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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The Difference Between Qualification and Validation [Video]

There is a general saying within the life sciences:

“We qualify a system and/or equipment and validate a process”

A system and/or equipment must be qualified to operate in a validated process.

For example:

“You qualify an autoclave, whereas you validate a sterilization process”

Manufacturers should identify what validation and qualification work is done. All systems, equipment, processes, procedures should be reviewed and the manufacturer should decide what qualification and validation work needs to be performed.

Direct, Indirect or No Impact

All facility areas, utilities and process equipment must be assessed and classified as direct impact, indirect impact or no impact following an analysis of their impact on the identity, strength, quality, purity or safety of products manufactured at the facility and also the safety of the operators & environment.

Impact on Quality

Each system or item of equipment having direct or indirect impact on the product quality must be validated. The extent of validation or qualification should be determined by performing the risk assessment of that particular system or equipment.

Join the Discussion

Use our community to find our more about validation and qualification.
http://community.learnaboutgmp.com/t/qualification-vs-validation/874

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The Difference Between Prospective, Concurrent and Retrospective Validation

Unless you’re starting a new company you will need to plan on a variety of approaches.

Prospective validation occurs before the system is used in production, concurrent validation occurs simultaneously with production, and retrospective validation occurs after production use has occurred.

In this article we will discuss all three and also discuss the role the master validation plan (MVP) performs for each one.

1. Prospective Validation

Prospective validation is establishing documented evidence, prior to process implementation, that a system performs as is intended, based on pre-planned protocols.

This is the preferred approach.

Production is not started until all validation activities are completed.

The MVP need not go into much detail about this approach since it’s the standard method, however, prospective validation follows a step wise process illustrated here.

The process commences with the development of a Validation Plan and then passes through the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed which are followed by a final report.

After which the instrument or equipment will be subject to preventative maintenance and requalification on a routine basis.

Periodic Basis

On a periodic basis all instrumentation and equipment should be reviewed. This review is intended to identify any gaps which may have developed between the time it was last qualified and current requirements.

If any gaps are identified a remediation plan will be developed and the process will start again.

The MVP

The MVP may need to describe what is done with product produced during prospective validation. Typically, it is either scrapped or marked not for use or sale.

The product may be suitable for additional engineering testing or demonstrations, but appropriate efforts need to be made to ensure this product does not enter the supply chain.

Ideally, all validation is done prospectively; i.e., the system is validated before use. However, there are cases and conditions which may prevent this.

2. Concurrent Validation

Concurrent validation is used to establish documented evidence that a facility and process will perform as they are intended, based on information generated during actual use of the process.

In exceptional circumstances (for example, in a case of immediate and urgent public health need) validation may need to be conducted in parallel with routine production. The MVP needs to define how product is managed throughout the process.

Typically, the product batches are quarantined until they can be demonstrated (QC analysis) to meet specifications.

The Right Decision?

The decision to perform concurrent validation should not be made in a vacuum. All stakeholders including management, Quality Assurance and the government regulatory agencies should all agree that concurrent validation is an acceptable approach for the system under consideration.

As always the principal requirement is patient safety is not compromised. The rationale to conduct concurrent validation should be documented along with the agreement to do so by all the stakeholders. This can be part of the Validation Plan or documented as a deviation.

The Process

The concurrent validation process is identical to that of prospective validation. The process starts with the development of a Validation Plan, followed by the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed, ending with a final report.

Again, routine preventative maintenance, requalification and periodic review are performed.

3. Retrospective Validation

Retrospective validation is validating a system that has been operating for some time. There are various schools of thought on how to approach retrospective validation. Some may feel that a full-blown validation is required to assure the system is functioning properly.

Others may feel that since the system has been in use, presumably without issues, validation is not necessary and a memo to file justifying why validation is not necessary may be issued.

Doing a full validation may not be required, since you already have proof that the system functions as required – at least in the situations in which production was conducted. Doing nothing, though, is a risk.

It’s likely that the controls haven’t been challenged so there may be some hidden flaws that haven’t been identified that could lead to non-conforming product, hazardous operating conditions, extended delays, etc.

Historical Data

Historical data can certainly be used to support validation. For example, if there is detailed and statistically-significant evidence that production runs are well controlled you could rationalize and justify not doing full validation.

During retrospective validation, it’s advisable that existing product be quarantined, and production put on hold until validation is complete.

As an exception, producing product as part of the validation exercise would follow concurrent validation. This may not be practical since product may have already been distributed, but caution is advised for the reasons outlined.

General Process

The general process for retrospective validation follows the same process as for prospective and concurrent validation except DQ is seldom performed, as the system has already been in use for some time.

Instead a survey and review of available information is performed. This normally occurs before the validation plan is created.

The MVP should also provide guidance on managing inventory during retrospective validation.

One Major Issue

One potential major problem that can occur with retrospective validation the determination of what action should be taken if an issue is found with the system during retrospective validation?

As with everything else, a risk-based decision is warranted. This could be anything from product recall, to customer notifications, to just documenting the justification of the decision why nothing was done.

Again, the MVP should provide guidance on dealing with situations concerning out of specification conditions revealed during retrospective validation, which should also definitely include involving regulatory support.

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