Risk Assessment in Cleaning Validation – An Overview

The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a risk assessment based approach for the validation can be used.

Introduction

It is an ethical worldwide acceptable aspect to use clean item / objects for use / consumption. Irrespective of manufacturing process, cleaning is the first aspect which is ensured by the individuals / organizations even in day-to-day life. This article will cover the basics of cleaning concepts employed to ensure how much clean is clean.

Application

Cleaning aspect is employed with a general objective i.e. for removal of contaminants / residue. In case of pharmaceutical industry, pharmaceutical products & APIs can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by other materials (i.e. dust, lubricants, air-borne particles) & by micro-organisms.

In many cases same equipment may be used for processing of different products & to avoid the contamination, adequate cleaning procedures are essential.

Cleaning Validation in Pharmaceutical Industry

Since the pharmaceutical industries are involved in business of vital life saving drugs, hence it is required by law & with aspects of patient safety. Let’s have a quick view on requirements by law:

1. 21 CFR Part 210 & 211, USFDA [$211.67. Equipments & utensils shall be cleaned, maintained & sanitized at appropriate intervals to prevent malfunctions or contaminations that would alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established requirements] & [$211.113 Control of microbiological contamination].

2. Schedule-M [Equipment design, size & Location: $4.2 If the equipment is used for different intermediates & APIs, proper cleaning before switching from one product to another becomes particularly important].

In addition to above mentioned laws there are so many other laws from various regulatory agencies.

Key factors of cleaning validation:

  • Selection of equipments [Based on worst case approach].
  • Appropriate solvent / detergent [Based on Solubility data].
  • Cleaning procedure [Hand scrubbing / solvent wash /Clean In Place / Clean Out of Place / Quantities / time / Pressure / temperature].
  • Level of cleaning required [Based on the risk assessment].
  • What is clean [Acceptance criteria based on the visually clean / Rinse Limit / Swab Limit / Microbiological aspects]

No. of times cleaning required [To achieve acceptance criteria, however “test until clean” is not acceptable].

  • Interval between the end of production & the beginning of the cleaning procedures [Dirty Equipment Hold Time Study].
  • The period and when appropriate, conditions of storage of equipment before cleaning & the time between cleaning and equipment reuse [Clean equipment Hold time study].
  • Analytical Methods / Recovery studies
  • Training of personnel

In addition to all these consideration the Top most requirements are sequential, accurate, scientifically justified & reliable documentation.

Risk assessment in Cleaning validation

In order to minimize the amount of validation required, a worst case approach for the validation can be used; instead of the investigation of each individual cleaning situation similar situation could be grouped.

Worst case rating priority will then support a conclusion that the cleaning procedures are effective for all drug substances within the bracket, including those not individually tested

In order to select the extent of cleaning process formal risk assessment should be carried out based on the factors under considerations i.e. Toxicological / pharmacological activity of the previous product, its side products or degradants, Maximum daily dose of the next product, Microbiological growth, Batch size of the following product, Solubility, experience, difficult to remove previous product etc. This will results in scientific justified rational for cleaning validation in multi product manufacturing facility.

Benefits of Risk Assessment

1. Required extent of cleaning can be evaluated & reduced.
2. Practical, achievable and verifiable limits can be decided based on the grouping into groups of risk (e.g. Very soluble products, similar potency, highly toxic, difficult to detect].
3. Scientific rational based study, hence more convenient to explain during Audits

References

1. 21 CFR Part 210 and 211 [USFDA].
2. Good manufacturing practices and requirements of premises, plant & equipment for pharmaceutical products [Schedule-M].
3. GUIDE-MQA-008-007 “cleaning Validation” Dec-2008 [Health Science Authority].
4. “Guidance on aspects of cleaning validation in active pharmaceutical ingredient plants” Dec-2000 [Active Pharmaceutical Ingredient Committee].

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  • metalslayer

    It is very helpful information. And, How to do risk assessment for sampling points also should be discussed.

  • metalslayer

    It is very helpful information. And, How to do risk assessment for sampling points also should be discussed.

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How 21 CFR Part 11.3(7) Applies to Electronic Batch Records [Video]

When dealing with Part 11 it’s important to understand what an electronic signature actually means

The definition of electronic signatures or e-sigs can be found in 21 CFR Part 11.3(7).

Electronic Signature

An electronic signature or e-sig means a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.

Handwritten Signatures

We also need to understand what a handwritten signature means in the context of Part 11.
The definition of handwritten signatures can be found in 21 CFR Part 11.3(8).

Handwritten signature means the scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form.

The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark.

Electronic Batch Records

Eric works in a Pharmaceutical company and he is responsible for the filling process of the batch been manufactured.

Each time Eric performs the filling process he has to populate a batch record with the appropriate details

After each step Eric must also fill in his signature and date to verify that he actually performed each task.

Eric is manually handwriting these details and they are legally binding to Eric.

21 CFR Part 11.3(8)

This is when 21 CFR Part 11.3(8) applies.

Fast forward 12 months and Eric’s company has implemented a brand new Manufacturing Execution System (MES) where all details around the batch manufacturing process are recorded electronically.

21 CFR Part 11.3(7)

Now when Eric performs the filling process he now populates everything electronically and signs with his username and password combination to verify that he has performed those tasks.

This is when 21 CFR Part 11.3 (7) applies.

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Your Guide to Software Validation PQ’s [Video]

Performance Qualification, often abbreviated to PQ, is the set of tests that verifies the system for perform correctly under conditions representing normal use.

Least Understood

The PQ is likely the least understood protocol in a validation exercise. The genesis of the PQ is manufacturing systems validation where PQ shows the ability of the equipment to sustain operations over an extended period, usually several shifts. Those concepts don’t directly translate well for many software applications.

Web Based Applications

However, there are good cases where a PQ can be used to more fully validate. Web-based applications, for example, may need to be evaluated for connectivity (i.e., what happens if a large number of users hit the server at once).

Database Applications

Another example is a database application. Performance can be shown for simultaneous access and for what happens when the database begins to get large. PQ is the place where, as applicable, confirmation is made that the system properly handles stress conditions applicable to the intended use of the equipment.

Validation Plan

There may even be cases where operators can, through marginally different use of the system, can influence the outcome. Critical thinking about what could impact performance is key to developing a PQ strategy.

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