Cleaning Validation in Pharma | Pharma Q

Cleaning Validation in Pharma 

Equipment cleaning /Cleaning Validation is a discipline that requires a high level of chemical, toxicological, pharmacological and process engineering know-how. Only when all technical disciplines work together can the most economical yet reliable process for multipurpose systems be established and validated. In this article, chemical, toxicological and pharmacological aspects for planning and designing the cleaning process and procedural evaluation of bracketing and sampling are discussed.

Introduction and History

The foundation stone for the need for cleaning validation was laid with the introduction of penicillins. The FDA "Guide to Inspections - Validation of Cleaning Processes" 7/93  states that most product recalls were caused by cross-contamination by penicillins. In terms of cleaning, poor hygiene and dust control were another reason for the authorities to set regulatory requirements. The FDA Guide dates from 1993 and contains all of the main features of cleaning validation. The guide relates to the manufacturing processes in the chemical and biotechnological pharmaceutical industries. The reasons for the creation of this guide lie in previous scandals such as pesticide residues in medicinal products and insufficient evidence for the absence of residues.

Today, for every cleaning validation, a risk-based consideration of all substances that can get into the subsequent product must be carried out. This includes residues of active ingredients, cleaning agents and possible breakdown products. In order to avoid possible cross-contamination in the subsequent product, acceptance criteria are defined. In accordance with ICH Q9 [9], these are determined on a risk basis for each active ingredient in a multi-purpose system. Acceptance criteria for microbiological limit values are not mentioned, but the microbiological aspects are mentioned in the relevant regulations and recommendations such as the FDA Guide [5], EU GMP guidelines, Annex 15 [4] and PIC / S [11].

Limit values for residues of products, cleaning agents and possible degradation products

 

With the 2015 revised Annex 15 EU GMP guidelines, a new approach for the consideration of possible residues was published. With the innovations, the previous acceptance criteria for product residues, 1/1000 dose criterion and 10 ppm quantity criterion can no longer be used alone. Rather, the applied criterion should be based on a risk assessment of the contaminants, which in addition to toxicological considerations also include the assessment of the pharmacological and physicochemical properties (eg solubility).

The previous limit values are to be replaced by the science-based limit value for daily exposure PDE (Permitted Daily Exposure) or a TTC (Threshold of Toxicological Concern) value. This is to be determined for each individual active ingredient and each cleaning agent. For generic active substances, the values can be determined by commissioning the creation of a corresponding expert opinion.

If the values are not available, e.g. for new developments, there is the possibility for pharmaceutical manufacturers to use the quantity or dose criteria in connection with the OEL value (Occupational Exposure Limit). To do this, the manufacturer must demonstrate that the criterion used so far is greater than or equal to the respective OEL value of the active ingredient, including consideration of the route of intake. The OEL value is a limit value derived from toxicological data.

The reasons for these innovations are, on the one hand, that the dose and quantity criteria were chosen arbitrarily without risk-based approaches and that there was no scientific approach. The different therapeutic index of drugs was not taken into account. In addition, the therapeutic dose is proportional to the residue, which leads to high product residues with high-dose substances. Long-term intoxications and teratogenic toxic effects must also be included in the risk assessment

PDE Criterion

PDE (Permitted Daily Exposure) describes the dose of a substance at which no negative effect is observed with daily intake over the entire lifespan. The acceptance criterion is based on scientific data such as clinical or toxicological studies and contains a risk assessment. ADE (Acceptable Daily Exposure) is a synonym of the criterion. The dose calculation is based on toxicological studies according to the EMA "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities" .

PDE =

NOAEL · Weight Adjustment

F1 + F2 + F3 + F4 + F5

 

PDE: Permitted Daily Expose [mg/Tag]

NOAEL: Highest dose at which no adverse critical effect is observed (No Observed Adverse Effect Level) [mg / (day kg)] Weight Adjustment = standard body weight 50 kg.

F1: factor for the extrapolation between the species

F2: factor for the distinction between the species

F3: factor for the calculation of short-term / long-term studies

F4: factor for severe toxicity –

F5: variable factor if none NOAEL known, but PDE is derived from LOEL (Lowest Observed Adverse Effect Level).

If the NOAEL is not available, the LOAEL (Lowest Observed Adverse Effect Level) can be used. There is no general validation obligation for product-specific equipment (Dedicated Equipment) with regard to drug residues. However, an assessment of possible degradation products, cleaning agent residues and microbiological contamination must be made.

A risk assessment should be used to assess whether a multi-purpose or product-specific facility can be used to manufacture the medicinal products. When determining the PDE, it must be taken into account that the route of the administration of the follow-up product must be known and must be included in the calculation of the PDE. With subcutaneous use, for example, many local anesthetics can tolerate a higher PDE than for intravenous use.

The cleaning of the systems after use often requires the addition of cleaning substances. These too can adversely affect the health of the patient by exerting their own toxic effects or impairing the effectiveness of the follow-up medicinal product. A limit value must therefore be determined for both active and auxiliary substances as well as for the cleaning agents. As with active substances, this limit value must be achievable and measurable. In the case of a cleaning routine that consists of several steps, the analysis should be based on the last-to-rinse substance. In any case, the composition of the cleaning agent must be known and the supplier must give a long-term guarantee on the formulation. Surfactants are usually suitable as cleaning agents, but a sequence of acids, alkalis and complexing agents is also common.

If the PDE has been determined for the planned follow-up application, the maximum permissible residue quantity for all residues (products, degradation products, cleaning agents) must be calculated.

GRAS Status:

For substances that have GRAS status (generally regarded as safe) according to CFR 21 Part 184 and no known PDE is available, analogous to ICH Q3C, the PDE for residual solvents with low toxic potential PDE = 50 mg can be used as a basis.

10 PPM Criterion

If the toxicity of the substances is very low or harmless substances are used, it is advisable to set a "best practice" limit value. Here it is recommended to use the 10 ppm criterion as a technically feasible limit. A maximum of 10 ppm of the previous product may be carried into the successor product. This results in a maximum residue level mmax for the load on the subsequent batch.

The 10 ppm criterion has its origin in the food industry and does not take into account the toxicological or pharmacological properties of the substance. However, it is still a useful criterion for calculating a limit for toxicologically harmless substances.

The 1/1000 Dose Criterion

Even if the toxicological criterion has to be taken into account when calculating the maximum amount of residues, Annex 15 requires that the pharmacological properties and thus also the dosage be included in the risk assessment . Therefore, one should continue to determine the usual dosage of the secondary product and include it in the discussion of the limit value. In the past, the usual or the minimum dosage with a fixed risk factor was used as the basis for the limit value calculation. The daily dose of the subsequent product should not contain more than one thousandth of the lowest therapeutic daily dose of the preliminary product. Based on the smallest possible batch size and the area of the plant, the maximum permissible amount of residues is obtained, which may pass from the product-contacting area to the next batch

Visually-Clean Criterion

The system surface must be visibly clean. This requirement generally applies to cleaning validation. However, it is difficult to quantify the observation “clean”. The attempt to quantify the criterion for the visual inspection was empirically determined by means of “spiking” studies (dilution levels) for a group of substances. The limit at which the substances examined were visually around 4 µg / 100 cm² . Since this value has only been tested for a few products, it cannot be applied to all products. A manufacturer must prove by means of its own “spiking” studies, from which concentration a product can just be visually detected. The test surface property must correspond to the quality of the system surface from production. Furthermore, products with strong staining properties pose a problem when assessing visual cleanliness. It is recommended to assess the harmlessness of dyes as part of a risk analysis and, if necessary, to include the corresponding products in the cleaning validation.

Worst case concept

After determining the limit values, knowledge of the PDE (and possibly other limit values) is used to calculate a limit value depending on the product. You can then determine a worst-case scenario from the preliminary / subsequent product for the entire product range and consider this limit value for the entire cleaning validation. This limit value must be verifiable; ie a validated analytical method must be able to prove this limit value. When producing new products on the system, the validity of the worst-case scenario must be checked.

In the case of highly potent active ingredients and drugs such as steroids, antibiotics and cytostatic, the risk assessment shows that these products have to be manufactured with “dedicated equipment” because, for example, a determined limit value is below the analytical detection limit or the authority requires this for certain product groups.

Switch from dose criterion to PDE

If cleaning validation was established before 2015, the limit values established in the past had to be questioned and adjusted since then. Sometimes better cleaning methods have to be established, but sometimes the previous limit value is stricter. A widening of already established limit values is not acceptable, since you have to maintain a technically feasible quality of cleaning.

Microbiological limit values

While the consideration of product and detergent residues is important to avoid cross-contamination and carry-over from the previous product and cleaning process, the consideration of the bacterial count relates to the monitoring and the preventive measures. Such measures are, for example, that the equipment must be kept dry after cleaning. The times between the end of production and the start of cleaning "dirty-holdtime" not only have an impact on cleaning but also on the microbial load, which plays a special role in sterile production.

The downtimes between the end of cleaning and the start of production must also be validated. These two factors affect microbial growth. The limit values for bacterial counts on surfaces can be derived from the requirements of Annex 1 of the EG-GMP guidelines  for sterile drugs. A further orientation regarding the microbiological purity of medicinal products are the specifications of the respective pharmacopoeias. For phytopharmaceuticals, the European Pharmacopoeia provides information on the microbial purity of drugs in the various processing stages. In this case, the microbiological limit values for cleaning validation can be derived from the product requirements.

Sterilization represents a special position here. Although the sterilization proof of the equipment is provided by the validation of sterilization processes, it cannot be guaranteed that pyrogens or endotoxins have been eliminated. From this point of view, the microbiology in the context of cleaning validation and service life validation of cleaning processes in sterile production should not be neglected.

Plant Design

With the help of a risk analysis, the influence of product, system and process-related parameters on the cleaning goal should be assessed. In order to reduce the effort involved in cleaning validation, a grouping, the so-called “bracketing”, can be carried out by considering the similarity with regard to the design of the systems and products with comparable chemical-physical properties

Components that are easy to clean are essential for a successful cleaning process. The hygienic design describes how the systems and system components are designed for cleaning. Every surface in contact with the product must be wettable with the cleaning agent and easy to dry. In the hygienic design of the system, the material and surface of the system also play a decisive role in cleanability. For example, a lack of surface smoothness, unclean weld seams, unsuitable sealing constructions and retrofitting can cause massive cleaning problems.

Cleaning process

In addition to the manual cleaning process, there is also the option of an automatic cleaning process (CIP system). In many cases, however, a CIP cleaning system cannot be implemented and is too expensive, which is why cleaning has to be done manually. Compared to the CIP cleaning system, this is clearly at a disadvantage in terms of reproducibility and validation. The manual cleaning process depends heavily on the person in question. That is why it is not only regular training and the right motivation of the staff that work, but also the need for detailed instructions, planning and monitoring for cleaning success.

The CIP system is a continuous process that can be reproduced and standardized. The disadvantage is that the cleaning success is difficult to inspect due to the closed system. Portholes and sampling points would have to be planned for the optical control of the cleaning success and the sampling of the cleaning water. CIP systems can also be cleaned within the framework of qualification by determining the residue of riboflavin. Riboflavin has good detectability and is also harmless. It should also be borne in mind that many other steps, such as programming process parameters, securing access or archiving the data, must be taken.

CIP systems are stationary systems that are permanently integrated in the production system. All processes and products relevant to the production system have to be adjusted to the system accordingly. The critical measuring, control and regulating units must be checked in the CIP system and regularly recalibrated. With the help of the spray ball installed in the CIP systems, the entire surface of the system is wetted with cleaning solution. The ball can be static or rotatable. The flow rate of the cleaning agent must be set via the pressure so that atomization of the solution is avoided. Static and dynamic pressure losses can be avoided with a variably defined pump output.

Chemical properties of the detergent

Water is often used to bypass the detergent analysis. The cleaning result is often poor or a lot of water is used. Here it is worth taking a look at the chemistry of the substance to be cleaned. Sometimes a component (auxiliary) from the formulation in low concentration can be used as a cleaning additive. The following effects can be used, for example, for cleaning in an aqueous environment

pH shift for drugs that can be protonated

- increased salt content increases the solubility of poorly soluble substances (activity is reduced)

 - solubilizers / emulsifiers from the formulation of emulsions

The advantage of this procedure is that no additional components are added and the system is not burdened with additional chemicals that have to be verified again.

Sampling

In the cleaning validation plans, the sampling locations and a reason for the location selection must be described. There are two recognized types of sampling: direct and indirect sampling. Direct sampling is the wipe test (swab), in which a defined surface is sampled with a suitable solvent using cotton swabs. A prerequisite here is the accessibility of the sampling points, which also has the main disadvantage: the entire surface is not sampled and it cannot be assumed that the contamination is distributed uniformly in one system. In addition, this type of sampling has a low reproducibility. The advantage is that the analytical result can be assigned directly to a defined point in the system. Residues that are difficult to dissolve can also be detected with the wipe test.

Indirect sampling (rinse) is used in areas that are difficult or impossible to reach, such as piping, but also the inside of containers and internals. The disadvantage of the method lies in the uncertainty as to whether all residues have been rinsed out, whether the residues are water-soluble and whether they are removed in poorly accessible places. A major advantage, however, is the ability to sample a large surface. In general, another disadvantage of the rinse method is that the substances to be detected are greatly diluted, making it difficult to prove the calculated limit value analytically. Another way of sampling is to combine the two methods, for example, swab sampling on nozzles and subsequent rinse sampling of the entire interior. The recovery rate must be determined for both types of sampling.

Analytical Methods

The cleaning success of a method must be proven with analytical methods. The FDA "Guide to inspections validation of cleaning processes” calls for the specificity and sensitivity of the analytical methods. It must always be noted that results below the detection limit do not mean that there are no residues in the sample. The result can only be as good as the sensitivity, specificity and accuracy of the test. Therefore, the analytical methods have to be validated. The following analysis methods are usually used in cleaning validation.

• HPLC

• GC

• Color Tests / Ready-Made kits

• Color reactions to proteins (eg BCA) Sum parameters

• TOC

• Conductivity

• UV / VIS spectroscopy