FDA guidance documents

The FDA guidance document on impurities in drug substances recommends that individual impurities greater than 0.1% should be fully characterized and quantified by a validated analytical method. In addition, the USP permits up to 2% of ordinary nontoxic impurities in APIs. Such impurities may include residual starting materials, intermediates, reagents, by-products, degradation products, catalysts, heavy metals, electrolytes, filtering aids, and residual solvents. 

Multiple changes in site, scale, and manufacturing processes are considered to be PAS-type changes and require prior approval from the FDA. More detailed information is provided in the current FDA guidance documents. (See the Bibliography.)... 

The integrated IND team brings three important advantages. First, many sections of the IND, while defined in FDA guidance documents as self-standing descriptions, actually represent interactive results of input from different organizational subunits. The connection between CMC stability results and Quality Assurance review of the manufacturing site and procedures is a prime example. 

This process serves three important purposes. First, it provides a fourth detailed review of the document. Second, it serves as practice for the FDA presentation meeting. And third, it provides an opportunity to discuss strategy and tactics. While this independent review is certainly not mandatory (it does not appear as even a suggestion in any FDA guidance document), it is a common practice and highly recommended. 

The FDA guidance document recognizes the difficulty of extrapolating the results obtained with recombinant enzymes to the situation in liver microsomes. Experiments with recombinant CYP enzymes provide valuable information on which CYP enzymes can and which ones cannot convert a drug candidate to a particular metabolite, and this information alone is particularly valuable in guiding the design or interpretation of correlation analysis, chemical inhibition, and antibody inhibition experiments. 

Current FDA guidance documents can be accessed from the internet at http //www.fda.gov/cder/ guidance/index. htm... 

The FDA refers to a few official documents for guidance in accomplishing a valid preclinical development program. These include International Conference on Harmonization (ICH) accepted guidances as well as US FDA guidance documents ... 

The figure clearly shows that the systems where Part 11 compliance is required are a subset of the GXP-relevant systems. Especially under the narrower scope for Part 11 as given by the new FDA guidance document,many systems used for regulated purposes will come under the classification that they require validation, but not Part 11 compliance. On the other hand, if a system does not require validation, it will definitely not fall under the purview of Part 11. 

However, Norwood and Qiu observe that for orally inhaled and nasal drug products (OINDPs), FDA guidance documents require a greater degree of excipient characterization and stricter quality control... 

According to two FDA guidance documents issued in 2005, and presented in synoptic form below,... 

The FOI Online Web site (cited previously) also enables keyword searching of a huge retrospective collection of FDA Warning Letters, as well as FDA Guidance documents. Both of these compilations complement those offered on the FDA web site. Since the database supplier is also a document delivery service, the online file serves as a catalog of materials stored in-house after being obtained through Freedom of Information Act provisions. This means that items not separately listed or readily searchable on the FDA Web site are indexed at FOI Online. For example, the database provides separate... 

FDA Guidance Document Concerning Use of Pilot Manufacturing Facilities for the Development and Manufacturing of Biological Products. Docket No. 95D-0131 Food and Dmg Administration Rockville MD, 1995. 

We will look at five specific FDA guidance documents the formatting of the statistical section of an application, the integrated summary of effective-ness, statistical review template, conducting a safety review for a new product application, and guidance for DILI. ... 

Table 12.1 summarizes some of the tests discussed in the FDA guidance document Data Requirements for Ultra-High Molecular Weight Polyethylene (UHMWPE) used in Orthopedic Devices (FDA 1995). If the new polyetirylene has almost identical properties to a polyethylene already on the market after stage 1 testing, no further testing may be required. If it does differ in properties from an existing... 

Specific polymeric materials traditionally used for medical applications have been recently withdrawn from the medical market. Silicone elastomers are among those withdrawn. To maintain continued supply of vital implants, methods of determining equivalence for withdrawn elastomers with new or existing ones has been adopted by the FDA in the form of an FDA Guidance Document. 

Standard methods of testing elastomers used for medical applications are given by specific ASTM test methods. Physical and biological tests are provided here to serve as references for the data cited in the tables and listed in Table 4.17. They are also designated in the FDA Guidance Document. 

An excellent overview of the problem, particularly as it affects bioanalytical data and information submitted to the US FDA, was published by the Society for Quality Assurance (SQA 2000). The relevant regulatory documents on electronic documents and signatures are found as Part 11 of the US Code of Federal Regulations (CFR21 2003) and an FDA Guidance document is available (FDA 2003a). (Note that the FDA interprets the word equipment to include hardware and software as well as instrumentation.) The review of qualification of anal54ical instrumentation (Bansal 2004) includes a section on software validation and the same phases (DQ, IQ, OQ and PQ, see Section 9.5.1a) apply. 

The FDA Guidance document (FDA 2001) describes a circumstance somewhat related to abbreviated validations but one that is applicable to modifications of existing fully validated methods. The validation procedures required for such circumstances are called partial validations. In general, the required components of a partial validation wiU depend on what type of modification was made and the vahdation parameters that may have been affected the requirements can range from as little as one determination of intra-assay accuracy and precision to a nearly full vahdation. Examples of the modifications to existing methods that require some form of partial vahdation (FDA 2001) include method transfers from one laboratory to another (but it has been argued that this circumstance is... 

---