Quality Risk Management

 

QRM – Quality Risk Management – is not new. It has been around for a long period of time and is also mentioned in the present Annex 1, in Volume 4 of the Eudralex (4). However, the draft Annex 1 (2017) (5) states in its first and introductory part: “This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product”.

 

Although much “detailed” guidance is presented in the draft Annex 1 regarding cleanroom garments, in practice, both the handling and the use of these important cleanroom tools always must be subjected to QRM.

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Quality Risk Management Cleanroom garments

 

Even though QRM has been generally described and used for quite a long period of time, cleanroom garments have not truly been subjected to risk management principles in detail. Furthermore, the development of fabrics, cleanroom garments and all the parts of a garment system, has not been emphasized. The bottom line: Not much has happened during the last 20 years, when it comes to re-usable textile cleanroom garments.

 

Cleanroom use and cleanroom garments in the future

The new demands stated in the draft Annex 1, indicate the need to look more thoroughly at all aspects on cleanroom garments. Longstanding and well-known test methods must be scientifically judged, to determine if, and in what respect, they can be used in the context of QRM, and (or) if new test methods or totally new approaches must be developed and adopted for cleanroom garments.

 

The part covering Aseptic Preparation (5), section 8.9 states: “Where possible, the use of equipment such as RABS, isolators or closed systems, should be considered in order to reduce the need for interventions into the grade A environment and minimize the risk of contamination”. The intent of this guidance is to minimize the potential risk of contamination from operators during interventions.

 

Isolators as well as closed systems, for aseptic production, can be placed in a surrounding cleanroom with lower cleanliness, whereas RABS (Restricted Access Barrier Systems) must be used in Grade B cleanrooms, the same cleanliness level needed when using open clean zones, UDF- and (or) microbial safety cabinets class II.

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When working in lower classification cleanrooms, (Grade C or Grade D), and using isolators and closed process systems, a lower degree of body coverage could be considered. However, Grade B garments will still be used to a very large extent, since all processes cannot be performed in isolators or closed systems, and RABS will still demand a Grade B background. In sum, the demand of the Grade B cleanroom garment system will remain strong, even in the future.

 

 

Testing cleanroom garments

 

Since cleanroom garments are of fundamental importance for the outcome of the manufacturing process, the quality of the final products, and hence patient safety, different test methods have been developed. The overall purpose of these test methods can be divided into two parts:

 

• To obtain information of the performance of the garment

• To give the end-user guidance on which garments to chose

 

The Institute of Environmental Sciences and Technologies (IEST) has published several Recommended Practices that are to be used as practical tools when getting cleanrooms working to desired specifications. In the Recommended Practice covering cleanroom garments, (IEST-RP-CC 003.4) (6) different test methods are specified, focusing on the garment material, the fabric, and on ready-made garments, respectively. The different tests described in this document, shown in respect to their purpose, are:

 

Cleanliness of fabric and (or) garment:

• Releasable large particles test

• The Helmke drum test

 

Filtration efficiency

• The particle penetration test

• The microbial penetration test

• The body box test

 

Test for equivalent pore size diameter

• The bubble point method

 

 

Filtration efficiency testing

The three tests normally used to study the filtration efficiency of cleanroom fabrics are:

 

• The particle penetration test

• The microbial penetration test

• The body box test

 

The two penetration tests above are not subjected to undesired variations, such as using different test persons, differences in movement pattern of the test persons, etc. This might be a problem when performing the body box test. The body box test is performed on persons dressed in different cleanroom garments, and performing different movements in a test chamber, in which the particles generated during test are measured.

 

The particle and microbial penetration test give an idea of the quality of the fabric, whereas the body test is a tool to compare the different garments and (or) garment systems in an environment that comes closer to real use. For comparison purposes body box testing should, however, be done with the same operator and under exactly the same test conditions. The body box test gives an idea on how the garment is performing as a whole.

 

 

Equivalent pore size diameter

The bubble point test is used to determine the equivalent pore size diameter of a fabric. This term is normally used to describe the filtration efficiency of the fabric. This is not fully accepted, since the filtration efficiency is not based on “pore size” only, but also on the thickness of the fabric. When performing the bubble point test on a single as compared to a double layer of fabric, the same equivalent pore size diameter will be obtained, even though double layers of fabric will enhance the filtration efficiency enormously.

 

 

Use the correct cleanroom garment parameters

All the different tests have one thing in common: they serve as means to describe different aspects of the garment material, the fabric and (or) the cleanroom garment. However, the problem remains that these results are not easily understood by the end-user. This is troublesome, since many of these parameters are not discussed with end-users, making it extremely hard to understand the properties of cleanroom garments, and ultimately to produce a User Requirement Specification (URS).

 

Cleanroom garment end-users normally reference the recommendations stated in the Recommended Practice from IEST when choosing the correct garment system, which outlines the recommended choice of different apparel. By combining this information with, for example, the Annex 1 of Volume 4 in the EudraLex, the end-user can be confident that they have chosen a cleanroom garment system that is in “compliance” with the stated demands.

 

 

The life cycle of cleanroom garments - Practical approach today

At present textile cleanroom garments are used to a major extent. The use of textile garments demands that these are repeatedly used which means that these garments must be washed, or washed and subsequently sterilized, when used in Grade B cleanrooms for aseptic production. The process of washing and even more sterilization will have a negative impact on the function of the garments and must be considered when discussing the life cycle of the garment.

 

Re-usable cleanroom garments are washed and, if to be used in Grade B/A applications, also sterilized. From a general point of view, the “cleanroom” laundry companies around the world have full control of their washing process, and in most cases the washing processes and the sterilization processes are validated. In some parts of the world, cleanroom garments are washed in “in house” laundries or “industrial” laundries, where chemicals, temperatures as well as air cleanliness used for washing and drying also have an impact om the life span of the garments, and not always considered in quality performance of laundries.

 

Many of the “cleanroom” laundry suppliers also have historical knowledge of the impact of these processes regarding the impact on the garments handled, but normally the actual garments used by the end-users, have not been subjected to a full validation.

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Contamination Control Strategy – CCS

In the draft to Annex 1 (2017) a new term is introduced – Contamination Control Strategy – CCS, which is explained in the following way:

 

“Quality Assurance is particularly important, and manufacture of sterile products must strictly follow carefully established and validated methods of manufacture and control. A contamination control strategy should be implemented across the facility in order to assess the effectiveness of all the control and monitoring measures employed. This assessment should lead to corrective and preventative actions being taken as necessary.

 

The strategy should consider all aspects of contamination control and its life cycle with ongoing and periodic review and update of the strategy as appropriate.

 

Contamination control and steps taken to minimise the risk of contamination from microbial and particulate sources are a series of successively linked events or measures. These are typically assessed, controlled and monitored individually but these many sources should be considered holistically.”

 

One way to explain the purpose of a Contamination Control Strategy is to detect and fill gaps that are identified when assessing the system and controlling and monitoring individual events from a holistical point of view.

 

A Contamination Control Strategy must, therefore, incorporate cleanroom garments, the production of the garment, and all the different treatments that the garment is subjected to, such as washing and sterilization, packaging, transportation, use, … etc.

 

In other words, suppliers’ recommendations on garment life, in respect to repeated washing and sterilization is not good enough. A proper validation based on scientific evidence is the only way to ensure patient safety.

 

 

Cleanroom garment supplier’s recommendation

In the Nordic countries there is a widespread understanding that traditional cleanroom garments made from 100 % polyester can withstand 150 washing cycles, or 50 washing cycles followed by sterilization in an autoclave. This has been known for over 25 years. However, to my knowledge, the end-users or wearers of cleanroom garments do not perform their own tests to validate whether or not this is true. Instead, they rely on the supplier of laundered and in some cases sterilized garments for this validation.

 

In a warning letter (FDA) from 2016 (7) the following was stated:

 

“In response to this letter, provide an action plan that describes how your firm will do the following.

• Select appropriate gown suppliers. Include the role of the quality unit in making supplier selection and ongoing qualification decisions.

• Reduce your maximum number of gown sterilizations to ensure that gowns are discarded before they show signs of breakdown. Provide the maximum number of re-sterilizations you will allow and describe how you will document and validate this procedure.

• Correct your visual inspection procedures for sterile garments to improve detection and rejection of defective garments.

• Ensure that the quality unit makes final decisions relating to release of raw materials and supplies (e.g., garments) you use in production.

• Conduct a risk assessment of the effects of damaged garments on your drugs. “

 

In two Inspection Reports from FDA from 2017 (8) the following is stated:

 

“… the QA department has not validated the number of cleaning and sterilization cycles through which the garments and goggles can be processed without compromising the integrity of the sterile equipment”.

 

“However, you have not validated the number of cleaning and sterilization cycles through which the garments can be processed and are relying on the supplier's recommendation of cycles.”

 

These report findings, together with the wording found in the draft Annex 1 (2017) of the Eudralex, Volume 4, stating “After washing and before sterilization, garments should be checked for integrity” confirm that the integrity of cleanroom garments over time, is quite significant!

 

The key points are: How is a cleanroom garment to be integrity tested? Is it even possible to integrity test cleanroom garments?

 

 

Single-use or re-usable cleanroom garments?

From a quality risk management perspective, the use of re-usable cleanroom garments, that have been used in operation and washed and sterilized up to 50 times, is a big challenge. The impact of multiple use in operation, repeated laundering and repeated sterilization will negatively influence the filtering and barrier performance of re-usable garments. Furthermore, it is impossible to integrity-test cleanroom garments individually, in order to confirm the protective ability of the garment, due to lack of practically approved technologies, as well as time constraints.

 

Single-use garments do not suffer from these drawbacks, since these are only washed and sterilized once, and discarded after use. From a historical point of view, when facing the option of selecting single-use versus re-usable garments, re-usable garments where often the simpler choice, due to lack of good enough alternatives. However, from a quality risk management perspective, together with the wording stated in draft Annex 1 (2017), from a patient risk perspective, single-use garments might be a better and much safer option in Grade B/A in the future.

 

The raw material used in single-use cleanroom garments as well as the preparation of the garment, should be produced under controlled conditions, and the garment must offer consistent properties.

 

What differentiates single-use from re-usable cleanroom garments is that these garments are only used once, and subjected to washing and subsequent sterilization only one time. Therefore, when using single-use garments, the impact of repeated use, repeated washing as well as repeated sterilization are not issues.

 

 

End-user responsibility for the future

Until now, many end-users have been relying on the recommendations of their supplier regarding the use of re-usable cleanroom garments. When working with aseptic production in Grade B cleanrooms and Grade A clean zones, this will be a challenge for the future. Contamination Control Strategy – CCS, which is the holistical evidence, including the scientifically based validations obtained 

through QRM, shows that the operation is in total control. In this context, suppliers’ recommendations will not be good enough.

 

The end-user must therefore put much stronger demands on their supplier for validation data, and not only rely on their recommendations. The challenge for re-useable cleanroom garments is to give proof of the performance during its full life cycle. Today the life cycle of re-usable garments is much too long.