3.

5 SQC as Pharmaceutical Quality Assurance Solution

Content

SQC in Pharma means Quality Assurance Tablet Testing Packaging SQC Product Range FreeWeigh.Net Success Examples

Internal usage only

Application Areas for Quality Assurance Solutions

1. Dispensing

2. Mixing

3. Tableting

4. Packaging

Quality control of tablets or capsules directly in the tableting room and/or nearby in a dedicated in-process control (IPC) Lab

Filling control of single blisters and completeness control of entire consumer packages (box, blisters & leaflet)

Internal usage only

Weight Quality Control in Pharma Preparations

The exact mixture and concentration of API
and excipients is crucial for consumer health

A tablet or capsule must be pressed or filled

with the precise quantity

Both underfilling and overfilling are a health

risk and must be avoided at all costs:

- Underfill can render the treatment

ineffective

- Overfill could endanger the health of the

patient
Fill weight

Therefore tolerance systems used

for pharmaceutical products follow strict rules of over AND underfill.
X
Tolerance limit T2+ Tolerance limit T1+ Average Tolerance limit T1Tolerance limit T24

Internal usage only

For Pharma SQC equals Quality Assurance (QA)

QUALITY = Consumer Health and public safety: ASSURANCE = GMP regulatory requirement:

The tablet weight is a direct function of

potency and therefore crucial for the drugs effect Besides the weight, many other tablet characteristics are checked during quality control: Hardness, Thickness, Diameter, Disintegration, Dissolution, Friability, etc. Quality and consumer health is also maximized by foreign body inspection (metal detection) Furthermore, attributes are also checked during packaging: Blister pack full ? Expiration date OK? Package inlet existing ?

Processes must be validated and

quality must be built into processes Good Documentation Practice (GDP): Who did what, when and according to which SOP Operators must be trained and processes must be fail-proof See chapter 3.1 GMP for further information

For pharmaceutical applications doing just statistical quality control is not enough Quality must be ASSURED by Good Manufacturing Practice and validation With FreeWeigh.Net we can offer the customer an integratable, electronic quality control
solution, which only after being validated becomes a complete Quality Assurance solution !
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Typical integrated Quality Assurance Solution

Internal usage only

Major Benefits of FreeWeigh.Net QA Solution

1. Accelerated tablet testing through integration and automation: Automatic weight control and further tablet data integration into one central quality report

2. Paperless, electronic, part 11conform documentation: Error free, consistent, archivable batch documentation, saving resources and speeding up release procedures, while ensuring Good Documentation Practice

3. Fully validated: Comes with easy to execute, proven best-practice validation manuals and consulting support

Internal usage only

Further Benefits
- Less user errors with streamlined procedures
Enforced and unified procedures are more easy to learn. Computer supported data collection and automated data processing prevents errors and misinterpretations!

- Less danger of insufficient quality or lost batches thanks to online control

Online monitoring and availability of data can save a batch while it is in production! Countermeasures can be taken immediately!

- Timesavings through automated and predefined reporting

Automated reporting is a huge saving potential for companies because manual data recording can be abandoned!

- Note: The reduction of loss through overfill, which is an important argument

in food applications, is not really relevant here. Of course, potential savings could be realized by minimizing overfill, but this becomes neglectable in relation to the quality assurance aspects.

Internal usage only

Tablet Testing
Press force, weight, diameter, thickness, hardness, dissolution, friability and other characteristics are monitored and controlled by electronic in-process control solutions.

Weight

Disintegration tester

Friability tester

Diameter & Thickness

Hardness

Dissolution tester

All-in-one Quality Assurance solution

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European Pharmacopeia: Uniformity of Mass

European Pharmacopeia says:
Weigh individually 20 units taken at random (...) and determine the average mass. Not more than 2 of the individual masses deviate from the average mass by more than the percentage deviation shown in table and none deviates by more than twice the percentage.
Pharmaceutical Form Average Mass 80mg and less Tablets (uncoated and film-coated) More than 80mg and less than 250mg 250mg and more Less than 300mg 300 mg and more More than 40mg All masses Less than 300mg 300mg and more Percentage deviation 10 7.5 5 10 7.5 10 5 10 7.5

Capsules, granules (uncoated, single-dose) and powders (single-dose)

Powders for parental use (single-dose) Suppositories and pessaries

Powders for eye-drops and powders for eye lotions (single-dose)

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US Pharmacopeia: Uniformity of Dosage Units

US Pharmacopeia specifies two methods to ensure "Uniformity of dosage units,
depending on the galenical form of the product.

Weight variation: Under the assumption that the formulation of the substance is known and homogeneous, weighing is considered suitable for the measurement. Weigh accurately 10 ("units") individually. From the result of the Assay, obtained as directed in the individual monograph, calculate the content of active ingredient in each of the 10 tablets, assuming homogeneous distribution of the active ingredient. Unless otherwise specified in the individual monograph, the requirements for dosage uniformity are met if the amount of the active ingredient (...) lies within the range of (e.g.) 85.0% to (e.g.) 115.0% of the label claim and the relative standard deviation is less than equal to (e.g.) 6.0%.

Content uniformity: This method requires an analysis of the substance in order to determine the contents of active ingredient, e.g. a titrator or an HPLC. This analysis cannot be carried out by weight or mass determination only.

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SQC Solutions for Tablet Testing

Quality Control
SQC14 & SQC-AX Suitable weighing ranges available LV11 Tablet feeder connectable Quick and easy documentation on the spot

QUALITY ASSURANCE
Connectivity to precision balances, (also with LV11), Metal Detectors and Checkweighers Device Integration Utility for all types of tablet testing equipment 21 CFR Part 11 compliance module Huge saving potential with reporting capabilities Comes with ready-to-use validation documentation
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Special Equipment for Tablet Testing

A wide range of special equipment is used for in-process control tablet testing

Weight

Metal detection

Hardness Thickness Diameter

Length/ Diameter

Disintegration

Moisture

Dissolution

pH

Temperature Automated tablet tester

Many of them can be integrated into a FreeWeigh.Net system by means of the Device Integration Utility if they have a communication interface 13

Internal usage only

Packaging
Filling control of single blisters or completeness control of entire consumer packages (box, blisters and leaflet) This stage of quality assurance is mainly used for completeness checks. Typically checkweighers are used here, however, for smaller batch sizes and/or smaller companies manual equipment can be used as well.

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Internal usage only

Final Check of the Product

In addition to the control of each individual tablet and its correct amount
of active ingredient the following elements make a pharmaceutical product to a sellable product:

- The correct amount of dosage units (tablets) for a complete treatment - No contaminants in the product, such as metallic parts - Damage-free packaging for safe transportation and to guarantee cleanliness
and durability Product leaflet in each package Correct expiry date Batch identification for traceability Proper package to bring the healthy image towards the consumer

There is more in a product than just the declared contents!

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Integrated Quality Control

Product Quality A function of countless individual attributes

Product Quality Control beyond weighing for all applications

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SQC Solutions for Packaging Control

SQC14 & SQC16
Wide range weighing ranges available Quick and easy documentation on the spot

FreeWeigh.Net and/or intrinsic checkweigher specific SQC functionality

Connectivity to Garvens and Hi-Speed CheckWeighers as well as Safeline Metal Detectors Online data acquisition from in-process devices Collection of attribute data from visual checking 21 CFR Part 11 compliance Comes with ready-to-use validation documentation

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Brief SQC and QA product overview

Capability
Fr e h.N eig W ee t

t .Ne igh t e eW ac Fre omp C

Focus

SQC16 (4-Series/Viper)

SQC-AX (AX)

SQC14 (4-Series, AG, AX)

Single station

Network system

SQC Compact Systems I

SQC-AX
Embedded SQC system as optional
firmware for top-level analytical balance line

Statistical quality control in

pharmacy production and laboratory

Easy operation with touch-screen

Weighing range

Alphanumeric keyboard on screen Clearly arranged display 8 users, individual password

protection

AX: MX/UMX:

22g - 510g 2.1g/5.1g

Readability

AX: MX/UMX:

0.01mg-1mg 0.1g/1g
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SQC Compact Systems II

SQC14
Up to 60 articles in SQC14/60 Printer and controller in one unit

For balances from micrograms to

tons: MX, AX, MT, AT, AB, AG, PG-S, PB, 4-Series, Spider, Viper, MultiRange

Graphical representation of the

sample mean values, standard deviation, histograms

User definable Tolerance Systems EU Tolerance System

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Internal usage only

SQC Compact Systems III

SQC16
300 Articles Individual tare:
Up to 20 Articles, resp. Different random samples series with a maximum of 50 individual values can be done at the same time

Statistics:
3 long-term statistics / 2 with selectable duration, 1 batch (selectable per article)

3000g to 35kg balances:

Allows the control of goods with a nominal weight from 5g up to 30kg

MonoBloc or Strain-gauge Technology:

For every application the suitable weighing technology With and without W&M approval available

A4 Printer:
Not only a stripe printer, but also an A4 printer can be connected

PC Backup / Restore:
Safeguarding data and time

Keyboard and Barcode reader:

Easy and quick data input
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Brochures
The following brochures are available for SQC Compact Systems,
peripherals and product know-how:

SQC14

SQC16

LV11

METTLER TOLEDO SQC Competence

Further information and documents can be obtained from the product

manager in charge. Please write to support.sqc@mt.com!

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Internal usage only

FreeWeigh.Net Quality Assurance Software

n

Features and Functions Statistical methods for analyzing and

controlling process variance

s s x

Qualitative and quantitative production

& laboratory data acquisition

Production planning, product data management and test planning

FDA 21 CFR Part 11 compliant functions

Online multi-language support Open client server architecture MS SQL database Ethernet networking SAP interface
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Data Acquisition
Manual
Automatic

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Internal usage only

Process Control
Manual
Online Status, messages and adjustment suggestions

Adjustment

+0.3

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Internal usage only

Batch Reports and Records

Manual with questionable traceability! Automatic and fully traceable!

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Internal usage only

Reporting Capabilities

Configurable Reports
for... - Samples - Statistics
Hourly Daily Weekly Monthly Yearly Batch

- Alarms - Activities

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Internal usage only

Alarm and Monitoring

Alarms
- T- T+ - Mean > UCL - Mean < LCL - Range / Standarddeviation > UCL Range / Standarddeviation < LCL Hourly, Shift, Daily, Weekly mean < Nominal

Monitoring
- Mean, Standard deviation, Range,
Range / Standard deviation
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Big Savings with automatic Reporting (only*)

1. Cost of preparing line control charts
Cost for manual reporting a) b) c) Total number of charts per month (one chart per line x 9 lines x 20 days per month Average time to record data per chart [min.] Average time for chart calculations [min.] 180 480 (sampling) 35 (collection) 1'545 EUR 50.00 EUR 77'250.00 Cost with FreeWeigh.Net 180 300 (sampling) 0 (automatic) 900 EUR 50.00 EUR 45'000.00

* Savings due to improved quality, prevention of bad batches and increased line operation data availability not included

Total time preparing charts [hours] [b) + c)] x a) /60 d) Average hourly pay for line operator

Monthly cost to prepare charts

2. Cost of preparing daily and monthly reports

FreeWeigh.Net provides online monitoring and automatic report generation. e) Number of reports per month 30 f) Average time to prepare each report [min.] 20 10 EUR 50.00 EUR 500.00 30 0 (automatic) 0 EUR 50.00 EUR 0.00

Total time preparing reports [hours] e) x f) / 60 g) Average hourly pay of staff

Monthly cost to prepare reports

3. Return on investment
Total monthly labor cost (1. + 2.) Total monthly savings with FreeWeigh.Net Customer investment for Freeweigh.Net system EUR 77'750.00 EUR 45'000.00 EUR 32'750.00 EUR 193'520.00

ROI =

New System Investment Total Monthly Savings

5.91
29

Months
Internal usage only

Big Savings with automatic Reporting (only*)

Investment example of customer A: Total EUR 193520.-Enduser (1 unit) EUR 4'700.00 3'530.00 440.00 15'000.00 18'000.00 6'000.00 1'500.00 1'800.00 N/A 3'608.00 362.00 362.00 504.00 1'804.00 1'660.00 1'082.00 1'082.00 3'246.00 1'442.00 722.00 1'896.00 2'652.00 1'122.00 1'302.00 units 6 6 3 2 3 1 2 1 N/A 1 11 1 1 1 1 1 1 1 1 1 1 1 7 12 Enduser (Total) EUR 28'200.00 21'180.00 1'320.00 30'000.00 54'000.00 6'000.00 3'000.00 1'800.00 500.00 3'608.00 3'982.00 362.00 504.00 1'804.00 1'660.00 1'082.00 1'082.00 3'246.00 1'442.00 722.00 1'896.00 2'652.00 7'854.00 15'624.00

XP4002S + Remote + Ethernet LV11 Barcode Scanner Schleuniger 8M Garvens S2 ID30 PC Hardware MS SQL Server Connectivity (IT stuff, cables, hubs) FreeWeigh.Net Basic License FWN Device License FWN Testplace Module FWN Batch FWN Attributes & Testplans FWN CheckWeigher FWN Device Integration Utility FWN FreeReporting FWN Audit Trail FWN Errors & Interventions FWN Monitoring Process FWN Validation Manual I FWN Validation Manual II Installation Validation

* Savings due to improved quality, prevention of bad batches and increased line operation data availability not included

Total
30

EUR

193'520.00
Internal usage only

FreeWeigh.Net Compact
The single station version of FreeWeigh.Net with full functionality for customers needing a highly capable SQC system with SQL database and upgrading possibilities. The following modules are available: Attributes and test plan module Adjustment algorithms module Free reporting module Batch handling module SPC module Device integration utility module Audit trail, 21 CFR Part 11 module Schleuniger AT4 module Not available are: Data I/O module SAFRIN - SAP Interface - module CheckWeigher / CombiChecker module
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The networked SQC system, for factory wide data acquisition, MS SQL database and vast expansion flexibility.

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Internal usage only

FreeWeigh.Net Options
The following modules are available:

Attributes and test plan module Adjustment algorithms module TestPlace module Free reporting module Batch handling module SPC module Device integration utility module Audit trail, 21 CFR Part 11 module Data I/O module SAFRIN - SAP Interface - module CheckWeigher / CombiChecker module Schleuniger AT4 module

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Internal usage only

FreeWeigh.Net Device Family

Broad range of integrated data acquisition equipment for any application

Static weighing

Metal detection

Hardness Thickness Diameter

Length

Dissolution

Dynamic weighing

pH

Moisture

Temperature

Automated tablet testing

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Internal usage only

FreeWeigh.Net Static Weighing

Remote Balance or TestPlace module? Remote Balance
Compact and easy solution with only one device Easy to install and maintain Less cost Less effort for validation "Plug and play"

TestPlace module
Possibility to execute Testplans Graphical mean charts and histograms Expandability with additional 3rd party devices or software Easy software updates

No Testplans No graphical statistics

Additional hardware Higher cost More maintenance

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Internal usage only

FreeWeigh.Net Static Weighing

A wide range of remote balances and terminals are now available for FreeWeigh.Net:

Remote XP Remote AX PR with RemoteR option PM with Keypad option 4-Series Remote ID5 with DataPac ID7 with DataPac

Remote XP

Spider 3S

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Remote 4-Series

Internal usage only

FreeWeigh.Net Static Weighing

All these balances can be locally connected to FreeWeigh.Net or FreeWeigh.Net Compact with TestPlace module:

XP AX PR PB 4-Series

XS AT PM AG / PG Viper/Spider

IDNet platform connected to ID30

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Internal usage only

FreeWeigh.Net Dynamic Weighing

CheckWeighers: - Garvens CheckWeigher TopLine
(VL, VS, VS+, VO)

- Garvens S-Series - Garvens S-Series CombiChecker - Garvens E-Series

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Internal usage only

FreeWeigh.Net Metal Detection

Contaminant

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Internal usage only

FreeWeigh.Net Tablet Tester AT4

The tablet tester Dr. Schleuniger AT4 measures 4 parameters
Thickness, Weight, Diameter, Hardness The AT4 is fully integrable into FreeWeigh.Net

A TestPlace module is required

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Internal usage only

Modularity and Options

With its modular concept FreeWeigh.Net can be tailored to customer requirements
Monitoring Process Errors and Interventions MetalDetector

Device License (Metal Detector) Device License (CheckWeigher)

(3 users) (3 users) license license Basic Basic

Free Reporting Attributes and Testplans Batch Handling Audit Trail / Part 11 Adjustment Algorithms SPC Data I/O SAFRIN

(5 users) (5 users) package package Client Client

CheckWeigher

Device License (Remote Balance) Test Place Device License Modules (Std. Balance) Device Device License Integration (3rd Party) Utility AT4 AT4 Basic Device License License
Internal usage only

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Options Monitoring Process Module

Online monitoring Quick overview about - Current activities in each
department and filling line - Alarms of quality characteristics - Number of metal detections Fast access to monitoring screens - Quality Status

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Internal usage only

Options Errors & Interventions Module

Complements thorough quality
control with an assessment why quality problems occur

Generates predefined handling

instructions for appropriate actions in order to overcome quality problems in production

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Internal usage only

Options Free Reporting Module

Simultaneous display of selected related product information in one
report: - Activities / Alarms - Combined variable / attribute - samples / statistics - Variables: mean value, standard deviation, range control charts, histograms - Attributes: pareto, trend graphic for individual attributes, c-charts, u-charts

Freely selectable time period Data pin-pointing

allows filtering tolerance violators from the report.
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Options Attributes & Testplans Module

Input of product quality attributes from visual inspection and execution of Testplans - linking individual measurements and checks together to a "Macro" - Ensures completeness of quality data - Simple operation - Graphical representation with Pareto charts showing the frequency of errors

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Internal usage only

Options Batch Handling Module

Ideal for customers working with batch oriented processes - Authorization of batch release in the batch catalog - Batch oriented statistics - Possibility for two concurrent batches

Raw material Batch1 = 23278

Batch 23278

Batch 23277 time

C569

C568

C567

C566

C565

C564

C563

Customer/Delivery order (Batch2) = Cxxx

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Options Audit Trail / Part 11 Module

The Audit Trail / Part 11 module provides all necessary functions needed for compliance with the FDA 21 CFR Part 11 regulations: - Electronic Signatures - Audit Trail - User profiles and access control - Device control See also Chapter 3.1 for more information

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Internal usage only

Options Adjustment Algorithms Module

Automatic monitoring of filling
and display of messages for adjustment of the filling head without violation of QA tolerances - Optimize Product Quality Algorithm regards scatter and calculates a configurable adjustment message
Filling/Tabletting Filling / Tablet Pressing IPC

+Adjustment Control / Evaluation

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Internal usage only

Options SPC Module

Statistical Process Control with - Control limits for mean value of random sample - Control limits for std. deviation and range of random sample - CuSum - Cp/Cpk

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Internal usage only

Options Data I/O Module

Seamless data import and export from FreeWeigh.Net with other
systems: - Text file (e.g. Tab-Text format) - Database access Automatic and manual exchange of: - Product data - Statistics data Host program - User data (e.g. ERP system) - Activities log Import/Export module - Alarms / Warnings Data I/O module - More

Text file or Database Interface

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Internal usage only

Options SAFRIN Module

SAP data interface for download of Testplans and upload of results (measurements, statistics and alarms acquired by FreeWeigh.Net)

SAP R/3

ERP

Module QM quality management

Stand. Interface QM -IDI

or

LIMS, JD Edwards, POMS, Oracle or AS400 applications ....

Import/Export Program

Enterprise resource planning- host system

SAFRIN

Data I/O module

ASCII File or Database Interface

MES

METTLER TOLEDO SAP FreeWeigh Interface

In-process and net weight control system

In-process and net weight control system

Instrumentation for product quality management

Metal detection CheckWeigher Net weight control Hardness and length pH and Temperature Moisture analysis

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Internal usage only

Brochures
The following brochures and documents are available for FreeWeigh.Net,
peripherals and product know-how:

FreeWeigh.Net Pharma Brochure

FreeWeigh.Net Product Brochure

FreeWeigh.Net Compact Product Brochure

FreeWeigh.Net Sales Brief

METTLER TOLEDO SQC Competence

Further information and documents can be obtained from the product

manager in charge. Please write to support.sqc@mt.com!

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Internal usage only

Successful Pharma Installations & Happy Customers

Successful Pharma Audits

We have been successfully audited on-site by the following major
pharmaceutical companies:

2004

2004

2001

2003

This shows that our processes are in accordance with pharma

customers GMP requirements It confirms us as competent supplier into the pharmaceutical industry.

-CONFIDENTIAL-

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Internal usage only

Success of FreeWeigh.Net in Pharma I

The number one in pharma uses FreeWeigh.Net in their Brooklyn plant because it is the only system providing the 21 CFR Part 11 readiness required by FDA.

Pfizer has deployed 33 FreeWeigh.Net test places in Brooklyn with

ID30 terminals for: - Tablet testing - Laser room - Encapsulation - Packaging control Contract value: USD 500'000.--CONFIDENTIAL55 Internal usage only

Success of FreeWeigh.Net in Pharma II

Roche, number one in diagnostics, was not only looking for an outstanding SQC system, but also for professional project management and validation support.

Roche uses 6 FreeWeigh.Net test places with ID30 terminals in their

Penzberg plant in Germany. They ordered services for: - 5 days process analysis, specification meeting - 2 days pilot installation - 3 days training - 3 days validation consulting Contract value: EUR 100'000.--CONFIDENTIAL56 Internal usage only

Success of FreeWeigh.Net in Pharma III

GlaxoSmithKline audited BASY on-site by their centralized auditing specialists for their global SQC project started in Germany.

GSK has ordered a FreeWeigh.Net system including integration into

SAP PP module with the FWN Data I/O. The system went alive in January 2005 and will globally be rolled-out in a standardized configuration.

-CONFIDENTIAL-

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Internal usage only

Computer System Validation & Consulting Support

Validation is the hottest GMP topic and one main if not the biggest value-add in our solution offering !

User requirements specification Functional specification

Project-cycle of a computerized system

Performance qualification

Operational qualification

Design specification

Installation qualification

Implementation

See Chapter 3.1 GMP for more information !

58 Internal usage only