Need to Know about CMC Regulatory Affairs? Consider What Makes a Great Philly Cheesesteak!

Helping Our Best Clients Accept A Healthy Level of Regulatory CMC Risk (Ed or Op-ed?)
May 22, 2019

This blog provides an overview of CMC information which should be reviewed as part of routine activities in drug development.

Everyone wants to know where to find the best Philly cheesesteak (what goes into it and where it’s made), but there’s not a definitive answer as there’s no perfect or secret recipe (just as there are no two drug development programs that progress the same). The argument of what, where, how, and when will never be totally settled because it’s truly a matter of personal preference.

Like a great Philly cheesesteak, to appropriately develop a pharmaceutical or biologic specific process and finished product, product characteristics and specifications must be well-defined in order to ensure that the product is safe, effective and consistent. These activities are known as CMC, or chemistry, manufacturing and control.

All stages of the drug development life cycle involve CMC. During preclinical drug development, the proper analytical methods are qualified and validated to ensure the product is consistent with expectations. Stability testing is initiated, the physicochemical properties of the product are determined, raw materials are chosen and tested. When development moves into the clinical stage, additional characterization of the drug product is needed. As clinical trials progress, any scaled-up process must ensure that the larger batches are the same and meet the same specifications as the drug tested in earlier trials. After the manufacturing process is qualified, lot release and in process testing should continue to take place.

So, what makes a drug development program then? Much like a Philly cheesesteak, the pursuit of greatness is the assurance that any given compound meets requisite technical and quality elements in each stage of development to allow for the ultimate successful commercialization of the drug.

When it comes to Philly cheesesteaks, some people like the rolls toasted and crispy while others prefer them soft and chewy. Some like it dripping with grease, while others complain that too much grease makes the roll soggy. Some like the meat diced as thinly as possible, while others prefer slightly larger slices or small chunks. Much like managing all the CMC Regulatory Affairs activities during development the requirements to achieve the preparation of a drug product, there’s no perfect or secret recipe.

Learn the facts about the key ingredients that go into making any great cheesesteak. Once you do, there are plenty of great cheesesteak “manufacturers” to try to figure out your own personal favorite. But first, be sure to read up on How to Order a Philly Cheesesteak so you’ll look cool while doing it.

The Roll – much like the General Properties of a Drug Substance, and the Composition and Excipients of its Dosage Form (Modules 3.2.S.1, 3.2.P.1 and 3.2.P.4)

All great cheesesteaks start with a solid Roll. It should be chewy, not too airy or too tough. But no matter what, the roll should have some chew. While potato rolls are just fine for hot dogs or lobster salad, they do not cut it for a cheesesteak.

In a similar manner, the physical and chemical properties of the drug substance, the active ingredient within the drug product, must be understood in order to develop an adequate formulation. The rationalization of the selection of the salt or free acid/base for example should be considered regarding the resultant quality of the drug substance and the ability to formulate the drug product.

The purity profile for multiple lots should be examined. Reversed phase High Performance Liquid Chromatography (HPLC) is typically employed for the analysis. Is the purity profile reproducible? Are impurities at International Conference of Harmonization (ICH) thresholds appropriately reported, identified, and qualified?

An examination of the solution stability of the drug substance in various solvents early on also may provide an indication of the propensity for the drug substance to degrade in liquid formulations or during wet processing steps. Physical properties such as hygroscopicity, polymorphism, hydrate/solvate formation, solid-state stability, and powder characteristics must also be explored.

In turn, the drug product components of the formulation are categorized according to their function. and its route of administration. A description of the drug product qualitative/quantitative composition provides a list of all ingredients, including solvents used in the manufacture of the drug product.

The functional aspects of each component (excipients) of the drug product are central to the development rationalization of the formulation and serve as reference points in the examination of supportive development data. The functional aspects of excipients can be divided into four basic categories that may impact

  • stability of the drug substance
  • physical characteristics
  • in vivo absorption, and
  • manufacturability.

While these general classifications can be applied, excipients may have multifunctional roles, and, thus, the degree of physical characterization of the excipient is dependent upon complete elucidation of the excipient function.

Much like a dosage form needs justification, the ideal roll should be long, uniform and slender, but not skinny. The ends should be rounded, and not pointy — like the wider side of an egg so that the steak fills the roll evenly and every bite will yield the same bread to meat ratio.

The Meat – much like the Manufacturing Process and Process Controls during Clinical Development (Modules 3.2.S.2 and 3.2.P.3)

The meat in a Philly cheesesteak should generously fill the roll like the allowable excess volume and labeled vial fill size in an injectable drug, or content uniformity with an oral form. Leaving an inch of meatless roll is a definite no-no. While beef is the standard meat, the only slightly healthier chicken cheesesteak, in which chicken is substituted for the beef, is also very popular. Both are delicious, but first-timers should go for the beef. Because why not?

For the drug substance and drug product, a detailed narrative description of each step in the manufacturing process is typically available from early phase regulatory documents. This narrative is compared with actual batch records from the manufacturing facility. A detailed analysis of the process includes a review of quantities of raw materials, solvents, catalysts, reagents, identification of critical steps and process controls, the type and size of processing equipment, and operating conditions, such as temperature, pressure, pH, and mixing time for final drug product. If the process has been scaled-up from earlier batches used in toxicological studies, the impurity profile is compared with the earlier toxicology batches. An examination of the raw materials includes the availability of reagents and safety concerns (handling and need for special processing equipment and protective requirements for the operator).

Subsequent to the characterization of the drug substance, the excipients, and their interaction potential, manufacturing process development for the drug product can proceed. Process development begins at the small scale and proceeds to a minimum of 10% before full production scale is made prior to validation of the process.

Process development should include an emphasis on the reproducibility of the critical quality attributes (CQAs). Changes to the method of manufacture should be detailed as the process moves from initial phase 1 studies through to the final commercial process. The focus should be on any process changes made subsequent to the first clinical study. A review of all clinical studies and the manufacturing process used to provide the clinical supplies should be documented.

Development studies should clearly detail the effect of process changes on CQAs associated with the intermediates and the finished drug product.

For sterile products, a review of the pre-sterilization bioburden data should be performed because this is essential to demonstrate the ruggedness of the process. For nonsterile liquid products, a review of the microbial limits testing data should be performed. For components in contact with liquid products during manufacture, compatibility data should demonstrate no deleterious effects to the product quality (e.g., drug adsorption onto processing filters or tubing) or unacceptable extractable components.

Whether the drug product is a tablet manufactured via a simple direct compression process or a lyo product manufactured through a complex, multistep process, the knowledge and the control of critical process parameters is fundamental to demonstrating a well-controlled, robust process.

For the direct compression tablet, the flow behavior of the formulation prior to tableting is an essential characteristic that will impact the control and selection of ranges of process parameters. Parameters of importance to the direct compression process may include mixing/ blending time, order of addition of excipients, and flow rates of the blend to the tableting press. The impact of water absorption by the powder during manufacture may require special humidity controls in the manufacturing facility.

For a lyo product, the parameters that control the lyophilization should be well-defined, including the impact of deviating from the set points for critical operations. Ultimately, the design process can be determined as successful only with predefined quality requirements and a developed testing plan.

Options abound for each dosage form just like the Philly cheesesteak. Various cuts. Naturally flavorful, unseasoned products. Hand-packed. Single cut, seasoned. Blended seasoned. Fully cooked. And don’t forget Chicken! Specifications do apply.

The Cheese – much like the Specs, Analytical Procedures and Validation (Modules 3.2.S.4 and 3.2.P.5)

Some people love the bright yellow (read: artificial) Cheez Whiz, but most locals opt for American or Provolone cheese. Now, while Cheez Whiz can hit the spot after a late night, American cheese is much preferred, because, if you think about it, Cheez Whiz is just kind of revolting. And do not ask for any other kind of cheese, like Swiss. Not only does it just not go well, but you might be laughed out of the line as American and Provolone are the two traditional cheeses.

The type of cheese used should complement the flavor of the steak. Likewise, the specifications for drug substance or drug product consists of the test methods and their associated acceptance criteria and should be selected based on the nature of the product e.g. a small Molecule, Biologic, Solid Oral or Liquid Parenteral etc. Each specification should be offered with a rationale for the limits specified.

The following tests and acceptance criteria are applicable to all drug substances;

Typically, a qualitative statement or description regarding the appearance of the drug substance. Identification testing should distinguish between the drug substance and closely related compounds. Characteristically, two identification tests are performed with one test being the HPLC retention time match with a reference standard material. The second test is typically a spectroscopic technique such as IR. It should be noted that UV-Vis absorbance spectra are not generally specific enough to distinguish related compounds. HPLC methods are commonly used to control impurities. The methods should be specific and stability-indicating.

There are additional specifications that may be applicable depending upon the nature of the drug substance and drug product. These specifications include: Particle Size, Melting Point, Polymorphic Form, Loss on Drying, Karl Fischer, etc.

For drug substances used in suspensions and solutions, additional physico-chemical characteristics may impact the drug product formulation. These characteristics include: pH of Solution, and Microbial Limits. The specifications should be consistent with current process capability and drug safety study results.

Specifications for impurities in early development will be controlled primarily by qualification limits determined by toxicology studies. During early stages of development, full justification of specifications is not available, nor necessary as final specifications are determined by the comprehensive development experience. At Phase III, the drug substance process should be well-defined and not open to any significant changes since Phase III stability batches and pivotal clinical studies will use material from the current process.

For all drug products, a Description, typically a qualitative statement regarding the appearance of the drug product is required. The acceptance criteria entail the observed drug product meeting the given qualitative criteria. Identification testing should distinguish between the drug substance in the drug product and closely related compounds. Typically, again, two identification tests are performed with one test being the HPLC retention time match with a reference standard material. The second test typically is a spectroscopic technique such as IR. The most common Assay procedures are titration methods and HPLC methods. If a titration method is used for assay, an additional specific, stability indicating method should be used to control impurities in the drug product. HPLC methods commonly are used to control impurities in drug product. The methods should be specific and stability-indicating again as well.

Like the drug substance there are additional specifications that may be applicable, depending upon the nature of the drug product. These specifications include: Disintegration, Dissolution, Moisture (water), Residual solvents, Microbial limits.

For drug product suspensions and solutions, additional physicochemical characteristics of the drug product may impact the drug product performance. These characteristics include: pH of solution. Particle size of suspended drug. Clarity of solution (turbidity). Color of solution. Viscosity. Volume of fill. Preservative testing.

The pervasive misconception from folks not from the Philly area is that a legitimate Philly cheesesteak must be smothered with Cheese Wiz. This is not true. Sliced White American followed by sliced provolone are the most popular types of requested cheese on cheesesteaks throughout Philly and the rest of the country in fact. The cheese should not be overwhelming in sharpness or salt. When choosing a white American, look for specs that imparts a creamy taste. For provolone, go for a mild or medium profile with a light smoky flavor.

The Onions – much like the Reference Standards, Container Closure and Product Stability (3.2.S.5, 3.2.S.6, 3.2.P.7 and 3.2.P.8)

Unless you just hate fried onions, add them to your cheesesteak. It makes it better. Hot or sweet peppers are also common additions, but beyond that, you’re getting into fancy territory. Some add pizza sauce, making it a pizza steak, or tomato, lettuce, onion, and mayo, making it a cheesesteak hoagie. While each of these varieties is delicious, cheesesteak virgins are advised to keep it simple and stick with the classic—a beef cheesesteak with fried onions and American cheese—at least for their first time.

In drug development, the validity of the analytical results (noted above) provided is, in part, reliant upon the use of appropriate reference standards, not unlike the meat, the cheese the roll etc. Reference standards used in the analysis of drug substance, starting materials, intermediates and drug product must have additional testing to verify the identity and purity of the reference standard. Typically, the reference standard is fully characterized including structural elucidation data as well as extended testing for impurities. Once the reference standard is fully characterized, a secondary reference standard may be tested against the primary standard and used for routine testing.

A primary package used in storage should be available. The potential for any incompatibility between the package and compound should be considered. The chemical and physical reactivity will dictate the type of packaging needed. For example, hygroscopic drug substances may require the inclusion of desiccants in the primary package. For drug substances sensitive to environmental conditions, (e.g., heat, light, moisture), data on the qualification of the packaging component should be given. Once the critical packaging parameters are identified, these parameters should be tested routinely upon receipt of the container prior to its use in the holding of drug substance.

On the other hand,, based upon the knowledge of the physical and chemical behavior of the drug product in pre-formulation and subsequent stability studies of model formulations, an appropriate package should be selected. For stable products with no sensitivity to environmental conditions (e.g., moisture or oxygen) the justification of the package requires data enough to show the acceptability of the drug product’s physicochemical attributes during storage. For oxygen- or moisture sensitive products, a package that provides an effective barrier must be demonstrated. In addition, it may be necessary to demonstrate via headspace analysis that the packaging conditions provide an acceptable internal atmosphere or that the addition of some appropriate inert gas is necessary. The selection of the packaging components for liquid formulations is determined during preformulation development.

Any secondary package used for the drug product may also be necessary (e.g., cardboard box). If the secondary packaging material provides protection to the product, test results of stability studies ‘wit’ and “without” the secondary package should demonstrate the adequacy of the secondary package.

A good stability protocol early in development goes a long way. A review of all stability batches should be performed once product in put on stability. Special attention is given to any increase in impurities or appearance of a new degradation product. The amount of variability seen between batches in the level of degradation products may be indicative of the robustness of the process. The appearance of new impurities or changes in impurity levels are consistent with poorly controlled processes. The degradation pathway and any critical intermediate should be elucidated.

Like stability, many would argue Onions to be an essential, but in the big picture for a cheesesteak, it’s an “add-on” but not just any “add-on”, it’s the most notable for those who prefer the extra flavor of “with” or “wit”. There are three decisions to be made when considering the onion for your cheesesteak luncheon: Type, Cutting Method, Preparation. Nothing is ever easy, is it?

The Location – much like the Supply Chain (Modules 3.2.S.2.1 and 3.2.P.3.1)

Now that you have a grasp of the intricacies of the development and ordering process for a Philadelphia cheesesteak, it’s time to try one for yourself. Fortunately, it’s easy to find awesome Philly cheesesteaks around the City of Brotherly Love – they’re all over. And no matter if it’s your first cheesesteak or your 100th, each bite is always worth savoring.

Like a cheesesteak shop, a contract manufacturing organization (CMO), sometimes called a contract development and manufacturing organization (CDMO), is a company that serves other companies in the industry on a contract basis to provide comprehensive services from drug development through drug manufacturing. This allows major pharmaceutical companies to outsource those aspects of the business, which can help with scalability or can allow the major company to focus on drug discovery and drug marketing instead.

Services offered by CMOs include, but are not limited to; pre-formulation, formulation development, stability studies, method development, pre-clinical and Phase I clinical trial materials, late-stage clinical trial materials, formal stability, scale-up, registration batches and commercial production. CMOs are contract manufacturers, but they can also be more than that because of the development aspect.

Customers are not only expecting competitive pricing but also regulatory compliance, flexibility on the production capability and on time delivery. Overall it is required that CMO complies with good manufacturing practice from their client and official organization such as Food and Drug Administration (FDA).

The name, location, and current Good Manufacturing Practice (cGMP) status of the CMO of key starting materials and drug substance should be available. An overview of the quality assurance aspects of the manufacturers may provide insight into, the viability of the process.

A request from the manufacturer for the report of the most recent cGMP manufacturing inspection from the United States Food and Drug Administration (FDA) European Union (EU) authority enables a broad overview of the cGMP compliance aspects of the facilities. Specific indications of issues concerning testing practices or general cGMP compliance may help determine the reliability of the various data supplied by the manufacturer. If testing is performed at another facility, an investigation as to the cGMP status of the testing facility should be pursued.

While slightly more complex, once you learn the facts about the key ingredients that go into making any great Philly cheesesteak, there are plenty of great cheesesteak spots to try to figure out your own personal favorite, but first, be sure to read up on Finding a Great Philly Cheesesteak! so you’ll look cool while doing it.

We want to help you find some of the best cheesesteaks in Philadelphia because, well, here in the City of Brotherly Love, cheesesteaks are a civic icon, a draw for visitors and a cultural obsession. Often imitated around the world, the Philly cheesesteak is rarely duplicated successfully outside of Philadelphia.

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Whether you have a CMC question, or you’re just thrilled about our Cheesesteaks, we love hearing from our customers.

Disclaimer: We know more about CMC than Cheesesteaks

DSI is a Philadelphia based Regulatory Drug Development consulting firm that serves the needs of small emerging biotech throughout the United States and Europe. Being based in Philadelphia we wanted to take a closer look at what makes a Philly cheesesteak so unique. Whether you need CMC support or just a cheesesteak fix, we are here for you!