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欧盟实施GMP的经验计算机验证和GDP的运输过程验证

D Si f i d S h itt PAREXELDr Siegfried Schmitt, PAREXEL

EU GMP EXPERIENCE: COMPUTER VALIDATION AND GDP TRANSPORTATION VALIDATION

AGENDA

Computer Systems Validationdand

Good Distribution Practice (Transportation) Validation

New developments and requirements in the EU and Chinap q

COMPUTER SYSTEMS VALIDATION

Applicable Regulations

The latest Guidance Documents

Industry Experience

THE EUROPEAN UNION

COMPUTER SYSTEMS VALIDATION - APPLICABLE REGULATIONS

EU

EudraLex Volume 4 Annex 11 Computerised Systems

EudraLex Volume 4 Annex 15 Qualification and Validationcame into force October 2015 (e.g. applicable to automatedequipment IT Infrastructure)equipment, IT Infrastructure)

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

COMPUTER SYSTEMS VALIDATION - APPLICABLE REGULATIONS

ChiChina

Articles 109 and 241 in MOH Decree No. 79 GoodManufacturing Practice for Drugs (2010 Revision)Manufacturing Practice for Drugs (2010 Revision)

http://www.cfdi.org.cn/ccdweb/main?fid=open&fun=show_news&nid=6643

Article 42 in Annex 2 Validation and Verification (Draft forComment May 2015)

Annex 1 Computer Systems (Draft for Comment May 2015)

COMPUTER SYSTEMS VALIDATION - APPLICABLE REGULATIONS CONTINUED

China

Articles 109 and 241 in MOH Decree No. 79 Goodf f ( )Manufacturing Practice for Drugs (2010 Revision)

http://eng.sfda.gov.cn/WS03/CL0768/65113.html

Article 42 in Annex 1 Qualification and Validation (Draft forComment June 2014)

htt // fd /WS01/CL0778/109640 ht lhttp://www.sfda.gov.cn/WS01/CL0778/109640.html

Guideline for Technical Review of Medical Device SoftwareRegistration ( August 2015)Registration ( August 2015)

http://eng.sfda.gov.cn/WS03/CL0757/126488.html

COMPUTER SYSTEMS VALIDATION - THE LATEST GUIDANCE DOCUMENTS

EU

UK - MHRA GMP Data Integrity Definitions and Guidance for// /Industry January 2015 http://tinyurl.com/q2th2sy

Handbook on European data protection lawhttp://tinyurl com/olbzgeuhttp://tinyurl.com/olbzgeu

Sweden - Medical Information Systems http://tinyurl.com/ol8tq8l

G Aid é i 07121202 C t l f t i dGermany - Aide-mémoire 07121202 Control of computerizedsystems http://tinyurl.com/l73x3t9

EMA Questions and answers: Good manufacturing practiceEMA Questions and answers: Good manufacturing practicehttp://tinyurl.com/ozxtaox

COMPUTER SYSTEMS VALIDATION - THE LATEST GUIDANCE DOCUMENTS

Industry Associations

www.ispe.org

COMPUTER SYSTEMS VALIDATION - INDUSTRY EXPERIENCE

There are few Subject Matter Experts with CSV expertise

There are also few inspectors with CSV expertise

CSV is critical for data integrity assurance - this is a big, bigissue!

COMPUTER SYSTEMS VALIDATION - INDUSTRY EXPERIENCE CONTINUED

There is a widespread misconception that automated systemswill always make a paper / manual process better

Many, many automated systems in industry are not validated,i.e. the validation documentation is insufficient

There is great reluctance in industry to increase automationThere is great reluctance in industry to increase automationand / or to network automated systems


The most difficult aspect of CSV are intelligent, complete andtestable user requirement specifications - really, truly, honestly

Once you actually know what the user wants, the system canbe validated not before!!!be validated - not before!!!

Differentiate between must have and nice to haverequirementsq

Conversely, if the users have not defined what they want, theymay or may not get what they wish for - it will be just luck


IT does not own business applications - there is a businessowner

SSomeone with IT skills will be able to explain the validationapproach

Common omissions and mistakes in CSV:Common omissions and mistakes in CSV:

The system has not been validated for its intended use

Th CSV t d tThe CSV report does not say:

• The system is validated and meets the URS

• The rationale why you consider testing was complete andchallenging


Common omissions and mistakes in CSV:

Testing is not risk-based:

• Which functionality, configuration or data are GMP-critical?

• How much testing is required for these (e.g. positive,negative or challenge testing)

Trying to resolve all deviations - good luck

There is no such thing as 100% testing

Automated testing tools are ok - validate them

Part 11 is not a problem - CSV is!

GOOD DISTRIBUTION PRACTICE (TRANSPORTATION) VALIDATION

Applicable Regulations

The latest Guidance Documents

Industry Experience

GDP (TRANSPORTATION) VALIDATION -( )APPLICABLE REGULATIONS

EU

EC (2011/62/EU) Falsified Medicines Directive

Scope:

• Control of API (Active Pharmaceutical Ingredients) Importation

• Safety Features: a unique identifier and an anti-tampering device

• Internet Sales

• Good Distribution Practices

http://tinyurl com/6ftor7thttp://tinyurl.com/6ftor7t

http://tinyurl.com/o6hyeor


EU

EC Falsified Medicines Directive

Control of APIs (Active Pharmaceutical Ingredients) ImportationWhite List or Written Confirmation

http://tinyurl.com/npagjrh


EU

EC Guideline 2015/C 95/01 on Good Distribution Practice off factive substances for medicinal products for human use

(March 2015)

http://tinyurl com/ohk8wjhhttp://tinyurl.com/ohk8wjh

European Commission Guidelines on Good DistributionPractice of Medicinal Products for Human Use

http://tinyurl.com/6hba9nt

EMA http://tinyurl.com/d6r22mn


China

Good Supply Practice for Pharmaceutical Products CFDA( )Decree No. 13 (July 2015)

http://www.sfda.gov.cn/WS01/CL0053/123040.html

Good Supply Practice for Medical Devices (December 2014)

www.sfda.gov.cn/WS01/CL0087/110920.html

GDP (TRANSPORTATION) VALIDATION - THE ( )LATEST GUIDANCE DOCUMENTS

EU

EMA Concept paper on new guidance for importers of( )medicinal products (May 2015)

www.ema.europa.eu

HPRA Guide to Good Distribution Practice of MedicinalProducts for Human Use (April 2014)

htt //ti l / jtkhttp://tinyurl.com/pjtkwqz

Most EU member states publish specific guidance documents

GDP (TRANSPORTATION) VALIDATION - THE ( )LATEST GUIDANCE DOCUMENTS CONTINUED

EU

MHRA New mandatory logo for selling medicines online

http://tinyurl.com/plm56sj

GDP (TRANSPORTATION) VALIDATION - THE ( )LATEST GUIDANCE DOCUMENTS


ISPE Supply Chain Security: A Comprehensive and PracticalApproach

ISPE Good Practice Guide: Cold Chain Management

www.ispe.org

GDP (TRANSPORTATION) VALIDATION - THE ( )LATEST GUIDANCE DOCUMENTS CONTINUED


PDA TR 64 Active Temperature-Controlled SystemsQ f GQualification Guidance

PDA TR 58 Risk Management for Temperature-ControlledDistributionDistribution

PDA TR 52 Guidance for Good Distribution Practices (GDPs)for the Pharmaceutical Supply Chainpp y

PDA TR 72 Passive Thermal Protection Systems for GlobalDistribution

www.pda.org

GDP (TRANSPORTATION) VALIDATION AMBIENT ( )CONDITIONS - INDUSTRY EXPERIENCE

All shipments are influenced by ambient conditions, not onlycold chain shipments

C ffConsideration the seasons and the differences in expectedambient temperatures throughout the year

Calibrations should be performed at three points (at least)Calibrations should be performed at three points (at least)across the range of temperatures, i.e. at 0, 15 and 30oC forambient warehouse probes

UK: Returns from an unlicensed site must be completed within5 days for non defective ambient medicinal products

http://tinyurl.com/p6e6s3n

GDP (TRANSPORTATION) VALIDATION AMBIENT ( )CONDITIONS - INDUSTRY EXPERIENCE CONTINUED

Ambient = ?

+15oC to +25oC = normal range?

-5oC to +45oC = extreme range?

+2oC to +30oC = EU Continental range?

Controlled Room Temperature (CRT) = a sort of controlledambient, e.g. “do not store above +25oC” - monitoring may be

d t d ( S di A bi T k I l th C hmandated (e.g. Saudi Arabia, Turkey, Israel, the CzechRepublic and South Korea.)

TAT = Time at Ambient TemperatureTAT = Time at Ambient Temperature


The Global Controlled Room Temperature LogisticsThe Global Controlled Room Temperature LogisticsSurvey conducted August - October 2014


Validation Approaches:

In draft PDA TR XX Passive Thermal Protection Systems forGGlobal Distribution


Validation Approaches Continued:pp

URS to detail: Product, Product Stability Data, Size of load,Shipment duration, The environment and available controlsalong the shipping lane, Logistic requirements, Regulatoryrequirements, and Lane/Route Analysis

Dynamic / Distribution Testing e g ASTM 4169Dynamic / Distribution Testing, e.g. ASTM 4169

Operational Qualification Testing

P f Q lifi ti T ti ti li t dPerformance Qualification Testing: consecutive, replicatedfield transportation tests to demonstrate that the selectedsystem is effective and reproducible

User Acceptance Criteria


Industry fear and expectation:

Mandatory temperature and relative humidity monitoring for allambient temperature shipments

The move is from cold chain management to temperature (andrelative humidity) transport management

GDP (TRANSPORTATION) VALIDATION - INDUSTRY ( )EXPERIENCE

Supply Chain and Distribution Management is often outsidethe company’s quality management system (QMS)

f (Therefore suppliers (e.g. transportation, warehousing,brokers, etc.) are often not covered by the company’s QMS

Several countries develop specific unique identifiers -complication of the supply chainp pp y

EU GMDP database not current and search results are notEU GMDP database not current and search results are notreliable

COMPUTER VALIDATION AND GDP (TRANSPORTATION ) VALIDATION

Inspection Findings become more and more public:

Chinaf / / f / /f / fwww.cfdi.org.cn/ccdweb/kindeditor_file/68/file/1429857417.9.pdf

EU

http://eudragmdp.ema.europa.eu/inspections/displayWelcome.do

http://tinyurl.com/ogpntso

http://tinyurl.com/q9fskv8

SUMMARY AND OUTLOOK

Increased supply chain complexity will require increased automation

Computerised systems compliance scrutiny is going to increase not least because of data integrity concernsincrease, not least because of data integrity concerns

Th h th i h i ti f th l ti thThough there is no harmonisation of the regulations, the overall trends are the same globally

YOUR PRESENTER

Siegfried Schmitt, PhD FRSC CChem CSci

Principal Consultant

PAREXEL International

+44 7824 592401

[email protected]