INN/WHO Has Issued a Proposal
for a Biological Qualifier (BQ) to be appended to INNs
Preliminarily, this looks rather useless, if not making things worse for the U.S. and the worldwide biopharmaceutical industry. INNs (which I assert are just too incoherent and inappropriate as names for biopharmaceuticals, including being neither generic nor unique enough) are proposed to optionally be a little less generic by appending a 4-letter code for manufacturing site (and implicitly, the manufacturer). However, reading the proposal, it is totally unclear what BQs are being based on, assigned to and how they will be used! Are they based on and to be used to track API manufacturing sites, responsible companies, specific APIs and/or the finished products? The proposal is thoroughly unclear regarding this. As noted in the first sentence of the Executive Summary, the goal is to "develop a system for assignment of Biological Qualifiers to similar biotherapeutic products (SBPs)," i.e., assign identifiers to marketed products (totally out of reach for INN system, since it solely is based on and dedicated to maximal generic names for APIs, not products). However, BQs are also throughout the proposal rationalized and presented as manufacturing site registration. Products, APIs, manufacturing sites, responsible parties - what is being registered? If APIs, products and approvals are be tracked, that is something totally different vs. tracking manufacturing sites; and WHO needs to quickly clarify this. Will BQ registration provide API and even product de facto WHO approvals? Also, seemingly much or most site data may not be disclosed, the same API-based INN BQs will often apply to multiple products, and products will often have multiple INN BQs, making these useless or worse for real-world use (unless the BQs are made so generic as to not be informative about manufacturing sites, companies, APIs, products, or whatever they are intended to track).
Are BQs a win-win for biosimilar-related vested interests? Could well be. Biogeneric interests and, particularly, lesser-regulated countries get to retain generic INNs enabling automatic name-based interchangeability and get WHO "registration" of their APIs. What other reason is there for tracking APIs vs. products, what are actually bought, sold, approved and used? Innovators get much the same quasi-generic names that continue to be dysfunctional for most any other use (with chaos - no useful names - favoring established marketers). And what exactly is a biopharmaceutical API according to WHO? What defines a biopharmaceutical or "similar biotherapeutic product (SBP)" API, and what changes make it a new one (1; 2; 3; 4). INN/WHO needs to specifically define what "similar biotherapeutic products (SBPs)" and "biosimilar" APIs (and/or products or whatever will actually be tracked) actually are, and tell us how these relate to INN BQs. Otherwise, the proposal is not worthy of consideration!
A core problem remains that this proposal and what everyone wants and needs are names/identfiers for marketed products; and this is made worse by API names (INNs) being used for products (5). For example, BIO has issued a press release supporting the INN BQs proposal, e.g., it "strongly support[s] its intent to ensure that all biological medicines are distinguishable." But BIO makes the major leap and mistake in presuming that INNs and BQs apply to products, i.e., "biological medicines," not APIs as they are designed. What's happened to the need for unique names and "one process=one product," the assumption that biopharmaceuticals are not (bio)similar, much less identical and interchangeable, until proven (i.e., approved) otherwise? With chaos [no either genuinely usable unique or (bio)generic/biosimilar names for either products or APIs] favoring established products, have top-level biopharmaceutical industry leaders now abandoned seeking unique names, and are now supporting even more dysfunctional names (INNs) as a way to hold back U.S. adoption of biosimilars (likely an effective strategy)?
And INN/WHO does the same thing as BIO (and essentially everyone else), leaping from INN BQs being inherently generic APIs identifiers to specific regulated product identifiers! For example, the very first sentence of the Executive Summary states, "the INN Expert Group recommended that WHO develop a system for assignment of Biological Qualifiers to similar biotherapeutic products (SBPs)." Again, the real concern is products (which INNs are not concerned with), not active agents/APIs. Of course, lacking any authoritative names for products, everyone will, without any thought, use these INN BKs the same as they use INNs, as names/identifiers for products, adding even more chaos to biopharmaceutical nomenclature and commerce.
Regarding potential uses and users of INN BQs, the first thing INN/WHBO cites is, "As a database of sites of manufacture of biological active substances," and then, "As an information source of approved biological substances." Further. BQs are cited "As a means of identifying selected products and their authorisation" WOW! So, INN BQs are to be used to identify related products AND their approvals? BQs, rationalized and portrayed as manufacturer-based identifiers needed to differentiate marketed biosimilar products, are not actually site identifiers! INN BQs are to be used as identifiers for biologic APIs, and seemingly applied to finished products too! INN/WHO needs to clarify this! Are BQs modifiers actually API manufacturing site codes that countries can use as identifiers to differentiate their marketed biosimilar products; are they some type of formal tracking and "registration" of SBPs or "biosimilar" APIs (unregulated substances; raw ingredients); and/or do they also or actually confer some type of registration or approval to finished products?
Since when has INN/WHO ever collected any information or concerned itself with biologic products vs. generic names for APIs? INN/WHO needs to, with emphatic clarity and high visibility, make it well known that INN BQs will be inherently generic identifiers for biologic APIs, which are just unapproved/unregulated raw ingredients; and that INN BQs are not intended nor should ever be used as sole identifiers for finished products. Rather, INN BQs are useful as codes or descriptors, along with other more suitable descriptors/identifiers, to differentiate product names/identifiers, with BQs presumably conveying API manufacturing site data. INN/WHO must publicly confirm that INN BQs (and INNs too) for biopharmaceuticals alone never designate products, unless ruled so, including official/Adopted Names, e.g., USANs, each countries' pharmacopeia, etc., with these only valid in that country; and that specific countries' product approvals do not mean approvals of all products including that API (having an API with the same INN BQ), i.e., that product approvals do not in an way confer or imply API approvals (with no one actually regulating biopharmaceutical APIs, with these just another raw materials, with countries' approving products and their manufacturing). Unless someone actually gets a DMF or equivalent approval specifically covering an biopharmaceutical API, with this including full-approval-like validation of GMP bioprocessing (proving ability to make consistent API), there is no such thing as an approved biopharmaceutical API (much as there is no such thing as biosimilar APIs).
BQs are proposed as needed for "biosimilar" APIs. A fallacy, ridiculous! There is no such thing as a biosimilar API! Biosimilars are products, not raw materials (APIs). Only products can be biosimilar, not APIs. APIs are unregulated/unapproved raw materials used for manufacture of approved fully-formulated final products, no different than other individual components that go into finished products such as excipients and WFI. Only biosimilar products, not their APIs, ever receive approvals.  Biosimilars, like other biopharmaceuticals, are products, each defined by its approval, presumably, as a biosimilar. Biosimilars require proving similarities between finished products, not APIs. There is no and likely rarely, if ever, will be any comparative analytical and never any clinical testing of biosimilar/biogeneric and reference product APIs, just products! So what will these INN BQs for "biosimilar" APIs be used for? And since when does INN, which only assigns generic names as INNs to APIs, get involved in nomenclature/identifiers for marketed products, here "biosimilars" but in reality surely encompassing all marketed biopharmaceuticals?
WHO is clearly assuming that 'biosimilars' includes the biogeneric knock-offs in non- and lesser-regulated international commerce; and seeks to legitimize and facilitate their international trade (5). Something along these lines has to be done sooner or later, somehow, but these BQs look ill-conceived for this. 'Biosimilars' in WHO's view apparently includes all the "biosimilar" APIs and products that often fill lesser-regulated country-based suppliers', even whole countries', purchases through contracts/tenders. Rarely do these APIs or products ever receive any real "biosimilar" or other testing, much less approvals, anywhere. Even if an API sharing the same INN BQ were even incorporated in an approved product somewhere, sometime, these APIs (vs. finished approved products) in international commerce are rarely ever documented to be consistent from lot-to-lot (no GMP-type bioprocessing validation studies are done unless needed for product approvals), so different lots/batches can only ever be presumed to lack analytical and clinical comparability with each other and their reference products, i.e., not be the same in any biopharmaceutical context. This is unless, seemingly like INN/WHO, one assumes that any APIs (and also products made from these) with specific INN BQs (generic INN--manufacturing site code pair) are comparable, the same, presumably even interchangeable. INN/WHO needs to clarify this point. Are finished products worldwide formulated with the same INN BQ-identified API in any way comparable, the same? And what is the strange backwards extrapolation of countries' product approvals as being approvals for the APIs they contain? This seems technically wrong and ill-advised, if not dangerous.
WHO clearly wants to support the lower-end facilities, but is proposing (but again, it's not clear) simplistic "site" registrations (which many or most will interpret as manufacturer, API and/or product approvals). But with no incentives for or ways to differentiate based on specifications, quality, safety, consistency, better documentation, meeting cGMP or not, etc., BQs are not a good way to do this. And what about the manufacturers that feel it necessary to hide, get their secret INN BQs, with WHO not disclosing "details about manufacturing site(s)" or or "commercially sensitive information." This is vague and suggests likely problems (much data kept secret), with WHO looking predisposed to not disclose whatever companies ask. My experience with biopharmaceutical companies universally is, if you go through proper channels and ask, as will be done here, everything agent- and product-related (other than medical/use and corporate PR information) is proprietary, trade secret. Why not all the information fully public? What could be trade secrets among the scant, trivial data proposed to be collected?. None of the information to be collected will in any way help competitors develop their "biosimilar" APIs. Why does INN/WHO need any trade secret information to register API manufacturing sites? For a system supposedly concentrating on bioprocessing facilities, there is zero interest in and data being collected regarding bioprocessing.
INN BQs, in practice, as currently proposed, will elevate even the lowest-end manufacturer, granting not just facility, but an API-specific "registration" that will surely be cited as WHO approval. Are INN BQs designed to "register" the non-mainstream facilities selling their non-GMP, non-documented, never-actually-approved-anywhere-that-matters, largely uncharacterized biogeneric APIs (and products) in international commerce? Is this the real goal of developing BLQs? My BIOPHARMA: Biosimilars/Biobetters Pipeline Database already tracks about 200 biogenerics (or aspirational biosimilars) in lesser-regulated international commerce, - just the tip-of-the-iceberg (5). Many of these often really involve virtual APIs/products, just clones/cell lines ready to go and offers to make APIs/products to fill orders for products. There are 100s of aspirational biosimilar manufacturers, many already starting to offer APIs. But many of these facilities simply appear clearly unsuited for manufacturing any human biopharmaceutical products, with even the whole country simply lacking such things as a needed analytical and other equipment, a QC testing lab. (much less one meeting GLP), bioprocessing grade water (WFI), cold storage/chain facilities, suitable cleanrooms and HVAC, infrastructure of support vendors, and needed knowledgeable bioprocessing professionals. And I have not even mentioned issues related to counterfeiting, parallel imports, data falsification, lack of oversight and auditing of the BQ process and its effectiveness, etc. .
Another fundamental flaw is that this proposal has the explicit goal of stopping countries from developing their own nomenclature/identifier and tracking systems. This is totally counter to what is needed! See my Citizens Petition information (introduced at www.biopharmacopeia.com) seeking to get FDA to do exactly this! And coming from INN/WHO, which offers nothing in the way of identifiers for products, this is rather ridiculous. Each country needs to track its own approved products and APIs with their own relevant names/identifiers for products and APIs, and include INNs and BQs as appropriate. Also, why the lack of transparency, the meager information being collected not being fully dislosed, likely including secret BQs? As indicated in the proposal, some or many "biosimilar" API manufacturers (or whatever consituency actually want BQs) feel compelled to hide BQ-related information. This will be new for the biopharmaceutical industry, and can only negatively impact perception of the industry and its products.
Yet another flaw is that this proposal involves tracking and identifiers for "sites" (facilities?) with this never defined, making the proposal rather useless. Actually tracking bioprocessing 'sites' or facilities seems like an impossible task for a UN bureaucracy. The trends for bioprocessing facilities and any new bioprocesses, particularly for biosimilars/biogenerics that generally target smaller markets, is to be increasingly flexible, multi-product with rapid turnover, using single-use equipment, with whole modular factories coming soon (6, 7). Bioprocessing lines, suites and even whole factories are on track to essentially be single product manufacturing campaign-dedicated, make 1 API/product lot or batch, then be disposed of. Single-use and modular factories are ideally suited and are already being widely adopted, including in developing countries. Companies, both reference and biosimilar products developers, are already planning on local foreign manufacture of their biologic APIs (not selling their APIs in general commerce) on an episodic, as-needed or ordered basis, primarily using single-use or modular facilities. But flexible facilities are harder to define and track. With single-use and modular bioprocessing, you essentially have a totally new manufacturing facility ("site?") with each product manufacturing campaign. And I haven't even mentioned CMOs, which will be the manufacturer in many or most cases, and the complications they bring. WHO needs to address these issues. BQs make sense, if "sites" are static, unchanging; but if "sites" are the bioprocessing facilities, that's increasingly just not the case. And otherwise, it is totally unclear whether it would be much better for INN BQs to actually be based on something different, such as the company responsible for making the API/product, not a code specifying a bioprocessing manufacturing facility.
So, what is a "site?" How are API site data useful for designation of specific "biosimilar" APIs, the main stated goal? What is going to be tracked, registered? Biologics manufacturing' sites or facilities are best defined as the physical process line(s), the specific suite(s)/room(s) and building(s), where the upstream manufacturing [the bioreactor(s)] and downstream purification are housed. So, ideally, INN BQs ("sites") should relate to specific manufacturing areas within buildings within a manufacturing facility. Tracking both up- and downstream manufacturing "sites" seems the most relevant way to define/identify API manufacturing sites in any real bioprocessing context. Anything else is just making things generic - more of the same problems inherent with the INN system. Or does WHO consider the facilities to be properties (real estate), e.g., a company's R&D and manufacturing campus; or will BQs actually just identify sites to the level of cities or even countries? Or perhaps what is really needed, particularly in the context of INN/WHO citing countries needing to differentiate biosimilars, and likely way more important than tracking API manufacturing sites, is tracking the responsible party/ies, the owner(s). Citing the internationally-recognized name associated with the owner company might be preferred, e.g., using Roche rather than Genentech or other country-specific subsidiary/affiliate names. But are countries such as Japan and Australia, the presumed initial targets for adoption of BWQs, really going to differentiate, assign official names, using INN BQs based on manufacturing "sites," with unfixed, constantly changing codes, rather than a code for a top-level familiar company name? Will Japan and Australia be labeling their products and physicians prescribing using specific INN BQs to specify say a Herceptin biosimilar manufactured by say Genentech/Roche sites at one of its sites in California, Europe, Singapore, etc.?? Or do these countries really just want to specify the product manufacturer or marketing company?
Is what is really needed is to register the API responsible parties, the companies responsible (the API owners), not "sites?" This seems much more critical for WHO and international commerce than trying to track increasingly virtual/pop-up sites. The proposal's fixation on 'sites' ignores tracking owners, sellers or buyers of APIs. If BQs really seek to track responsible parties, the term "site" is not appropriate. An who/what is the manufacturer, the "site," or owner - the company or even individual that orders-up and sells the API, e.g., a trading company; the actual original API manufacturers, often contract manufacturers? The proposal needs considerable clarification regarding "sites."
The process for providing manufacturing site identifiers is simply off-base and needlessly too complex. Why not have manufacturers (sites) themselves apply, as with INNs? Why must a manufacturing site (or is this really a backhanded API, even product) registration only come after and be linked to "submission of a marketing authorisation application" (i.e., a product application); and "The assigned BQ code is provided by WHO to the applicant and to the pertinent regulatory authority." Why/how is a site identifier being formally granted to countries' regulatory agencies? Why are countries' regulatory authorities involved at all in a WHO/UN manufacturing site registration system, one that is being set up totally without any consideration for their own long-established regulation of product manufacture? Why not simply let companies directly request the BQ site identifiers whenever they want, such as during API and bioprocessing development and scale-up? What do product applications, often filed by another company and even in another country than the API manufacture, have to do with a registration system for biopharmaceutical API manufacturing sites?
The stated goal of INN BQs is to reduce needless work by regulatory agencies worldwide. But reading the proposal, INN/WHO will be demanding product registration information for all biologics from every country, on a continuing basis, as it somehow tracks what APIs go into what products worldwide. The only source for needed information and its constant updating is countries's regulatory agencies, and this looks to require considerable constant work by every one. INN notes information to be collected includes, "where and when the substance has been approved by other authorities, tradename(s)." What authorities (what countries?) anywhere are approving biologic "substances" or APIs," and what APIs have tradenames? And since when can product approvals be construed as approvals for APIs in commerce?" INN/WHO even describes the BQ system as tracking biologics supplementary approvals worldwide. So, as INN/WHO claims, it will be tracking each API, identified by its INN BQ, as it is incorporated into each specific regulated product worldwide, and further tracking all relevant, including supplemental, approvals? This is far removed from being an API manufacturing site registration system countries can use to make INNs for biosimilars more unique, less generic.
The U.S. (FDA) and other highly-regulated countries and their biopharmaceutical industries should emphatically reject this proposal! Making API names a little less generic does nothing to address any U.S. nomenclature needs, such as genuinely unique and biosimilar/(bio)generic/class names for biopharmaceutical products and APIs (5). And there is simply too much totally unclear about the proposal.
The new INN BQs are even less useful than unmodified INNs are for use as FDA official non-proprietary/established/USAN-type names (7). Will INN BQs be adopted by FDA? What will they be used for? Will product inserts include INN BQ API manufacturing site identifiers? The INN BQs seem particularly unsuited for U.S. use. For example, most major U.S. APIs and products are manufactured at 2 or even more facilities ("sites?"), so many products will have multiple associated INN BQ identifiers. Also, many BQs will be assigned to CMO facilities, not the familiar BLA holder or marketing company. Many approved products (BLAs) would have multiple associated INN BQs (which really only apply to the APIs, not the products), including for defunct APIs, sites and products, for sites with the 'same' APIs not coming under FDA product approvals, with CMOs involved, etc., with this information changing often - all kinds of complications. With no association between BLAs (approved products, including their APIs) and INN BQs (API identifiers), with multiple BQs for many or most products, with INN BQs subject to constant change (unless made so generic they refer to something other than the bioprocessing), with the identifiers controlled by a UN bureaucracy, use of INNs BQs as U.S. official names would be total chaos. How will FDA use INN BQs? What will be their requirements for use, such as product labeling, in marketing, etc.? The agency needs to tell us during this proposal evaluation period!  How will physicians, pharmacists, patients and the general public deal with multiple even more complex and vaguer API-, not product, -based names/identifiers (INN BQs) for what FDA and everyone considers the 'same' products (and same APIs too)?
Conclusions: Yes, we need full(er) disclosure of what approved biologic APIs and
finished products are manufactured where.
Yes, including a facility/manufacturer identifier may be useful in constructing
both (more) unique and generic product and API names/identifiers. But these are things FDA and other regulatory
agencies should do
for its own approvals, not the WHO/UN!
These INN BQ modifier codes for APIs lack relevance, rationality and utility
in the U.S.
and other countries where biopharmaceutical commerce, treatment, regulation, etc. involve approved products, not interchangeable
APIs from secret manufacturing facilities.
BQs look to be a rather inept proposed solution for whatever the real problem and need is, which is unclear.
It seems that the rationale for BQs is that some countries, with INNs inherently generic, need to be
more specific, less generic, in associating INN names/identifiers with their approved biosimilar products.