APPROPRIATE QUALITY LEVEL

During early stage research, analytical methods are often not fully validated and this is entirely appropriate - "fitness for purpose" being the key. As a product moves through its development lifecycle, however, it is important that the analytical methods employed and their quality level develop alongside the product - the worst case scenario being where development stalls or is misdirected for want of sufficiently accurate, precise, robust and specific analytical methods.

The level of validation of the analytical method is driven principally by quality assurance and regulatory considerations. Analytical method validation is a cGMP requirement.

cGMP

The Good Manufacturing Practice guidelines (and associated regulations / directives)describe the way in which the manufacturing and quality control testing of pharmaceutical products is controlled in order to protect the patient.

cGMP takes the holistic approach of regulating the manufacturing and laboratory testing environment itself. An extremely important part of GMP is documentation of every aspect of the process, activities, and operations involved with drug and medical device manufacture. If the documentation showing how the product was made and tested (which enables traceability and, in the event of future problems, recall from the market) is not correct and in order, then the product does not meet the required specification and may be considered to be contaminated (adulterated in the US). Additionally, GMP requires that all manufacturing and testing equipment has been qualified as suitable for use, and that all operational methodologies and procedures (such as manufacturing, cleaning, and analytical testing) utilised in the drug manufacturing process have been validated (according to predetermined specifications), to demonstrate that they can successfully perform their purported function(s).

STABILITY STUDIES

Storage stability evaluations are used to understand the stability of a product or material when stored in various packaging configurations for specified periods of time under a range of specified environmental conditions (temperature, relative humidity).

Samples are periodically pulled from storage and analysed ? typically via HPLC (chemical stability ? potency and impurity assay) and dissolution testing (product performance testing), but also other methods as appropriate to the molecule. Physical stability (crystallinity determination, polymorphism determination) may be of particular interest in some instances. Any changes identified may be indicative of an unstable product.

During development, short term studies are normally carried out on multiple formulations to help determine the optimum final product. Subsequently, longer term studies involving the finished product contained in the final packaging are used to determine product shelf life.

BIOBURDEN TESTING

Bioburden or microbial limit testing is performed on pharmaceutical products and medical products as a quality control measure. Products or components used in the pharmaceutical or medical field require control of microbial levels during processing and handling to ensure the quality of the final product. Bioburden or microbial limit testing on these products prove that the requirements are met.

Bioburden testing of raw material as well as finished pharmaceutical products are required, to ensure full compliance with the requirements of the BP, EP or USP.

The bioburden of a sample is measured in cfu (colony forming units) per gram (or mL) of material. There are clear regulatory guidelines indicating the cfu/g permitted for the various pharmaceutical dosage forms (parenterals, topicals, orals, inhaleables etc.). These limits are required by the FDA and similar regulatory bodies to ensure the safety of the final product. 

Per the FDA's CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS, 1987 "Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed.

MICROBIAL ENVIRONMENTAL MONITORING

The FDA comment Here that the purpose of Environmental Monitoring is to demonstrate that the environmental quality of a pharmaceutical manufacturing area is consistently within specified levels, also to provide a timely and sensitive warning if the environmental quality or its control is becoming unacceptable, and to initiate a timely, comprehensive planned course of action whenever environmental monitoring results are indicative of unacceptable environmental quality or control.

Further, they comment that routine monitoring of the "clean" environment and operations is important to insure that all modes of potential microbiological contamination are under control. They require the routine monitoring of viable particulates (those of microbiological origin) during processing and when the area is at rest via settle and contact plates plus, in certain circumstances, active air sampling. Clear standards are established for different classes of area describing permitted levels of microbiological contamination.

The principal goal of microbial environmental monitoring is to protect the product and by extension the patient, by demonstrating that the manufacturing environment is clean and functioning as designed. In addition to routine facility monitoring, work in this area includes risk assessment and appropriate operator training.

QA MATERIAL RELEASE

A certificate of analysis presented to support the release of material under Quality Assurance guidelines is the final result of a complex process involving: agreeing the appropriateness of the specifications, developing and validating robust analytical methods, purchasing and qualifying the required analytical equipment, designing and building an appropriate laboratory and recruiting and training the appropriate laboratory personnel to carry out those tests.

A fundamental element to Quality Assurance is operational separation between those responsible for the manufacturing and testing of the product and those responsible for authorising the release of the material.

METHOD DEVELOPMENT

Method development is the development of an analytical procedure that will be appropriate (precise, accurate, specific, robust) for the analysis of a particular sample for a particular purpose.

Method development begins with the choice of the technique, which will be dependent on the critical product characteristics to be tested. From there, the skill and experience of the analyst will be used to investigate and determine the optimum analytical parameters - instrument configuration, sample preparation and presentation, data outputs and interpretation. A draft analytical method will be prepared and, when the development stage of the product requires, the method will be validated to ensure the quality of the data generated.

Method development will also give consideration to any sample handling issues (environmental sensitivity, storage conditions, toxicity, potency). An appropriate method will not only provide the data to answer the analytical problem and guide product development, but also demonstrate suitable sensitivity, ruggedness, accuracy and precision.

USP/EP TESTING

In the EU, the European Pharmacopeia dictates the standards to which all prescription, over-the-counter and other healthcare products manufactured and sold in Europe much reach. In the US, the equivalent is the United States Pharmacopeia (USP).

Both Pharmacopeias set standards for the quality of these products, and work with healthcare providers to help them reach the standards. Whilst there are many similarities between the tests described in the two publications, there are also subtle differences in e.g., the way tests are carried out or the success criteria set. Thus, for a globally marketed product, it is often necessary to meet both sets of standards. Agenda1 can test to both EP and USP requirements.