Quality Control of Insulins and Biosimilar Insulins

Background

The quality of drugs manufactured for human use is something all of us assume to be a fundamental right as health care consumers. Once the manufacturing process is complete all pills/insulin vials/pens should look like the preceding lots produced. We take it for granted that the quality control system each manufacturer is required to have is working efficiently, that is, that any batches of insulin that do not fulfill minimum specifications will be quarantined and will not enter the market. This is at least the theory; however, it might not always be the case, at least not in all countries/regulatory worlds and we now have a global supply chain to consider. The object of this editorial is to openly discuss aspects that could have an impact on the quality of insulin available in this new global market. It is not our intent to find fault with any manufacturer of insulin (might it be the originators or those who manufacture biosimilar insulins), but to increase awareness of a lack of knowledge/information about this topic.

Manufacturing

Manufacturing of biologics is a highly complex process with many variables that are not easy to control. Therefore, there are good (statistical) chances that something may go wrong with a given batch and the final product does not fulfill the minimum quality requirements. Unfortunately we have no information about how much money may be lost by the manufacturer due to the costs incurred with bringing all the necessary ingredients for filling a fermenter with a bacteria or yeast broth and all associated processing and purification steps required. The assumption is that this type of event is included in risk assessment as being within reasonable cost of production, that is, throwing away the biologic protein collected after a full production cycle for not meeting minimum specifications is something that should not happen too often (something that may be a daily business decision in other highly complex manufacturing systems such as the production of computer chips). Given this financial risk there may be internal economic pressure to declare a batch as OK for global distribution if the specifications fall just outside the allowed variance limits. In principle, the people that are doing quality control shall be independent from such considerations and report to the upper management without fear of repercussion.

To ensure that rigid quality management has taken place regulatory agencies should, and in many markets do, inspect pharmaceutical companies without announcement. Given the proprietary nature of each manufacturer’s process, our knowledge about batch-to-batch variability is low; however, there are at least hints in literature showing differences in miscellaneous protein content for glargine products.¹ The authors invite all insulin manufacturers to share their internal quality standard ranges for final product potency and miscellaneous protein content. Meeting the minimum established standards has been proven to be sufficient for regulatory approval and initial market acceptance but maintaining these standards over time can be difficult. Additional steps taken and/or tighter internal ranges applied to help ensure lot-to-lot quality could help in determining future interchangeability if that designation is desired.

Inspections

One measure that was established by the regulatory authorities to ensure high quality of drug and medical device manufacturing is that regulatory bodies like the FDA inspect the plants in which the products are manufactured with irregular regularity. During these visits they also carefully check the quality control system that each manufacturer has to have in place. Each manufacturer can tell long stories about inspectors that inspect a variety of different types of manufacturing plants and their methods of controlling and checking every little detail and SOP, but without having a full understanding of the entire manufacturing process. All manufacturers have specific routines or protocols established to handle inspections. However, for example the FDA has stated that their travel budgets are limited, so they can’t inspect all plants in other countries that produce drugs/insulin for the US or EU market in as timely of a fashion as they might want. In addition, such inspections may have to be announced due to different rules that exist in other countries. Any preannounced inspection allows time for manufacturers to have their paperwork in order and key personnel available to address concerns or findings which reduces the inspector’s advantage of surprise.

Patient Experience

One of the advantages of insulin is, if the metabolic effect of a given insulin dose is not sufficient, that is, blood glucose remains too high, the patient is empowered to adjust the next dose to control glycemia more adequately again. This is at least what patients do that are on an intensified insulin regimen, the story is bit different with a fixed insulin dose regimen. If blood glucose is too high, the usual assumption is the patient has not estimated the amount of carbohydrates in a given meal adequately, did not calculate or prepare the appropriate insulin dose correctly (which can be an issue with NPH insulin not mixed sufficiently), did not leave the needle in as long as they should, and so on. That a given vial or pen of insulin might differ in concentration or protein content from a previous one the metabolic effect induced is a rarely considered option for health care professionals. Nevertheless, personal interactions with patients have raised questions about varying potency of different lots of the same brand insulin. Occasionally different patients ask why the “last box of pens or vial” required a higher dose than previous ones did. Our standard reply is diet, exercise (or many other factors that might influence insulin sensitivity), timing or lot of test strips may have been different but patients denied any changes. New product dispensing often resulted in return to earlier doses used. The question becomes: was the lot of insulin subpotent or, were previous ones super-potent? Bottom line is, there are many sources of variations present that could impact patient outcome; however, the consideration that the potency/quality of the lot of insulin may vary is usually not taken into consideration. It should be noted that it is not just during the manufacturing process that issues can occur but also during storage and transport the potency/quality of insulin could be hampered. When it comes to biosimilar insulins, the question is: will such issues show up more often? Clearly the manufacturing capabilities of established and new insulin manufacturers do not differ in principal from each other, that is, countries outside the US and EU can manufacture insulin of high quality under exacting conditions. Our point is that the shortage of consumer and provider knowledge about long-term quality of manufacturing and batch-to-batch variability (again, this holds true for all drug and device manufacturers).

Erythropoetin and Other Biosimilars

The concern of sufficient quality is clearly not limited to biosimilar insulin but also holds true for other biosimilars. There are reports about considerable differences between batches of erythropoetin.² Potency difference and immunogenicity concerns have also been reported with other biosimilar products.^3,4

Given the complexity in the manufacture and purification of therapeutic protein drugs the question becomes; how does the provider and consumer determine that there are not significant differences between lots of same manufacturer? Simply no independent institution has regularly bothered to check this given the costs involved and the need for appropriate equipment available to conduct sophisticated tests.

Interchangeability and Substitution

Approval of biosimilarity does not mean that a given biosimilar is interchangeable, that is, that a prescription for a given insulin formulation can be changed to that of another insulin with presumably the same formulation but with a lower price. The requirements for a biosimilar to become interchangeable (which is a property) are higher; however, it is not completely clear what this means in reality. For example in the US the FDA has described 3 different levels: biosimilar, highly biosimilar and highly biosimilar with a fingerprint similarity. The policy toward substitution is a process that means not providing the patient with the insulin the physician has prescribed but with a biosimilar one. This differs between countries and even within a given country, like it is the case in the US. A number of states in the US try to promote substitution to enable cost savings but have conflicting guidelines for biosimilar products.⁵ In an effort to educate prescribers, nurses and pharmacists about biosimilar products the FDA has just released a free Continuing Education Course. This course will help in understanding how a biosimilar can be prescribed and dispensed and how and when an interchangeable product can be substituted for another biologically similar product.⁶

Independent Evaluation of Quality

One option to solve this issue is to support independent evaluation of insulin quality. Well established, fully equipped labs do exist that can serve as reference sources. A stepwise approach is likely the most reasonable:

• - The first step for such an evaluation is a more analytical one, that is, in a specialized lab protein content, types of protein, and so on are measured by HPLC or highly sensitive QTOF spectrometry. An additional genomics test could be performed to validate cell culture source as indicated by the manufacturer label. If differences are observed between insulins/batches when compared to FDA/EMA approval baseline standards provided by manufacturers both the regulatory agency and the manufacturer would be notified of the nonconforming lot. Additional sample containers of the nonconforming lot would be subjected to the same testing to confirm results. If approval baseline standards are not provided, sample lots would be compared to the average range of potency and miscellaneous protein content of 3 different lots of laboratory sourced product drawn from the supply pipeline. Any product found to be out of the potency range of ±5% and/or containing greater than perhaps 10% variation in miscellaneous protein content when compared to baseline should be evaluated under in-vivo conditions. Such a comparison relies critically on the quality definition of a “reference insulin.” In the evaluation of biosimilarity this may default to the originator insulin standards used for its market approval. For parity, random samples of both the originator insulin product and the biosimilar product should be periodically drawn from the supply pipeline and compared to the original reference insulin data on file. Information generated could also help determine when and where supply chain management may impact product quality.

• - In the second step of such an evaluation a “clinical study” with glucose clamps would be performed in healthy subjects or patients with type 1 diabetes to evaluate the time-action profiles of such insulin under highly standardized conditions. There are good reasons why regulatory authorities do not rely purely on analytical data but require performance of in-vivo studies/glucose clamps for market approval. In lieu of long-term product comparison clinical trials the sample lot content data recorded in Step 1, along with pharmacy dispensing and billing records of insulin products, could be made available for cross reference to the FDA Sentinel program database. Aggregate Medicare/Medicaid claims data indicating any spikes in treated and billed adverse effects such as hyper/hypoglycemia and immunogenic reactions could be readily traced to geographic area and narrow the search for specific product substitution impact or supply chain issues involving excess heat or cold shipping/storage conditions.

As even the most advanced and modern analytical tools do not allow adequate description of the metabolic effect of insulins this stepwise approach should to be discussed as a valid option for assurance of product quality and improving patient safety.

Source of the Batches

If such measurements are performed randomly in, for example, up to 3 different lots of each type of insulin once per year or biannually, this would provide insight into the quality of insulin that is circulating in the global market. Ideally these batches would be purchased in different market regions. It might be that a given manufacturer distributes select batches of the same product with different quality to different market areas where the risks that the lesser quality product may be discovered are lower.

With India pushing to produce biosimilar insulin for local and global distribution quality could become an issue given some manufacturers recent history with small molecule production quality and knowledge that no one is checking the actual product distributed, just the plant conditions and paperwork.

As stated earlier, an issue with this approach is that differences between batches might be induced by differences in the cold chain transportation required for adequate handling of sensitive drugs like insulin. Maintaining adequate shipping and storage conditions is a problem all manufacturers face and should be included in their overall quality review systems. Control of the cold supply chain is of particular concern for some portions of the US and Europe as well as large areas of Asia, China, Africa, and the Middle East where diabetes is becoming more prevalent.

Golden Batch

One might wonder how a manufacturer could get a market approval for their drug when later questions arise surrounding the quality of the same drug reported to be produced in the same way. Initially the manufacturer may have produced a good or excellent “golden” batch by carefully following their manufacturing standards for the initial approval process. Later, as production volume increases, they may provide inspectors a paper trail that indicates that appropriate quality measures are in place and being followed, and that only minute differences between batches exist. However, they are not required to regularly report about the quality of their product to anyone outside their company’s internal management. Regulatory agencies lack the resources to check every step of the production process and must rely on the honor system for portions of their inspection. Trust but verify should be the regulatory gold standard but system constraints result in lesser quality product occasionally reaching the consumer. Waiting until a noticeable increase in adverse event reporting occurs introduces a delay in official action and tracing where the problem lies takes additional time and expense by both enforcement officials and manufacturers. In order to reduce existing gaps in the system the samples used for an external and independent quality assurance program should be bought from different sources in the field. If possible at least 3 lot batches of the same insulin should be evaluated in a head-to-head comparison to see if differences between batches exist and, if so, how prominent they are.

Funding of Such Quality Evaluations

A major issue is funding of such evaluations. Who would be motivated to fund such studies? If the funding comes solely from original manufacturers they could be perceived as trying to protect market share even though independently determined differences in quality (if any) may be real. Companies that are new or desire to enter the market could regard this as an additional regulatory step that is not required by any law—why should they finance such an activity?

One option might be to involve a patient advocacy organization like the JDRF for truly independent funding. However, they regard themselves more as a research supporting institution trying to find a solution to cure diabetes. Also in view of the costs that are associated with regular quality evaluations they might say, this is not our business, it’s a regulatory issue. As long as no external or regulatory pressure exists for more in-depth quality evaluations it might be difficult to find sufficient funding to support ongoing efforts in biosimilar evaluation. Linking data collected to the FDA Sentinel program to help close the product quality evaluation loop might be an option but that program operates as a public/private partnership with limited funding sources as well.

If consumer, provider and manufacturer support for such a program is present, funding could come from a fee paid by all bio-therapeutic manufacturers that would be pooled for independent testing. A fee of 5 cents a pen/vial of insulin produced for US distribution could generate as much as $2 million a year. This total assumes an average of 10 pen units (2 boxes of 5 pens) or 10 ml vials dispensed daily 5 days a week in 16 000 US retail pharmacies, not including mail order distribution or the VA system, and would be sufficient to support random pipeline tests while remaining affordable to both consumer and manufacturer. This measure would help manufacturers in improving quality control (if needed) before shipment and lower costs of possible recall and/or reduce risk of intensive regulatory investigation and penalty. Over time the system could also help identify issues in the cold supply chain that need correction. The EMA could support similar funding options to support testing in Europe. A potential downside for branded insulins is that the biosimilar insulins might be found to be of equal quality!

Many of the topics discussed above might sound theoretical, trying to create an issue where none exists; however, things might change from one moment to another if significant differences between content or potency of insulins that are on the market is found. Independent validation of biologic product quality by recognized neutral parties could go a long way when other biosimilar products reach the market. Formulary inclusion as the preferred product is critical to a manufacturer’s market share, if no direct head-to-head comparison evaluations are available for the plan formulary committee to review the product choice falls to cost comparison only. Without data at hand one cannot argue that one product is possibly better than the other.

Ways Ahead

We see the need for a joint effort by all parties interested in this topic: patients, physicians, pharmacists, payers, and manufacturers. An independent organization should take a leading/coordinating role in this respect. Quality evaluation can be performed by independent experts/institutions and should be ideally performed in parallel in a European reference lab and a US reference lab for confirmation of each other’s work. Ideally such evaluations would be performed by the same sites over and over again using the same methodology to guarantee sufficient quality at the evaluation site.

The key question at the end is, if significant quality issues are encountered during such evaluations, what are the consequences? In order to have a relevance the regulatory authorities and manufacturer should be notified of lot nonconformance, the evaluation should be repeated (by a second site?) to make sure that the observed differences are real and such results should be publicized to users.

Biosimilar Insulin and Other Biosimilars

Due to its high importance is might be that insulin is a front-runner again, like it was the case with the first description of the molecular structure of a protein, the first protein that was produced with recombinant technologies, and so on. If the quality of biosimilar insulins is evaluated in a well described and highly transparent process, this might act as a “proof of concept” for other biosimilars as well. One can anticipate the need for larger and more complex biosimilar (like monoclonal antibodies) comparison evaluation, with insulin serving as part of the validation process for sophisticated equipment. With such biologics considerable genomic capabilities/experience could be useful in cell culture identification both prospectively and retrospectively. Combining both might be useful in quality control and not as prohibitively expensive as one might think when scaled up a bit. Careful structuring of process and uniform recording of findings would be essential.

Summary

In summary, the issue of batch-to-batch differences and therefore certain quality issues should be discussed more openly and diabetologists should be aware of the fact that when a patient complains about differences in the metabolic effect of a given insulin, that they should not immediately assume changes in the patient’s habits as the cause, but should consider that the patient is right in suspecting their insulin may be the issue. We should understand more in detail what is happening at the manufacturing front and how the quality of drugs used in diabetes treatment is guaranteed with each supplier. To clarify this again, this is not attempt to support an established insulin manufacturer and keep newcomers from the insulin market, it is somewhat a call for action to take the issue of a sufficient quality control method applicable for each insulin vial as a serious one.

Our hope is that this editorial helps to drive regulatory agencies and manufacturers toward a common goal of maintaining the best quality possible and thus their reputations as well. Waiting for something bad to happen before we act is not an option, especially for insulin!