Drug substances testing

Precision reflects a procedure s ability to reproduce the same, but not necessarily the correct or expected, result each time it is correctly performed. Precision is assessed by repetitively injecting a number of samples and statistically evaluating the resulting data. Important issues related to the precision determination include the number of replicates required and the type of sample to be tested. For the determination of repeatability, recommendations include 1) Five to ten replicates for release or stability assays 2) duplicate measurements made on 10 samples at each of three different analyte levels 3) five replicates at three levels (limit of quantitation, midrange, and upper calibration bound) 4) replicate samples at analyte levels of 80-120% of expected for dosage forms and drug substance tests. 

Information on impurities, including their structure, acceptance limits, and control, is to be briefly described. For control of a drug substance, specifications (including justifications) and analytical procedures (including validation information) used for testing are to be summarized. Data on reference standards or reference materials used for drug substance testing are to be provided. Information on batches and the results of batch analyses are to be described. 

Frequency of testing should be sufficient to establish the stability characteristics of the drug substance. Testing under the defined long term conditions will normally be every three months, over the first year, every six months over the second year and then annually. 

The main details of the formulation and the limits of the experimental domain were given in table 10.8. Other components not noted in the table were the drug substance (1 - 2%) and a lubricant (magnesium stearate). Tablets at 6 mg were made by direct compression of the mixture. The concentration of drug substance (a soluble salt) were allowed to vary between 1% and 2%. Thus, the domain shown in figure 10.7 may be considered as being repeated for each concentration of drug substance tested. 

In November 1997, the Department of Health and Human Services along with the International Conference on Harmonisation (ICH) released a draft guidance for the selection of test procedures, which included chiral drugs. For the development of an enantiopure drug substance, acceptable criteria shall include, if possible, an enan-tioselective assay. This assay should be part of the specification for the identification of an enantiopure drug substance and related enantioenriched impurities [16]. 

International Conference on Harmonisation Draft Guidance on Specifications Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products Chemical Substances Notice, Fed Regist. Docket No. 97D-0448, 1997. 

HHS/FDA International Conference on Harmonisation Stability Testing of New Drug Substances and Products Guideline Availability Notice, Federal Register, September 22, 1994... 

The quality of a drug substance is controlled by its specification. An internationally harmonized guideline on specifications and tests for chemical substances as active ingredients and in drug products makes reference to chiral compounds. This has recently been finalized and is discussed in Section 13.5.2. 

The guideline on chiral active substances states that particular attention should be paid to identity and stereochemical purity. It states that specifications for a racemate should include a test to show that the substance is indeed a racemate and this is a position supported by the requirements of the European Pharmacopoeia for drug substance monographs [16]. 

For drug substances and drug products, applications for enantiomers and racemates should include a stereochemically specific identity test and/or a stereochemically selective assay. The choice of control tests should be based on the method of manufacture and stability characteristics and, in the case of the finished product, its composition. 

Methods of assessing the stereochemical integrity of enantiomeric drug substances and drug products should be included in the stability protocols for both, but stereoselective tests may not be required once it has been shown that racemization does not occur. 

Guidance on specifications is divided into universal tests/criteria which are considered generally applicable to all new substances/products and specific tests/criteria which may need to be addressed on a case-by-case basis when they have an impact on the quality for batch control. Tests are expected to follow the ICH guideline on analytical validation (Section 13.5.4). Identification of the drug substance is included in the universal category, and such a test must be able discriminate between compounds of closely related structure which are likely to be present. It is acknowledged here that optically active substances may need specific identification testing or performance of a chiral assay in addition to this requirement. 

The guideline states that the objective of validation is to demonstrate that an analytical method is fit for its purpose and summarizes the characteristics required of tests for identification, control of impurities and assay procedures (Table 13-2). As such, it applies to chiral drug substances as to any other active ingredients. Requirements for other analytical procedures may be added in due course. 

In-vitro bioavailahility tests usually form part of the criteria for evaluating the individual batches of a product. These are based on monitoring the rate of release of the drug substance from the pharmaceutical form, usually by observing the dissolution rates of tablets or capsules. 

GL3 Stability 1 Stability testing of new drug substances and products... 

Initial Situation An experimental granulation technique is to be evaluated a sample of tablets of the hrst trial run is sent to the analytical laboratory for the standard batch analysis prescribed for this kind of product, including content uniformity (homogeneity of the drug substance on a tablet-to-tablet basis, see USP Section (905)" ), tablet dissolution, friability (abrassion resistance), hardness, and weight. The last two tests require little time and were therefore done first. (Note Hardness data is either given in [kg-force] or [N], with 1 kg = 9.81 Newton). 

AUC.dat Sixty-nine subjects were exposed to three different medications containing the same drug substance in a test of equivalence each had blood samples withdrawn at defined time points after administration so as to obtain a curve of plasma level of drug vs. time. The area under such a curve is a measure for the amount of medication the subject s body absorbed through... 

CREAM.dat A batch of cream containing two drug substances was put on stability and tested for at f = 0, 3, 7, and 24 months. Active component 1 remains stable, while AC2 degrades so fast that a shelf-life of only 26 months can be demonstrated for SL = 90%. Use with SHELFLIFE. 

Drug substance/drug product purity, potency, and other testing Drug substance/drug product stability testing Method development, validation, and transfer Drug product formulation development... 

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

The testing of impnrities in active pharmacentical ingredients has become an important initiative on the part of both federal and private organizations. Franolic and coworkers [113] describe the utilization of PLC (stationary phase — silica gel and mobile phase — dichloromethane-acetonitrile-acetone (4 1 1, v/v)) for the isolation and characterization of impurities in hydrochlorothiazide (diuretic drug). This drug is utilized individually or in combination with other dmgs for the treatment of hypertension. The unknown impurity band was scraped off the plate and extracted in acetonitrile. The solution was filtered and used for LC/MS and NMR analysis. The proposed procedure enabled the identification of a new, previonsly nnknown impurity. It was characterized as a 2 1 hydrochlorothiazide-formaldehyde adduct of the parent drug substance. 

The purpose of stability testing is to assess the effects of temperature, humidity, light, and other environmental factors on the quality of a drug substance or product. The data produced are used to establish storage conditions, retest periods, shelf loss, and to justify overages included in products for stability reasons. The most useful equation relating temperature and reaction rate is the Arrhenius equation. This equation (27) may be integrated and rewritten as Eqs. (31) and (32). 

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