PHARMACEUTICAL INSPECTION CONVENTION

PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

PI 053-1
1 June 2020

QUESTIONS AND ANSWERS ON

IMPLEMENTATION OF RISK-BASED
PREVENTION OF CROSS-
CONTAMINATION IN PRODUCTION AND
‘GUIDELINE ON SETTING HEALTH-BASED
EXPOSURE LIMITS FOR USE IN RISK
IDENTIFICATION IN THE MANUFACTURE
OF DIFFERENT MEDICINAL PRODUCTS IN
SHARED FACILITIES’

© PIC/S June 2020

Reproduction prohibited for commercial purposes.
Reproduction for internal use is authorised,
provided that the source is acknowledged.

Editor: PIC/S Secretariat

e-mail: [email protected]
web site: http://www.picscheme.org

PI 053-1 1 of 7 1 June 2020

 TABLE OF CONTENTS

Page

1. DOCUMENT HISTORY ........................................................................... 2

2. INTRODUCTION ..................................................................................... 2
3. SCOPE .................................................................................................... 3
4. QUESTIONS & ANSWERS ON IMPLEMENTATION OF RISK-BASED
PREVENTION OF CROSS-CONTAMINATION IN PRODUCTION AND
‘GUIDELINE ON SETTING HEALTH-BASED EXPOSURE LIMITS FOR
USE IN RISK IDENTIFICATION IN THE MANUFACTURE OF
DIFFERENT MEDICINAL PRODUCTS IN SHARED FACILITIES’.......... 3
5. REFERENCES ........................................................................................ 7
6. REVISION HISTORY .............................................................................. 7

1. DOCUMENT HISTORY

Adoption by Committee of PI 053-1 22 May 2020

Entry into force of PI 053-1 1 June 2020

2. INTRODUCTION
2.1 The present PIC/S Question and Answers are based on European Medicines
Agency (EMA) document EMA/CHMP/CVMP/SWP/246844/2018 Questions
and answers on implementation of risk-based prevention of cross-
contamination in production and ‘Guideline on setting health-based exposure
limits for use in risk identification in the manufacture of different medicinal
products in shared facilities’. This document has been transposed for PIC/S
purposes.

2.2 These questions and answers have been adopted by PIC/S to support the
PIC/S Guideline on setting health based exposure limits for use in risk
identification in the manufacture of different medicinal products in shared
facilities (PI 046). It is up to each PIC/S Participating Authority to decide
whether these documents should become a legally-binding standard.

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3. SCOPE
3.1 The scope of the present guideline is to support the PIC/S Guideline on setting
health-based exposure limits for use in risk identification in the manufacture of
different medicinal products in shared facilities (PI 046).

4. QUESTIONS & ANSWERS ON IMPLEMENTATION

OF RISK-BASED PREVENTION OF CROSS-
CONTAMINATION IN PRODUCTION AND
‘GUIDELINE ON SETTING HEALTH-BASED
EXPOSURE LIMITS FOR USE IN RISK
IDENTIFICATION IN THE MANUFACTURE OF
DIFFERENT MEDICINAL PRODUCTS IN SHARED
FACILITIES’
Q1. Are Health-Based Exposure Limits (HBELs) required for all medicinal
products?

A: Yes, HBELs should be established for all medicinal products.

The toxicological or pharmacological data, on which the HBEL calculation

relies, requires periodical re-assessment throughout a product’s lifecycle.

Q2. Is there a framework that could be used to define the significance of the
Health-Based Exposure Limit (HBEL) such that there can be broad
guidance on the extent of Quality Risk Management (QRM) and control
measures required?

A: Firstly, it should be recognised that hazard varies on a continuum scale and

that there are no firm cut off points, risk should be controlled on a proportionate
basis. However, as a broad hypothetical model the following figure could be
considered to show the increasing level of hazard (red being highest hazard)
presented by products and there should be a commensurate increase in the
level of control to prevent potential cross contamination in a shared facility.
Actual HBEL values should be used in QRM studies to determine the actual
controls required.

Diagram developed from an original concept published by ISPE. Source: ISPE Baseline®
Pharmaceutical Engineering Guide, Volume 7 – Risk-Based Manufacture of Pharmaceutical
Products, International Society for Pharmaceutical Engineering (ISPE), Second Edition, July
2017.

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Q3. How should manufacturers use the HBELs?

A: The role of HBELs in determining cleaning limits is explained in Q&A 6.

However, the purpose of generating HBELs goes beyond justification of
cleaning limits.

Once the health-based assessment has been completed and the HBEL
confirmed, these data should be used via a Quality Risk Management process
to determine what controls need to be put in place and to assess if existing
organisational and technical control measures are adequate or if they need to
be supplemented. This Quality Risk Management process should be carried
out prospectively in the case of new equipment/facility to determine what
control measures are required.

It is expected that for products which present a higher potential harm to

patients/animals, more elaborate organisational and technical control
measures will be required. Using a structured Quality Risk Management
process, manufacturers should consider the risks of cross contamination down
to the established level from the HBEL. During the QRM study manufacturers
should consider how easily such a quantity of contamination could occur,
without detection, at batch and unit dose level.

The level of detail in the QRM process should be commensurate with the
potential harm as indicated by the HBEL and the suitability of control measures
supported by practical and science-based evidence.

Manufacturers should be mindful that cross contamination controls

implemented previously may not adequately assure control of the cross-
contamination risk in the context of the HBEL approach.

Additional observation of working practices, investigation and analysis may be

required to provide full practical confidence in the effectiveness of controls.

Where control measures cannot adequately assure that the potential

contamination is consistently controlled to a level below that of the HBEL or
where scientific data from the toxicological evaluation does not support a
controllable risk (e.g. allergenic potential from highly sensitising materials such
as beta-lactams) then the products concerned should be manufactured in
dedicated facilities.

Q4. What competencies are required for the person developing the Health-
Based Exposure Limits (HBEL)?

A: Health-Based Exposure Limits should be determined by a person who has

adequate expertise and experience in toxicology/pharmacology, familiarity
with pharmaceuticals as well as experience in the determination of health-
based exposure limits such as Occupational Exposure Levels (OEL) or
Permitted Daily Exposure (PDE).

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 Where experts are contracted to provide the HBEL, contractual agreements in
compliance with PIC/S GMP Guide Chapter 7 requirements should be in place
prior to work being conducted. It is not considered acceptable for
manufacturers to ‘purchase’ HBEL assessments without recording an
assessment of the suitability of the provider (including the specific technical
expert) as a qualified contractor.

Q5. What responsibility do contract givers have to contract manufacturers

in relation to data to support a HBEL assessment?

A: Contract givers should either provide a full HBEL assessment to contract

manufacturers or provide the data to allow the contract manufacturer to
conduct the HBEL assessment. In either case the HBEL assessment,
including data references and relevant experts should be available on request
during inspection of the manufacturer.

Q6. How can limits for cleaning purposes be established?

A: Although the PIC/S Guideline on setting health based exposure limits for use
in risk identification in the manufacture of different medicinal products in
shared facilities (PI 046) may be used to justify cleaning limits (as per
Introduction section 2.4), it is not intended to be used to set cleaning limits at
the level of the calculated HBEL.

For existing products, manufacturer’s historically used cleaning limits should

be retained and can be considered alert limits provided that when taking
cleaning process capability into account, they provide sufficient assurance that
excursions above the HBEL will be prevented. A similar process should be
adopted when establishing cleaning alert levels for products introduced into a
facility for the first-time.

Results above the alert cleaning limit should trigger an investigation and,
where appropriate, corrective action to bring the cleaning process
performance within the alert cleaning limits. Repeated excursions above the
alert cleaning limit will not be considered acceptable where these indicate that
the cleaning method is not in control. Recognised appropriate statistical
methods may be used to determine whether the cleaning process is in control
or not.

Q7. Is analytical testing required at product changeover, on equipment in

shared facilities, following completion of cleaning validation?

A: Analytical testing is expected at each changeover unless justified otherwise

via a robust, documented Quality Risk Management (QRM) process. The
QRM process should consider, at a minimum, each of the following:
 the repeatability of the cleaning process (manual cleaning is
generally less repeatable than automated cleaning);
 the hazard posed by the product;
 whether visual inspection can be relied upon to determine the
cleanliness of the equipment at the residue limit justified by the
HBEL.

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Q8. What are the requirements for conducting visual inspection as per
Q&A 7?

A. When applying visual inspection to determine cleanliness of equipment,

manufacturers should establish the threshold at which the product is readily
visible as a residue. This should also take into account the ability to visually
inspect the equipment, for example, under the lighting conditions and
distances observed in the field.

Visual inspection should include all product contact surfaces where

contamination may be held, including those that require dismantling of
equipment to gain access for inspection and/or by use of tools (for example
mirror, light source, boroscope) to access areas not otherwise visible. Non-
product contact surfaces that may retain product that could be dislodged or
transferred into future batches should be included in the visual inspection.

Written instructions specifying all areas requiring visual inspection should be

in place and records should clearly confirm that all inspections are completed.

Operators performing visual inspection require specific training in the process

including periodic eye sight testing. Their competency should be proven
through a practical assessment.

Q9. Is it acceptable to simply segregate products of a common therapeutic

classification in a dedicated area as a means of controlling risk of cross
contamination?

A: Manufacturers cannot just segregate common products from other product

types as a means of dealing with the risk to patient and animal safety. Although
this may prevent contamination of other product classes it does not address
the possibility for cross contamination within product classes. The approach
taken to control cross contamination between individual products within a
class produced in the same dedicated area should follow the principles in Q&A
3. This should include implementation of appropriate organisational and
technical control measures to prevent contamination between such products
within product specific HBELs.

Q10. Is the use of LD50 to determine Health-Based Exposure Limits for drug
products acceptable?

A: No, LD50 is not an adequate point of departure to determine a HBEL for drug
products.

Q11. Can Ectoparasiticides be manufactured or primary packed in common

equipment with other categories of medicinal products for human or
veterinary use?

A: If a HBEL cannot be determined or data cannot support manufacture in shared

facilities then the Ectoparasiticides should be manufactured in dedicated
facilities.

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Q12. What needs to be taken into account when manufacturing Veterinary
Medicinal Products for different species in the same facility?

A: The guideline on setting health-based exposure limits indicates that the carry
over limit should generally be derived using the human HBEL.

However, in cases where there is concern relating to known susceptibility of a

particular species (e.g. monensin in horses) the HBEL approach should take
into account knowledge of specific animal toxicity when evaluating products
manufactured in shared facilities/equipment.

Q13. Should the HBEL be re-assessed throughout the phases of development

of Investigational Medicinal Products (IMPs)?

A: Health-Based Exposure Limits should be established based on all available

data, and particularly as the knowledge base for IMPs is continually evolving
the basis for establishing the HBEL, should be regularly reviewed taking
account of any new relevant data. Similarly, for commercial products, newly
available information (e.g., pharmacovigilance data, new scientific knowledge)
should be periodically reviewed to determine if the original hazard analysis is
still appropriate.

5. REFERENCES
PIC/S PE 009 Guide to Good Manufacturing Practice for Medicinal Products, Part I;
Basic Requirements for Medicinal Products

PIC/S PE 009 Guide to Good Manufacturing Practice for Medicinal Products,

Annexes including PIC/S Annex 20 Quality Risk Management

PIC/S PI 043 Aide-Memoire Cross-Contamination in Shared facilities

PIC/S PI 046 Guideline on Setting Health Based Exposure Limits for use in
Risk Identification in the Manufacture of Different Medicinal
Products in Shared Facilities

PIC/S PI 052 Aide-Memoire Inspection of Health Based Exposure Limit

(HBEL) Assessments and use in Quality Risk Assessment

6. REVISION HISTORY
Version
Date Reasons for revision
Number

PI 053-1 7 of 7 1 June 2020