Susan Haigney

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 on Sept. 23, 2024 (1), Darby Kozak, PhD, deputy director for the Center for Drug Evaluation and Research (CDER), Office of Generic Drugs, in FDA, provided a look back at the Hatch-Waxman Amendments of the Federal Food, Drug, and Cosmetic Act, also known as the Drug Price Competition and Patent Term Restoration Act of 1984. The Hatch-Waxman Amendments established an approval pathway for generic-drug products and granted FDA authority to approve abbreviated new drug applications for generic versions of branded drugs (2).

According to Kozak, the amendments were created to increase market competition between generic-drug companies and pharmaceutical companies. “Before the Hatch-Waxman Amendments, there weren’t many generic-drug products available, given the legal and regulatory challenges generic[-drug] companies faced. Unlike today’s process, generic-drug applicants couldn’t rely on the agency's determination of safety and effectiveness of the brand-name drugs they hoped to replicate. To apply for FDA approval of a generic drug, companies had to submit a full application package, which often included conducting their own clinical trials to establish safety and effectiveness of the generic drug. Repeating those clinical trials was expensive and unnecessarily time-consuming, since the brand-name drugs were already determined to be safe and effective,” said Kozak.

The amendments resulted in a growth in the generic-drug market, according to Kozak, with generic drugs increasing from 19% of the market in 1984 to 90% in 2024. The amendments also led to the Orange Book being created, which provides information on the safety and effectiveness of approved generic drugs.

“Additionally, the Amendments provided generic-drug companies a ‘safe harbor’ from patent infringement lawsuits during their generic-drug development and testing,” said Kozak. “Under Hatch-Waxman, a company can seek FDA approval to market a generic drug before the expiration of patents related to the brand-name drug that the generic seeks to copy. Brand-name drug manufacturers gained certain benefits as well, such as the ability to market their drug exclusively for required periods of time before a generic drug can be approved by FDA for market entry.”

Since the passage of the Hatch-Waxman amendments, Kozak points to the enactment of the Generic Drug User Fee Amendments (GDUFA) as a significant advancement in the generic-drug approval process. GDUFA provides predictable and timely review of generic drug applications, which, according to Kozak, is important because the volume of generic-drug applications has significantly grown, and the products have become more complex.

“When the amendments established the framework for generic drug review, most drugs were simpler small molecules in non-complex formulations with uncomplicated delivery devices,” said Kozak. “These products also generally used well-understood manufacturing processes and were easier to characterize and evaluate through traditional bioequivalence methods, such as systemic pharmacokinetic studies. Forty years later, many drugs have more complicated active ingredients, formulations, dosage forms, routes of delivery, and delivery devices, and therefore are harder and more costly to develop and assess. As a result, there are fewer of these ‘complex drugs’ on the market for the patients who need them.”

Kozak stated that he sees the complexity of generic-drug products as a challenge that needs the Generic Drug Program to facilitate their development and approval. “We also continue to grow the Generic Drug Program by creating and maintaining opportunities to communicate with the public and drug developers, so that we can respond to patients’ and consumers’ needs. We provide collaborative research, training, and facilitate exchange of resources among groups interested in the development of complex generic products,” he stated.

FDA. 40th Anniversary of the Generic Drug Approval Pathway. CDER Conversations. 

, Sept. 23, 2024 (accessed Sept. 25, 2024).

Congress.gov. "H.R.3605–98th Congress (1983-1984): Drug Price Competition and Patent Term Restoration Act of 1984." Sept. 6, 1984. https://www.congress.gov/bill/98th-congress/house-bill/3605.

Articles

FDA’s Darby Kozak provided commentary on the anniversary of the Drug Price Competition and Patent Term Restoration Act of 1984.

Hatch-Waxman Amendments Turn 40

The European Medicines Agency (EMA) announced on Sept. 19, 2024 that it recommends that the indication for the use of the smallpox and mpox vaccine, Imvanex, be extended to adolescents from 12 to 17 years of age. Imvanex contains a live, weakened form of “modified vaccinia virus Ankara” (MVA-BN) and is currently authorized in the European Union for smallpox and mpox in adults.

The agency’s Committee for Medicinal Products for Human Use (CHMP) decided to extend the indication after interim results of a study that compared the vaccine’s immune response in 515 adolescents to 211 adults showed the response was similar in both groups.

“Therefore, it is inferred that the vaccine will provide similar protection in adolescents to that expected in adults,” the agency said in the press release (1). “According to the submitted data, the safety profile of Imvanex in adolescents was comparable to that seen in adults and no additional risk has been identified.”

The marketing authorization holder has been asked by EMA to provide the agency with the final results of the study by May 30, 2025.

The World Health Organization (WHO) declared mpox a public health emergency of international concern in August 2024 (2).

"The emergence of a new clade of mpox, its rapid spread in eastern DRC [Democratic Republic of the Congo], and the reporting of cases in several neighboring countries are very worrying,” said WHO Director-General Tedros Adhanom Ghebreyesus, in a press release (2). “On top of outbreaks of other mpox clades in DRC and other countries in Africa, it’s clear that a coordinated international response is needed to stop these outbreaks and save lives.”

WHO announced the MVA-BN vaccine as the first vaccine on its prequalification list in September 2024.

“This first prequalification of a vaccine against mpox is an important step in our fight against the disease, both in the context of the current outbreaks in Africa, and in future,” said Ghebreyesus in the press release regarding that announcement (3). “We now need urgent scale-up in procurement, donations, and rollout to ensure equitable access to vaccines where they are needed most, alongside other public health tools, to prevent infections, stop transmission, and save lives.”

According to EMA, this assessment to extend the indication may impact the global response to the mpox outbreak in the DRC and other countries; EMA is the regulatory agency responsible for prequalification of this mpox vaccine (3).

“This means that CHMP’s assessment constitutes the basis for WHO prequalification approval to facilitate timely and increased access to this vaccine in communities with urgent need. Previously, EMA’s assessment was also taken into account by the national regulatory authority of the DRC in the fast-track approval of the vaccine. In addition, WHO has cooperated in EMA’s assessment of the extension of indication in adolescents, a population that is particularly vulnerable to mpox,” the agency said in the press release (1).

EMA. EMA Recommends Extending Indication of Mpox Vaccine to Adolescents. Press Release. Sept. 19, 2024.

WHO. WHO Director-General Declares Mpox Outbreak a Public Health Emergency of International Concern. Press Release. Aug. 14, 2024.

WHO. WHO Prequalifies the First Vaccine against Mpox. Press Release. Sept. 13, 2024.

The agency is recommending the extension of the smallpox and mpox vaccine, Imvanex, to adolescents aged 12 to 17.

EMA Recommends Mpox Vaccine for Adolescents

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The lungs are one of the most complicated organs in the body. Therefore, there are several considerations that come into play when formulating a new inhaled drug. “I don’t think I would be exaggerating if I [said] that [the] lungs are probably one of the most complex organs in the body,” said Vivek Gupta, PhD, associate professor, Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, in 

1). “We are talking about multiple branching going from trachea to brochi, and … millions of air sacs, where most of the blood gas exchange happens, [and] where the lungs will give oxygen into the blood for circulation all over the body.”

Because the trachea branches off, the delivery pathway decreases. Therefore, according to Evonne Brennan, consultant at Evonne Brennan Consulting, “To reach its region of impact, a precise micronized dose of drug substance will need to be delivered in an aerosolized state, through the aid of a device and a formulation designed for delivery from that device, through simple actuation or a synchronized undertaking by the patient, the aerosolized particles travel with the patient’s airflow through a series of pathways where it is deposited.”

Obstacles caused by disease could restrict delivery further and cause increased mucus, remarks Brennan. “Deposition of the drug substance is required to deliver its pharmacological response,” Brennan stresses. Other complications for delivery of drug substance via inhalation can be caused by age, post-reflux cough, and patient compliance.

“For a given indication and drug substance, there are many physiological factors that need to be considered during product development for inhalation, such as patient pulmonary function, clearance mechanisms, etc., and these are addressed in an integrated way at the formulation and device development levels,” says Eunice Costa, R&D director–Inhalation and Advanced Drug Delivery, Hovione.

Attributes such as formulation particle size and density and inhaler dispersion performance need to be controlled to ensure successful deposit of the product into the lungs, according to Costa. “Once deposited, bioavailability of the drug becomes a function of additional factors such as intrinsic chemical properties as well as solid state and formulation composition, being that dissolution and/or permeation needs to occur at a faster rate than the clearance mechanisms in place in the local diseased microenvironment,” Costa says.

When referring to this article, please cite it as Haigney, S. Formulating Inhaled Medicines. 

Pharmaceutical Technology Trends in Formulation 

Excipient and delivery device selection play crucial roles in the formulation of inhaled drugs.

Formulating Inhaled Medicines

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Having the correct materials for the formulation and manufacture of drug products is crucial. But what happens if a supplier can no longer provide the needed product? Changing a supplier mid-development or mid-production can be tricky. Contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) can assist sponsor companies with this difficult task.

“Changing suppliers mid-cycle can affect various aspects such as chemistry, equipment, scale, testing methods, and other analytical controls and specifications, potentially impacting the quality of material made by different suppliers,” says Joshua Hoerner, general manager and executive vice president, Purisys (part of the Noramco Group).

When a product is already in production, making changes such as a new supplier or a raw material requires attention to regulations and quality considerations. “Depending on where you are at in a process, changing anything can have a deep impact, so it is important to take proper steps,” says Iain McGhee, vice-president of Quality at Ascend Advanced Therapies. “And, of course, materials should only be changed when necessary and with full agreement of the sponsor.”

Sundar Narsimhan, chief procurement officer at Neuland Labs, stresses that a careful review of the following important factors should be done before switching material suppliers:

 “It is possible that in some markets, sponsors must test, validate, and ensure stability before incorporating the supplier’s material into their supplies. Other markets follow a ‘do and tell’ regime, where, if the synthesis route remains unchanged, the material can be utilized with minimal additional testing,” says Narsimhan.

Capability of new supplier to meet requirements. 

“Their relationship/control over the upstream supply chain, risk, and likelihood of non-supply must be verified,” says Narsimhan. “This is paramount since any supply disruption or quality incident can derail and sabotage the market performance of their product and can prove very costly.”

. “Any new changes or variations, for example, in the impurity profile or stability of the drug product can be disruptive and should be avoided at all costs,” says Narsimhan.

Jonathan Rush, head of Supply Chain at Andelyn, stresses that comparability should be considered first when switching from one supplier to another. He also points to the importance of organization alignment between a company’s analytical and quality groups. “Our analytical development group is continually evaluating the latest testing and technologies in our space,” Rush says.

Regulatory and compendial compliance requirements need to be followed, according to Rush. “For example, if material is tested according to USP [US Pharmacopeia] but the client requires [European Pharmacopoeia compliance], even though they are harmonized, certain differences still arise. So, it’s important to manage the specification to the most stringent guideline among the various guidelines to ensure the highest level of qualification,” says Rush.

To ensure compliance with regulations when changing suppliers mid-lifecycle, Mayank Nagar, vice-president and head–Tech Services & New Product Launches, North Americas, Dr. Reddy’s Laboratories, and Himanshu Joshi, director, New Product Launches, North Americas, Dr. Reddy’s Laboratories, suggest evaluating a new supplier’s quality management systems. They also say comprehensive risk assessments should be performed. “Maintain clear communication with regulatory authorities and stakeholders throughout the transition. Implement a robust change control process to manage the switch seamlessly and mitigate risks associated with the supplier change,” Nagar and Joshi say.

“These [supplier] changes may have regulatory implications, especially if the product is commercially filed, as products are expected to remain equivalent or at least comparable between the old and new suppliers, if in the middle of a product’s lifecycle,” says Hoerner.

When it comes to material specification issues to consider when switching suppliers, McGhee says specification limits need to be maintained so performance is consistent. He also suggests that manufacturers determine if a change in supplier will result in changes to the manufacturing and in-process controls and how the materials will be handled.

Quality control includes determining validation ranges for release tests. McGhee suggests asking if validated in-process controls and release tests are comparable to the original material. Shelf life and stability studies parameters may also need to be validated, according to McGhee, as well as impurity profiles.

“When changing material suppliers during production, it's crucial to consider the validation status of the process. Ensure the new supplier's quality program is robust, reliable, and has a strong performance record. Conduct a thorough re-qualification of the new material to confirm it meets the original material's quality parameters and all necessary documentation requirements,” says Kim Arsenault, quality compliance manager at BIOVECTRA. “This ensures continuity in product quality and compliance with regulatory standards, minimizing risks associated with supplier changes.”

“Validate the consistency and compatibility of the new materials with existing processes through rigorous testing. Assess potential impacts on product efficacy, safety, and stability, and update all relevant documentation,” say Nagar and Joshi.

Packaging and transportation of the product should also be considered. “Is the product packaging the same or do additional studies (e.g., leachable/extractible tests) need to be performed? Where is the new facility located, will this involve longer and more complex transportation routes? Are there security risks with the route?” McGhee asks.

“There are often upfront costs associated with setting up a new supplier, including process and analytical technology transfer expenses,” adds Hoerner. “Lastly, changing suppliers can impact the continuity of supply. It is essential to consider the new supplier’s project management capabilities and the experience of its project managers in implementing new products on time and within budget,” he concludes.

Contract organizations offer assistance when managing changes to material suppliers during a product’s lifecycle.

Navigating a Material Supplier Change

On Sept. 20, 2024, the European Medicines Agency (EMA) announced that its Committee for Human Medicinal Products (CHMP) has recommended approval for eight new medicines and extended indications for an additional 12 drugs. The approvals include drugs for the treatment of cancers, hemophilia, meningococcus, and two biosimilars for treating age-related macular degeneration.

The recommended cancer treatments include Elahere (mirvetuximab soravtansine) for the treatment of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Hetronifly (serplulimab) was approved for treating extensive-stage small-cell lung cancer. The generic medicine, Pomalidominde Teva (pomalidomide), was approved to treat the rare bone marrow cancer, multiple myeloma, that impacts plasma cells that produce antibodies.

Other medicines that received recommendations include the following:

Hympavzi (marstacimab), to treat bleeding episodes in patients 12 years old and above with severe hemophilia A or B

Penbraya, a vaccine for immunization against 

Theralugand (lutetium (177lu) chloride), for radiolabeling of carrier medicines developed for radiolabeling with lutetium chloride

Biosimilars, Afqlir (aflibercept) and Opuviz (aflibercept), for the treatment of age-related macular degeneration.

Updates to COVID-19 messenger RNA vaccines Spikevax (to target the SARS-CoV-2 JN.1 variant) and Comirnaty (for the KP.2 subvariant) were also given positive opinions by CHMP.

“The revision of these vaccines is in line with the 

 issued by EMA’s Emergency Task Force to update COVID-19 vaccines to target the SARS-CoV-2 variants for the 2024/2025 vaccination campaign,” the agency stated in the press release (1,2).

CHMP also extended indications for the mpox vaccine, Imvanex, as well as Aflunov, Buccolam, Darzalex, Dupixent, Esperoct, Fasenra, Keytruda, Otezla, Pravafenix, Synjardy, and Zavicefta.

CHMP also confirmed its refusal to grant authorization to Syfovre (pegcetacoplan). The committee is also planning to re-examine its opinion of Leqembi (lecanemab) at the request of the applicant.

These approvals bring the 2024 yearly total of positive opinions for new medicines to 79. There have been four negative opinions in 2024 so far, and 63 extensions of indications.

In addition, EMA announced that Bruno Sepodes, a specialist in pharmacology, has been elected as the new chair of CHMP. He has a been a member and vice-chair of CHMP in the past, as well as a member of the agency’s Committee for Advanced Therapies, Committee for Orphan Medicinal Products, and the Emergency Task Force.

“As chair of the CHMP, my number one priority is ensuring the highest standards of medicine quality, safety and efficacy for patients in the European Union (EU),” said Sepodes in a press release (3). “Together, we will address the challenges and opportunities presented by novel technologies, including complex advanced therapies, the integration of digital health technologies and the use of artificial intelligence. We strive to facilitate rapid development and deployment of medicines, in particular when faced with health threats. Advancing regulatory science to support more efficient and evidence-based decision making remains crucial to deliver for patients across the EU."

Sepodes will begin a three-year term on Sept. 21, 2024.

1. EMA. Meeting Highlights from the Committee for Medicinal Products for Human Use (CHMP) 16-19 September 2024. Press Release. Sept. 20, 2024.

2. EMA. EMA Confirms its Recommendation to Update the Antigenic Composition of Authorized COVID-19 Vaccines for 2024-2025. Statement. July 19, 2024. 

https://www.ema.europa.eu/en/documents/other/ema-confirms-its-recommendation-update-antigenic-composition-authorised-covid-19-vaccines-2024-2025_en.pdf

3. EMA. EMA’s Human Medicines Committee Elects New Chair. Press Release. Sept. 18, 2024.

Approvals were recommended for treatments of ovarian cancer, lung cancer, bleeding disorders, respiratory disease, and more.

EMA Gives Approval to Several Cancer Treatments

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There are a variety of factors pushing innovation in formulation of drug products forward. The desire to create new delivery methods for biologics, the need to increase patient adherence, and technologies such as artificial intelligence (AI) are some of the trends drug developers in the industry are cultivating.

According to Sibaji Biswas, executive director and chief financial officer at Syngene International, patient-centric approaches have led to formulation strategies being reshaped, especially for biologics, with compounds for low solubility and oral bioavailability in small-molecule drugs continuing to see growth. “This has increased demand for solubility and bioavailability enhancement technologies, with CDMOs [contract development and manufacturing organizations] now needing more comprehensive capabilities so they can take a ‘fit-for-purpose’ approach to any challenge,” says Biswas. “Solid dispersion technology and other solubility enhancement methods are gaining prominence, while AI and machine learning [ML] are helping transform pharmaceutical formulation by predicting properties and behaviors.”

The use of ML and AI has been increasing in the bio/pharmaceutical industry. For formulation, they are being used to enhance modeling and predictive approaches, according to Shahrzad Missaghi, senior manager of Product Development, at Colorcon.

ML and AI allow for rapid innovation, according to Asma Patel, VP, Integrated Development Services, Quotient Sciences, as long as members of the industry are open to using these technologies. “From a discovery perspective, this can continue to fuel complexity in small new chemical and new molecular entities (NCEs/NMEs). Regardless of AI/ML, NCEs/NMEs continue to see an increase in average molecular weights and generation of new classes such as PROTACs [Proteolysis targeting chimeras], both creating solubility challenges for pharmaceutical formulation,” says Patel.

Vincent Levet, PhD, director, Formulation Development and Production, Ardena, agrees. “[AI] is showing great potential to revolutionize formulation development, from supporting excipient selection to predicting outcomes and optimizing processes.”

Additional formulation trends include delivery through lipid nanoparticles, ultra-high protein concentration formulations, continuous manufacturing, automation, and the creation of orphan drugs.

Automation has had a significant impact on the development of medicines delivered in capsule and tablet forms, according to Vinay Patil, Product Development Manager at Sharp Services. “Modern machines offer high-speed, precision filling and can handle various fill materials such as powders, granules, pellets, and even liquids,” says Patil. “Even more currently, micro-dosing technology allows us to accurately dose small quantities of API, which is critical when working with potent drugs. These advancements have increased the speed and precision of drug production and expanded the range of materials that can be used.” Patil also points to advances in granulation, compression, and coating that have impacted formulation.

“The introduction of high-shear granulators, fluid-bed processors, and roller compaction has enhanced the production of tablets with better mechanical properties and dissolution profiles. Coating technologies have also advanced, with enteric coatings and controlled-release formulations becoming more common,” says Patil. “Recently, continuous manufacturing processes have improved tablet production efficiency, allowing for real-time monitoring and increased production speed. One very recent advancement is the use of 3D printing technology, which has allowed for the production of tablets with controlled release profiles personalized to individual patients.”

®
eBook: Trends in Formulation 2024
September 2024
Pages: 34–37

When referring to this article, please cite it as Haigney, S. Forging Ahead in Formulation. 

Pharmaceutical Technology®/Pharmaceutical Technology EuropeTM

New and existing technologies, as well as a patient-centric focus, are pushing drug formulation into exciting directions.