drug manufacture
Companies which assist in clinical trial development: Amarex
Center for Biologics Evaluation and Research (CBER) (the center within the FDA which regulates biological products for human use under applicable federal laws).
Medicine and Healthcare Products Regulatory Agency (MHRA) (drug regulation in UK)
Chemical vs. Biological Products:
RNA:
While mRNA vaccines are considered as biological products, the classificaiton of chemical or biological products and the definition of gene therapy medicinal products may require updating or alignment to accommodate advancements in mRNA technology. Currently, plasmid DNA serves as the starting material for manufacturing mRNA va in vitro transcription method. Essentially, this involves using the plasmid. With advancements in cell free production technology, there may be a future where mRNA will be entirey synthetically produced. This raises the challenge of defining what constitutes a biological product.
Currently smaller RNAs such as siRNAs are typically considered chemical products due to their purely syntehtic nature. Barker, “Evolution of mRNA-based vaccines: a regulator’s view” Vaccine Insights 2024; 3(3), 97-105)
However, as mRNA becomes more syntehtically produced, utilizing cell free systems without biological components like plasmid, questions arise about whether they should still be classified as biological products. According to regulatory definitions, biological products typically involve substances produced or extracted form a biological source, necessitating specific testing and product controls. While mRNA has some similarities to shorter oligonucleotides like siRNAs, its great complexity and size warrant advanced characterization tools to ensure structural integrity, morphology and interactions with drug delivery systems. These are then more similar to biological products than to a well defined chemical product. Given that mRNA vacines fall under the category of immunogloical medicinal products, it may be appropriate for them to be classified as biological products. However, a mRNA production transitions away from plasmids toward cell free systems, updates to the definition may be necessary to accurately reflect the nature of these products. (Barker, “Evolution of mRNA-based vaccines: a regulator’s view” Vaccine Insights 2024; 3(3), 97-105)
Upstream manufacturing process of mRNA is maturing. cGMP quality plasmid, polymerases, and enzymes needed for in vitro synthesis of mRNA are available but can be costly. Poly(A) tails can be created by inclusion in the teplate or by use of enzyme. Capping options include high-efficiency, co-synthesis reagetns such as TriLink Biotechnology’s CleanCap and enzyme treatment with high efficiency. (Cytiva, “mRNA vaccines and therapeutics: current trends and perspectives” Fe 17, 2025.)
Accelerated Approval:
Accelerated Approval. (FDA may approve drugs for serious or life-threatening diseases or conditions where there is an unmet medical need and the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (improving how patients feel or function, or whether they survive longer).
In 2012, Congrewss passed the Food and Drug Adminsitration Safety Innovations ACT (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint. A surrogate endpoint used for accelerated approval is a marker -a laboratroy measurement, radiographic image, physical sign or other measure that is thought to predict clincial benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therpaeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).
The FDA bases its decision on whether to accept the propsoed surrogate or intermedate clincial endpoint on the scientific support for that enpoint. Studies that demonstrate a drug’s effect on a surrogate or intermediate clincial endpoint msut be adequate and well control as required by the FD&*C Act.
Using surrogate or intermediate clincial endpoints can save valuable time in the drug approval process. Instead of haivng to wait to elarn if a drug actually extends survival for cnacer pateints, for exaple, the FDA may approve a drug based on evidence that the drug shrinks tumors, becasue tumor shrinkage is considered reasonably likely to predict a real clinical benefit.
Fast Track:
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious coditions and fill an unmet medical need. Determining wehther a condition is serious generally is based on wehther the drug will ahve an impact on such factors as survival, day-to-day functioning, or the likelihood that the codition, if left untreated, will progress form a less severe condition to a more serious one. AIDS, Alheimer’s, heart failrue and cancer are obvious examples of serious conditios.
Filling an unmet medical need is defined as providing a therapy where none exists or providing a therpay which may be potentially better than available therapy.
Fast track designation must be requrested by the drug company. A request for the designation may be made at the same time, or any time after, the applicaton submission for the investigation (study) of the drug under section 505(i) or section 351(a)(3) of the Public Health Service Act. FDA will review the request and make a deciion with 60 days based on whether the drug fills an unmet medical need to a serious condition. Once a drug recives Fast Track designation, early and frequent communication between the fDA and a drug company is encouraged throughout the entire drug development adn erview process.
Laws:
FDA Development & Approval Process.
21 CFR 211.65 (equipment construction)
ICH Q7: Good Manufacturing Practice for Active Pharmaceutical Ingredients, US Fed. Reg. 66(186) 2000: 49-28-49029
FDA: FDA blog
European Union good manufacturing practice
BIOSECURE act (proposed; US House of Representatives bill H.R. 7085; US Senate bill S. 3558) would restrict the US activity of 5 Chinese biotech companies on national security grounds. The act is expected to drive mroe business to CDMOs outside China).
Definitions:
ANDA: In order to being manufacturing a generic product, the manufacturer must submit an Abbreviated New Drug Application (ANDA) to the Orange Book before the patent on the branded product expires, certifying that the generic dose not infringe on the current patent. However, when submitting this ANDA, the eneric manufacturer must also certify for each unexpired patent in the ORange Book. Depending on the number of patents associated with a single product, this can create a substantial hurdle for generic entry, as it requires the gneeric manufacturer to go to the epxense of assessing each patent to determine infringement potential. (Campanelli, “Feeling evergreen: a case study of humira’s patent extension strategeis and retroactive assessment of seocnd-line patent validity”, 2022).
Biosimilars: Biosimilars cannot be approved by the FDA until the reference biologic has been on the market for at least 12 years.. This is different than in the small molecule drug space, where generics can enter a market after 5 years. As a result, biosimilars can only enter the market towards the end of the lifecycle of the reference biologic drug, which limits their overall potential earnings. (Campanelli, “Feeling evergreen: a case study of humira’s patent extension strategeis and retroactive assessment of seocnd-line patent validity”, 2022).
Section 351(K) of the Public Health Service Act (PHS) provides an abreviated licensure pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA licensed reference product. As part of a demonstration of biosimilarity, a 351(k) applicaiton generally will contain data derived form a clinical study or studies sufficient to demonstrate safety, purity and potency in one or more appropriate conditions of use for which the reference product is licensed and for which the biosimilar or interchangeable biosimilar product applicant is seeking licensure. 351 (K)(2)(A)(i)(I)(cc) of the PHS Act. (Labeling for biosimilar and Interchangeable Biosimilar Products Guidance for Industry” September 2023).
FDA recommends that biosimilar and interchangeable biosimilar product labeling incorporate relevant data and information form the reference product labeling, with appropriate modificaitons.
Evergreening (“patent thickening”): a legal strategy employed by any company with a proprietary patent by which they intend to extend the life of the original patent either through taking out new patents or by buying out a frustrating competitor. “Patent thicketing” invovles many patents being conferred at the same time, oten on overlapping aspects of the innovation. Each component of the drug is protected separately, for example the cotaing, the delivery system, the formulation, and the composition would all be protected under separate patetns. Onre reprot revealed that hte top 12 products on the market are protected by an average of 71 patents per drug. (Campanelli, “Feeling evergreen: a case study of humira’s patent extension strategeis and retroactive assessment of seocnd-line patent validity”, 2022).
Orange Book: The FDA maintains a list of approved drug products with therapeutic equivalence evlautions, known as the “Orange Book”. This keeps tract of all branded drugs with generic coutnerparts, as well as the use codes or cases for the branded products.
US Orphan Drug Act:
The US Orphan Drug Act was passed in 1983 to encourage research and development of therapies for rare diseases thorugh tax inventives, market exclusivity, and user fee exemptions. The act results in a marked increase in rare diease research, from fewer than 10 drugs before its passage to more than 300 drugs for rare dieases over the past 25 years.
Biosimilar Markets and Regulation
The pipeline of follow-on (biosimilar) products in developmetn includes nearly 800 biosimilars. See Biosimilarspipeline
BPCI Act:
Biosimilars are defined as “similar” or highly similar” to the reference medicinal products following the EMA (European Medicines Agency ) adn the US FDA regulatory guildielines. In 2012, the EMA issued guidelines on the development of biosimilar monoclonal antibodies. In 2012 the FDA released draft guidance for teh development and regulatory review of biosimilars. In India, the biosimilars are termed as “similar biologics” in accordance with the guidelines issued by the Central Drugs Standard Control Organization (CDSCO). (Bandyopadhyay “physicochemical and functional characterization of a biosimilar adalimumab ZRC-3197, Biosimilars, 2015: 5, pp. 1-18).
The BPCA Act was enacted to establish an abbreviated pathway for FDA licensure of biological products that are demonstrated to be biosimilar to or interchangeable with an FDA licensed reference product.
Contract Testing Organization (CTOs) and Contract Research Organization (CROs)
CTOS are specialized laboratories offering epxertise with characterization and preclinical testing. Examples include Charles River Laboratoreis and SGS. Others include BioAgilytix, Creative Proteomics, Eurofins Scientific, Intertek, Myoderm and SSCI.
CROs focus on managing clinical trials. Quintiles IMS and Parexel are examples. Others include Altasciences, IDDI, INC Research, inVentiv Health and Pharmaceutical Product Devleopment (PPD).
Good Manufacturing practice (CGMP):
World Health Organization (WHO)
21 CFR 211.65 states that equipement shall be constructed so that surfaces that contact components, in process materials, or drug products shall not be reactive, additive, or adsorptive so as to alter the safety, identity, strengh, quality, or purity of the drug product beyond the official or otehr established requriements.
US FDA CGMP for biologicals, 21 CFR 600.11 provies that all surfaces that come in contact with products shall be clean and free of surface solids, leacable contaminants, and other materials that will hasten the deterioration of the product or otherwise rend it less suitable for the intended use.
ICH Q7 Good Manufacturing Practice for Active Pharmacetuical Ingredients guidelines tates that equipment hsould be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the itnermediates and APIs beyond official or other established specifications.
FDA Process:
A drug compound must pass three phases of huamn clinical trials in order to obtain FDA approval.
IND:
A threshold step is to gain the FDA’s permission to test the coumound in humans in the first place. After a drug developer has conducted preclinical studes (i.e., tested the compound in vitro and in animals, it submits an Investigational New Drug (IND) application to the FDA. An IND submission includes an investigator’s brochere, which disclsoes informaiton such as animal safety and preclinical efficacy data, clinical trail proposlas, and toxicology data. If the FDA approves the IND, then Phase I studies can commence.
Phase I:
Phase I studies involve administering the compound to a small group of healthy volunteers or advanced cancer patients with a vareity of tumor types. Phase I studies are conducted primarily to evaluate safety, to determine a safe dosgin range, and to idnetify any side effects.
Phase II:
Clinical trails do not focus on efficacy until Phase II, which typically involved adminsitering the compound to a specific patient population. The goals of a Phase II study include evaluating efficacy in specific patient populaiotns, determining dose tolerance and optimal dosage and identifying possible adverse effects and safety risks.
Phase III:
Phase III studies are large scale and are undertaken to evaluate clinical efficacy and safety in an expanded patient population. After completing Phase III studies, a developer submits a New Drug Applicaiton to the FDA for approval.