Regulatory issues

Regulatory issues may arise throughout the duration of a tolling process. The type of issues experienced is dependent upon the mechanical aspects of the process, chemical makeup and quantity of the specific raw materials, intermediates, products, emissions and wastes. 

Are materials subject to the requirements of the OSHA Process Safety Management Rule (29 CFR 1910.119) or the EPA Risk Management Program Rule (40 CFR 68)  

Are there any specific, high profile environmental, safety, or health issues or concerns with materials  

Are any of the toll products sold under Food and Drug Administration (FDA) regulations as direct or indirect food additives  

In Europe and the United Kingdom, there are two issues to address. Fust, herbal drinks should avoid using levels of herbal extracts that are high enough to render them liable to be considered as a herbal remedy. In simple terms, this means using levels of extracts that avoid delivering cumulative therapeutic levels of herbal actives from a typical daily consumption of the herbal drinks. Information and guidance on these matters should be available from herbal extract suppliers or consultants. 

The second issue is that of claims. This subject is difficult to write upon definitively as new or changed regulations are often put into effect. However, the trend seems to be that claims will need some form of substantiation based upon scientific reports. In the future, folklore and anecdotal information about herbs are less likely to be permitted on product labels, advertisements and point-of-sale literature. 

As gene therapy and stem cell research progress, we can expect more regulatory requirements to be developed to ensure proper safeguards are implemented. Similarly, xenotransplantation and control of biopharmaceutical products will experience specific regulatory controls as new advances are made. Exhibit 11.14 presents the FDA s current oversight on gene therapy. 

The reason is speed. At only days after the availability of an expression vector, milligrams to hundreds of milligrams of a recombinant protein can be delivered into the hands of the researcher. Vectors for transient expression do not require a selection marker - the goal is to deliver DNA to a maximal number of cells in the population. Several vectors can be transfected simultaneously into cells and will be expressed simultaneously. With calcium phosphate as a vehicle, it was shown that approximately 20000 plasmid molecules per cell can be delivered [132]. After a few days, the copy number of plasmid molecules will decline in the nucleus and the production ofmRNA ceases. Depending on the protein at the time point of the highest accumulated yield, the product is harvested and cells are discarded. A new production can be re-started at any time when sufficient fresh cells can be provided and a new DNA-vehicle preparation is ready for transfection. 

Large-scale transfection requires significant quantities of DNA. With both calcium phosphate and PEI, approximately 1-2 mg of plasmid DNA are usually needed per H-ter of suspension culture. Media and culture conditions for large-scale transient transfection are under further development, as are the vehicle preparation techniques. With calcium phosphate as a vehicle, a small concentration (1-2%) of fetal bovine serum may be required for high transfection elBciency. Here as well, it is a goal to generate processes that are low or free of undefined components. 

It remains to be seen whether transient expression technologies wiU eventually be used under conditions for clinical production and thus provide eventually products for human medical use. 

All mammalian cells used for the large-scale production of recombinant proteins are considered immortalized , as they can be grown continuously for an indefinite period if correct culture conditions are provided. This is an exceptional characteristic for animal-derived cells, since the tissues and organs of animals are constructed of cells with a defined lifespan. The limited lifespan of cells in animals was detected first by Hayflick [133], and is linked -among other reasons - to a declining telo-merase activity on chromosomes of somatic cells, but not in germ cells. 

The climate for permission by regulatory agencies, particularly by the FDA in the United States to use immortalized CHO cells for the production of recombinant proteins was not favorable in the early 1980s. Discussions about risks associated with the use of mammalian cells were controversial and had been initiated more than two decades earlier [134] when a first generation of classical biological products (i.e., vaccines and the natural interferons) were developed on the basis of primary monkey kidney cells, human diploid cells and, later, transformed mammalian cells. 

Determination of the appropriate level of documentation for an exploratory or advanced biomarker application is made by the organization or laboratory responsible for the biomarker study. In general, an analytical procedure and a validation memo containing the summary data should be adequate for exploratory application. For an advanced validation, the record keeping and reporting may be similar to that of the methods for PK support. The basic idea is that the data should be traceable and subjected to QC and QA review. The final method should be documented in an analytical procedure and the results presented in a validation report. 

FIGURE 6.14 Workflow diagram of in study validation and sample assay of biomarker. 

Sometimes a consistent supply of the same kit lot is not possible in a lengthy clinical study. Experiments should be performed upon a kit lot change to compare the new kit standard against the previous lot. If the previous kit standard lot is exhausted, charts of a common set of SC can be useful to detect lot differences, as shown in Fig. 6.12. 

Assay acceptance criteria for biomarkers do not solely depend on the deliverable method accuracy and precision, as is the general rule in bioanalytical laboratories. Instead, the consideration should be on the assay suitability for the intended applications considering three major factors (a) the intended use of the data during various stages of drug development, (b) the nature of the assay methodology and the type of data that the assay provides, and (c) the biological variability of the biomarker that exists within and between populations. Thus, the first factor helps shape the assay tolerance or acceptance criteria for biomarkers. 

The acceptance criteria for a novel biomarker can initially be determined by assay performance in prestudy method validation. Data obtained from the in-study validation using subject samples can then be used to refine the initial acceptance criteria set during the prestudy validation. For example, an assay with 50% total error may still be acceptable for detecting a twofold treatment effect observed in a clinical trial. Setting acceptance criteria a priori may not be appropriate (or even possible) in an exploratory application of novel biomarkers, since the values seen in the incurred samples may not be what is expected or predicted. 

In the USA, the passage of the Food Quality Protection Act (FQPA) of 1996 has had a significant impact on the determination of residues in drinking water. FQPA requires that all sources of a pesticide be included in its risk assessment, so the potential exposure from drinking water containing a particular pesticide could be a significant 

Source World Health Orga nization. Pharmaceuticals Restrictions in Use and Availability, http // www.who.int/medicines/publications/restrictedphann2005.pdf[accessed October 3,2007]. 

As if making a drug in an efficient and cost-effective manner is not a sufficient challenge, those involved in drug synthesis and manufacturing must keep detailed records on every aspect of the synthesis. 

General LIS applications, outside blood collection or transfusion services, are not subject to FDA regulations, but many laboratories voluntarily subject their LIS to inspection and accreditation. The College of American Pathologists 

Compliance with regulations is not only a legal necessity and an ethical duty for any corporation seeking to display social responsibility to its stakeholders, but compliance can also help ensure successful manufacturing business performance in the long term. 

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Regulating Pesticides in Food The De/anej Paradox, Report of Board on Agriculture, Committee on Scientific and Regulatory Issues Underlying Pesticide Use Patterns and Agricultural Innovation, U.S. National Research Council, National Academy Press, Washington, D.C., 1987, 272 pp. 

Vaccines are used in either the general population of children or adults or for special groups. Recommendations for vaccine usage are made by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control. The Committee on Infectious Diseases of the American Academy of Pediatrics (Redbook Committee) also makes recommendations for infants through adolescents, and the American Academy of Family Physicians makes recommendations for adults. An excellent review of vaccine history, development, usage, and related regulatory issues is available (2). 

Murphy, J. A., 1996, Risk-Based Regulation Practical Experience in Using Risk-Related Insights to Solve Regulatory Issues, PSA 96, pp 945-948. 

Before beginning work on PSM in another country, it is important to understand local priorities and influences. These include regulatory issues, cultural expectations, internal company requirements, and systems already in place. 

Polyester thermosets, bodi UPR and alkyd resins, are facing severe regulatory issues for limiting VOC and toxic compound emissions. Although these issues are not new, only pardy satisfying solutions have been proposed until now, and further research is clearly needed in this domain. 

This chapter briefly discusses the future of SAS programming and the SAS programmer in the world of clinical trials. The impact of the business environment, regulatory issues, technological changes, and standards organizations on the future of SAS programming in clinical trials is addressed. 

Scrip World Pharmaceutical News. Published twice weekly, Scrip World Pharmaceutical News [100] covers the commercial pharmaceutical marketplace with news, products, R D, regulatory issues, market data, business, and finance. This product is commercially available in several formats. 

Phillips, L. E., 1990, Resolution of U.S. Regulatory Issues Involving BWR Stability, Proc. Int. Workshop on BWR Instability, Hottsville, NY, CSNI Rep. 178, OECD-NEA, Paris. (6)... 

Grindley, J. and Ogden, J. 2000. Understanding Biopharmaceuticals. Manufacturing and regulatory Issues. Interpharm Press. 

Streatfield, S. 2005. Regulatory issues for plant-made pharmaceuticals and vaccines. Expert Review of Vaccines 4(4), 591-601. 

Daughton CG (2001) Illicit drugs in municipal sewage in Pharmaceuticals and personal care products in the environment scientific and regulatory issues. In Daughton CG, Jones-Lepp TL (eds) ACS symposium series 791. The American Chemical Society, Washington, DC, p 116-139... 

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