EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?


In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.

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In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.

The document altogether comprises five pages with 14 questions and answers.

The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?

The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.

Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.

There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.

The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.

Please also see the draft 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’on the EMA website.

At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.

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Cleaning Validation

Cleaning Validation


Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. The focus of cleaning validation is those cleaned surfaces that, if inadequately cleaned, could potentially contaminate the product subsequently manufactured in that same equipment.

This primarily covers product contact surfaces in the cleaned equipment. Cleaning validation is not performed only to satisfy regulatory authorities. The safety of patients is the primary objective, and product contamination presents serious liability issues for any pharmaceutical manufacturer or contract organization.

The history behind cleaning validation

The unhygienic conditions in Chicago’s meat- packing plants revealed in Upton Sinclair’s novel, “The Jungle”, allowed the government investigators and congress to enact the meat inspection law and the Pure Food and Drugs Act in 1906, the law forbade adulteration, misbranding adulteration, misbranding of foods, drinks, and drugs.
Thirty years later the drug tragedy “elixir of sulfanilamide” which killed over 100 people, greatly dramatized to broaden the existing legislation. On June, 25th 1938 Franklin D. Roosevelt signed the Federal Food, Drug, and Cosmetic Act, it required manufacturers to provide scientific proof of drug safety before it could be marketed.
All these events brought the current regulatory requirements for cleaning validation.


Cleaning can be defined as removal of residues and contaminants. The residues and contaminants can be the product themselves manufactured in the equipment or residues originating from the cleaning procedure (detergents / sanitizers) or degradation products resulting from the cleaning process itself.

The basic mechanisms involved in removing the residues and contaminants from the equipment are mechanical action, dissolution, detergency and chemical reaction.

1.Mechanical action – It refers to the removal of residues and contaminants through physical actions such as brushing, scrubbing and using pressurized water.

2.Dissolution – It involves dissolving the residues with a suitable solvent. The most common and practical solvent is water being non-toxic, economical, environment friendly and does not leave any residues. Alkaline and acidic solvents are sometimes preferred as it enhances the dissolution of the material, which are difficult to remove.

3.Detergency-Detergent acts in four ways as wetting agent, solubilizer, emulsifier and dispersant in removing the residues and contaminants from the equipment

4.Chemical reaction- Oxidation and hydrolysis reaction chemically breaks the organic residues and contaminant to make them readily removable from the equipment

What is cleaning validation ?


It is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits.

Why cleaning validation ?


To verify the effectiveness of cleaning procedures and to ensure no risks are associated with cross contamination of active ingredients or detergent/sanitizer.

When cleaning validation ?


· Initial qualification of a process/equipment
· Critical change in a cleaning procedure
· Critical change in formulation
· Significant change in equipment
· Change in a cleaning process
· Change in a cleaning agent.


Why we do validation for 3 times ?


Once an FDA was asked why do we do it 3 times?
His answer was – Because if it comes out right once it is an accident, twice coincident, three times validation.


Regulatory requirements for cleaning validation

• FDA has required that the equipment to be cleaned prior to use (GMP regulation-Part 133.4) This is one of the basic GMP requirement and it is indicated in more than one section of 21CFR 211 (FDA, April 1998)
• Section 211.63 relates to the equipment design, size, location, and requires that equipment used in the manufacture, processing, packaging, holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
• Section 211.65 states that a) the construction of equipment which contact the in-process materials, or drug products shall not be reactive, additive or absorptive so as to alter the safety, identity, strength, quality or purity of the drug product beyond official or other establishment requirements.
b) Any substances required for operation, such as lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality or purity of the drug product beyond official or other establishment requirements.
• Section 211.67 further requires that the equipment and the utensils shall be cleaned, maintained and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product in form of written procedure including all the parameters during cleaning.
• Section 211.180 and 211.182 relates to the record that should be kept for the maintenance, cleaning, sanitation and inspection of equipment.


The Common elements of Cleaning Validation

· Written cleaning procedures should be established. Attention should be addressed to dedicate certain equipment to specific products, such as fluid bed dryer bags and to residue originating from the cleaning detergent or solvent themselves.

· Procedure on how validation will be performed should be in place.

· Who is responsible for performing and approving the study.

· Acceptance criteria should be set.

· Procedure dealing with the subject of when revalidation study stating issues such as sampling procedure and analytical methods.

· Study should be conducted according to protocol.

· Approved report should state the validity of the cleaning process.


Cleaning procedure

The two common cleaning procedures are,

· Manual cleaning

· Automated cleaning procedures such as CIP (Cleaning In Place

Manual Cleaning Sequence
CIP Cleaning Sequence
Dismantle the parts of equipment to be cleaned
Pre-wash the parts in tap water
Pre-wash the parts with tap water
Wash the pre-washed parts with cleaning solution
Wash the pre-washed parts with cleaning solution
Blow out using compressed air
Rinse the parts in tap water
Rinse the parts with tap water
Rinse now with purified water
Final rinse using purified water
Dry the parts using hot air
Blow out using compressed air
Visual inspection is done to check whether the equipment is clean
Drying using hot and compressed air
Reassemble the parts finally

In all cases cleaning procedure must prove to be effective, consistent and reproducible.

FDA recommends (CIP) should be used to clean process equipment and storage vessels in order to reproduce exactly the same procedure each time (FDA, March 1998).

With manual procedure one must rely on the operator skills and thorough training of the operator is necessary to avoid variability in performance. However in some instances, it may be more practical to use only manual procedures.


Sampling methods for Cleaning Validation

There are three known sampling methods:

1.Swabbing (or direct surface sampling) method

2.Rinse sampling method

3.Placebo method.

Swabbing technique involves the use of a swabbing material, often saturated with solvent, to physically sample the surfaces.


· Dissolves and physically removes sample

· Adaptable to a wide variety of surfaces

· Economical and widely available

· May allow sampling of a defined area

· Applicable to active, microbial, and cleaning agent residues


·An invasive technique that may introduce fibres

·Results may be technique dependent

·Swab material and design may inhibit recovery and specificity of the method

·Evaluation of large, complex and hard to reach areas difficult (e.g., crevices, pipes, valves, large vessels)

·Subject to the vagaries of site selection

Rinse Sampling involves passing a known volume of solution over a large area and analyzing the recovery solution.


·Adaptable to on-line monitoring

· Easy to sample

· Non-intrusive

· Less technique dependent than swabs

· Applicable for actives, cleaning agents and excipients

· Allows sampling of a large surface area

· Allows sampling of unique (e.g., porus) surfaces


· Limited information about actual surface cleanliness in some cases

· May lower test sensitivity

· Residues may not be homogeneously distributed

· Inability to detect location of residues

· Rinse volume is critical to ensure accurate interpretation of results

· Sampling methodology must be defined since rinse sampling method and location can influence results

· May be difficult to accurately define and control the areas sampled, therefore usually used for rinsing an entire piece of equipment, such as a vessel

· Reduced physical sampling of the surface

Placebo sampling can be used to detect residues on equipment through the processing of a placebo batch subsequent to the cleaning process. It is appropriate for active residue, cleaning agent, particulates and microbial testing. Placebos are used primarily to demonstrate the lack of carryover to the next product. The placebo should mimic product attributes. The equipment characteristics also impact the choice of the placebo batch size.


· Placebo contacts the same surfaces as the product

· Applicable for hard-to-reach surfaces

· Requires no additional sampling steps


· Difficult to determine recovery (contaminants may not be evenly distributed in the placebo)

· Lowers analytical specificity and inhibits detectability

· Takes longer and adds expense since equipment must be cleaned after the placebo run

· Placebos must be appropriate for each potential product

· Residues may not be homogenously distributed

· No direct measurement of residues on product contact surfaces

The preferred sampling method and the one considered as the most acceptable be regulatory authorities is the swabbing method.

The Common analytical methods and their basic requirements

Specific and non-specific are the two analytical methods used widely to detect any compound. The choice of using a specific or non specific method can be difficult. If a drug active is highly toxic, a specific method is always recommended.

Chromatographic methods are preferred for cleaning validation studies because of their sensitivity, specificity, and ability to quantify.

Specific method:

It is a method that detects a unique compound in the presence of potential contaminants.

Some examples of specific methods are high performance liquid chromatography (HPLC), Ion chromatography, Atomic absorption, Capillary electrophoresis, and other chromatographic methods.

Non-specific method:

It detects any compound that produces a certain response.

Some examples of non specific methods are Total Organic Carbon (TOC), pH, Titration, and conductivity.

It is always wise to choose the simplest technique that can be used to reach the desired goal.

The basic requirement for the analytical method

The sensitivity of the method shall be appropriate to the calculated contamination limit.

The method shall be practical and rapid, and, as much as possible use instrumentation existing in the company.

The method shall be validated in accordance with ICH, USP, EP requirements.

The analytical development shall include a recovery study to challenge the sampling and testing methods.



Cleaning Validation Resources

1) http://apic.cefic.org/pub/4CleaningVal9909.pdf
2) http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074922.htm
3) http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_r…
4) http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/validation/gui-002…

Cleaning Validation and Analytical methods used for detection of residue

Cleaning Validation and Analytical methods

The specificity and the sensitivity of the method used for detection of contaminants after cleaning process are of great importance.
If the residues of previous product or the cleaning process is not detected in the analysis, which doesn’t mean that it is completely absent, it may be a case where the sensitivity of the analytical method and the limits may not be able to trace them in present concentration in the sample. The poor sampling method may be a cause of the absence of residue after cleaning as well. Therefore it is advisable that the analytical method must be challenged with different combination of sampling methods which are particularly used to demonstrate that the contaminant residue can be removed from an equipment surface at the level of 50% and 90% etc .Cleaning process evaluation and production in process quality control tests.
In process quality assurance tests can be used as tools to evaluate the efficacy of cleaning process, some of the indirect test like conductivity of last wash water can be used to predict and monitor the cleaning process. There must be a correlation between the in process test used to monitor effectiveness of cleaning, and during validation these tests should document that the the equipment not cleaned completely fail the in process tests employed. good manufacturing practices

Test for Total Organic Carbon (TOC) (TC ) for evaluation of efficacy of cleaning process:

Yes ! We can set this one of the test for evaluating cleaning effectiveness . in US FDA’S publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.

Total Organic Carbon (TOC) (TC ) will be an acceptable method for monitoring residues routinely and for cleaning validation. To make this test TOC to be functionally suitable, we should first establish with suitable study that a substantial amount of the contaminating material(s) is of organic origin which contains carbon that can be oxidized by conditions applied in TOC test. This is an important exercise because some organic compounds cannot be reliably detected using TOC.

Test for TOC may be used to for direct surface sample testing as well as indirect (rinse water) sample testing. In both cases. As TOC does not identify or distinguish between different compounds containing oxidizable carbon, any detected carbon is to be therefore attributed to the target compound(s) for comparing with the established limit. Thus, a pharmaceutical manufacturing firm should limit ‘background’ carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are required to be stored for long periods of time before analysis, a pharmaceutical manufacturing firm should verify the impact of sample storage time on accuracy and limit of quantization.

What are the References for above discussion:

21 CFR 211.67: Equipment cleaning and maintenance.
21 CFR 211.160(b): General requirements (Laboratory Controls)
USP 643 Total Organic Carbon
Guide to Inspections of Cleaning Validation, 1993



Laboratory Validation / Analytical Method Validation. Laboratory Validation is a process that is employed to ensure that laboratory test data and results are consistent, accurate and precise. The validation process for test methods, as well as the instrumentation that is used to perform the analysis, have IQ, OQ and PQ protocols. There are eleven main principles to the PQ laboratory test validation protocol. These points are to be applied to each and every laboratory test that is critical to the pharmaceutical manufacturing process as well as the stability program and any process validation. Not all of the eleven principles may apply to each type of testing that is performed, however, a thorough review must be done in order to ensure a complete protocol has been written. VCI’s experience with a broad range of analytical methods can make your laboratory validation project run flawlessly.
The eleven PQ principles are listed below:

  • Specificity
  • Linearity
  • Accuracy
  • Precision
  • Robustness
  • Range
  • Detection Limit (LOD)
  • Quantitation Limit (LOQ)
  • Ruggedness
  • Selectivity
  • System Suitability

Cleaning Validation. This validation is used to show proof that the cleaning system consistently performs as expected and provides scientific data that consistently meets pre-determined specifications for the residuals.

The cleaning validation process must be written into protocols and standard operating procedures which are detailed and specific for the different pieces of equipment and instrumentation used by the facility for each type of drug product produced. Other protocols and SOP’s are also required based on the type of product manufactured or process used (such as a batch or bulk process or shared versus dedicated equipment).

A final report on the cleaning validation system will attest that the studies and data prove that the process is in control and cleans as expected. This report will also detail when and why revalidation needs to take place. Call on VCI to help you clean up your cleaning validation backlog.

Hazard Analysis and Critical Control Points (HACCP). The HACCP process is a prevention-based food safety system. These HACCP programs are to be designed to prevent the occurrence of potential food safety problems. The system appears to be simple at first glance, however, it requires a methodical, systematic approach. A pre-requisite to a well-developed and implemented HACCP system must be a solid current Good Manufacturing Practices (cGMP) program as well as strongly committed management.