computer system validation - waters corporation
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© 2016 Waters Corporation 1
Computer
System
Validation
What is it and
why is it needed? An Overview
© 2016 Waters Corporation 2
• Regulatory background and history
• The elements of CSV
GAMP, PICS and CSV
• What can different partners do for you?
Selecting a Validation Partner
Minimizing Validation Costs
© 2016 Waters Corporation 3
• Regulatory background and history
• The elements of CSV
GAMP, PICS and CSV
• What can different partners do for you?
Selecting a Validation Partner
Minimizing Validation Costs
© 2016 Waters Corporation 4
Radiation therapy machine used in the late 1980s
Parts of the software were from an earlier model that had hardware interlocks for safety - Therac 25 did not have hardware interlocks
The hardware and software combination in the Therac 25 was never tested before it was installed at the hospital
6 recorded accidents
After this, software validation for medical devices was required
In the 1990s, regulators started to ask about CSV for pharma systems
– GAMP was born!
Therac 25 – the start of CSV
© 2016 Waters Corporation 5
GAMP
GAMP 5
–GAMP is a set of guidelines
–It is written by volunteers
–It is NOT a regulation
–Practical and pragmatic
GAMP is referenced by:
–US FDA
–EMA
–PIC/S
Other approaches are acceptable
© 2016 Waters Corporation 6
Regulations for Pharmaceuticals
If you manufacture:
– active pharmaceutical ingredients (APIs),
– finished pharmaceuticals,
– or provide research and clinical trial services to such manufacturers,
then there are regulations and guidelines which should be followed
These are referred to as Good Manufacturing Practices (GMP)
Some of these GMP regulations focus on the integrity of data used to make decisions about product quality and product release (data integrity, and critical data), especially when computerized systems are used to create and store that critical data (the data are then classified as electronic records).
© 2016 Waters Corporation 7
Main Body PIC/S GMP Guide – Part I: Basic Requirements For Medicinal
Products
– Part II: Basic Requirements For Active Pharmaceutical Ingredients
GMP Annexes
– Annex 1 Manufacture of sterile medicinal products
– Annex 2 Manufacture of biological medicinal substances and products for human use
– Annex 3 Manufacture of radiopharmaceuticals
– Annex 4 Manufacture of veterinary medicinal products other than immunologicals
– Annex 5 Manufacture of immunological veterinary medical products
– Annex 6 Manufacture of medicinal gases
– Annex 7 Manufacture of herbal medicinal products
– Annex 8 Sampling of starting and packaging materials
GMP Annexes (continued) – Annex 9 Manufacture of liquids, creams and
ointments
– Annex 10 Manufacture of pressurised metered dose aerosol preparations for inhalation
– Annex 11 Computerised systems
– Annex 12 Use of ionising radiation in the manufacture of medicinal products
– Annex 13 Manufacture of investigational medicinal products
– Annex 14 Manufacture of medicinal products derived from human blood or plasma
– Annex 15 Qualification and validation
– Annex 16 Qualified person and batch release
– Annex 17 Parametric release
– Annex 18 GMP Guide for active pharmaceutical ingredients
– Annex 19 Reference and retention samples
– Annex 20 Quality risk management
PIC/S GMP Guide PE 009-12 (October 2015)
© 2016 Waters Corporation 8
Focus on Asia Pacific
APAC country or Region
GMP Regulation PIC/S Member
Population
ASEAN Countries
Earlier version PIC/S (PE 009-9)
Some 625 million
Japan Equivalent JGMP; PIC/S as official ‘guidance’
Yes 127 million
Republic of Korea
Equivalent KGMP
Yes 50 million
Australia Earlier version PIC/S (PE 009-8)
Yes 23 million
Republic of China (Taiwan)
Earlier version PIC/S (PE 009-10)
Yes 23 million
Hong Kong PIC/S PE 009-11 from October 2015
Yes 7.2 million
New Zealand
Ealier version PIC/S (PE 009-8)
Yes 4.5 million
People’s Republic of China
China GMP No 1.35 billion
Indian sub-continent
Separate country GMPs
No 1.7 billion
PIC/S member
Follow PIC/S GMP
Non Member
© 2016 Waters Corporation 9
Compliance
Compliance is meeting the applicable regulations for the target
market
– For a pharmaceutical company selling within ASEAN
o PIC/S GMP covers all GMP requirements for manufacturing,
processing, distributing API and finished goods
o PIC/S Annex 11 covers computerized systems
• Any combination of hardware and software which fulfils a
functionality
• Requires security controls, procedures, training and validation
• “The application should be validated”
– There are also regulations for food, chemicals, pesticides etc.
o Generally all regulations are focussed on:
• The system is fit for intended use
• Being able to trust the data (data integrity)
© 2016 Waters Corporation 10
Paper vs. Electronic Data
“the printed chromatograms used in drug manufacturing and testing do not satisfy the predicate rule requirements in 21 CFR Part 211. The electronic record must be maintained and readily available for review by, for example, QC/QA personnel or the FDA investigator”
© 2016 Waters Corporation 11
Paper vs. Electronic Data
Even where paper records may still be acceptable:
– There is no audit trail for the inspector to review with paper records
– The inspector has no way to know if this is ALL of the data
All test results
© 2016 Waters Corporation 12
Data Integrity
Regulatory agencies want:
– To see all of the data and metadata (electronically)
– Data recorded at the time it happened, by the person that did it
– Full history about everything that happened to the sample and its
data (audit trail, method versions)
– To be able to recreate the final result from the raw data
– Records to be available for the full retention period
– Only validated computerized systems to be used
This includes all of your mistakes!!
© 2016 Waters Corporation 13
Compliant System
Release Testing
Qualification Validation
Compliant System
All three elements are required to achieve a
compliant Computerized System
© 2016 Waters Corporation 14
Qualification vs. Validation
“Validation Cake” IQ/OQ qualification are just two
ingredients in the Validation Cake
© 2016 Waters Corporation 15
Application Qualification vs. Validation
SOPs
Validation Plans/ Reports
Risk-based testing
Specifications/ RTM
IOQ
Product
Qualification: The product is installed and operating correctly to vendor specification at that point in time
Computerized Systems Validation (CSV): The product will meet its intended use throughout its operational life Ongoing compliance!
© 2016 Waters Corporation 16
Computerized System Validation Life Cycle – V model
Computerized System Validation (CSV): achieving and maintaining compliance with applicable GxP regulations and fitness for intended use by:
• the adoption of principles, approaches, and life cycle activities within the framework of validation plans and reports
• the application of appropriate operational controls throughout the life of the system
© 2016 Waters Corporation 17
Compliance for System Components
S T A N D A R D O P E R A T I N G P R O C E E D U R E S
© 2016 Waters Corporation 18
Spanish Agency of Medicines Inspection January 2016, Spain
…use in quality control of non-qualified chromatographic
equipment, with operating faults, and with an unvalidated
computerized management system. As a result, the integrity,
reliability, up-to-dateness, originality and authenticity of the data
that are obtained cannot be guaranteed.
Consequences:
suspension of the manufacturing and quality control of medicinal products
activities
withdrawal from the market of all batches of all medicinal products that have been
manufactured by this pharmaceutical company during 2014, 2015 and 2016
to prohibit to place on the market any batch manufactured by the pharmaceutical
company
to stop supply to customers of medicinal products
Report ID INS16-001c
© 2016 Waters Corporation 19
• Regulatory background and history
• The elements of CSV
GAMP, PICS and CSV
• What can different partners do for you?
Selecting a Validation Partner
Minimizing Validation Costs
© 2016 Waters Corporation 20
If the system was a car…
© 2016 Waters Corporation 21
Specification: Vendor vs. URS
USER REQUIREMENT SPECIFICATION
Engine Diesel
Seats 7
Transmission Auto; 4 WD
Load Space Camping / Fishing
Suspension Comfortable
Vendor’s Specification (page 1 of 20)
© 2016 Waters Corporation 22
Making the Car “Fit for Use”
Car Computerized System
Diesel (fuel) IQ/OQ Qualifications
Oil, Coolant, Tyre pressure Validation Documents
Driving Licence Trained Users
Insurance, Registration SOPs
Annual Service Periodic Review
© 2016 Waters Corporation 23
Life Cycle in Detail
Functions identified as high risk priority are given focus in the
Test Plan
Detailed Test Plan
Design & Configuration Specification
Controls to reduce risk are included in the SDS, and pass into the System
Configuration
Risk Assessment
Functions from the URS are assessed in the Risk
Assessment
Configuration
Project Planning Initial Definition
User Requirements Specification
Definition is expanded to capture
requirements
Validation Plan
Verification Activities
Verification activities challenge the risk-reduction
controls
Validation Summary Report
Summary report details any
deviations and residual
risks
© 2016 Waters Corporation 24
Responsibilities
FDA CPG Sec. 425.200 Computerized Drug Processing;
Vendor Responsibility
– The end user is responsible for the suitability of computer systems
(hardware and software) used in manufacture, processing or holding of
a drug product.
GAMP 5, Main body §6
– Responsibility for the compliance of computerized systems lies with the
regulated company.
PIC/S document PE-011-3, §4.4
– The co-operation of the supplier is essential and it is important for
suppliers to anticipate the needs of regulated users for relevant product
development life cycle quality and validation information. Such an
approach also provides added value for the automated products.
© 2016 Waters Corporation 25
Compliance for System Components
S T A N D A R D O P E R A T I N G P R O C E E D U R E S
© 2016 Waters Corporation 26
Compliance for System Components
S T A N D A R D O P E R A T I N G P R O C E E D U R E S V E N D O R A S S E S S M E N T
© 2016 Waters Corporation 27
Vendor X
– IQ/OQ protocol execution
– Validation ‘certificate’
Waters
– Validation Plan
– User Requirement Specification
– Risk Assessment
– Design & Configuration Specification
– IQ/OQ protocol execution
– Extended / customised OQ/PQ
– Traceability Matrix
– Validation Summary Report
– Training
– SOP generation
Range of Vendor Offerings
© 2016 Waters Corporation 28
Vendor X
Customer Validation Load
Vendor Assistance
Final Responsibility for Compliance Time
CSV effort required
© 2016 Waters Corporation 29
Waters
Customer Validation Load
Vendor Assistance
Final Responsibility for Compliance Time
CSV effort required
© 2016 Waters Corporation 30
Leveraging Your Vendor
© 2016 Waters Corporation 31
Regulated Manufacturer
• Has final responsibility for
compliance (under law)
• Has to defend the risk assessment
and validation approach during an
inspection
• Is liable for any penalties for non-
compliance
• May have limited in-house resource
available to conduct validation
Waters
• Has products based on an
accredited quality management
system
• Is able to support effective
customer validation
• Can offer onsite and remote
assistance with validation activities
• Has recognised expertise in CSV
• Is working to internationally
accepted guidelines (e.g. GAMP,
PIC/S) and applicable regulations
Responsibilities
An ideal software vendor like Waters can significantly reduce
the cost and time for the customer to complete validation
© 2016 Waters Corporation 32
• Regulatory background and history
• The elements of CSV
GAMP, PICS and CSV
• What can different partners do for you?
Selecting a Validation Partner
Minimizing Validation Costs
© 2016 Waters Corporation 33
Using Infrastructure to Minimise the Time and Cost of Compliance
Imagine you have a lab with…
– Multiple vendors…Waters, Vendor A, Vendor B, Vendor C
– All workstations
– Let’s take the case where you have 3 of each vendors
workstation….what is the impact of this on the time and cost to
validate?
– For each, unique data system, it will take roughly the same effort
and cost for each system.
o For the sake of discussion lets use…
= 3 Months = $100K USD
© 2016 Waters Corporation 34
Scenario 1: Change Nothing
Waters
Vendor A
Vendor B
Vendor C
D
D
D
D
D
D
D
D
D
D
D
D
$ 800K USD 24 Months
© 2016 Waters Corporation 35
Scenario 2: Centralise Data
Waters
Vendor A
Vendor B
Vendor C
D
D
D
D
$ 400K USD 12 Months
D
D
D
D
D
D
D
D
© 2016 Waters Corporation 36
Scenario 3: Minimise Vendors
Waters
Vendor A
Vendor B
Vendor C
D
D
D
D
$ 100K USD 3 Months
© 2016 Waters Corporation 37
Questions/Discussion
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