Susan Haigney

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On Sept. 15, 2023, FDA announced the publication of a draft guidance to assist sponsors of biosimilars and interchangeable biosimilars develop draft labeling. The labeling recommendations are only for prescribing information, “except for certain recommendations in section V, FDA-Approved Patient Labeling of Biosimilar and Interchangeable Biosimilar Products, pertaining to FDA-approved patient labeling (e.g., Patient Information, Medication Guide, Instructions for Use).” The guidance pertains to applications under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)) (351(k) application).

The final version of the guidance will replace 

Guidance for Industry, Labeling for Biosimilar Products

 from July 2018. Changes to that guidance include:

“Labeling for interchangeable biosimilar products

“Product identification when the reference product labeling describes a clinical study conducted with a non-US-approved biological product Pediatric use statements

“Incorporating relevant immunogenicity data and information from the reference product labeling in the biosimilar or interchangeable biosimilar product labeling.”

The draft guidance includes sections on general principles for draft labeling of proposed biosimilar and interchangeable biosimilar products, specific recommendations on content of biosimilar and interchangeable biosimilar product labeling, revising biosimilar and interchangeable biosimilar product labeling, and how to submit initial and revised biosimilar and 607 interchangeable biosimilar product labeling.

According to the guidance, “Section 351(i) of the PHS Act defines biosimilarity to mean ‘that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components’ and that ‘there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.’ To meet the standard for interchangeability, an applicant must provide sufficient information to demonstrate biosimilarity and also to demonstrate that the biological product can be expected toproduce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. Interchangeable biosimilar products may be substituted for the reference product without the intervention of the prescribing health care provider.”

Articles

The draft guidance document discusses the development of labeling for proposed biosimilars and interchangeable biosimilars for submission under section 351(k) of the Public Health Service Act.

FDA Issues Guidance on Biosimilar Labeling

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Excipients are the ingredients of a therapeutic that change an API into a medicine and perform roles such as preservatives, diluents, buffers, binders, and drug release controllers. These excipients work in combination with the API to ensure the benefit of the drug product, according to the International Pharmaceutical Excipient Council of the Americas (IPEC-Americas). The high levels of excipients in drugs, compared to the API, mean the quality of these substances are just as important as the active ingredient. “Such excipient performance expectations as enhancing drug bioavailability, enhancing drug stability, providing controlled and sustained-release characteristics, enabling dosage form processability are but a few of the crucial roles excipients provide to ensure the drug performs as intended over its shelf life,” says IPEC-Americas.

“Excipients used in drug products may be compendial (i.e., there is a monograph for the excipient in a recognized pharmacopeia) or non-compendial.For blended excipient mixtures and co-processed excipients, unless there is a monograph for that exact blend or co-processed mixture, they are classed as non-compendial, even if all the components individually have pharmacopeial monographs,” says IPEC-Americas.

Low-quality excipients may be unsafe and present risks to the patient, including exposure to toxic substances such as benzene and diethylene glycol.“Any low-quality ingredient or adulteration that could compromise drug product quality, safety, or performance could lead to undesirable consequences, such as adverse events, lack of efficacy of the drug, hospitalizations, or at worst, death,” stresses IPEC-Americas.

According to Subba Reddy Inta, vice president and head-Quality, Dr. Reddy’s Laboratories, North America Generics, excipients may interact with the API and, therefore, lower the titer or assay. Impurities may also be generated, or the absorption, distribution, metabolism, and excretion (ADME) may be altered.

According to Catherine Sheehan, Senior Director at the US Pharmacopeia (USP) and Otilia Koo, Chair, USP Complex Excipients Expert Committee and Executive Director, BMS, ensuring the safety of excipients is extremely important. Excipients often make up the majority of a drug’s composition, Sheehan and Koo reveal, and perform a variety of functions such as maintaining pH and stability and making the drug palatable via tastemasking, coating, and coloring. Sheehan and Koo also point to the complex supply chain of excipients that lacks regulatory oversight.

“Unlike APIs, there are times when the quality of excipients is not given the necessary level of importance because excipients are inactive ingredients. Unfortunately, the impact of this can be devastating, for example, the recent deaths of reportedly 300 children in as many as seven countries due to diethylene glycol (DEG) and ethylene glycol (EG) contamination in cough syrups and oral analgesics for children,” say Sheehan and Koo.

® spoke with Sheehan and Koo to find out more about the regulations involved in excipient quality. In addition, 

 What are the USP requirements for excipients?

 Pharmacopeias worldwide contain standards and test methods to test for several excipients required for determining their quality. The 

United States Pharmacopeia–National Formulary

] General Notices 3.10. Applicability of Standards requires excipients recognized in 

to be prepared according to recognized principles of GMP [good manufacturing practice] and from ingredients complying with specifications designed to ensure that the resultant substances meet the requirements of the compendial monographs. In addition, 

 contains general information chapters on GMP requirements for bulk pharmaceutical excipients <1078>, Good distribution practices for bulk pharmaceutical excipients <1197>, and Significant change guide for bulk pharmaceutical excipients <1195>.

USP is a member of the Pharmacopeial Discussion Group (PDG) with representatives from the 

 (including the very recent addition of a pilot membership for the 

 as it prepares for global expansion), with WHO [World Health Organization] as an observer, to retrospectively harmonize standards for excipients monographs, general chapters, ICH [International Council for Harmonisation] Q4B chapters, and biotechnology chapters. The 

 has over 500 documentary standards for excipients, including high-risk for adulteration (e.g., EG/DEG) excipients such as Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, and Sorbitol Solution.

According to General Notices 3.10. Applicability of Standards, standards for excipients recognized in the 

 are expressed in the excipient’s monograph, applicable general chapters, and General Notices. The identity, quality, and purity of excipient standards are determined by the official tests, procedures and acceptance criteria, and other requirements incorporated in the monograph, in applicable general chapters, or in the General Notices.In addition,

 excipient monograph standards have over 320 

 to support the test methods included in excipient monograph standards.

What are the requirements for complex excipients such as polysorbates?

 excipient standards contain standards that include test methods and acceptance criteria required for determining their quality. Excipients can be small molecules with a very well-defined chemical structure that can be characterized well analytically. Many are mixture-based products (e.g., fats and oils). Some may come in multiple grades that can be natural or synthetic or semisynthetic. Some are more complex, like polysorbates and some may vary in degree of characterization.

Polysorbates (PS) are considered complex excipients and are amongst the most versatile surfactants in pharmaceutical use used across almost all routes of administration and dosage forms. [These complex excipients] are also used as emulsifiers, solubilizers, and stabilizers. Some of the PS are well characterized in traditional routes of application in terms of their chemistry. However, they need additional characterization in some of the newer applications, such as when used in therapeutic biological drugs (e.g., in preventing protein aggregation and denaturation and stabilizing therapeutic proteins formulations).

One of the main challenges with complex excipients such as PS is identifying appropriate test methods for analyzing their complex composition and setting appropriate and meaningful specifications. The composition of such excipients can vary by inherent variations in the source of the raw materials used to manufacture the excipient and the manufacturing process. Further, their performance is highly dependent on their composition. Thus, these excipients should have standards for not only their identification, and levels on impurities, but also their composition.

One such example is the use of the fatty acid composition tests and specific tests on fats and fixed oil content in current 

 monographs of PS 20, 40, 60, 80. USP is also considering strengthening the quality control of PS by adding a direct assay testing procedure to determine the content of intact PS. Another example of a complex polymeric type of excipient is Lactide and Glycolide polymer for which a new monograph proposal was published in USP 

 and includes tests for monomer ratio and terminated group.

“In comparison to APIs, the repercussions of low-quality excipients can be equally significant. While APIs are the active components responsible for the therapeutic effect of a drug, excipients act as essential delivery vehicles and support structures. Substandard excipients can adversely affect the API’s stability, safety, and performance, rendering even a high-quality active ingredient less effective or potentially harmful,” caution Aryo Nikopour, VP, Global Market-Pharmaceuticals, and Shiri Hechter, senior manager, Scientific and Technical Services, both with Nelson Labs. Nikopour and Hechter also point to the business risks of poor-quality excipients, such as recall of products, legations, and damage to the company or brand reputation. But IPEC-Americas states the finished drug may be impacted regardless of the API.

Excipients are usually sourced by either the sponsor company or the contract manufacturing organization (CMO) from ingredient manufacturers and then used in the final product. The sponsor company and the CMO are responsible for ensuring the quality of the final pharmaceutical product. So, how may a sponsor company and/or a CMO ensure that the excipients purchased from third-party vendors are safe and best suited for the dosage form they are creating?

According to Catherine Sheehan, senior director at the US Pharmacopeia (USP) and Otilia Koo Chair, USP Complex Excipients Expert Committee and Executive Director, BMS, excipients should be sourced from qualified suppliers and sponsors should also evaluate those suppliers. Additionally, sponsors should check that the supplier has a testing program in place. Sponsors should also know who the original manufacturer of the ingredient is if it is not the supplier and an original manufacturer’s certificate of analysis should be obtained. Furthermore, each shipment of incoming raw materials should be tested for applicable standards and regulations.

According to IPEC-Americas, it is important to make sure the manufacturer of the excipient is producing the excipient under good manufacturing practices (GMPs) appropriate for excipients with the intent of that ingredient being used in pharmaceuticals. “Finally, for excipients not purchased directly from the manufacturer or a manufacturer authorized distributor, it is important for sponsors to understand the full supply chain back to the manufacturer,” says IPEC-Americas.

A comprehensive risk assessment that begins with a questionnaire is also imperative. “Ingredient samples are requested and received for assessment against specification acceptance criteria. Excipient manufacturers whose products are used for the first time should be audited either directly or by an accredited third party acquainted with pharmaceutical and excipient manufacturing requirements such [as] the appropriate level of GMP,” according to IPEC-Americas. Assessment of the manufacturer’s standard operating procedures (SOPs), batch records, and other procedures and documents should also be performed.

In addition to GMPs, according to IPEC-Americas, “Compendial excipients conform to the appropriate monograph using the compendial methods or validated equivalents. Non-compendial excipients should
be adequately characterized and properly vetted through a risk assessment to ensure the excipient meets specified quality requirements,” says IPEC-Americas.

Key elements of a quality management program, according to Nikopour and Hechter, include supplier qualification and auditing, quality agreements with suppliers, risk assessments, testing of raw materials, and change control management. In addition, stability testing, documentation, and quality matrices should be performed. “By implementing a robust quality management program encompassing the above elements, pharmaceutical manufacturers can ensure that the excipients used in their products are of high quality and safe for patients,” say Nikopour and Hechter.

Received excipient materials should go through testing and analysis, says Nikopour and Hechter. Samples should be tested regularly to determine that they meet quality specifications.The US Pharmacopeia–National Formulary (USP–NF) provides methods for testing compendial excipients.

To test non-compendial excipients, IPEC-Americas says that suppliers should develop validation methods that show that the quality and composition of their products are consistent from batch to batch. Inta points out that additional test methods may be needed based on the functional requirements of the sponsor. “Sometimes the supplier develops the different grades of a material to meet the formulation development requirement,” he says.

Manufacturers can use many of the analytical techniques used in chemical analysis for testing excipients, according to IPEC-Americas. These include infrared spectroscopic techniques (FTIR, NIR), atomic absorption (AA), inductively coupled plasma (ICP), mass spectrometry, X-ray crystallography, pH, conductance, Karl Fischer water determination, as well as the many compendial test methods (LOD, ROI, etc.). “In addition to chemical analysis, functional performance can be assessed by a variety of methods; however, functionally related characteristics (FRCs) can pose some challenges if not considering context of use.Not all FRCs will be applicable to all materials or cases,” says IPEC-Americas.

“When a compendial monograph does not exist, excipient users should determine if other regulations, compendia, or guidelines can be used to characterize suitable quality,” say Nikopour and Hechter.

According to IPEC-Americas, no formal regulatory process exists for evaluation a novel excipient outside of the drug product. However, for novel excipients that have yet to be used in a drug formulation, Nikopour and Hechter suggest following IPEC recommendations for safety evaluation of a novel excipient (1). FDA also provides guidance on safety testing for novel excipients (2).

According to IPEC-Americas, “often, sponsors don’t do all they should to qualify an excipient. However, because they don’t, that means they may accept low quality materials without knowing it ... low quality excipients may be the wrong grade of product (not intended for use in pharma), adulterated, the result of supply chain failures or from manufacturers who intentionally do not follow GMPs or regulations.”

Low-quality excipients present as much of a risk to patients as low-quality APIs, especially because they may impact the efficacy of the API. They are the support system and play a significant role in ensuring drugs are safe and work as intended. It is imperative that both sponsor companies and ingredient manufacturers have the appropriate management plan in place to perform the vital risk assessments, testing, and
verification of excipients.

The International Pharmaceutical Council Excipient Safety Guide for Pharmaceutical Excipients

Guidance for Industry, Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients 


Vol. 47, No. 9
September 2023
Pages: 12–16

When referring to this article, please cite it as Haigney, S. In Equal Measures: The Importance of Excipient Quality. 

Excipients should be treated equally when it comes to quality management, risk assessment, and testing.

In Equal Measures: The Importance of Excipient Quality

Manufacture of medicines is most often required to be performed in a sterile environment to ensure the quality and safety of these products. Microorganisms lurking in the air or on surfaces may degrade APIs and impact their effectiveness, according to Anne-Grit Klees, PhD, BioMonitoring Portfolio Manager for The Life Science business of Merck KGaA, Darmstadt, Germany. “Furthermore, pathogenic and even many non-pathogenic microorganisms can cause serious and life-threatening infections in patients, especially if immunodeficient. For this reason, particularly injectable drugs must be sterile. This can be achieved by final sterilization of the drug or, if not possible, by aseptic manufacturing.”

It is recommended by regulators that microbial monitoring of cleanrooms and isolators is performed by a combination of methods, says Klees. “Air monitoring is performed with a combination of volumetric microbial air samplers (active air monitoring) and settle plates (continuous passive air monitoring). Surfaces and personnel should be monitored with contact plates or swabs. Using alternative methods is also permissible if these have been validated and show comparable or superior efficacies.”

® spoke with Anne-Grit Klees to find out some environmental monitoring (EM) best practices manufacturers can follow to ensure the safety of their products.

What are the differences between environmental monitoring in aseptic versus non-aseptic manufacturing?

Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany):

 The environmental monitoring methods are usually the same for both. The higher the cleanroom grade, the higher the monitoring frequency and number of sample locations. The monitoring equipment and culture media should possess features to match the cleanroom-grade requirements. For air samplers, features such as cleanability, resistance towards disinfectants, emission of particles, and disturbance of the unidirectional air flow are important to consider and should match the cleanroom concept. For culture media, there is a choice between single bagged ones for lower risk areas and irradiated, double, or triple bagged ones for the different manufacturing lines.

 What are some best practices for air monitoring?

Anne-Grit Klees (The Life Science business of Merck KGaA, Darmstadt, Germany): 

When selecting an air sampler, important features to consider are sampling volume accuracy, a good efficiency of the method to collect small particles, and whether damage to microorganisms is avoided during the sampling process. The recovery efficiency should be validated by the supplier according to ISO [International Organization for Standardization] 14698. What also matters is ease-of-use to minimize the risk of human errors, low particle emissions to prevent contamination of the cleanroom, good cleanability, and minimal disturbances of the unidirectional air flow. If the air sampler can be integrated into external tracking software systems, all data can be handled. This helps to observe trends.

What are some best practices for surface monitoring?

Surface monitoring is usually performed either with contact plates or swabs, depending on the accessibility of the sample location. Culture medium selection should be based on the ability over the complete shelf-life to detect a broad range of microorganisms. Furthermore, the media formulation should ensure that any potential growth-inhibiting substances such as disinfectant residues or antibiotics are inactivated. To maintain the cleanliness of the sampled surface any culture media residues should be removed after sampling.

 What are some best practices for personnel monitoring?

Personnel monitoring is always performed on the gloves, but also on gowning. The growth promotion properties of the selected media must [often] allow in-house skin flora of the personnel to grow. It is important that contact plate samples are taken of the personnel’s gowning or gloves before leaving the cleanroom. If glove tests are performed after critical interventions, the outer gloves should be replaced before continuing manual work.

 What are the latest advancements in processes and workflows for environmental monitoring?

 These are stated in the current 2022 version of the EU [European Union] CGMP [current good manufacturing practice] Annex 1. While the well-established volumetric air samplers, settle plates, contact plates, and swabs are still recommended to be used frequently, a new focus is on the importance of a contamination control strategy of the pharmaceutical company. This should include a risk-based sample plan that states the frequency and sample locations for those methods. There are additions about using validated rapid or automated technologies, also for continuous volumetric air sampling. These need to be equal to or superior to the above-described methods.

What are some of the best tools for performing environmental monitoring of cleanrooms?

Some portable microbial air samplers (e.g., the MAS-100 NT) offer high accuracy and excellent sampling efficiency. It is small enough to sample close to critical sample locations, can take up to 30 samples in one cleanroom, is easy to disinfect and available with an exhaust filter. It minimizes disturbance of the unidirectional air flow and is compatible with several EM software systems. Triple-bagged and gamma-irradiated ICR or ICR+ culture media for grade A and B cleanrooms reduce the contamination risk because outer bags can be removed in the material lock. Plate versions with locks allow safe transportation for incubation after sampling.

 What are some of the best tools for performing environmental monitoring of a restricted-access barrier system (RABS)?

In a RABS the same environmental monitoring tools can be used as in a cleanroom. However, if a RABS system is decontaminated with vaporized hydrogen peroxide (VHP), it must be ensured that the culture media within the RABS during decontamination are protected by VHP-impermeable bags. These can be hung up during decontamination. To prevent false negative results, all ICR settle plates, contact plates and ICR swabs are formulated to neutralize VHP residues. The MAS-100 NT can also withstand VHP decontamination if in switched-off mode. Alternatively, MAS-100 air samplers specially designed for isolators can be used.

 What are some of the best tools for performing environmental monitoring of isolators?

 In isolators, space is limited, so the control unit of the dedicated air samplers (e.g., MAS-100 Iso line) for isolators are positioned on the outside, saving space inside. The distance can be up to 10 m. A double-valve system prevents cross-contamination and the air tubing can be decontaminated with VHP (e.g., with the MAS-100 Iso MH, one control unit can handle up to four sampling locations.)

Certain packaging designs (e.g., IsoBag rapid transfer bags) save space in isolators. They readily provide ICR settle or contact plates in a DPTE [differential pressure transmitter for air] beta bag. Plates can be safely transferred via rapid transfer alpha ports whenever needed.

How are data obtained from environmental monitoring? How are these data used in pharma manufacturing?

 The data are usually obtained as colony forming units from the culture media used in active and passive air sampling as well as surface and personnel sampling. The new EU GMP Annex 1 suggests using the data both for batch release decisions and for trending analyses. It is possible to detect adverse trends by increasing excursions from action limits or consecutive excursions from alert levels. Also, noticing changes in the microbial flora is important. This helps to maintain the level of cleanliness and address issues by corrective and preventive actions.

Are there specific analytical tools that work best for different types of environmental
monitoring?

As the amount of data generated by environmental monitoring is huge, the PDA [Parenteral Drug Association] Technical Report No. 13 outlines computer-based tracking tools as essential. Specific software systems designed for environmental monitoring help to find adverse trends, and the stored data may allow conclusions as to what the root cause is. One important feature of the sampling equipment is that it should allow data transfer into such software systems, so that all tracked data are handled in a single database. This helps to stay compliant with the standard rules for data integrity.

Environmental monitoring data can help keep sterile environments sterile.

Microbe Monitoring

The European Medicines Agency (EMA) announced on July 11, 2023 that its Pharmacovigilance Risk Assessment Committee (PRAC) is reviewing data on glucagon-like peptide-1 (GLP-1) receptor agonists, which are used to treat type 2 diabetes and weight loss, after reports were received of suicidal thoughts in patients taking the drug. The agency is analyzing approximately 150 reports of thoughts of self-harm by patients using liraglutide and semaglutide medicines. The review of Ozempic (semaglutide), Saxenda (liraglutide), and Wegovy (semaglutide) began on July 3, 2023 and has been extended to include other GLP-1 receptor agonists.

The review is being performed as a signal procedure, which is information on new adverse events associated with a medicine or a new aspect of a known adverse event. However,

EMA stated in a press release that the drugs are widely used and there is no clear indication that the reports are linked to the medicines or instead to other factors.

“As with all medicines, patients and healthcare professionals are advised to use GLP-1 receptor agonists in accordance with the approved product information. Patients and healthcare professionals should also report suspected side effects to authorities. Information on how to report suspected side effects is available in the package leaflets and on the websites of national medicines authorities,” EMA stated in the press release.

The agency is reviewing the medicines after receiving reports of self-injury and suicidal thoughts in patients using the type 2 diabetes treatments.

EMA Reviews GLP-1 Receptor Agonists for Self-Harm Risk

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The European Medicines Agency (EMA) announced on July 6, 2023 that the agency, the European Commission (EC), and the Heads of Medicines Agencies (HMA) are starting the process for ending regulatory flexibilities for medicines that were put in place during the COVID-19 pandemic. This action follows the 

World Health Organization’s end to the public health emergency

The European regulators put these measures into place in the areas of marketing authorizations, API and finished product manufacturing, quality requirements, and related regulatory procedures. This was done to mitigate disruptions to the drug supply chain that might have been caused by delays in facility inspections and other procedures. These measures will now be phased out, according to EMA.

“From now on, the regulatory flexibilities that were introduced jointly by the HMA, EC, and EMA specifically during the COVID-19 pandemic should no longer be granted. For already approved labelling flexibilities, e.g., the English-only labelling for COVID-19 vaccines, their application will be extended until the end of 2023, in order to ensure a smooth phase-out and avoid any supply difficulties or other disruptions due to a sudden change in applicable requirements. After 2023, the regular mechanisms foreseen in the legislation in relation to labelling exemptions should be followed,” the agency stated in a press release.

EMA also stated that on-site good manufacturing (GMP) and distribution practice (GDP) inspections have restarted that were either previously postponed or done remotely during the pandemic. The validity of GMP and GDP certificates has been extended to the end of 2023, and the approach to 2024 certificates will be discussed by the GMDP Inspectors Working Group in upcoming months. “This Group has also reviewed experiences with remote working arrangements of qualified persons during the pandemic, and will issue guidance on how those specific arrangements can be applied in the future,” EMA stated in the release.

The agency went on to say that experiences learned through the handling of the pandemic will be collected and considered so the agency can inform best practices for future health challenges.

EMA, the European Commission, and HMAs are phasing out the flexible regulations put into place during the pandemic.

Europe Phases Out COVID-19 Flexible Regulations

Novavax announced on July 6, 2023 that the European Commission has granted the company’s COVID-19 vaccine, Nuvaxovid, full marketing authorization for use in the European Union. The vaccine can now be used as a primary series in people 12 years and older and as a booster in adults over 18 to prevent COVID-19. A conditional authorization was previously granted in the EU for the vaccine.

The decision was made after the European Medicines’ Agency’s Committee for Medicinal Products for Human Use recommended the vaccine for approval. A Phase III PREVENT-19 trial assured the “safety profile as well as efficacy as a primary series in adults, the immunogenicity and safety as a booster dose in adults, and the efficacy and safety as a primary series in individuals aged 12 and older,” Novavax said in a press release.

"This marketing authorization establishes the foundation for all future regulatory approvals for updated versions of our COVID vaccine, a necessity to ensure we can quickly get our vaccine to individuals in the EU," said John C. Jacobs, president and chief executive officer, Novavax, in the press release. "In addition to the EU, we are preparing to file for full approval in the US as well as other markets and are committed to ensuring protein-based options are available worldwide. Vaccine choice remains an integral part of public health measures."

Full Marketing Authorization has been granted for Novavax’s COVID-19 vaccine by the European Commission.