual alarms are installed to indicate excessive open door situations within the cold stores.

CONTROLLED ROOM TEMPERATURE WAREHOUSE The 215 m2 warehouse (3005) is used for the storage of materials at controlled room temperature (18 to 25°; ≤65% RH). Capacity in the warehouse is optimized by use of narrow aisle pallet racking, the warehouse can accommodate 72 pallets.

REFRIGERATED STORAGE (2-8°C)A 72 m² cold storage unit (3031) is available for the storage of products at 2 to 8°C. Capacity within the cold store is 12 pallets. Segregated space is available for the processing of cold-chain shipments, as needed.

FROZEN STORAGE (-25°C TO -15°C) A walk-in 24m² cold storage unit (3033) is available for the storage of products between -25°C and -15°C. Access to the unit is through an anteroom maintained at 2 to 8°C in order to limit the affect of outside room temperatures in the freezer area.


MANUFACTURING AND PACKAGING - PRIMARY PRODUCTION

The primary production rooms are designed to PIC/S GMP PE 009-11 Annex 1 Grade D, EU GMP Annex 1 Grade D and EN ISO 14644-1 Class 8 cleanroom standards with negative air pressure differentials of ≥15 Pascal relative to the primary production corridor (3019) and a minimum of 20 air changes per hour.

Temperatures are maintained in all primary production areas at 18 to 25°C. Environmental conditions are continuously monitored by the SmartStruxture Building Management System.

Utility spaces accessible off the production corridors include the Clean Parts Store and the Washroom.

This area provides two primary production rooms (3021, 3022). The rooms are designed to provide standard humidity conditions of 35 to 55% (+/- 10%) relative humidity. Both rooms are accessible through a shared corridor (3019).

MANUFACTURING AND PRIMARY PACKAGING OF CLINICAL SUPPLIES OCCURS WITHIN THE PRIMARY PRODUCTION AREA ON THE GXP FLOOR OF THE FACILITY.

Primary Production room

PRIMARY PRODUCTION ROOM

GOWNING AIRLOCK

Differential Pressure (corridor to room) ≥ 15Pa

PRIMARY PRODUCTION CORRIDOR

Airflow

Figure 3: Diagram of the airflow within Primary

Production

THE PRIMARY PRODUCTION ROOMS WERE DESIGNED TO SUPPORT THE FOLLOWING FORMS OF MANUFACTURING AND EXPOSED-DRUG PACKAGING:

PRIMARY PRODUCTION ACTIVITIES AND EQUIPMENT


BOTTLING • Blister / bottle leak test unit

• Swiftcount Batch Counting machine

• Benchtop bottle cleaner

• Hand-Held capper

• Bench-top induction sealer

Swiftcount table-top tablet/capsule counter

Torque Tester

BLISTERINGKlockner Blister Packing machine (includes vision system & pinhole detection)

• Widespread and flexible machine

• Manual feeding

• Can be used for coldformor thermoform

• 100mm wide base reel

• Forms 1 row of blisters at a time andthen cuts at pre-determined intervals

• Suitable for all batch sizes

• Used for single or mixed product

Klockner Blister Packing Machine

ENCAPSULATION ELANCO• Suitable for all stages of

Clinical Trials

• Single and Multi-product filling

• Handles all shapes & sizes of input unit

• Suitable when breaking a largeinput unit in two to fit in a shell

• Metal Checker

• Capsule Checkweigher

• Capsule Polisher/Deduster

Encapsulation - Elanco Encapsulation Ring


PERSONNEL AND MATERIAL ACCESSPersonnel access to the primary production areas from the main outside corridor is through the primary production changing area (3016). After correct gowning, personnel access the primary production corridor via a dedicated airlock (3018).

In order to access the primary production corridor, personnel are required to gown as follows:

• Hair net

• Facial cover (if applicable)

• Clean room trousers and shirt(over Almac street clothing)

• Dedicated production shoewear or shoe covers

In order to access an operating primary Packaging room, personnel are required to wear additional personal protective equipment when applicable, this may include:

• Eye protection

• Disposable vinyl gloves

• Face cover near open product

In order to access an operating primary Manufacturing room, personnel are required to wear additional personal protective equipment, including:

• Eye protection

• One-piece clean room coverall

• Shoe covers

• Disposable vinyl gloves

• Face cover near open product

Primary changing room & step-over bench

Starting and in-process materials are transferred from the Warehouse into a transfer airlock (3035) by Warehouse personnel and received onto the production floor by Production personnel.

At the completion of manufacturing and primary packaging operations, in-process materials are returned to the Warehouse through the same transfer airlock. Personnel are not permitted to access Production via this transfer lobby.

Production corridor / warehouse lobby


THE PRIMARY PRODUCTION AREA IS CONSTRUCTED USING THE FOLLOWING SUBSTRATE FINISHES:

• Floor finish: trowelled epoxywith coved skirting

• Wall finish: proprietary cleanroompanels with coved internal corners

• Room ceiling finish: proprietarywalk-on cleanroom ceiling panelswith coved corners

• Lobby ceiling: proprietary walk-oncleanroom ceiling panels withcoved corners

• Corridor ceilings: proprietarywalk-on cleanroom ceilingpanels with coved corners

• Doors: Proprietary integratedcleanroom doors

• Windows: proprietary integratedflush windows

Primary Production Rooms - Gowning Airlocks

CONSTRUCTION AND FINISHES

ENVIRONMENTAL CLEANLINESS

CLEANLINESS IN THE PRIMARY PRODUCTION ROOMS IS MAINTAINED THROUGH A NUMBER OF DESIGN AND OPERATIONAL CONTROLS INCLUDING:• Dedicated primary production area

with a separate air handling unit

• Individual production rooms withinterlocking airlocks

• Trowelled epoxy floors withcoved skirting

• Proprietary cleanroom walls andceilings with coved internal corners

• Flush mounted vision panels

• HEPA filtered single pass airconditioning and mechanicalventilation system

• Continuous differential pressuregradients from corridor toroom (≥15 Pa)

• Continuous monitoring (with alarm)of air pressure gradients

• Polyester based cleanroomgarments

• Continuous room andcorridor cleaning

Environmental monitoring within the primary production area will be performed on a regular basis by Quality personnel in order to confirm ongoingroom cleanliness per PIC/S GMP PE 009-11 Annex 1 Grade D and EU GMP Annex 1 Grade D cleanroom standards (at rest).

ENVIRONMENTAL MONITORING WITHIN THE PRIMARY PRODUCTION AREA

Monitoring was performed during the initial Performance Qualification and then on a monthly basis during the first six months of operations. On-going monitoring will be performed on a regular basis.

Primary production clean store


TESTING PERFORMED:• Particulate

• Active Air Sampling

• Passive Air Sampling

• Surface Monitoring (Walls/Floors) -Microbiological

• Surface Monitoring (Contact Parts) -Microbiological

• Compressed Air Monitoring -Microbiological

• Compressed Air Monitoring -Chemical Analysis

• Water - Microbiological

TEST ACTION LIMIT ALERT LIMITParticulate

Non-viable (0.5µm) 3,520,000 particles/m3 2,350,000 particles/m3

Non-viable (5µm) 29,000 particles/m3 19,300 particles/m3

Active Air

Microbial Count 200 CFU/m3 100 CFU/m3

Yeast Fungal 40 CFU/m3 20 CFU/m3

Surface Monitoring

Microbial Count (Wall) 50 CFU/25cm2 25 CFU/25cm2

Microbial Count (Floor) 100 CFU/25cm2 50 CFU/25cm2

Yeast Fungal (Wall) 10 CFU/25cm2 5 CFU/25cm2

Yeast Fungal (Floor) 20 CFU/25cm2 10 CFU/25cm2

Passive Air

Microbial Count 12cfu 8cfu

Audible / Visual alarms are present in each primary production room in order to alert staff if environmental conditions (temperature, relative humidity, and / or differential pressure) go outside of specifications. These alarms will also alert staff of a fire alarm during active operations.

CLEANINGCleaning of production rooms and equipment is performed using Almac’s validated cleaning method. A major clean is performed between all primary operations and cleaning is performed regularly within the primary production corridor.

Primary production washroom

Within two of the production rooms a portable wall system is in place to expand room size as needed.

Temperatures are maintained in all secondary production areas at 18 to 25°C. Relative humidity is maintained at ≤65% RH. Environmental conditions are continuously monitored by the SmartStruxture Building Management System (BMS) via room sensors.

SECONDARY PACKAGING OF CLINICAL SUPPLIES OCCURS WITHIN THE 187M² SECONDARY PRODUCTION AREA. THIS AREA PROVIDES THREE PRODUCTION ROOMS ACCESSIBLE THROUGH A SHARED PRODUCTION CORRIDOR.

• 6 Station Rotary Table, ControlPanel and Heat/Sealing Station

• Custom seal board with cavitycut-outs are placed on the mainboards of the six stations

WALLETING - ZED WALLET PRESS

SECONDARY PRODUCTION ACTIVITIES AND EQUIPMENTClinical material enclosed within its primary packaging is handled within the secondary production area. The secondary production area was designed to support the following forms of packaging and assembly:

• Manual Labelling

• Automated vial labelling

• Cartoning and Patient Pack AssemblyVial Labeller

Zed Wallet Press

SECONDARY PRODUCTION

Secondary production room

• Seal boards are used to properlyalign the blister / wallet packagesto prevent damage

• Upon completion of the sealingprocess the wallet cards aremanually removed

2 to 8º SECONDARY PRODUCTION PACKAGING AREAA 15m2 refrigerated packaging area (3032) is designed for the temporary storage and processing of clinical supplies at 2 to 8°C. The installed humidity controller is capable of controlling and maintaining a constant humidity level ≤65% RH within the chamber during normal operation. Temperatures within the refrigerated packaging room are continuously monitored via the SmartStruxture Building Management System.

PERSONNEL AND MATERIAL ACCESSPersonnel access to the secondary production floor f om the main outside corridor is through the changing room.

In order to access the secondary production area, personnel are required to gown as follows:

• Hair net

• Facial cover (if applicable)

• Clean room smock (over Almacstreet clothing)

• Dedicated production shoewear or shoe covers

Starting and in-process materials are transferred by Warehouse personnel to staging area (3009) and received onto the production floor by Production personnel. At the completion of secondary packaging operations, in-process or finished goods ma erials are returned to the Warehouse using the same staging area.


Cold packaging room

Secondary production changing area

CONSTRUCTION AND FINISHES The secondary production area is constructed using the following substrate finishes

• Floor finish: trowelled epoxywith coved skirting

• Wall finish: gypsum wallboardwith acrylic paint finish

• Room ceiling finish: gypsuwallboard with acrylic paint finiswith coved corners

• Doors: steel doors with visionpanels and key locks

• Windows: sloping steel sill framewith frameless glass panel

ENVIRONMENTAL SPECIFICATIONS• Environmental conditions

(18 to 25°C / <65%RH) are continuouslymonitored by the SmartStruxtureBuilding Management Systemvia room sensors.

UTILITY SPACESUtility spaces accessible off the secondary production corridor include the following:

• Office area• Personnel changing area

CLEANINGCleaning of production rooms and equipment is performed using Almac’s validated cleaning method. A minor clean is performed between all secondary operations and a major clean is performed every two months.

LABEL CONTROL

THE LABEL CONTROL AREA PROVIDES DEDICATED SPACE FOR THE PRINTING AND STORAGE OF CLINICAL LABELS.

Initially, the supply of clinical labels will be supported by Almac Clinical Services’ Headquarters in the United Kingdom and the United States.

Temperatures are maintained in the Label Control areas at 18 to 25°C. Relative humidity is maintained at ≤65% RH. Environmental conditions are continuously monitored by the SmartStruxture Building Management System via room sensors.


Label control

DISTRIBUTION

THE DISTRIBUTION AND DISPATCH AREAS ARE DEDICATED TO THE PROCESSING OF CLINICAL SUPPLY ORDERS.

• Five distribution booths used forthe verification and packing ofindividual clinical supply orders.

• Distribution processing andpacking area within the 2 to 8ºCcold storage area

• Staging area for the holdingof released orders prior tocourier pick up.

• Just-In-Time Labelling (JIT)of clinical material.

• Bulk shipment processingand packing of pallet sizeddistribution orders.

• Two fast-action shutter doorssegregate the inner staging areafrom the materials elevator lobbyto mitigate the impact of outdoortemperature and humidity onconditions within the distributionwarehouse.

• The outside dispatch interface iscovered by a cantilevered roof whichaffords protection from the weatherduring loading activities.

Quality will perform physical inspections of shipments prior to the release of the distribution order.

Dispatch area

Palletised Shipper

FACILITIES MANAGEMENT

BUILDING MANAGEMENT SYSTEMEnvironmental conditions within the GxP areas will be continuously monitored and controlled via the SmartStruxture Building Management System, provided by Schneider Electric. The system will monitor and control the Air Conditioning and Mechanical Ventilation (ACMV) systems serving the area.

The system will provide the following function:

• Maintain environmental conditions(temperature, %RH, pressure)

• Monitor and report environmentalconditions

• Provide action alarms for conditionsimpacting on product quality

The system is used for GMP regulated activities. Areas deemed GxP relevant are monitored using calibrated sensors for relevant environmental conditions (i.e. temperature, relative humidity, differential pressure). Data for GxP points are captured and stored at pre-defined intervals.

GxP points within the system are alarmed at alert and action levels with varying set points and delays based on the point application. Alert alarms indicate potential issues with the system, where an out of specification scenario has not yet been encountered. Action alarms indicate that an out of specification scenario has been encountered and must be formally addressed.

HVACEnvironmental conditions are provided by three individual air handling units (AHU). These are located in an internal plant room. The chiller system is designed such that total plant shut down is not required for the completion of preventative maintenance.

• PAHU-03-01: Primary Production

• AHU-03-01: Warehouse andDistribution

• AHU-03-02: Secondary Production

All three air handlers are equipped with 30% efficient pre filters and 95% efficient bag filters. The 30% pre fil ers and 95% bag filters will be changed routinely in accordance with a planned preventative maintenance programme.

The AHU serving Primary Production is also equipped with HEPA filters with 99.99% efficiency. HEPA filter challenge testing will be performed every 12 months. Two of the low humidity production rooms provide single pass air flow (100% exhaust) and HEPA-filtered air supply for consideration in processing higher potency compounds.COMPRESSED AIRCompressed air is available for use in operating pneumatically controlled equipment and devices in primary and secondary packaging rooms. The system is designed to meet ISO 8573-1:2010 Class 2.2.1 with respect to solid particulates, water and oil.

WATERPotable water used for cleaning is provided to the facility from Singapore’s National Water Agency (PUB). Water quality is regulated by the Environmental Public Health (EPH). Domestic water ports on the primary production floor will be tested regularly for total aerobic count and absence of Escherichia coli.

BACKUP POWER GENERATIONBackup power generation is provided to ensure that mains power loss will not affect facility environmental conditions.

ACCESS AND SECURITYAccess to and security of the Singapore facility will be controlled and monitored.

• Controlled access points throughout the facility will restrict personnel movement based on job responsibility and regulatory security provisions.Access through these points will beby individual access cards. The authority to issue cards to employees,including the granting of accesschanges, is restricted to seniorAlmac management.

• Closed circuit TV will monitor activitiesat key access and operation points.

• Intruder detection sensors at perimeter doors and windows.

PEST CONTROL A formal Pest Control program, overseen by Quality, ensures that the facility is free from infestation. The integrated pest management program incorporates the use of strategically placed pest control devices. Pest control services are provided through an approved vendor and include regular inspections by trained technicians.


Plant room

CERTIFICATION AND LICENSING

ALMAC WILL BE INSPECTED AND APPROVED BY SINGAPORE’S REGULATORY BODY, THE HEALTH SCIENCES AUTHORITY (HSA). ALL REQUIRED LICENSES AND CERTIFICATES WILL BE IN PLACE PRIOR TO THE COMMENCEMENT OF OPERATIONS.

GMP CERTIFICATEThe GMP certificate issued by the HSA relates to the manufacture of a medicinal product, an active pharmaceutical ingredient or a cosmetic product attesting to its conformity with the relevant GMP standard as appropriate.

The GMP certifica e will reflect Almac s compliance with the HSA’s GMP standards following Inspection. The HSA have stated that Almac does not require a GMP License for the manufacturing and packaging activities performed in Singapore.

WHOLESALER DEALER’S LICENSEThe Wholesale Dealer’s License for Medicinal Products permits Almac to sell Singapore registered medicinal products to others. The Wholesale Dealer’s License reflectsAlmac’s compliance with the HSA’s GDP standard following Inspection. Licensed Wholesale Dealers may only deal in registered medicinal products and are not permitted to deal in medicinal products of which the product licences are no longer valid.

IMPORT LICENSEThe Import License will allow Almac to import medicinal products for the manufacturing, packaging and/or distribution activities performed at the Singapore facility. Under the Medicines Act, importers of medicinal products who do not hold the relevant product licenses must apply for an Import License to import registered medicinal products. Possession of an Import License reflects Almac s compliance with the HSA’s GDP standards. Products authorised for importation will be listed in the license.

FORM A POISONS LICENSEPoisons are defined as any substances specified in Singapore’s Schedule of the Poisons Act, Chapter 234. Listed on the Schedule of the Poisons Act are over a thousand medicinal products/substances. The Form A Poisons Licence issued under the Poisons Act will allow Almac to import, store and sell these medicinal products at the premises stated in the licence.

QUALIFICATION OF FACILITIES, EQUIPMENT, PROCESSES, AND SYSTEMS

VALIDATION MASTER PLAN Almac has utilized an integrated, 3-phase, leveraged approach to verify the design, build, and performance of the Singapore facility. The approach was based primarily on two cutting-edge, industry standards, ASTM E2500 and GAMP 5. This method relies on a risk-based approach in order to ensure key areas are considered, reviewed, and tested.

Vendor Start Up - Contractor submittals and testing (drawings, manuals, run-in/test documents, FAT, etc.).

Commissioning - The Almac Engineering Services business unit are responsible for completing on-site commissioning activities utilizing commissioning packs for definedareas and utilities. The commissioning documentation compiled for turn-over is completed in a manner consistent with GMP expectations, thereby reinforcing its value as completed testing, capable of being leveraged into the validation activities.

Validation - The Almac Clinical Services Validation Department prospectively executed facility protocols, including those for warehouses, cold stores, and production spaces in accordance with the Validation Policy, Validation Master Plan, and supporting procedures. This is completed by leveraging applicable commissioning activities into the Installation Qualification (IQ)and Operational Qualification (OQ)activities, and then completing the Performance Qualification (PQ)

FACILITY, EQUIPMENT, SYSTEMProjected Actual

Building Management System - 16 Feb 2015Receiving / Warehouse / Distribution Areas 15 Jun 2015 -Walk-in Refrigerator 26 Jun 2015 -Primary Production 22 Jun 2015 -Secondary Production - 09 Jun 2015Packaging Equipment 30 Jun 2015 -Compressed Air - 30 Apr 2015

In addition to facility-related testing, qualification of new and relocated GMP equipment will occur per the Validation Policy, Validation Master Plan, and supporting procedures.

The benefit of using a leveraged approach is to maximize efficiency by removing redundant exercises while still maintaining the full scope of the project. This approach does not reduce the overall amount of time needed to verify the project but starts it earlier in the construction timelines. As a result, timelines have thus been reduced to the point of facility turn-over. The focus of the validation effort, then, is on the PQ through end-to-end scenarios.

VALIDATION MASTER SCHEDULEValidation activities are performed by Almac Clinical Services and commenced immediately upon turn-over of the facility. Validation release must be obtained for a respective area prior to the startup of GMP activities. The target release of GMP areas and systems is as per the schedule below:


VALIDATION RELEASE DATE

INTRODUCING A NEW ALMAC FACILITY

STANDARD OPERATING PROCEDURESA full review of all Almac’s standard operating procedures (SOPs) was performed in order to ensure their adequacy upon commencement of operations in Singapore. All SOPs will be accessible for review during on-site audits and visits to the Singapore facility.

STAFFAlmac has recruited a team of local personnel to staff the Singapore facility. To support these efforts a number of staff from the United Kingdom and United States Almac divisions have also been seconded to support operations in Singapore.

EMPLOYEE TRAINING Curricula were created for each role within the Singapore organisational structure, identifying the training requirements associated with achieving competency in all aspects of each job. Training was delivered in a range of ways. A number of Singapore staff in key managerial roles travelled to the UK to receive training within Almac’s Clinical Services and Clinical Technologies business units.

This included classroom-based training, demonstration of tasks within an operational environment, and observation of on-going work.

Upon return to Singapore this training was cascaded to other staff by the Singapore managers, with support from UK and US operational colleagues, and the Almac Human Resources Development team.

In addition to this, a full scale operational simulation took place prior to the facility becoming operational. The objectives for operational simulation where:

• To bring together key elementsof Almac’s GxP operations -Personnel, Premises, Product,Procedures, Paperwork - withinthe Singapore facility.

• To provide an opportunity forSingapore staff to apply theirtraining to representativeoperational scenarios.

• To provide clients andregulatory bodies with documentedevidence that core services canbe successfully delivered withinthe Singapore facility.

AUDITING THE SINGAPORE FACILITYAlmac invites your organization to visit us at our new Almac facility in Singapore. If you would like to schedule an audit or a general visit to the facility or would like to request additional information or documentation which supports this Guide, please feel free to contact Lo Suk Sze Quality Manager.


ALMAC HAS RECRUITED A TEAM OF LOCAL PERSONNEL TO STAFF THE SINGAPORE FACILITY


GET IN TOUCH

UK Almac Group(Global Headquarters)Almac House20 Seagoe Industrial EstateCraigavonBT63 5QDUnited Kingdom

[email protected]+44 28 3833 2200

USAlmac Group(US Headquarters)25 Fretz RoadSouderton, PA 18964United States of America

[email protected]+1 215 660 8500

SINGAPOREAlmac Pharmaceutical Services Pte. Ltd.(Asia Pacific Headquarters)9 Changi South Street 3# 01-01Singapore 486361

[email protected]+ 65 6309 0728

WELCOME TO OUR NEW SINGAPORE FACILITY...•Blister manufacture •Packing of tablets or capsules...

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