6 regulatory requirements

Regulatory agencies are continuously pushing the quahty systems that appear in the early phases of drug development. The ICH (International Conference on Harmonization) offers several guidelines for the characterization of the drug substance. Notably, these include  

Q1A(R2) Stability Testing of New Drug Substances and Products (Issued 11/2003, Posted 11/20/2003)  

QIC Stability Testing for New Dosage Forms (Issued 5/9/1997, Posted 3/19/1998)  

Regulatory requirements the world over dictate that hazardous chemicals and chemical products carry warning labels on them that convey health hazard information about such chemicals and products. Well-communicated warnings are instrumental in saving lives and protecting the health of people who use or are incidentally exposed to hazardous chemicals. Chemical product warnings that fail to warn, on the other hand, are often responsible for serious injuries and even death. 

The manufacturer using DWAs must determine if a FDA approved DWA is required in their product market. The number of DWAs meeting FDA technical requirements is small and these DWAs command a premiiun in the marketplace. The qualification of new DWAs is expensive and takes a long time. DWA chemistry type. Molecular weight (Mw), Molecular number (Mn), PolyDIspersity (PDI = Mw/Mn), imreacted monomer concentration and concentration in the final product are some of the major factors the FDA considers and the candidate must pass technical specifications in these areas in order to obtain approval. 

RI T°C Miscibility Curve D 1218 Yield calculation, solvent composition Used to set solvent composition for each stock to avoid immiscible operation 

Gas Chromatographic Distillation D2887 GCDs may be for troubleshooting and predicting dewaxing performance 

Feed Cloud Point D 2500,05551 D 5771,0 5772, D7773 Helps set feed precooler outlet temperature 

Water-in-Solvent D 6304-03, E 203-1 Excess water may lead to immiscible operation and icing of solvent chillers 

The current Japanese guidance document, titled Test Methods for Biological Safety Evaluation of Medical Devices, Assessment of Medical Device, Notice 36,2003, partially embraces ISO 10993, but it has technical specifications to perform tests that differ from the procedures specified in ISO 10993. As a consequence, many Japanese regulators do not readily accept testing conducted according to ISO 10993. Such reluctance will likely to continue until the techifical sections of these two standards are harmonized. At present the techifical conduct of many studies differs enough for the end point requirements of a Japanese test to be different from the requirements of ISO, and vice versa. Additional testing may thus be required to submit a medical product for Japanese approval. 

Proper manag ent of the relationship between a medical device manufacturer and a CRO is important in order to speed up completion of biocompatibility testing. Generally, the device manufacturer needs to consider three important questions. 

Ethical, economic, and competitive reasons, as well as those of safety and efficacy, support the need to monitor impurities in drug products.9 However, monitoring impurities and controlling these impurities mean different things to different people or to the same people at different times, even those in the pharmaceutical sciences and industry.2 A unified terminology is necessary to assure that everyone uses the same vocabulary when addressing questions related to impurities. In this context, the leadership provided by ICH is very helpful. 

A number of requirements have an effect on monitoring impurities (see Chapter 2). For example, a country s pharmacopeia or the one accepted by that country often provides the primary guidance as to how impurities are to be monitored and regulated. In a majority of countries these pharmacopeias are run under the auspices of the government. The USP is a notable exception to this case. If a product is considered a pharmacopeial item, it must meet the compendial requirements. 

In the United States, the federal FD C Act and its amendments require that a manufacturer demonstrate the safety and efficacy of a new drug prior to introducing it into interstate commerce. The requirements are clearly spelled out in the Notice of Claimed Investigational Exemption for a New Drug (IND) and the NDA. 

NDAs demand more specific and explicit information, including stability studies to guarantee that the identity, quality, and purity of the drug product is maintained until its expiration date. 

The FDA may initiate action under the Food and Drug Act to bring about removal of a product from the market, or, as is granted in the law, a manufacturer may voluntarily withdraw from the marketplace any batches that do not meet the approved specifications. 

A large part of the US diet is made up of crops which originate outside the USA. Currently, a US tolerance achieved through the submission of data obtained from residue trials run exclusively within the USA permits the importation of commodities grown in Latin America or other countries. Within the past 5 years, the ERA has initiated programs to ensure that residue testing to achieve a US tolerance better reflects the climatic and cultural conditions under which the commodity is grown. 

Generally, for a US tolerance, there will be a requirement for additional residue 

Cranberries Not likely to require foreign residue data. Cranberries account for an extremely low percentage of the US diet. In this case, ERA would probably not require submission of foreign residue data because dietary exposure to residues in imported cranberries is very low and ERA determines that US field trials would be representative of growing conditions in Canada.  

In the European Union (EU), the Committee on Proprietary Medicinal Products (CPMP) issued a draft Note for Guidance on Safety Pharmacology Studies in Medicinal Product Development in 1997 [3], but it was not finalized or put in force until the middle of 2001. The U.S. Food and Drug Administration (FDA) promulgated equivalent guidance at the same time, but the exact details of compliance and implementation, as will be seen in this volume, are still being worked out. 

A further consideration arose in 2008 with the promulgation of guidance requiring safety assessment of significant human metabolites including their safety pharmacology aspects [4]. 

Safety assessment of pharmaceuticals M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals [6] Guidance for Industry Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals [7] N/A New Drugs Division Notification No. 9/99 Guidelines for Toxicity Studies of Drugs 

Safety Guidance for Industry Guidance for Industry CPMP Not for Notification No. 4  

QT interval Safety Pharmacology Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals [9] N/A Points to Consider The Assessment of the Potential for QT Interval Prolongation by Noncardiovascular Medicinal Products N/A 

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To ensure disposal water quality is in line with regulatory requirements (usually 40 ppm), the oil content in water is monitored by solvent extraction and infrared spectroscopy. The specification of 40 ppm refers to an oil in water content typically averaged over a one month period. 

The business activity of the organi2ation dictates quaUty requirements for the LIMS. Security and regulatory requirements for LIMS data define the level of effort expended to vahdate a LIMS and the data being stored. In addition, the quahty of the hardware and software used to implement the LIMS both play a role in determining overall system quahty. 

Chemical methods to determine the crystalline content in silica have been reviewed (6). These are based on the solubility of amorphous silica in a variety of solvents, acids or bases, with respect to relatively inert crystalline silica, and include differences in reactivity in high temperature fusions with strong bases. These methods ate qualitative, however, and fail to satisfy regulatory requirements to determine crystallinity at 0.1% concentration in bulk materials. 

Specialized training is an absolute requirement for technical service personnel. A typical example is a person involved in supporting a polymer for which the use is the manufacture of rotationaHy molded consumer products. The technical service person is expected to be reasonably familiar with topics such as polymer rheology evaluations, gel-permeation chromatography, rotational mol ding, color science, regulatory requirements for use, mechanical and photochemical behavior of the pigmented polymer, optics, and so forth. Expertise of this variety caimot be expected to be obtained without careful... 

Modification of cellular polymers by incorporating amide, imide, oxa2ohdinone, or carbodiimide groups has been attempted but only the urethane-modified isocyanurate foams are produced in the 1990s. PUIR foams often do not require added fire retardants to meet most regulatory requirements (34). A typical PUIR foam formulation is shown in Table 6. 

The air stream exiting a stripper may requite some type of emissions control, depending on local and regulatory requirements. Carbon adsorption is often used catalytic oxidation is another option. 

Drinking water suppHed to carbonated soft drink manufacturing faciUties from private or municipal sources must comply with all regulatory requirements. Treated water must meet all U.S. Environmental Protection Agency primary maximum contaminant levels and may also be subject to additional state requirements. Treated water is routinely analyzed for taste, odor, appearance, chlorine, alkalinity, iron, pH, total dissolved soHds, hardness, and microbiological contamination. 

Historically the use of mona2ite, a thorium-containing mineral, as the principal lanthanide resource led to confusion regarding the relation between radioactivity and the lanthanides. Inadequate separations produced Th-contaminated Ln products. Modem processing technology results in products that meet all regulatory requirements. 

Whether or not a firm is subject to these regulatory requirements, examples of questions to ask candidate tollers at this stage of initial qualification are ... 

Differences in each country s regulatory requirements may, in turn, cause differences in operating philosophies. It is important to clearly review expectations with regard to health, safety and environmental matters during initial assessments of foreign tollers. 

A successful tolling project depends upon defining the project objectives at the outset and clearly communicating those objectives. The objectives take into account the rights and expectations of both the toller and the client. Specifics such as ownership, specifications, timing, regulatory requirements, product quality, and documentation are considered. Each project or process is unique and consequently the agreements reached between the parties and the... 

Will the client conduct audits to assure that regulatory requirements are being met ... 

The issue that must be managed is the appropriate threshold to communicate the change and initiate appropriate approval processes. Tolls subject to regulatory requirements may use the regulatory guidance as the threshold for management of change processes other tolls must establish the threshold appropriate to process risks, quality systems, and business concerns. 

Provide an explanation of the method(s) used by the site to verify that the control device(s) are operating as designed and m compliance with all regulatory requirements. 

What kind of training is provided over and above regulatory requirements ... 

Impact estimates by specific models are required to meet some regulatory requirements. 

How does the job market for air pollution control personnel respond to changes in regulatory requirements and to the state of the economy ... 

The monitoring of pollutant concentration or mass flow of pollutants is of interest to both plant owners and control agencies. Industry uses such measurements to keep a record of process operations and emissions for its own use and to meet regulatory requirements. Control officials use the... 

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