Originally Published IVD Technology October 2003
Biochemicals and chemical reagents
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| Golgi membranes can be seen in normal rat kidney cells that have been stained with an anti-giantin polyclonal antibody by Covance Research Products Inc. (Berkeley, CA). |
Biochemicals and chemicals used in IVDs include reagents as simple as salts and as complex as recombinant enzymes, antibody fragments, and synthetic nucleic acid polymers, not to mention various conjugates of these. All reagents are critically important to the performance of an IVD manufacturer’s product. Therefore, they must be reliably consistent in order to ensure a smooth transfer from R&D to production and to support uniform high final product quality over the course of manufacture.
The consistency of simpler components like buffers, salts, detergents, and such organics as cross-linking reagents is easily assured. More-complex reagents, such as enzymes, antibodies, and nucleic acid polymers present a greater challenge. The various man-made, or defined, reagents typically are much more controlled, and therefore more consistent, than those containing animal products. Even the highly complex polyethylene glycols, polyvinyl acids, and microparticles of numerous sorts are produced in such large batches that a single lot of one of these polymers can be used for several years’ worth of
IVDs.
Previous editions of the IVD Technology Buyers Guide have described and categorized the varieties of chemical and biochemical reagents available. There is little to add to those essays. Although it is of course very important to understand the nature of each reagent, it is equally important to understand essential factors in its production and how they should be documented.
Sourcing Reagents from Vendors
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| Quad Five (Ryegate, MT) provides sterile donor-animal blood fractions for the production of microbiological prepared media. |
Many, if not most, IVD products are subject to regulation by FDA, as well as by other federal and international agencies. These regulations require uniformity of end-product performance, which can be crucially affected by a single component. For example, it is well known that the monoclonal antibody selected for an assay will determine the performance of that assay with respect to specificity, sensitivity, and other factors; but how each lot of that antibody is produced is just as critical for performance and is important to control.
Such control is more or less easy for IVD manufacturers that produce their own assay materials in-house. These companies are probably in the minority, however. Most manufacturers purchase monoclonal antibodies from a third source, often via a broker. Therein lies the challenge. A company providing an antibody derived from ascites, for example, might encounter problems in obtaining mice of the required strain, age, or sex. Going to an alternative animal source could change the yield of antibody obtained, if not its performance as well. In vitro production can face similar challenges.
Consider antibody specificity in an IVD for an infectious disease. In most cases, a monoclonal antibody is required to meet the specificity criteria. The antibody’s development phase entails detailed analysis of cross-reactions with many different species and strains of pathogens. Such testing is extremely difficult to incorporate into a manufacturing process so as to assure lot-to-lot product consistency. If the manufacturer’s supply of the antibody derives from in vivo production, the possibility of lot-to-lot performance varying is good. Animals used to produce the antibody can contribute serum antibodies to the harvested ascites. Failure by the vendor to adequately control exposure of the animals can therefore affect specificity in ways unforeseen and difficult to detect in a manufacturing environment. This can lead to release of a product that will elicit complaints from end-users experiencing false-positives or other unwelcome results.
Many vendors of such assay materials go to great trouble and expense to control such variables as part of their production method. Adherence to approved good manufacturing practice (GMP) is required of makers of regulated products, and that includes documenting all operations and the personnel conducting them. For a GMP plan to be instituted and maintained, everyone involved in the production process must have specialized skills and training.
These same considerations apply to every chemical and biochemical component that goes into an IVD product, not just antibodies. Enzymes, cofactors, and substrates, even salts and buffers, can adversely affect lot-to-lot IVD performance if they are not adequately controlled. Many immunoassays require the use of accelerators to meet performance criteria. These accelerators are usually man-made polymers produced in huge quantities from many different raw materials. Controlling the characteristics of such a component as that is a difficult and exacting task. Yet, a minor contaminant in this complex product—what the IVD manufacturer regards simply as raw material—can do damage to the marketed IVD device.
Auditing Vendors
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| The bovine serum albumin (BSA) by Serologicals Corp. (Norcross, GA) is derived from U.S.-sourced serum and plasma collected in USDA-licensed abattoirs. |
Manufacturers of regulated IVDs are required to provide assurance that the materials used in their products meet the stated requirements. Such assurance relies on documentation received from component suppliers. To be certain that this documentation is based on valid methods and procedures, the manufacturer of the final product must audit each outside source of critical materials.
The vendor audit should be thorough and should cover all aspects of production of the component in question. It is not to be regarded as a single event. Rather, the audit should be a continual process, with periodic updates.
Examining documentation is not alone sufficient. The audit must cover aspects of production by the vendor that are difficult to judge at second hand. No audit process is complete without a full and careful inspection of the laboratories and facilities in operation. Do staff members understand not only what they must do, but also why and how the quality of their observations and documentation affects the final product outcome? Too often, staff training covers only correct procedures and fails to impart a clear understanding of how a process fits into the whole manufacturing enterprise and what about it is important. This results in a manufacturing process that may produce material of technically acceptable quality but lacking in robustness. The supplier may meet the letter of the law, but can it really assure delivery of a consistent product upon which a manufacturer can confidently base its own products and future?
Attention must be paid to how the vendor assures quality in critical components it obtains. The materials a vendor incorporates into the product it supplies not only can spoil an IVD device, but also may limit its manufacturer’s market. To return to the monoclonal antibody example, in vitro methods typically require the use of animal components, which are purchased by the vendor, for maximum cell viability. The spread in recent years of bovine spongiform encephalopathy into countries thought safe from that disease has caused a great deal of justified concern. The requirements for the importation of manufactured goods containing animal by-products must take into account such developments as this.
Selecting a Vendor
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| The Cliniqa hsCRP controls by Cliniqa Corp. (Fallbrook, CA) are intended for use in the clinical laboratory as an assayed quality control material for serum C-reactive protein analysis. |
In choosing a vendor for a chemical or biochemical component, an IVD manufacturer should look for several things. Has the vendor done business with the company in the past, perhaps with a different division, and if so, what was the nature of any problem encountered? Was any audit of the vendor that may have been performed thorough and applicable to the manufacturer’s intended needs? Does the vendor maintain a department to oversee quality and regulatory concerns that is separate from the staff that produces the reagent and has an up-to-date organizational chart? If not, then there are serious potential quality concerns, not to mention probable violations of GMP. Finally, does the vendor obtain some component of its product from more than one supplier? If so, how is this documented, and is variability controlled?
Selecting a vendor is a much more complex task than it might seem. To be able to ensure that its product can always be delivered from stock and will perform as promised, an IVD manufacturer needs to have a deeper understanding of the supply process than can be gained from first inspection. It is always advisable to work with suppliers that have attained and then kept good reputations in this area, and it may be important to do so.
Richard T. Root, Roche Diagnostics/Boehringer
Copyright ©2003 IVD Technology
