Product Capture Stage in Biopharmaceutical Downstream Processing

1.Introduction:

In this paper, the importance of a parts washer used to clean filtration equipment used in the product capture stage in biopharmaceutical downstream processing will be discussed. A parts washer is a clean-out-of-place system. The filtration equipment is disassembled and placed into this mechanical washer where they are cleaned, rinsed and dried. Parts washers use an aqueous solution for cleaning, rather than chemical solvents and so are more environmentally friendly than other washing systems.

Filtration equipment is essential for product capture in downstream bioprocessing, as this is where the final drug product and active pharmaceutical ingredients (APIs) are retained within the filter, as unwanted components from the mixture pass through its pores. For this reason, it is vital that they undergo strict cleaning regimes in a validated parts washer.

Parts washers require strict validation in order to be used for the cleaning of filtration equipment. This includes, conforming to user requirements, performing Failure Mode, Effects and Critical Analysis (FMECA) on all parts, defining and passing qualification tests to be performed on the equipment, identifying Installation Qualifications, Operation Qualifications and Process Qualifications to be met and identifying the relevant regulations, standards and guidelines for the filtration equipment to adhere to for its use in a good manufacturing practice (GMP) facility.

2Results

2.1User Required Specification

2.1.1 Objective

The aim of this document is to define the user requirements for a parts washer that is used to clean filtration equipment used in the product capture stage in the biopharma upstream processing.  Key design and regulatory requirements will be outlined for the system

2.1.2 System description

• A chemical action is used first- a soap is placed on the parts to be washed

• A thermal action then follows- heating up the machine to 37°C

• A mechanical action is the brush being used in the machine to clean off the parts.

• Time is given- this allows the parts to soak in the soap solution

2.1.3 Design criteria

The final design for the parts washer must be in line

• Regulatory standards and guide

• Current good manufacturing practice

• Industry best practice

• Relevant company guidelines

• Standard operating procedures

• Suitable drains and waste systems must be in place

2.1.4 Vendor documentation

• Materials certificate

• Materials finish certificate

• EC declaration of conformity

• Instrument calibration certificate

• Approved as built drawings (P and ID, isometric)

• Pressure testing

• Weld procedures

• Vendor manuals

• Degreasing and passivation procedures and certification

2.3 Diagrams

Figure 1 Parts Washer Apparatus

Figure 2 Clean/Rinse Operation

2.3 FMECA

Table 1 Information on FMECA

Table 2 FMECA

2.4 IQ, OQ,PQ, Description of qualification tests, acceptance criteria and purpose of test

Table 3.Installation Qualification

Table 4.Operational Qualifications  

Table 5.Performance Qualifications

2.5 Regulations and use in GMP facility

Cgmp is current good manufacturing practice the US food and drug Administration (FDA) ensure the quality of drug products by carefully monitoring drug manufacturing compliance with Cgmp regulations. These regulations make sure that the piece of equipment is safe to use and that it has the uses it claims to have.

FDA Cgmp regulations for a parts washer can be seen in the code of federal regulations (cfr) title 21, parts 210 and 211. In section 211 63 it is the regulation of the size, equipment design and location. 

Pharmaceutical washer’s characteristics can be grouped into categories including:

• Manufactures quality assurance program

• Mechanical design

• Process monitoring

• Design, manufacturing and qualification documentation

Manufacturers quality assurance program: The ASME-BPE standard will indicate that “the manufacture needs to implement an assurance program describing the method, materials, drawings, specification assembly techniques etc”. A third party cert such as the ISO 9001 is usually accepted.

Mechanical design: The ASME-BPE 2014 parts system provides guidelines to create the design framework using tests like the bioburden test etc. This is meant to prevent contamination. The article ASME-BPE is very hard to summarize but some sections relate directly to the design of washing.

Clean ability:  This describes how the equipment should be designed that all the surfaces of the equipment are cleanable. Example crevices and gouges.

Process components: This describes how piping, connection and fittings should be designed to be hygienic. Amount of connections should be minimized.

Discussion:

In this project we looked at the importance of a parts washer which can be used to clean filtration equipment. From the user required specification we saw the criteria which the parts washer must meet to be validated. This document outlines what is needed by the end user. This shows the requirements from the system.

During the cleaning process, a mixture of purified water and CIP such as caustic is used to generate the results that meet the required standards. The parts to be washed are placed in a rack which is transferred to the parts washer by means of a trolley. Parts being washed enter the parts washer on the side which is referred to as the ‘dirty side’. Once the parts enter the washer and the process is complete, they then are removed from the wash chamber on the opposite side which is referred to as the ‘clean side’. By implementing this process it maintains an aseptic environment for the washed equipment and reduces the risk of re-contamination. An effective method of obtaining cleaner results is achieved by heating the purified water and caustic mixture as an increase in temperature has the ability to remove contaminants such as oil if present. The detergent, in particular caustic, reacts well with the increase in temperature achieving more superior results. The purified water and CIP are contained in separate reservoirs where determined volumes of each are then fed through a pipeline into the wash chamber of the parts washer. The wash spindle contained inside the wash chamber then releases the mixture as it rotates to spray the surface of the parts to be washed which are supported on a rack placed inside the chamber. Washed equipment is then passed through to the clean side where they can then be used where required for the next process.

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From looking at the Failure Mode, Effects and Critical Analysis (FMECA), in Table 2, it can be seen that the cleaning of filtration material using a parts washer is a six-part process, starting with the sealing of the machine and ending with ensuring the waste generated during the process is properly drained away. Each step has its own severity, occurrence and detection rating. Severity ratings are based on whether the problem incurred can be corrected or if it will pose problems for the filtration equipment. The results show that the severity ratings for this process range from 2 to 3. This shows that any failure that may occur during the washing of this equipment would not be major, cause reportable regulatory problems or major defects affecting safety. The failure to seal the washer door, failure to dry equipment and failure to drain waste, causing a build-up of unclean waste, were given severity ratings of 2. This is because in the event of any of these occurring, a manufacturing delay may occur, however, the cleaned product after washing would not be rejected for use. The failure to add required amounts of aqueous solution and cleaning agent, failure of hot water added to be of required temperature (55֯C) and failure to rinse equipment were given severity ratings of 3. If problems were to occur during these stages it would be slightly more serious, possibly resulting in batch rejection, meaning filtration equipment may need to be put through the parts washer again. It is important to note that at these stages, only cleaning is taking place and not sterilization, hence, ratings are not higher. Further sterilizing action would be required for this equipment for its use in the product capture stage in biopharmaceutical upstream processing. Occurrence ratings also range from 2 to 3. The occurrence ratings of 2 indicate the failure may occur 2-3 times out of 100 washes, while the possible failure modes with ratings of 3 may occur 4-6 times out of 100. The detection ratings give an insight into how well the controls currently put in place by the parts washer can detect the failure of the system. These ratings have the highest range, 2-4. This is due to the nature of the control that monitors the failure detection. The FMECA highlights that the failure detection methods that used a computer or probe connected to a computer had the lowest detection ratings numerically, however, this indicates they had a good chance of detecting the existence of a failure, as the lowest score is indicative of higher detection rates. The failure to rinse cleaning agents from equipment was given a detection rating of 3, meaning the control which was a qualified water supply was moderately capable of detecting the failure. It is the failure detection methods that were most labour intensive, were the least likely to detect the existence of the failures, as these steps required controls (SOPs and validation documents) to be manually monitored.

The three tables above outline the tests performed during the validation of a parts washer for filtration equipment. Installation qualification, Operational qualifications and Performance Qualifications are some of the most vital steps of the validation process. Installation qualification ensures that everything ordered was correct, what was received in the order was installed correctly, and that all important paperwork required for the parts washer was also received and controlled. Operational qualifications then continue on from the installation qualifications by ensuring all personnel are trained correctly to use the equipment. Vital tests are also carried out to ensure the different parameters of the machine function properly such as temperature, pressure, speed, and volume to name a few. Performance qualification establishes that all equipment facilities and utilities work well together.  Further tests are carried out after the use of the washer to ensure that there is repeatability with the washer. This includes vital tests such as swab samples for endotoxin and bioburden validate that the washer is correctly cleaning the filtration equipment, so that there is no contamination when they are taken out of the parts washer, and therefore do not lead to discrepancies when they are being used in studies or practicals. These qualifications are a vital part of the validation process.

A parts Washer must meet the standards and regulations of the FDA (Food and drug regulation) and they also must meet cGMP (current good manufacturing practice) the objectives of this are as follows cleaning validation, equipment validation and  aseptic manufacturing facility. This can be seen in the pharmacopeia in subpart c building and facilities section which states that the facility should be a suitable size and the location of machinery should be suitable for workers to get at. In this case the parts washer should be located in an appropriate size room away from sources of contamination etc.  A parts washer should also have proper design and construction features some of these include Receipt, ID, and storage to name a few.  Overall a parts washer must adhere to current good manufacturing practice (ie) must have proper quality, safety and efficiency.

Conclusion:

In conclusion, the importance of a parts washer to clean filtration equipment used in the product capture stage of the biopharmaceutical downstream processing was looked at in this paper. A user required specification was written, a diagram showing the key areas of the parts washer was drawn, a failure mode effects and critical analysis (FMECA)on all parts with qualifying tests was drawn up for the parts washer. Installation, operation and process qualifications to be met were outlined and the relevant regulations and guidelines for use in good manufacturing practice facility to be met were identified.

References:

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