Bracketing and Worst Case Rating in Cleaning Validation

The cleaning processes of multiple product use equipment in the facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used.

By means of a bracketing procedure the substances are grouped.
A worst case rating procedure is used to select the worst case in each group.

Bracketing Procedure
The first thing to do is to make groups and sub groups – which we will term “bracketing”, from which worst cases will later be selected based on the results from the rating. The bracketing procedure should be included in a company policy, or an SOP or an equivalent document on cleaning validation.

Bracketing procedure can be applied by following way:

Based on Equipment Train: The first grouping criteria is that the substances/products in a group are produced in identical equipment trains and cleaned out following the same cleaning procedure/SOP.
Based on Substances/Products: a choice of which products to be produced in each of the trains used for the same purpose.

Cleaning Procedures

For one train, in which several substances are being produced, several cleaning procedures often exist. In order to be able to defend the bracketing into groups, the second criterion is that the same cleaning procedure (method) shall be used for the substances/products within a group. Where the substances/products in the same class are cleaned in the same way, using the same solvents and usually exhibit some chemical similarity with each other (e. g. salts, chemical structure etc.).

For example, here we four cleaning procedure classes are mentioned:

Class I: water soluble substances.
Class II: methanol soluble substances.
Class III: acetone soluble substances.
Class IV: separate class for special substances with defined solubility

Investigations and Worst Case Rating (WCR)

A worst-case rating study/Risk assessment will prioritize existing drug substances, in a cleaning validation program, based on information on applicable criteria chosen by the company. A company can chose the following criteria which are relevant to the molecule preparation in their facility (companies should evaluate individual situations):

a) Hardest to clean: experience from production (Category 1 = Easy; Category 2 = Medium; Category 3 = Difficult);

b) Solubility in used solvent (Category 1: Very soluble, freely soluble; Category 2: Soluble, sparingly soluble; Category 3: Slightly soluble, very slightly soluble, practically insoluble, insoluble);

c) Lowest Acceptable Daily Exposure or Permitted Daily Exposure (Category 1: >500 µg; Category 2: 100 – 500 µg; Category 3: 10 – 99 µg; Category 4: 1 – 9 µg; Category 5: <1 µg) [If ADE / PDE data are not available, other data such as pharmacological dose, OEL or toxicity data ( LD50 ) may be used];

d) Lowest therapeutic dose or toxicity data (Category 1: >1000 mg; Category 2: 100 – 1000 mg; Category 3: 10 – 99 mg; Category 4: 1 – 9 mg; Category 5: <1 mg)

In order to present documented evidence supporting the scientific rating for each criterion, investigations (a formalized Risk assessment) should be carried out and formal reports should be written.

Worst Case Rating

The substances or products are to be scientifically matrixed by equipment class (train/equipment) and cleaning class (procedure). Each existing combination of the classes is considered as a group. When this bracketing has been carried out, the – “Worst Case Rating (WCR)”- can start. For at least one worst case in each group, cleaning validation studies shall be carried out.

Evaluation of Rating

The worst case rating can be executed according to an issued protocol in which the methods and procedures for the rating will be identified. A matrix system, for each equipment class (such as a dryer), can be set up as evident from the following table: