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Qualtech Consulting Corporation
Taiwan, China, Japan, Singapore, Hong Kong, Malaysia, Philippines, Vietnam, Australia, Germany, Korea, Thailand, USA
A specialized medical device consulting firm offering a one-stop solution for complex global regulatory challenges. We offer real-time regulatory and clinical support, local representation, and QMS services across 13 markets, ensuring efficient market entry and compliance.
Cobridge Co., Ltd.
Tokyo, Japan
We assist medical device companies with the medical device registration and approval in Japan. Regulatory consulting services and DMAH services for foreign manufacturers to enter Japanese market.
MDREX, Medical Device, Digital Health Consulting Group
Seoul, Republic of Korea (HQ), Japan Office
We offer total solutions for market entry in South Korea and global expansion (e.g., Japan, USA, Europe). Key areas include product approval, reimbursement listings (HIRA), and Quality System certification (KGMP). They are particularly strong in innovative products like SaMD, medical wearables, and 3D printing for medical use, and provide in-depth expertise in cybersecurity and clinical trial planning.
CMIC Holdings Co., Ltd.
Tokyo, Japan (HQ), Osaka, Japan, Beijing, China, Seoul, South Korea, Taipei, Taiwan, Singapore, New York, USA, London, UK, Frankfurt, Germany, Sydney, Australia
We operate globally, specializing in accelerating the development, manufacturing, and commercialization of drugs and medical devices. Their expertise spans Phase I to IV clinical trials, regulatory affairs, quality assurance, and manufacturing, with a strong focus on the Japanese and Asian markets. Key services include clinical operations (CRO), manufacturing (CDMO/CMO), site management (SMO), and comprehensive health analysis and solutions.
November 14, 2025
Approximately 5 minutes
Guidelines for Bioequivalence Studies of Generic Products in Japan: What the 2020 Revision Requires
1) Regulatory context and where the English guideline comes from
On September 14, 2021, Japan’s MHLW issued an Administrative Notice announcing the English translations of the 'Guidelines for Bioequivalence Studies of Generic Products' and the related Q&A, noting that the guideline was partially revised on March 19, 2020 (PSEHB/PED Notification No. 0319-1) and that the translated documents are publicly available via the National Institute of Health Sciences (NIHS). Reference (Administrative Notice): PMDA PDF
Key English guideline referenced by the notice:
2) Purpose and scope of the guideline
The guideline explains the principles and procedures for BE studies of generic products, with the objective of assuring therapeutic equivalence to innovator products; when direct bioavailability comparison is not feasible, pharmacodynamic or clinical comparisons may be used. The Q&A clarifies that the guideline can be applied broadly to generic drugs that are required to undergo a BE study.
3) Reference product and test product: selection and manufacturing expectations
Selecting the reference (innovator) product lot
For oral immediate-release products, dissolution testing is used to select a reference lot (generally using three innovator lots and choosing the lot with intermediate dissolution; if all lots reach 85% dissolution within 15 minutes, any lot may be used). The guideline also prefers that the reference lot content/potency is as close as possible to label claim, and that the difference between test and reference content/potency is within 5% of label claim.
Test product batch size and commercial representativeness
The guideline recommends using a test lot manufactured at full-scale; however, a lot at a scale of at least 1/10 of full-scale production can also be used (with additional nuance for homogeneous liquids). The Q&A reinforces that ensuring 'at least 1/10 of full production' helps address scale-up risk and supports international harmonization.
Practical Q&A flexibility
If obtaining three innovator lots is difficult, selecting fewer lots may be acceptable with adequate justification.
4) Core in vivo BE study design (typical oral immediate-release)
Study design
Crossover designs are the general rule, with randomized assignment.
Dosing conditions: fasted vs fed
For single-dose studies under fasting conditions, subjects fast for more than 10 hours, receive the drug with 100–200 mL water (normally 150 mL), and continue fasting for at least 4 hours post-dose.
Fed studies may be used when postprandial dosing is specified or when fasting bioavailability is very poor / severe adverse events are anticipated. In a standard fed BE study, the guideline specifies a low-fat meal of 700 kcal or less with no more than 20% of calories from fat, consumed within 20 minutes; dosing is per the regimen or 30 minutes after the meal if timing is not specified.
For solubility-enhanced products, BE should be evaluated in both fasted and fed states; for postprandial administration, a high-fat meal of 900 kcal or more and 35% lipid content is used, with dosing within 10 minutes after finishing the meal (and certain safety-driven substitutions are described).
Sampling considerations
The guideline provides minimum expectations for sampling: at least 7 time points including baseline, points around Cmax, and elimination phase sampling; and continuing sampling until AUCt exceeds 80% of AUC∞ (with specific handling for very long half-life drugs).
5) Key PK parameters and statistical acceptance criteria
Parameters
The guideline focuses on standard PK parameters such as AUC and Cmax as primary measures for BE assessment, with log-transformation generally applied to parameters other than tmax.
Standard acceptance criterion (most common pathway)
For AUC and Cmax, the bioequivalence acceptance range is 0.80 to 1.25 when expressed as the ratio of population means (test/reference), and BE is concluded when the 90% confidence interval for the difference of log-transformed parameters lies within log(0.80) to log(1.25).
Additional acceptance pathway when CI is outside 80–125%
Even if the 90% CI is not within log(0.80)–log(1.25), the guideline allows acceptance when specific conditions are met, including total sample size ≥ 20 (n≥10/group), tighter point estimates (e.g., log(0.90)–log(1.11) for certain comparisons), and supportive dissolution similarity/equivalence depending on dosage form.
6) Operational Q&A points commonly used in submissions
Can foreign subjects be used?
The Q&A states that BE data from subjects ethnically different from Japanese can be acceptable if ethnic differences have negligible impact on BE results; however, if formulation characteristics and physiology differences could affect BE evaluation, a BE study in Japanese subjects may be required, and the Japan-approved reference product must be used.
7) Practical compliance checklist (submission-ready)
- Confirm scope early: verify the product is a generic requiring BE and align the evidence pathway (in vivo BE vs PD/clinical when justified).
- Lock reference product strategy: document innovator lot selection logic (including dissolution-based selection) and justify any deviation from three lots.
- Ensure commercial relevance: use full-scale or at least 1/10-scale test batches and show manufacturing comparability to marketed product.
- Design fasting/fed conditions correctly: apply the specified meal composition/time rules and apply fasted+fed where required (e.g., solubility-enhanced products).
- Pre-specify stats and acceptance: 90% CI approach with 80–125% criterion for AUC/Cmax; document any use of the alternative acceptance route.
References
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