JP2014529473A - Pharmaceutical product and method for analyzing exposure of pharmaceutical product - Google Patents

Abstract

A container wherein the pharmaceutical product has an outer surface and an inner chamber, an active ingredient disposed in the inner chamber and whose photosensitivity changes based on cumulative exposure to light having a wavelength in the range of at least X to Y; and the container And a layer of photosensitive material that is disposed on or in a container and is exposed to environmental conditions that are present simultaneously with the active ingredients disposed within the interior chamber. The photosensitive material is reactive to light having a wavelength in the range of X to Y and undergoes a characteristic change in the threshold of cumulative exposure to light in the range of X to Y with respect to the change in photosensitivity of the active ingredient. The photosensitive device can also be placed along a path followed by a pharmaceutical product in the facility. [Selection] Figure 1

Description

  This patent is directed to a pharmaceutical product, particularly a photosensitive pharmaceutical product comprising a photosensitive device that partially defines the product, and a method of using the photosensitive device in conjunction with a pharmaceutical product.

  It has been observed that proteins can degrade when exposed to visible and ultraviolet (UV) light. See, for example, Bruce Kerwin and Richard Remmle, Protect from light: Photogradation and protein biologics in Journal of Pharmaceutical Sciences, vol. 96, June 2007, pp. See 1468-80. This degradation can be both chemical and physical in the form of photooxidation, covalent aggregation, and deamidation of Asn residues. Although relatively little is known about how this exposure affects biologics, the authors found that photodegradation of proteins in biologics leads to conformational changes and induces aggregation. This suggests that low concentrations of aggregates can act as nucleation centers to produce visible fine particles. Other problems can include altered protein immunogenicity or reduced biological activity.

Bruce Kerwin and Richard Remmle, Protect from light: Photogradation and protein biologicals in Journal of Pharmaceutical Sciences, vol. 96, June 2007, pp. 1468-80

  As pointed out by Kerwin and Remmele, products can be exposed to visible and UV light sources during manufacturing, storage, and / or transportation, and during use in clinics and other healthcare facilities. is there. For example, during manufacture, the product may be exposed to a light source during filling and finishing operations, visual inspection, and packaging. During use, the product may be exposed when removed from the protective packaging stored prior to delivery, and into a solution in a clear IV bag that can be performed when the product is delivered intravenously. In the case of a dilution of, delivery time may also be exposed.

  Solutions proposed by Kerwin and Remmele and others address photolysis either indirectly through packaging, or directly through the use of excipients or packaging under an inert atmosphere. For the former solution, blocking incident light depends on the fabrication of the barrier. As the authors pointed out, such a solution necessarily identifies all possible areas of the container where the product can be exposed (eg from the inspection window), and in each such area. Rely on establishing a barrier to exposure. For the latter solution, existing publications suggest the use of excipients and expectations for packaging in an inert atmosphere, but the literature is limited and may lead to unintended consequences There is.

  As will be shown in more detail below, the present disclosure presents a pharmaceutical product that uses an advantageous method instead of the conventional devices discussed above.

  In an aspect of the present disclosure, a pharmaceutical product is disposed in a container having an outer surface and an inner chamber, and the photosensitivity changes based on cumulative exposure to light having a wavelength in the range of at least X to Y. And a layer of photosensitive material that is disposed on the outer surface of the container and exposed to environmental conditions coexisting with the active component disposed within the interior chamber. The photosensitive material is reactive to light having a wavelength in the range of X to Y and undergoes a characteristic change in the threshold of cumulative exposure to light in the range of X to Y with respect to the change in photosensitivity of the active ingredient.

  In another aspect of the present disclosure, a pharmaceutical product includes a container made of a material having an inner chamber and a light resistance, and a layer of a light resistant material disposed in the inner chamber of the container. The photosensitive material is reactive to light having a wavelength in the range of X to Y and undergoes a characteristic change in the threshold of cumulative exposure to light in the range of X to Y with respect to the change in photosensitivity of the active ingredient.

  In a further aspect of the present disclosure, the pharmaceutical product is its photosensitive based on a cumulative exposure to a container having an outer surface and an inner chamber and light disposed in the inner chamber and having a wavelength at least in the range of X to Y. An active ingredient that varies, a first region applied to the outer surface of the container, to which the layer of photosensitive material is applied, and a second region to which the layer of photosensitive material is applied detachably attached to the outer surface of the container Wherein the first region and the second region are exposed to environmental conditions that are present simultaneously with the active ingredient disposed within the interior chamber. The photosensitive material is reactive to light having a wavelength in the range of X to Y and undergoes a characteristic change in the threshold of cumulative exposure to light in the range of X to Y with respect to the change in photosensitivity of the active ingredient.

  In a further aspect of the present disclosure, a method for verifying correct handling of a photosensitive material includes applying a layer of photosensitive material to an outer surface of a container having an active ingredient disposed therein, the active ingredient comprising at least X to Y. The photosensitivity material is sensitive to light having a wavelength in the range of X to Y, and the photosensitivity of the active ingredient. Is subject to a characteristic change in the threshold of cumulative exposure to light in the range of XY with respect to the change in. The method includes delivering a container to a recipient, retrieving the container from the recipient, inspecting the photosensitive layer to determine whether the photosensitive material has undergone a property change, and the photosensitive material is characterized. This includes identifying the container as mishandled if it has undergone a change.

  In yet another aspect of the present disclosure, a method of analyzing exposure of a pharmaceutical product is to identify a passage for the pharmaceutical product in a facility that includes at least one space through which the pharmaceutical product passes, wherein the pharmaceutical product is at least Identifying a path for a pharmaceutical product comprising an active ingredient having photosensitivity that changes based on cumulative exposure to light having a wavelength in the range of XY, and at least one photosensitive device along the path A cumulative exposure threshold for light in the X to Y range, wherein the at least one photosensitive device includes a layer of photosensitive material that is reactive to light having a wavelength in the X to Y range. Placing at least one photosensitive device that undergoes a characteristic change at. The method reads as at least one photosensitive device after placing it along the path as evidence of a change in the characteristic of the photosensitive device to the photosensitive material, and if the characteristic change occurs with respect to the photosensitive material of the photosensitive device. , Including changing the passage of pharmaceutical products within the facility.

  The present disclosure will be more fully understood using the following description in conjunction with the accompanying drawings. Some of the drawings may be simplified by omitting selected elements for the purpose of more clearly showing other elements. Such omission of elements in some of the drawings does not necessarily indicate the presence or absence of particular elements in any of the exemplary embodiments, except where expressly depicted in the corresponding description. The drawings are not necessarily to scale.

1 is a perspective view of a pharmaceutical product according to the present disclosure having a container with a layer of photosensitive material disposed on an outer surface. FIG. FIG. 6 is a perspective view of another pharmaceutical product according to the present disclosure having a container with a layer of photosensitive material disposed on an outer surface. It is a graph which shows the color change of the layer of the photosensitive material which was described using the colorimeter with the increase in UV exposure. It is a graph which shows the color change of the layer of the photosensitive material with the increase in visible light exposure described using the colorimeter. 2 is a graph showing one measurement of degradation of a protein exposed to visible light. It is a graph which shows the measurement (% increase rate of a high molecular weight seed | species) of the monoclonal antibody polypeptide exposed to visible light referred with the colorimeter with reference to the color change of the coupling layer of the photosensitive material. It is a graph which shows the measurement of decomposition | disassembly (yellowness index) of the monoclonal antibody polypeptide exposed to visible light referred with the colorimeter with reference to the color change of the coupling layer of the photosensitive material. Graph showing measurement of degradation (increase in basic peak of cation exchange HPLC) of monoclonal antibody polypeptide exposed to visible light with reference to color change of light-sensitive material binding layer expressed using a colorimeter It is. A graph showing the measurement of degradation (increased acid peak of cation exchange HPLC) of a monoclonal antibody polypeptide exposed to visible light with reference to the color change of the binding layer of the light-sensitive material, expressed using a colorimeter. is there. It is a graph which shows the measurement of the decomposition | disassembly (absorption fluctuation | variation) of the small molecule exposed to UV light referred with the colorimeter with reference to the color change of the coupling layer of the photosensitive material. It is a graph which shows the measurement of decomposition | disassembly (yellow degree index) of the small molecule exposed to UV light referred with the colorimeter with reference to the color change of the coupling layer of the photosensitive material. It is a graph which shows the measurement of decomposition | disassembly (% increase rate of a high molecular weight species) of the monoclonal antibody polypeptide exposed to UV light referred with the colorimeter with reference to the color change of the coupling layer of the photosensitive material. It is a graph which shows the measurement of the decomposition | disassembly (% increase rate of a low molecular weight species) of the monoclonal antibody polypeptide exposed to UV light referred with the colorimeter with reference to the color change of the coupling layer of the photosensitive material. It is a graph which shows the measurement of the decomposition | disassembly (yellow degree index) of the amino acid exposed to UV light referred with the colorimeter with reference to the color change of the coupling layer of the photosensitive material. It is a graph which shows the color change of the layer of the photosensitive material accompanying the increase in visible light exposure in the temperature of a fixed range described using the colorimeter. FIG. 2 is a perspective view of an alternative to the pharmaceutical product of FIG. 1. FIG. 2 is a perspective view of a pharmaceutical product including an alternative to the label shown in FIG. 1 with a light resistant cover. 2 is a perspective view of a pharmaceutical product including a label in place of the label shown in FIG. 1 having a first removable area and a second removable area. FIG. FIG. 19 is a perspective view of a system including a product including the label and syringe of FIG. 2 is a perspective view of a pharmaceutical product including a label in place of the label shown in FIG. 1 having a first removable area and a second removable area, and a cover covering the second area. FIG. FIG. 21 is a perspective view of a system including a product including the label and syringe of FIG. FIG. 2 is a perspective view of a pharmaceutical product including a main label similar to the label shown in FIG. 1 and a secondary label for determining temperature changes in a first state. FIG. 23 is the product of FIG. 22 with a secondary label in a second state that changes at least one characteristic to emphasize that the product has been exposed to high temperatures. FIG. 6 is a perspective view of another pharmaceutical product according to the present disclosure having a container with a layer of photosensitive material disposed therein. Graph showing the color change of the layer of photosensitive material placed in the container shown in FIG. 23, expressed using a colorimeter, by increasing the UV exposure for the range of materials used to make the container It is. 1 is a schematic diagram of a manufacturing plant arrangement in which a phototracking unit according to the present disclosure is arranged along a path P through which a pharmaceutical product passes through the manufacturing plant. With increasing UV exposure, the different sensitivity of photosensitive materials that can be used in the products, systems and methods disclosed herein (in order of increasing sensitivity; “sen1”, “sen2”, “sen3”, “sen4 "," Sen5 ") is a graph showing the color change. It is a graph which shows the color change of the layer of the photosensitive material stored at 4 degreeC by the comparison with the control | contrast described with the colorimeter. It is a graph which shows the color change of the layer of the photosensitive material stored at 25 degreeC by the comparison with the control | contrast described with the colorimeter. It is a graph which shows the color change of the layer of the photosensitive material arrange | positioned inside and outside a container about the material range used for preparation of a container.

  The following text sets forth a detailed description of different embodiments of the invention, but it is understood that the legal scope of the invention is defined by the language of the claims set forth at the end of this patent. It must be. Since it is impractical, if not impossible, to describe each possible embodiment of the present invention, the detailed description should be construed as merely illustrative, and each possible embodiment described. It is not described. Numerous alternative embodiments may be implemented using either current technology or technology developed after the filing date of this patent, which are still within the scope of the claims that define the present invention. .

  Unless the term is clearly defined in this patent using the sentence "The term" "as used herein is defined by this specification to mean ..." or similar sentences, It is not intended to limit the meaning of the term, either explicitly or by implication, beyond the ordinary meaning, such terms being based on any representation made in any section of this patent (claims It should not be construed as limiting the scope (other than the language of the scope). To the extent that any term cited in the claims at the end of this patent is referenced in this patent in a manner consistent with its single meaning, it facilitates interpretation so as not to confuse the reader It is not intended to be construed as limiting the term of such claims solely by implications or otherwise. Finally, unless the elements of a claim are defined by quoting the language “meaning” and function without quoting any structure, the scope of the elements recited in any claim is It is not intended to be construed based on the application of 35 USC 112, sixth paragraph.

  The pharmaceutical product disclosed herein includes a container having an outer surface and an inner chamber, wherein the inner chamber may be defined by an inner surface. A material such as a polypeptide may be placed in the interior chamber, the material may be photosensitive, and may be degraded by exposure to light at a specific range of wavelengths. The layer of photosensitive material may be disposed either on the outer surface of the container or in the interior chamber, and according to certain embodiments, may be exposed to environmental conditions that are present simultaneously with the polypeptide disposed in the interior chamber. Good. According to other embodiments, exposure of the layer of photosensitive material to environmental conditions may be delayed. The photosensitive layer may be sensitive to light of a specific wavelength and thus undergo a property change at the threshold of cumulative exposure, and the property change of the photosensitive layer is related to a change in the photosensitivity of the polypeptide or other material. May be. As an example, the property change of the material defining the photosensitive layer is a color change that is “detectable by a colorimetric method” (ie, a color change that can be detected visually or by using a colorimetric device). May be.

  As an example of such a product, a pharmaceutical product 100 comprising a container 110 having an outer surface 112 and an inner chamber 114 is shown in FIG. 1, where the chamber 114 may be defined by an inner surface 116. The outer surface 112 and the inner surface 116 may be defined by walls 118 made of a single layer, or the surfaces 112, 116 may be defined by different layers of, for example, a multilayer structure.

  According to the exemplary embodiment of FIG. 1, the container 110 may be a glass vial having an open end 120 and a closed end 122, the open end 120 having a narrow neck section defined by a rim. The opening may be closed by a rubber stopper held in place with a metal crimp ring or seal. Although an exemplary embodiment of the container 110 is shown in FIG. 1, the present disclosure is not limited to this exemplary embodiment. For example, the container 110 may be made of a polymer material such as polycarbonate, polypropylene or Teflon instead of glass. Further, the container 110 may be larger or smaller than the illustrated embodiment, and may have a different shape than that illustrated in FIG. For example, the container 110 may be a large container used for storage and transportation, such as a carboy (see FIG. 2), or a small container used for a single dose procedure, such as the container shown in FIG. It may be a single-dose vial that is similar in structure but smaller in size. The container may have a non-rigid shape, for example in the form of a plastic bag.

  As described above, the pharmaceutical product 100 may include material disposed within the inner chamber 114 of the container 110. Generally speaking, the material disposed within chamber 114 may typically refer to (ie, contain) active ingredients such as polypeptides, amino acids, and / or small molecules, and / or In addition to polypeptides, amino acids and / or small molecules, it may refer to (ie contain) inactive ingredients or excipients. The active ingredient may include a virus, which may contain cDNA or RNA encoded by a glycoprotein and a lipid layer. The one or more active ingredients may be therapeutically active ingredients, stabilizers (eg, amino acids) or diagnostic reagents, or a combination of therapeutic molecules, stabilizers, and / or diagnostic reagents. In particular, the material disposed in the inner chamber 114 may be a photosensitive material. When the material is being exposed, the light can change the characteristics of the material in the container. In certain instances, the exposure can cause the material to decompose and may not be useful or not useful for the intended purpose.

  As one non-limiting example, the material disposed within the interior chamber 114 of the container 110 may be a polypeptide. More particularly, the polypeptide may be suspended in an aqueous medium and may be fluid (liquid state) or frozen (solid state). The polypeptide may have a photosensitivity that varies based on, for example, cumulative exposure to light having a wavelength in the range of at least X to Y. According to other embodiments, it may be desirable to monitor exposure even if no association has been previously established between the change or degradation of the polypeptide or other material and the exposure. .

  In this regard, it should be noted that polypeptides and proteins are used interchangeably herein and include molecular chains of two or more amino acids covalently linked through peptide bonds. These terms do not refer to a specific length of the product. That is, peptides and oligopeptides are included in the definition of polypeptide. These terms include post-translational modifications of the polypeptide, such as glycosylation, acetylation, biotinylation, 4-pentinoylation, PEGylation, phosphorylation and the like. In addition, protein fragments, analogs, mutant or mutated proteins, fusion proteins and the like are included within the meaning of a polypeptide. The terms also include molecules containing one or more amino acid analogs or non-standard or unnatural amino acids that can be recombinantly expressed using known protein genetic engineering techniques.

  Non-limiting examples of materials that can be placed in the inner chamber 114 include darbepoetin alfa (such as Aranesp®), epoetin alfa (such as Epogen®), anakinra (Kineret®), pegfil Mention may be made of glasstim (such as Neulasta®), denosumab (such as Prolia® or XGEVA®), and filgrastim (such as Neupogen®). Aranesp®, Epogen®, Kineret®, Neulasta®, Prolia®, XGEVA® and Neupogen® are available from Amgen Inc., Thousand Oaks, Calif. Manufactured by. In addition, etanercept (such as Enbrel (registered trademark)), adalimumab (such as Humira (registered trademark)), infliximab (such as Remicade (registered trademark)), certrizumab Pegor (such as Cimsia (registered trademark)), golimumab (registered trademark) Trademark), abatacept (such as Orencia (registered trademark)), tocilizumab (such as Actemra (registered trademark)), panitumumab (such as Vectibix (registered trademark)), cetuximab (such as Erbitux (registered trademark)), trastuzumab (registered trademark) Trademarked), bevacizumab (such as Avastin®), pegylated epoetin beta (such as Mircera®), pegine satide (such as Hematide ™) and li Products such Kishimabu (Rituxan (TM), etc.) may be disposed in inner chamber 114. Further non-limiting examples include epoetin beta, epoetinzieta, epoetin theta, mogamulizumab, omalizumab (such as Xolair (R)), brodalumab, secukinumab, nimotuzumab, and ixekizumab.

  The materials actually placed in the inner chamber 114 are: flt3 ligand (described in WO 94/28391, which is incorporated herein by reference), CD40 ligand (US patents incorporated herein by reference). 6,087,329), erythropoietin, thrombopoietin, calcitonin, leptin, IL-2, angiopoietin-2 (Maisonpierre et al. (1997), Science 277 (5322), incorporated herein by reference. ): 55-60), Fas ligand, NF-kappa B receptor activator ligand (RANKL; described in WO 01/36637, incorporated herein by reference), Tumor necrosis factor (TNF) -related apoptosis induction GAND (TRAIL; described in WO 97/01633, which is incorporated herein by reference), thymic stromal lymphopoietin, granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor (GM-CSF; see Described in Australian Patent No. 588819, incorporated herein by reference), mast cell growth factor, stem cell growth factor (eg, described in US Pat. No. 6,204,363, incorporated herein by reference). ), Epidermal growth factor, keratinocyte growth factor, megakaryocyte growth differentiation factor, RANTES, human fibrinogen-like 2 protein (FGL2; NCBI accession number NM — 00682; Ruegg and Pyterra (1995), Gene 160: 257-62) growth hormone , Insulin, y Interferons including thrinotropin, insulin-like growth factor, parathyroid hormone, alpha interferon, gamma interferon, and consensus interferon (US Pat. Nos. 4,695,623 and 4, 897,471, etc.), nerve growth factor, brain-derived neurotrophic factor, synaptotagmin-like protein (SLP1-5), neutrophin-3, glucagon, interleukins 1-18, colony-stimulating factor, phosphorus photo All or part of one of the proteins of xin-β, tumor necrosis factor (TNF), leukemia inhibitory factor, oncostatin-M, and various ligands of cell surface molecules ELK and Hek (such as ligands for eph-related kinases or LERKS) Is the same as Or it may comprise a protein having a substantially similar amino acid sequence. Another description of proteins can be found, for example, in Human Cytokines: Handbook for Basic and Clinical Research, Vol. II (Aggarwal and Gutterman eds, Blackwell Sciences, Cambridg, MA, 1988.); Growth Factors: A Practical Approach (. McKay and Leigh eds, Oxford University Press Inc., New York, 1993); and The Cytokine Handbook (A. W. Thompson ed., Academic Press, San Diego, CA, 1991).

  Other exemplary proteins include proteins comprising all or part of the amino acid sequence of any of the aforementioned proteins, antagonists of such receptors or any of the aforementioned proteins, and / or such receptors. Or a protein substantially similar to an antagonist can be mentioned. These receptors and antagonists include: both forms of tumor necrosis factor receptor (TNFR; referred to as p55 and p75; US Pat. Nos. 5,395,760 and 5,610, incorporated herein by reference). , 279), interleukin-1 (IL 1) receptors (types I and II; European Patent 0 460 846, US Pat. No. 4,968, incorporated herein by reference). 607, and 5,767,064), IL-1 receptor antagonists (such as those described in US Pat. No. 6,337,072, incorporated herein by reference), IL-1 antagonists or inhibitors (US Pat. Nos. 5,981,713, 6,096,7, incorporated herein by reference) No. 8, and those described in US Pat. No. 5,075,222), IL-2 receptor, IL-4 receptor (European Patent No. 0 367 566, incorporated herein by reference) Patent No. 5,856,296), IL-15 receptor, IL-17 receptor, IL-18 receptor, Fc receptor, granulocyte-macrophage colony stimulating factor receptor, granulocyte colony stimulation Factor receptor, receptor for oncostatin-M and leukemia inhibitory factor, receptor activator of NF-kappa B (RANK; WO 01/36637 and US Pat. No. 6,271, incorporated by reference) 349), osteoprotegerin (eg, described in US Pat. No. 6,015,938, incorporated by reference), TRAIL Body (TRAIL receptors 1, 2, 3, and 4), and Fas or Apoptosis inducing receptors such (AIR), receptors and the like, including death domain.

  Further exemplary proteins can include proteins containing all or part of the amino acid sequence of a differentiation antigen (referred to as CD protein) or their ligand, or a protein substantially similar to any of these. Such antigens are disclosed in Leukocyte Type VI (Proceedings of the VIth International Works and Conference, Kishimoto, Kikutan et al., Eds., Japan, Kobe, 19), incorporated by reference. Similar CD proteins will be disclosed in subsequent workshops. Examples of such antigens include CD22, CD27, CD30, CD39, CD40, and ligands thereof (CD27 ligand, CD30 ligand, etc.). Some of the CD antigens are members of the TNF receptor family that also includes 41BB and OX40. The ligand is often a member of the TNF family, as are the 41BB and OX40 ligands.

  In addition, enzymatically active proteins or their ligands may be included as part of the product 100. Examples include proteins comprising one or all of the following proteins or all or part of their ligands, or proteins substantially similar to one of these: metalloproteinase-disintegrin family members, various kinases , Glucocerebrosidase, superoxide dismutase, tissue plasminogen activator, factor VIII, factor IX, apolipoprotein E, apolipoprotein AI, globins, IL-2 antagonist, alpha-1 antitrypsin, TNF- Alpha converting enzymes, ligands of any of the enzymes mentioned above, and numerous other enzymes and their ligands.

  Furthermore, the product 100 may include an antibody or a part thereof. The term “antibody” includes intact antibodies for specific binding, including human, humanized, chimeric, multispecific, monoclonal, polyclonal, and oligomers, or antigen-binding fragments thereof, unless otherwise noted. Includes reference to both glycosylated and non-glycosylated immunoglobulins of any isotype or subclass that antagonize, or antigen binding regions thereof. The antibody may be any class of immunoglobulin. Also included are Fab, Fab ′, F (ab ′) 2, Fv, diabody, Fd, which contain at least a portion of an immunoglobulin sufficient to confer specific antigen binding to the target polypeptide. Proteins having antigen-binding fragments or regions such as dAbs, maxibodies, single chain antibody molecules, complementarity determining region (CDR) fragments, scFvs, diabodies, triabodies, tetrabodies and polypeptides. The term “antibody” includes, but is not limited to, those prepared, expressed, produced or isolated by recombinant techniques, eg, antibodies isolated from a host cell transfected to express the antibody.

  That is, examples of the antibody include a human antibody or a part thereof, and a chimeric antibody or a humanized antibody. A chimeric antibody comprises a human constant antibody immunoglobulin domain, fragment thereof, or a substantially similar protein bound to one or more murine variable antibody immunoglobulin domains. Humanized antibodies comprise a variable region comprising a framework portion of human origin and a CDR portion of non-human source. Product 100 may include an antibody conjugate and a cytotoxic or luminescent material. Examples of such substances include maytansine derivatives (such as DM1); enterotoxins (such as Staphylococcal enterotoxins); iodine isotopes (such as iodine-125); technium isotopes (such as Tc-99m); cyanine fluorescent dyes (Such as Cy5.5.18); and ribosome inactivating proteins (such as bouganin, gelonin, or saporin-S6). Product 100 is in vitro to bind to specific target proteins and modify their activity, such as those described in WO 01/83525 and WO 00/24782, incorporated by reference. It may further contain a selected chimeric protein.

  Other examples of antibodies, chimeric proteins selected in vitro, or antibody / cytotoxin or antibody / luminophore conjugates include, but are not limited to, any of the above proteins and / or proteins including: Those that recognize one or a combination of these may be mentioned. CD2, CD3, CD4, CD8, CD11a, CD14, CD18, CD20, CD22, CD23, CD25, CD33, CD40, CD44, CD52, CD80 (B7.1), CD86 (B7.2), CD147, IL-1α, IL-1β, IL-2, IL-3, IL-7, IL-4, IL-5, IL-8, IL-10, IL-2 receptor, IL-4 receptor, IL-6 receptor, IL-13 receptor, IL-18 receptor subunit, FGL2, PDGF-β and analogs thereof (such as those described in US Pat. Nos. 5,272,064 and 5,149,792), VEGF, TGF, TGF-β2, TGF-β1, EGF receptor (including those described in US Pat. No. 6,235,883B1, incorporated by reference), VEGF receptor Condition, hepatocyte growth factor, osteoprotegerin ligand, interferon gamma, B lymphocyte stimulating factor (BlyS; also known as BAFF, THANK, TALL-1, and zTNF4; Do and Chen-Kiang (2002), Cytokine Growth Factor Rev 13 (1): 19-25), C5 complement, IgE, tumor antigen CA125, tumor antigen MUC1, PEM antigen, LCG (gene product expressed with lung cancer), HER-2, tumor-associated glycoprotein TAG-72, SK-1 antigen, tumor-associated epitopes present in high levels in the serum of colon cancer and / or pancreatic cancer patients, breast cancer, colon cancer, squamous cell carcinoma, prostate cancer, pancreatic cancer, lung cancer, and / or kidney On cancer cells and / or melanoma, glioma, or Or neuroblastoma cells, cancer-related epitopes or proteins expressed on the necrotic center of the tumor, integrin alpha4beta7, integrin VLA-4, B2 integrin, TRAIL receptors 1, 2, 3, and 4, RANK, RANK ligand, TNF-α, adhesion molecule VAP-1, epithelial cell adhesion molecule (EpCAM), intercellular adhesion molecule-3 (ICAM-3), leucointegrin adhesin, platelet glycoprotein gpIIb / IIIa, cardiac myosin heavy Chain, parathyroid hormone, rNAPc2 (Factor VIIa-inhibitor of tissue factor), MHC I, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), tumor necrosis factor (TNF), CTLA-4 (cytotoxic T Lymphocyte-related antigen), Fc-γ-1 receptor, HLA-DR10 beta, HLA-DR antigen, L Selectin, respiratory syncytial virus, human immunodeficiency virus (HIV), B-type hepatitis virus (HBV), Streptococcus mutans (Streptococcus mutans), and Staphylococcus aureus (Staphlycoccus aureus).

  Specific examples of known antibodies include, but are not limited to, adalimumab, bevacizumab, infliximab, abciximab, alemtuzumab, bapineuzumab, basiliximab, belimumab, briakinumab, canakinumab, certolizumab, cetuximab, cetuxumab golimumab, ibritumomab tiuxetan, labetuzumab, mapatumumab, matuzumab, mepolizumab, mogamulizumab, motavizumab, muromonab -CD3, natalizumab, nimotuzumab, ofatumumab, omalizumab, oregovomab, palivizumab, panitumumab, pemtumomab, pertuzumab, Ranibizumab, rituximab, Roberizumabu, tocilizumab, tositumomab, Trastuzumab, us Kinumabu, zalutumumab, and zanolimumab the like.

  Product 100 is an anti-idiotype antibody or substantially anti-idiotype antibody or substantially anti-idiotype antibody against an antibody targeting tumor antigen gp72; an antibody against ganglioside GD3; an antibody against ganglioside GD2; or an antibody substantially similar thereto. It may contain similar proteins.

  Product 100 may include a recombinant fusion protein comprising any of the proteins described above. For example, in addition to one of the proteins described above, a recombinant fusion protein comprising a multimerization domain such as a leucine zipper, coiled coil, Fc portion of an antibody, or a substantially similar protein can be obtained using the method of the present invention. Can be generated. See, for example, WO 94/10308; Lovejoy et al. (1993) Science 259: 1288-1293; Harbury et al. (1993) Science 262: 1401-05; Harbury et al. , (1994), Nature 371: 80-83; Hankanson et al. (1999), Structure 7: 255-64. Specifically included in such recombinant fusion proteins is a protein in which a portion of TNFR or RANK is fused to the Fc portion of antibody etanercept (ap75 TNFR: Fc) and veratacept (CTLA4: Fc). TNFR: Fc comprises a TNFR cell comprising an amino acid sequence substantially similar to amino acids 1-163, 1-185, or 1-235 of FIG. 2A of US Pat. No. 5,395,760, incorporated by reference. Contains the Fc portion of an antibody fused to the outer domain. RANK: Fc is described in WO 01/36637, incorporated by reference.

  In addition, the pharmaceutical product 100 shown in FIG. 1 includes a layer 140 of photosensitive material disposed on the outer surface 112 of the container 110. The photosensitive material may be reactive to light having a wavelength in the range of X to Y so as to undergo a property change. According to certain embodiments, the color of the material may change, for example from yellow to green. Non-limiting examples of photosensitive materials that can be used for layer 140 are UV Process Supply, Inc. of Chicago, Illinois. Available as a UV FastCheck ™ brand.

  In view of this, FIG. 3 shows that the color change with increasing UV exposure (changes in colorimeter readings) performed at a peak wavelength of about 350-370 nm and a wavelength range of about 315-400 nm (UVA). 2 shows a graph produced for a light-sensitive material that has received). Similarly, FIG. 4 shows a graph produced for a photosensitive material subjected to a color change (indicated by a change in the colorimeter reading) with increasing visible light exposure, performed in the 401-750 nm wavelength range. . These and similar measurements are available from Hunter Associates Laboratory Inc., Reston, Virginia. Can be determined using a colorimeter such as the HunterLab UltraScan PRO colorimeter available from X-Rite Inc. of Grand Rapids, Michigan. A color reflection spectrophotometric densitometer such as the X-Rite Model 530 available from can be used with other embodiments.

  A threshold of cumulative exposure to light received within a range of X to Y with respect to a property (eg, color) change in the material in the photosensitive layer 140 is a sensitivity of the polypeptide or other material or substance disposed in the container 110. It will be appreciated that it may be related to sexual changes. For example, the change in photosensitivity of a polypeptide can be quantitatively measured using a separation technique such as chromatography. In particular, size exclusion (SEC), cation exchange (CEX) and hydrophobic interaction (HIC) chromatography can be used to correlate exposure to product degradation. FIG. 5 shows the relationship between the readings made using HIC with an exemplary polypeptide exposed to visible light, where the increase in HIC reading is due to increased exposure and inactive species of the polypeptide. Represents an increase. Given these results and the known performance of the material in the photosensitive layer 140 shown in FIG. 4 by way of example, the correlation between the colorimeter reading and the HIC reading in the range of exposure. Can be associated with a particular degree of inactivation or degradation of the indicated polypeptide.

  In further support for these colorimetrics, the graphs of FIGS. 6-14 show that (i) quinine monohydrochloride dihydrate (as an example of a small molecule) or tryptophan (amino acids), with increased exposure to visible or UV light. The relationship between various measurements of the degradation of a monoclonal antibody polypeptide (as an example of a polypeptide) and (ii) a colorimeter indication of the color change of the light-sensitive material binding layer. Directly shows. Although not an attempt to limit the degradation discussion expressed in a particular mechanism in the results of this test, the degradation may be both chemical and physical, such as photo-oxidation, covalent aggregation, and / or It is also noted that it may be in the form of deamidation of Asn residues. In particular, FIGS. 6-9, 12 and 13 relate to experiments performed with monoclonal antibodies, while FIGS. 10 and 11 relate to experiments performed with quinine monohydrochloride dihydrate (2% solution), FIG. Relates to experiments carried out with tryptophan (1 mM aqueous solution). 6-9 relate to experiments performed using visible light, while FIGS. 10-14 relate to experiments performed using UV light. These experiments are performed with light having a wavelength range of 190-1100 nm, UV exposure is performed at a peak wavelength of about 350-370 nm and primarily at a wavelength range of about 315-400 nm (UVA), and visible light exposure is , Mainly in the wavelength range of about 401-750 nm.

  For these experiments, all were performed at room temperature (25 ° C.) and 40% relative humidity. A 3 cc glass vial was filled with a sample of monoclonal antibody (“mAb”), quinine monohydrochloride dihydrate (“quinine”), or tryptophan, and the vial was capped. A layer of photosensitive material was then applied to the outer wall of an empty 3cc glass vial. As shown in the graphs of FIGS. 6-14, three different sensitivities of the photosensitive material were used in these experiments, and the material labeled “sen1” had the lowest sensitivity, labeled “sen3”. Material has the highest sensitivity, and the material is manufactured by UV Process Supply Inc. of Chicago, Illinois. Commercially available as CON-TROL-CURE® UV Fastcheck ™ Strips, part number N010-002. The three sensitivities (“sen1”, “sen2”, “sen3”) are identical to the three similarly named sensitivities (“sen1”, “sen2”, “sen3”) found in FIG. 27 discussed below. It is. Filled and empty vials were exposed to the same light source (cold white light with 10 klux intensity setting or UV light with 30 W / m2 intensity setting).

  In all experiments, the color of the layer of photosensitive material was measured using an X-Rite spectrocolorimetric densitometer (manufactured by X-Rite, Grand Rapids, Mich.), But the device was set up in such an experiment. 2 is an illustration of the types of color measurement equipment that may be used in Various measurements regarding the degradation of monoclonal antibodies or kinin samples were performed using appropriate techniques. For example, size exclusion HPLC is used to determine measurements related to the percent increase in high or low molecular weight species (FIGS. 6, 12, 13), and cation exchange HPLC is used to vary basic and acidic peaks. Was used to determine the measurements related to (Figs. 8 and 9). In this regard, high molecular weight species are typically in the form of aggregates that can induce immunogenic reactions or adverse events upon administration, whereas low molecular weight species are typically in the form of degradation products. An Ultrascan® PRO spectrophotometer (manufactured by Hunter Associates Labs., Inc., Reston, Virginia) was used to determine measurements related to the yellowness index (FIGS. 7, 11, 14). . It will be appreciated that the yellowness index reference refers to a single value calculated from spectrophotometric data to account for the clear or white to yellow color change of the test sample, , Generally related to overall product degradation, and is used primarily to quantify this degradation, for example, as calculated by Hunter Associates Laboratory Inc. of Reston, Virginia. Application Record for Yellowness Index provided by, Vol. 8, Issue 15 (2008), the application record of which is incorporated herein by reference in its entirety. A Beckman Coulter spectrophotometer was used to measure the absorbance at 400 nm (FIG. 10).

  It will be appreciated that in each of the graphs of FIGS. 6-14, the color change of the photosensitive material increases with increasing exposure. Similarly, sample degradation measurements increase with increasing exposure. That is, the increase in high molecular weight or low molecular weight species is similar to the increase in acidic or basic peaks generated using cation exchange HPLC representing changes in charged species (FIGS. 8 and 9), as well as degradation of mAb polypeptides. (FIGS. 6, 12, and 13). In a similar manner, an increase in yellowness index (FIGS. 7, 11) represents degradation of mAb polypeptide, small molecule (eg, kinin), or amino acid (eg, tryptophan). Furthermore, the change in absorbance of kinin represents a change in small molecules. In each case, the color change of the photosensitive material and the sample decomposition measurement cannot be the same for all the properties examined, but there is a direct relationship between the color change of the photosensitive material and the measurement of active ingredient decomposition. Since it is true that the sexuality exists, the photosensitive material can be used as a real-time indicator of changes that occur in the active ingredients in the container.

  The correlation between the degradation of the material (eg, polypeptide) disposed in the inner chamber 114 and the change in the property (eg, color) of the photosensitive layer 140 is related to the change and / or degradation of the material in the inner chamber 114. Use as a real-time indicator and indicator of the present invention provides multiple opportunities for optimizing the product 100 through selection of the photosensitive material of the layer 140. Multiple factors may also need to be responsible for providing stable and reliable indications and indicators. Specific examples of optimization conditions and causative factors are provided herein, but the listing is not intended to be exhaustive.

  For example, if the material in the inner chamber 114 (eg, a polypeptide) undergoes degradation in response to light of a specific wavelength or wavelength range, the photosensitive material is selected to respond only to light of that wavelength or wavelength range. May be. In fact, the sensitivity of the material to the wavelength of interest is a more sensitive (reactive) material for the photosensitive layer 140 and a more sensitive (reactive) material placed in the container 110 for the wavelength considered. It may be selected to match or relate to (eg, a more sensitive polypeptide).

  Alternatively, the material (eg, polypeptide) in the inner chamber 114 may undergo degradation as a result of multiple reactions that can be attributed to light of different wavelengths. It can be the case if all of these factors contribute to reduced effectiveness of the material treating a particular medical condition, and if none of the factors prevail. Based on this analysis, a photosensitive material that is responsive to a wide range of wavelengths may be used for layer 140.

  A material or substance (eg, a polypeptide) within the inner chamber 114 may exhibit degradation when exposed to light in a specific wavelength range, but the environment selectively excludes or provides only specific wavelengths within that range. It is also possible. As a result, rather than selecting the material based on the entire wavelength range known to cause degradation of the material disposed in the inner chamber 114, it is known that the photosensitive material is present in a given environment. The wavelength may be selected according to the wavelength to be selected. As a result, the photosensitive material selected for the layer 140 applied to the container 110 that is primarily used in the manufacturing facility, such as carboy, is applied to the container 110 that is carried by a medical assistant or the like for use in the field. The photosensitive material selected for the layer 140 may be different.

  On the other hand, factors such as temperature can affect the stability or robustness of the correlation between the performance of the photosensitive material, that is, the change in properties of the photosensitive material and the change in the material placed in the container 110. There is. In view of this, FIG. 15 shows the change in colorimetric readings of the photosensitive material that can be used in layer 140 at a range of exposures and multiple temperatures. From FIG. 15, it can be observed that the change in the colorimeter reading cannot vary dramatically at lower temperatures (eg, 4 ° C.) than at higher temperatures (37 ° C.). In conclusion, not only can the material be selected for the layer 140 according to the reactivity of the material (eg, polypeptide) in the container 110, but the material for the layer 140 can be selected for the photosensitive material at the expected operating temperature range. It can also be selected according to performance characteristics. Instead, knowledge of variations in colorimeter readings based on temperature is utilized to correct the correlation between material changes in layer 140 and material changes in temperature-dependent container 110. And further modifications can increase the stability and reliability of the correlation.

  Although it is believed that temperature can affect the rate of color change, FIGS. 28 and 29 are exposed at a wide range of temperatures (eg, 4 ° C. (FIG. 28) or 25 ° C. (FIG. 29)), and then further This indicates that there is almost no reversibility in the color change of the light-sensitive material stored in an unexposed (ie, dark room) space. That is, there is little difference in color measurements between a control sample and a sample stored at a specific temperature in the dark for an extended period (eg, approximately 48 hours). The sample was controlled for humidity and the measurements were performed using an X-Rite spectrophotometer, but the device is an example of the type of color measurement instrument that can be used in such an experimental setting.

  The size and position of the layer 140 may be selected to improve the stability of the reading. This, on the one hand, can affect the reliability of the correlation obtained and the reliability of the condition evaluation of the material (eg, polypeptide) in the chamber 114 performed depending on the correlation. In particular, the reading obtained from layer 140 that appears to be, or appears to be substantially flat, to the measurement device or instrument used to obtain the color indication of layer 140 is a curve. It may be more consistent than the reading obtained from the layer 140 with the profile. In conclusion, when handling generally cylindrical objects (such as vials or carboys) having a specific length and diameter, the wider layer 140 appears to have a more curvilinear profile to the measuring instrument, and the narrower layer The indicated value of 140 appears to be more variable. In conclusion, this potential cause of variability is due to the broader mapping of the potential curve of the layer 140 applied to the container 110, or the indication value obtained by selecting the size and / or scale of the layer 140. Can be addressed by minimizing the effect of the curve of layer 140 on the variability (ie, making layer 140 appear more planar to the equipment used to obtain the reading) .

  As a result of these various judgments and factors, an exemplary embodiment is shown in FIG. 1 in which a single layer 140 of material is disposed on the outer surface 112 of the container 110, but as will be described in more detail below, Layer material may be disposed on the outer surface 112 of the container 110 or may be coupled to the container 110. According to such embodiments, each layer can be useful in measuring exposure of light to different wavelengths, or can have a different sensitivity to temperature, or can be of a different size and shape. Of course, the presence of multiple layers 140 on a single container 110 can be confusing to the user in certain circumstances, for example, the photosensitive material in the layers can no longer be detected by property changes, such as colorimetry. If it is not possible to undergo a change in properties, the layers 140 may be placed separately from each other on a portion of the outer surface 112 of the container 110, or in such a manner that at least one layer of the layer 140 may be removed from the outer surface 112. It may be arranged.

  As described above, the layer 140 may be exposed to environmental conditions that exist concurrently with the polypeptide disposed within the interior chamber 114. That is, the layer 140 is disposed on the outer surface 112 of the container 110 and at the same time that the material (eg, polypeptide) is disposed in the inner chamber 114 of the container 110 or before or after the time that the material is disposed in the chamber 114. For a short period of time, the material may be exposed to the same conditions as it was exposed. The period determined to be present at the same time may be determined, for example, by the sensitivity of the material in the chamber 114 and / or the sensitivity of the material used to define the layer 140.

  As described above, and as described in more detail below, layer 140 is exposed to environmental conditions at multiple times that are not determined to be present simultaneously with the material (eg, polypeptide) disposed within inner chamber 114. May be. When the reaction of the material placed in the container 110 occurs rapidly, it may be determined that it is not the same period even if it passes through a very short period. More generally, however, this will shield layer 140 as desired from exposure to the same conditions as the material disposed in chamber 114, for example through the use of a physical barrier or a photo-resistant material. It can encompass the situation.

  Returning again to the embodiment of FIG. 1, it will be appreciated that layer 140 is disposed on outer surface 112 through the use of label 160. The label 160 may include a substrate 162 having a first surface 164 and a second surface 166, the surfaces 164, 166 being disposed on opposite sides. The size of the substrate 162 with respect to the size of the layer 140 has been enlarged in FIG. 1 depending on the purpose so that the substrate 162 can be more easily visualized and identified. According to a preferred embodiment, the layer 140 extends to the edge of the substrate 162, but the edge of the layer 140 can be spaced from the edge of the substrate 162 as shown. Again, the corners of the substrate 162 typically exist along the surface 112 when assembled, but once again returning to FIG. 1, the corners expose the surface 166.

  The substrate 162 may be, for example, a paper product, but may be made of plastic or other polymer. One surface (166 in the illustration) may be provided with an adhesive or other compound that may be used to affix, adhere or adhere the label 160 to the surface 112. Of course, for that matter, the substrate 162 may be attached to the outer surface 112 by applying a material over the surface 164 of the label, so that the layer 140 can be visualized or scanned, and the layer 140 Is selected to be sufficiently transparent so that the operation of (i.e., the photosensitivity of layer 140) is not affected. For example, a transparent single-sided tape product may be used to attach the substrate 162 (and thereby the label 160) to the surface 112. By applying an additional layer, the substrate 162 may not only be attached to the surface 112, but the layer may be protected from environmental conditions (eg, humidity) so that the additional layer attaches the substrate 162 to the surface. It may be present even if it is not used. Use of the adhesive label 160 may facilitate assembly of the product 100 including the label 160 during manufacture.

  As one alternative, FIG. 16 shows an embodiment in which a layer of photosensitive material 140 is applied directly to the outer surface 112 of the container 110. According to such embodiments, the surface 112 may need to be prepared prior to applying the layer 140 to the surface 112. Preparation of surface 112 may require that other chemicals be applied to surface 112 to provide sufficient bonding or bonding between the material of layer 140 and the material of container 110. It will also be appreciated that such chemicals may technically exist an intermediate layer between the layer 140 and the surface 112 of the container 110, but the layer 140 is the surface of the container 110 for purposes of this disclosure. It can be understood that it is applied to 112.

  The label 160 may include elements other than the layer 140. For example, the label 160 may include evidence for identifying the material (eg, polypeptide) placed in the chamber 114, such as the name of the material, the name of the manufacturer, a description related to the use of the material, and the like. . As a further example, to know if the material (eg, polypeptide) in chamber 114 is safe for administration, the user knows how to interpret layer 140 without further reference to additional material. To do so, the label 160 may include evidence associated with the layer 140, such as a color scale. This color scale may be based on the correlation between the material change in layer 140 and the material change in chamber 114 discussed above.

  The label 160 may include other structures that cooperate with the layer 140. For example, as described above, layer 140 may be shielded or hidden from exposure. In conclusion, FIG. 17 shows a label 160 comprising a substrate 162 on which a layer 140 is disposed, and a further layer 180 of removable photoresistive material applied over the layer 140 of photosensitive material. According to certain embodiments, the photo-resistive material of layer 180 can block all of the exposure, but according to other embodiments, the photo-resistive material of layer 180 blocks only a portion of the exposure. Can do. In the particular embodiment shown, the removable layer 180 of photoresistive material is a cover that is removably attached to the outer surface 112 of the container 110 over the layer 140 of photosensitive material that blocks light of all wavelengths. And may be made of coated paper, coated plastic, or metal (eg, aluminum) foil having a peelable adhesive applied to at least a portion of the surface 182 facing the layer 140. This cover 180 may be removed if necessary. The cover 180 may be detachably attached directly to the outer surface 112 of the container 110 according to certain embodiments, but according to the embodiment of FIG. 17, the cover 180 is detachably attached to the substrate 162, The substrates are sequentially disposed on the surface 112 of the container 110.

  A further example of an alternative structure for label 160 is shown in FIG. According to this embodiment, the label 160 is disposed on the outer surface 112 of the container 110 and is detachably disposed on the first region 190 to which the layer 191 of photosensitive material is applied and the outer surface 112 of the container 110. And a second region 192 to which a layer of material 193 is applied. The first region 190 and the second region 192 of the label may be attached together (ie, formed as one piece), but the first region 190 and the second region 192 The boundary between them may be defined by a perforated portion 194 that may facilitate separation of the first region 190 and the second region 192. According to other embodiments, the boundary between the first region 190 and the second region 192 may be defined solely by a marker on the label 160.

  According to the illustrated embodiment, the first region and the second region 190, 192 may be exposed to environmental conditions that are co-existing with the material (eg, polypeptide) disposed within the inner chamber 114. Good. As such, layer 191 and layer 193 should receive substantially the same exposure as the material in chamber 114. Thus, regions 190, 192 and each layer 191, 193 may be referenced in a similar manner to determine the overall exposure history of the material in chamber 114.

  Regarding how the label 160 as shown in FIG. 18 may be used, the container 110 may be used for storage of material, but after the material is removed from the container 110 and placed in the delivery device. Consider that the material is likely to be administered to the patient. For example, if the container 110 is a single dose vial, for example, material placed in the container 110 is removed from the container using a syringe 200 with a needle (see FIG. 19) or a syringe with a luer tip and a vial adapter. May be. In either instance, there may be some time before the material in the syringe is administered to the patient. Since the exposure continues during this time, by removing the second region 190 of the label 160 and attaching the second region 192 to the syringe 200 so that the layer 193 can be observed, It may be advantageous to continue exposure monitoring. In conclusion, monitoring of the exposure of the material in syringe 200 can continue after the material has been removed from container 110 using such a system.

  Further, it will be appreciated that the label features shown in FIG. 17 can be incorporated into the label features shown in FIGS. For example, a further embodiment of label 160 is shown in FIG. According to this embodiment, the label 160 includes a substrate 162 having a first portion 190 and a second portion 192, each portion having a respective layer 191 and 193 of photosensitive material. However, the cover 210 of FIG. 21 is disposed on the layer 193 arranged on the second portion 192 of the substrate 162. This cover 210 may be defined by the cover 182 discussed above in that it may be defined by a layer of photoresistive material removably attached to the outer surface 112 of the container 110 over the layer 193 of photosensitive material. May be similar. As shown, the cover 210 may be removably attached to a portion of the substrate 162 that defines the second portion 192 of the label such that the second section 192 and the cover 210 are in container 110. May be removed as a single part.

  The label shown in FIG. 20 may be used similarly to the labels shown in FIGS. That is, when the material in the chamber 114 of the container 110 is transferred to the syringe 220 (see FIG. 21), the second section 192 and the cover 210 may be removed from the container 110 and affixed to the syringe 220. . The cover 210 may then be removed from the second section 192 of the label 160 to expose the layer of photosensitive material 193 under the cover 210. Monitoring the exposure of the material in syringe 220 may thus be continued by layer 193. It will be appreciated that a similar effect can be achieved when the second section 192 is applied to the syringe 220 after the cover 210 is first removed from the second section 192 (and thus the layer 193) of the label 160.

  A label such as that shown in FIGS. 20 and 21 has the effect of filtering and blocking light that the material used to make the container 110 is exposed to the container 110, for example, but the same material is useful in the manufacture of the syringe 220. It can be advantageous if not used. According to such an embodiment, using a layer 191 of photosensitive material selected to more closely correlate exposure of the material (eg, polypeptide) when placed in the container 110, and the syringe 210. It may be appropriate to use a layer 193 of photosensitive material that is selected to more closely correlate exposure of the material (eg, polypeptide) when placed within. In order to prevent layer 193 from incorrectly displaying the exposure of the material in syringe 220, cover 210 is placed from container 110 to syringe 220 rather than when a polypeptide or other substrate is placed in chamber 114. The material is removed simultaneously with the movement of the material.

  It is also possible to design a label or labeling system that incorporates a layer of photosensitive material together with a layer of material that is responsive to other environmental conditions such as temperature or humidity. For example, FIGS. 22 and 23 show a container 250 in which, for example, a polypeptide is placed. The container 250 is used in conjunction with a label or labeling system that allows exposure and temperature monitoring, for example. Such a device can be useful when the polypeptide has a photosensitivity that varies based on exposure to light having a wavelength in the XY range and also has temperature sensitivity. Alternatively, if the photosensitive material of the photosensitive layer 252 is temperature sensitive, the temperature sensitive layer can be used to signal the user to utilize a different correlation for the photosensitive layer 252 (see FIG. 15 above). .

  To address photosensitivity or potential photosensitivity of the material (eg, polypeptide) in container 250, a layer of photosensitive material 252 is disposed, for example, on outer surface 254 of container 250, and the polypeptide disposed within the interior chamber. At the same time, it may be exposed to existing environmental conditions. The photosensitive material is responsive to light having a wavelength in the range of X to Y and exhibits a change in properties at a threshold of cumulative exposure to light in the range of X to Y that is related to a change in the photosensitivity of the polypeptide. You may receive it. It will be appreciated that any of the variables relating to layers of photosensitive material exemplified and / or discussed above can be used in conjunction with layer 252.

  In addition, a label 256 that includes a layer 258 of temperature sensitive material may be disposed on the outer surface 254 of the container 250. Layer 258 is subjected to a characteristic change (eg, a characteristic change detectable by a colorimetric method) at a temperature exposure threshold related to the temperature sensitivity change of the material in container 250, ie, the polypeptide according to this embodiment. Also good. This layer 258 may be placed on or with a background of various colors 260 to facilitate detection or visualization of changes in layer 258 (eg, compare FIGS. 22 and 23). Wanna) In fact, a similar mechanism is utilized in this or other embodiments described herein in combination with layers of photosensitive material to change the characteristic of the photosensitive material (in this case, the characteristic change is a color change). Detection or visualization can be facilitated.

  Having a number of previously described embodiments of products according to the present disclosure with reference to FIGS. 1-23, multiple applications can be described herein for these embodiments.

  Initially, it will be appreciated that one application that may be made by a product according to the present disclosure is to determine the state of the material placed in the chamber 114 in real time. This determination can be made, for example, once a correlation is defined between the change in material properties of layer 140 and the photosensitivity of the material in chamber 114. Once the correlation is known, it can be used to define a scale (eg, a color scale) and examine the layer 140 used to determine the state of the material placed in the chamber 114. Correlation can be achieved, for example, by placing the material in the chamber 114 at the same time as the placement of the label 160 on the outer surface 112 of the container 110 to change the property of the material in the layer 140 and the photosensitivity of the material in the chamber 114. Both can be determined, for example, by monitoring in a series of time increments during the examination period and collecting the data. Data collected for the material of layer 140 and the material of chamber 114 may be compared and correlations or relationships may be defined. Based on the defined relevance, for real-time assessment of the state of the substance in the chamber 114, a scale is determined and the material property change in the layer 140 is used to determine the exposure level of the material in the chamber 114. Can be identified.

  The monitoring and / or determination of property changes of the photosensitive material in layer 140 will vary depending on the material used. For example, if the photosensitive material in layer 140 undergoes a color change, the property change can be determined visually by the user or by the optical colorimetric sensing device described above. The optical sensing device may be coupled to a computer system, which may program a correlation or relationship between a property change and state of the material (eg, polypeptide) in the chamber 114, The system may be further programmed to remove the container from the inventory if the determination of the condition suggests that the material is no longer safe and / or effective for administration.

  The pharmaceutical product thus described can also be used in a method for confirming the correct handling of a photosensitive material (for example, a polypeptide) in a container. In accordance with such a method, the layer of photosensitive material 140 is applied to the outer surface 112 of the container 110 within which the polypeptide or other material is disposed, the polypeptide or other material having a range of at least XY. Photosensitivity that varies based on cumulative exposure to light having a wavelength within the range, the photosensitive material is responsive to light having a wavelength in the range of X to Y, and is sensitive to the photosensitivity of the polypeptide. A characteristic change (e.g., a characteristic change detectable by a colorimetric method) is experienced at a threshold of cumulative exposure to light in the XY range related to the change. Thereafter, the container 110 may be a recipient within the pharmaceutical product manufacturing or distribution network, such as, but not limited to, storage, packaging or filling factories, vendors, testing facilities, pharmacies, examination rooms, clinics, hospitals or other Delivered to and recovered from a healthcare facility, healthcare provider, or patient. The layer of photosensitive material can be examined to determine whether the photosensitive material has undergone a property change, and if the photosensitive material has undergone a property change, the container can be identified as mishandled.

  For example, the product 100 may be packaged in a box or packaging material that is adapted to be removed only when the material of the container 110 is administered to the patient. In such a setting, the box or wrapping material may be used to limit the exposure of the material in the container 110. However, if layer 140 undergoes a property change detectable by a colorimetric method, this may indicate that product 100 has been prematurely removed from the protective packaging in violation of the displayed instructions for use. it can.

  Although all of the embodiments shown in FIGS. 1-23 relate to products in which the photosensitive material is disposed on the outer surface of the container, it is also possible to place a photosensitive layer within the interior chamber of the container as described in the introduction paragraph. Is possible. According to the embodiment shown in FIG. 24, a pharmaceutical product 300 is shown, which includes a container 310 having an inner chamber 314, the container being constructed from a material that is light resistant. As previously mentioned, the material may filter or block light in one or more wavelength ranges. As such, the exposure of the material disposed within the chamber 314 of the container 310 may be different than when the material is exposed to environmental conditions.

  The product may include a layer 340 of photosensitive material disposed within the inner chamber 314 of the container 310. As shown, the layer 340 may be disposed on a monitoring card 360 that includes a substrate 362 having a first side 364 and a second side 366. According to other embodiments, material may be applied to both sides 364, 366 of the substrate 362. As shown, the substrate 362 may be made of a hard material such as hard card paper or plastic that allows the substrate 362 to stand upright in the chamber 314 when the container 310 is placed on the surface. The layer 340 is readable. According to other embodiments, the surface 366 may be coated with an adhesive and the card 360 may be attached to a specific location within the chamber 314.

  As with layer 140, the material of layer 340 is a photosensitive material that is reactive to light having a wavelength in the range of X to Y and is in the range of X to Y with respect to changes in the photosensitivity of the polypeptide. Characteristic changes may be experienced in the threshold of cumulative exposure to light. A polypeptide or other material may be placed in the chamber 314 with the card 360, but the material may not be in the chamber 314 and the card 360 may be placed in the chamber 314.

  For example, the photoresistance of the material used for the container 310 is unknown or not well known, or at least the photoresistance of the material used for the container 310 is placed in the chamber 314 of the container 310. Consider situations where the sensitivity of the material is unknown or unknown. In such a setting, the card 360 may be placed in the chamber 314 of the container 310, after which the container 310 may be exposed to the appropriate light source. While the card 360 and in particular the layer 340 are being exposed, changes related to property changes (eg, property changes detectable with colorimetry) may be monitored. Communication of property changes of layer 340 may be collected, for example, in a series of time increments of the inspection period.

  The collected data may be used for various purposes. For example, the collected data is placed in another container 310 made of another material with known photoresistance (perhaps known at least regarding the photosensitivity of the material placed in chamber 314). It may be compared with the data collected in the example of the played card 360. Based on the comparison, it may be determined whether to use the material for the container 310 or not to use the material for the container 310.

  FIG. 25 shows an example (represented in colorimeter readings) that measured exposure with various materials of glass, polycarbonate, and Teflon using a system similar to that shown in FIG. ing. As an example, the lowest plot of data points corresponds to a card 360 placed in a glass vial, and the top two plots correspond to cards placed in a polycarbonate and Teflon container. In conclusion, it appears that greater exposure is taking place in glass vials rather than in polycarbonate or Teflon containers.

  This conclusion is further supported by the graph of FIG. 30 plotting UV intensity measurements from inside and outside of Teflon, polycarbonate (“PC”) and glass containers. In this test, UVP LLC 3UV-38 3UV Lamp from Upland, California was used, and measurements inside and outside the container were taken from Solar Light Co., Glenside, PA. PMA 2110 UVA detector. The inner and outer detectors were placed approximately 47-48 cm from the lamp, and the inner detector was placed inside a container with a cap or lid on top. The smallest difference between the values measured inside and outside the container occurs for the glass container, so that less light is absorbed by the glass wall by the walls of the other container, so a larger exposure can be achieved with other materials. It is suggested that it occurred in a glass vial as opposed to that produced.

  As another example of the use of the product shown in FIG. 24, the material may be placed in the chamber 314 at the same time as the card 360 to change the property of the material in the layer 340 and the sensitivity of the material in the chamber 314. Both may be monitored and collected, for example, in a series of time increments of the examination period. Data collected with the material in layer 340 and the material in chamber 314 may be compared and correlation or relevance may be defined. Based on the defined relevance, the scale can be determined and the exposure level of the material in the chamber 314 can be identified by the property change of the material in the layer 340.

  Yet another system and application for the technology of the present invention can be described according to FIG. 26 according to a schematic diagram of a facility, such as a manufacturing facility, for example, for a system and method for analyzing exposure of a pharmaceutical product passing through the facility. May be included. This system and application may be particularly useful, for example, when and where exposure of products passing through a facility cannot be limited due to regulatory directives. For example, the European Council Directive 89/654 / ECC (November 30, 1989) states that workplaces must receive as much natural light as possible, and artificial lighting suitable to protect the safety and health of personnel. We are looking for things that must be equipped. Therefore, it may not be possible to comply with the light requirements of the Council Directive on employee safety and health while limiting exposure to products.

  In particular, the manufacturing facility or factory 400 may include at least one space (a plurality of spaces according to the embodiment shown in FIG. 26) through which a pharmaceutical product according to the present disclosure can pass. These spaces may be physically separated from each other by the presence of walls or other barriers; in other examples, the spaces may be bounded from an organizational standpoint, but one space There may be no physical barrier defining the boundary between the area or region and the other. The product may include a label according to any of the previous embodiments. However, in addition to such a label affixed to the pharmaceutical product, once a passage P through which the product passes through the factory is identified, additional photosensitive devices 402 or phototrackers are placed around the factory 400. Also good. Information regarding exposure generated through the use of device 402 may be utilized in conjunction with information from a label associated with the product, or alternatively may be utilized separately.

  As shown, the factory 400 includes a first space 410 in which a pharmaceutical product is prepared. For example, a polypeptide that represents the active ingredient in the product may be mixed within the space 410 with a medium in which the polypeptide is stored and administered to a patient. A polypeptide may have a photosensitivity that varies based on cumulative exposure to light having a wavelength at least in the range of XY. The active ingredient and medium may then be placed in a container as shown in FIG. A smaller container, such as that shown in FIG. 1, may be filled with active ingredients and media and then passed from space 410 through space 412.

  The filled container may then move to the scrutiny space 416 or storage (or storage) space 418 after passing through the movement space 414. As indicated by the arrows along the flow path P, the product may flow directly from the filling space 410 through the moving space 414 to the scrutiny space 416 or may bypass the storage space 418. In addition, the product may return to the storage space 418 before moving along the path P from the scrutiny space 416.

  Once the container has passed scrutiny within the scrutiny space 416, the product may be assembled with other articles in the assembly space 420 to define a system or kit. As shown, the product may be delivered to the assembly space 420 from either the review space 416 or the storage space 418. The product may define a system or be packaged as part of a kit in combination with a syringe, eg, in the clamshell of an infusion kit, as shown in FIG. Alternatively, the product may be assembled as part of a system in the form of a medical device such as an auto-injector (shown in FIGS. 22 and 23), micro-injector. Once the assembly is complete, the system or kit may be removed from the factory 400 after passing the loading dock 422.

  It will be observed that the device 402 is disposed along the path P through the spaces 410, 412, 414, 416, 418, 420, 422. Device 402 includes a layer of photosensitive material that is responsive to light having a wavelength in the range of X to Y, and changes in characteristics (eg, ratio) at a threshold of cumulative exposure to light in the range of X to Y. Characteristic change detectable by a color measurement method). In many examples, such as in spaces 410, 412, 418, 420, 422, device 402 is located on either side of passage P. In certain spaces, such as spaces 414, 416, device 402 is located on only one side of passage P. Spaces 414, 416 have only a single device, but spaces 410, 412 have two devices, space 420 has three devices, space 422 has four devices, and space 418 has six devices. As with devices, the number of devices may vary from space to space. The device 402 may be attached to a particular structure, device or machine, such as a mixing tank or syringe / cartridge filling machine, disposed within the spaces 410-422, for example, by use of an adhesive back.

  It will be appreciated that the installation and number of devices used may be defined by several factors. For example, certain rooms, certain equipment or other environmental light sources (lamps, ceiling lights, windows, etc.) may be located primarily on one side or the other side of the aisle. In addition, it may be more desirable to install additional devices in larger rooms, or in rooms where the passages have multiple entry and exit points, or more complicated passages. For example, space 418 may be qualified with all these criteria because it includes more devices 402 than other spaces.

  However, using a photo tracker or photosensitive device along the path P has at least one significant advantage. The arrangement of the device 402 along the path P allows identification and isolation of points along the path P where light of a particular wavelength or intensity affects the product. Through use of the device 402, this identification and isolation may be performed in real time. For example, the photosensitive device 402 may read evidence of property changes using an optical sensing device in the vicinity of the device 402, where the optical sensing device is a computer that indicates an indication of exposure received by at least one device 402. Connected to the device. As a result, changes can be made to the equipment (eg, using different mixing tanks, syringe filling machines, etc.), the environment surrounding the passage P (eg, upright walls, screens, etc.), products (eg, changes in the containers used) Or a passage P (eg, improving the passage P between or within the various spaces 410, 412, 414, 416, 418, 420, 422) and exposing at points along the passage P It may be minimized or eliminated.

  That is, the label affixed to the product may be used to determine the cumulative exposure of the individual product or as a conclusion whether the product should be used or discarded. However, the label does not provide a history of where the product has been recorded exposure through the use of the label on the product. Even if the label attached to the product is to be scrutinized for cumulative exposure to light at various points along the path P, the exposure information obtained in this manner can be used to Identification and isolation of localized spaces, areas or regions that are exposed to high or specific wavelength exposures may still be difficult. Since the product can be transported, scrutinized and transported between storage spaces 414, 416, 418, the product can pass through a specific space such as the space 420 after passing through any of the plurality of spaces. This is especially true when considered.

  In contrast, the use of a photo tracker or photosensitive device 402 located along path P causes the exposure of the product in factory 400 to be analyzed separately from the product itself, resulting in movement of the product along path P. It may be considered without necessity. For example, from the indication value obtained from the device 402 arranged in the space 418, the product moving along the passage P is relevant for the product in the part of the space where the product is stored between the inspection space 416 and the assembly space 420. Exposure to a significant amount of light having a wavelength or multiple wavelengths. The additional device 402 may then be placed in the space 418 to further identify the light source, or along with another path in the space 418, determined the feasibility of these other paths of the product. Thereafter, the passage P in the space 418 may be changed. If the label is used only on the product, identification of such a light source or another passage can only be done by an additional amount of exposure that results in product degradation and may require disposal of the product.

  This suggests that the information from the light sensitive label cannot play a cooperative role with the light sensitive device 402 and there is no need to attempt to reverse the exact trajectory of a particular example of the product along the path P. It is not. For example, device 402 may be used to identify the level of product exposure to light along path P, but the spatial arrangement of device 402 may not capture each potential source of undesirable exposure. Sometimes it is. Alternatively, if the conditions along the path P are changed with respect to the past appropriate distribution of the device 402, the past distribution may not be suitable for identifying and isolating unwanted light sources for exposure. For this purpose, it is possible to scrutinize the labels associated with the product and compare the results of the scrutiny against the indicated values determined at various points along the path P, e.g. a distribution is used. It may be determined whether the location or number of devices 402 need to be changed.

  It will also be appreciated that many of the foregoing views have general utility in selecting the materials used within device 402 and the shape and location of device 402. For example, device 402 may provide a real-time indication of cumulative exposure at a predetermined part of the factory, but device 402 is not always monitored continuously. In conclusion, it is desirable to select a less sensitive material for use within the device 402 because the device 402 is intended to be exposed to environmental illumination conditions for the length of time being monitored. there is a possibility. FIG. 27 shows the range and nature of possible color changes of five different sensitivities of materials that can be used in the device 402 when exposed to various amounts of visible light, the color changes being Measured by L * a * b index. It will also be appreciated that the use of this system and method is not limited to manufacturing facilities, but may be used in other buildings or structures such as healthcare facilities, laboratory facilities, hospitals or clinics.

  It will be appreciated that a device according to the present disclosure may have one or more advantages over the prior art, one or more of which, in certain embodiments, are included in the embodiments disclosed herein. May exist due to the characteristics of Other advantages not specifically listed herein may be recognized.

Claims (83)

A pharmaceutical product,
A container having an outer surface and an inner chamber;
An active ingredient disposed within the interior chamber and having a photosensitivity that changes based on at least cumulative exposure to light having a wavelength in the range of X to Y;
A layer of photosensitive material disposed on the outer surface of the container and exposed to environmental conditions simultaneously with the active ingredient disposed within the inner chamber;
Including
Since the photosensitive material experiences a characteristic change related to the change in photosensitivity of the active ingredient at a received light cumulative exposure threshold in the range of X to Y, it is responsive to light having a wavelength in the range of X to Y. A pharmaceutical product.   The product of claim 1, wherein the layer of photosensitive material is applied to a label affixed to an outer surface of the container.   The product of claim 1, wherein the layer of photosensitive material is applied directly to an outer surface of the container.   The product of any one of claims 1 to 3, further comprising a removable layer of photoresistive material applied to the layer of photosensitive material.   5. The product of claim 4, wherein the removable layer of photoresistive material includes a label removably attached to an outer surface of the container over the layer of photosensitive material.   The product according to claim 1, wherein the characteristic change of the photosensitive material in the layer on the outer surface of the container is a characteristic change detectable by a colorimetric method.   The product according to any one of claims 1 to 6, wherein the active ingredient is a polypeptide, an amino acid, or a small molecule.   The product of claim 7, wherein the polypeptide is an antibody polypeptide.   9. The product of claim 8, wherein the antibody polypeptide is a monoclonal antibody polypeptide.   The product of claim 9, wherein the change in photosensitivity comprises an increase in the amount of high molecular weight species present in the active ingredient.   The product of claim 9, wherein the change in photosensitivity comprises an increase in the amount of low molecular weight species present in the active ingredient.   The product of claim 9, wherein the change in photosensitivity is a characteristic change detectable by a colorimetric method.   13. The product of claim 12, wherein the change in photosensitivity comprises a color change in yellowness index.   The product of claim 9, wherein the change in photosensitivity comprises a change in the amount of charged species present in the active ingredient.   The product of claim 7, wherein the active ingredient is a small molecule.   The product of claim 15, wherein the change in photosensitivity is a change in absorbance.   The product of claim 15, wherein the change in photosensitivity comprises a color change in a yellowness index.   The product according to any one of claims 1 to 6, wherein the active ingredient is a virus.   The product according to any one of claims 1 to 6, wherein the active ingredient is a diagnostic reagent.   The product according to any one of claims 1 to 19, wherein the range is 190 to 1100 nm.   21. The product of claim 20, wherein the range is 315 to 400 nm.   21. The product of claim 20, wherein the range is 401-750 nm. A pharmaceutical product,
A container having an inner chamber and made of a photo-resistant material;
A layer of photosensitive material disposed within the inner chamber of the container;
Including
Since the photosensitive material experiences a characteristic change related to the change in photosensitivity of the active ingredient at a received light cumulative exposure threshold in the range of X to Y, it is responsive to light having a wavelength in the range of X to Y. A pharmaceutical product.   24. The product of claim 23, wherein the characteristic change of the photosensitive material in the layer disposed in the inner chamber of the container is a characteristic change detectable by a colorimetric method.   25. A product according to claim 23 or 24, wherein the active ingredient is a polypeptide, an amino acid or a small molecule.   25. A product according to claim 23 or 24, wherein the active ingredient is a virus.   The product according to claim 23 or 24, wherein the active ingredient is a diagnostic reagent. A pharmaceutical product,
A container having an outer surface and an inner chamber;
An active ingredient disposed within the inner chamber and having photosensitivity that changes based on at least cumulative exposure of light having a wavelength in the range of X to Y;
A first region affixed to the outer surface of the container to which a layer of photosensitive material is applied; and a second region removably affixed to the outer surface of the container to which a layer of photosensitive material is applied. The first region and the second region are exposed to environmental conditions simultaneously with the active ingredient disposed in the inner chamber;
Including
Since the photosensitive material experiences a characteristic change related to the change in photosensitivity of the active ingredient at a received light cumulative exposure threshold in the range of X to Y, it is responsive to light having a wavelength in the range of X to Y. A pharmaceutical product.   29. The product of claim 28, wherein the property change of the photosensitive material in the layer applied to the label is a property change detectable by a colorimetric method.   30. The product of claim 28 or 29, wherein the active ingredient is a polypeptide, amino acid, or small molecule.   32. The product of claim 30, wherein the polypeptide is an antibody polypeptide.   32. The product of claim 31, wherein the antibody polypeptide is a monoclonal antibody polypeptide.   33. The product of claim 32, wherein the change in photosensitivity comprises an increase in the amount of high molecular weight species present in the active ingredient.   33. The product of claim 32, wherein the change in photosensitivity comprises an increase in the amount of low molecular weight species present in the active ingredient.   33. A product as set forth in claim 32 wherein the photosensitivity change is a characteristic change detectable by a colorimetric method.   36. A product as set forth in claim 35 wherein the photosensitivity change comprises a yellowness index color change.   33. A product as set forth in claim 32 wherein the photosensitivity change comprises a change in the amount of charged species present in the active ingredient.   32. The product of claim 30, wherein the active ingredient is a small molecule.   40. The product of claim 38, wherein the change in photosensitivity is a change in absorbance.   39. A product as set forth in claim 38 wherein the photosensitivity change comprises a yellowness index color change.   30. A product according to claim 28 or 29, wherein the active ingredient is a virus.   30. A product according to claim 28 or 29, wherein the active ingredient is a diagnostic reagent.   43. A product according to any of claims 28 to 42, wherein the range is 190 to 1100 nm.   44. The product of claim 43, wherein the range is 315 to 400 nm.   44. The product of claim 43, wherein the range is 401-750 nm. A method for confirming the correct handling of photosensitive materials,
Applying a layer of photosensitive material to the outer surface of the container in which the active ingredient is placed in order to experience a characteristic change related to the change in photosensitivity of the active ingredient at a received light cumulative exposure threshold in the range of XY. Wherein the active ingredient has a photosensitivity that changes based on at least cumulative exposure to light having a wavelength in the range of X to Y, and the photosensitive material that is reactive to light comprises: Having a wavelength in the range of ~ Y,
Delivering the container to a recipient;
Collecting the container from the recipient;
Inspecting the photosensitive layer to determine whether the property change has occurred in the photosensitive material;
Identifying the container as poor handling if the characteristic change has occurred in the photosensitive material;
Including a method.   47. The method of claim 46, wherein the characteristic change of the photosensitive material in the layer on the outer surface of the container is a characteristic change detectable by a colorimetric method.   48. The method of claim 46 or 47, wherein the active ingredient is a polypeptide, amino acid, or small molecule.   49. The method of claim 48, wherein the polypeptide is an antibody polypeptide.   50. The method of claim 49, wherein the antibody polypeptide is a monoclonal antibody polypeptide.   51. The method of claim 50, wherein the change in photosensitivity comprises an increase in the amount of high molecular weight species present in the active ingredient.   51. The method of claim 50, wherein the change in photosensitivity comprises an increase in the amount of low molecular weight species present in the active ingredient.   51. The method of claim 50, wherein the photosensitivity change is a characteristic change detectable by a colorimetric method.   54. The method of claim 53, wherein the photosensitivity change comprises a yellowness index color change.   51. The method of claim 50, wherein the change in photosensitivity comprises a change in the amount of charged species present in the active ingredient.   49. The method of claim 48, wherein the active ingredient is a small molecule.   57. The method of claim 56, wherein the change in photosensitivity is a change in absorbance.   57. The method of claim 56, wherein the photosensitivity change comprises a yellowness index color change.   48. The method of claim 46 or 47, wherein the active ingredient is a virus.   48. The method of claim 46 or 47, wherein the active ingredient is a diagnostic reagent.   61. A method according to any of claims 40-60, wherein the range is 190-1100nm.   62. The method of claim 61, wherein the range is 315 to 400 nm.   62. The method of claim 61, wherein the range is 401-750 nm. A method for analyzing the exposure of a pharmaceutical product comprising:
Identifying a passage for the medicinal product in a facility that includes at least one space through which the medicinal product passes, wherein the medicinal product is at least cumulative to light having a wavelength in the range of XY Containing active ingredients with photosensitivity that changes based on exposure,
Placing at least one photosensitive device along the path to experience a characteristic change at a received light cumulative exposure threshold within a range of XY, wherein the at least one photosensitive device is from X to Y. A layer of photosensitive material that is reactive to light having a wavelength in the range of Y;
Reading the at least one photosensitive device after placing it along the path to find evidence that the characteristic change has occurred in the photosensitive material of the photosensitive device; and If it occurs in the photosensitive material, changing the passage of the pharmaceutical product in the facility;
Including a method.   65. The method of claim 64, wherein the facility is a manufacturing facility. 65. The method of claim 64, comprising:
Reading the at least one photosensitive device disposed along the path includes disposing an optical sensing device in the vicinity of the photosensitive device, wherein the optical sensing device comprises the at least one photosensitive device. A method coupled to a computing device that displays exposure experienced by the device.   The method according to claim 64, wherein the characteristic change of the photosensitive material in the layer is a characteristic change detectable by a colorimetric method.   68. The method of any of claims 64-67, wherein the active ingredient is a polypeptide, amino acid, or small molecule.   69. The method of claim 68, wherein the polypeptide is an antibody polypeptide.   70. The method of claim 69, wherein the antibody polypeptide is a monoclonal antibody polypeptide.   72. The method of claim 70, wherein the change in photosensitivity comprises an increase in the amount of high molecular weight species present in the active ingredient.   71. The method of claim 70, wherein the photosensitivity change comprises an increase in the amount of low molecular weight species present in the active ingredient.   71. The method of claim 70, wherein the photosensitivity change is a characteristic change detectable with a colorimetric method.   74. The method of claim 73, wherein the photosensitivity change comprises a color change of yellowness index.   71. The method of claim 70, wherein the change in photosensitivity comprises a change in the amount of charged species present in the active ingredient.   69. The method of claim 68, wherein the active ingredient is a small molecule.   77. The method of claim 76, wherein the change in photosensitivity is a change in absorbance.   77. The method of claim 76, wherein the photosensitivity change comprises a yellowness index color change.   68. The method according to any one of claims 64 to 67, wherein the active ingredient is a virus.   68. The method according to any one of claims 64 to 67, wherein the active ingredient is a diagnostic reagent.   The method according to any one of claims 64 to 80, wherein the range is 190 to 1100 nm.   82. The method of claim 81, wherein the range is 315 to 400 nm.   82. The method of claim 81, wherein the range is 401-750 nm.

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