eu gmp change - impact on cleaning and process validation

EU GMP change – impact on cleaning and process validation

Walid El Azab Technical Service Manager

STERIS Life Science

Conference agenda

Current European change and link 1

Impact on cleaning and process validation 2

U.S. and E.U approach for carryover setting limits 3

Benchmark and Frequently Asked Questions 4

Conclusion 5

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Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation

cGMP evolution – cleaning and process validation history

Thalidomide 1962

EU

ICH

WHO

ASTM ASEAN

1987

Medecine Act – UK

1968

1st GMP guide – Orange

1968

QP releasing 1970

EC Law

1992 1996

Q7 GMP API

2000

Annex 15

2001

Note for Guidance process

validation

2007

E2500

2008

Q10 QMS

Q8R2: QbD Q9: RM

2009 2010

API GMPs

EU GMP Part II 1972

2012

PV draft

Q11: DS

PV v3 ASEAN

2013

PV v3 ASEAN

2014

2015

Annex 15

PV ((biotech)

FDA General

principle of Process

Validaation

21 CFR part 211 –

subpart L

Risk based cGMP

PV new draft 2011

PV draft non-sterile

Barr laboratoires trial 1988

State of the art document: PIC/S 006 PDA TR 29 and TR49

2004


European directive change and impact on the EU GMP guide

2001/83/EC Medicinal product for human use

2003/63/EC Biological medicinal product

GMP in respect for medicinal products for human and investigational medicinal products for human use

GLP in the conduct of clinical trial for human use

Falsified medicinal products: SQIPP responsibility QP responsibility increased -> Annex 16 Excipient use suitability determine through risk assessment -> ICH Q9 Control and traceability supply chain: avoid illegal supply chain Control falsified product Packaging safety features

2001/20/EC 2003/94/EC 2011/62/EU

Falsified medicinal product

EC guide GMP part I, II and Annexes

National Laws

GDP

2013/C 68/01 GDP of medicinal products

revision 94/C 63/03

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EU GMP revision focus on introducing element of ICH and modern manufacturing technology

EC GMP guide Annexes

ICH Q8

EC GMP Guide Part I

ICH Q9 ICH Q10 ICH Q11

Chapter Title date

1 Pharmaceutical quality system 31 Jan 13

2 Personnel 16 Feb 14

3 Premises and Equipment 01 Mar 15

5 Production 01 Mar 15

6 Quality Control 01 Oct 14

7 Outsourced Activities 31 Jan 13

8 Complaints and recalls 01 Mar 15

Annexes Title date

1 Manufacture of Sterile Medicinal Products

Concept Paper

2 Manufacture of Biological active

substances and Medicinal Products for Human Us

31 Jan 13

15 Qualification and validation 01 Oct 15

16 Certification by a Qualified person and Batch Release 15 Apr 16

17 Parametric Release* Draft

21 Product importation Concept paper

Operation date of the EU GMP guide chapters revised: Operation date of the EU GMP guide annexes revised:

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Manufacturer selling products into EMA regulated market should comply to these changes

Who is impacted by these changes?

EU GMP manufacturers producing : Human drugs Veterinary drugs Biological and biotechnology products Active pharmaceutical ingredient (API) manufacturers

Manufacturers in other non-EU but PIC/S regulated markets could be impact

indirectly. Because, PIC/S has align partially its document to the EU GMP guide changes

Medical devices manufacturers are not directly affected….

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EU GMP Annex 15 revision: introducing element of ICH, modern manufacturing technology and EU GMP guide changes

EC Annex 15

EMA concept paper (Nov. 2012) On the revision of the annex 15

EC GMP guide Part I

US FDA Guide on Process Validation ASTM E2500-07

ICH Q8 – Q10 Manufacturing Technologies

EMA draft on process validation

EC Annex 11

EMA guideline on process validation (PV)

PIC/S

ICH Q8: Design space ICH Q9: Risk-based approach ICH Q8 & Q10: Knowledge management ICH Q11: Life cycle validation & qualification

Computer System Validation software & hard ware back up

Alignment with the EMEA guidance on setting limits Modern manufacturing technology Alignment with:

Chapter 3 Chapter 5

EMA setting health based limit and

Process Validation

Include modern aspect: ICH Q8 – Q10 PAT, RTRT QdB Harmonization with FDA guidance on process validation

Cleaning validation Process validation Transport validation Packaging validation Qualification Utilities Analytical method continuous process verification and On-going verification concept

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EMA guidance provide insight on future direction for process validation

EMA guideline on process validation (PV)

EC Annex 15

US FDA Guide on Process Validation ASTM E2500-07

ICH Q8 – Q10 Manufacturing Technologies

EC Annex 11

PIC/S

ICH Q8: Design space ICH Q9: Risk-based approach ICH Q8 & Q10: Knowledge management ICH Q11: Life cycle validation & qualification

Computer System Validation software & hard ware back up

Submission for market authorization modern method for process validation flexible approach : CPV, combination 3 runs + scientifically based decision

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Agenda





Conclusion 5


Role of QP/QA and senior management is to ensure quality, compliance to the MAH and cGMP

10 Prepared by Walid El Azab – STERIS

QP has the ultimate responsibility over product lifetime; safety, quality and efficacy Ensure batch in accordance with its MAH, with EU GMP and applicable law Has an on going assurance that his reliance on the QA system is well founded Senior management has the responsibility to ensure QA system and lifecycle product

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Changes in the annex 15 impact the industry validation process

Annex 15 2015

▪ Start a RM before cleaning validation ▪ Worst case approach is required for manual cleaning ▪ Grouping equipment in CV ▪ Carry over of product based on Toxicological data – PDE (2014 – New) ▪ Worst case definition should include PDE data ▪ CHT, DHT, campaign time ▪ Rational for WC position choice using a risk assessment ▪Visual inspection alone is not sufficient ▪ Sampling methods swab, rinsing ▪ Number of validation run determine by RM – link to PDA TR 29 ▪ Cleaning verification for rarely manufactured product ▪ Qualification : DQ ->FAT/SAT->I/O/PQ combined step is possible ▪Planning and documentation for qualification and validation ▪ Major revision for process validation: on going process verification,

countinous process verfication, hybrid approach ect… ▪The chapter “re-validation” replaced by “re-qualification”

Rationale for change: adjustment with annex 11 – ICHQ8-11, PAT, EMEA PDE, EMA PV and process validation and part I of the EU GMP:

Cleaning validation change

Changes in the EMA PDE setting guidance impact the industry validation process

Guideline on setting health based exposure limits (PDEs) 2014

Rationale for change: implement the scientific approach chap 3 and chap 5 of EU GMP, scientific rationale for cytotoxic and antibiotic to be produced in dedicated equipment :

▪ NOEL is now NOAEL ▪ 10ppm approach is enhance by the calculation of the PDE based on all

toxicological and pharmacological data NOAEL – present in the ICHQ3C (R4) ▪ Threshold of Toxicological Concern (TTC) or 1.5 µg/person/day – Ex.

Genotoxic ▪ Dedicated equipment are needed for substance which lowest

threshold is not known ▪ Not applicable on macromolecule since could be inactivate by

chemically or thermally actions ▪ PDE animal < PDE human ▪ VICH GL18 residual solvent and link with EU CMP chap 3 and Chap 5

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Changes in the EMA PDE setting guidance impact the industry validation programs

Nov 2014

Final Published

Jun 2015

Effective date

Dec 2015

Effective for new product

Jun 2016

Effective for existing product

Impacted: Annex 15 EUGMP (October 2015) Chapter 3 EUGMP (March 2015) Chapter 5 EUGMP (March 2015) WHO guidance on cleaning validation

Time line for implementation:

Cleaning strategy

Active residue proprietary

Identify active residue

Portfolio management

Visually clean +

Lowest MACO

Worst case active residue =

Lowest MACO

Therapeutic daily dose

Extrinsic source of active residues: Active and/or cleaner residue, material degradation, leachable/extractible

Intrinsic source of active residues: Product intrinsic impurity

Minimum therapeutic dose that give a

pharmacological effect 1/1000th

Setting acceptance criteria (MACO)

MACO= TDD*MBS TDDN * SF

1/1000th

Toxicological based

Minimum dose with kill of 50% population

(LD50) NOAEL limit

MACO= NOAEL *MBS TDDN*SF

LD50* BW SF

Health based

MACO= PDE *MBS TDDN

NOAEL * BW F1*F2*F3*F4*F5

Minimum dose with toxicological and pharmacokinetic

(NOAEL) PDE/ADE limit

Cleaning program strategy for acceptance criteria setting


Process validation include site transfers, ongoing process verification

The annex 15 should be read in conjunction with EMA guideline on process validation:

Design space

Process validation

Prospective validation

Continuous process

verification

Hybrid approach

Retrospective Validation

Concurrent Validation

Ongoing process verification

Process development Process validation Life Cycle


Description of current validation, traditional approach, continuous process and ongoing verification

▪May be acceptable in exceptional circumstance : "where there is a strong risk – benefit to the patient" ▪ Decision must be justified and documented in the VMP and approved ▪ Allowed in routine production to confirm reproducibility ▪ Number of batches and sample must be define through QRM : "a high level of assurance that

the process is capable of consistently delivering quality product" ▪Minimum 3 runs but support by data of "subsequent batches as part of an on-going process

verification exercise” ▪ Product with robust quality by design vs traditional approach ▪ Number of batches should be scientifically justified : "science based control strategy for the

required attributes for incoming materials, critical quality attributes and critical process parameters to confirm product realization" ▪ Regular control strategy, PAT, RTRT… ▪ “hybrid approach” = Traditional approach + Continuous process verification

▪ Ongoing monitoring of the validated state of the process – PQR, statistical tools, ect… ▪ Part of the validation life cycle

▪ Required periodically to ensure state of control – approved protocol and report ▪ The period should be based on “process understanding and process performance”, QRM ▪ Support PQR – assess the variability and capability of the process during product lifecycle

Explanations

Current Validation Traditional approach Continuous process verification Continued process verification Ongoing verification

Terms


Unlike the EMA guide on process validation the US FDA does break the lifecycle validation concept


Stage 1

Stage 2

Stage 3

Design space and pilot scale Adequate quality by design will enhance the use of modern approach. Ex.: CPV

EMA allow traditional approach BUT combine with CPV Hybrid approach – understanding quality design

EMA call for continued process verification CPV encourage to remove traditional approach Historical data driven:

Statistical tools Deviations Complaints ect…

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EMA Guidance does not intend to be equivalent to the US guidance on process validation LIST NON EXHAUSTIVE

Similarities EMA guidance US FDA Guidance

Product life cycle

Quality risk assessment – ICHQ9 concept

Incorporation of the ICH Q8-Q11

Continued process verification through pre and post release analysis

Recognition of PAT, RTRT concept

Explain the regulator expectations

What to consider for process validation strategy development for dossier submission

Encourage the use of product development

Min. of 3 runs prior marketing authorization

Emphasis on the CPV to

replace traditional approach

Process validation approach ≠ Equipment & facilities qualification

Differences and other

Assist the development and execution of process validation – more prescriptive approach

Emphasis the documentation of the process development

Sufficient runs number to

ensure statistical confidence

Respect the 3 stages

Equipment and facility validation ≈ process validation approach


Performance qualification (PQ) different understanding

EU GMP Guide Annex 15 PIC/S 006-3 US FDA Process validation guidance

Include equipment and utilities qualification

Revalidation replaced by requalification

Process should be under process validation

Cleaning validation consider

Include equipment qualification and process validation

It includes a definition for Process Validation, However, states that “the term Performance Qualification or PQ may be used also”

Confusion by using the abbreviation “ PQ” : define as Process Qualification - 2 elements:

Qualification of

equipment and utilities

Process performance qualification (PPQ): control the process design and confirm the manufacturing process performed as validated (Equipment, facility, process, SOP, personel…

AUTHOR INTERPRETATION

Agenda





Conclusion 5

MACO calculation: European guideline

EMA: setting health based limit (2014)

EC guide:

Annex 15 (2015) Before: Visually clean After : Cleaning validation

Chapter 3 and 5 Part II

PIC/S: Guidance - cleaning validation in active pharmaceutical ingredient plants (2014)

Integrating MACO data

US FDA: 21CFR211.42 21CFR211.167 Cross contamination management

ISPE : Risk MaPP (2010) First document on ADE, TTC, pharmacological and toxicological data calculation for MACO.

ADE (mg/day) = NOAEL (or LOAEL) x BW / (UFC × MF × PK)

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Equivalency between the ADE and the PDE can be demonstrated by a toxicologist

PDE = (NOAEL* BW)/(SF1xSF2xSF3xSF4xSF5) ADE = NOAEL (or LOAEL) x BW / (UFC × MF × PK)

NOAEL: No Observed Adversible Effect Level BW: weight adjustment - 50kg for human medicinal products 1Kg for veterinary medicinal products F1: A factor (values between 2 and 12) to account for extrapolation between species F2: A factor of 10 to account for variability between individuals F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

NOAEL: No Observed Adversible Effect Level LOAEL: Lowest Observable Adversible Effect Level BW: weight adjustment - 50kg for human medicinal products UFC: composite Uncertainty factor: UFH: Intra species differences UFA : Inter species differences UFS: Subchronic to chronic extrapolation UFD: database completeness – toxicity database UFL: LOAEL to NOAEL extrapolation MF: Modifying factor – to adress residual uncertainty PK: pharmacocinetic adjustment

The determination of the ADE and equivalent PDE involves hazard identification by reviewing : all relevant data, identification of critical effects or effects, determination of the NOAEL of the findings that are considered to be critical effects and use several adjustments to account for various uncertainties.

Agenda





Conclusion 5

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The worst case soil have to be confirmed based on toxicological data (PDE)

Equipments

Equipments group

Cleaning SOP 1

Cleaning SOP 2

Cleaning SOP 3

Equipments group Cleaning SOP 1

Product 1

Product 2

Product 3

Determine MACO worst case – MDD

Determine worst case product to clean

3 runs

Equipments

Equipments group

Cleaning SOP 1

Cleaning SOP 2

Cleaning SOP 3

Equipments group Cleaning SOP 1

Product 1

Product 2

Product 3

Determine MACO worst case

Determine worst case product to clean

3 runs

“Current” approach: MACO was determine using therapeutic daily dose or the 10 ppm

New guideline: MACO should be determine using therapeutic daily dose, health and/or toxicological based

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Health based limit is consider as the scientific methods

[

Source: Cleaning Limits—Why the 10-ppm Criterion should be Abandoned The 10-ppm criterion for the acceptable concentration of potential API in cleaning validation is no longer necessary and a risk-based approach should be universally adopted. Jan 01, 2016 By Michel Crevoisier [1], Ester Lovsin Barle [2], Andreas Flueckiger [3], David G. Dolan [4], Allan Ader [5], Andrew Walsh [6] Pharmaceutical Technology Volume 40, Issue 1

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FAQ by pharmaceutical industries to suppliers (1/4)

Q: Should TOC or Conductivity data in routine for cleaning control is a must? TOC and Conductivity is routinely used to monitor cleaning control but it is not a requirement. The frequency monitoring will depend on cleaning knowledge and cleaning performance data and based on the results of the QRA. “ visually clean only is not sufficient in validation and in routine” if traditional approach is used then it is necessary to gather sufficient data through continuous verification and/or on-going validation

Q: As a sub-contractor who has the responsibility to determine the PDE ?

It depend what the Quality or supply agreement states Generally, if product contact it should be manufacturer. However, for operator contact it is the responsibility of the sub-contractor.


Q: Does the guideline apply to my company ? When do I need to calculate PDE limit?


Yes the guideline applies to shared facilities of medicinal products and APIs, where cross-contamination is a concern

Q: How the PDE for a cleaner should be calculated?

by an experienced toxicologist and it is the supplier responsibility Q: How did you calculate the PDE for STERIS’s cleaner? Using or LOAEL value determined by an experienced toxicologist Toxicity information on raw materials and final formulations was used by the toxicologist to determine the NOAEL or LOAEL value

Q: What is the difference between PDE, ADE and ADI? With the new EMA guideline: PDE = ADE, if equivalency between the safety factors is demonstrated… These are health based limits with no observable adverse effect given any route of administration over the lifetime of exposure. An ADI value is specific to oral dose limits.


Q: how to calculate the MACO for development product that the PDE is not available?


The toxicologist need to assess the LOAEL data

Q: How I can set the limit if the veterinary product go to the human food chain? ?

The calculation will depend if the animal enter in the human food supply chain MACO veterinary < MACO human

Q: can I continue to use empirical data if I have no toxicological or health based limit data?

Q: My company is biotechnology therefore I should not worry about the PDE.

You have to demonstrate that your product has no pharmacological or toxicological or sensitive effect if you use cleaner: determine the MACO


FAQ by pharmaceutical industries to Regulators (4/4)

Carryover for product – safety for the patient Carryover for operators – safety for the personnel Scientific understanding

Q: Does PDE apply only to the patient ?

Q: If a company does not have the PDE data for their product after the deadline?

STOP the cleaning Dedicate the equipment Perform risk assessment Q: Do you think PDE should also be apply to non product contact surface?

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Agenda





Conclusion 5


Conclusion


EU GMP guide update: align with the current industries practice, ICH and other guidance

Managment should have appropriate oversight to implement the change in timely manner Plan the change before acting: SOP & policy revision, ressourcing, training to be able to meet industry best practices

Integrate and develop a life cycle approach for equipment and process

Scientifically based choice through risk assessment approach and process knowledge / performance

Review SOP to align with current update and assess the impact on the validation program


Thank You

For your listening

El Azab Walid Technical Service Manager – STERIS

[email protected] +32479790273


References

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[1] Medicines & Healthcare products Regulatory Agency (MHRA) top deficiency. Accessed on April 05, 2015 at: http://www.gmp-compliance.org/enews_03189_MHRA-publishes-GMP-Deficiency-Data-Review-April-2011---March-2012.html [2] Medicines & Healthcare products Regulatory Agency (MHRA) top deficiency. Accessed on April 05, 2015 at: http://webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con464241.pdf [3] European Medicine Agency (EMA), Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, November 2014 [4] Lai Yeo Lian, M. Ovais. (2008) Setting Cleaning Validation Acceptance Limits for Topical Formulations Pharmaceutical Technology, Volume 32, Issue 1 [5] European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 15, Qualification and Validation, 2015. [6] European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 3, Premises and equipment, 2015. [7] European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 5, Production, 2015. [8]Fourman, G., and Mullen, M., “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations,” Pharmaceutical Technology, April 1993 [9]Active Pharm aceutical Ingredients committee (APIC), Guidance on Aspect of Cleaning Validation in Active Pharmaceutical Ingredient Plants, May 2014. [10] International Society for Pharmaceutical Engineering (ISPE), Risk-Based Manufacture of Pharmaceutical Products, September 2010 Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial.

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MACO determined by scientific based data

Intrinsic source

Product degradation: Impurities Microorganism

Extrinsic source

Contaminants: Previous product Microbes Material degradation Cleaner Solvent

Therapeutic daily dose

Minimum therapeutic dose that give a pharmacological effect 1/1000th = limit!

Minimum dose with pharmacokinetic on individual and individual species (NOAEL) PDE/ADE limit

Health based

Toxicological based

Minimum dose with kill of 50% population (LD50) PDE/ADE limit

MACO MACO= TDD*MBS TDDN*SF

MACO= NOAEL*MBS TDDN*SF

MACO= PDE*MBS TDDN

1/1000th based TTC

NOAEL * BW F1*F2*F3*F4*F5

LD50* BW SF

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The validation documentation template and program should be adapted (1/2)

The VMP should define the element of validation:

“Current validation status” “On going validation strategy” Cross reference template format for protocol and report Assessment of resources required Deviation management Material to be used for the validation Integrate routine monitoring:

on-going verification continuous process verification

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The validation documentation template and program should be adapted (2/2)

The protocol “could” define the element of validation: Critical systems Critical attributes (CQA) Critical parameters (CPP) Acceptance criteria Sampling testing Approval process – define conditional vs approval authorization Inter-relationship between documentation and third party documentation (GDP – Good Documentation Practice) Deviation handling - "Any changes to the approved protocol during execution should be documented as a deviation and be scientifically justified."

The report “could” define the element of validation:

Summary of the results Acceptance criteria - change to the acceptance criteria should be scientifically justified approval process

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Cleaning and process validation is on the TOP 10 deficiencies observed

Validation deficiencies observed in FY 2012

Source: http://webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con464241.pdf

Most deficiencies observed 2007 -2014

eu gmp change - impact on cleaning and process validation

Health & Medicine