Drug Product Registration Processes

Drug Product

Registration

Processes

ABSTRACT

Regulations in the US and Europe require technologies for registration of medicinal products in a structured format to facilitate inspections, safety tracking and licensing. The US Food and Drug Administration (FDA) system is based on a technology called “Structured Product Labeling” and is used in Drug Registration and Establishment Listings (DLER). The European Medicines Agency (EMA) has built a system primarily for pharmacovigilance, called Extended EudraVigilance Medicinal Product Dictionary (XEVMPD), which was instituted in 2012 based on an earlier, simpler format.

Both of these provide a bridge to a 2012 ISO standard called Identification of Medicinal Products, or IDMP, which is expected to go into production use in 2015 or 2016. While there are features in common to all three, there will be a significant effort required to provide a system that can migrate the required data to the international standard.

All biopharmaceutical companies will need to update the existing databases to the new standard. For the current standards, companies have been driven to create one-off registration documents in the specific formats, requiring long-term

relationships with vendors familiar with the standards. However, that process does not build the knowledge base within the company.

This paper addresses the requirements of the two current and one future

standard, as well as the processes used by pharmaceutical companies to maintain such information, and suggests best practices for maintenance of such databases within a company.

A key outcome is a solution architecture and set of processes for knowledge structures that would permit creation of SPL/DLER, XEVMPD and IDMP product registrations from a common set of data. This impacts a variety of roles throughout a company including obtaining, verifying and maintaining data.

Joel Finkle

CSC

[email protected]

CSC Grants

March 2013

DRUG PRODUCT REGISTRATION PROCESSES

TABLE OF CONTENTS

1 BACKGROUND ... 1

1.1 Business Case for Drug Product Registration ... 1

1.2 Product Terminology ... 2

1.3 Regulation and Implementation ... 2

1.4 CSC Current Offerings ... 3

2 DATA FORMATS FOR DRUG REGISTRATION ... 4

2.1 SPL Data Listings and Establishment Registration (DLER) ... 4

2.2 Extended Eudravigilance Medicinal Product Dictionary ... 5

2.3 Identification of Medicinal Products (IDMP) ... 7

2.4 Commonalities and Differences ... 25

3 CHALLENGES FOR IDMP IMPLEMENTATION ... 27

3.1 Substance Registration ... 28

3.2 Data Ownership ... 28

3.3 Data Maintenance ... 29

4 DRUG SPONSOR COMPANY PROCESSES ... 30

4.1 Regulations ... 30

4.2 Data Maintenance Processes ... 30

4.3 Message Authoring ... 31

4.4 Registration Process ... 31

5 DRUG SPONSOR REQUIREMENTS ... 33

5.1 Consulting and Other Strategic Services ... 33

5.2 Conversion and Authoring Services and Tools ... 34

5.3 TRS Tracker and other Total Regulatory Solution software ... 34

6 CONCLUSIONS ... 36

7 BIBLIOGRAPHY ... 38

LIST OF FIGURES

DRUG PRODUCT REGISTRATION PROCESSES

LIST OF APPENDICES

APPENDIX A : COMPARISON OF DATA ELEMENTS ... 41

Appendix A-1 : Medicinal Product (ISO 11615) ... 42

Appendix A-2 : Pharmaceutical Product ID (ISO 11616) ... 52

Appendix A-3 : Structured Substance (ISO 11238) ... 55

APPENDIX B : ENTITY RELATIONSHIP MODELS ... 68

Appendix B-1 : TRS Tracker Data Model ... 68

DRUG PRODUCT REGISTRATION PROCESSES

1 BACKGROUND

1.1 Business Case for Drug Product Registration

Current regulations in the US and Europe require substantially different technologies, terminologies and vocabularies for registration of medicinal products that are approved for use in human medical treatment, or for clinical trials. Registration of medicinal products is part of the licensing process, and is a paper activity in most countries. Europe and the US are ahead of the game by having electronic file formats specific to the drug product registration.

By providing an electronic medical products “dictionary,” the regulatory agencies are able to swiftly follow up on cases of counterfeiting, illegal import, contamination, patient safety, and supply shortages, as well as maintain the inspection audits of establishments involved in the manufacture, quality testing, packaging, import and distribution of medicines.

It is also worth noting that one of the major industry is for monitoring of drugs across classes and geographies rather than as discrete marketed products. This means that not only do market authorisation holders have to provide internally consistent data but also they need to provide data that can be sensibly aggregated with data from other companies for other products in other markets. 1.1.1 TECHNICAL CONSIDERATIONS

It is important to note that the message formats used by the electronic standards are designed for consumption by an agency, and do not necessarily reflect the processes used by pharmaceutical companies for maintaining that information.

In the US, the FDA requires a “Drug Registration” and an “Establishment Listing”, both of which are based on the HL7-developed standard “Structured Product Labeling” (SPL). These describe the product, and the facilities in which it is manufactured, imported, and otherwise processed. In Europe, the EMA initiated a new standard in 2011 called Extended Eudravigilance Medicinal Product Dictionary (XEVMPD), with a requirement that all marketed products be registered with the agency by July 2012 for the purposes of rapid access to a database of products in the case of safety issues.

The two systems have many features in common, and a number of items that are unique to each. 1.1.2 INTERNATIONAL APPROACH

A third system, IDMP (IDentification of Medicinal Products) was approved in November of 2012 as an ISO standard (actually five standards, see below). IDMP was developed as an outgrowth of the Common Product Model (CPM) at HL7, so it has many features in common with SPL. The European XEVMPD standard has been stated as having a sunset date of when IDMP becomes implemented. This is estimated at 2015 or more likely 2016.

All biopharmaceutical companies will need to update existing databases to the new standard. If previous regulatory agency behavior is followed, a short (less than one year) period to adapt to the new standards will be granted for all companies to register all existing products.

For previous standards initiatives, companies have been driven to create one-off registration documents in the specific formats (SPL and XEVMPD), often requiring long-term relationships with vendors familiar with the standards, but this does not build the knowledge base within the company. Development of a process for maintaining and messaging the information would improve the value of the information within customers’ enterprise knowledge warehouses, and improve their bottom line through the use of fewer contracted services to create and maintain such registration data.

DRUG PRODUCT REGISTRATION PROCESSES

Among the cases used to justify the system that will improve patient health and safety include:

• Tracking abused drugs – Realization of the level of Oxycontin abuse led to changes in its formulation to make it less appealing when a crushed tablet is inhaled.

• Product Labeling and Packaging – the accidental overdose of heparin in actor Dennis Quaid’s children has led to changes in how products are packaged and labeled (different dosage strengths now have different color labels on the bottles)

• Avoidance and mitigation of drug shortages (e.g. temporary importation from another country of the same product with a different approval number)

• Tracking drugs used in clinical trials may permit mining trial data for new uses (such as previous side effect), and tie efficacy and safety to genotypes

• Tracking generic drug usage, since generic drugs are now 80% of medicines used (but only 20% of the dollars spent), but having the same name with different manufacturers makes it difficult to gather the sum of any substance’s usage.

1.2 Product Terminology

The data standards used for drug product registration include a number of similar terms which can be difficult to distinguish. They build on top of one another, and occasionally loop back into recursive structures.

The key thing to understand is the set of layers of the product definition. The product registration systems at various agencies are concerned with tracking a product for such reasons as ensuring supply, ensuring that supply is genuine and uncontaminated, and tracking any issues with using that product. For that reason, it is necessary to distinguish between what is administered to a patient, as a different thing from what is sold by the sponsor, but both have their own means of unique

identification.

• MEDICINAL PRODUCT: This is a product administered to humans (or animals) for treating, preventing, diagnosing disease or restoring, correcting or modifying physiological function. The Medicinal Product is the form of a dose of the product as sold. It may have multiple components or ‘manufactured items’ and one or more ‘pharmaceutical products.’Invalid source specified.

• MANUFACTURED ITEM: This is the description of a product contained in the packaging of the Medicinal Product. Invalid source specified.. The manufactured items may include administration devices such as syringes.

• PHARMACEUTICAL PRODUCT: This is the version of the product as administered. The ISO standards described below define this as “qualitative and quantitative composition of a Medicinal Product in the dose form approved for administration in line with the regulated product information.’Invalid source specified.. In many cases, this may be the same as the Medicinal Product (e.g. a tablet), in others (e.g. a powder and solution which must be combined), a process is needed before it can be administered. In a small number of cases, there may be multiple pharmaceutical products in a medicinal product package: an antibiotic tablet packaged with a topical cream is two pharmaceutical products.

• PACKAGED MEDICINAL PRODUCT: This is the product as soldin its outermost container, e.g. a bottle of tablets, or a carton containing vials. The packaging is typically marked with an identifier of what batch it came from, to assist in tracking quality or safety issues in the product.

• PACKAGE ITEM: A Packaged Medicinal Product may contain multiple package items, such as vials or blister packs, which have their own containers. This may have several nested layers (e.g., a vial in a pouch in a carton). At the bottom level, these will contain

Manufactured Items.

1.3 Regulation and Implementation

Currently, only the US and the European Union members of the European Medicines Agency have a standard electronic data format for drug listings. These formats are rather different from each other,

DRUG PRODUCT REGISTRATION PROCESSES

partly due to differences in how the data is used, and the timing of the standards: the US has a focus on inspection of manufacturing and processing facilitiesInvalid source specified.), the EMA format was designed as a stopgap until the IDMP standard became available.

The Identification of Medicinal Product (IDMP) standard will be adopted by all three regions participating in the International Conference on Harmonisation (ICH) – adding Japan to the above US and EU countries. In addition, because it is an ISO standard, other jurisdiction are more likely to adopt an existing standard than design one from scratch. Countries that have followed ICH guidance for other electronic standards include Canada, Switzerland, and Australia for marketing applications, with influence also seen on the standards used in Russia, China, Southeast Asia (ASEAN countries), South America and the Gulf Cooperation Council. The ISO ICSR standard which is being

implemented through ICH group E2B is will be used in Australia as well as the ICH partner nations. It is expected that the US and EU will move to the IDMP standard within about two years after the development of implementation guides. Since the ICH guidance is expected in March of 2013, with regional guidance following shortly after, this should be in 2015 or 2016. It is unknown at what speed sponsors will be required to meet the new standard, but past experience has shown that agencies may be insensitive to the costs of rapidly implementing a new standard: The initial implementation of SPL for the Content of Labeling in 2005, and the update to the Physician’s Labeling Rule format in 2006 provided less than a year between distribution of the final guidance and required use. Similarly, the XEVMPD standard in the EU was announced in September 2011 for implementation by July of 2012, but the final version of the standard was not made available until March of 2012 – a mere four months prior to the deadline.

The short timeframes between final issuance of guidance and the requirement to comply mean that service and software companies will need to prepare services, software and related training and implementation services prior to the final guidance and implementation guides, with anticipation of last-minute changes to those products.

1.4 CSC Current Offerings

The Life Sciences groups within CSC offers the following services and software related to drug registration dictionaries:

• SPL Conversion Services –The Regulatory Services group provides translation from Word and other formats into SPL for Content of Labeling and DLER.

• Regulatory Information Management Consulting – the author has been assigned to contracts involved in implementing Regulatory Information Management systems for clients. Other consultants have been involved in implementation of TRS Tracker, XEVMPD

implementation, and data gathering in Europe.

• TRS Tracker Software and Implementation – Version 5.2 of TRS Tracker can produce reports on the Drug Product Tracking database that can be used to create XEVMPD records in the EVWEB system at EMA (see below), and create XEVMPD records directly

TRS Tracker can also be extended in the future to deliver IDMP messages, and with small changes could be delivering SPL DLER today (although content of labeling would be a significantly different effort).

DRUG PRODUCT REGISTRATION PROCESSES

2 DATA FORMATS FOR DRUG REGISTRATION

The following sections detail the data formats of the three registration standards, and how their concepts build on each other. While the level of detail is daunting, the introductions and summaries of each section are valuable for understanding the implementation requirements, and the scope of work that medicinal product manufacturers will need to go through to implement these requirements.

2.1 SPL Data Listings and Establishment Registration (DLER)

The Structured Product Labeling format was developed in 2004 by Health Level 7 (HL7) for FDA’s use, initially for the content and format of labeling. Release 3 was the first version required for use by the public, and Release 4 (SPL R4) was developed specifically to send structured data for Drug Listings and Establishment Registrations (DLER)Invalid source specified.. Per Section 510 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), it is required for “firms that manufacture, prepare, propagate, compound, or process drugs in the U.S. or that are offered for import into the U.S. to register with the FDA. These domestic or foreign firms must at the time of registration, list all drugs manufactured, prepared, propagated, compounded, or processed for commercial distribution in the U.S. Foreign establishments must identify a U.S. agent at the time of their registration.”Invalid

source specified..

The Drug Listing file is designed to replace the previous paper FDA forms 2657 and 2658, and includes the following information from those forms:

• Name of establishment(s) manufacturing or processing the listed drug and the type of operation(s) performed;

• DEA schedule;

• Route(s) of administration;

• Inactive ingredients;

• Marketing information (e.g., category, start/stop date);

• Information related to the application (e.g., type and year of approval) or OTC monograph citation number;

• Package size and type.

In addition to the information required on the older paper forms, the Drug Listing SPL file also includes:

• NDC Product Code for the Source Drug Repacked or Relabeled

• Unique Ingredient Identifiers (UNII)

• Data Universal Numbering System (DUNS®) Number for establishments and sponsor

• Confidentiality Flag

• Distinctive Characteristics (flavor, color and an image of solid dosage forms) The Drug Listing and Establishment Registration may be created using the FDA-supplied E-Submitter tool, or delivered directly through the Electronic Submission gateway.

Although the SPL format is also used for the Content of Labeling, the Drug Listing and Establishment Registration does not include the sections that include the narrative labeling document. One of the criticisms of the SPL format is that it has a lot of complexity, but each document type uses only a portion of that total complexity. While that makes each document type manageable, it makes using standard XML technologies such as Microsoft Office tools extremely difficult, as the applications can not differentiate between the document types.

Approximately 8000 compounds in 50,000 unique packages are registered in SPL.Invalid source

DRUG PRODUCT REGISTRATION PROCESSES

has managed to reduce this from 1600 separate labels in the old format to a mere 11 on eight compounds.

The most recent version of the SPL standard, Release 5, also includes structures for Device Listings. Compared to the product models in section 1.2, it’s not as complete: The Pharmaceutical Product concept is not included as a separate concept, and there is no detail on package items or

manufactured items that are subsets of the whole.

2.2 Extended Eudravigilance Medicinal Product Dictionary

The XEVMPD message format is called Extended Eudravigilance Product Report Message (XEVPRM). The format’s initial specifications as part of EMA Article 57, issued in September of 2011, were extensive. With a requirement to implement by July 2012, many pharmaceutical companies complained that the requirements were beyond reasonable costs of implementation, especially the information required for the “structured substance information” (SSI), which specified detailed information about active and inactive substances in each product. Coupled with this was the problem that many of the controlled vocabularies, and details on implementation of parts of the standard, had not yet been provided. This would have greatly increased the risk that sponsor organizations would not be able to comply.

EMA, however, was limited by European Union legislation, and could not delay implementation of the Eudravigilance medicinal product dictionary. The only options available were to (a) reduce the requirements to a minimum, and (b) have a flexible attitude to enforcement of compliance. The latter is significant because EMA could have removed products from the marketplace from sponsors that had not filed the XEVPRM data by July 2, 2012, but did not.

Updated specifications were issued in March of 2012Invalid source specified. – just four months prior to the deadline for submission. These updated specifications were based mainly around a subset of the requirements of the EMA Summary of Product Characteristics (SmPC)Invalid source

specified.. It should be noted that the SmPC includes preclinical safety data, shelf life and

Contra-indications, none of which are required by XEVMPD.

Each approved or investigational (development) product must be submitted to each country where it is marketed, in every official language of that country. The XEVPRM standard is designed as a single message (plus an acknowledgement message format from the agency) that indicates items to be registered, or changes to existing registered items. The types of items that can be registered or changed include:

• Approved or Development Products

• Approved or Development Substances

• Organisations (e.g. Sponsors, Regulatory Authorities)

• Attachment Files

• Master File Locations

• Sources for information references

• Updates to controlled vocabularies: ATC Codes, Pharmaceutical Dose Forms, and Administration Routes

Each new item registered is sent with a “local key”, and the acknowledgement message will assign an official “EV Code” which is to be used for all future references to that item. Some items such as Attachments are meant to only be submitted, never modified – instead, a new file is submitted with its own code if an attachment such as labeling or the SmPC document is sent. The use of EV Codes enables references to substances. In other words, for the item types listed above, other parts of the XEVPRM message can just use the code, and not completely specify the entire set of data each time

DRUG PRODUCT REGISTRATION PROCESSES

and place where it is used.a Each place where EV Codes are used also requires indicating whether it is a local or EV-issued (called the Resolution Mode), and previous codes used by the same item. Development and Approved Substances in EVPRM specify the following items:

• A valid reference source for the substance name

• The English name of the substance

• The Chemical Abstracts Service (CAS) Number (optional)

• The molecular formula (optional)

• The class of the substance (e.g. chemical, protein, etc.) (optional)

• The Chemical Biological Description (CBD) (optional)

• Translations and Aliases of the substance name

• International Codes used to identify the substance

• Attachments such as the Printed Substance Information

• Structured Substance Information (optional)

Development and Approved Products in EVPRM specify the following items:

• Sponsor or Market Authorisation Holder information

• Reference to the Qualified Person for Pharmacovigilance (QPPV) location

• Contact Information

• Market Authorisation, which consists of

• Country

• Procedure

• Status

• Number

• Authorisation and Withdrawal Dates

• MRP Number

• EU Number

• Orphan Drug Status

• Intensive Monitoring Status

• Presentation Name

• References to ATC Codes

• Indications

• Attachments

• Pharmaceutical Product information, consisting of

• Reference to the Pharmaceutical Form Codes

• Administration Routes

• Active Ingredients

• Excipients (optional)

• Adjuvants (optional)

• Medical Devices (optional and rare, such as cell scaffolding)

The EVPRM model aligns closely with the product model in section 1.2. It includes the

Pharmaceutical Product and Medicinal Product concepts, although its packaging information is scant.

a

It is unfortunate that the same approach was not also applied to the XEVMPD documentation, as repeated sections such as references are described in identical detail every place they are used, increasing the size and

DRUG PRODUCT REGISTRATION PROCESSES

As of September of 2012, EMA had received 229,401 XEVPRM messages, but had not yet acknowledged 20% of the total messages. This covered 236,827 products – much less than the 450,000 expected. Some of this is based on backlog of registration of applicants.

The EVPRM messages are sent to EMA by one of two methods: if the Market Authorisation Holder/Sponsor has capabilities to create the XML, files may be submitted via the EMA Gateway. This provides for greater efficiency, but requires more technical expertise on the part of the drug’s owner. Otherwise, the EVPRM messages may be created – and eventually maintained – through the EVWEB interface, a web-based application that permits entry of all information in the EVPRM data structure. This can be tedious for creating multiple records but requires little technical expertise. EMA offers an online course for using EVWEB as a series of videos on YouTube, and in fact requires the course to be taken before certifying staff for use of the system.Invalid source specified. An area which has made penetration of the service market for EVPRM difficult is that software and service vendors are not granted access to the production or test EVWEB or Gateway systems except on behalf of a market authorisation holder. As of the most recent Article 57 EMA meeting, EMA has stated that they will reconsider this position.

One of the challenges of the XEVMPD system is that EMA has spent a lot of time and effort getting compliance with the initial submission, but as of this writing has not yet completed guidance on updates to drug product information. For instance, they have stated that most updates should be done within 30 days of a change to the approved product (close of the procedure). However, they have not stated if it is necessary to send all changes or only those that require prior approval or waiting period processes, or also those that use the “do and tell” process. Those changes that are ordinarily immediately implemented and communicated to the agency within twelve months may end up requiring a more-immediate XEVMPD submission.Invalid source specified. Formal guidance on maintenance of data is not expected until March or April of 2013.

2.3 Identification of Medicinal Products (IDMP)

The IDMP standard began in 2003, with a primary goal to align it as a set of identifiers for use with the ICSR (Individual Case Safety Report) standard for safety reporting. It was approved as a set of ISO standards in November of 2012:

• ISO 11238:2012: Health informatics — Identification of medicinal products — Data elements and structures for the unique identification and exchange of regulated information on

substances Invalid source specified.

• ISO 11239:2012: Health informatics — Identification of medicinal products — Data elements and structures for the unique identification and exchange of regulated information on

pharmaceutical dose forms, units of presentation, routes of administration and packagingInvalid source specified.

• ISO 11240 2012: Health informatics — Identification of medicinal products — Data elements and structures for the unique identification and exchange of units of measurement Invalid source specified.

• ISO 11615:2012: Health informatics — Identification of medicinal products — Data elements and structures for the unique identification and exchange of regulated medicinal product informationInvalid source specified.

• ISO 11616:2012: Health informatics — Identification of medicinal products — Data elements and structures for unique identification and exchange of regulated pharmaceutical product information Invalid source specified.

For the sake of brevity, these will be referred to throughout this document without the “2012” suffix, which only indicates the year of approval.

DRUG PRODUCT REGISTRATION PROCESSES

The standards were developed as an expansion of the Common Product Model at Health Level Seven (HL7). This builds on the technology and experience of the SPL standard, and the Common Product Model is used at the heart of many health standards to describe medicinal products. The five standards build from basic concepts up through the full Medicinal Product definition. ISO 11239 is essential for understanding the concepts of dosage forms, units of presentation, routes of administration, and packaging, which are used in the ISO 11615 standard. ISO 11240 specifies the methods of communicating units of measurement, used across the rest of the standards in the set. ISO 11238 is a detailed definition of how to describe a substance (active or inactive) that is used in making up a medicinal product, from its chemical structure to its methods of manufacture, and is referenced in ISO 11615 and 11616. ISO 11616 is relatively brief: it covers only a set of identifiers used to describe the pharmaceutical product, which is the administrable form of the medicinal product. Lastly, ISO 11615 is the over-arching specification for the medicinal product, which references all of the other standards.

The primary purpose of IDMP is to create the authoritative identifiers for a medicinal product within a given regulatory authority’s jurisdiction. The specific case it was created for is the ICSR standard created by HL7, approved as ISO 27953-2:2011Invalid source specified. and implemented by

ICHInvalid source specified.. By having a definitive identifier for a packaged product within each

participating country, it should be possible to trace patterns in adverse drug experiences and gather statistics on where labeling should be changed, or products withdrawn. Because ICSR was approved before IDMP was completed, ICSR was implemented without requiring an IDMP identifier in their messages. After IDMP is implemented, ICSR will likely change to mandate the use of the Medicinal Product Identifier (MPID – see below).Invalid source specified.

2.3.1 UNITS OF MEASUREMENT (ISO 11240)

ISO 11240 builds on the earlier ISO Guide 99:2007, which describes the SI (International System) of units, and creates data structures for communicating values and units for electronic

messaging.Invalid source specified. Distinct in the ISO 11240 methodology is splitting the unit type (e.g. “grams”) from the scale (e.g. “milli”), so instead of just measuring in “mg”, the standard specifies “M” and “G” as separate terms.

There are three additional concepts crucial to measurements for medicinal products: 1. Ratios of measurements. This is typically in the form of a numerator quantity per

denominator units, e.g. 5 mg/ml, which should technically be 5 mg per 1 ml.

2. Units of Presentation. For many dosage forms, the form itself is a single object, which means that the strength of a product might be expressed as “per tablet” or “per spray.” This is the presentation unit, and is an used instead of the denominator unit mentioned above. 3. Reference measurements. Some products are formulated as, for instance, a salt of a drug

substance. In cases such as this, the measurement may be expressed both as the absolute (e.g. 300mg of Lithium carbonate), and its reference substance (12.2 mmol lithium). There are other reference measurements such as a particular measurement procedure.

These concepts are critical underpinnings of the Substance (11238) and Medicinal Product (11615) portions of the standard. The EVMPD uses a very similar data structure for measurements, but does not include the reference measurements as part of the standard data structure. The SPL R4 Drug Listings do not use the above means of specifying units or reference measurements.

2.3.2 ADMINISTRATION AND DOSAGE FORM TERMINOLOGY (ISO 11239)

The Product definitions describe the packaged and consumed items, but additional information is needed to describe how a product is prepared for use, and how it is actually used. This is as simple

DRUG PRODUCT REGISTRATION PROCESSES

as a tablet, or as complicated as a powder and solution which must be combined, placed in a syringe, and then injected in a particular location.

The primary dose form information is a coded value, which will be supplied as a controlled

vocabulary as part of the ICH Implementation Guide. The dictionary for dose forms is defined in ISO 11239 to further classify each value with a Basic Dose Form (e.g. “Tablet” versus “Extended Release Tablet”), Release Characteristics (the “Extended Release” portion), Transformation (e.g. dissolution of the powder in a solvent for a “Powder and Solvent for Injection”), Intended Site (e.g.

“intramuscular” for an injection dose form), and Administration Method (e.g. “injection”). Not all dose forms will use all five modifiers. Because existing standards of SPL and XEVMPD have different dictionaries for dosage form and administration method, these modifiers will assist in mapping one IDMP to many XEVMPD or SPL forms, or one SPL or XEVMPD to many IDMP forms.

In addition, there are combined dose forms, where multiple dose forms listed above are transformed into a single administrable form For example, a powder may be packaged with a vial of solvent, to be combined as a “powder and solvent for solution for injection.”

It also defines the structures for the packaging class, which includes a container, its closure, and administration devices. At a minimum, there is a Packaging Category (a coded value), but it can be subdefined by one or more of the closure (“screw-cap”, “stopper”), container (“box”, “ampoule”) and administration device (“needle”, “oral syringe”) categories.

ISO 11239 also defines the controlled vocabulary that will be created for units of presentation, and the Route of Administration controlled vocabulary structure. Invalid source specified.

2.3.3 SUBSTANCE DEFINITION (ISO 11238)

Unique in the ISO IDMP standards, 11238 does not have an approved message format that is already in use: There is no existing standard for substance specification. The XEVPRM format originally included one, but it was made optional: not only was it removed from the most recent guidance, to this author’s knowledge, it has not been implemented by drug sponsors. The US drug listing sections require nothing more than the identification of the substances, not a description of them, using the Unique Ingredient Identifier (UNII). In the US, the existing Substance Registration System consists of data entered by National Library of Medicine staff, based on drug submissions – it’s a system designed for use by experts to exactly match their specificationsInvalid source

specified., which can then be downloaded from the NLM website.Invalid source specified. From

this system are issued the Unique Ingredient Identifiers.

It is anticipated that the NLM system will become the basis for the international Substance Registration System used by IDMP, with the difference that the data will be supplied by the drug sponsor. It is not clear who is responsible for substances off patent or for common, inactive substances (water, corn starch and silicon dioxide, for instance). The current systems at the US National Library of Medicine used for maintaining the UNII identifiers are proprietary, and would do not provide information in publicly available formats. The UNII provides a unique, easy to validate identifier, and is likely to remain the ISO 11238 identifierb – although its name may change. A key benefit of the centralization of substance IDs will be that companies will have an alternative to the expensive commercial registration of a CAS Number.

Currently, countries may maintain their own substance systems. Germany has a system with 41,000 unique substances and 182,000 names. The US system is of a similar size (50,000 compounds), but not all items are the same, due to the substances which are regulated, and local pharmacopeias.

b

DRUG PRODUCT REGISTRATION PROCESSES

ISO 11238 specifies the following information be provided for each active or inactive substance. Invalid source specified.

• For all substances

• A Substance ID will always be listed. Without an implementation guide, it is unknown how new substances will get identified. It is likely a mechanism similar to the EVMPD “local key” will be used.

• Some substances may be subclassed into Specified Substances, indicating substances not easily otherwise defined, or specific versions of a substanceInvalid source

specified.. Specified substances may be specific to a regional authority, such as a

country’s pharmacopaeia’s registry. Note that Specified Substances are not yet part of the US SRS.

• Group-1: Multiple-substance materials, such as allergenic and herbal extracts

• Group-2: Manufacturer and minimal manufacturing information

• Group-3: Graded materials (US Pharmacopeia, European Pharmacopeia, technical, standardized substances)

• Group-4: Detailed manufacturing information

If a substance is described as a Specified Substance, it will have a Parent Substance ID – Group 4 can have a parent of any of the others including a non-specified substance, Groups 2 and 3 can have a parent of Group 1 or a non-specified substance, and Group 1’s parent would only be a non-specified substance.

In some cases, the use of a specific specified substance is critical: The source of a starch, for instance corn versus potato, could affect the allergenicity of a product. Product manufacturers should be encouraged to use as specific a substance as possible.

• Detailed Name information is provided, including the official names specific to each jurisdiction (in other words translations), and reference sources for each name (e.g. US Pharmacopaeia)

• Structure information, including optical activity, molecular formula, attachments further describing the structure, and isotope information for radiolabeled compounds indicating what atoms are substituted with which nuclides.

• Where needed, Modification information, which describes how a substance is changed from a basic form. This can include any number of modifications, which may be physical, structural, or agent modification.

• Where needed, Reference information which includes classification of the substance, gene or gene elements that are the source of the material, and the target gene to be affected, and relationships with other substances. Each of these items may have a reference source.

• Source Materials, optionally indicating the organism (and specific parts or fractions) from which the material is obtained

• For Chemical Substances

• Stoichiometric Information

• Comments

• Properties (type, name, ID, reference substance name and amount)

• Moieties (Role, ID, Name, and Amount)

• Reference Sources

• For Protein Substances

• Protein Sequence Type

• Subunits (sequence, length, terminal modifications)

• Comments

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• Molecular weight (may be multiple if different methods are used)

• Properties

• Glycosylations (of N, O and C type)

• Reference Sources

• For Nucleic Acid Substances (DNA, RNA)

• Nucleic Acid Sequence Type

• Subunits (sequence, length, terminal modifications)

• Comments

• Molecular weight (again, may have multiple if different methods are used)

• Modifications, if any

• Properties

• Reference Sources

• Polymer Substances

• Polymer Class (e.g. homopolymer, copolymer)

• Polymer Geometry (e.g. linear, branched, network)

• Sequence type (random, block, alternating)

• Comments

• Monomers (ID, name, amount)

• Structural Repeats (orientation of polymerization, degree of polymerization)

• Molecular Weights

• Source Materials, optionally

• Modifications, if any

• Reference Sources

• Properties

• Structurally Diverse Substances (e.g. extracts from biological sources that cannot be enumerated, such as orange oil, cells and tissues)

• Comments • Molecular Weights • Source Materials • Modifications, if any • Glycosylations • Properties • Reference Sources

• Mixture Substances – These are essentially just lists of other substances

• Two or more Constituents (ID, Name, Requirement)

• Mixture Type

• Source Materials

• Modifications

• Specified Substances Group 1

• Constituents (Substance ID, Name, Role, Amount)

• Properties

• Physical Form (State, Form-Type, Amount)

• Reference Sources

• Specified Substances Group 2

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Critical Process Version Number, Reference Sources)

• Specified Substances Group 3

• Parent Substance

• Grade (Type, Name, Reference Source)

• Specified Substances Group 4

• Parent Substances

• Grade (Type, Name, Reference Source)

• Analytical Data (Specifications, jurisdictions for a specification, analytical method, values, reference sources)

• Constituents (Substance ID, Name, Role, Amount)

• Properties

• Physical Forms (State, Form-type, Amount)

• Manufacturing (more detailed than Group 3, includes resultant materials, processing materials, starting materials, processing equipment)

• Reference Sources

How that substance is used is specified in the product: for example, Dextrose may be an inactive ingredient in a tablet, but the active substance in intravenous nutrition.

2.3.4 PHARMACEUTICAL PRODUCT ID SETS (ISO 11616)

ISO 11616 is relatively brief, defining a sub-structure that is part of the ISO 11615 Medicinal Product. It weaves the concepts of the substances and specified substances of 11238 plus the dosage forms of 11239 and the units of measurement and reference strength of 11240. This set of identifiers is used to describe the administrable product form, after any reconstitution or transformation of the Medicinal Product.

A single Pharmaceutical Product ID Set (PhPID Set) will be described in terms of a set of active ingredients: either substances or specified substances, with an optional device (e.g. a cell substrate framework), and sub-IDs for the product with strength and unit of presentation, the administrable dose form, and both the dose form and strength. Each of the sub-IDs includes a set of substances, each with a role (active, inactive, adjuvant), and a reference strength.

The PhPIDs are generic for a given clinically equivalent product: product alone, product and dosage form; product and strength; and product, dosage form and strength. This enables tracking safety issues for, for instance, 325 mg aspirin tablets, aspirin of unknown dose, or aspirin of 325 mg of unknown dosage form, etc., all regardless of brand.Invalid source specified. It would be expected that all aspirin tablets would include two common PhPID in their sets (aspirin, aspirin tablet); all 325 mg dosage forms would have two common IDs (aspirin, aspirin 325 mg regardless of whether it’s a tablet, a capsule, or a gelcap) and so on. A similar concept exists in previous standards: The SNOMED Clinical Terms document includes a “Non-Proprietary Medicinal Preparation”Invalid

source specified., and The US National Library of Medicine’s RxNorm has the concepts of

Semantic Clinical Drug (SCD), Semantic Clinical Drug Form and Semantic Clinical Drug Component.Invalid source specified.

It is still not clear why each of these PhPIDs must carry their own sets of ingredients – it would be just as effective to reference a common set of ingredients for the common Pharmaceutical Product. 2.3.5 MEDICINAL PRODUCT DEFINITION (ISO 11615)

The overall medicinal product in ISO 11615 combines all the concepts of the other four standards documents. Corresponding to the product model concepts presented in section 1.2, an approved

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medicinal product (or investigational product approved for clinical trials) would be assigned a Medicinal Product Identifier (MPID) or Investigational Medicinal Product Identifier (IMPID)c. Each packaging type (e.g. a 20-capsule bottle versus a 50-capsule bottle) would receive a unique (Investigational) Medical Product Package Identifier PCID (or IPICID).

Each batch of the outermost packaging, and each batch of any intermediate packaging would receive Medicinal Product Batch Identifiers (BAID_1 and BAID_2 respectively, with IBAID_1 and IBAID_2 for investigational batches). From any of those identifiers, the product can be immediately traced to determine its name, its marketing status, which Regulatory Authority authorized it, its composition (manufacturing, ingredients, dosage form, etc.), adverse experiences and Contra-indications, and other documentation.Invalid source specified. Currently, only biological products marketed in the US have batch IDs submitted to the FDA. It is unclear whether this would be expanded beyond biologicals.

The product information is organized hierarchically in two ways: For packaged items, the data is organized from the outermost to innermost contents, down to their ingredients. For the

pharmaceutical product that is actually consumed, data is organized from the administrable form down to the items that make up that form – those will be the same items as those specified in packages, although no linkage is provided between the two sets of of structures..

For the identification of a medicinal product, a change to any of the following items would constitute a different identifier:

• Product Name, Brand and Description

• Formulation (active ingredients)

• Strength

• Dosage or Usage

• Net Quantity (weight, volume or other dimension in a package)

• Packaging Configuration, including sub-packagingInvalid source specified.

The MPID must indicate the ISO country code, market authorisation holder and the medicinal product code. It is expected that existing local identifiers will continue, so the MPID for a product approved in the US would have a code of US + the market authorisation holder’s DUNS number + the product’s National Drug Code (NDC) number. Other jurisdictions have their own IDs that will be repurposed for the MPID including the RVG in the Netherlands and the EU Number for European centrally-approved products. New numbers would be assigned for situations such as changes to the strain used in each season’s flu vaccine, for a change to “over-the-counter” drug sales, in addition to any physical changes to the drug or its packaging.

The rest of the identifiers will be prefixed with the MPID, then append a package code, and for batch IDs, a specific batch identifier.

The overall data structure is indicated in Figure 1. This shows the relationship between the Medicinal Product itself, the names it has, the versions (this and any previous), manufacturing information, clinical particulars (Indications, Contra-indications and Adverse Events), pharmaceutical products, packaging, and market authorisations for the product and the packaged product. The detailed structure can be found in Appendix B-2.

c

It’s unknown why ISO and HL7 chose a completely separate structure for Investigational Medicinal Products, as there are few differences between them except for a few fields required in one but not the other. Note that EMA followed that lead with the EVPRM model also.

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Figure 1 – IDMP Data Model

Source: ISO Standard 11615:2012Invalid source specified.

The following subsections describe each of the boxes in detail, starting with the Medicinal Product itself and moving clockwise from the Medicinal Product Name.

2.3.5.1 Medicinal Product

The root object of the standard, the Medicinal Product, provides the broadest identification of the product:

MPID (IMPID) This is the identifier for the product or investigational

product. The standard specifies that the ID should always be provided, but does not specify what should be done on an initial filing, before the ID has been issued. For the IMPID, the number may include a regulator- or sponsor-provided code, depending on the jurisdiction.

Combined Pharmaceutical Dose Form

This is an optional field used only for combined products, such as “Powder and solvent for solution for injection.” IMPID/MPID Cross

Reference

The IMPID Cross Reference is used in non-investigational products, to refer to a previous investigational ID for the product. An Investigational product may have an MPID Cross Reference if being investigated in a different formulation, packaging or indication than the authorized product.

Sponsor Product Code This is found only in Investigational products. Either this or the Regulatory Product Code will be specified

Regulatory Product Code This is found only in Investigational products. Either this or the Sponsor Product Code will be specified.

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Paediatric Use Indicator This is found only in Investigational products, indicating whether this is a specific paediatric formulation.

Additional Monitoring Indicator

This is a safety monitoring term used in the EU, such as “Black Triangle”

Special Measures This is an optional field used to describe any additional steps that are still required as part of approval, such as

“Requirement to conduct post-authorization studies.” This is not found in Investigational Products

Medicinal Product Classification

One or more classification terms may be provided, listing both a code system and value, such as ATC (World Health Organization’s Anatomical Therapeutic Chemical system) DEA Schedule, etc. It is expected that ATC code will be required.

The Medicinal Product should not provide much difficulty to assemble. Except for the “chicken-and-egg” problem of getting the initial MPID, this all seems clear. The implementation guide is likely to specify a system similar to XEVMPD, where a ‘local key’ is provided and flagged as such, until the official number is issued, but the standard does not indicate any means of linking to an earlier local value the way XEVPRM does. This will likely be specified in the ICH implementation guide.

Note that many portions of the Medicinal Product structure have a near-duplicate structure for Investigational Medicinal Products. In implementation in a database, it may be more effective to have a single structure that can accommodate both the Investigational and Authorized Medicinal Products, with record-level validation to specify which fields are valid for Investigational versus Authorized products.

2.3.5.2 Medicinal Product Name

The Medicinal Product Name object permits multiple names to be listed for the product. There must be at least one. Each name may be associated with one or more countries and languages.

Name This is the full name of the product as it is labeled. This may include a number of components, as described below. The rest of the terms are optional “Parts” of the whole approved name, used to assist in positively identifying variations on a product. Examples are given below. For an investigational product, a code may be present instead of a name.

Code This is only found in Investigational Products if the product is only referred to as a code instead of a name.

Invented Name Part The brand or trade name. Typically either this or the scientific name will always exist

Scientific Name Part The generic name, typically the INN.

Strength Part Example: “Extra-Strength”

Pharmaceutical Dose Form Part

Example: “Easy-Swallow Gelcaps” Formulation Part Example: “Sugar-Free”

Intended Use Part Example: “Arthritis Pain Formula”

Target Population Part Example: “Children” (as in “Cough Syrup for Children”) Container or Pack Part Example: “Multidose Vial”

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Trademark or Company Name

The company name if it appears in the labeled name Time / Period Part Example: “2013” (as in ”Myvaccine Flu season

2012-2013”

Flavour Part Example: “Cherry”

Country / Language Includes the ISO codes for country, sub-country jurisdictions, and language, for example Canada / Quebec / French. Again, this should not be a difficult set of information to manage. EVMPD uses a similar, though less extensive structure.

2.3.5.3 Version

One or more version sub-objects can be specified that list the date of changes to the IDMP message and one or more regulated documents associated with that version. Jurisdictions may use this to provide the approval letter, Summary of Product Characteristics, etc. A key factor is that a new version must not be a change that would cause the creation of a new Medicinal Product, e.g. the marketing authorization, legal status of supply, name, dose form, ingredients, strength, device provided and indications.

Version Date Date at which the change occurred Version Identifier A text identifier

Regulated Document Document Type Document Identifier Regulated Document Document Effective Date

Associated documents, such as SmPC, Package Leaflet, Approval Letter, Content of Labeling, etc. The information provided includes the type, an identifier for the document, the document itself as an attachment, and the time period when the document became effective.

It will be interesting to see how much Version data must be provided for a product which has been on the market for some time, or if the regulatory authorities will only require the current version with the first IDMP submission. Another question will be whether documents need to be provided with each update to the IDMP message, or if they can be sent and registered once and kept “on file.” The XEVMPD solves this by having the documents be a separate category of objects with their own identifiers, and the product parts of the message only refer to the identifier of the document. 2.3.5.4 Manufacturer

The manufacturer information corresponds relatively closely to the US Establishment Registration, specifying locations, the operations they perform, and how those establishments were authorized for those operations. This information is optional for Investigational products.

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This includes an identifier (which may be an international ID such as DUNS), name, address, confidentiality, contact names and telecommunications codes (email, phone), and other addresses and their roles (e.g. Batch Release, Qualified Person for Pharmacovigilance [QPPV]).

Manufacturing Operation Operation Type Manufacturing Authorisation Reference Number Effective Date Confidentiality Indicator Medicines Regulatory Agency

One or more operations at the particular establishment. Operation Type may be items such as Batch Release, Re-Packaging, Re-Labelling, Manufacture, Testing.

The Authorisation Reference Number, Date and Agency reflect the authorisation to perform the operation.

This information should provide little stress to drug sponsors: It’s essentially similar to what is provided for the US Drug Listing / Establishment Registration, although this information is not required for XEVMPD.

2.3.5.5 Marketing or Clinical Trial Authorisation

The Marketing Authorisation is a more complex structure than the items above, containing sub-objects for periodic reporting, marketing status, and marketing authorisation procedures and applications. For Investigational Products, this is a clinical authorisation with slightly different information.

Marketing Authorisation Number

The ID number of the authorisation, which becomes part of the MPID. This may be a licensing number if there is no authorisation number (e.g. a grandfathered product) Country One or more countries where the authorisation applies. Legal Status of Supply This indicates the type of marketability, e.g. prescription or

over-the-counter. Only for authorized products.

Authorisation Status Status of the product, e.g. Active/Valid, Expired, Renewed, Not Renewed, Withdrawn. Only for authorized products. Authorisation Status Date The date at which the status changed

Validity Period Start and end date of the authorisation. Marketing Authorisation

Holder

This is the information about the organization that is

marketing the product, or in some cases the distributor. This is the same information provided for the

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Medicines Regulatory Agency

This is the information about the organization that has authorized the product. The same organizational information for the Manufacturer/Establishment applies here too.

Marketing Status Country Jurisdiction Marketing Authorisation Number Marketing Date (Start/Stop) Jurisidictional Legal Stats of Supply

This structure, while similar to the Marketing Authorisation, reports on when the product is actually marketed in each jurisdiction within the authorizing country if needed.

Marketing Authorisation Procedure Procedure Identifier Procedure Type Procedure Date Marketing Authorisation Application Application Identifier Application Type Application Date

If procedures are used (such as EU Centralized, Mutual Recognition and Decentralized Procedures), include the information about it here. It seems likely this may be used for other health authorities, as the Marketing Authorisation Application structure is within it, and would otherwise not be possible to add for a US application without this structure.

Periodic Safety Update Report Submission

Frequency of

Submission of Safety Report

Dates of Submission International Birth Date Reference Date Data Lock Point

This information specifies when Safety Update and Product Benefit-Risk Evaluation Reports must be filed. The

frequency may be complex, e.g. every six months during the first two years and once a year for the next two years.

The information for a Clinical Trial Authorisation is somewhat different:

Registration Number The ID number of the clinical trial registration, which becomes part of the IMPID.

Investigation Code This is the code for a particular trial.

Country One or more countries where the authorisation applies. Protocol Number The number assigned to the clinical trial protocol.

Authorisation Date The date at which the clinical trial authorisation was granted Anticipated End Date The date when the clinical trial is anticipated to be completed Sponsor This is the information about the organization that is the

sponsor to which the authorisation has been granted. This is the same information as a Manufacturer/Establishment above.

Medicines Regulatory Agency

This is the information about the organization that has authorized the clinical trial. The same organizational

information for the Manufacturer/Establishment applies here too.

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Local Clinical Trial Authorisation

Local Clinical Trial Registration Number Local Investigation Code Jurisdiction

Local Authorisation Date Local Anticipated End Date

This information is used for countries within a jurisdiction, such as countries within the European Union, and provides equivalent information to the overall Clinical Trial

Authorisation.

Drug Safety Update Report Submission

Frequency of

Submission of DSUR Dates of Submission Development

International Birth Date Reference Date Data Lock Point

This information is essentially the same as the authorized product’s Periodic Safety Update Report Submission information, but for pre-authorization safety update reports.

Although the information may be complex, it should be possible to compile this information without extensive effort. The only factors making this difficult is that such information previously would be maintained by local market companies, and not necessarily provided to a central regulatory database.

2.3.5.6 Packaged Medicinal Product

The Packaged Medicinal Product is something of a new concept compared to previous standards, which were more concerned with the sum of the parts than the individual pieces. Here, the product is described from outer package to inner, including their components, as it is sold or supplied. The packaged product has batch identifiers listing what has shipped, and containers which may have sub-containers. This information is optional for investigational products.

PCID / IPCID This is the overall identifier for the product as packaged. Each different package (quantity, packaging material) will have its own ID. The IPCID is for Investigational Product Packages

Package Description Text Description

Marketing Authorisation Same structure as the authorisation for the product – this may only be needed in situations where different packages have different authorisation requirements.

Batch Identifier BAID_1 / IBAID_1 BAID_2 / IBAID_2

This is the list of batch IDs for the innermost and outer packaging. The “I” versions are for batches of Investigational Products

Package Item A container of either other containers or manufactured products. See below for the full structure.

The Package Item is a complex structure in its own right. This can either be a single item, a package of different items, or a set of the same item. Each contaner may have subcontainers, and at the bottom level, manufactured items. In addition, each level may have its own storage conditions, its

DRUG PRODUCT REGISTRATION PROCESSES

own identifiers, packaging materials, and an application or integrated device. The manufactured items are where the individual ingredients are listed.

Package Item Type This is a coded item indicating values such as box, vial, pre-filled syringe, etc.

Package Item Quantity This is the number of this kind of item in the package enclosing it. The top-level Package Item always has a quantity of 1.

Material This is the substance that makes up the package, using an ISO 11238-registered material (e.g. cardboard).

Alternate Material If multiple materials are permitted for the package (e.g. plastic for a blister pack), they should also be listed. Physical Characteristics Height, Width, Depth, Weight, Nominal Volume, External

Diameter, Shape, Colour, Imprint, Image. Images are provided as attachments.

Other Characteristics Lists a code system and value for any other recorded characteristics

Shelf Life / Storage Shelf Life Type Shelf Life Time Period Special Precautions for Storage

Multiple shelf life periods may be listed for types of

“Unopened”, “After first opening”, “After dissolution” etc. The special precautions are coded information including

temperature, light and humidity descriptions. The time period will include a number and units (e.g. 3 years).

Data Carrier Identifier Code System Value

These are additional identifiers that may be on this particular level of product, such as a GTIN barcode.

Package (Component) Component Type Component Material Component Alternate Material Physical Characteristics

This is used for components of the packaging itself, not components of the product. Examples include closures, vials, etc.

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Device

Device Type Device Trade Name Device Quantity Device Listing Number Model Number Device Material Device Alternate Material Allergenicity Indicator Sterility Indicator Sterilisation Requirement Indicator Device Usage Device Nomenclature Nomenclature System Nomenclature Value Device Batch Identification Batch Number Expiration Date Physical Characteristics Other Characteristics Shelf Life / Storage Manufacturer

Devices will either be Administration (e.g. droppers or oral syringes), Integrated (pre-filled syringe), Medical Device (cell scaffold) or other (e.g. swabs) typeInvalid source

specified..

If there is a trade name, it should be listed. The quantity is always listed, even if 1.

Listing and model numbers should be listed where applicable.

Materials, like package materials, should be coded as ISO 11238 substances.

Allergenicity would be listed when it is a material of concern such as latex. The Sterility Indicator will specify both whether the device is provided as sterile, and whether it must be sterilized before use.

Usage indicates the number of times the device may be used, e.g. “For single use only”

Nomenclature may include any means of identifying the device, but should include the Global Medical Device Nomenclature (GMDN), which is ISO 15225, and the Unique Device Identification System (UDI).

Device Batches may be listed where applicable, including their expiration date and shelf life.

Devices may also have physical and other characteristics, and have a manufacturer similar to that of the product itself.

Manufactured Item Manufactured Dose Form Unit of Presentation Manufactured Item Quantity Physical Characteristics Other Characteristics Ingredient

This is the actual manufactured drug product, or one of them in the case of a combination product such as a pill plus external use ointment, powder plus solvent, or multiple antibiotics in one blister, etc. How they are combined is indicated in the overall pharmaceutical dose form, and in the Pharmaceutical Product structure below.

Each item has its own manufactured dose form.

For items not specified by weight or volume (in other words vials, powders, etc.), a unit of presentation (tablet, spray, etc.) should be listed.

The quantity is the number of items of this type in the container.

Physical and other characteristics may be specified here also.

The ingredient structure is described below,

The ingredient consists of either a substance or a specified substance, strength and optionally a reference strength. Its structure is used in the same way for both Manufactured Items and the Pharmaceutical Product (which is the combined set from all Manufactured Items).

Ingredient Role The role indicates whether the ingredient is active, inactive or adjuvant.

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The substance or specified substance will be listed as per ISO 11238 substance identifiers, 11239 units of presentation and 11240 units of measurement. The substance group and confidentiality indicator only apply to Specified Substances. Strength can be expressed as a range if needed (high, low and average), and a numerator and denominator each with its own units is included (for example, 5mg/ml is really 5 mg per 1 ml). Strength of presentation is the strength as

sold/supplied. Strength concentration is as administered. So if a 10mg envelope of powder is to be dissolved in 20ml of solvent, it would be expressed as 10mg/20 ml for

presentation, and .5 ml / 1 ml for concentration.

Concentration strength is only needed if the denominator of the presentation is non-unary – thus it is not needed for solid dosage forms.

The measurement point may be needed for items such as distance from an inhaler, per certain jurisdictions.

The country is used only with a measurement point. The reference strength may be needed if a medicinal product is measured per another product. The example given in the standard is 300mg Lithium Carbonate, which is equivalent to 12.2 mmol of lithium.Invalid source

specified.. The same features apply to the reference

strength as to the strength.

It is anticipated that the level of detail for packaged items will be very complex to represent, report and compile for submission to agencies. In particular, currently the only jurisdiction that requires reporting of batch identifiers is Germany’s BfARM, and only for biological medicines – this may prove to be a large burden for manufacturers.

Strength is currently only required for the active ingredient. FDA is suggesting that the strength (quantity) of an inactive ingredient be supplied, but would be marked confidential for public databases.

2.3.5.7 Pharmaceutical Product

The pharmaceutical product contains the sum of the ingredients in all the manufactured items in each manufactured product (note that if there are multiple pharmaceutical products such as a tablet plus topical cream, each has its own ingredient list), Routes of Administration, PhPID sets,

Characteristics, and optionally Devices – similar to the Device model in the Packaged Product, differing only in the lack of Shelf Life / Storage and Manufacturer information.

Administrable Dose Form This is the dosage form as consumed/applied to the patient or subject. It is frequently the same as the medicinal product, except where a transformation (e.g. dissolution of a powder) is specified

Unit of Presentation This is used when the product is not a measured weight or volume. Examples include tablet, spray, actuation, etc. For a vial or bottle, it is the container, not necessarily the single dose volume or weight.

Pharmaceutical Product Quantity

Expressed as a value and a unit, this is typically “1 unit” for solid dose forms. For items administered by weight or volume, this would be the amount and units, e.g. “10 ml”.

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(Dosing and) Route of Administration

Route of Administration First dose in humans Maximum single dose Maximum dose per day Maximum dose per treatment period Maximunm treatment period

One or more terms for how the medicinal product is applied. For authorized products, this is only the route of

administration. For investigational products it includes the full set of information about how the trial can be conducted

PhPID Set One or more PhPIDs as described in ISO 11616. There can be multiple sets, but it is not clear why one Pharmaceutical Product would have multiple PhPID sets.

Pharmaceutical Product Characteristics

These are code systems and values for the pharmaceutical product, as required by the regulatory authority (not specified in the standard)

Ingredients Described as in the previous section

Device Described as in the previous section, but the Shelf

Life/Storage and Manufacturer sections are not included. For a Pharmaceutical Product, devices are only included where the device is part of the applied/consumed product –

essentially an ingredient – and not the means of delivering it (like a syringe). The device most frequently described for this situation is cell scaffolding for a biologic product.

Except for the rare cases of the device, this is relatively straightforward. There are some annoyances to maintaining the ingredients both for the manufactured items and the pharmaceutical product, but again this is only significant if there are differences between the manufactured and pharmaceutical products – combination packs or items that must be transformed in some way. Most products should be straightforward to construct.

It is curious why the dosing information is not required for authorized products, since it would still be part of the package label in most countries.

What may be missing from this standard is a hard linkage between the manufactured products and the pharmaceutical product it makes up. While it’s pretty clear to a human being that a “powder and solvent for solution for injection” contains a powder and a vial of solvent, a (theoretical) package that has two solvents and two powders isn’t clearly identified as which one goes with which. In any case, figuring out which manufactured products are the result of the pharmaceutical product may be a non-trivial task for a computerized system to calculate.

2.3.5.8 Clinical Particulars

Clinical particulars are the reasons why or why not to be using this product, and any expected adverse experiences and interactions. It is a more detailed structure than the XEVMPD requirements, and XEVMPD only details indications, not adverse experiences, interactions or Contra-indications. The DLER does not include clinical particulars, but they are included in the SPL Content of Labeling. The standard indicates that all of these categories of information may be rendered as optional by a given jurisdiction. The Clinical Particulars consist of the following information:

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