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October 30, 2019 Cleaning

Cleaning Validation Guidelines - A

Complete List [Updated 2019]
Vivek Gera

Cleaning Validation is a critical component of an e ective GMP Compliance program at

any regulated drug manufacturing facility. In fact, Cleaning Validation in pharmaceutical
industry has been one of the most evolving and debated topic of the year 2018-19 as the
industry transitions towards a risk and science based validation from traditional V model
and towards Health Based Exposure Limits (HBEL) from traditional methods.
Every major regulator has either revised the Cleaning Validation Guideline in the last 2
years or in the process of revising. In this article, we take a look at the current status of
where the Cleaning Validation Guidelines stand for all major regulators and organisations.

1. U.S. Food and Drug Administration (USFDA)

FDA revised its guidance on Equipment Cleaning under Section 211.67 in 21CFR on April 1,
2018. FDA requires that:

Equipment and utensils shall be cleaned, maintained, and, as

appropriate for the nature of the drug, sanitized and/or sterilized at
appropriate intervals to prevent malfunctions or contamination that
would alter the safety, identity, strength, quality, or purity of the drug
product beyond the official or other established requirements.

Apart from the 211.67, there are many other documents published by the FDA that guide
the industry. Some of these links are given at the end of this section. Here are a few
noteworthy points:

1. Acceptable Residue: FDA has mentioned clearly in the Questions & Answers on
Current Good Manufacturing Practices—Equipment that the Contamination that is
reasonably avoidable and removable is never considered acceptable. Hence,
Cleaning Procedures must not be designed sub-optimally to remove a calculated
"acceptable" level of residue but rather based on scienti c understanding of the
substance and its interaction with other resources within the manufacturing facility.
Similarly, analytical methods should not be designed solely on the basis of the
acceptable residue that needs to be achieved.

2. Total Organic Carbon: FDA has come to terms with using TOC as an acceptable
method for monitoring residues routinely and for cleaning validation given that the
contaminating material(s) is organic and contains carbon that can be oxidized under
TOC test conditions.

3. Rinse Sampling: For cleaning validation, rinse samples alone would not be
acceptable; rms should also measure the residue or contaminant on the equipment
surface using a direct method such as swab (if feasible).

4. Continuous Process Veri cation: Many rms have not implemented this yet. FDA
is very clear that a Continuous Veri cation Program needs to be in place for routing
residue monitoring after Cleaning Validation. The frequency of this program will need
to be determined based on risk.

FDA doesn't really delve into the methodologies used to establish the residue limits
however it refers to some of the traditionally used criteria such as dosage and 10ppm.
Useful Links:

Read the complete FDA Cleaning Validation Guideline from CFR 211.67 here: CFR211.67

Read the full CFR 211 here: 21 CFR Part 211

Inspection References: Guide to inspections validation of cleaning processes

Validation of cleaning processes

Questions & Answers on Current Good Manufacturing Practices—Equipment

Leucine Micro Article on A discourse on calculating residue limits

2. European Medicines Agency (EMA)

EMA has certainly been a frontrunner when it comes to establishing risk-based cleaning
validation guidelines for prevention of cross-contamination in shared production facilities.
In guidance, e ective June 01, 2015, EMA made it mandatory to establish Health-Based
Exposure Limits for all the drug products based on Permitted Daily Exposure Values as
described in Appendix 3 of ICH Q3C (R4).

The guideline was soon followed up by a Q&A on the implementation of the above
guideline. The full Q&A is a must-read however a few key items are listed here.

HBELs should be established for all medicinal products.The

toxicological or pharmacological data, on which the HBEL calculation
relies, requires periodical reassessment throughout a product’s
lifecycle.

How To Use HBELs: Establishing HBELs is just the start. These values work as a basis to
determine the additional controls that may need to be put in place via a Quality Risk
Management process.

Acceptance vs Alert Limits: While HBELs work as Residue Acceptance Limits, the
manufacturers still need to set alert limits based on the historically used Cleaning Limits
(such as based on dosage) while ensuring that the Cleaning Processes are capable. This
means that if your historical dosage based limit is the worst but that results in CpK < 1.33,
the alert limit needs to be set based on the statistical evaluation and not based on the
dosage limit.

Analytical Testing at Product Changeover: This is now required unless the risk is
quanti ed low. Risk quanti cation is done based on the Severity (Toxicity Scale),
Probability (Cleaning Process Capability) and Detectability (Visual Threshold).
Using LD50: For drug products, now LD50 can not be used as an adequate point of
departure to determine HBELs.

Useful Links:

EMA Cleaning Validation Guideline on setting HBELs EMA HBEL Guideline

QnA on the implementation of the above guideline EMA HBEL Guideline QnA

3. World Health Organization (WHO)

WHO Cleaning Validation Guideline is very similar to that of FDA. WHO Good Manufacturing
practices for active pharmaceutical ingredients (Annex 2) lays out the basic requirements
throughout the document but speci cally under Sections 5.2 and 12.7. Here are a few
things to keep in mind:

Worst Case Approach: WHO clearly accepts the worst product approach to select
representative APIs to validate Cleaning Procedures. It further adds that the selection
should be based on the solubility and di culty of cleaning and the calculation of residue
limits based on potency, toxicity, and stability. It is very unclear though how to incorporate
stability into residue limits.

Continuous Process Veri cation: WHO recommends continuous monitoring using

methods such as analytical testing and visual examination. It gives a hint to the risk-
based methodology but lack of any further details leaves a lot to be desired.

Useful Links:
 WHO good manufacturing practices for active pharmaceutical ingredients Download
Here

Quality assurance of pharmaceuticals: A compendium of guidelines and related

materials Download Here

4. Pharmaceutical Inspection Co-operation

Scheme (PIC/S)
PIC/S followed EMA quickly and released its own version of the new Cleaning Validation
Guideline to the prevention of cross-contamination PI 046-1 Guideline on setting HBELs in
shared facilities to be e ective from July 01, 2018.

This was a monumental step in moving towards a risk-based cleaning validation program
since PIC/S has about 50 countries as it’s members. Does this mean that the regulators of
over 50 countries will start expecting the cleaning program that is in-line with the EMA
regulations? Only time will tell.

Soon after the release of the above-mentioned PIC/S guideline, an AIDE-MEMOIRE was
released which is a great resource for every pharma manufacturer as it details the things
that the regulators will look for in very speci c details. Not only it is an absolute must-
read, not following it will lead to a lot of regulatory troubles. It’s referenced in the link
below.

During an inspection attention should be paid to the risk management

of cross-contamination; however, the amount of time allocated will
depend upon the hazard level of the molecules, the type and number
of products handled, and the degree to which facilities are proven to
be separated and dedicated.

For those who may not be aware: PIC/S, which became operational in November 1995, is
meant as an instrument to improve co-operation in the eld of Good Manufacturing
Practices between regulatory authorities and the pharmaceutical industry.

Useful Links:

Aide-Memoire on cross-contamination in shared facilities PI-043-1

Guideline on Setting HBEL for use in risk identi cation in the manufacture of di erent
medicinal products in shared facilities PI 046-1

Guide to GMP for medicinal products Part 1 PE 009-14 (Part I)

5. Therapeutic Goods Administration (TGA)
TGA pretty much adopted the PIC/S Cleaning Validation Guideline to Good Manufacturing
Practices (PE009-13). This gives us the rst sign that the remaining countries may soon
come on board to the new ship that is the Risk and science-based Cleaning Validation
SOP.

The TGA is adopting version PE009-13 of the PIC/S Guide to Good

Manufacturing Practice for Medicinal Products (PIC/S Guide to GMP),
excluding Annexes 4, 5 and 14, as the manufacturing principles for:
Medicines and active pharmaceutical ingredients and Biologicals that
comprise or contain live animal cells, tissues or organs

TGA also published a notice about the transition to new GMP requirements for medicinal
products, which is worth having a look.

Useful Links:

TGA interpretation and expectations for demonstrating compliance See Here

A presentation on Cleaning Validation by TGA

6. Health Canada
Health Canada, in its Cleaning Validation Guidelines (Guide-0028), has listed down quite a
few unique requirements that are actually well known in the industry but surprisingly not
mentioned in many other guidelines.

We also slightly disagree with Principle 3.5 which speci es the worst-case risk as
acceptable along with the actual risk. We feel that the guidelines should not promote the
behavior of defaulting to the lazy approach of taking the worst-case risk rather than
putting e orts to identify the actual risk.

3.5 Cleaning procedures for products and processes which are very
similar do not need to be individually validated. This could be
dependent on what is common, equipment and surface area, or an
environment involving all product-contact equipment.

Taking all product-contact equipment approach often results in severe ine ciencies in
terms of the number of validation batches as well as the cost of compliance. We have
described it in more depth in one of the earlier Micro Articles 5 Data-driven strategies to
improve GMP cleaning e ciency by 5X.
Another unique guidance is related to doing a cost-bene t analysis of dedicating vs
sharing equipment.

4.2 In a multi-product facility, the effort of validating the cleaning of a

specific piece of equipment which has been exposed to a product and
the cost of permanently dedicating the equipment to a single product
should be considered.

Health Canada has done the best job of describing the revalidation requirements. It
requires a real-time mechanism to assess the impact of relevant changes on the cleaned
status of the facility. These changes may be: 

Changes in the cleaning procedure;

Changes in the raw material sources;

Changes in the formulation and/or process of products;

New products;

Changes in the formulation of detergents;

New detergents;

Modi cations of equipment.

11.1 A change control system is in place to ensure that all changes that
might impact the cleaning process are assessed and documented.
Significant changes should follow a satisfactory review and
authorization of the documented change proposal through the
change control procedure. Minor changes or changes having no direct
impact on final or in-process product quality should be handled
through the documentation system. The review should include
consideration of the re-validation of the cleaning procedure.

Useful Links:

Health Canada Cleaning Validation Guideline Guide-0028

7. Parenteral Drug Association (PDA)

PDA has published two separate documents related to Cleaning Validation. PDA Technical
Report 29 for Actives and PDA Technical Report 49 for Biotechnology products.

PDA Cleaning Validation Technical Reports are the most comprehensive guides when it
comes to going into the depths of the Cleaning Validations and establishing a Cleaning
Validation SOP for your rm.

We highly recommend every reader to get a copy and dive deep into the details.

Useful Links:

PDA Technical Report 29: Points to Consider for Cleaning Validation PDA TR 29

PDA Technical Report 49: Points to Consider for Biotechnology Cleaning Validation
PDA TR 49

8. International Society For Pharmaceutical

Engineering (ISPE)
ISPE also revised its Baseline Guide on Risk-MaPP (Risk-Based Manufacture of
Pharmaceutical Products) and published in 2nd edition in 2017. The revisions are mostly
related to the 2015 EMA guideline on setting HBELs. 

EMA guideline has done a wonderful job in describing the high-level principles of
establishing a Cleaning Validation SOP that is based on science and risk. However, it has
been interpreted in many di erent ways by di erent individuals, organizations and even
regulators and that have instilled a sense of confusion within the industry. This is the
primary reason why the 2015 EMA guideline has not been fully implemented by many
organizations yet. 

Risk MaPP 2nd Edition addresses the confusion really well. We believe that pharma
manufacturing rms can use it as a “baseline standard” for designing the Cleaning
Validation SOP. Since the Risk-MaPP is a rather lengthy document, we’ll be publishing a
short article on it soon.

Useful Links:

Baseline Guide Vol 7: Risk-Based Manufacture of Pharma Products 2nd Edition ISPE
Risk-MaPP

9. Active Pharmaceutical Ingredients Committee

(APIC)
APIC Cleaning Validation Guideline is used by many organizations especially the ones that
produce only raw API materials. APIC also revised its 2014 Guideline on aspects of
Cleaning Validation in Active Pharmaceutical Ingredient plants in the year 2016 to
incorporate the EMA guidance on using HBELs. The main changes were introduced in
Chapter 4, Acceptance Criteria.

Even though a popular and widely adopted guideline, and appreciated by many for the
details that it provides related the uniqueness in managing small molecules, APIC is
criticised frequently for its confusing terminology and inconsistencies throughout the
document. Here is an example of a blatant mistake that was present in APIC 2014 and
carried over to APIC 2016. Apparently, the Maximum Allowable Carryover of mistakes is
pretty relaxed when it comes to APIC!

We would still recommend reading it if you looking to deep dive into the speci cs of
handling small-molecules.

Useful Links:

Guidance on aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants

APIC Cleaning Validation 2016

10. American Society For Testing and Materials

(ASTM)
ASTM E3106 - 18e1 (Standard Guide for Science-Based and Risk-Based Cleaning Process
Development and Validation) is the latest document that has come out related to the
Cleaning Validation Standards. A unique thing about these standards is that it
incorporates many of the science-based, risk-based, and statistical concepts and
principles introduced in the FDA’s Guidance for Industry Process Validation. This guide
supports and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, and ICH Q11.

This standard is gradually becoming popular and, in our opinion, is really what the industry
needs: science-based, risk-based and statistics-based approach to establishing a
Cleaning Validation SOP.

Useful Links:

ASTM Standard is available here: ASTM E3106

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