In China, complex generic drugs are considered to be high-tech, which lies in complex formulations and special manufacturing process, making the drug’s development and manufacture more difficult compared with ordinary generic drugs.
Due to the improvement in formulation and manufacturing process, complex generics usually have high clinical value in terms of higher bioavailability, lower dosing frequency, fewer adverse drug reactions (ADRs), and higher patient compliance. Due to such advantages over simple generics, particular chemistry, manufacturing, and control (CMC) studies are required, possibly with further non-clinical and/or clinical studies, to prove the generics’ equivalence to the reference listed drugs.
This article introduces China’s CMC requirements for injectable complex generics, which are deemed competitive in the Chinese generic market impacted by the volume-based procurement (VBP) policy (which is introduced in Part 2.3 of this article).
1. Definition of Complex Generics
China National Medical Products Administration (NMPA) gives a description rather than a definition of complex generic injections in the Technical Requirements for the Quality and Therapeutic Equivalence Evaluation of Injectable Complex Generics:
“Compared to ordinary injections, special injections’ quality and their active ingredients’ performance are more affected by the formulation and manufacturing process, which can further influence the finished drug product’s in vivo safety and efficacy. Special injections include those with liposomes, emulsion for venous transfusion, microspheres, suspension, oil solution, micelles, etc.”1
According to U.S. Food and Drug Administration (FDA),
“a complex generic drug product generally means the following:
1. A product with:
a complex active ingredient(s) (e.g., peptides, polymeric compounds, complex mixtures of APIs, naturally sourced ingredients)
a complex formulation (e.g., liposomes, colloids)
a complex route of delivery (e.g., locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions, or gels)
a complex dosage form (e.g., transdermals, metered dose inhalers, extended release injectables)
2. Complex drug-device combination products (e.g., auto injectors, metered dose inhalers); and
3. Other products where complexity or uncertainty concerning the approval pathway or possible alternative approaches would benefit from early scientific engagement.2
NMPA’s description of complex generic injection fall into the FDA’s definition of complex generic drug. Thus, China’s complex generic injections will hereafter be referred to as injectable complex generics.
2. Complex Generics’ Competitive Edge in China Market
Complex generics are advantageous in terms of technology, clinical value, and price.
On the one hand, complex generics are more difficult to develop than simple generics. Apart from the general requirements of equivalence evaluation for all generic drugs, complex generics should also comply with special requirements concerning formulation study, manufacturing process, quality control, and stability study. Not many companies can fulfill the requirements to become players in the complex generics market.
On the other hand, complex generics as not as difficult as innovative drugs, whose R&D is even more demanding and riskier.
2.2 Clinical Value
Complex generics usually outperform simple generics regarding bioavailability, dosing frequency, adverse drug reactions (ADRs), and patient compliance. Thus, in terms of adequately meeting clinical needs, complex generics are more desirable than simple generics.
China’s pharma market is influenced by the National Reimbursement Drug List (NRDL), a list of drugs reimbursed or covered by China’s social health insurance fund. For NRDL-listed drugs with high prices but low clinical value, China replaces them with newly selected drugs via NRDL adjustment, which takes place almost annually.
Another market-impacting policy is China’s volume-based procurement (VBP), known for price slash and bulk purchase. VBP prevents the commissions from pharma companies to some doctors at public hospitals, and provides patients with affordable drugs that have passed equivalence evaluations.
China’s purposes for NRDL and VBP are not exactly the same: NRDL is in innovative drugs’ favor. For example, it is difficult for a company to sell expensive innovative drug products if it does not lower the price to negotiate for a place on NRDL so that the product remains ineligible for reimbursement by the social health insurance fund. VBP is mainly targeted at the generic drug market, trading huge volumes of lower-priced generics needed in public hospitals. Few innovator companies attend VBP, which would bruise them too much in profitability.
In short, drug price is a significant factor in China’s considerations for NRDL or VBP to increase the affordability of quality-assured drug products.
3. CMC Requirements for Injectable Complex Generics
To gain edges over non-complex counterparts, complex generics should go through particular CMC studies. China has released three product-specific guidelines for injectable complex generics and one general document Technical Requirements for the Quality and Therapeutic Equivalence Evaluation of Injectable Complex Generics.
Issued and Enforced
Center for Drug Evaluation (CDE)
In addition to the guidelines and requirements specifically targeted at them, complex generics should also comply with requirements for all (including complex and non-complex) generics.
Due to the complexity of the product attributes, researchers should conduct the comparison study step by step:
CMC and non-clinical comparative study
In vivo bioequivalence (BE) study
3rd step (only when necessary)
4th step (only when the CMC study and/or non-clinical study show that the test drug is not equivalent to the RLD)
The applicant should improve the formulation and the manufacturing process, and then re-conduct studies from the 1st step.
The following part focus on CMC studies of injectable complex generics.
3.1. Formulation Study
The applicant should select a reference drug from China’s Catalog of Reference Listed Drugs (RLDs). The current RLD catalog includes some injectable complex generics, e.g., Fulvestrant Injection, Paclitaxel for Injection (Albumin Bound), Amphotericin B Liposome for Injection, Leuprorelin Acetate Microspheres for Injection, Posaconazole Injection, etc.
However, chances are that the applicant cannot find an appropriate drug on the list. In such situations, the applicant can apply for adding a drug to the RLD catalog. The application process can be found at BaiPharm’s article China Abbreviated New Drug Application (ANDA) for Generic Drugs. China NMPA is expected to continue releasing new lists of RLDs and updating the information on the previously released lists. View the full RLD catalog at BaiPharm Database.
In principle, excipients of the generic drug and the reference drug should be the same qualitatively (Q1) and quantitatively (Q2). The difference in the amounts of excipients between the test injection and the RLD should be no more than 5%.
Applicants should also study the excipients that affect the finished dosage form’s critical quality attributes (CQAs) and/or in vivo performance. Take Fulvestrant Injection as an example. In the drug’s guidelines, castor oil is noted as a critical excipient that affects the dispersion and absorption of fulvestrant. CDE advises applicants to establish strict internal control standards no lower than those in Chinese domestic and foreign pharmacopoeias. Applicants should provide evidence proving that test and reference products are equivalent in the CQAs (e.g., fatty acid composition, free fatty acid/acid value, viscosity, moisture, peroxide value, saponification value, and iodine value). Applicants should also pay attention to safety-related substances (e.g., pesticide residues, aflatoxins, plant proteins, and pigments) that may exist in plant-based excipients, and refine the castor oil when necessary.3
3.2. Manufacturing Process
To manufacture injectable complex generics, especially those with carriers such as liposomes, micelles, and microspheres, applicants should pay attention to the RLD’s technical principles, dosage form’s attributes, and route of administration when considering the manufacturing techniques.
For example, Paclitaxel for Injection (Albumin Bound) (brand name: Abraxane) is made by Celgene with emulsification solvent evaporation method. If the generic drug applicant plans to adopt a different method, it must state the reasons and conduct studies to prove the different method does not affect the generic version’s safety or efficacy.
Applicants should pay particular attention to the effect of manufacturing process and batch sizes on quality control. In principle, the registration batches and the commercialization batches should be consistent in manufacturing process and batch size. The post-approval change to the batch size is categorized as major change, so the applicant has to submit an application for approval.4
3.3. Drug Quality Study and Quality Control
In principle, applicants should provide the quality comparison data of at least three batches of RLDs and generics, to prove that the two are equivalent in CQAs.
For instance, applicants of generic Paclitaxel for Injection (Albumin Bound) should consider the following CQAs in addition to the general quality attributes of injections:
(1) Particle morphology;
(2) Particle size and particle size distribution;
(3) Zeta potential;
(4) Paclitaxel crystallinity;
(5) The ratios of free and bound paclitaxel as well as free and bound albumin in the two phases of the suspension after reconstitution;
(6) Nature of bond between paclitaxel and albumin;
(7) In vitro disintegration kinetics;
(8) Recovery of paclitaxel after the reconstituted suspension filtered through a 0.22μm filter membrane;
(9) Ratios of albumin (monomer, dimer, oligomer, and polymer) in both the albumin excipient and the final drug product.
(10) Stability of the reconstituted suspension.
3.4. Stability Study
On the basis of obeying stability study requirements for routine drugs, applicants of injectable complex generics should establish evaluation methods and standards considering the CQAs confirmed by quality study & control that may affect the final product’s attributes. For example, Paclitaxel for Injection (Albumin Bound)’s CQAs related to microparticle formulations (e.g., particle size and particle size distribution, zeta potential, crystallization state of paclitaxel, in vitro disintegration kinetics, etc.).
During clinical use, injections are usually dissolved and diluted with infusion solutions. For such generic injections, applicants should design and conduct the in-use stability study modeling the clinical use and amount as specified in the reference drug’s medication package inserts. In the study, applicants should consider the following factors: the highest/lowest concentration for clinical use, temperature for clinical use, maximum time (including infusion time) for clinical use, etc.
Contact BaiPharm if you’d like to know more about generic drug registration in China.