As larger pharmaceutical companies continue the reciprocal of mergers and acquisitions (M&A), namely divestitures and outsourcing, the pressure is on contract manufacturers to be at least as good as the company that developed the dosage form. That is because product developers are outsourcing production of proprietary products while they are still under patent protection. This means producing not a close imitation to a marketed product, which, I believe, is the definition of generic, but one which is identical, such that there is no difference in content, visual appearance, or performance.

Making an “equivalent” to an existing small molecule product is difficult enough for a company not involved in its development, but when you include the provisions of the Question-based Review (QbR) Guidance, it becomes more arduous. The QbR for Generic Drugs: An Enhanced Pharmaceutical Quality Assessment System, has as one of its main thrusts requiring ANDAs (Amended New Drug Applications) from disparate companies follow a common form for style. Previously, when each of the large number of generic companies submitted their documents, each used their own internal style. This resulted in reviewers at the U.S. FDA having to navigate dozens of different types of applications, causing long wait times for the generics to get a yes/no answer on their new product’s fate. Imagine an English teacher allowing each student to write a term paper in his/her individual manner. The result would be chaos. This style requirement, alone, made the Guidance an excellent idea and, like a class receiving a term paper assignment, they all understood what was needed and in what order it should be presented. This did, indeed, speed up review times.

Unfortunately, it also included some responsibilities for the generic company that were new to them. The responsibility for the purity of the product was extended to both earlier and later than had been the case previously. The existing responsibility was to “simply” produce a product, often covered by a monograph in the USP, that met the requirements of purity, assay, disintegration or dissolution times, and so on. Prior to QbR, it was sufficient to depend on the Certificate of Analysis (CoA) for purity, potency, etc. of an active pharmaceutical ingredient (API).

But, under new Guidances for both FDA and ICH, the generic drug company, including contract manufacturing organizations (CMOs), now needs to ascertain the synthesis route for the API such that they can prove (validate) that their incoming RM testing and stability-indicating assays can identify and quantify any breakdown product from the synthesis of any of API, no matter the synthesis route by which they were produced. This extends to stability programs: each analysis method must be capable of finding and quantifying materials from the breakdown of the dosage form APIs.

This means a constant feed-back loop between suppliers and the company’s labs, such that any analytical method can separate any and all potential by-products from synthesis and any and all break-down products from stability samples. Now, in a normal or traditional generic company or contract manufacturing facility, there are a number of trained analytical chemists, allowing the methods to morph to the specificity needed. It only adds a small amount of labor and time to the existing workload when small molecules are involved.

However, when it comes to biological or biosimilar production and sales, all bets are off. Whether the CMO is producing a biological product that was the “original”—under contract to the patent-holder—or generating a product that is “similar,” the process is far more complicated than merely mixing powders and compressing a tablet or encapsulating the mix into a capsule. Understanding the effects of an API on the final dosage form is even covered in ICH Q11:

“The identification of CQAs (critical quality attributes) for complex products can be challenging. Biotechnological/biological products, for example, typically possess such a large number of quality attributes that it might not be possible to fully evaluate the impact on safety and efficacy of each one. Risk assessments can be performed to rank or prioritize quality attributes. Prior knowledge can be used at the beginning of development and assessments can be iteratively updated with development data (including data from nonclinical and clinical studies) during the lifecycle. Knowledge regarding mechanism of action and biological characterization, such as studies evaluating structure-function relationships, can contribute to the assessment of risk for some product attributes.”

This control/understanding of biologicals for the companies who have developed the drug is difficult enough, even with a large number of biochemists, molecular biologists, analytical and QC chemists. For smaller companies—both producers of the bioproducts and the generics who package them as dosage forms—largely used to performing small molecule analyses, this makes the task even more difficult. There are two levels of difficulty for a company to prepare to be able to produce and analyze biologically produced medicines:

1. Previously Characterized Bio-Product
This would be a biologically-produced drug substance, developed and patented by a major company and contracted to a CMO for production and distribution.

• Even if all the preliminary analytical and process procedures are worked out by the initiator company, the CMO/generic will need to add analysts familiar with bioassays, purchase new equipment, and such. There will be a relatively small monetary outlay and time to full speed, assuming guidance by the parent company.
• If the synthesis is done in-house, the facilities need to be expanded and more specialists added to staff. If the API is made by the CMO, all the necessary facilities need to be installed, unless they are already equipped for biosynthesis.

2. New Synthesis Route for API or “Biosimilar”
In this case, we still have the needs of analysts and analytical equipment for analyses, hardware and biochemists to make and purify the API, and all the equipment needed for example number one, plus the need to:

• Isolate any and all byproducts from the expression and determine the effects of each, both short- and long-term, on patients. For example, if a strain of e coli was used to produce the protein. While the major component of the bioreaction may be “identical” to the patented entity, the secondary molecules are likely to be different.

This will require a level of expertise above merely isolating and following the byproducts from a previously well-researched and characterized API. It will necessitate that the CMO either receives significant technical support from a larger (parent/client) company, or greatly expand its staff and equipment. For example, more stability ovens may be in order, as well as the chromatographs, mass spectrometers, and so forth, which will lead to staff increases to run this additional equipment.

• Develop stability methodology to follow the major and minor components of the “biosimilar” to be able to track potential toxic effects. This requires considerable analytical development time and effort and would require biological testing of the short- and long-term effects in patients.

This last point may be the most critical. When a small molecule is synthesized, the initial chemicals, in-process materials, and potential by-products are relatively simple to elucidate. This makes assay methods and evaluation of the results relatively straightforward. There are tests for carcinogenicity and mutagenicity available, and have been for decades, for small molecules. There are commonly used parameters for limits on breakdown products and impurities (USP, for example) for easily identified chemicals.

With biological impurities, often proteins not seen previously, the stakes are potentially higher. Not only are there potential carcinogenicity and mutagenicity dangers, but, with unknown proteins, there are also potential immediate allergic reactions. Assuming there are no immediate reactions, there are potential long-term potential harmful effects, depending on the therapy for which the biological is being used. If the drug is a one-time application, such as heparin, there would not likely be a chance for the minor impurities to do much harm. On the other hand, long-term use of a bio-drug such as insulin, often used for decades, would allow even the smallest impurity the time to do harm to the patient.

One might assume that a company that develops an NDE (new drug entity), based on a bioprocess, will spend years assessing potential harmful effects. A biosimilar would have, by definition, less time for any potential side-products to be evaluated before marketing. While the major active may be identical to the patented one, any biological process expresses numerous proteins, each particular to the mode of expression. When all is said and done—excluding potential lawsuits for patent-infringement, etc.—the most problematic feature of any biosimilar will be the exotic side products and potential side-effects.

Considering the benefits to patients both therapeutic and financial, I truly wish that biosimilars can be produced safely. In any case, when contract manufacturers and/or generic companies embark on the bioprocessing trek, they will need to staff up with some experienced biochemists and such and do some bio-testing, if not their own clinical studies. But, in the end, the work is worth it.

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Emil W. Ciurczak
DoraMaxx Consulting

Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.