Introduction

Pharma equipment is cleaned after the completion of every batch, specifically after every product. Among all of these, its primary aim is product safety from cross-contamination and product mix-up. Regulatory bodies also thoroughly investigate the cleaning process due to their routine inspection.

What is meant by cleaning in pharmaceutical industry

Cleaning is a process that removes all visible and non-visible particles, contaminants, and microorganisms that can infect different pharma equipment parts, specifically during routine production. These contaminants also includes dirt and product residues. Some contaminants can be removed using simple accessories, such as a plain cloth, while some may require complex tools and cleaning agents.  The selection of accessories, tools, and agents depends on the contamination types and is selected during validation studies. 

The cleaning is performed according to the approved SOP, which describes all the steps in a cleaning process. The SOP is prepared by the relevant department and with the approval of the Quality department; the SOP is specific for specific equipment and cannot be used for equipment other than for which it has been prepared.

After cleaning , the equipment is verified for its effectiveness. It is performed through visual inspection and analytical methods.

In the visual method, a supervisor of the personnel who has performed the cleaning visually verifies the cleaning for any physical trace, residual, contaminated fluid, and others.

In the analytical method, laboratory instruments are used to verify the absence of any residual or contaminant by taking samples from the cleaned equipment.

Like other manufacturing processes, cleaning is also validated for its effectiveness. The cleaning validation is performed with appropriate frequency, & resources and proper documentation are generated. 

Cleaning Records

Like all other processes in the pharma industry, records of equipment cleaning must be maintained, which are reviewed explicitly during their routine inspection. 

For the United States, record keeping must follow FDA guidelines 21CFR 211.180 and 21CFR 211.182.

• The 21CFR 211.182 is the cGMP for finished pharmaceuticals, and its subpart J Records and Reports, general requirements, describes general record-keeping guidelines related to the pharma industry.  

• The 21CFR 211.182 is the cGMP for finished pharmaceuticals, and its subpart, J Records and Reports, equipment cleaning and log, describes general record-keeping guidelines related to the pharma industry, and describes the records guidelines as per the following 

• A written record of equipment cleaning for each piece of equipment must be included in each equipment log.

• If equipment is dedicated to a single product, individual equipment logs are not required and must be part of the batch record.

• The person responsible for performing and checking cleaning shall initiate the logs chronologically.

How is equipment cleaned in the pharmaceutical industry?

Traditionally, the manual method was commonly used to clean the equipment. However, now automated cleaning is also becoming popular. Let's briefly discuss these.

Manual Cleaning

In manual cleaning, the equipment is dismantled from its place, transferred to the cleaning bay or area, and then cleaned using different tools and cleaning agents. If the equipment is large enough to be shifted to the cleaning area, the equipment is dismantled at its current place ( in the production area) and then cleaned. 

Brushes, scrapers, buckets, and other tools are used during manual cleaning. This is a relatively simple method, where the efficiency of the cleaning process depends on the operator's performance and effectiveness. It includes pre-rinsing, using cleaning agents (or water), and finally, post-rinsing.

The disadvantage of manual cleaning is that it cannot be replicated due to inconsistencies related to human performance. Another disadvantage is that it is a human resource-intensive activity, especially if the equipment's size is large.

On the other hand, it provides an opportunity to clean & reach difficult-to-reach locations

Automated Cleaning

In an automated system, the equipment to be cleaned undergoes the cleaning process in an automated manner; the cleaning mechanism is provided with the required cleaning agents, such as chemicals and water, in a central storage. Different mechanical components, such as nozzles, clean the equipment.

The cleaning steps are pre-programmed and are automatically advanced through different stages. 

In most cases, cleaning is performed on-site without dismantling the equipment. An example of automated cleaning is the Clean in Place System - CIP. 

CIP System

The clean-in-place system consists of different tools and mechanisms to clean equipment in its place. 

The heart of CIP system are the nozzles spraying the cleaning agent inside the equipment. It sprays the cleaning agent in the storage tanks, which flows into the nozzles through an appropriate piping system. The cleaning cycle is pre-defined through a central controller and follows according to its instructions. 

The CPI system can be fixed with any equipment, or can be a standalone type. In fixed type, CIP can only be used with which it is connected. In standalone type, it can be used to clean multiple equipment. However, care must be taken when cleaning multiples, as it can cause cross-contamination. It is better to follow guidelines from the quality department to prevent hazards.

Regulatory Guidelines

Cleaning pharma equipment makes the production process and product reliable and improves product quality. Additionally, regulations require pharma manufacturers to establish an effective cleaning strategy and maintain proper resources. 

Let's discuss some essential regulatory guidelines related to pharma equipment cleaning.

United States Food and Drugs Administration

The United States FDA is the regulatory body for the drugs marketed and manufactured in the US. some cleaning regulations include

21 CFR 211.67 Subpart D

• The FDA's guidance "Current Good Manufacturing Practice for Finished Pharmaceuticals" and its subpart D, Equipment Cleaning and Maintenance, provide guidelines for cleaning pharma equipment. According to this guideline

• Equipment and utensils must be cleaned and maintained according to the  nature of the drug. The equipment must be sanitized or sterilized to prevent contamination from affecting product quality, safety, identity, and strength beyond its limit.

• Written procedures shall be established to clean and maintain the equipment used in pharma product processing, manufacturing, packaging, or holding.

• Written procedures must be effectively followed.

• Written procedures should include the following.

• Assigning responsibility for cleaning and maintaining equipment

• Cleaning and maintenance schedules

• A detailed description of the equipment cleaning procedure. Additionally, the method for disassembling and reassembling equipment, when required during cleaning and maintenance

• Removal of previous identification 

• Protecting clean equipment from contamination before it is used in manufacturing operation

• Cleanliness inspection before it is used for manufacturing operation

• Cleaning records should be maintained following the FDA guidelines 21CFR 211.180 and 182 ( as mentioned earlier in this article)

European Countries

• The EU GMP is the guidelines related to medicine in European countries. Chapter 3, Premises and Equipment, outlines cleaning as follows.

• The layout and design of premises and equipment must minimize errors and allow effective cleaning and maintenance.

• Premises should be laid out in such a way as to enable production to the required cleanliness levels.

• Where primary packaging materials and IBC are exposed to the environment, it must permit easy cleaning.

• Pipework, ventilation points, and other services should be designed for easy cleaning.

• Open channels for drains must be avoided, and where they are not possible, they should facilitate easy cleaning.

• When dust is generated, special care should be taken to prevent cross-contamination and facilitate cleaning.

• Storage areas should be thoroughly cleaned. 

• Receiving days should be designed to allow containers of incoming materials to be cleaned before storage. 

• Manufacturing equipment should be quickly and thoroughly cleaned according to the detailed and written procedures. 

• Equipment used in cleaning should not become a source of contamination.

Cleaning Validation

The cleaning process for pharma manufacturing equipment must be validated by performing validation activities. Its primary purpose is to establish documented proof that cleaning shall yield results according to the acceptance criteria. 

Cleaning validation is performed to ensure the cleaning effectiveness against contaminants to protect product quality and safety. Because, if all resources are put into the cleaning process, and results are not satisfactory, then it is useless, and validation ensures its effectiveness. 

FDA perspective

In a reference document, the FDA describes the cleaning validation as 

• FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.

• FDA expects to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment.

• FDA expects firms to conduct validation studies and document the results using the protocols.

• The final validation report is approved by management and states whether the cleaning process is valid.

Validation Protocol

Before initiating cleaning validation, a protocol is created that contains the details of the entire validation process, which can include the following:

• Responsible person for performing validation, such as Quality and Production

• Persons responsible for authorizing the validation activity

• Details such as make, model, location, and functionality of the equipment under      consideration

• Cleaning procedures

• Quality & monitoring tools and accessories used during the validation to gauge the      cleanliness level

• Cleaning procedure for each product or manufacturing equipment, as described in the      cleaning SOP

• Cleaning cycle

• Sampling method to assess the cleanliness after the cleaning process

• Analytical methods,

• Acceptance Criteria

• Selection of cleaning agent