IDMP Medicinal Product: How complex could it get?

Transcription

1 A White Paper Presented By ArisGlobal IDMP Medicinal Product: How complex could it get? Pratyusha Pallavi, Subject Matter Expert - Regulatory Affairs

2 Introduction Regulatory authorities and the life sciences industry engage in an intensive information exchange during every phase -- such as molecule development, drug evaluation and approval phase and the post-authorization phase -- of the drug development lifecycle. The standardization of medicinal product information as envisioned in the International Organization for Standardization (ISO) Identification of Medicinal Products (IDMP) standards is regarded as the key towards a global and unified means of defining and sharing information by: Improving efficiencies of information exchange Improving the accuracy of the evaluation and comparison of medicinal product-related information across the regions, especially in the context of pharmacovigilance Providing major human and financial savings for the life sciences industry by avoiding regional data administration and investing in a single set of processes and systems that cater to these data needs Achieving consistency in the use of terminology in the health care community In order to achieve the intended benefits of ISO IDMP, an important step for the industry is to perform an internal readiness assessment from the following perspectives - process, people, technology and data. While the assessment effort and the resulting impact on process, people and technology cannot be underestimated, the first step that most companies will naturally take as they are gearing up for IDMP is the data perspective. Given this, it is critical to understand the complexities in the ISO IDMP Medicinal Product data model, given the granularity and detail at which this data and corresponding identifiers at various levels in the hierarchy of Medicinal Product are expected to be maintained for each region. This paper focuses on these complexities and gives the reader additional insights to consider while performing the data readiness assessment. 2

3 Summary of the key ISO IDMP Concepts Let us look at how the ISO IDMP standards define and detail a Medicinal Product. Note that this paper uses the Authorized Medicinal Product concept to discuss the topics of interest, but most of those topics also apply to an Investigational Medicinal Product. For simplification, the term Medicinal Product will be used when referring to an Authorized Medicinal Product, unless the concept of Investigational Medicinal Product needs to be explicitly made. Although the overall definition of a Medicinal Product is explained in the ISO IDMP standard, the definitions for the supporting components of the Medicinal Product come from the other ISO IDMP Standards 11616, 11238, and Here is a layman s version of those definitions. Figure: How the ISO IDMP Standards contribute to the definition of an Authorized Medicinal Product 3

4 A Medicinal Product is made up of Ingredients which can be a substance having a Substance ID or a specified substance having a Specified Substance ID (defined in ISO IDMP 11238). A substance of specific strength and a specific pharmaceutical dose form when administered to a patient via a specific route of administration forms a Pharmaceutical Product (defined in ISO IDMP 11616). Each Pharmaceutical Product has a set of Pharmaceutical Product IDs or PhPIDs. The Pharmaceutical Product is obtained either directly or after reconstitution from its manufactured form, called the Manufactured Item (defined in ISO IDMP 11615). The Manufactured Item is packaged in an immediate packaging. This in turn may be packaged in one or more intermediate packaging layers and finally an outermost packaging layer. The complete packaged form of the product that is manufactured and packaged for sale is called the Packaged Medicinal Product (defined in ISO IDMP 11615). The Packaged Medicinal Product may be assigned a Packaged Medicinal Product ID or PCID. Individual packaging Items starting from the outermost container to the innermost container are linked in a nested hierarchy. Each such item is defined by a Package Item (as defined in ISO IDMP 11615), and may be assigned Batch Identifiers BAID_1 and BAID_2. One or more Packaged Medicinal Products (representing different packaging configurations of the product), when authorized by an agency for a region for use against approved clinical particulars, manufactured as per authorized establishments and sold under appropriate approved trade names, constitute an Authorized Medicinal Product (as defined in ISO IDMP 11615). They are assigned a Medicinal Product ID or MPID. In all the above definitions, specific attributes -- namely Packaging Type, Pharmaceutical Dose Form, Route of Administration and Unit of Presentation -- are defined as controlled terminologies (as explained in ISO IDMP 11239). In all the above definitions, units of measurements for expressing numeric concepts of various types is governed and defined by ISO IDMP Some Practical Examples Let us understand the above-mentioned concepts with some examples. Simple Product with Nested Packaging Consider a film-coated oral tablet of Acetylsalicylic Acid 75 mg that comes as a carton box containing 2 blisters of 10 tablets each. In this example, there are distinct outer and inner packaging layers. A product like this can be explained using the ISO IDMP data model as follows: A single Medicinal Product containing a Pharmaceutical Product for the 20 (2 x 10) Oral film-coated tablets and a Packaged Medicinal Product for the carton box of 2 aluminum blisters will be present. The Packaged Medicinal Product in turn will have one Package Item for the carton box, which represents the actual outermost packaging. This carton Package Item in turn will contain another Package Item for 2 aluminum blisters representing the innermost packaging. The blister Package Item in turn contains the Manufactured Item representing 10 oral film coated tablets. Note: The Pharmaceutical Product Quantity (20 Tablets in this example) versus Manufactured Item Quantity (10 Tablets in this example) has been deduced based on current understanding of the ISO IDMP Standards. The standard does not clearly explain the impact of multi-layer packaging hierarchy on these quantities. It needs to be seen if this is clarified in the Implementation Guide. 4

5 Figure: Simple Product with Nested Packaging Simple Product with Multiple Packaging Configurations Consider an oral tablet of Paracetamol 200 mg that comes in two package configurations a blister and a bottle. This is an example where the significance of the Packaged Medicinal Product comes into play. Here, a single Medicinal Product contains two Packaged Medicinal Products (one for the blister and one for the bottle). Each of the Packaged Medicinal Products in turn will have a Package Item, which represents the only layer of actual physical packaging, i.e., the blister and the bottle respectively. Each Package Item contain the same Manufactured Item, although in different quantities. Figure: Simple Product with Multiple Packaging Configurations 5

6 Multi-Product Kit Consider a multi-product therapy kit consisting of an oral capsule of Fluconazole 150mg in a blister and a vaginal cream of Clotrimazole 2% in a tube authorized to be used as part of a single therapy. This is an example where the same Medicinal Product can have more than one Pharmaceutical Product. A product like this can be explained using the ISO IDMP data model as follows: A single Medicinal Product contains two Pharmaceutical Products first for the single oral capsule and second for the vaginal cream. The Medicinal Product will also have one Packaged Medicinal Product representing the entire kit as a single authorized package configuration. The Packaged Medicinal Product in turn will have a Package Item representing the outermost packaging of the kit, i.e., the carton box. This carton Package Item in turn will contain two Package Items one for the aluminum blister and the second for the tube. The blister Package Item in turn contains the Manufactured Item representing the oral capsule. The tube Package Item contains the Manufactured Item representing vaginal cream. The Pharmaceutical Product and Manufactured Item representing the capsule have the same substance as the active ingredient, i.e., Fluconazole 150mg. Also, the Pharmaceutical Product and Manufactured Item representing the cream have the same substance as the active ingredient, i.e., Clotrimazole 2%. Figure: Multi-Product Kit Kit with Administration Device Some products may be accompanied by an administration device. Extending the above example, the carton could also contain 5 plastic pouches, each with a one-time use cream applicator. In that case, the Packaged Item representing the outer carton will contain another Package Item for 5 plastic pouches, which in turn will contain a Device, representing the applicator. 6

7 Figure: Multi-Product Kit with Administration Device Device as Packaging A different example of a product with a device is a solution for injection that comes in a pre-filled syringe. Here, the Package Item itself is the syringe. Hence, it will contain a Device for representing the syringe details. The same Package Item will also contain the Manufactured Item representing the solution for injection. Figure: Device as Packaging 7

8 Reconstituted Product A final example is that of a reconstituted product consisting of a powder of Amoxicillin Dihydrate1.2g in a vial and 10 ml of a solvent of sterile water in a glass ampoule. This is an interesting example where the difference between the Pharmaceutical Product and Manufactured Product is highlighted. A product like this can be explained using the ISO IDMP data model as follows: A single Medicinal Product contains only one Pharmaceutical Product representing the reconstituted product of 10 ml of solution of Amoxicillin 1.2g/10ml. The active ingredient of this Pharmaceutical Product is Amoxicillin. The Medicinal Product will also have one Packaged Medicinal Product representing the entire kit as a single authorized package configuration. The Packaged Medicinal Product in turn will have a Package Item representing the outermost packaging of the kit, i.e., the carton box. This carton Package Item in turn will contain two Package Items one for the glass vial and the second for the glass ampoule. The vial Package Item in turn contains the Manufactured Item representing 1.2 mg of the powder for solution. This Manufactured Item is different from the Pharmaceutical Product not just in its dose form but also in its composition, as it contains 1.2 mg of the substance Amoxicillin Dihydrate as its active ingredient. The tube Package Item contains the Manufactured Item representing 10 ml of sterile water Figure: Reconstituted Product 8

9 Many interesting variations of the reconstituted product may arise. The solvent may not be included as part of the kit and all of the powder is directed to be taken with water as a single dose. In such a case, only one Manufactured Item for the powder and one Pharmaceutical Product for the reconstituted solution needs to be represented. Another variant can be when a therapy kit for 10 days comes with 5 yellow vials of a high-dose powder, 5 white vials of a reduced-dose powder and 10 ampoules of the solvent. In such a case, the Packaged Medicinal Product will contain 3 Manufactured Items first for the high-dose 2mg powder, second for the reduced-dose 1 mg powder and third for the 10 ml solvent. The Package Items for each of these will contain the information on the number of units (5 vials or 10 ampoules). The Medicinal Product will also contain 2 Pharmaceutical Products the first for the high concentration reconstituted solution obtained by mixing 1 vial of high-dose powder with 1 ampoule of the solvent; and second, for the low-strength reconstituted solution obtained by mixing 1 vial of reduced-dose powder with 1 ampoule of the solvent. Figure: Therapy with Multiple Reconstitutions Understanding the ISO IDMP IDs and Its Impact on Data Maintenance The key purpose of ISO IDMP standards is to enable unique identification of Medicinal Products during exchange of information between various industry stakeholders. ISO IDMP enables this by laying out the definition of Medicinal Product ID or MPID that will be assigned in a distributed way by each participating regulatory authority in conformance with the ISO IDMP. Similarly, Packaged Medicinal Product Identifiers and Batch Identifiers (BAID_1 and BAID_2) may also be assigned. 9

10 Quick Refresher on the ISO IDMP IDs Let s quickly recap the definition of the ISO IDMP Identifiers to set the context for the following discussion. A unique Medicinal Product Identifier or MPID is assigned each time a marketing authorization holder (MAH) receives marketing authorization for a product in a new country. If the MAH for an existing authorized product changes, a new MPID will be assigned. Additionally, if any of the following information of an authorized product changes, then a new MPID should be assigned: Marketing Authorization Number: This could happen in some regions where, for example, there is such a significant change in the product that it is considered as a new line extension, instead of a change to the same product. In such cases, the region s authority will assign a new MPID to this line extension as well. Legal Status of Supply: If the legal status of the supply of the product as a whole or for one or more of its Packaged Medicinal Products or in specific jurisdictions of the country changes, then the Authorized Medicinal Product will be assigned a new MPID. This can happen even though the marketing authorization number remains the same. Medicinal Product Name: The Medicinal Product Name, i.e., the full product name in which the product is registered, contains many names. Even if one part of the medicinal product name changes, the product gets a new MPID. In a later section, the paper discusses the impact of the medicinal product name on MPID. Pharmaceutical Dose Form: If a company decides to launch a product currently administered as a solution for injection in a country in a new dose form, e.g., solution for infusion, the Medicinal Product with this new dose form will be assigned a new MPID. Ingredient Substance(s) and their strength: If either the ingredient or its strength changes, then a new MPID will be assigned. This topic is of more interest and is dealt with in more detail below. Medical Device(s) presented as part of the Medicinal Product: Note that if the product comes with a device which solely serves the purpose of drug administration or drug packaging but has no contribution towards the pharmacological, immunological or metabolic action of the Medicinal Product, then that device is not considered to have an impact an MPID. Thus, if the needle dimension or piston material of the injectable syringe that comes along with a bottle of solution for injection changes, then the Medicinal Product will continue to have the same MPID. Therapeutic indication(s): This means that any change in the complete set of indications for which the product is authorized will lead to assignment of a new MPID. Any other change to the properties of a Medicinal Product will result in a new version of the Medicinal Product but the same MPID. A unique Packaged Medicinal Product Identifier or PCID is assigned to the Packaged Medicinal Product each time a new MPID is assigned or when any of the following information on the Packaged Medicinal Product changes: Packaged Items: The type, quantity, materials and alternate materials Package Components: The type, materials and alternate materials Manufactured Items: Manufactured dose form, unit of presentation and quantity 10

11 A unique Medicinal Product Batch Identifier 1 or BAID_1 is assigned to the outermost packaging each time a new PCID is assigned or whenever a new batch of the outermost packaging is manufactured (i.e., a new batch number, a new expiration date, or both). A unique Medicinal Product Batch Identifier 2 or BAID_2 is assigned to the innermost packaging each time a new PCID is assigned or whenever a new batch of the innermost packaging is manufactured (i.e., a new batch number, a new expiration date, or both). Let s take a simple example. Consider the product Ecosprin 10 mg oral tablets that comes in a box of 2 blisters with 10 tablets per blister. The diagram below illustrates how these different IDs are assigned at different levels. Figure: ISO IDMP Identifiers It is understandable that ISO IDMP requires us to assign unique IDs at various levels for each of the above- listed changes. After all, any change to the above-listed medicinal product information is likely to change the significance of the situation when product information about it is shared in the context of pharmacovigilance (the main benefit of ISO IDMP). Yet, the implications of this for IDMP data administrators can be nightmarish. Let us see how. Impact of Authorization Number on MPID and PCID A unique Medicinal Product (MPID) and its unique packaging configuration (PCID) is defined based on how the regulatory authority assigns it the authorization number. There are 3 possibilities. 11

12 Authorization Number at Product Level (for one or more products): A regulatory authority could assign a single authorization number at the Medicinal Product level that covers all the registered packaging configurations of the product. In this case, a single unique MPID is to be assigned. For example, if a single authorization number is assigned to ColdOff Paracetamol 10 mg tablets, 10 per blister and ColdOff Paracetamol 10 mg tablets, carton of 3 blisters of 10 each, then both these packaging configurations are assigned a single MPID. Note that a PCID would most likely not be assigned to either of the 2 packaging configurations in the above example as they do not have a separate authorization number. This aspect can be indirectly deduced from the Note in section of the ISO IDMP Standards Document and from section 9.1 of the ISO IDMP Implementation Guide, which states that PCID may be assigned when applicable. However, this aspect remains to be confirmed once the final implementation guidelines are out. Authorization Number at Product Level (for one or more products): A regulatory authority could assign an overarching authorization number at the Medicinal Product level and additionally, linked authorization numbers, for all the registered packaging configurations of the product. In this case, a single unique MPID is assigned to the Medicinal Product and a unique PCID to each of the packaging items. Consider the example of the product SuperDrugX 250 mg oral tablets that comes in 2 configurations of a blister of 10 tablets and a bottle of 50 tablets. A regulatory authority may assign an overarching authorization number #1 to the Medicinal Product SuperDrugX 250 mg oral tablets, and package specific authorization numbers of #1.A and #1.B to the blister and the bottle respectively. In this example, the following IDs would be assigned: MPID#1 to the Medicinal Product against the Authorization number #1 PCID#1.X to the blister against the Authorization number #1.A PCID#1.Y to the bottle against the Authorization number #1.B 12

13 Authorization Number at Product Presentation Level (Per Product Presentation): A regulatory authority could assign a separate authorization number to each complete presentation of the Medicinal Product. In this case, a single unique MPID as well as a unique PCID is assigned to each of the authorized presentations of the product. Hence, from the ISO IDMP perspective, these 2 presentations are considered as 2 separate Medicinal Products. Consider the example of 2 product presentations: - MagicSolX 50 IU/ml solution for infusion, vial of 5 ml and MagicSolX 50 IU/ml solution for infusion, syringe of 10 ml. A regulatory authority may assign separate authorization numbers #1 and #2 to the 5 ml vial and the 10 ml syringe respectively. In this example, the following IDs would be assigned: MPID#1 to the product presentation MagicSolX 50 IU/ml solution for infusion, vial of 5 ml against the authorization number #1 PCID#1.A to the 5 ml vial of the product presentation MagicSolX 50 IU/ml solution for infusion, vial of 5 ml against the same authorization number #1 MPID#2 to the product presentation MagicSolX 50 IU/ml solution for infusion, syringe of 10 ml against the authorization number #2 PCID#2.B to the 10 ml syringe of the product presentation MagicSolX 50 IU/ml solution for infusion, syringe of 10 ml against the same authorization number #2 While the correlation as explained above between MPID, PCID and authorization number needs to be ratified once the final ISO IDMP Implementation Guides are out, it is obvious that a great deal of thought needs to be given to the way in which medicinal product data should be organized and stored in software systems. One approach could be that for each new MPID, a new record for the Medicinal Product with all properties as per the ISO IDMP Authorized Medicinal Product data model is stored in your IDMP database. This is a fair approach for the IDMP receiving systems of the agencies. 13

14 However, such an approach can be disastrous for a life sciences company who may need to regularly update certain properties of the Medicinal Product that is applicable for multiple MPIDs. A normalized data structure where a single product definition could be linked to one or more MPIDs at various levels in the product structure would be a more logical approach. The degree to which this data normalization should be achieved is a fine balance. The normalization can come only after a thorough analysisof the type of products your life sciences company creates, the range of modifications that can potentially happen, the IDMP data entry and reporting use cases that will interact with the database, and the resource availability to manage this multiplying data. Impact of Ingredients on MPID Uniqueness of a MPID also depends on the ingredient substance(s) (including their strength) present in the Medicinal Product. This seems a logical and justified approach while talking about active substances and adjuvants. However, the fact that all ingredients including excipients are included to uniquely define a MPID may make it difficult for the life sciences industry. Any change in flavor or colorant of the product will lead to a new MPID. We also need to consider trace materials or excipients that are normally not listed in regulatory documents like Summary of Product Characteristics. Just like in the case of an xevmpd submission, these regulatory documents will most likely serve as supporting material for an IDMP submission. Such documents may not list all trace materials or excipients of less than.1% strength. It may be impossible to identify or measure strength of such excipients, to be able to reliably report to the ISO IDMP database and get a new MPID. Even if this were possible, it would be extremely unwieldy to manage the explosion of MPIDs. Let us note that each minor change to the manufacturing process has an impact on such excipients. An interesting point to note is that Investigational Medicinal Product Identifier or IMPID assigned to Investigational Medicinal Products are most likely to be impacted only by actives and adjuvants. This approach is understandable as the molecule and dose form under investigation may not have a final composition yet. If it is not considered necessary to uniquely identify Investigational Medicinal Products when they differ in excipients, then is it really necessary to uniquely identify Authorized Medicinal Products based on excipients? Possibly yes, as the reach of an Authorized Medicinal Product is much larger. Yet, this is one of the aspects where organizations developing the ISO IDMP implementation guides need to achieve the fine balance between the granularity of Medicinal Product identification and the administrative costs of managing variants of ISO IDMP data. Another aspect that IDMP data administrators in life sciences companies should watch out for is whether the ingredients of the manufactured product have any implication on the MPID. This fine distinction becomes important in the case of reconstituted products where ingredients and their strength change when Manufactured Items are reconstituted to form the administrable composition (namely, the Pharmaceutical Product). When defining the uniqueness criteria for MPID, the ISO IDMP standards only refer to ingredients without any reference to Pharmaceutical Product or Manufactured Item. Given the purpose of the ISO IDMP standard, it may be concluded that it is the composition of the Pharmaceutical Product and not the Manufactured Items that would be relevant to base the uniqueness of MPID, since the Pharmaceutical Product is what is taken by the patient and mentioned in any case report. However, this is an aspect to watch out for once the technical specifications and user guidance on ISO IDMP comes out. 14

15 Impact of Medicinal Product Name on MPID The medicinal product name, i.e., the full product name in which the product is registered, contains many name parts. Even if one part of the medicinal product name changes, the product gets a new MPID. Now, most of the name parts are related to the other identifying attributes on which MPID depends. For example, a change in the Target Population Name Part (for example, the term for children in the registered product name KiddiCold Cough Syrup for children ) also means that the Therapeutic Indications (to the level of detail that is described in ISO DIMP) have changed, so there is ample reason to change the MPID. It is interesting to note that there are some name parts which summarize a concept that otherwise doesn t affect MPID. Consider the Container or Pack Name part of the medicinal product name. A medicinal product name could contain the Container or Pack Name Part and have 2 different presentations authorized under a single authorization number. Yet these 2 different presentations would get a different MPID due to the difference in the way their medicinal product name has different package name parts. Consider a product MagicDrug, which comes in a blister of 10 tablets and a monthly use bottle of 30 tablets. The blister is registered with the name MagicDrug tablets for adults, while the monthly pack is registered with the name MagicDrug bottle of tablets for adults. Even if both these product presentations got the same authorization number and all other defining attributes on which MPID is dependent are the same, yet these 2 presentations would get a different MPID due to difference in the Container or Pack Name Part. 15

16 Conclusion The Medicinal Product data model of ISO IDMP is highly complex. The model has been designed to address multiple possibilities that could arise from different ways in which the product is manufactured, packaged, approved by agencies, marketed and administered to patients. This paper discusses how the model can be used to describe some of these possibilities - products with multiple packaging configurations, multi-product kits, kits with devices as packaging or as administration device and reconstituted products of various types. But these are only some of the most basic product forms. Most therapy areas require more complicated product kits. Putting together information about such products in the ISO IDMP data model can be quite a challenge if an organization doesn t understand the intricacies of the data model. Therefore putting together the data for your products along the lines of the ISO IDMP data model is the first step. The next more complicated step is to understand how and at which levels of your product unique identifiers are assigned. This paper focuses on Medicinal Product Identifier, Packaged Medicinal Product Identifier and Batch Identifiers primarily from the point-of-view of how they could be impacted by two aspects marketing authorization number and ingredients. However, this is only the tip of the iceberg. A number of other aspects, like region-specific authorization procedures, countries and jurisdictions involved, legal status, etc., can affect the granularity of the product, at which MPIDs and hence, the remaining dependent IDs like PCIDs and batch identifiers, are assigned. Pharmaceutical Product Identifier is another big demon a topic that deserves a focused white paper of its own. Aspects like how 2 different Pharmaceutical Products could share some of the IDs from the PhPID Set, how usage of the crystalline form of the substance or substance from a specific manufacturer could impact the entire PhPID Set, how representation of strength of presentation and concentration could differ, and many such topics, can be quite complicated. There cannot be enough stress on how important it is to understand and appreciate such aspects of the ISO IDMP data model before any data readiness assessment can be performed. Until this is done, any effort on IDMP datagathering and cleansing will only lead to future re-work when IDMP submissions are rejected, as the submitted HL7 file won t comply with the guidelines. 16

17 About the Author Pratyusha has been with ArisGlobal for almost 6 years, working in Regulatory, Enterprise Business Analytics, Clinical and Safety verticals. In her current role as SME for the Regulatory Vertical of ArisGlobal, she serves as a member of the domain management team, contributes in setting strategic direction for regulatory software products and works with Sales and Professional Services teams for engaging prospects and customers. Prior to joining ArisGlobal, Pratyusha was with GE Healthcare leading teams to define and build products for Electronic Health Records and Clinical Information Systems. Pratyusha has done her Bachelors in Engineering (Comp. Sc) from Pune University, India and Post Graduate Diploma in Management from S. P. Jain Institute of Management & Research, Mumbai, India. About ArisGlobal ArisGlobal is the leading provider of integrated solutions for pharmacovigilance and safety, regulatory affairs, clinical research and quality and compliance for medical inquiries. Life science companies using ArisGlobal s solutions can better build and maintain the trust they need with their customers, medical practitioners and regulatory bodies around the world ArisGlobal LLC. All rights reserved. The ArisGlobal logo is a registered trademarks of ArisGlobal in the US Patent and Trademark Office and other jurisdictions. Other marks may be trademarks or registered trademarks of their respective owners and are acknowledged as such.the information you see, hear or read on the pages within this presentation, as well as the presentation s form and substance, are subject to copyright protection. In no event, may you use, distribute, copy, reproduce, modify, distort, or transmit the information or any of its elements, such as text, images or concepts, without theprior written permission of ArisGlobal. Trademarks, service marks, and logos (collectively the trademarks ) displayed on the pages within this booklet, are the property of their respective owner. No license or right pertaining to any of these trademarks shall be granted without the written permission of ArisGlobal, LLC (and any of its global offices and/or affiliates). ArisGlobal reserves the right to legally enforce any infringement of its intellectual property, copyright and trademark rights 17