Poor Biosimilarity Practices, Impurities and New Technologies Debated At European Pharmacopoeia Event
Executive Summary
Some regulators are wrongly using monographs rather than a biosimilarity exercise to show comparability of a biosimilar with its reference product, it was suggested at the European Pharmacopoiea’s latest conference. Also discussed were issues such as how to align the PhEur with the new ICH guideline on elemental impurities, and how advances in technology are being dealt with.
A number of key international product quality issues were discussed at the European Pharmacopoeia Conference in Tallinn, Estonia, last week, including the misuse of pharmacopoeial monographs to demonstrate biosimilarity in some countries with “less stringent” regulations. In addition, there was discussion on the need to align the European Pharmacopoeia (PhEur) with the new International Conference on Harmonisation guideline on elemental impurities.
Also debated in conference workshops were the implications for pharmacopoeias of new technologies such as continuous manufacturing, developments in chemometrics, spectroscopy and process analytical technology (PAT), and progress with a pilot on monoclonal antibody monographs, starting with infliximab.
Participants at the conference came from a total of 41 different countries including Brazil, Canada, India, Japan, South Africa, Taiwan and the US, as well as the World Health Organization. There was also a mix of representatives from regulators and industry “because we wanted all the stakeholders around the table for an open and frank exchange,” according to Susanne Keitel, director of the European Department for the Quality of Medicines and Healthcare (EDQM), which operates the PhEur.
“The meeting was quite intense,” Keitel declared. “I am very happy, it went very nicely and we got a lot of information to digest and discuss with the European Pharmacopoeia Commission.”
One key issue was the question of establishing biosimilarity with a reference drug, amid suggestions that some regulators around the world are using the pharmacopoeial monograph as proof, rather than a proper biosimilarity exercise. The topic was discussed at a workshop on setting pharmacopoeial standards for biotherapeutic products.
“During the discussion it emerged that there is a perception, and probably not only a perception, that while people in developed parts of world understand the intention of a monograph that also covers biosimilars, there are some regions of the world where not so stringent regulators might think that compliance with the pharmacopoieal monograph is basically a demonstration of biosimilarity,” Keitel told the Pink Sheet in an interview. “That of course is not the case.”
Latin America seems to be one of the trouble spots in this respect, Keitel said, noting the decree that was passed in Colombia in 2014 and, to the consternation of the R&D-based industry, introduced an “abbreviated” route for the approval of versions of originator biologic drugs. (Also see "Colombian decree will allow 'non-comparable' biologics, say R&D firms" - Pink Sheet, 1 Oct, 2014.)
“The pharmacopoeial monograph cannot and is not intended to replace demonstration of biosimilarity”
Rather than a full regulatory assessment, that decree stated that biosimilarity could be demonstrated by compliance with the monograph, according to Keitel. “So there are clear cases where that has happened. Clearly the pharmacopoeial monograph cannot and is not intended to replace demonstration of biosimilarity.”
She said that “of course there is a need for flexibility in monographs on biotherapeutic products, because these products are heterogeneous, even different batches of one [reference biological] product are not as identical as you would expect in the case of small molecules. But if you are too flexible then what is the meaning of a monograph?”
She also noted that the European Pharmacopoeia Commission was working on a pilot phase for drafting texts on monoclonal antibodies, using infliximab as a case study. The commission said in June this year that it would publish a draft monograph on infliximab (possibly during October) to collect comments from users, although it said a decision as to whether to publish a final monograph would be taken on the basis of a public consultation.
In respect of the concerns about monographs being used to show biosimilarity, Keitel said it would be good to have the infliximab draft monograph as a concrete example “because then it is easier to discuss it.”
One of the conclusions from the workshop was there was “room for improvement as regards training and capacity building, for regulators as well as for industry,” she said. This is an area where the WHO could play a role, she noted, adding that the EDQM is also planning to publish a scientific article on the difference between the intention of monograph and the demonstration of biosimilarity. “This is clearly something we will take on board, and it will probably be published within a month.”
Impact Of ICH Q3D Guideline
Another topic addressed during a workshop at the meeting was ICH guideline Q3D, which outlines a risk-based approach to assessing and controlling elemental impurities in drug products and establishes permitted daily exposures (PDEs) for elements of toxicological concern. Keitel said that this guideline was in a way “a new paradigm because, in contrast to other purity guidelines, it focuses on the control of elemental impurities at the level of the finished product” although she added that it also allows for an option to control them at the component level.
The guideline, which was signed off at the end of 2014, came into effect in Europe for new marketing authorization applications in June 2016, and will apply to already authorized medicines from December 2017.
The guideline has replaced that of the European Medicines Agency’s scientific committee, the CHMP, but there is also a need to align the PhEur with the guideline and to ensure a consistent approach between the regulatory authorities and the European Pharmacopoeia Commission, Keitel said.
Under this process, chapter 5.20 of the PhEur, which deals with metal catalyst and metal reagent residues, will be replaced with a verbatim copy of the ICH Q3D guideline. However, just reproducing a guideline in a PhEur chapter does not make it legally binding – to do so it must be referenced in a PhEur monograph.
“What we presented [at the meeting] were the general strategy and proposals for the revision of our general monographs on pharmaceutical preparations [2619] and on substances for pharmaceutical use [2034],” Keitel said. The idea is to add a cross reference in monograph 2619 to the revised chapter 5.20, while for monograph 2034 there is a need to clarify how to handle substances used in drug products that are outside the scope of the guideline, she added.
“It was important for us to get feedback from users because [the proposals] are due for adoption at the upcoming November session of the pharmacopoeia commission and we wanted to be sure they had input from all stakeholders.”
Continuous Manufacturing
Keitel also flagged up another development that has implications for the PhEur and that was discussed at the conference: continuous manufacturing. This is a concept that is increasingly being used by manufacturers, particularly larger ones with high-selling drugs, to make manufacturing more efficient. Among those involved are GlaxoSmithKline PLC, Johnson & Johnson and Novartis AG. The technology was discussed at an American Association of Pharmaceutical Scientists meeting last year. (Also see "Industry Proponents Make the Case for Continuous Manufacturing" - Pink Sheet, 29 Apr, 2015.)
According to Novartis, which has set up the Novartis-MIT Center for Continuous Manufacturing with the Massachusetts Institute of Technology in Boston, US, continuous manufacturing speeds up new drug introductions through efficient production processes, allows the use of smaller production facilities, saves on waste, energy and raw materials, and allows drug quality to be monitored on a continuous basis rather than through post-production, batch-based testing.
“The European Pharmacopoeia supports the introduction of continuous manufacturing”
“Personally I was very happy,” Keitel said, “because from our side the request was ‘what can we do to support you?’ And the response from the person from Novartis who made this presentation was that he was happy with the current general chapters and he mentioned chemometrics and Raman spectrometry as examples, and also the flexibility provided in the general notices in the PhEur. So there was a clear statement that the European Pharmacopoeia supports the introduction of continuous manufacturing.”
She said she believed there were advantages for the pharmaceutical industry here. “The technology is already broadly used in food and other industries, and the pharmaceutical industry is introducing it, but I personally don’t think it will be the technology for the future for every single product and every manufacturer as it requires quite a lot of upfront investment, but it definitely sounds very interesting for blockbuster products. Of course a number of issues will need to be addressed over time, [and] there will be lots of discussions between industry and regulators.”
New Technologies
The PhEur is pressing on with its internal harmonization initiative to ensure that the general monographs elaborated over time follow the same structure, and at the same time it is embracing new technologies, Keitel said, such as chemometrics and Raman spectroscopy, a form of vibrational spectroscopy that is used to produce a “molecular fingerprint” to identify compounds.
The revised general chapter on Raman spectroscopy was published in January this year, when the EDQM noted that this technique is being increasingly used in pharmaceutical applications such as verifying raw materials and manufacturing quality control, and for the identification and characterization of material in the lab environment. It is also being used in process analytical technology (PAT) and for chemical imaging. One aim of the revised chapter was to ensure its full applicability to the potential use of this technique in a PAT environment, the EDQM said.
The conference also featured a presentation on chemometrics and chemical imaging – these general chapters of the PhEur are not legally binding “but the feeling was they served as a good basis for discussions with authorities,” Keitel said. “These are sometimes very specific technologies and not every assessor or every single pharmaceutical company might be up to speed with them,” she suggested. The possibility of using chemical imaging outside the scope of the PhEur, for example in identifying counterfeit products, was also brought up.
As for harmonization among the various pharmacopeias, Keitel said there was a wish that good pharmacopoieal practices “should be linked to the websites of all the collaborating pharmacopeias to give broader visibility. Also, people are often confused about the multitude of international activities that were explained in one of the plenary presentations,” she added.
“But overall everyone agrees that there is a need for harmonization beyond the Pharmacopoeial Discussion Group, because the PDG is us, Japan and the US Pharmacopeia, and the question we often get is, how do you interact with the Indian and Chinese pharmacopoeias? There I think good pharmacopoeial practices play a crucial role.”
Asked whether there was any representation from these last two countries at the conference, Keitel said there was a representative from India but not from China. “The problem was one of timing – two weeks after the seventh meeting of world pharmacopoieas in Japan on Sept. 13-14. This was unfortunate and we knew from the beginning that many representatives of sister pharmacopoeias would not want to travel too much. But we did have someone from Anvisa [the Brazilian regulator] responsible for the Brazilian pharmacopoeia.”
From the editors of Scrip Regulatory Affairs.