End product testing

Why are medicines different from other consumer products Why is there so much regulation of the pharmaceutical industry Why, in the light of modem analytical techniques, can t we rely on thorough testing of the final product (end-product testing) and do away with all of these bureaucratic systems These are just some of the questions that are always asked of quality professionals in toe pharmaceutical industry and 1 will try and answer them. 

Medicines are special because virtually no other product is consumed by toe public on such utter ttust - ttust that toe medicine will not do them more harm than toe illness it is meant to cure. Their doctor prescribes toe medicine it is dispensed by a pharmacist and is taken by toe patient in toe belief that it will cure their ill health and that it will not make it worse This trust can only be assured if toe medicine has been adequately tested during development. This testing should assure that side effects have been established and that toe medicine is efficacious. When toe medicine is given to patients it must have been appropriately manufactured, tested and packaged to assure that  

It is free from harmful impurities and micro-organisms. It has not been contaminated. 

End-product testing (quality control) is toe reliance only on appropriate analytical tests to demonstrate toe quality of a medicinal material. End-product testing alone is considered as testing quality into the product. You only accept those materials that pass specification. This is not adequate to ensure that toe medicine is free from all manufacturing faults, that test methods employed are adequate to establish its purity and that a small proportion of defective materials would be detected. I will give several examples to iUustrate this point. 

Example 1.1. All pharmaceutical industry regulators prohibit toe manufacture of penicillins in toe same facihty as other medicinal materials. The reason for this is toe very high potential of extremely low levels of penicillin to cause serious side effects in individuals who are sensitised to this class of compounds. For this reason, cross-contamination levels are set at zero and toe only way to ensure compliance is to not have toe penicillin there in toe first place. Firstly, toe penicillin may contaminate at such a low level that existing analytical methods would not detect toe presence of it, even if it were suspected of being 

---

Although the Izod and Charpy tests are widely used for plastics, other types of test are also popular. These include tensile impact tests and flexural plate (falling weight) tests. The latter is particularly useful in situations where the effects of flow anisotropy are being assessed. In addition, arbitrary end-product tests are widely used to provide reassurance that unforseen factors have not emerged to reduce the impact performance of the product. 

It would be considered prudent to prohibit the premature release of product if you did not have an adequate traceability system in place. If in fact any nonconformities in a component will be detected by the end product tests, it may be worth allowing production to commence without the receipt tests being available, in which case the tests will only be confidence checks and not verification checks. If only one product is received and released prior to verification one would think that, as the requirement applies prior to verification, there is no need to positively identify the product to permit recall because you would know where it was if you found it to be nonconforming. However, the nonconformity may have been reported to you by the supplier after delivery. The standard does not stipulate when and by whom the nonconformity may have been detected. If you lose the means of determining conformity by premature release, don t release the product until you have verified it is acceptable. 

Propellant Acceptance. There are two principal areas in the control of CTPB propellants (1) the preproduction tests which include raw material acceptance and the end product tests to determine the best prepolymer-curing agent ratio for a specific composition of solids, and... 

The frequency of the validation review should be addressed in the final validation report and may be determined against elapsed time or the number of batches processed, anomalies in results of in-process and end-product testing, and questions arising from internal or external audits. 

U.S. Department of Health and Human Services (DHHS) (1987), FDA guidelines on validation of the Limulus amoebocyte lysate test as an end product test for human and animal parenteral drugs, biological products and medical devices, DHHS, Rockville, MD. 

According to the FDA, assurance of product quality is derived from careful and systemic attention to a number of important factors, including selection of quality components and materials, adequate product and process design, and (statistical) control of the process through in-process and end-product testing. 

Gather the numerical data from the completed batch record and include assay values, end-product test results, and in-process data. 

In-process monitoring of critical processing steps and end-product testing of current production can provide documented evidence to show that the manufacturing process is in a state of control. Such validation documentation can be provided from the test parameter and data sources disclosed in the section on retrospective validation. 

End-product testing End-product testing End-product testing End-product testing... 

Figure 14 illustrates the construction of a table containing the results of end-product testing of 22 batches of a tablet dosage form. For simplicity, the product will be referred to as drug F. There are 22 rows and 14 columns, for a total of 308 data points. Each column has an abbreviated heading that describes the information contained therein. The headings are not needed for computer... 

These major limitations demonstrate that reliance on end-product sterility testing alone in ascertaining the sterility of a parenteral product may lead to erroneous results. One purpose of validation in the manufacture of sterile products is to minimize this reliance on end-product testing. Three principles are involved in the validation process for sterile product. 

Sterilization validation involves establishing that a system sterilizes, whether or not testing is performed on the end product. The need for such evidence stems from the fact that sterility is not an absolute product attribute that can be determined by end-product testing alone. 

Furthermore, the drafted guide suggests that the level of end-product testing for those products will depend on the associated risk connected to the scale of operation, shelf life of the product, frequency of preparation, as well as type of product (parenterals, orals) and type of facility where the product has been prepared. 

Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices Food Drug Administration, December 1987. 

Despite the attention, capital and resources given to the Test for Sterility, batches of product cannot be confirmed to be sterile by end-product testing. The Test for Sterility is in fact only a test for a specific broad range of microbial contaminants, and its sampling statistics are not capable of disclosing frequencies of contaminated units that would put patients at risk owing to non-sterility. This has been recognized by the pharmacopeias, notably the PhEur, which for some years has carried a statement in Section 2.6.1 (formerly V.2.1.1) ... 

Design standards intrinsically must be more detailed, more complex, more arbitrary, and more authoritarian than performance standards. Specific formulas can be specified by USP-NF, as can methods of compounding or processes of manufacture if necessary. However, end-product testing is believed by most pharmaceutical scientists to be adequate public... 

At early clinical stages (Phases I and II), where only limited GMP batches of product will have been produced, and where product and process changes make batch replication difficult, only limited process validation may be possible. In such cases, the regulatory authorities will expect to see data from extensive in-process and end-product testing to demonstrate that the batch is adequately qualified, yielding a finished product which meets specification and quality characteristics. 

It will check for equivalence, for both the drug substance and pharmaceutical product, between that used in the pivotal clinical studies, the pivotal stability studies and commercial production. This is usually achieved by inspecting product and control data such as clinical trial batch records, in-process and end-product test results and raw material, component and product specifications. During an R D PAI the FDA will also check for general compliance with cGMP, will inspect the facilities and equipment used and check the appropriateness of control systems and procedures. 

Disintegration testing is an important part of in-process control testing during production to ensure batch-to-batch uniformity, but its role in end-product testing has largely been superseded by dissolution testing. 

In future, attention will be directed to a greater degree of automation and miniaturization of analytical techniques, primarily for in vivo (PK, PD) but partly also for in vitro QC use. In order to assure the quality of new medicines, there are promising initiatives to optimize in-process testing, to control strategies, and (probably) to carry out less end-product testing as process analytical techniques (PAT). 

---