Distribution rights are property of the PHSS, permission must be … · 2018-03-31 · Di...

09:00 09:15Welcome from PHSS Chairman and UCL Q3P Course Director

James Drinkwater and Professor Duncan Craig, Director UCL School of Pharmacy

09:15 10:00Revision of Annex 1 Manufacture of sterile medicinal products – a GMP inspector’s point of view.

Andrew Hopkins MHRA Senior Inspector

10:00 11:00 Panel Discussion – Annex 1 revision.Discussion panel: MHRA, PHSS, A3P, PDA, ISPE, R3 Nordic and ECA.

11:00 11:45 Coffee and Viewing ExhibitionsBlue Badge - Square LoungeGreen Badge - MLT Exhibition Area

11:45 12:30

Data Integrity: Considering non-conformances, challenges, requirements and impact on product/ batch release.

Di Morris: GSK Global auditor,Ex-MHRA senior inspector.

12:30 13:30 Lunch and Networking

13:30 14:15

Stream 1: Main Lecture TheatreChanges and their impact in revisions of EU GMP Regulations: Orange Guide; chapters 3, 5, 8 and annex 15: Qualification and validation.

Malcolm Holmes: Consultant/ Freelance GMP/ PHSS regulatory update author.

13:30 14:15

Stream 2: Workshop RoomAnnex 16: Certification of a Qualified person and batch release.The impact of the revision and new requirements.

Richard Funnell – Funnell Pharma Consultants Ltd

14:15 14:45 Coffee and Viewing ExhibitionsBlue Badge - MLT Exhibition AreaGreen Badge - Square Lounge

14:45 15:30

Stream 3: Main Lecture TheatreISO 14644 (part 1 & 2) revision update.Key points about the revisions and potential impact on GMP qualification and operations.

Gordon Farquharson: GMP Consultant; Critical systems

14:45 15:30

Stream 4: Workshop RoomImpact of regulations in filling multiple products in the same facility, considering aseptic processing of non-hazardous product, cytotoxic products and biologically hazardous products, including live virus.

James Drinkwater: F Ziel Head of Aseptic processing technologies and GMP compliance.

Please hand in your feedback forms.Course notes will be sent electronically.We would be delighted to welcome your colleagues as members.Thank you for coming.

PHSS Annual Conferencein association with UCL Q3PUCL School of Pharmacy, LondonFriday 11th September 2015

Impact of changes in GMP regulations including Annex 1 & ISO standard revisions.

over 25 years of advancing pharmaceutical and healthcare sciences

Distribution rights are property of the PHSS, permission must be obtained for use.

James Drinkwater

Chairman of PHSS –

Pharmaceutical &

Healthcare Sciences Society

1

Introduction and Welcome

PHSS & UCL QP Annual Conference 2015

UCLQP3


UCL School of Pharmacy Welcome

2

General guidance for conference:

Fire exits…. No planned fire alarm tests.

Toilets/ Rest rooms; off stair wells… directions from PHSS/ UCL staff

Blue badge and Green badge coffee break and lunch rota; Exhibitors split between break rooms. Directions from PHSS/ UCL staff.

Blue badge coffee break Square lounge, lunch MLT roomGreen badge coffee break MLT room, lunch Square lounge.

Presentations downloaded via link provided after the conference.


Conference Welcome

3

The PHSS wish to thank Dr. Khalid Sheikh,Director, UCL QP Course, Department of Pharmaceutics and his UCL School of Pharmacy colleagues for the collaboration with the PHSS.

Announcement: Kay O’Hagan is to take over as Editor in Chief of the EJPPS: European Journal of Parenteral & Pharmaceutical Sciences from Gordon Farquharson – Our sincere thanks to Gordon for his professionalism and dedication to the role over many years. We also take the opportunity to welcome Professor Bengt Ljungqvist from R3 Nordic to the conference. Bengt is also on the main editorial board of the EJPPS.

Announcement: Jenni Tranter is take over from Kay O’Hagan as the Vice Chairperson of the PHSS. Our good wishes to Jenni in this new role and sincere thanks to Kay who will continue on the PHSS Management team.

A special thank you to Andrew Hopkins, Senior MHRA GMP Inspector, and his colleagues at the MHRA for the continued support of the PHSS.

Thank you to our partners in collaboration, PDA, R3 Nordic, A3P, ISPE and ECA for your contribution to the Annex 1 revision discussion panel.


Annex 1 revision Discussion panel

4

PHSS Moderator: Kay O’Hagan: Senior Qualified person, Hospira UK.

MHRA, EMA: Andrew Hopkins: Senior GMP MHRA Inspector, Head of EMA Annex 1 revision working group.

PDA Worldwide: Richard M. Johnson, President & CEO, microbiologist.PDA UK Chapter President: Dr Siegfried Schmitt Principal Consultant PAREXEL international

PHSS: Di Morris: GSK Compliance Audit Manager, Compliance Audit Group (CAG), Quality Systems and Compliance. PHSS Management team member.PHSS: James Drinkwater: F Ziel GmbH, Head of Aseptic processing Technologies & GMP compliance. Chairman of PHSS.

ISPE/ ISO: Gordon Farquharson: Chair BSI LBI030, Chair CEN TC243, Convenor ISO TC209 wg1, and member ISPE Sterile and HVAC CoP. Consultant Critical systems.

A3P France: Dr Roland Guinet, Ex AFFSAPS GMP Inspector, WHO GMP auditor, GMP Consultant, University Professor of Microbiology, Head of A3P Annex 1 Interest group.

R3 Nordic: Berit Reinmüller, PhD, Associate Professor in Safety Ventilation, Chalmers University of Technology, Gothenburg, Sweden, R3 Nordic journal editor.

ECA (European Compliance Academy): Dr Jean-Denis Mallet, NNE Pharmaplan, Senior Technology Partner, GMP Expertise, QP, Pharmacist. Head of ECA annex 1 comment working group.


GMP Change and impact

5

GMP Annex’s

have changed

or are

changing;

Annex 1

Product

profiles are

changing: more

biologicals

ISO 14644‐1&2ISO 14698Revisions

GMP Chapters have

changed

The challenge

of change

through

advancement

Targeted delivery systems &

improved efficacy

Improved efficiencies, cost

reductions and competitiveness

New

Technologies

and practice

IMPACT


6

Risk based initiatives –

science based processes

Impact of GMP regulation + ISO Standard revisions

EU GMP

ANNEX 1,

15, 16 Revisions

EU GMP

Orange Guide

Chapter

changes; 3, 5, 8

ISO 14644‐1&2ISO 14698Revisions

Control Strategy for

sterile’s manufactureHolistic EM, Trend

metrics, no averagingMeasurements:

5 Micron & UDF

Process Simulation;

Alternative media Position of final

sterilising filter RMM – Real time

micro cfu vs bio‐counts


PHSS Bio‐contamination monograph 20

7

Bio-contamination monograph now published in hard copy and e-book.

The monograph e-copies are free downloads to PHSS members.

R3 Nordic-PHSS Bio-contamination workshop event in Denmark 29 October.

The PHSS are now publishing more on-line GMP regulation change impact statements to support members.

The Risk Management of Contamination (RMC) guidance is under review for update and publication as a PHSS monograph.


8

New PHSS guidance:

Worked examples of Risk assessments for EM sample location selection and risk based EM

sampling plan/programs.

Risk based Environmental Contamination Control to follow.

PHSS Bio-contamination Special Interest Group (SIG)


9

Andrew Hopkins, MHRA/ Head of EMA Annex 1 revision group.

Ian Symonds, GSK head of Global Aseptic manufacturing Quality – GSK Barnard Castle UK.

Mike Davies, GSK Global quality auditor, GSK Worthing UK QA Director.

Di Morris, Ex‐MHRA, GSK Compliance auditor manager. PHSS management team member.

Una Hearty, Pfizer Grange Castle, Global Quality.

Benoit Ramond, Sanofi France Global Quality, Microbiology

Tim Eaton, Astra Zeneca, Macclesfield, Sterile product manufacturing specialist.

Alan Dillon, Allergan Westport Ireland Filling line project manager.

Seamus Lyons, Amgen Ireland Aseptic processing QA

Tim Sandle, Bio Products Ltd (BPL) Head of microbiology.

Tim Triggs, DOP systems Director, PHSS management team member.

Tim Russel, TSI (RMM) field developer.

David Jones, Rapid Micro Bio‐systems, Director.

John Wallingford, Pharmagraph (EMS systems) Managing Director.

Steven Robbins, NHS (National health service) Blood transfusion service.

Carl McDonald, NHSBT, Head of bacteriology.

Adam Bird, Oxford Biomedica (Biotech), Head of QA.

Tim Sizer, HNS Regional Quality Pharmacist.

Mark Oldcorne, All of Wales Quality Pharmacist.

Adulmajeed Raji, Porton Biopharma, Microbiologist

Patrick Nieuwenhuizen, Genzyme Ireland Manager Quality Control Microbiology

Corinna Maier, F Ziel GmbH Aseptic processing technologies microbiologist.

Jenni Tranter, Business development manager Synergy Health

Kay O’Hagan, Hospira Quality auditor/ QP.

Wenzel Novak, Groninger GmbH Director of research and development

Michael Pratz Head of Bausch & Stroebel Compliance/ training academy

Johannes Rauschnabel GMBH Bosch packaging GMP expert.

Marc Van Laere Mithra Belgium QA Manager,


10

PHSS – QP Discussion Forum Brecon, Wales

Next meeting 29 October 2015

PHSS QP Forum meeting 2015

QP presentations, Regulatory updates, compliance scenario discussions


James DrinkwaterChairman of PHSS – Pharmaceutical & Healthcare

Sciences Society

F Ziel GmbH Head of Aseptic processing technologies

& GMP compliance.

11

Sterile Medicinal & Therapeutic product manufacturing, filling, packaging &

pharmacy dispensing to GMP

First quarter 2016 ‐

TBA

Next Major PHSS Conference 2016


12

Annex 1 Discussion panel

QUESTIONS

PHSS QP UCL Annual Conference


Introductions to Discussion panel

13

PHSS Moderator: Kay O’Hagan: Senior Qualified person, Hospira UK.

MHRA, EMA: Andrew Hopkins: Senior GMP MHRA Inspector, Head of EMA Annex 1 revision working group.

PDA Worldwide: Richard M. Johnson, President & CEO, microbiologist.PDA UK Chapter President: Dr Siegfried Schmitt Principal Consultant PAREXEL international

PHSS: Di Morris: GSK Compliance Audit Manager, Compliance Audit Group (CAG), Quality Systems and Compliance. PHSS Management team member.PHSS: James Drinkwater: F Ziel GmbH, Head of Aseptic processing Technologies & GMP compliance. Chairman of PHSS.

ISPE/ ISO: Gordon Farquharson: Chair BSI LBI030, Chair CEN TC243, Convenor ISO TC209 wg1, and member ISPE Sterile and HVAC CoP. Consultant Critical Systems.

A3P France: Dr Roland Guinet, Ex AFFSAPS GMP Inspector, WHO GMP auditor, GMP Consultant, University Professor of Microbiology, Head of A3P Annex 1 Interest group.

R3 Nordic: Berit Reinmüller, PhD, Associate Professor in Safety Ventilation, Chalmers University of Technology, Gothenburg, Sweden, R3 Nordic journal editor.

ECA (European Compliance Academy): Dr Jean-Denis Mallet, NNE Pharmaplan, Senior Technology Partner, GMP Expertise, QP, Pharmacist. Head of ECA annex 1 comment working group.


Annex 1 revision Discussion panel Questions

14

General Concept/ Principles questions

Question 1

The Annex 1 revision concept paper considered the revision may cover Sterile and Non-Sterile product manufacturing.

How does the panel think guidance can be differentiated?



15


Question 2

The PHSS Bio-contamination special interest group prepared a White paper on Control strategy for manufacture of sterile products and drug substances.

Does the panel believe the requirements for a Control strategy for Sterile products should be included in the Annex 1 revision?



16


Question 3

Considering data trends are a key performance indicators what trend metrics would the panel consider should be covered in Annex 1 revision?



17


Question 4

Should Annex 1 include more detailed guidance on Aseptic processing with the increase of aseptic processing used in manufacture of biological products that cannot be terminally sterilised?

Considering the FDA guidance to Industry provides specific guidance on Aseptic processing and currently there are just a few paragraphs in Annex 1 on Aseptic preparations.



18


Question 5

Concerning the various non-injectable sterile pharmaceutical dosage forms, does the panel consider Annex 1 revision should contain more precise details or dedicated paragraphs?



19

Question 6 - specifics

Often firms/ end users implement minimum requirements for environmental control, followed by inadequate design layout. Should Annex 1 reinforce the risk based approach over minimum requirements or replace minimum requirements with more specifics?

For example; different processes and barrier technology combinations require different background environments.

Should Annex 1 define when a Grade D (the current minimum) is not considered a suitable background when using Isolator barrier technology in ‘Open system’ Aseptic processing/ manufacturing as defined in the PHSS Bio-contamination monograph 20?



20


New technologies including Rapid Micro Methods (RMM) are to be considered in the revision of Annex 1. How can conventional microbiological ‘Not to exceed’ CFU levels detailed in Annex 1 be reconciled with fluorescent based Bio-count levels for GMP compliance?

PHSS comment: It is unlikely there will be widespread adoption of RMM-RT (Real time) methods in Grade A filling zones where environmental data is considered in Batch records and higher recoveries reported as ‘Bio-counts’ will be difficult data to manage without an Annex 1 reference or guidance on correlation with CFUs.



21

Question 8 – specifics

In an aseptic processing area what is the expectation for grade A continuity for product contacting parts, components and their primary packaging that are sterilised out of place and then subsequently transferred for aseptic assembly.

Is there an expectation that this can be provided by double wrapping parts or is the use of UDF grade A supply transfer carts recommended?



22


Is it expected to review in detail the way Annex 1 is written for years to prevent misinterpretation of some statements?

An example is the following: current paragraph 50 contains a sentence that states:

“Sinks and drains should be prohibited in grade A/B areas used for aseptic manufacture”.

Interpreting this statement a company (or several companies?) considered that it was acceptable to install a Grade B washing room that was not an aseptic manufacturing area but adjacent to a filling suite with direct operator access, therefore, the washing room was constructed with a drain and operators go in and out the washing room and the filling room during production operations?



23


With the increased complexity and diversity of aseptic formulations, the classic use of nutrient media to replace the formulation for process simulation trials (PSTs) is not always feasible, or scientifically justifiable.

Alternative approaches based on risk assessment and scientific rationale could be regarded as equivalent to ensure an acceptable level of aseptic assurance. Is this approach consistent with the intent of the revised Annex 1 document?



24


Concerning the MAL (Material Airlocks) can it be considered that a “two door” MAL would be sufficient from Grade D to Grade B material transfers providing it is separated with a “line” in the middle and provided the D operators will never cross that line and additionally the B operators will also not cross the same line from the other side?



25


When using gamma irradiated single use systems with integrated point of fill filtration is pre use integrity testing appropriate for this set up?



26


When factoring a facility upgrade, in terms of dispensary operations is there a regulatory move for these to be carried out as a minimum within a Grade C environment?



27

Thank you

The Q&A will be documented and published on the PHSS Website for download

and

shared with our collaboration partnersfor sharing with their association members.

The PHSS will follow the progress of Annex 1 revision to remain engaged with this important development and

advancement


Revision of Annex 1 Manufacture of sterile medicinal products – a GMP inspector’s point of view.


Annex 1

Scope•History and Background•Process of revision•Current Status•Why update•Summary


Annex 1

History and Background•The original version was revised in 1996, 2003, 2005, 2007 and 2009 however there has not been a complete review of the document since it was originally issued• Since the original issuance and the revisions there have been changes in technologies and significant changes in GMP consequent to the adoption of the ICH Q9 and Q10 guidelines.


Annex 1

History and Background•In 2012 The German Authorities (ZLG) issued a concept statement to the EMA’s IWG proposing revision of the Annex and a subsequent request was made to PIC/S for support in updating•2014 PIC/S Working group was set up and started work in August.•September 2014 a draft concept paper was re- issued to IWG (by the MHRA) supporting the update.


Annex 1

Process of revision•Combined working group (PIC/S and EMA) with a task of assessing the requirements of revision:

– Update of Question and answer document– Revision of the Annex– Complete re-write


Annex 1

Process of revision•Combined working group with a task of assessing the requirements of revision:

– Understand Industry concerns– Understand Regulatory concerns


Annex 1

Process of revision•Draft Concept paper proposed at EMA IWG September 2014•Following regulatory comments and PIC/S input issued for public consultation on 5th February 2015•Deadline for comments was 31st March 2015


Annex 1

Current Status•Joint working group agreed a new structure•Joint working group commenced work on revision process of content.•Sub groups concentrating on specific areas•Proposing new timelines


Annex 1

Why update •New Issues

– QRM– Monograph on WFI– Biofilm


Annex 1

Why update - General opinions•Better clarification

– EM how often (especially lower grade areas)– What does “Grade A Air supply” mean


Annex 1

Why update - General opinions•Ambiguities?

– Microbiological limits “these are average values”– Freeze Drying Para 34 (Grade A or in sealed

trays under B) conflicts with para 116 (A at all times


Annex 1

Why update - General opinionsGeneral points for discussion•ISO 14644 5.0µm or not?•Closed systems •Small batch product such as ATMPS•Facility

– Isolators?– RABS ?


Annex 1

Why update - General opinionsGeneral points for discussion

•Filter integrity testing pre use post sterilisation•Scope – Also applicable to Non sterile manufacturing?•Bioburden sampling


14

Annex 1

Why update - my opinion(what is the target audience?)


Annex 1

Why update My opinions•People still don’t understand so need more guidance•QRM ?


Annex 1

Why update •Losing technical skill level•New and emerging countries where the knowledge has not yet evolved (learning by deficiencies)•New and emerging technologies•Areas not covered

– Media fills, small batches, APIs Campaigns?– New BFS technology– Closed systems


17

Annex 1

Why update - my opinion(technical knowledge)


18

Annex 1

Why update - my opinion(process design)


Annex 1

Why update - My opinions


Annex 1

Summary• There are lots of reasons why Annex 1 needs

updating • It is happening• It is a shared project between PICS and EMA


Annex 1

Thank you for Listening

Any Questions?

[email protected]


23

Copyright

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The MHRA authorises you to make one free copy, by downloading to printer or to electronic, magnetic or optical storage media, of these presentations for the purposes of private research, study and reference. Any other copy or use of Crown copyright materials featured on this site, in any form or medium is subject to the prior approval of the MHRA.

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PHSS Annual Conference 2015 – Annex 1 Discussion panel

Final version 8 September 2015

MHRA, EMA: Andrew Hopkins: Senior GMP Inspector Medicines and Healthcare products Regulatory Agency (MHRA), Head of EMA Annex 1 revision working group.

PDA Worldwide: Richard M. Johnson, President & CEO

PDA UK Chapter: Dr Siegfried Schmitt Principal Consultant PAREXEL International

PHSS: Di Morris: GSK Audit Manager, Compliance Audit Group (CAG), Quality Systems and Compliance. PHSS Management team member.

PHSS: James Drinkwater: F Ziel GmbH, Head of Aseptic processing Technologies & GMP compliance. Chairman of PHSS.

ISPE/ ISO: Gordon Farquharson: Chair BSI LBI030, Chair CEN TC243, Convenor ISO TC209 wg1, and member ISPE Sterile and HVAC CoP.

A3P France: Dr Roland Guinet, Ex AFFSAPS GMP Inspector, GMP Consultant.

R3 Nordic: Berit Reinmüller, PhD, Assoc Professor in Safety Ventilation, Chalmers University of Technology, R3 Nordic journal editor. ECA (European Compliance Academy): Dr Jean-Denis Mallet, Senior Technology Partner, GMP Expertise, QP, Pharmacist. Head of ECA annex 1 comment working group.


1

PHSS Annual Members Conference 2015

Di Morris

Data Integrity


Data Integrity

• Are concerns over data integrity something new?– No

• Is it just an issue for Quality Control– No its all departments in a company

• Is it happening more– No, we are more aware

• Is it always intentional acts– Not always; a lot are due bad GMP practices

2


Definitions – Data Integrity

3


Data Integrity

• It is all in the GMPs for EU, USA and WHO– Chapter 4– Annex 11– 21CFR211 and Part 11

• Examples– Records include the raw data which is used to generate other records. For

electronic records regulated users should define which data are to be used as

raw data. (Eudralex Vol 4 Ch 4)

– Based on the complexity and reliability of computer systems there must be

procedural controls and technologies to ensure the accuracy and security of

computer systems, electronic records and data. Computer systems

must have

adequate controls to prevent unauthorized access or changes to data,

inadvertent erasures, or loss.(21CFR Part 211.68)

4



The Quality, Safety and Efficacy

of the medicines we make is

assured by applying the regulations and best practice

If we don’t......

Would you be happy taking those medicines

5



• ALCOA– Attributable– Legible/Permanent

– Contemporaneous

– Original– Accurate

• ALCOA+– Complete

– Consistent– Enduring– Available

Ref MHRA Symposium Dec 2014 and has been used by FDA for many years

This applies to both Paper

and Electronic Systems

The following are examples 6


Data Integrity ‐

Attributable

Paper Record

• Initials• Hand written signature

They have to be equivalent.

Electronic Record

• Log‐on User identification

• Electronic signature

7

Traceable to a UNIQUE person

You should be able to tell who created, modified, or deleted a record. AND, you can judge if that person was appropriately authorized to do it!


Data Integrity ‐

Legible

Paper Record• Legible

• No Pencil

• No Correction Fluid

• Permanent Ink

• Correct Amendment of an Error

• Appropriate Archival

Electronic Record• No data annotation tools enabled

• No Over Writing

• No Deletions

• No Hidden Fields

• Changes captured in Audit Trail

• Back‐up and Archive

• Enforced Saving

8

Readable, Traceable Changes, Permanent

You should be able to read all the entries on the paper record. If a change was made, the original value was crossed out with a single line, and the change was dated and initialled.You should be able to see in an electronic files data changes and deletions. Is it clear what the original value was? When it was created and who created it?


Data Integrity ‐

Contemporaneous

Paper Record• No back‐

dating

• No pre‐completion of a record

• Record the date (and time) of the

activity

Electronic Record• Records saved immediately the

data is entered

• Synchronised clocks

• Locked date and time stamps

9

For a paper record the creation, modification, and deletion of data happens at the right time in the process.For an electronic record when it was created in a process, the audit trail should confirm that.

Record the activity at the time it occurred


Data Integrity ‐

Original

Paper Record

• Original Document –

Manufacturing record;

laboratory record;

Electronic Record

• Original electronic file

including metadata – a UV

spectra, FTIR spectra

10

The first record made by the appropriate person

if not original should be exact copy - Original records and true copies must preserve the integrity (accuracy, completeness, content and meaning) of the record. Exact (true) copies of original records may be retained in place of the original record (e.g. scan of a paper record), provided that a documented system is in place to verify and record the integrity of the copy. You must be able to reconstruct the activity from the data


Data Integrity – Certified Copy

• A certified copy is:– Verified by a second person– Compares the copy to the original

– Confirms the copy is accurate and complete

– Documents the verification

– Stamped a ‘true copy’

• What is not a certified copy– A pdf or printout – these are flat files of for example

• A FTIR spectra• A HPLC chromatogram

– They do not preserve the content and meaning

11


Data Integrity ‐

Accurate

• Accurate, consistent and real representation of facts.

• No editing without documented amendments /audit trail

entries by authorised personnel– Make sure of the information that you are recording is correct,

honest and transparent

– Record the data directly into the controlled unique blank record/bound book/electronic programme

– Where possible use automatic data capture

– Are the electronic record the same as the paper record

12


Data Integrity – ALCOA+

• Complete– All data from an analysis, from the start of analysis to the end

and any

repeated or reanalysis performed on the sample.

– For electronic systems, the paper output must be linked to the

underlying electronic records used to produce it.

• Consistent– All elements of the analysis, such as the sequence of events, follow on

and data files are date (all processes) and time (when using electronic

systems) stamped in the expected order

• Enduring– Recorded on authorised media e.g. laboratory notebooks, numbered

worksheets, for which there is accountability or electronic media

• Available– The complete collection of records can be accessed or retrieved for

review over the lifetime of the record.13


Data Integrity – Data Governance

14

• MHRA Definition:• The sum total of arrangements to ensure that data, irrespective of the format

in which it is generated, is recorded, processed, retained and used to ensure a

complete, consistent and accurate record throughout the data lifecycle.

– It should be integral part of the Pharmaceutical Quality System

– There should be clear Management Responsibilities

IT should be part of Management Reviews/Quality Councils

Everyone should be trained to understand the terms and implications of IT

systems

—

There should be data owners such as process owners in computer

systems

—

There has to be data integrity training

—

There has to be procedures and processes in place

—

Create a blame free, open and transparent culture


Data Integrity – Data Definitions

Record Observation Hybrid Electronic

Raw Data

Written record

Electronic files of the

analysis

Electronic files of the

analysis

Metadata

Further written data about

the sample and analysis e.g.

batch, test, analyst, date,

etc.

Electronic Files for control

of the instrument, data

acquisition, interpretation

and reporting of data.

Identification of who tested

the sample, etc.

Audit trail entries of data

changes



batch, test, etc.

Electronic Files for control

of the instrument, data

acquisition, interpretation

and reporting of data.

Identification of who tested

the sample, etc.

Audit trail entries of data

changes



batch, test, etc.

Review

Reportable result

Handwritten signatures of

tester and reviewer

Printout of reportable result

Handwritten signatures of

tester and reviewer

Linkage to underlying

instrument raw data and

spreadsheet file

Reportable Result

Electronic signatures of

tester and reviewer

Linkage to all data and

metadata via application

database

15


Data Integrity ‐

Impact

16

• Access to raw data for staff performing data checking

activities (MHRA)

– This is similar to the FDA GMP requirement for complete

data and for the second person review to see all data

generated in the course of an analysis.

– This means a review of the source data eg electronic HPLC

data

What about QPs certifying for release batches not made on site?


Data Integrity

• The MHRA guidance (v1.0) stated that organizations are “not

expected to implement a forensic approach to data checking,

….”.

However the revised version now reads “not expected to

implement a forensic approach to data checking on a routine

basis, ….”

• QPs must ensure systems, procedures, training, culture and

management responsibilities for data integrity are clearly in

place and they have time to do this on all their suppliers to be

able to certify batches

17


Data Integrity ‐

Consequences

• So what does this mean:– What happens when data integrity is breached? The worst

case scenario is impact on patient safety and the loss of lives.

– the recent New England Compounding Pharmacy incident

in the United States can be used as an example of the

consequences of fraudulent activity. Here, 64 patients

died and over 750 were sickened from fungal meningitis as

a result of sterility negligence and data integrity issues. In

this case, a FDA official said pharmacy technicians were

instructed to lie on cleaning logs, showing rooms as being

properly cleaned when they had not been

18


Data Integrity ‐

Consequences

– we have to embed ALCOA+ principles into our ways of working

across the WHOLE

of the business –

Development to

commercial manufacturing

– Data generated in development impacts the Quality attributes

in commercial manufacture – the data has to be trusted

to be

complete and accurate

– Stability data supports product in the market any data integrity

concerns impact the product and may result in recall

– Data Integrity issues can result in loss licence, recalls, loss of jobs and patients not having their medicines

19


Data Integrity – Recent Issues

• pH meters and balance printers:– Date and time not locked

– Evidence of data being changed and reprinted– Undated records found in a bin

• Batch record had pre‐populated sections

• Validation protocol had typed in results that had been signed

and dated ‘on the day of the test’

• Reprints of worksheets not tracked and reconciled

20


Data Integrity – Recent Issues

• Failure to record activities at the time they are performed and

destruction of original records

• Batch records were completed after the operations had

ended

• Failed to maintain original manufacturing data for critical

steps – had uncontrolled loose paper, unbound, rough notes,

transcribed and then originals destroyed

• Back dated batch records

• Laboratory equipment lacked controls to prevent raw data

from being deleted or altered.

21


Data Integrity ‐

HPLCs

How do the

Part 11 regulations and "predicate rule requirements" (in 21 CFR

Part 211)

apply to the electronic records created by computerized

laboratory systems

and the

associated printed chromatograms that are used in drug manufacturing and testing?Some in industry misinterpret the following text from “The Guidance for Industry – Part 11,

Electronic Records; Electronic Signatures – Scope and Application”

(Part 11 Guidance; lines 164

to 171) to mean that in all cases paper printouts of electronic records satisfy predicate rule

requirements in 21 CFR Part 211.The printed paper copy of the chromatogram would not be considered a “true copy”

of the entire electronic raw data used to create that chromatogram, as required by 21

CFR 211.180(d). The printed chromatogram would also not be considered an “exact

and complete”

copy of the electronic raw data used to create the chromatogram, as

required by 21 CFR 211.68. The chromatogram does not generally include, for

example, the injection sequence, instrument method, integration method, or the

audit trail, of which all were used to create the chromatogram or are associated with

its validity. Therefore, the printed chromatograms used in drug manufacturing and

testing do not satisfy the predicate rule requirements in 21 CFR

Part 211. The

electronic records created by the computerized laboratory systems must be

maintained under these requirements.

Date: 8/3/2010 22


Data Integrity ‐

HPLCs

Why do HPLCs attract so much attention?

•Because we don’t use them as they are meant to be used

•We treat them as we did with ‘integrators’

•We should not be running unintegrated chromatograms and

then putting in the processing parameters

•We should be:– Second person checking the sample sequence then locking it

– We should be locking the method and ALL processing parameters

– We should be using the system to generate the data at time of

analysis

– We should be giving sufficient time for the column to equilibrate and

not use ‘trial’

injections

•We should not be manually manipulating certain

chromatograms (assay, dissolution) 23


Data Integrity ‐

Issues

• The computer system access rights

– The system administrator worked in the laboratory

– The administrator must be independent of the department

– The independent department must have appropriate

procedures and controls

– The analyst/operator had the access to modify the

method/recipe

– How to modify was clearly documented in the equipment use

procedure

– Only the administrators procedures should have that level of

detail

24


Data Integrity ‐

Issues

• The HPLC system did not have proper controls in place to prevent

unauthorised manipulation of the laboratories raw electronic data.

• The HPLC systems did not have access controls to prevent

alteration or deletion of data

• The HPLC software lacked an audit trail recording any changes to

the data, including previous entries, who made changes and when

the changes were made

• The laboratory and manufacturing personnel shared common log‐

ins and passwords to access the system

• The Quality Unit was unable to retrieve the original raw electronic

data because the back‐up discs were unreadable/over written

25


Data Integrity ‐

Conclusion

• The message for data integrity is clear.

• It’s not a new concept; it’s about getting back to the roots of training all

staff on the importance of data integrity in cGMP documentation and

honesty.

• It is critical to ensure employees understand the accountability

and

traceability requirements for retention of raw data and the consequences

of data manipulation.

• Training operators and analysts to document the performance of a task by

recording what happened at the time it occurs, including information

about the person who performed it along with clearly documenting

and

investigating deviations, is vital for patient safety and product efficacy.

• This is achievable by providing the training and creating a company

culture that promotes and rewards ethical behaviour as a core value from

top to bottom of an organization.

26


Data Integrity

Thank you

27


Changes in EU GMP / MHRA Orange Guide chapters 3, 5, 8 and annex 15

1Malcolm Holmes ‐

PHSS 2015 members

conference


Chapter 3:

Premises and

Equipment

Chapter 5:

Production

Chapter 8:

Complaints,

Quality Defects

and Product

Recalls

Annex 15:

Qualification and

Validation

2Malcolm Holmes ‐

PHSS 2015 members

conference


Changes Chapters 3 & 5

Chapter 3 Chapter 5

Malcolm Holmes ‐

PHSS 2015 members

conference3

With transitional arrangement for toxicological evaluation


Additional Changes Ch 5

Malcolm Holmes ‐

PHSS 2015 members

conference4

Section


Background Need For Dedicated Facilities

5Malcolm Holmes ‐

PHSS 2015 members

conference


Why

6Malcolm Holmes ‐

PHSS 2015 members

conference


Potential Impact

7Malcolm Holmes ‐

PHSS 2015 members

conference


Dedicated Facilities

Regulator positioning ?

• Its a highly potent product

of a type which would

previously have been

manufactured in dedicated

facilities. Therefore that

would appear to be a good

starting point.

Manufacturer positioning ?

• Its a highly potent product

of a type which would

previously have been

manufactured in dedicated

facilities. I want you

“techies”

to find me a way

to safely manufacture it in

shared facilities.

Malcolm Holmes ‐

PHSS 2015 members

conference8

All parties must be very careful not to manipulate their risk

management decisions to facilitate their pre‐determined

desired outcome


CH 5 – Reporting Product Shortage Due To Manufacturing Constraints

Malcolm Holmes ‐

PHSS 2015 members

conference9


Ch 5 Testing Of Starting Materials

Malcolm Holmes ‐

PHSS 2015 members

conference10


Ch 5 Rationale For Outsourcing Of Testing

Malcolm Holmes ‐

PHSS 2015 members

conference11


Ch 8 ‐

Complaints, Quality Defects and Product Recalls

Malcolm Holmes ‐

PHSS 2015 members

conference12


Annex 15: Qualification And Validation

Malcolm Holmes ‐

PHSS 2015 members

conference13


Annex 15: Some Significant Changes

Malcolm Holmes ‐

PHSS 2015 members

conference14


Validation – A State Of Mind

15Malcolm Holmes ‐

PHSS 2015 members

conference


Summary

Basics

• In general more detail is

given. New versions

substantially longer than

previous versions

• All based on significant

modernisation of GMP

thinking ‐

ICH Q8, Q9 &

Q10 – Particularly ICH Q9

(Quality Risk Management)

Remember ICH Q9 key principles

Malcolm Holmes ‐

PHSS 2015 members

conference16


Culture

Kim Sandell ‐

Pfizer

17Malcolm Holmes ‐

PHSS 2015 members

conference


Communication MHRA & Industry

Malcolm Holmes ‐

PHSS 2015 members

conference18

Over last 12 months or so MHRA through

its Innovation Office has published

convincing summaries of how it has been

able to help Industry make appropriate

choices in design of facility/ process /

product.

This is good risk management by both

MHRA and Industry which leads to better

patient safety.


Workshop

Malcolm Holmes ‐

PHSS 2015 members

conference19


1

PHSS Annual Members Conference in association with UCL Q3P 2015

Richard Funnell

FunnellPharma

ConsultantsLtd

Annex 16:What is changing?

What are the implications?When is it going to happen?


Annex 16: Introduction

•

Work on revision started 4 years ago!

•

Still not issued.

•

Most recent public draft has moved on.

•

Annex 16 rebuilt and designed to:

–

Reflect increasing supply chain complexity.

–

Include new legislation.–

IMP legislation

–

Falsified Medicines Directive

–

2009 reflection paper on unexpected deviations

–

Increase consistency across the EEA.2


Annex 16: Introduction

•

We will:

–

Pick out eleven key points.

–

Examine the controversial areas.

–

See what the practical implications may be.

–

Have some discussion.

3


Access to MA

• 3.3. “…

it is expected that the QP has access to the necessary details of the MA…”

Hopefully obvious but now formal. Should help

the QP.

4


Shared responsibility

• 3.3. “…responsibility may be shared with other QPs who have confirmed compliance of specified steps in

the manufacture and control of a batch…”

Reflects increased manufacturing across different companies.

Previously implicit?

Legal implications?

5


“Virtual”

importers

• 3.4.2. “Importation activities including at least receiving, sampling, storage of the unreleased and

uncertified batch, QC testing, certification and release should be conducted by authorised sites…”

What does “authorised”

mean?

UK currently allows physical receipt at WDA holder (with conditions).

CONTROVERSIAL.

Still not agreed!

6


Imported batches –

location of sampling

• 3.4.6. “Samples of imported product should in full be representative of the batch and therefore, be taken

after arrival in the EEA...”

REMAINS CONTROVERSIAL

A 50/50 split across member states:– 50% accept samples being taken at manufacturing site

– 50% require at least some samples to be taken after arrival in EU.

7


Location of sampling continued

• A further iteration allowed reliance on samples taken at manufacturing sites but with certain conditions. For

example:• Need a formal risk assessment and study to justify samples

representative (e.g. comparative analysis of samples taken in

both places).

• Review time between sampling and eventual shipment to EU.

• “Random periodic analysis of samples taken after importation...”

Reflects industry desire?

8


Location of sampling continued

• 3.4.8. Covers further importation of the same bulk batch.

– Subsequent imported amounts should be subject to ID and assay

within EU.

– Storage and transportation “similar”

on each occasion.

– Samples originally tested should be representative of all

subsequent

batches.

ALSO REMAINS CONTROVERSIAL – PUSH TO RETAIN STATUS QUO

9


Allowable QP delegation:

• 3.5. onwards ‐

a short list of what QP must do personally.

• 3.5.4. onwards ‐

a longer list of what QP is responsible for but may delegate.

Clarifies and reflects QP codes of practice (a UK document).

10


API responsibilities

• 3.5.5. and 3.5.9. State QP must have supply chain knowledge and responsibility for API GMP and GDP.

– QP should have a documented supply chain available

– QP needs to ensure API manufactured and sourced according to GMP

and GDP.

Now well entrenched. Reflect Falsified Medicines Directive

11


Parallel importing

• 3.7. A new section on parallel importation and distribution.

– QP should confirm compliance with national requirements and EU

rules on this.

– “The re‐packager should ensure that product …has been obtained

from the authorised supply chain.”

– “Re‐packager must ensure authenticity by verifying safety features

where applicable.”

Much more common than when original Annex

16 was published.

12


Control reports

• 3.8.2. “The control report … or another proof of certification should be made available … for the batch to be exempted from controls when entering

another member state…”

This is an existing legislative requirement.

Therefore difficult to ignore!

Not widely adhered to?

13


Audits by third parties:

• Section 4 “Relying on GMP assessments by third parties e.g. audits.”

• Six sub‐points. Quite a bit of detail……..

14


Unexpected deviations:

• Section 5: Principle of 2009 reflection paper in Orange Guide but stripped right down.

– API, excipient and FP registered specs no room for manoeuvre–

need

a batch specific variation (in UK).

– The impact of the deviation should be assessed under a quality risk

management process such as described in Part III.

– Evaluate impact on safety, quality and efficacy.

– Consider putting on stability.

15


Shipment under quarantine:

• 6.1. “Until a batch is released it should remain at the site of manufacture or be shipped under quarantine

to another authorised site.”

“Authorised”?

Some member states allow shipment under quarantine to a WDA holder.

Others would only allow shipment to an MIA holder.

ALSO CONTROVERSIAL

16


The future:

• Final wording still not agreed.• Don’t know when final version will be issued.• Two areas in particular may change.

• Annex 21.

17


1

PHSS Annual Members Conference in association with UCL Q3P

News from ISO TC209By Gordon Farquharson

Chair BSI LBI/030; Chair CEN TC243;

Convenor ISO TC209 WG1

September 2015

September 2015 © 2015

2

Revision of BS/EN/ISO 14644-1 & 2

By Gordon Farquharson

Chair BSI LBI/030; Chair CEN TC243;

Convenor ISO TC209 WG1

September 2015



Agenda Review of all the standards in the ISO 14644 family Background to why a revision of part 1 & 2 was required. The status of current ISO 14644-1 & 2. The challenge of improving ISO 14644-1:1999 Timeline for the new standards. ISO 14644-1

New – classification by table. New – number of sample locations. Update to sequential sampling procedure. Handling Ultrafine particles – now in Nano-particle monitoring standard. Keeping the concepts of Macro-particles Test methods update.

Revision of ISO 14644-2 Change to a standard for monitoring only. The monitoring plan. Guidance about critical parameter monitoring.

September 2015 © 2015 3

Quick overview of all the ISO ‘Cleanroom’ Standards

© 2015 4September 2015


Review of all the standards [1]

September 2015 © 2015 5

Review of all the standards [2] 14644-9 – Surface cleanliness classification by particles. (current)

14644-10 – Surface cleanliness classification by chemicals. (current)

14644-12 – Air cleanliness monitoring by nano-particles DIS 1st Qtr 2014 – approved. Being revised for a 2nd DIS as a monitoring

standard. 14644-13 - Cleaning of surfaces

New work in progress – UK has consistently voted against this work.

14644-14 & 15 – Equipment suitability New work recently started. Part 14 DIS passed vote.

14644-16 – Energy considerations New work started 2015, based on BS 8568:2013; Cleanroom energy. Code of

practice for improving energy efficiency in cleanrooms and clean air devices.

14698-1 & 2 – Bio-contamination The 14698 standards are still in place. New standard in ISO TC209 WG2, work stopped– Air and surface cleanliness

by viables. Work taken up by CEN TC243

September 2015 © 2015 6


ISO TC209 confirms the essential attribute of a cleanroom “Air cleanliness by particle number concentration”

There has been some confusion !!ISO TC209 standards we have several different cleanliness attributes:

Airborne & surface particles

Airborne & surface chemicals

Airborne & surface micro

Question - Should we be able to designate (classify) a cleanroom by any one of the cleanliness attributes?

In October 2014, ISO TC209 clarified the position

A “cleanroom” must be characterised by air cleanliness class by particles. If other attributes are important for a particular industry or process/product, then we can monitor for these in addition.


Revision of ISO 14644-1 & 2



Background to the revisions


Why where the revisions to ISO 14644-1:1999 needed?

At the systematic review Vote, P-nations decided they wanted to improve standard.

Reconsider the statistical model– consider removing the need to evaluate the 95% UCL for 2-9 test locations.

When the work started, experts found problems with the existing statistical methods.

There has been 3 years debate over the statistical confidence of finding non-compliant locations when classifying a cleanroom or clean-zone.

September 2015 10© 2015


Why where the revisions to ISO 14644-2:2000 needed?

September 2015 11© 2015

Status of ISO 14644-1 & 2

© 2015 12September 2015


13

Very important !!!!!

Status of ISO 14644-1 & 2The information here is for information only.

Not to be used for classification or monitoring of cleanrooms.

EN/ISO 14644-1:1999 & 14644-2:2000 remain the applicable standard for classification by airborne particles !!!!! No change until replaced by the new standards.

September 2015© 2015

Revision timeline

© 2015 14September 2015


ISO TC209 WG1 Timeline (10 years + in the making!) Target publication December 2015

FDIS enquiry vote August 2015 2nd DIS enquiry PASSED vote in November 2014 1st DIS enquiry vote December 2010 CD vote out October 2009 (This stage delayed due to

challenging discussions) NWIP = WD 2 = CD complete Sept 06 4th WG 1 meeting Beijing 6-8 September 06. 3rd WG 1 meeting June 06 Sweden (SIS Stockholm)

Start 12th Nov 2005September 2015 © 2015 15

ISO 14644-1 revisions

© 2015 16September 2015


The basis for classification

Change fromClassification by Formula (+ table to illustrate)TOClassification by Table+ Formula for Intermediate Sizes

Keep decimal classes; but now just 0.5 steps (1.5; 2.5; etc)

Remove ≥ 5.0 micron limit for ISO 5 (29) & ISO 5.5

ISO 14644-1Changes

September 2015 17© 2015

ISO Formula ISO Formula –– retained for intermediate retained for intermediate

particle sizes onlyparticle sizes only

ISO Cn = 0.1 2.08 x 10N(class)

D( )

September 2015 18© 2015

For example ≥ 0.4 micron


The The formula formula

illustrated illustrated by an by an

Informative Informative TableTable

Existing Existing -- EN/ISO 14644EN/ISO 14644--1:19991:1999Classification by Particles Classification by Particles

September 2015 © 2015 19

20

Proposed - ISO 14644-1 Class TableAnnex 1 EU GMP Annex 1 EU GMP ––Outside Class limitsOutside Class limits

Very Low Very Low values deletedvalues deleted

Low values have Low values have sample size warningsample size warning

September 2015© 2015


21

Now closer to OLD US Fed Std 209EClassification by Table (Particles)

No 5.0No 5.0in oldin old

Class 100Class 100September 2015© 2015

Proposed decimal class table

© 2015 22September 2015

Concentration of particles (particles/m3) a

ISO classification number (N) 0,1 0,2 0,3 0,5 1,0 5,0

ISO Class 1,5 [32] b d

d d d e

ISO Class 2,5 316 [75] b [32] bd d e

ISO Class 3,5 3 160 748 322 111d e

ISO Class 4,5 31 600 7 480 3 220 1 110 263e

ISO Class 5,5 316 000 74 800 32 200 11 100 2 630e

ISO Class 6,5 3 160 000 748 000 322 000 111 000 26 300 924

ISO Class 7,5c c c

1 110 000 263 000 9 240

ISO Class 8,5c c c

11 100 000 2 630 000 92 400

Examples of intermediate decimal air cleanliness classes by particle concentration (only 0.5 class steps allowed)


This proposed change is not a major impact on the principle of classification .

Helps prevent poor selection of size vs class.

Means Annex 1 Grade A and B ≥5 clearly outside the ISO Class system! Means we will have to use the Macro-particle descriptor (see later).

Major discussions Good science of particle counting removes ≥ 5 micron limit for ISO5

REMEMBER that the table doesn’t represent typical distribution of particles in a cleanroom.

How to deal with Annex 1 or the EU/PIC/S GMP

ISO 14644-1Impact

September 2015 23© 2015

The proposal is to use adapted macro-particle descriptor concept.

EU & PIC/S Annex Impact

September 2015 24© 2015

Class limit of 20 parts ≥5.0 micron is also

outside scope of the standard

Class limit of 29 parts ≥ 5.0 micron outside scope of

standard –≥ 5.0 micron cannot be used

for an ISO5 classification


Using the macro-particle descriptor for 5 micron particles GMP should use the macro-particle concept for

Grade A 20 particles/m3 @ ≥ 5.0 micronGrade B “at rest” 29 particles/m3 @ ≥ 5.0 micron

We use this terminologyISO M (20;≥ 5.0); LSAPC

© 2015 25September 2015

M =Macroparticles

20 =Class limit from GMP

5.0 =Considered particle size

LSAPC = Light scattering airborne

particle counter

This is how we would define Annex 1 Grade A & B using ISOAn extrapolation of the Macro-particle concept.

Grade AISO 5; at rest, operational; ≥ 0.5

M (20≥ 5.0); at rest, operational; LSAPC

Grade BISO 5; at rest; ≥ 0.5, and M (29≥ 5.0); at rest, LSAPC.

ISO 7; operational; ≥ 0.5, 5.0 .

© 2015 26September 2015


Simplification: The 95% UCL Evaluation for 2-9 locations has been removed.

Each sampling location now evaluated separately. All must complyfor room or zone to comply.

There is a Look-up table, based on ensuring 95 % level of confidence that at least 90 % of the cleanroom or clean zone will comply with the class limit.

Will increase the number of locations up to 1000m2.For > 1000m2, very similar to the current Area rule.

Placement of sample points: Even distribution, at representativelocations In N-UDF cleanrooms with non-diffused airflow, avoid placement directly under HEPA filter supply

air terminals.

ISO 14644-1Changes to sampling statistics

September 2015 27© 2015

This is an important change to the basic mechanics of classification.

Organisations will have to redefine their classification sampling plans & data evaluation.

Does not affect Real-time monitoring.

Discussions How to select the locations – can be randomised or fixed.

You can add locations to deal with Risk-Based requirements.

You re-test same locations after a repair or remediation?

Can now better deal with unusually large cleanrooms > 1000 m2

ISO 14644-1Impact

September 2015 28© 2015


29September 2015

Required minimum sampling locations

1. Determine the number of sample locations NL from table A1.

2. Distribute the sample locations throughout the cleanroom (or clean air device) at representitive locations (not under undiffused HEPA filter terminals).

3. Take sample at each location (as existing standard)

4. If all measured particle concentrations comply with the class limit, the classification is passed.

5. For larger rooms >1000m2, extrapolate the location density from the 1000m2 requirement.

© 2015

Area of cleanroom (m2) less than

or equal to

Minimum number of sample locations

to be tested (NL)2 14 26 38 4

10 524 628 732 836 952 1056 1164 1268 1372 1476 15104 16108 17116 18148 19156 20192 21232 22276 23352 24436 25636 261000 27

> 1000 See Equation A.1

Table A.1 — Sample locations related to cleanroom area

Sample number comparison

To deal with very large cleanrooms,

extrapolate the location density above 1000 m2

September 2015 30© 2015


Sequential sampling retained.

Now Annex D

The specification in existing Annex F is difficult to follow and has improved presentation and explanation.

The clarified specification of sequential sampling would assist its use for classification of clean-zones with low particle concentrations limits.

ISO 14644-1Change Impact

September 2015 31© 2015

Ultrafine Descriptor.

Removed to a new standard (ISO 14644-12) dealing with nano-particle cleanliness monitoring in cleanrooms and associated controlled environments.

No impact on life-sciences industry.

Micro-electronics and nano-technology industries need new standards.


September 2015 32© 2015


Test methods & Instruments

ISO TC 209 has decided that each classification standard needs to have its own test method and test instrument guidance on-board.

Better than in a separate standard.

Makes revision of standards easier to keep coordinated.

Annex F imported from ISO 14644-3 with some updating.

Most important reference is ISO 21501-4:2007.

No direct impact on users.

Makes each standard more complete and easier to use.

ISO 14644-3 will now only deal with the support tests for cleanrooms: Filter leak

Airflow velocity and volume

Pressurisation

ISO 21501-4:2007 describes a calibration and verification method for a light scattering airborne particle counter (LSAPC), which is used to measure the size and particle number concentration of particles suspended in air. The light scattering method described in ISO 21501-4:2007 is based on single particle measurements. The typical size range of particles measured by this method is between 0,1 µm and 10 µm in particle size.


September 2015 33© 2015

Now on to 14644-2 revision Quick summary in the time available

This standard will now just focussed on MONITORING !

The title has changed:

FromEN ISO 14644-2:2000 Cleanrooms and associated controlled environments

Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1

ToEN ISO 14644-2:2015 Cleanrooms and associated controlled environments

Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration

September 2015 34© 2015


Tables of frequency removed; guidance retained in text.

Annual classification required, and after modifications, or after monitoring deviation and rectification.

Annual classification is the default minimum monitoring required, but interval can be extended if automated monitoring system provides satisfactory data.

Monitoring should include: Air cleanliness Pressure differential Airflow velocity in UDF Airflow volume in non-UDF.

This change will make it easier to use RISK BASED decision making about testing frequency.

Means if GMPs need to be specific, they can in the context of the ISO guidance.

e.g. In Pharma sector, US FDA’s 6 monthly leak testing of HEPA filters in the aseptic core.


September 2015 35© 2015

ISO 14644-2 Essential principlesNormative

Proposed to be a simpler standard.

The minimum requirement is to undertake annual classification using ISO 14644-1. Frequency can be extended if a real-time monitoring system is used.

Reinforces that “Demonstration of control by monitoring” requires: A documented monitoring plan.

Undertaking the monitoring.

Acting on the results.

September 2015 36© 2015


ISO 14644-2 Informative Annexes

Guidance providedAirborne particle monitoring systems.

Pressure differential monitoring systems.

Air velocity and volume monitoring systems.

Generally specifies matters to consider when specifying and configuring such systems.

Not prescriptive or limiting.

September 2015 37© 2015

Conclusion

© 2015 38September 2015

I hope you found this update of ISO standards changes useful.

Look out for the new ISO 14644-1& 2 this year. ISO Classes 1-9 will be defined by a table.There will be changes to the details of undertaking

cleanroom classification.The classes don’t change.The existing standards from 1999 and 2000 apply until

they are superseded.


Thanks for your attention Questions?

September 2015 39© 2015

40

This presentation has been preparedand delivered by:-

Gordon J FarquharsonPrincipal

Critical Systems LtdConsulting in Safety & Quality Critical Systems

Guildford, Surrey, GU1 2SY, UKtel +44 (0)1252 703 663

[email protected]


CRI ICAL

SYSTEMS

CRI ICAL

SYSTEMS


1

Filling multiple products in the same facility, considering aseptic processing of non‐hazardous

products, cytotoxic products and biologically hazardous products, including live virus.

James L Drinkwater F Ziel GmbH Head of Aseptic Processing

Technologies & GMP Compliance


Amgen FlexPro50V 0.1 I 07/2015 I © FZ 2

Content

Filling Multiple products in the same facility

1.

Risk based initiatives –

overview of requirements in Aseptic

processing.

2.

Environmental zoning related to type of barrier technology

(Isolator or RABS) used in Aseptic processing & Filling.

3.

Risk based process design/ solutions for processing multiple

products in the same facility.

4.

Risk based Environmental monitoring plan and programs

including considerations in applying RT‐RMM: Real time

Rapid Micro methods for critical processes, including Filling.


3

cGMP Compliance Risk based

Risk management ICH Q9 – GMP Annex 20

Change & Deviation

management

investigations CAPA

Risk control measures

Organizational

Product and Process Knowledge

from Development phases – Tech

transfer

Understanding CQAs, CPPs &

toxicological and pharmacological

product profiles

Risk factors: Human,

Machine, Environment

Process design,

combining science,

equipment & facilities

QbD – Risk based

Risk control

measures Technical

Risk based

Operations Process

instructions/ SOPs &

Training

Overview of Risk based initiatives Distribution rights are property of the PHSS, permission must be obtained for use.

4

Risk based sterile product manufacturing Control Strategy

Product and process

knowledge: basis of

risk assessment and

risk control measures

Organisational control

measures

Sterile medicinal/

therapeutic Products

derived by chemical or

biological synthesis

Technical control

measures


Zonation of classified areas

3

Unclassified Areas / zones

Aseptic core EU Grade A

ISO 5 in operation

EU Grade B in operation

ISO7 in operation

EU Grade C in operation

EU Grade D : at Rest ISO8: In Operation

ISO8 in operation

EU Grade C at Rest

ISO7 in operation

Cleanrooms

RABS

Isolators

*BFS* PCCA

Air Flow &

Pressure

Cascade


7

Unclassified Areas / zones / PCCA

Isolator +veEU Grade A

ISO 5 in operation



ISO8 in operation

EU Grade C at Rest

ISO7 in operation

Cleanrooms with Isolator separation barriers operated at a positive pressure differential to minimum background EU Grade D / ISO 8

Isolators positive pressure operation Aseptic processing Zonation


8

Unclassified Areas / zones / PCCA

RABS EU Grade A

ISO 5 in operation

EU Grade B in operation

ISO7 in operation



ISO8 in operation

EU Grade C at Rest

ISO7 in operation

Cleanrooms with RABS Separation Barrier Systems operated at positive pressure to minimum EU Grade B / ISO7 background (in operation).

RABS Zonation – Open system processingDistribution rights are property of the PHSS, permission must be obtained for use.

Process design solutions for filling multiple product types



Balancing Process Design

GMP Annex 1,

Annex 2

Containment

Open

Systems

processing

Closed

Systems

processing

ResourceCosts/ ROI

capacity

efficiency

Risks toQuality Efficacy

Patient safety

Balancing measures:Technical & Organisational

control measures

Process Design: Science and Risk

based combining facility,

equipment, process operations with

GMP


11

De‐Lid++

De‐nest++

Formulation

VH

PRapid D

econ

VHP MT change

QC

inspec

t

releas

e

Labelling/

packaging final

product QC and

batch release

De‐Bag

NTT.+RABS

Vial

CappingRABS. +

Stoppers

Caps

Tub‐nest

SUS/ EM/ Rejects/ waste/ tools

Product

White Cart

Grey Cart

SBI+

Grade C Surround

Aseptic Filling RTU containers

with Containment

Through Process design, Project, Qualifications into Process Operations

OEMSFilling/ process Machine

vendors

Isolator/ RABS vendorsEnvironmental monitoring

equipment vendors.

Users are

developing new

products requiring

new process

solutions

Developing process solutionsDistribution rights are property of the PHSS, permission must be obtained for use.

12

Reduced

project time

line.Faster to

market

Flexibility in

Line

configurations

for product

types

Modularity via

pre‐designed

Filler & Isolator

modules

Increasing requirements for process Flexibility

Flexible and Modular Filling systemsDistribution rights are property of the PHSS, permission must be obtained for use.

13

Aseptic processing with Containment Isolation

Aseptic

Processing

Bio‐hazard

products

Aseptic

processing

Toxic products

Aseptic

processing

Non‐Hazardous

products

New products types requiring Contamination control,

Cross contamination control and Operator protection


14

Rapid Decon Hatch & stations (VHP) + Material Transfer Chambers,Transfer carts: Cart to Cart transfers or Battery operated UDF carts

Contamination control in material transfers

White Cart

Grey Cart

UDF/ LAF Carts

RTUSUSRTP


Sterile Product Transfer into Isolated Filling Lines

Autoclaved ‐

sterilised Product pathways

Gamma –

sterilisedSingle use system (SUS)

Product pathways

Transfer systems – product pathway

Pictures: Sartorius Stedim Biotech


16


Aseptic

processing

Non‐Hazardous

products




17

Aseptic Filling of non-hazardous productsPrinciple requirements

• Aseptic processing in Barrier Isolator technology providing Grade A/ ISO5 controlled

environments with integrated risk based environmental monitoring

systems.

• Cleanroom background environment to Isolator barrier: Grade C for ‘Open processing’

of pharmaceutical products. Filling zone positive pressure to surround.

• Cleanroom HVAC configured for part recirculation and fresh air exchange.• Isolator air‐handling system configured for part recirculation and air exchange (that can

take supply from the surrounding environment and discharge back to the same

environment).

• Secure ‘Closed’

material transfer devices required for all process support materials

(including environmental monitoring).

• RTU: pre‐sterilised containers may enter the Grade A Filling environment via de‐bagger/

No‐Touch‐Transfer (NTT) using a combination of barriers, pressure differential and

aerodynamic protection contamination control measures.

• VHP‐H202 surface decontamination to be used for Isolator barrier, non‐contact machine

surfaces, surface sterilisation of stopper bowls/ track ways, packaging materials difficult

to manually disinfect.


Formulation

VHP

Rapid Decon

VHP MT change

QC

inspec

t

releas

e

Labelling/

packaging final

product QC and

batch release

De‐Bag

NTT.+RABS

Vial

CappingRABS. +

Stoppers

Caps

Tub-nest


Product

White Cart

Grey Cart

SBI++

Grade C Surround

VHP Rapid Decon Station (RDS) for SUS/ EM/ Cleaning materials: delivery in RTP canisters plus Cross contamination control decontamination (at material exit from process).

Material/ waste VHP Surface Decon In/Out

Example of a process flow diagram showing areas of interaction

with a Pre‐sterilised Syringe Filling process in an Isolator


19


Aseptic

processing

Toxic products




20



systems.

• Cleanroom –

Isolator background environment: Grade C for ‘Open processing’

of

pharmaceutical products. Filling zone positive pressure to surround but less positive than

additional adjacent Isolator Grade A modules to provide a containment measure.

• Cleanroom HVAC configured for part recirculation and fresh air exchange.• Isolator air‐handling system configured for part recirculation and air exchange: Air supply

taken supply from surrounding environment and vent discharge ducted to outside via

double HEPA filtration and Bag‐in/Bag‐Out filters on primary containment boundary.

• Secure ‘Closed’


(including environmental monitoring).

• Wash/ Decontamination in‐place systems for primary containment boundary.• RTU: pre‐sterilised containers may enter the Grade A Filling environment via de‐bagger/

No‐Touch‐Transfer device via Isolator modules each side of Fill zone to provide a high

pressure barrier so air flows into grade A Fill zone and into de‐bagger (without mixing).

• Active ‘Mouse’

hole and external vial washer/ Decon

may be required.• VHP‐H202 surface decontamination used for Isolator barrier, non‐contact machine

surfaces, surface sterilisation of stopper bowls/ guides, packaging difficult to manually

disinfect.

Aseptic Filling of Toxic (cytotoxic) productsPrinciple requirements


De‐Lid++

De‐nest++

21

Process Flows: Aseptic filling hazardous products

Formulation

VH

PRapid D

econ

VHP MT change

QC

inspec

t

releas

e

Labelling/

packaging final

product QC and

batch release

De‐Bag

NTT.+RABS

Vial

CappingRABS. +

Stoppers

Caps

Tub‐nest


Product

White Cart

Grey Cart

SBI+

Grade C Surround

VHP Rapid Decon Station (RDS)

for SUS/ EM/ Cleaning materials:

delivery in RTP canisters plus

Cross contamination control

decontamination (at material

exit from process).

Material/ waste VHP Surface Decon In/Out

Aseptic‐Toxic design: Room HVAC Recir/exchange + Isolator

air exhaust to outside + safe change primary HEPA filters.

Aseptic‐Bio:Hazard design: Room HVAC Once through +

Isolator air recir and exhaust outside + Safe change exhaust

ULPA filters.


22


Aseptic

Processing

Bio‐hazard

products




23



systems.• Cleanroom background environment to Isolator barrier: Grade C for ‘Open processing’

of

pharmaceutical products: Best practice cGMP.

• Cleanroom HVAC configured for once through air exchange with terminal HEPA filters at

Cleanroom barrier air supply and double Exhaust filters with primary exhaust barrier filter

of ULPA grade, considering Biological safety (BSL) requirements (balanced with cGMP).

• Isolator air‐handling system configured for part recirculation and air exchange.• Secure ‘Closed’


entering/ exiting the Isolator.

• Isolator air supply taken supply from surrounding environment and vent discharge ducted to

outside via double ULPA/HEPA

filtration: Bag‐in/Bag‐Out filters on primary containment

boundary. Clean‐Decon in‐place systems/ spill kit required for primary containment

boundary of Isolator.

• RTU: pre‐sterilised containers may enter the Grade A Filling environment via de‐bagger/

No‐Touch‐Transfer (NTT) device together Isolator modules each side of Fill zone) to provide

a high pressure barrier so air flows into grade A Fill zone and into de‐bagger (without

mixing).

• VHP‐H2O2 surface decontamination to be used for Isolator barrier, non‐contact machine

surfaces, surface sterilisation of stopper bowls/ guides and packaging difficult to manually

disinfect. VHP‐H202 also specified for environmental viral clearance (end of batch/

i )

Aseptic Filling Bio-Hazard (biologic) productsPrinciple requirements


24

Multiple products filling facility

QC

MicrobiologyProductio

n office

INChang

e 1

Warehouse

officeQC

VHP

Material

s Out

FormulationClean Wash

areaSterile&

Clean

supplies

Packaging

Waste

Supplies

Non‐hazardous

Racking

FilledProduct

exit

QC

inspec

t

releas

e

Labelling/

packaging final

product QC and

batch release

WasteOut

Materials In

EXITChang

e

INChang

e 2

VHPM

Tchange

Supplies

Hazardous

VHPM

Tchange VHP

M

Tchange VHP

M

Tchange

VHPM

Tchange VHP

M

Tchange VHP

M

Tchange VHP

M

Tchange

Fillin

gFillin

gFillin

gFillin

g

Fillin

gFillin

gFillin

gFillin

g

Decon

Process

support

area

TechnicalPlant

area

Viewing Gallery – Glass walls

STI

MTMaterials IN

Change

OutChange

In

VH

P

Samples

M

T

M

T

Corridor

KeyChange = personal

change rooms.

MT = Material transfer manual disinfection.

VHP = Gaseous surface decontamination

Rapid Decon

Deliveries

Product Release

ThawTemp

contro

l

Aseptic Fill suites – non hazardous products

Aseptic Fill suites –

Toxic/ bio‐

hazardous products

Cold

roo

m


Risk based Environmental Monitoring plan and programs



Risk based EM Sampling plan: (4) combined EM programs

EM sampling planQualification stage programs

Characterisation at Start up and

Classification

at rest/ in‐operation (OQ).

Qualification (PQ) in establishing

environmental control: Process simulation /

media fills (PQ). Qualify interventions.

Routine EM in operation risk based sampling

locations environmental monitoring results

and deviation incidence rates trended

End of batch/ campaign EM environmental

monitoring including surface sampling

(Trended)

Taking a risk based approach there an

Environmental monitoring plan

combines different EM sampling

programs at different qualification

stages.

Holistic monitoring (Isolator/ RABS

and Cleanrooms together) provides a

more complete picture of bio‐

contamination control status and

contamination risk escalation to

contaminating A/ISO5 – PHSS

initiative: Risk profiling and proactive

response; RPPR detailed in Technical

monograph 20 refers.



Classification at Start up and at rest (OQ) and characterisation

to study more

of the complete area of the Isolator with more sample locations.

Qualification (PQ) in establishing environmental control: Process simulation /

media fills (PQ)

Routine EM in operation environmental monitoring (Trended data)

End of in Aseptic hold shift/ finish of batch/ campaign end. (Trended data)

Isolator EM sampling Plan – Risk basedDistribution rights are property of the PHSS, permission must be obtained for use.

28V 0.1 I 17/07/2015 I © FZ Isolator EM Risk based Sampling plan

Risk based Environmental Control & monitoringRisk register – for risk assessment: Filling pre-sterilized

containers; Vials, Syringes, Cartridges.

Point of critical risk of contamination Point of inherent risk of contamination

Sterilised product container entry to Isolator Point contacts/ load pattern during VHP

Pathway/ transfers of open product containers EM plate positioning and recovery

Point of Fill –

Contamination risk ‘Hot spot’ Filled product container exit points

Pathway of filled containers until closing Inherent Glove Interventions in‐process

Entry of stoppers/ plugs into Isolator Glove interventions for corrections

Feeder bowls/ path: stoppers to container In‐process glove leak integrity testing

A Glove management rationale is required for the life

cycle


Point of critical risk of contamination Point of inherent risk of contamination

Pathway of open product containers EM plate positioning and recovery

Point of Fill Filled product container exit points

Pathway of filled containers until closing Inherent Glove Interventions in‐process

Entry of stoppers/ plugs into Isolator Glove interventions for corrections

Feeder bowls/ path: stoppers to container In‐process glove leak integrity testing

Sterilised product container entry to Isolator Point contacts of load items during VHP

A Glove management rationale is required for the life cycle

Risk based Environmental Control & monitoringRisk register – for risk assessment; Batch filling of Vials


Risk based Environmental monitoringConsidering operator interactions and Holistic EM

Product In

Sp

Syr

Product out

RTP Port

Routine EMRisk based

Grade C / ISO8 Background

ActiveSettleParticleContactsSwabs

SWipes S

wabs

Sterile parts

Sterile partsWipes

62

RABS

Pre-sterilized container Filling

Isolator

Monitoring outside the Isolator at Operator interaction points, including gloves

provides information on extent of microbiological challenge to Grade A zones.



Environmental Monitoring (EM) Rapid – Real time Micro MethodsStatus of development and use in GMP/ Aseptic processingRapid – Real Time Environmental monitoring systems are developing and are

increasingly being implemented in Aseptic processing, currently in support areas

(outside grade A) and for root cause investigations

These technologies employ fluorescence based analytical systems that are

‘intervention free’

(no need to position a sample plate) with Real time feed back

in detection/ warning of Bio‐counts that are above alert and action levels hence a

change in the control state.

Conventional microbiological monitoring employs growth based systems with

inherent low recoveries. Not to exceed cfu levels/ limits defined in EU GMP

Annex 1 and FDA Guide to Industry for Aseptic processing are based on cfu’s.

RMM – RT measurements in bio‐counts are more sensitive with higher recovery

(from air samples) and subject to ‘false positives’

as a result of measuring non‐

biological fluorescing molecules e.g. cellulose.

Until EU GMP Annex 1 and PICS (FDA aligned) recognise the difference in cfu

and bio‐counts there will be limited implementation for Grade A/ ISO5

manufacturing areas where the EM data is considered in Batch release/ part of

Batch records.


32

New PHSS guidance:

Worked examples of Risk assessments for EM sample location selection and risk based EM

sampling plan/programs.

Risk based Environmental Contamination Control to follow.

PHSS Bio‐contamination Special Interest Group (SIG)


33

Andrew Hopkins, MHRA/ Head of EMA Annex 1 revision group.

Ian Symonds, GSK head of Global Aseptic manufacturing Quality – GSK Barnard Castle UK.

Mike Davies, GSK Global quality auditor, GSK Worthing UK QA Director.

Di Morris, Ex‐MHRA, GSK Compliance auditor manager. PHSS management team member.

Una Hearty, Pfizer Grange Castle, Global Quality.

Benoit Ramond, Sanofi France Global Quality, Microbiology

Tim Eaton, Astra Zeneca, Macclesfield, Sterile product manufacturing specialist.

Alan Dillon, Allergan Westport Ireland Filling line project manager.

Seamus Lyons, Amgen Ireland Aseptic processing QA

Tim Sandle, Bio Products Ltd (BPL) Head of microbiology.

Tim Triggs, DOP systems Director, PHSS management team member.

Tim Russel, TSI (RMM) field developer.

David Jones, Rapid Micro Bio‐systems, Director.

John Wallingford, Pharmagraph (EMS systems) Managing Director.

Steven Robbins, NHS (National health service) Blood transfusion service.

Carl McDonald, NHSBT, Head of bacteriology.

Adam Bird, Oxford Biomedica (Biotech), Head of QA.

Tim Sizer, HNS Regional Quality Pharmacist.

Mark Oldcorne, All of Wales Quality Pharmacist.

Adulmajeed Raji, Porton Biopharma, Microbiologist

Patrick Nieuwenhuizen, Genzyme Ireland Manager Quality Control Microbiology

Corinna Maier, F Ziel GmbH Aseptic processing technologies microbiologist.

Jenni Tranter, Business development manager Synergy Health

Kay O’Hagan, Hospira Quality auditor/ QP.

Wenzel Novak, Groninger GmbH Director of research and development

Michael Pratz Head of Bausch & Stroebel Compliance/ training academy

Johannes Rauschnabel GMBH Bosch packaging GMP expert.

Marc Van Laere Mithra Belgium QA Manager,


34

James L Drinkwater F Ziel

Head of Aseptic processing Technologies & GMP Compliance

Risk Based process solutions in Environmental Control and Monitoring for

Aseptic processing and Filling


over 25 years of advancing pharmaceutical and healthcare sciences

PHSS Annual Conference in association with UCL Q3P

Meet Your Exhibitors

Biomerieux Antoine Bloch [email protected]

Christie Downing-Kay Industry Product Manager M: +44 (0) 776 416 [email protected]

Charles River Matthew Reynolds M: +44 (0) 7717 [email protected]

Cherwell Labs Andrew Barrow [email protected]

Sandra [email protected]

Contec Alison Livsey Product ManagerT: +44 (0) 7500 667556 [email protected]

Karen Rossington Marketing Manager

DOP Solutions Tim Triggs DirectorM: +44 (0) 7809 868444 [email protected]

Andy WorsickUK Sales Manager M: +44 (0) 7715 425368 [email protected]

EMS Les Dodd Business Development Manager T: +44 (0) 7825 [email protected]

Dave Nolan [email protected]

John Chapman [email protected]

Franz Ziel GmbH Olaf Ziel (49) 254312335 [email protected]

James Drinkwater T: +44 (0) 7557 [email protected]


Helapet Tony Phelps M: +44 (0) 7970 090228 [email protected]

Sam ByottM: +44 (0) 7500 944882 [email protected]

ILS Limited Stewart Neithercut Head of Business [email protected]

Rutjit Durve Pharmaceutical Chemistry Laboratory [email protected]

Ravinder Nizzer Pharmaceutical Chemistry Laboratory [email protected]

Micronclean Sian Lovatt M: +44 (0) 7584 [email protected]

Jenny [email protected]

Morris [email protected]

Pharmagraph Janice Wallace M: +44 (0) 7730 [email protected]

Ken [email protected]

John Goodchild [email protected]

PMT GB Limited / TSI Peter Knott [email protected]

Tim Russell Field Market Developer [email protected]: +44 (0) 7715 488537

SGL – Southern Group Laboratory Tony Crawley National Sales Manager M: +44 (0) 7841 [email protected]

Steris Murray NicholsonM: +44 (0) 777 564 [email protected]

Kingslea GabbottM: +44 (0) 7711 [email protected]

Mike CurtisM: +44 (0) 7769 [email protected]

Andy [email protected]

Tristel Rob LewisM: +44 (0) 7827 [email protected]

Validair Dave Sears Tel: +44 (0) 1732 882984 [email protected]

Andy Dines [email protected]

Veltek Elaine Fraser M: +44 (0) 7768 970281 [email protected]


Distribution rights are property of the PHSS, permission must be … · 2018-03-31 · Di...

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