BPebook0320 - 012-024 - PharmacopeiaCompliance - Part 8 - Monographs
BPebook0320 - 012-024 - PharmacopeiaCompliance - Part 8 - Monographs
BPebook0320 - 012-024 - PharmacopeiaCompliance - Part 8 - Monographs
Monograph Development:
Why and When to Participate
This article explores another proactive advocacy approach that a
bio/pharmaceutical company may take through participation in
the development of new and revised monographs in the various
pharmacopoeias.
J. MARK WIGGINS AND JOSEPH A. ALBANESE
T
his article is a continuation of the series itor these revisions (7) to facilitate ongoing compliance
intended to provide a practical guide to phar- with current pharmacopoeia requirements. It was noted
macopoeia compliance for the bio/pharma- that monitoring only the official revisions published by
ceutical industry. The first articles provided the pharmacopoeias puts a company in a reactive posi-
details on why pharmacopoeia compliance is tion to achieve compliance with updated requirements.
necessary (1) and why compliance is difficult to achieve Working further upstream to include surveillance of
and maintain (2). Subsequent articles provided a his- proposed updates published by the pharmacopoeias
iQoncept - Stock.adobe.com
torical and global perspective of the pharmacopoeias provides an opportunity for companies to take a more
(3) and described the benefits of global pharmacopoeia proactive position by providing comments to poten-
standards (4) that may be achieved through ongoing
harmonization efforts (5). The process used to revise J. MARK WIGGINS is owner and compendial consultant with Global
the pharmacopoeias was described (6) as was the associ- Pharmacopoeia Solutions LLC. JOSEPH A. ALBANESE is the director of Analytical
Strategy and Compliance at Janssen Research and Development, LLC.
ated surveillance process used by the industry to mon-
standards to help ensure the quality ple test for loss on drying for an Drug substances and products
of medicines” (8). The GPhP guid- excipient, or a microbiological Divergent perspectives begin to
ance continues, “Pharmacopoeial test for a drug substance, or a dis- emerge across the industry when
monographs provide an important solution test for a tablet formu- considering the value and benefit
tool for assurance of the quality of lation, enable routine testing by of specific monographs for drug
marketed pharmaceutical ingredi- providing details on how to per- substances and drug products.
ents and products through testing form the test and, in some cases, Monographs for small-molecule drug
of their quality.” These monographs the applicable acceptance criteria. substances and products have long
are generally available for excipients, Importantly, the information in been established in the pharmaco-
drug substances, and drug products, pharmacopoeia general chapters poeias, and the quality requirements
providing the tests, analytical pro- is broadly accepted as an appropri- in the monographs apply to both
cedures, and acceptance criteria that ate quality standard by regulatory innovator and generic-drug com-
enable assessment of the quality of authorities around the world. panies alike. These monographs,
the material. Taken together with however, do not typically become
the other requirements contained Excipients available until later in the drug prod-
in the pharmacopoeia, these mono- There is also general agreement uct lifecycle. Indeed, the new drug
graphs can help safeguard the health across the industry regarding the substances and products must first
of patients around the world through value and benefit of having spe- be discovered and developed by an
the availability of public quality cific tests and acceptance crite- innovator company, and the appli-
standards. ria contained in monographs for cable monographs follow. The initial
The bio/pharmaceutical indus- excipients. From the perspective quality requirements are approved
try is focused on delivering quality of excipient suppliers, the avail- by health authorities as submitted in
products to patients. Earlier in this ability of a monograph provides a new drug applications.
series of articles, the content of the quality standard for the material
pharmacopoeia was described with that should be acceptable to mul- Generic drugs
consideration of the impact of the tiple customers. For bio/pharma- As with the innovator company,
pharmacopoeia throughout the life- ceutical companies, the benefits drug substance and product mono-
cycle of a drug product (1). From a include having multiple suppli- graphs are generally not available for
practical business perspective, the ers that can provide excipients those generic-drug companies that
value and benefit of the pharmaco- meeting the same core require- are first to enter the market; prod-
poeia content to a specific company ments, simplifying the sourcing uct development work is typically
may vary based on the sector in of these materials, and reducing well underway before specific mono-
which the company operates (e.g., the burden of laboratory assess- graphs are available for the materi-
innovator, generic-drug company, ments to determine comparabil- als. The value of the monographs
contract manufacturer) and the spe- it y of materials from alternate emerges with the approval of sub-
cific pharmacopoeia content under sources. Excipient monographs sequent generic versions, helping to
discussion. a lso fac ilitate com mu nicat ion ensure consistent quality, especially
with health authorities regarding as the availability of the product
General chapters excipient quality attributes. Using grows across today’s global supply
The general chapters in the phar- compendial-grade excipients in chain. It is here that the ultimate
macopoeias provide a wide range of drug products aligns with regula- value for patients is realized, with
information, including analytical tory expectations for review and the quality standard in the mono-
and biological procedures that are inspection, simplifying product graphs for the drug substance and
used to test materials and products. registrations by allowing refer- product applying to all companies.
It is broadly agreed these general ence to the pharmacopoeia mono-
chapters are beneficial for all bio/ graph as the standard of quality Biologics and vaccines
pharmaceutical companies because for the material. Referencing the There is, perhaps, even less agree-
they facilitate product development, monograph eliminates the need to ment throughout the industry on
enabling greater focus on specific include specific acceptance crite- the value or benefit of monographs
attributes that are critical to the ria, methodology, and validation for biological products and vaccines.
quality of a material or product. information for the excipient in The pharmacopoeias, and in partic-
These procedures, whether a sim- the drug product registration. ular the European Pharmacopoeia (Ph.
Eur.), have published monographs Pharmacopoeia (ChP) developing within a company to help ensure
for some biologicals since the 1990s, product-specific monographs, while pharmacopoeia compliance (2).
including human insulin, somatro- the British Pharmacopoeia (BP) and The upstream strategic activities
pin, interferon, erythropoietin, and the United States Pharmacopeia (USP) in the process were termed “pro-
vaccines (9). For vaccines, there are are exploring alternate approaches to active compliance” and included
typically only a few manufacturers quality control, including the estab- participation in the development
for a specific product, limiting the lishment of performance-based stan- of new monographs in the phar-
applicability of the monograph to dards (10, 11). macopoeias.
these companies. Despite this, the The perceived value of specific Bringing together the history,
public quality standard contained monographs by a particular com- the regulatory and legal frame-
in the vaccine monograph can be pany will likely guide the compa- work, the need for a company to
beneficial to regulatory agencies ny’s willingness to participate in comply, and the opportunity for
and medicine control laboratories monograph development. Given proactive engagement with the
involved with batch release of the the broad range of products across pharmacopoeias, there is one fun-
product. For other, simpler biologi- the bio/pharmaceutical industry, damental consideration to keep in
cal products, including peptides and it should be noted that the focus mind: monographs happen. This
some proteins, the size and structure of this article is on small-mole- simple truth conveys the reality
of the material itself can often be cule drug substances and drug that monographs will be developed
well-characterized by the tests typ- products and the development of and published by the pharmaco-
ically listed in a monograph, which new monographs for these materi- poeias whether a specific company
would be applicable to multiple man- als. The concepts and approaches, chooses to participate in the process
ufacturers for these products. however, may also be applied to or not.
For more complex biotherapeu- the development of monographs— Foundational to any company’s
tic products, in particular monoclo- whether new or revised—for the compendial process is the strategy it
nal antibodies (mAbs), the greater broader industry, including over- chooses to follow with monograph
complexity of the material and the-counter medications, dietary elaboration. This critical strategy
the associated challenges in prod- supplements, herbals, traditional decision affects resourcing of the
uct development and manufacture medicines, and excipients. The compendial function, because it
create potential challenges in the information provided here may also can require significant resources to
development and application of be extrapolated to the development elaborate a monograph. The deci-
quality requirements in product-spe- of new and revised general chapters sion also determines if a company
cific monographs, especially as the in the pharmacopoeias. is going to be proactive or reactive
number of companies working in in its approach to the development
this area continues to grow. There is BENEFITS OF PROACTIVE of compendial standards. There
concern that specific monographs ENGAGEMENT TO DEVELOP are pros and cons for a company to
cannot be considered as minimum MONOGRAPHS consider with each approach.
requirements for acceptability of Pharmacopoeias are embedded in
“similar” biological products, risk- the legal and regulatory framework Proactive approach
ing the false assumption of prod- in countries around the world (1, The reasons to proactively partic-
uct equivalence. This is in conflict 3). Pharmacopoeias contain mono- ipate in monograph elaboration
with regulatory guidance and patient graphs for specific drug products include the ability to influence the
safety considerations. Even while the and ingredients, which serve as outcome of the public standards
pathways for regulatory approval the public standard, providing that are developed. For an inno-
of biosimilar products continue to minimum quality requirements vator company in particular, the
evolve around the world, there is that all manufacturers must meet submission of monographs is part
ongoing debate regarding the appli- for the material. of a strong advocacy program that
cability of specific monographs to A n e nd -to - e nd comp e nd ia l brings the company’s knowledge
these complex products. The phar- framework was provided in the and experience to bear for its prod-
macopoeias are also considering dif- second article of the series to aid uct. Proactive participation should
ferent approaches to public standards in understanding the range of result in a monograph that has
for complex biotherapeutic prod- activities that may be carried out minimal impact to the innovator
ucts, with the Ph. Eur. and Chinese by the compendial affairs function company, because the core quality
standards contained in the mono- requirements developed by another best be summed up as “pay me now
graph should closely align with the company. Additionally, physical or pay me later”. Either approach,
requirements in the approved drug reference standard materials sup- whether proactive participation
product registrations. The result- plied by the innovator company or a reactive position, will require
ing standards in the monograph to support the monograph provide periods of resource-intensive effort.
for a drug substance can be used for similar benefits and potentially Either approach can have an impact
multiple product formulations and simplify the processes for the com- on the outcome of the final mono-
dual-active products. pany, eliminating the need to per- graph, determining how much lab-
Proactive engagement in the form comparison testing with an oratory work or how many filing
monograph development process in-house standard. updates may be needed to remain
helps build a strong collaborative compliant.
relationship with the pharmaco- Reactive approach It is useful for a company to
poeia authorities and enables those On the other hand, the case against determine its “typical” approach
involved in compendial activities in active participation in monograph to monograph development, while
a company to become acquainted development is that fewer resources understanding that it is not a one-
with individual scientists at the are needed upfront during the elab- size-fits-all outcome. There are
pharmacopoeias. This involvement oration process. No work is required scenarios where it may not be advis-
can be beneficial in other com- to pull together the information able for a company to participate
pendial activities for the company, needed for submission of the mono- in monograph development for a
including greater effectiveness with graph. During the time when particular product, depending on
responses submitted to other pro- there is no monograph, each com- scientific, regulatory, or business
posed revisions published by the pany having regulatory approval drivers. For example, if a product
pharmacopoeias. must comply with its own active is expected to have a short lifetime
Another potential benefit of registrations, meaning no work is in the market with limited utility
proactive participation is the pos- needed to demonstrate equivalence to patients because there are bet-
sibility of establishing a harmo- or implement new methodologies ter treatments in development,
nized monograph across multiple from the monograph. A company then a company may choose not
pharmacopoeias (see Sidebar, page can still comment when the pro- to work on monograph elaboration
22). Proactive participation, how- posal of the monograph is first pub- for that material. Additionally, for
ever, comes with a higher upfront lished, providing specific feedback older compounds (more than 25–30
resource cost to prepare the mono- on items of concern. This approach, years), if a monograph does not
graph submission and respond to which is more reactive, requires already exist, the benefit of creating
questions during its elaboration. higher resource commitment once one may not justify the resource
Additionally, the outcome of the the draft monograph is published, cost needed to complete the elabo-
monograph is not g uaranteed, with rapid evaluation needed for ration process.
so there could be impact to the any new methods it may contain. Ultimately, it is important for a
company’s product registrations It can be difficult for a company company to decide whether and
and quality testing despite collab- to significantly influence the draft how they will participate in mono-
oration with the pharmacopoeia publication given the work already graph development. This choice
authorities. invested by the pharmacopoeial will shape how the compendial
One important benefit of a pro- scientists. Once published as an affairs f unction is staffed and
active approach for an innova- official monograph, this reactive empowered for the company. The
tor company is avoidance of the approach potentially makes com- compendial affairs function should
development of a monograph by pliance more difficult for the com- communicate the risks and benefits
a competitor, which can create pany. of a proactive or reactive approach
compliance challenges. There are In the authors’ experience, there to monograph development to
benefits to an innovator company is a benefit in proactive partic- management and critical internal
having the public standard in the ipation in the monograph devel- stakeholders. It is common to have
pharmacopoeia based on the qual- opment process. However, neither to educate the product support
ity standards in their approved drug approach is right or wrong; it sim- team—product director, regulatory
product registration, rather than ply comes down to a company’s support, quality—as to the reasons
having to comply with monograph decision. The consequences can why monograph elaboration is
Figure 1. Monograph timing considerations for pharmacopoeias. IP is Indian Pharmacopoeia. Ph.Eur. is European
Pharmacopoeia. USP is United States Pharmacopeia. BP is British Pharmacopoeia. JP is Japanese Pharmacopoeia. ChP is
Chinese Pharmacopoeia. KP is Korean Pharmacopoeia.
Regulatory Submission/Approval
Marketing Exclusivity
IP Patent Expiration
When 2-3 Local Manufacturers
needed. It is a daunting task to get typically vary for each company, procedure (12), in which the nec-
approval for each new monograph for each situation, or even for each essary specifications and support-
submission, with the scientific data product in a company’s portfolio. As ing information are provided by a
required to support the elaboration with the prior question of whether single company, usually the inno-
activities. It is best to embed the a company should participate in vator, having regulatory approval
monograph strategy into estab- monograph development, exploring for the product in Europe. This
lished compendial processes, so it the subsequent question of when to t iming a lso cor responds w it h
becomes a “routine” activity that participate reveals there is not nec- the European Medicines Agency
requires limited internal approvals essarily a consistent, single answer. reg u lator y g u ida nce concer n-
to proceed. Focusing on the question of tim- ing mandatory renewal of a mar-
ing, two perspectives should be con- keting authorization within five
CONSIDERATION OF sidered: that of the pharmacopoeia years of its granting in Europe (13).
APPROPRIATE TIMING FOR and that of the industry. Under the P4 procedure, the Ph.
MONOGRAPH SUBMISSION Eur. Commission works to ensure
The GPhP guidance states that Pharmacopoeia timing that monographs are available a
pharmacopoeial standards should The process to develop a new few years before the patent expiry
be available for drug products and monograph in the pharmacopoeia date, thus making it possible for
their active ingredients at an appro- typically takes two to three years. regulators to assess dossiers on
ALL FIGURES COURTESY OF THE AUTHORS.
priate time to support and benefit Figure 1 shows the preferred tim- generic drugs based on existing
patients through the availability of ing for new monograph devel- monographs in the pharmacopoeia
medicines with consistent quality opment from the viewpoint of (14). If the monograph submis-
(8). The critical question within various pharmacopoeias, reflecting sion is too late to follow the P4
this statement is what is an “appro- several considerations. Typically, process, the Ph. Eur. monograph
priate time”. If a company decides the Ph. Eur. and USP monographs is developed (or revised) using the
to participate in the development are the earliest to be elaborated, P1 process (15), in which multi-
of a new monograph, they must with the preferred Ph. Eur. tim- ple companies with approval for
ask when they will start the pro- ing stated as five years post-ap- the drug product in Europe may
cess. The appropriate timing will proval to take advantage of its P4 participate in developing the tests,
analytical procedures, and accep- drug substance and product at the Ph. Eur. drug substance monographs
tance criteria that will make up the same time. The situation regarding and the associated BP drug prod-
public standard. Due to the partic- multiple product strengths, differ- uct monographs. Alternatively, the
ipation of multiple companies, the ent dosage forms, and combina- product monograph may be estab-
development of the Ph. Eur. mono- tion products also enters into the lished in the Ph. Eur. rather than the
graph by the P1 procedure is often decision-making process. Based on BP, with the Ph. Eur. product mono-
more difficult for the pharmaco- experience with the prospective and graph then published also in the
poeia. It may also be more diffi- informal harmonization of mono- BP. These considerations enter the
cult for individual companies to graphs, along with other practical determination of when and where
comply with the final monograph considerations, there are potential to submit the monographs for drug
because it may contain require- benefits in establishing the drug substances and their associated
ments from multiple sources. substance and product monographs products.
For USP, the preferred timing for at the same time. One of these ben- Turning to the other pharmaco-
monograph submission is seven to efits is standardizing the analytical poeias shown in Figure 1, the key
eight years prior to generic drug procedures across the monographs take-away is that the appropriate
entry to the market (16), which for the drug substance and drug time for monograph development
generally aligns with the preferred product portfolio, particularly tests is not consistently or precisely
Ph. Eur. monograph timing of for the determination of assay and defined, but typically would occur
five years post-approval. An addi- impurities, in setting consistent after the USP, Ph. Eur., and BP mono-
tional consideration for mono- pubic standards for quality of the graphs have been established, possi-
graph development timing is the product family. This standardiza- bly by several years. For the Indian
possibility of establishing “pro- tion of methodology also carries the Pharmacopoeia (IP), there appears
spectively harmonized” or “infor- potential risk of making it more dif- to be a correlation between the
mally harmonized” monographs ficult for a company to apply the approval of two to three companies
in collaboration with both the Ph. monograph methods if they are not in India and the development of a
Eur. and USP authorities. Details aligned with its approved product monograph, although this is not
regarding development of harmo- registrations. entirely clear in the authors’ expe-
nized monographs is provided in The publication of monographs rience. There seems to be a good
the Sidebar (page 22). In practice, for small-molecule drug products deal of variability in the IP mono-
many companies delay monograph in the Ph. Eur. is a fairly recent graph timing, and in some cases,
submission beyond this time hori- development, with the first such the IP monograph may be devel-
zon, choosing instead to consider monograph adopted in 2015 (17). By oped before the USP, Ph. Eur., or BP
the appropriate timing as three to contrast, the BP has long included monographs. For pharmacopoeias
five years prior to patent expira- monographs for small-molecule in other countries, including the
tion. Variability in the patent sit- drug products, in addition to all the Japanese Pharmacopoeia (JP), Korean
uation for a particular company, other content of the Ph. Eur. that is Pharmacopoeia (KP), and ChP, there
country, or product makes the required for pharmacopoeia com- also seems to be some correlation
actual date of submission using pliance in the United Kingdom. In with approval of several companies
this approach more difficult to the absence of an applicable Ph. Eur. for a particular drug product and
establish. Additionally, this delay monograph, compliance with BP the elaboration of a monograph.
in submission makes it more diffi- drug product monographs is often While this timing for IP, JP, ChP,
cult to pursue a monograph that is the expectation of regulatory agen- and KP activity seems to decrease
harmonized. cies throughout Europe and in the possibility of developing har-
A corollary consideration of many other countries around the monized monographs across several
monograph development is whether world. For several practical and reg- pharmacopoeias—monographs that
the submission should be first for ulatory reasons, the BP drug product could truly serve as global pharma-
the drug substance (shown as API monograph, however, cannot usu- copoeia standards—there is clear
in Figure 1), followed later—perhaps ally be established until after the Ph. interest and commitment by the
several years later—for the drug Eur. monograph has been developed pharmacopoeia authorities to col-
product, or whether the informa- for the drug substance. The pursuit laborate with each other and with
tion should be provided to support of harmonized monographs has the industry to establish consistent
monograph development of the enabled concurrent development of public quality standards.
Single-Source Multi-Source
Product Product
Manufacturer
Manufacturer …
Manufacturer 1 Manufacturer 2 3
• Identity • Identity
• Strength • Strength
• Quality • Quality
• Purity • Purity
Monograph Change
Prospective Harmonization
Control?
Official Monographs
(Drug Substance / Drug Product)
Industry timing approved, which may occur per- market access by, for example, favor-
The other timing perspective to haps 10–15 years after the inno- ing one manufacturer to the exclu-
consider for monograph develop- vator’s approval, followed by the sion of others should be avoided”
ment is that of an individual com- approval of other generic versions, (8). This statement is intended to
pany, and this, in turn, may vary potentially from many other com- maintain focus on the benefit to
based on whether the company is panies around the world, the prod- patients worldwide in having pub-
in the innovator or generic sector uct situation changes to reflect this lic standards that support access
of the industry (Figure 2). After an multi-source availability. to medicines from innovator and
innovator company (Manufacturer At some point during the prod- generic-drug companies with con-
1 in Figure 2) receives regulatory uct’s lifecycle, the possible devel- sistent and appropriate quality.
approval for a new drug applica- opment of a monograph emerges, The earliest opportunit y for
tion containing a new chemical at which point the need and value monograph submission belongs to
entity, there is a period of patent of this specific public standard is the innovator company having the
protection and marketing exclu- weighed against the existing reg- initial regulatory approval, during
sivity during which the innovator ulatory approval for the product. the period of patent protection and
is the single source for the prod- The monograph will contain the marketing exclusivity. Once the
uct. During this time period, gener- specifications—tests, analytical decision has been made whether
ic-drug companies begin to develop procedures, and acceptance cri- to submit the necessary informa-
similar versions of the drug sub- teria—that help ensure the iden- tion for monograph development,
stance and product, in terms of tity, strength, quality, and purity consideration then turns to when
pharmaceutical and therapeutic of the drug substance and product. to submit the information. Many
equivalence. One goal is to become It becomes necessary for all com- product-specific points are import-
the first company (Manufacturer panies with regulatory approval ant in this consideration, including
2 in Figure 2) to market a generic to comply with the requirements ongoing manufacturing and ana-
version of the product, realiz- established in the monographs for lytical changes that may impact the
ing all the business benefits that the drug substance and product. applicable specifications, as well as
accompany this position. Once Additionally, as stated in the GPhP the timing for potential entry of
the first generic version has been guidance, “Specifications that limit generic competition.
As suggested in Figure 2, there is the latest is three to five years materials to support monograph
potential benefit to the innovator prior to patent expiration (or loss development, with available inven-
company in having the monograph of marketing exclusivity) or even tory potentially limited early in the
established to reflect the quality later, and the third is the period of product’s lifecycle.
standard that has been approved time between these two (see Table For an innovator company, the
by the health authorities for the I). In the authors’ experience, from last of these time periods—three to
single-source product. This quality the perspective of innovator com- five years prior to patent expiration
standard must then be met by all panies, the first of these—zero to or even later, potentially extending
subsequent generic-drug compa- five years post-approval—is gener- after patents have expired and mar-
nies that wish to market the prod- ally too early. Among the reasons keting exclusivity has lapsed—may
uct, providing benefit to patients for this conclusion are the limited be considered too late, for several
through medicines with consistent value of a public standard for a sin- reasons. These include likely generic
quality. However, if the innovator gle-source product, with limited drug entry with submission of
company delays its monograph sub- available data about the product, information and reference standard
mission, or chooses not to submit at and ongoing process and analyti- materials from multiple sources;
all, then any of the approved gener- cal changes typical in the first few increased effort and reduced suc-
ic-drug companies have the oppor- years of the lifecycle, as additional cess in influencing the outcome,
tunity to submit the monograph. experience is gained with the man- resulting in greater likelihood of
Because monograph development ufactured product. There is also the need to adopt different meth-
by the pharmacopoeias generally concern about potential loss of ods and limits from what is con-
takes about two to three years after intellectual property, especially in tained in product registrations as a
the initial submission, more com- countries where there is less pat- result of comments received during
panies may begin work to develop ent protection. Experience has monograph development; and com-
generic versions of the product. shown, however, that this threat plexities due to different impurity
When the draft monograph is pub- is not significant in the larger pic- profiles, formulations, and degra-
lished by the pharmacopoeia for ture, because many generic-drug dation pathways for multi-source
public review, there will be more companies already have products products. As mentioned previously,
companies that may provide com- in development from an early stage, there is one potential benefit in later
ments on the proposed specifica- with information available in the submission of a new monograph,
tions, potentially impacting the literature and through reverse-engi- which is the delayed deployment
final monograph in the pharma- neering approaches. Another con- of resources for monograph devel-
copoeia. Once the monograph is sideration for early submission is the opment. However, the subsequent
official in the pharmacopoeia, there need to provide reference standard process to evaluate and address
is the ongoing possibility of subse-
quent changes to the monograph Table I: Considerations for appropriate timing of monograph development.
to reflect specifications approved
by regulators as more generic-drug The appropriate timing for monograph submissions is determined by individual companies, with particular
companies are authorized to mar- consideration for each individual product. Timelines can be defined based on a number of different
ket the product. The compliance considerations (including but not limited to):
challenges for any given company • Potential opportunity to achieve prospective or informal harmonization
are commensurate with the degree of the new monograph across several pharmacopoeias.
of difference between the mono- • New monograph development that is initiated by innovator companies
graph and its own approved product to avoid conflict with content in approved regulatory filings.
specifications, so the practical goal • New monograph development that is initiated by generic-drug companies
should be to collaborate to align the when an innovator delays or does not submit the monograph.
pharmacopoeia requirements with • Single-source vs. multi-source product availability, which determines the likely process to be used
the approved registration. in collaboration with the pharmacopoeias; generally, more comments are received on monograph
In broad terms, three time peri- development that occurs closer to the timing when multi-source product(s) are in the market.
ods may be identified for a com- • Timing based on an amount of time post-approval, or amount of time prior to
pany as they determine when to patent expiry, loss of marketing exclusivity, or generic entry to market.
submit a monograph: the earliest • Timeline for monograph development as recommended by the pharmacopoeia(s).
is zero to five years post-approval,
One reason given for proactive participation and earlier submission of a or product, the industry partnered with the pharmacopoeial authorities in
monograph was the possibility of prospective or informal harmonization a pilot project to develop “prospectively harmonized” monographs in the USP
across multiple pharmacopoeias. It is instructive to take a closer look at this and Ph. Eur. The approach taken was to submit the necessary information and
harmonization process. Some practical aspects of following the process to materials (samples and reference standards) to both USP and Ph. Eur. at the same
develop harmonized monographs are discussed in the companion article on time, with collaboration among the participants throughout the monograph
BioPharmInternational.com, which can be accessed by clicking here. elaboration process. The industry perspective on the details of this prospective
Historically, the development of a new monograph began with the submission harmonization approach was provided in an article published in the USP and Ph.
of information by a company to one pharmacopoeia. This information would Eur. pharmacopoeia forums (1, 2). With JP as an interested observer to this new
include specifications (e.g., the list of tests, reference to analytical procedures, and approach for monograph development, the industry article was also translated
acceptance criteria), as well as select details contained in product development into Japanese and published in the JP forum (3). The work was also shared with
reports, method validations, and drug product registrations. Typical timing the authorities of other pharmacopoeias, including BP, the Indian Pharmacopoeia
for the initiation of the monograph elaboration was driven by requests from (IP), the Korean Pharmacopoeia (KP), and the Chinese Pharmacopoeia (ChP),
the global pharmacopoeias, resulting in submissions going first to either the through individual discussions and presentations at the Global Summit of the
United States Pharmacopeia (USP) or the European Pharmacopoeia (Ph. Eur.). Pharmacopoeias (4).
Later, perhaps several years later, the same information would be provided The outcome of the initial pilot project was the publication of four new
by the company to the other pharmacopoeia, which had not been part of the monographs for drug substances that were prospectively harmonized in
original submission. Even later, the information would potentially be provided the USP and Ph. Eur. However, the conclusions published in a press release
to additional pharmacopoeias, including the British Pharmacopoeia (BP) and the from the pharmacopoeias pointed to the difficulty posed by the coordination
Japanese Pharmacopoeia (JP). One practical outcome of this sequential approach of the monograph development work between the pharmacopoeias using
to monograph development was that the resulting standards would often differ, the formalized process that had been established (5). They determined that
sometimes in significant ways, regarding methods and limits that were listed in achieving pharmacopoeia harmonization remained an important goal, and both
the monographs of the different pharmacopoeias. organizations were fully committed to continue collaboration on prospectively
Recognizing the compliance challenges resulting from divergent standards harmonized monographs, but this would be done using an “informal
contained in the various pharmacopoeia monographs for a particular material harmonization” approach.
Figure 1. Prospective/informal harmonization: current perspective. USP is United States Pharmacopeia. FBras is
Brazilian Pharmacopoeia. KP is Korean Pharmacopoeia. IP is Indian Pharmacopoeia. ChP is Chinese Pharmacopoeia.
JP is Japanese Pharmacopoeia. SP RF is Russian Pharmacopoeia. GPhP is Good Pharmacopoeial Practices.
Collaboration…then Expansion
Scope: Bio/
APIs and Products Pharmaceutical
Company
FBras IP ChP SP RF
KP JP
Secondary Work: PDG, MOUs, Observers
GPhPs
(Adopt / Adapt)
Further development of harmonized monographs for drug products was availability of multiple drug products on the market in the particular country,
undertaken by companies in collaboration with USP and BP. The first monographs leading to the goal of establishing a common quality standard that is applicable
achieved by this informal harmonization approach were published in USP and BP to all manufacturers.
in 2012 (6). Subsequent collaboration has resulted in the development of dozens of It is hoped that the development of new monographs that are harmonized from
new monographs for drug substances and products that are harmonized between the beginning will continue in order to establish global pharmacopoeia standards,
USP, Ph. Eur., and BP, with submissions for individual monographs coming from and that more companies and more pharmacopoeias will be engaged in this
several different companies. Some of these harmonized monographs have also collaborative process.
been adopted by other pharmacopoeias, including JP and IP. References
The authors’ current perspective on the process is provided in Figure 1, showing 1. J.M. Wiggins et al., “Ph. Eur/USP Prospective Harmonization—API Pilot
the primary, initial harmonization work consisting of a bio/pharmaceutical Project: Industry Perspective,” Stimuli Article, USP Pharmacopeial Forum 36
(6) 1792-1796 (November–December 2010).
company submitting the necessary information to USP, Ph. Eur., and BP to develop
2. J.M. Wiggins, et al., “Ph. Eur/USP Prospective Harmonization—API Pilot
the harmonized monograph. Subsequent or secondary effort would include Project: Industry Perspective,” Pharmeuropa, 22 (4) 415-418 (October 2010).
additional pharmacopoeias in partnership with the submitting company and 3. J.M. Wiggins, et al., “Ph. Eur/USP Prospective Harmonization—API Pilot
the initial pharmacopoeias through an “adopt/adapt” approach that is enabled Project: Industry Perspective,” Japanese Pharmacopoeial Forum 20 (1) 49-53
(March 2011).
by Good Pharmacopoeia Practices (7). This primary and secondary sequence for 4. J. M. Wiggins, “Monograph Harmonization: In Search of True North,”
monograph elaboration is not intended to suggest that the other pharmacopoeias Presentation at the 3rd Global Summit of the Pharmacopoeias (Baltimore,
are less important than USP, Ph. Eur., or BP in the development process, but rather MD, Sept. 19, 2013).
reflects the current situation that the timing for monograph development 5. EDQM, “Conclusion of Prospective Harmonization Pilot Project,” Press
Release, April 28, 2015.
occurs later for the other pharmacopoeias. This is depicted in Figure 1 of the 6. G. Macdonald, “USP and BPC Harmonize First Finished Product
main article (see Page 18), which displays the preferred timing for monograph Monographs,” in-pharmatechnologist.com (May 2012).
development by USP (seven to eight years before generic market entry), Ph. Eur. 7. WHO, Good Pharmacopoeial Practices, WHO Expert Committee on
Specifications for Pharmaceutical Preparations Fiftieth Report, Technical
(five years post-approval for the innovator), and BP for the drug product (following
Report Series No. 996, Annex 1, 67-85 (2016).
development of the drug substance monograph in the Ph. Eur.) The timing for the
—J.Mark Wiggins and Joseph A. Albanese
other pharmacopoeias is not as well understood, but typically correlates to the
monograph requirements, including development internally. This time- that must be further refined for a
additional laboratory effort needed frame is intended to give due regard specific product situation, but there
to investigate proposed methods to applicable intellectual property are several benefits to targeting this
and limits—which are likely based and patent considerations, while period for monograph development.
on information from another com- advancing its public policy goal of These include input from a single
pany—poses potentially greater ensuring that a monograph is avail- source, simplifying the process for
demands on available resources able for review and approval of fol- the pharmacopoeias, resulting in the
within a company. low-on or multi-source versions of innovator company criteria being
The US Pharmacopeial the product. There is an additional included in the monograph. The
Convention (USP) has recognized downside associated specifically with monograph would not block market
that some manufacturers may not USP monograph development; the entry of other companies, follow-
wish to submit a monograph until a potential impact on product labeling ing existing legal and regulatory sys-
product approaches multi-source sta- that may result from the USP flexible tems, but would establish the quality
tus, although its policy is to first seek monograph approach, if a company’s standard that all subsequent compa-
to work exclusively with an approved methods or acceptance criteria are nies must meet to gain approval for
manufacturer (typically the rele- not listed as “Test 1” in the mono- the product. Additionally, the USP
vant patent holder) until approxi- graph (19). flexible monograph approach will
mately five years prior to potential This means that in practical not impact the innovator’s labeling
generic entry (18). If the manufac- terms, the time between five years because its methods will be desig-
turer remains unwilling or unable post-approval to five years pre-pat- nated as “Test 1” when subsequent
to provide the necessary informa- ent expiry may be “just right” for revisions are introduced in the
tion, USP may work with another establishing monographs for drug monograph to reflect products from
manufacturer willing to sponsor a substances and products. This time- other companies. The information
submission or begin monograph frame represents a fairly broad range provided by the innovator com-
pany in the monograph submission and how to approach prospective 6. J.M. Wiggins and J.A. Albanese,
“Revision Process for Global/National
reflects greater process and analytical or informal harmonization of the Pharmacopoeias,” BioPharm International
experience with the product, reduc- monograph. These additional points Regulatory Sourcebook eBook 14-24
(December 2019).
ing the likelihood of revisions due to are detailed in a companion arti-
7. J.M. Wiggins and J.A. Albanese,
additional product knowledge and cle (20), which can be accessed at “Surveillance Process for Industry:
any associated regulatory updates. BioPharmInternational.com by click- Monitoring Pharmacopoeia Revisions,”
Pharmaceutical Technology Regulatory
The reference standards provided ing here. Sourcebook eBook 26-39 (December
by the innovator company to the 2019).
8 . WHO, “Good Pharmacopoeial
pharmacopoeias in support of the CONCLUSION Practices,” in WHO Expert Committee
monograph tests will become the The value of monographs is in the on Specifications for Pharmaceutical
official compendial reference stan- publicly available quality standards Preparations Fiftieth Report, Technical
Report Series No. 996, Annex 1, 67-85
dard, eliminating the work required they provide for drug substances (2016).
to demonstrate comparability of the and products, and the benefits for a 9. E. Charton, “The Role of European
Pharmacopoeia Monographs in Setting
in-house standard against the com- company to actively participate in Quality Standards for Biotherapeutic
pendial standard. the monograph development pro- Products,” Presentation at the European
Perhaps one of the most signifi- cess are clear, with considerations Pharmacopoeia Conference: Tackling
Future Challenges of the Quality of
cant benefits for an innovator com- for the optimal timing for a spe- Medicines, Tallinn, Estonia (Sept. 27–28,
pany in submitting a monograph cific monograph submission. The 2016).
10. Medicines and Healthcare Products
when theirs is the only approved next article returns to the chal- Regulatory Agency, “Strategy for
product is the opportunity to pursue lenges of pharmacopoeia compli- Pharmacopoeial Public Quality Standards
for Biological Medicines,” gov.uk (2019).
prospective or informal harmoniza- ance through an illustration of the
11. F. Atouf, “Latest Updates from USP on
tion in establishing the monograph difficulty with monograph require- Standards for Biologics/Cell and Gene
across multiple pharmacopoeias ments, which may differ from Therapy,” Presentation at Pharmacopeial
Interest Group Meeting, 2019 PDA/
(see Sidebar). In the final analysis, approved product registrations, FDA Joint Regulatory Conference,
a company’s decision of whether even when a company is proactive (Washington, DC, Sept. 16-18, 2019).
12. EDQM, “Elaborate a Monograph–
and when to submit monographs in the development process. Procedure 4” EDQM.eu (2013).
for drug substances and products is 13. EMA, “European Medicines Agency Post-
critical to helping ensure compliance ACKNOWLEDGMENT Authorisation Procedural Advice for Users
of the Centralised Procedure” (Dec. 20,
with the requirements contained The authors gratefully acknowl- 2019).
in the monographs. A company edge the contribution of Susan J. 14. EDQM, The Ph. Eur. Work Programme:
Elaboration & Revision, EDQM.eu.
can leverage the knowledge gained Schniepp for her technical review 15. EDQM, “Elaborate or Revise a
during the monograph elabora- and helpful suggestions during the Monograph–Procedure 1” (2013), EDQM.
tion process, including anticipated preparation of this series of articles. eu.
16. USP, “Prospective Harmonization:
changes to test methods and limits, A Donor Model to Common Testing
to plan for implementation of the REFERENCES Requirements,” Advanced Briefing
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Necessary,” BioPharm International 2014).
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Commission Enters A New Era! Adoption
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