Controlling Factors: Advice on drug-development product testing

Steve Alley, Reading Scientific Services, offers advice on finished product testing within the drug development life-cycle .

The quality control testing of pharmaceutical finished products is an essential role of the pharmaceutical industry and is pivotal in delivering drugs that are not only efficacious but do not pose significant safety risks to patients.

Formulations must be marketed as therapeutically active and safe, with consistent and predictable performance. As time progresses, newer and better medicinal compounds are emerging which tend to require the development of more challenging analytical methods for their determination (be that qualitative or quantitative).

Suitability criteria

The suitability of a drug product for its intended use is determined by (i) efficacy versus safety and (ii) conformity to specifications regarding identity, purity and other physical and chemical characteristics.  In terms of the latter, it is vital that appropriate specifications are set, which should be based upon an extensive body of data collected over the drug-development life-cycle. This would not only cover the drug product but also the raw materials (API and excipients), intermediates and packaging materials.

Specification

A specification is defined as ‘a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests described’.  It sets out a set of criteria to which a drug substance or drug product should conform to be deemed acceptable for its intended use.

The quality aspects of a product that could be covered by the specification include (but are not limited to) the following:

General characteristics of the dosage form (physical characteristics)

Assay of the active substance

Identification of the active substance

Identification and assay of excipients (if required)

Identification and assay of antimicrobial/antioxidant agents

Purity tests (related substances, residual solvents or other known process impurities)

Pharmaceutical tests (e.g. dissolution, disintegration)

In determining the specifications of the finished product, the quality characteristics relating to the manufacturing process should be considered.  The specification for each of the quality aspects studied during the development and validation of the manufacturing process should be established. As a minimum, those attributes considered to be critical to the drug product should be routinely verified. It is also important to consider the difference between ‘release specification’ and ‘shelf-life specification’. The former of these would be applicable to a product that has been newly manufactured; the quality required at the end of the shelf-life would be taken into account in determining the specification at the time of manufacture, which could, for example, include the need for an overage to account for product stability.

Different dosage forms

A variety of different pharmaceutical dosage forms exist, depending upon the nature of the condition being treated. These range from oral dosage forms (tablets/capsules), topicals (creams, gels, transdermal patches) to injectables. 

Each of these different types will require assessment of different product characteristics.  Many of the tests are shared across different formulation types, such as description, identification, assay, and related substances.  However, when looking at say, an injectable product, there would be an array of formulation-specific tests to be included, such as clarity of solution, pH, osmolality, fill volume, viscosity etc.  Tablets on the other hand, would generally require tests such as dissolution, disintegration, hardness/friability; the latter of these may only be required if they have a significant impact upon the quality of the drug product (such as for chewable tablets).  The tests selected would pertain to all of those characteristics that are considered key to the efficacy and safety of the product.

Outsourcing finished product testing

In light of the large body of specification testing that can be required, if testing is to be outsourced, it is key to make an informed decision when selecting a CRO to support the analytical activities for batch release.  It is very advantageous to select a CRO that can facilitate all of the necessary testing and adopt a seamless, flexible approach to project management; from a logistic perspective, this aids control of the overall process, and will serve to minimise any delays in batch release and hence supply of the product to the market place.