Worst-Case Product Selection Using Risk Assessment in Validation

Verification tools are always limited although many pharmaceutical manufacturing sites manufacture various products utilizing the same machines. It is neither sensible nor scientifically acceptable to validate each product separately. In its place, authorities want manufacturers to select typical worst-case products through a documented risk analysis process. If the validation proves that worst-case product performs well, it reassures that less critical products can also be produced under the same validated conditions.

Although the principle is generally accepted, the worst-case product selection process is one of the most misunderstood concepts in the pharmaceutical validation process. I have seen many companies justify their choice by saying: "This is our best-selling product," or "This product is always used for validation." These explanations are insufficient. Authorities provide the scientific justification backed by documents, not traditions or convenience.

The strong worst case selection process should show that the product chosen is, indeed, the most demanding for cleaning, manufacturing, analytical testing or equipment performance, depending on the goal of the validation process.

Worst Case Does not Always Mean the Strongest Product

Another prevalent misunderstanding is the belief that the product that has the highest API strength is also automatically the worst-case scenario. In actual fact, the strength of the active ingredient is merely one of the countless aspects determining validation risk.

For instance, some low-dose hormones can be much more difficult to clean than high-dose analgesics due to their very low acceptable levels of residues. In addition, sticky polymers in the products might also be more difficult to remove than formulations that have higher concentrations of active drugs.

To figure out which product represents the worst case, one needs to define the goals of validation and follow a systematic approach based on risk assessment.

Applications of Worst-Case Product Selection

Risk-based selection of products is used in various validation processes in the pharma industry. Some examples of applications include:

• Cleaning validation
• Process validation
• Validation of equipment
• Time of hold studies
• Verification of cleaning
• Risk evaluation of cross-contamination
• Visual cleanliness studies
• Recovery factor investigations

Despite different rules of the evaluation in use, the principle is constant: find the product presenting the maximum difficulty.

Building a Risk Assessment

A scientifically substantiated worst-case scenario evaluation commences with the identification of elements that impact the results of the validation procedure. Instead of assessing a single characteristic, it is advisable to focus on multiple factors that can influence the behavior of the product in the course of its preparation or cleaning. Typical indicators include:

• Solution in cleaning agents
• Riskiness or pharmacological properties
• Strength of the product
• Size of the batch
• Cleaning difficulty
• Product stickiness
• Area of contact with equipment
• Limits on residue acceptance
• Complexity of manufacturing process
• Degradation properties of the product

Each factor should be evaluated based on the pre-determined criteria established within the company's validation process.

Selecting Risk Factors for Cleaning Validation

In most cases, cleaning validation entails performing a very detailed worst-case assessment since the successful cleaning campaign depends on product properties and equipment design. Products that are identified as posing a high risk typically have:

• Low water solubility
• High pharmacologic potency
• Viscous formulations
• Strong coloring agents
• High viscosity after processing
• Low acceptance criteria
• Difficult-to-clean excipients
• Long contact with sensitive equipment

For instance, sustained release formulations with hydrophobic polymers may be more challenging to clean than conventional immediate-release formulations containing a higher concentration of active pharmaceutical ingredient (API).

Using a Risk Matrix

Numerous pharmaceutical firms employ a scoring matrix to classify their products in an objective manner. Each product is assigned a numeric score for specific risk factors, bringing an overall score which can help identify a potential problem candidate.

The example of a simplified scoring method is given below.

Risk Factor	Low Risk	Medium Risk	High Risk
Solubility	1	2	3
Potency	1	2	3
Batch size	1	2	3
Cleanability	1	2	3
Toxicity	1	2	3

Generally, the product with the best score is the one selected for validation.

Nonetheless, the need of human judgment is still very essential. In instances when two similar scores are obtained, disadvantaged factors (that may affect the manufacturer's regularity), like the production capacity or manufacturers' experience may also be taken into consideration.

Classification of Products into Groups

It is difficult to assess all products manufactured in a facility, therefore the choice of products can be made by grouping similar products. Grouping can be done according to one of the following:

• Pharmaceutical form
• Manufacturing process
• Prerequisites for manufacturing
• Properties of the API used in preparation
• Type of formulation used
• Cleaning method applied
• Toxicity of the product

Each group has to be assessed separately according to the worst-case scenario. For instance, due to some differences in the way the immediate-release tablets, sustained-release tablets and capsules are manufactured, it is likely that different worst-case possibilities will have to be chosen.

The Importance of Documentation

Official bodies generally place greater emphasis on the process used to determine the worst-case product rather than the product itself during their inspections. Thus, evidence must include an outline of:

• Product types analyzed
• Parameters used for selection
• Method used for scoring
• Scientific rationale
• Evidence that backs the claim
• Final conclusions
• Required approvals

Simply stating that “product A was chosen because it is the worst-case scenario” would not suffice for the inspectors if no supporting evidence were established.

When the Worst Case Changes

Worst-case selection is not one-off process, it is to be revisited when any changes occur. Examples of such changes include:

• Launching a new product
• New active pharmaceutical ingredient
• Equipment modification
• Introduction of a new cleaning agent
• Change of cleaning limits
• Change of batch size
• New toxicology data
• Possibly a new manufacturing technology

One product that was classified as the worst case five years ago may not be the one today.

Common Mistakes During Worst-Case Selection

During inspections and internal audits several common shortcomings were revealed. They include:

• Choosing products only based on API potency.
• Not paying attention to the features of formulations.
• Relying on old risk assessments.
• Not taking into consideration newly marketed products.
• Not documenting the criteria used to score products.
• Taking personal views instead of using measurable indicators.
• Applying the same worst case product to different types of equipment without any rational explanation.
• Treating all drug forms as one family of products.

These weaknesses often result in questions about the scientific basis of the validation program.

Practical Tips for a Defensible Assessment

From a validation viewpoint, the worst-case assessment needs to be simple enough to implement consistently and in a scientifically valid manner. The following approaches are effective:

• You should arrive at an objective scoring criterion before product evaluation.
• It’s advisable to get input from various departments such as Validation, Production, QA, Toxicology, etc.
• Decisions should be based on actual product data, not assumptions.
• Regularly review risk assessments as part of lifecycle management.
• Connect the evaluation with the change control process to ensure that new products call for re-evaluation.
• All calculations and references should remain with the validation documents.
• Make sure validation specialists have been trained in the scoring approach.

Moving Forward from Cleaning Validation

While worst-case choice is commonly linked to cleaning validation, there is no denying the reality that it may also be used in other forms of validation. For example:

• In process validation, we can choose the formula that presents most difficulty.
• In hold-time studies, we can select the product that is the most prone to spoilage or growth of microorganisms.
• In equipment qualification, we can function the equipment in the most extreme way.
• For cleaning verification, we can consider the product with the narrowest residue acceptance criteria.

By applying the same risk-based approach to different kinds of validations, we can achieve a less complicated and more effective validation strategy.

Worst-case product selection is a scientific process and not merely an administrative one. By having a proper risk assessment in place, manufacturers can devote their validation resources not only on products which pose real challenges, but also avoid carrying out unnecessary tests on products that are less challenging.

The aim is not simply to reduce validation effort, but to make sure that the product selected provides credible proof for process / cleaning procedure effectiveness in the worst situations.

Based on my experience, the best kind of validation programs is the one in which worst-case selection is done systematically and is backed up by real product data, is regarded as a part of the change control process and lifecycle management. When inspectors question an organization about why a product that was chosen, the answer should be based on a documented relevant risk assessment instead of being just a result of a company tradition or personal judgment.

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