Cleaning validation guide -Health Canada

1. Purpose

This document is for anyone involved in pharmaceutical, biological and radiopharmaceutical fabrication and packaging activities for drugs sold in Canada, including:

• regulated industry
• inspectors and evaluators

It provides guidance on cleaning validation. It will help you understand and comply with Part C, Division 2 of the Food and Drug Regulations (the Regulations).

This guide is also intended to establish inspection consistency and uniformity with respect to equipment cleaning procedures. Principles incorporated in international guidance have been taken into account when preparing this document.

2. Scope

This guide addresses special considerations and issues when validating cleaning procedures for equipment used to fabricate and package:

• active pharmaceutical ingredients (APIs)
• pharmaceuticals
• radiopharmaceuticals
• biological drugs
• veterinary drugs

It covers validation of equipment cleaning for:

• the removal of residues associated with products used in the previous production run, such as active ingredients, breakdown or by-products of concern, intermediates, residues of cleaning agents, and processing agents
• the control of potential microbial contaminants

Additional guidance on cleaning validation for certain veterinary drugs and Category IV drugs can be found in these Health Canada guidance documents:

3. Introduction

These guidelines interpret the requirements for good manufacturing practices (GMP) in Part C, Division 2 of the Regulations. They were developed by Health Canada in consultation with stakeholders.

Guidance documents like this one are meant to help industry and health care professionals understand how to comply with regulations. They also provide guidance to Health Canada staff, so that the rules are enforced in a fair, consistent and effective way across Canada.

Health Canada inspects establishments to assess their compliance with the Food and Drugs Act (the Act) and associated regulations. When Health Canada conducts an inspection, inspectors will use this document as a guide in assessing the site's compliance with GMP requirements with respect to equipment cleaning.

These guidelines are not the only way GMP regulations can be interpreted, and are not intended to cover every possible case. Other ways of complying with GMP regulations will be considered with proper scientific justification. Also, as new technologies emerge, different approaches may be called for. This document builds on other international guidance

Guidance documents are administrative and do not have the force of law. Because of this, they allow for flexibility in approach. Use this guide to help you develop specific approaches that meet your unique needs.

Guidance

4. Principles

Cleaning validation is performed to ensure that the equipment cleaning process will consistently reduce the possibility of cross contamination via carryover in a drug manufacturing process. It provides documented evidence that an approved cleaning process will reproducibly remove previous products, by-products of concern or cleaning agent residues that may remain on the equipment to below scientifically set limits.  These limits are calculated based on safe threshold values, which are determined by toxicological evaluation.

All cleaning processes for product contact equipment should be validated in accordance with Quality Risk Management (QRM) principles. Consideration should also be given to non-contact parts from which product may migrate. These should be based on risk.

Remediation actions must be implemented when a cleaning process is not capable of consistently producing adequate results. Examples of remediation actions include improved cleaning procedures and equipment/facility dedication. Continued cleaning failures and/or testing until clean (i.e. continually cleaning and testing until acceptable results are achieved) are not acceptable.

It is also important to demonstrate that the facility and equipment are designed, cleaned and used in a manner that will prevent microbial contamination of products.

4.1 About safe threshold values

It is Health Canada's intention to align with guidance adopted July 1, 2018 by the Pharmaceutical Inspection Co-operation Scheme (PIC/S) on use of toxicological evaluation in setting Health Based Exposure Limits (HBEL). With this approach, an evaluation of all pharmacological and toxicological data should be undertaken by a qualified person to determine a safe daily threshold value, such as Permissible Daily Exposure (PDE) or Threshold of Toxicological Concern (TTC).

The PDE represents a substance specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.

The TTC represents the genotoxic impurity exposure level associated with a theoretical cancer risk of 1 additional cancer in 100,000 patients when exposed over a lifetime.

Definitions are from PIC/S Guideline on exposure limits - Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (PI 046-1).

Additional information can be found in the following question and answer document published by PIC/S.

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' (PI 053-1).

The HBEL, such as the PDE or TTC, can then be used in risk identification and justification of maximum safe carryover limits into the next product. Other approaches to determining health based exposure limits may be considered acceptable in accordance with QRM principles and if scientifically justified.

It should be noted that the PIC/S Guideline also states that the PDE and ADE (Allowable Daily Exposure) are effectively synonymous.

5. Applying QRM principles to control cross-contamination risks

You have an obligation to prevent the cross contamination of drugs. This is achieved by developing a contamination control strategy, which will include designing and establishing appropriate controls of the premises, equipment and all associated processes. It should be recognized that equipment cleaning is only one of many measures that should be taken to control risk of cross-contamination in a multi-product facility or on equipment proposed to be shared.

1. Actions should be taken on a level proportional to the identified risks e.g. greater control is required for products with lower HBELs.
2. All potential sources of cross contamination should be assessed via a documented QRM process. The QRM process should evaluate risks based on scientific knowledge and assessment, and determine measures that can be taken to reduce those risks. 
3. The outcome of the QRM process should be the basis for determining the extent of the technical and organizational measures required to control risks for cross-contamination.  Refer to Appendices of this document for a list of technical and operational measures to consider.
4. Measures to prevent cross-contamination and their effectiveness should be reviewed periodically according to set procedures.
5. If the QRM process confirms that the drug can safely be made on shared equipment, validate any equipment cleaning process(es) to be used.

6. Cleaning validation master plan

You should maintain a Cleaning Validation Master Plan (or equivalent document) to outline the general cleaning validation policies at your site.

1. Product and equipment may be grouped in accordance with QRM principles:
1. You may choose to conduct cleaning validation studies on all products at the facility or on worst case products only (the product family approach).  You must stipulate and justify, as required, which approach is being used in the Cleaning Validation Master Plan. If a worst case approach is being used, you should document:
• the methodology/scientific rationale used in determining the worst case products
• the actual worst case products including a listing of all products deemed to be represented by the identified worst case products

Examples of factors that can be included in the assessment of worst case products include:

§  HBEL of the residue

§  difficulty in cleaning or product cleanability

§  solubility of residues in cleaning agents and cleaning solvents

§  physical characteristics of the product, active substance or excipients

§  past experience (for example during development and with similar products)

It should be noted that there may be multiple worst case products. For example, an insoluble product with a high HBEL value may be the most difficult product to clean but not necessarily worst case compared to a partially soluble product with a low HBEL value.

2. You may choose to conduct cleaning validation studies for all equipment or by grouping similar equipment, such as 'like for like' equipment. A representative approach is only suitable if equipment is equivalent in terms of size, design, function, cleaning procedure and cleanability. If there are any differences in equipment, the proposal to group them should be based on data. If an equipment grouping approach is being used, you should document:
• the approach/scientific rationale by which equipment were grouped together
• the listing of all equipment in each group, identifying the equipment in each group that is considered to be worst case, with proper justification.
1. All cleaning processes must be equivalent if cleaning validation studies are to be conducted following a worst case product and/or equipment grouping approach.