ElAzab EU GMP PDF

EU GMP change impact on
cleaning and process validation

Walid El Azab
Technical Service Manager
STERIS Life Science
Conference agenda
1 Current European change and link
2 Impact on cleaning and process validation
U.S. and E.U approach for carryover

3
setting limits
Benchmark and Frequently Asked

4
Questions
5 Conclusion
cGMP evolution cleaning and process validation history
Thalidomide QP releasing Barr laboratoires trial
1962 1970 1988
1968 1968 1987 1992 1996 2000 2001 2007 2008 2009 2010 2012 2013 2015
Note for
1st GMP
Medecine Annex Guidance EU GMP PV Annex 15
EU Act UK
guide 1972 EC Law
15 process 2004
Part II draft PV
Orange
validation ((biotech)
2014
General
21 CFR part
principle of Risk based PV new PV draft
FDA Process
211
cGMP draft 2011 non-sterile
subpart L
Validaation
Q7 Q10 Q8R2: QbD

ICH GMP API QMS Q9: RM
Q11: DS
ASTM E2500
PV v3 PV v3
ASEAN ASEAN ASEAN
State of the art document:

PIC/S 006 WHO API
GMPs
PDA TR 29 and TR49
3/
Copyright 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation
European directive change and impact on the EU GMP
guide
LIST NON EXHAUSTIVE
2001/83/EC 2003/63/EC
Medicinal product for human use Biological medicinal product
2011/62/EU
Falsified medicinal product 2001/20/EC 2003/94/EC
2013/C 68/01
GDP of medicinal products
revision 94/C 63/03
National Laws
EC guide GMP
part I, II and Annexes
Falsified medicinal products: SQIPP GLP in the conduct GMP in respect for
responsibility of clinical trial for medicinal products for
QP responsibility increased -> Annex human use human and
16 investigational
Excipient use suitability determine medicinal products for
through risk assessment -> ICH Q9 human use
Control and traceability supply
chain: avoid illegal supply chain
Control falsified product GDP
Packaging safety features
EU GMP revision focus on introducing element of ICH and
modern manufacturing technology
LIST NON EXHAUSTIVE
ICH Q8 ICH Q9 ICH Q10 ICH Q11
EC GMP Guide Part I EC GMP guide Annexes
Operation date of the EU GMP guide chapters revised: Operation date of the EU GMP guide annexes revised:
Chapter Title date Annexes Title date

1 Pharmaceutical quality system 31 Jan 13 Manufacture of Sterile Medicinal Concept
1
Products Paper
2 Personnel 16 Feb 14
Manufacture of Biological active
3 Premises and Equipment 01 Mar 15 2 substances and Medicinal Products 31 Jan 13
for Human Us
5 Production 01 Mar 15
15 Qualification and validation 01 Oct 15
6 Quality Control 01 Oct 14
Certification by a Qualified person
7 Outsourced Activities 31 Jan 13 16 15 Apr 16
and Batch Release
8 Complaints and recalls 01 Mar 15 17 Parametric Release* Draft
Concept
21 Product importation
paper
5/
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.
6/
EU GMP Annex 15 revision: introducing element of ICH,
modern manufacturing technology and EU GMP guide changes
LIST NON EXHAUSTIVE
EMA setting
EMA concept paper (Nov. 2012) US FDA Guide
health based limit and ASTM E2500-07
Process Validation On the revision of the annex 15 on Process Validation
Cleaning validation
Include modern aspect: PIC/S Process validation
ICH Q8 Q10 Transport validation
PAT, RTRT Packaging validation
QdB EMA guideline Qualification Utilities
EC Annex 15
Harmonization with on process validation (PV) Analytical method
FDA guidance on continuous process
process validation verification and On-
EC GMP guide Part I going verification
concept
EMA draft on Manufacturing

EC Annex 11 ICH Q8 Q10
process validation Technologies
Alignment with the EMEA guidance Computer System Validation ICH Q8: Design space
on setting limits software & hard ware ICH Q9: Risk-based approach
Modern manufacturing technology back up ICH Q8 & Q10: Knowledge management
Alignment with: ICH Q11: Life cycle validation &
Chapter 3 qualification
Chapter 5 7/
EMA guidance provide insight on future direction for
process validation
LIST NON EXHAUSTIVE
US FDA Guide
ASTM E2500-07
on Process Validation
PIC/S Submission for

market authorization
modern method for
EMA guideline process validation
on process validation (PV) flexible approach :
CPV, combination
3 runs + scientifically
EC Annex 15 based decision
Manufacturing
EC Annex 11 ICH Q8 Q10
Technologies
Computer System Validation ICH Q8: Design space

software & hard ware ICH Q9: Risk-based approach
back up ICH Q8 & Q10: Knowledge management
ICH Q11: Life cycle validation &
qualification
8/
Agenda
Impact on cleaning and process

2
validation
3
setting limits
4
Questions
5 Conclusion
Role of QP/QA and senior management is to ensure
quality, compliance to the MAH and cGMP
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
Copyright 2015 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation Prepared by Walid El Azab STERIS10
Changes in the annex 15 impact the industry validation
process
Rationale for change: adjustment with annex 11 ICHQ8-11, PAT, EMEA PDE, EMA PV and
process validation and part I of the EU GMP:
Annex 15 Start a RM before cleaning validation

Worst case approach is required for manual cleaning
Cleaning validation change

2015
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
11/
Changes in the EMA PDE setting guidance impact the industry
validation process
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 :
Guideline on
setting health
NOEL is now NOAEL
based exposure 10ppm approach is enhance by the calculation of the PDE based on all
limits (PDEs) toxicological and pharmacological data NOAEL present in the
2014 ICHQ3C (R4)
Threshold of Toxicological Concern (TTC) or 1.5 g/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
Changes in the EMA PDE setting guidance impact the
industry validation programs
Time line for implementation:
Effective Effective
Final Published Effective date for new product for existing product
Nov 2014 Jun 2015 Dec 2015 Jun 2016
Impacted:
Annex 15 EUGMP (October 2015)
Chapter 3 EUGMP (March 2015)
Chapter 5 EUGMP (March 2015)
WHO guidance on cleaning validation
13/
Cleaning program strategy for acceptance criteria setting
Visually clean
+
Cleaning strategy Lowest MACO
Worst case active residue

=
Lowest MACO
Active residue proprietary

Therapeutic Portfolio
Toxicological
management Health
daily dose based based
Minimum therapeutic Minimum dose with kill Minimum dose with
dose that give a of 50% population toxicological and
pharmacological effect (LD50) pharmacokinetic
1/1000th NOAEL limit (NOAEL) PDE/ADE
limit
MACO= TDD*MBS MACO= NOAEL *MBS MACO= PDE *MBS
TDDN * SF TDDN*SF TDDN
1/1000th LD50* BW NOAEL * BW
SF F1*F2*F3*F4*F5
Setting acceptance criteria (MACO)
Identify active residue

Extrinsic source of active residues:
Active and/or cleaner residue, material degradation, leachable/extractible
Intrinsic source of active residues:
Product intrinsic impurity
Process validation include site transfers, ongoing process
verification
The annex 15 should be read in conjunction with EMA guideline on process validation:
Concurrent
Validation
Ongoing process verification

Prospective
validation
Design Process
space validation Hybrid
approach
Continuous
process
verification
Retrospective
Validation
Process development Process validation Life Cycle

Description of current validation, traditional approach,
continuous process and ongoing verification
Terms Explanations
May be acceptable in exceptional circumstance : "where there is a strong risk benefit to the
Current Validation patient"
Decision must be justified and documented in the VMP and approved
Allowed in routine production to confirm reproducibility
Traditional approach 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

Continuous process Number of batches should be scientifically justified : "science based control strategy for the
verification 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
Continued process Ongoing monitoring of the validated state of the process PQR, statistical tools, ect
verification Part of the validation life cycle
Required periodically to ensure state of control approved protocol and report
Ongoing verification 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
Unlike the EMA guide on process validation the US FDA
does break the lifecycle validation concept
Stage 3
Stage 2
EMA call for continued

Stage 1 process verification
CPV encourage to
EMA allow
remove traditional
traditional approach
approach
BUT combine with CPV
Historical data driven:
Design space and Hybrid approach
Statistical tools
pilot scale understanding quality
Deviations
Adequate quality by design
Complaints
design will enhance the ect
use of modern
approach. Ex.: CPV
EMA Guidance does not intend to be equivalent to the US
guidance on process validation LIST NON EXHAUSTIVE
Differences and other

Similarities
EMA guidance US FDA Guidance
Product life cycle What to consider for process Assist the development and
validation strategy execution of process
Quality risk assessment development for dossier validation more
ICHQ9 concept submission prescriptive approach
Incorporation of the ICH Encourage the use of product Emphasis the

Q8-Q11 development documentation of the
process development
Continued process
verification through pre Min. of 3 runs prior marketing Sufficient runs number to
and post release analysis authorization ensure statistical
confidence
Recognition of PAT, RTRT
concept Emphasis on the CPV to Respect the 3 stages
replace traditional approach
Explain the regulator
expectations Process validation approach Equipment and facility
Equipment & facilities validation process
qualification validation approach
18/
Performance qualification (PQ) different understanding
AUTHOR INTERPRETATION
EU GMP Guide Annex 15 PIC/S 006-3 US FDA Process validation guidance
Include equipment Include equipment Confusion by using the

and utilities qualification and abbreviation PQ : define as
qualification process validation Process Qualification - 2
elements:
Revalidation It includes a
replaced by definition for Process Qualification of
requalification Validation, However, equipment and utilities
states that the term
Process should be Performance Process performance
under process Qualification or PQ qualification (PPQ):
validation may be used also control the process
design and confirm the
Cleaning validation manufacturing process
consider performed as validated
(Equipment, facility,
process, SOP, personel
Agenda

3
setting limits
4
Questions
5 Conclusion
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)
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 NOAEL: No Observed Adversible Effect Level
BW: weight adjustment - 50kg for human medicinal products LOAEL: Lowest Observable Adversible Effect Level
1Kg for veterinary medicinal products
BW: weight adjustment - 50kg for human medicinal products
F1: A factor (values between 2 and 12) to account for extrapolation UFC: composite Uncertainty factor:
between species
UFH: Intra species differences
F2: A factor of 10 to account for variability between individuals
UFA : Inter species differences
F3: A factor 10 to account for repeat-dose toxicity studies of short
duration, i.e., less than 4-weeks UFS: Subchronic to chronic extrapolation
F4: A factor (1-10) that may be applied in cases of severe toxicity, UFD: database completeness toxicity database
e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity
UFL: LOAEL to NOAEL extrapolation
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 MF: Modifying factor to adress residual uncertainty
could be used depending on the severity of the toxicity.
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.
24/
Agenda

3
setting limits
4
Questions
5 Conclusion
The worst case soil have to be confirmed based on
toxicological data (PDE)
Current approach: MACO was determine using New guideline: MACO should be determine using
therapeutic daily dose or the 10 ppm therapeutic daily dose, health and/or toxicological based
Equipments Equipments
Cleaning SOP 1 Cleaning SOP 1
Equipments group Cleaning SOP 2 Equipments group Cleaning SOP 2
Product 1 Product 1
Equipments group Equipments group
Product 2 Product 2
Product 3 Product 3
Determine MACO Determine worst case Determine MACO Determine worst case
worst case MDD product to clean worst case product to clean
3 runs 3 runs
26/
Health based limit is consider as the scientific methods
Source: Cleaning LimitsWhy 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 27/
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.
28/
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 STERISs 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)
LIST NON EXHAUSTIVE
Q: Does PDE apply only to the patient ?
Carryover for product safety for the patient

Carryover for operators safety for the personnel
Scientific understanding
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?
Agenda

3
setting limits
4
Questions
5 Conclusion
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
Walid_elazab@steris.com
+32479790273
References
[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.
Copyright 2015 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation 35
MACO determined by scientific based data
MACO MACO= TDD*MBS

Intrinsic source
TDDN*SF
Product degradation: Health based
Impurities Therapeutic daily dose
Microorganism Minimum dose with 1/1000th based TTC
Minimum therapeutic dose pharmacokinetic on
that give a pharmacological individual and individual
effect 1/1000th = limit! species (NOAEL) PDE/ADE
limit
MACO= PDE*MBS
TDDN
Extrinsic source NOAEL * BW

Contaminants:
Toxicological based F1*F2*F3*F4*F5
Previous product
Microbes Minimum dose with kill of
Material degradation
50% population (LD50)
Cleaner
PDE/ADE limit
Solvent MACO= NOAEL*MBS
TDDN*SF
LD50* BW
SF
37/
The validation documentation template and program
should be adapted (1/2)
LIST NON EXHAUSTIVE
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
38/
The validation documentation template and program
should be adapted (2/2)
LIST NON EXHAUSTIVE
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
39/
Cleaning and process validation is on the TOP 10
deficiencies observed
Validation deficiencies observed in FY 2012 Most deficiencies observed 2007 -2014
Source: http://webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con464241.pdf

ElAzab EU GMP PDF

Diunggah oleh

Informasi Dokumen

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

ElAzab EU GMP PDF

Diunggah oleh

Hak Cipta:

Format Tersedia

EU GMP change impact on

cleaning and process validation

1 Current European change and link

2 Impact on cleaning and process validation

U.S. and E.U approach for carryover

Benchmark and Frequently Asked

Q7 Q10 Q8R2: QbD

State of the art document:

ICH Q8 ICH Q9 ICH Q10 ICH Q11

EC GMP Guide Part I EC GMP guide Annexes

Chapter Title date Annexes Title date

Who is impacted by these changes?

EU GMP manufacturers producing :

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

Medical devices manufacturers are not directly affected.

EMA draft on Manufacturing

PIC/S Submission for

Computer System Validation ICH Q8: Design space

1 Current European change and link

Impact on cleaning and process

Annex 15 Start a RM before cleaning validation

Cleaning validation change

Time line for implementation:

Nov 2014 Jun 2015 Dec 2015 Jun 2016

Worst case active residue

Active residue proprietary

Setting acceptance criteria (MACO)

Identify active residue

Ongoing process verification

Process development Process validation Life Cycle

Product with robust quality by design vs traditional approach

EMA call for continued

Differences and other

Incorporation of the ICH Encourage the use of product Emphasis the

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

Include equipment Include equipment Confusion by using the

1 Current European change and link

2 Impact on cleaning and process validation

U.S. and E.U approach for carryover

EMA: setting health based limit (2014)

PIC/S: Guidance - cleaning validation in active

ISPE : Risk MaPP (2010)

ADE (mg/day) = NOAEL (or LOAEL) x BW /

1 Current European change and link

2 Impact on cleaning and process validation

U.S. and E.U approach for carryover

Equipments group Cleaning SOP 2 Equipments group Cleaning SOP 2

Cleaning SOP 3 Cleaning SOP 3

Q: Should TOC or Conductivity data in routine for cleaning control is a must?

visually clean only is not sufficient in validation and in routine

if traditional approach is used then it is necessary to gather sufficient data

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

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

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

by an experienced toxicologist and it is the supplier

Q: How did you calculate the PDE for STERISs cleaner?

The toxicologist need to assess the LOAEL data

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

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

if you use cleaner: determine the MACO

LIST NON EXHAUSTIVE