Generic Drug Development Process for Small Molecules
The Hatch-Waxman Act in 1984 established the foundation for generic drug development.The generic drug development program, a.k.a. abbreviated new drug application (ANDA), starts with the selection of the drug product which is already off-patent or about to go off-patent. The generic drug developer selects the drug candidate, or the program based on their core capabilities, focus area and dosage form expertise. Some examples of the most common pharmaceutical dosage forms include Solid oral (tablets/capsules), liquids (suspension, solution), topicals (cream, ointment, gel), injectables (vials, profiles syringe, IV bags) and transdermal patches etc. Selection of the program also depends on the ANDA application category such as Paragraph I, II, III, or Paragraph IV.
This link talks about the ANDA applicant certification process for Paragraphs I – IV: https://www.fda.gov/media/119718/download
Once the product is selected, the following activities will occur:
Literature Search and Collection of the Basic Product Information
The formulation development team will gather details about the reference listed drug (a.k.a. RLD) from the Orange Book, DailyMed listings, and FDA-approved product labels (links below). Information gathered during this phase includes dosage form, product strength(s), packaging configuration, list of inactive ingredients, patent(s), if any, and other basic technical information about the drug. Bioequivalence study requirement (a.k.a. Product-Specific guidance), if applicable, is also collected during this phase.
https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
Finding and Selecting API source
Typically, most generic drug companies will have a Rolodex of active pharmaceutical ingredients (API) or drug substance (DS) manufacturers to contact for their API sourcing needs. However, a place to perform basic research and market intelligence is to look at the list of approved drug master file (DMF) holders. Here is the link to FDA maintained and updated Excel sheet of API DMF holders: https://www.fda.gov/drugs/drug-master-files-dmfs/list-drug-master-files-dmfs
The FDA also publishes a list of DMFs that have passed the completeness assessment and are available for reference in Type II DMFs for APIs for Generic Drug Applications.
Some companies use Cortelis, IPD analytics and other paid subscription-based platforms to source API, but companies also use free websites such as PharmaCompass.
Lastly, vertically integrated companies will have their own source. For others, including virtual companies, there is an option to partner with API development and manufacturing to integrate vertically and start development.
For all others, contact the API suppliers from the sources above and start the procurement process. Selecting the right API partners is critical. Some companies offer API; however, they also develop their own finished product and could compete with you in the finished product market. Not having a well-negotiated contract and price guarantees may put you at a disadvantage. It is crucial to have a quality agreement and API supply agreement in place with your API vendor. Key areas to focus on in the API supply agreement would be pricing, a cap on price increase, facility audit rights, supply guarantees and failure clauses, and agreed product specifications, among others.
Reference Listed Drug (RLD) characterization/Reverse Engineering
The process of comparing a generic drug product to its RLD to demonstrate that it is bioequivalent is known as RLD characterization.
Here are some key steps involved in RLD characterization for a generic product:
- Selection of the RLD: Carefully select the RLD based on its therapeutic equivalence, dosage form, route of administration, and bioavailability. The RLD should also be available in the market. If possible, purchase multiple lots.
- Determination of the Active Pharmaceutical Ingredient (API): The API in the RLD and the proposed generic product should be identified and compared. The RLD characterization should include a comparison of the chemical and physical properties of the API, including its purity, particle size, and polymorphic form.
- Formulation Comparison: The formulation of the proposed generic product should compare to that of the RLD. That includes a comparison of the types and amounts of excipients used in the formulation.
- In Vitro Studies: In vitro studies should be conducted to compare the dissolution rate of the proposed generic product with that of the RLD. Using the same test method and equipment as specified by the regulatory authority, conduct dissolution testing.
Reverse engineering is a process of analyzing a finished product to determine its composition and manufacturing process. Here are the general steps involved in the reverse engineering of a generic drug:
- Obtain the Reference Product: The first step is to obtain the reference product, which is the brand-name drug that the generic drug product is intended to replicate. Analyze the reference product to determine its composition and manufacturing process.
- Analyze the Reference Product: The reference product is analyzed using techniques to determine its chemical and physical properties. That includes analyzing the active pharmaceutical ingredient (API) and its impurities, as well as the excipients and other components of the formulation.
- Develop a formula for the Generic Drug Product: Develop a formula for the generic drug product based on the analysis of the reference product. That includes determining the amounts and types of excipients to use in the formulation, as well as the API and its impurities.
- Optimize the Formulation: The formulation of the generic drug product is optimized through a series of experiments to ensure that it meets the necessary quality and performance standards.
- Conduct Analytical Testing: The generic drug product is subjected to various analytical tests to ensure that it meets the necessary quality standards. This includes testing the purity of the API and its impurities, as well as the dissolution rate and other characteristics of the finished product.
In summary, the reverse engineering of a generic drug involves a detailed analysis of the reference product, the development of a formula for the generic drug product, and a series of experiments and tests to optimize the formulation and ensure that it meets the necessary quality and performance standards.
Formulation and Analytical Development Activities
Once the RLD is procured, characterization/reverse engineering is completed, API and RM are acquired, then the formulator and analytical chemist will start pre-formulation, formulation and analytical method development activities. This step requires multiple small benchtop formulation trials, formulation/method tweaks, excipient compatibility studies, and trials and errors to develop a prototype finished product as identical to RLD as possible. Once the prototype and analytical methods are developed, fine-tuning of the formulation will happen, including an increase in the batch size and process optimization. The optimized prototype, in some cases multiple prototypes, then go on stability under room temperature as well as accelerated conditions to ensure all the critical quality attributes are maintained throughout the stability. This process repeats until optimized formulation and analytical methods are established, and the product can meet and maintain critical quality attributes for no less than 3 months under accelerated stability conditions. In some cases, companies will not allow you to produce ANDA batches unless 6 months of accelerated stability data are available.
ANDA Batch Manufacturing and Dossier Preparation
Once the formulation is locked in, all the analytical methods are developed, verified and/or validated, the ANDA batch manufacturing will start, which will require approval of the master batch record (or batch manufacturing record), master packaging record (or batch packaging record), sampling protocol, etc. Product development report (PDR) compilation is a parallel activity that typically starts at the time of the RLD procurement stage and continues until the ANDA dossier is submitted. PDR captures all the R&D activities, formulation and analytical, as well as all aspects of Quality by Design that includes but is not limited to Quality Target Product Profile (QTPP), Critical Quality Attributes (CQA), Critical Material Attributes (CMA), Critical Processing Parameters (CPPs), etc. PDR is required to file an ANDA application.
Clinical Study, if applicable, followed by Dossier Compilation and ANDA filing
Once the ANDA batches are manufactured and put on stability, the regulatory affairs team will start working on collecting various documents from the formulation and analytical development teams to start the dossier compilation. Typically, 6 months of accelerated stability study is required to submit ANDA. In many cases, a bioequivalence study is required, which happens while the product is on stability. While the six months stability is ongoing, a bioequivalence study is completed, and a report is available. Once the six-month stability samples are pulled and tested, the regulatory affairs team will submit an ANDA application to the FDA using eCTD format.
FDA’s eCTD submission standards: https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/ectd-resources
Deficiency Response, Approval, and Product Launch
FDA will review various sections of the ANDA application and start sending deficiency notifications if they find any gaps in the data or need some clarification. Typically, there are 1-2 cycles of deficiencies from the FDA and associated responses from the drug company. Once all the deficiencies and gaps are cleared between the drug company and the FDA, FDA will issue an ANDA approval letter. However, the manufacturing facility must be audited by the FDA and in full compliance before FDA will issue the acceptance letter. Similarly, drug substance manufacturers and all the listed facilities on the application, including outside laboratories, must be in good standing with the FDA before the product is approved.
While the application is being reviewed by the FDA, drug companies will start process validation activities, in which they may choose to increase the batch size. Typically, drug companies are allowed to increase the batch size up to 10x of the ANDA batch size. This activity requires at least 3 batches and extensive sampling. Once the process validation batches are completed, and all the reports are closed, QA will release the product in commerce once the ANDA approval letter is received by the FDA.
Post-launch and Pharmacovigilance
As a generic drug manufacturer, you are required to submit an annual report to the FDA (Food and Drug Administration) under the Code of Federal Regulations (CFR) Title 21, Section 314.81(b)(2)(i).
The annual report is due within 60 days of the anniversary date of the dru’s approval. The anniversary date is the day the drug was first marketed in the United States.
In addition to the annual report, generic drug manufacturers must also submit other reports and updates to the FDA as required by law, such as adverse event reports, labeling updates, and changes to manufacturing processes.
Pharmacovigilance for generic drug manufacturers refers to the process of monitoring the safety and effectiveness of their generic drugs after they have been approved and are being used by patients. The main goal of pharmacovigilance is to detect any potential adverse effects or safety concerns related to the use of the generic drug and to take appropriate measures to mitigate any risks to patient safety.
Pharmacovigilance activities for generic drug manufacturers may include:
- Monitoring Adverse Events: Generic drug manufacturers are responsible for monitoring any adverse events or side effects associated with the use of their drugs. That includes collecting data from patients, healthcare providers, and other sources, and analyzing the data to identify any patterns or trends that may indicate a safety concern.
- Reporting Adverse Events: Generic drug manufacturers are required to report any adverse events or safety concerns to regulatory authorities, such as the FDA, as part of their post-marketing surveillance obligations. These reports are used to identify potential safety issues and inform regulatory decisions about the drug’s safety and effectiveness.
- Conducting Post-Marketing Studies: Generic drug manufacturers may be required to conduct post-marketing studies to further evaluate the safety and effectiveness of their drugs. These studies may be required by regulatory authorities or initiated by the manufacturer as part of their pharmacovigilance efforts.
- Maintaining up-to-date Safety Information: Generic drug manufacturers are responsible for maintaining up-to-date safety information for their drugs, including product labeling and other informational materials. This information must be accurate, complete, and reflective of the latest safety data for the drug.
Overall, pharmacovigilance is an important part of generic drug manufacturing to ensure that the drugs are safe and effective for patients. It is essential for manufacturers to maintain ongoing monitoring and reporting of adverse events and safety concerns to regulatory authorities and to take appropriate measures to mitigate any risks to patient safety.
WiTii Consulting offers a full range of services to drug companies engaged in the ANDA application process. You can reach out to us at admin@witii.us
Acronym/ Abbreviation | Meaning |
ANDA | Abbreviated New Drug Application |
API | Active Pharmaceutical Ingredients |
CFR | Code of Federal Regulations |
CMA | Critical Material Attributes |
CPP | Critical Processing Parameters |
CQA | Critical Quality Attributes |
DMF | Drug Master File |
DS | Drug Substance |
eCTD | Electronic Common Technical Document |
FDA | Food and Drug Administration |
PDR | Product Development Report |
QA | Quality Assurance |
QTPP | Quality Target Product Profile |
RLD | Reference Listed Drug |
RM | Raw Material |
General Inquiries
Address: 1499 W. 120th Avenue, Suite 110, Denver, CO, 80234.
Email: admin@witii.us