1K.B. Institute of Pharmaceutical Education and Research, Gandhinagar.
2,4Department of Regulatory Affairs, K.B. Institute of Pharmaceutical Education and Research, Gandhinagar.
3RegTech India Solutions, Ahmedabad.
Bioequivalence tests are necessary to ensure that generic pharmaceuticals are equivalent to branded treatments. This comparison emphasizes the bioequivalence criteria in Tanzania, the Philippines, and Costa Rica, pointing out significant variances. In Tanzania, the Tanzania Medicines and Medical Devices Authority (TMDA) mandates bioequivalence studies for generic pharmaceuticals, which must adhere to international standards such as Good Clinical Practice (GCP) and Good Laboratory Practice (GLP), typically in conjunction with local clinical trials. In the Philippines, the Food and Drug Administration (FDA) emphasizes studies in healthy human subjects following international guidelines, including WHO and EMA standards, and requires detailed documentation and statistical analysis. Costa Rica's regulations, administered by the Costa Rica’s Regulatory authority, are less severe, allowing for international data yet requiring clinical research. Costa Rica also focuses on post-marketing surveillance of generics. In conclusion, while all three countries require bioequivalence studies, the specifics differ, affecting the approval process and market entry for generic drugs, requiring pharmaceutical companies to navigate these differences carefully and also there are important of Comparative dissolution profile study in all three countries.
When two formulations of the same medicine or two medicinal products are defined as bioequivalent, it means that they would have the same therapeutic effect or are therapeutically equivalent. In this case, most patients think that they can be used interchangeably. Two medications are identified as pharmaceutical alternatives to each other if they have a similar therapeutic component, but not necessarily in the same amount, dose form, or as the same salt or ester.1 BE studies generally use a “crossover design”, in which the test and reference products are supplied to healthy volunteers under closely monitored conditions. Pharmacokinetic properties are measured and compared, such as the area under the curve (AUC) and the maximum concentration (Cmax). The 90% confidence intervals for the ratio of these parameters must typically lie between 80 and 125% in order to meet the acceptance requirements for bioequivalence. 2
Introduction about selected countries
Selected countries for study
Costa Rica
Costa Rica is a country in Central America that borders the Caribbean Sea to the east, the Pacific Ocean to the west, Panama to the south and Nicaragua to the north. In Costa Rica, MOH is the regulatory author. Submit the generic drug's dossier to the MOH for registration and obtain CCSS permission for the drug's marketing.3
Table no. 1
Data of India Distributes of medicinal products to Costa Rica7
|
India Distributes of medicinal products to Costa Rica |
Cost |
Time |
|
Drugs |
$14.83M |
2023 |
|
Animal or Human Blood, Antisera and Other Blood Fractions, Vaccines, Toxins |
$2.79M |
2023 |
|
Medical Goods |
$1.81M |
2023 |
|
Medicaments |
$40.16K |
2023 |
|
Wadding, Gauze, Bandages and Similar Articles |
$4.03K |
2023 |
|
Glands, Other Organs; Extracts of Glands or Other Organs |
$17.58K |
2017 |
Philippines
Overview
The Philippine Food and Drug Administration (FDA) is the nation's main regulating body for pharmaceuticals and medical supplies
Functions and Responsibilities
Regulation and Oversight: The FDA controls the production, importation, sale, and distribution of medications, food, cosmetics, and medical equipment. This includes issuing licenses and permits as well as keeping an eye on adherence to legal requirements. 4
Table no. 25
Data of Philippines imports pharmaceutical products from India
|
Philippines imports pharmaceutical products from India |
Cost |
Time |
|
Drugs |
$323.03M |
2023 |
|
Animal or Human Blood, Antisera and Other Blood Fractions, Vaccines, Toxins |
$56.21M |
2023 |
|
Medicaments |
$2.70M |
2023 |
|
Pharmaceutical Goods |
$1.36M |
2023 |
|
Glands, Other Organs; Extracts of Glands or Other Organs |
$1.23M |
2023 |
|
Wadding, Gauze, Bandages and Similar Articles |
$104.62K |
2023 |
Tanzania
The regulatory agency in charge of guaranteeing the efficacy, safety, and quality of pharmaceuticals, medical equipment, diagnostics, biocides, and tobacco products in Tanzania is the “Tanzania Medicines and Medical Devices Authority (TMDA)”.6
Figure no.17
Top 10 Importing partners of Tanzania
Bioequivalance Study Regulatory Requirements
Regulation in Tanzania
Guideline – Guidelines on Therapeutic Equivalence Requirements Made under Section 52 (1) of the Tanzania Food, Drugs and Cosmetics Act, 2003) First Edition January, 2015 This guideline establishes guidelines for the development, implementation, and evaluation of bioequivalence studies for immediate and modified release dosage forms. This guideline defines guidelines for developing, carrying out, and evaluating bioequivalence studies for rapid release. And also modified-release dose formulations.8
Regulation in Philippines
Taken from the: Guideline on The Investigation of Bioequivalence (European Medicines Agency, London,20 January 2010, CPMP/EWP/QWP/1401/98 Rev 1) With some modification for the ASEAN application.
Table no. 3
Revision of Guideline 9
|
No. |
Date |
|
Final |
July 2004 (8th PPWG Meeting, Bangkok) |
|
Revision 1, Draft 1 |
June 2011, Singapore |
|
Revision 1, Draft 2 |
July 2012, Bangkok, Thailand |
|
Revision 1, Draft 3 |
May 2013, Bali, Indonesia |
|
Revision 1, Draft 4 |
June 2014, Kuala Lumpur, Malaysia |
|
Revision 1, Draft 4 _ Final |
March 2015 , Vientiane ,Lao PDR |
Regulation in Costarica
Previous work on updating regulations for the registration of medicines, good manufacturing practices, good laboratory practices, stability of medicines, and validation of analytical methods, among other areas, gave Costa Rica's process a boost in 2000. These efforts served as the foundation for the later implementation of criteria requiring bioequivalence studies in the registration of interchangeable generic products. 10 According to the WHO's bioequivalence guidelines, bioequivalence research is being conducted in Costa Rica. For the filing of a bioequivalence research, Costa Rica has its own requirements for the bioequivalence dossier.
Structure of the “Bioequivalence Dossier”
It is separated into many parts and contains two different types of documents:
Specific documents of the “Bioequivalence Dossier”
These documents, which are of a legal and technical nature describing the study presented and the quality of the data obtained, are vital and are especially requested by the Therapeutic Equivalence Regulation.
1) The Bioequivalence Study's Report and Evaluation Form of Results (FOREBI), along with the accompanying papers
2) “Comparative Dissolution Profiles” (PDC) Presentation and Evaluation Forms
3) One or more “Good Laboratory Practices certificates”
4) One or more “Good Clinical Practices certificates”
5) The product's Certificate of Bioequivalence in its country of origin.
6) The monitor's declaration regarding the validity of the study's final report.
7) The Independent Ethics Committee's letter approving the protocol.
8) “Certificates of Analysis” for the reference and test products that match the batches utilized in the bioequivalence investigation.
9) Evidence of Therapeutic Equivalency Fee Payment
Documents referable to the Processing File: These are documents that have already been asked for by the general registration or renewal process regulations,
1) Dissolution Profile Studies must be allowed by the Ministry before the bioequivalence study may be provided.
2) The full qualitative-quantitative formula for the final result.
3) Project labelling and insertion.
4)A monograph
Document Checklist
1. FOREBI. The form file in compatible Microsoft Word 2007 format that was printed out and presented in Section 2 of the Bioequivalence Dossier
2. Letter providing details on the product's safety and marketing history.
3. A certified copy of the acquisition paperwork for the bioequivalence study's reference product samples.
4. The bioequivalence protocol, including all of its addenda and modifications. The original document in a PDF file that cannot be altered
5. The final study report. The original document in a PDF file that cannot be altered
6. Researcher Curriculum Vitae.
7. Any other safety information provided to the Independent Ethics Committee by the study's sponsor and/or investigator, including notifications of severe or unexpected adverse responses. A PDF file containing the original documents that cannot be altered.
8. The Bioanalytical Method Validation Report. The original document in a PDF file that cannot be altered
9. A copy of the study's analyte(s) certificate (reference substance).
10.A copy of the internal employer's certificate
11. Raw data on each product's concentrations by participant and time at each sampling point. File in an MS Excel 2007-compatible format
12. The research center or laboratories where the following phases of the investigation were conducted issued a master list or lists of SOPs relevant to the study: 1. Clinical; 2. Bioanalytical; 3. Data processing and analysis (statistical and pharmacokinetic).
13. SOPs for the Bioanalytical Method Validation. The original document in a PDF file that cannot be altered
14. SOP for receiving and holding samples until the bioanalytical laboratory analyses them. The original document in a PDF file that cannot be altered
15. SOP for the bioanalytical laboratory's concentration quantification: Save the original document in an unchangeable PDF format.
16. SOP for repeated analysis: File with the original document in non-modifiable PDF format
17. SOP to explain lost, unused or spurious data. File with the original document in non- modifiable PDF format.
18. Case Report Forms (FRC's). File with the original document in non-modifiable PDF format
19. Study monitoring reports (General list and copies of each report)
20. Letter from the sponsor with information about the study audit
21. Letter from the sponsor with information about study inspections by health authorities 11
Regulation in Comparative Table
Table no. 4
Comparison of Regulations
|
No. |
BE Study Requirements |
Tanzania |
Philipines |
Costarica |
|
1 |
Regulatory Agency |
“Tanzania Food and Drugs Authority” (TMDA) |
Food and drug authority of Philippines |
Ministry of health COSTARICA |
|
2 |
Reference Product Type |
Choose the WHO recommended comparator product |
Have their own Comparator product list |
Have their own comparator product list |
|
3 |
Reference Source |
To select a product that has been approved and on the market in any of the ICH and associated nations for more than five years. |
The choices for comparators include ICH approval and related nations |
Compared to the product declared as an official reference in Costa Rica |
|
4 |
Subjects |
In general, the recommended number of 24 normal healthy subjects Not less than 12 subjects |
Minimum Number of subjects should not be smaller than 12. |
A minimum of 12 subjects is required |
|
5 |
Gender |
Both Gander |
Both Gander |
Both Gander |
|
6 |
Age Criteria |
18 – 50 years |
18 – 55 years |
18 and 55 year |
|
7 |
Test Product |
Test product should usually originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified. |
A batch of at least 1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified |
100000 units, whichever is larger, and are produced with the same formulation and similar equipment and process to that planned for commercial production batches. A bio batch of less than 100000 units may be accepted provided that this is the proposed production batch size, |
|
8 |
Body Mass Index |
18.5 and 30 kg/m2 |
18 and 30 kg/m2 |
18 and 30 kg/m2 |
|
9 |
Fasting Study |
Subjects should fast for a minimum of eight hours. |
Fast for at least 8 hours before to administering the products. |
FPPs are normally delivered after a minimum 10-hour overnight fast, with free access to water. Water is not allowed one hour before FPP administration on the morning of the study. |
|
10 |
Fed Study |
30 minutes before the final medicinal product is administered, begin the meal and finish it within 30 minutes. |
Subjects should start eating 30 minutes before the drug is provided and finish their meal within 30 minutes. |
The test food should be had beginning half an hour before the FPP is given. |
|
11 |
Water/fluid Intake |
A standardized volume of fluid (at least 150 ml) should be applied to administer the test and comparable items since fluid intake may impact stomach transit for oral administration types. Water should be permitted as desired, until one hour prior. |
Test and comparator items should be given through a standardized fluid volume (at least 150 ml). |
It is advised that the dosage be taken with a regular amount of water, typically 150-250 mL |
|
12 |
Subject replacements on dropout Or Withdrawal |
In general, dropouts shouldn't be replaced. |
Not replaced |
In order to account for potential withdrawals or dropouts, sponsors should choose a sufficient number of research participants. Dropouts should often not be replaced since doing so might make the statistical model and analysis more difficult. |
|
13 |
Washout Period |
Typically, a minimum of 5 elimination half-lives are required.
|
Typically, a minimum of 5 elimination half-lives are required.
|
All participants should have the same washout period, which is often greater than 5 times the median terminal half-life. |
|
14 |
Sampling points |
A minimum of three to four samples are required during the terminal log-linear phase. For multiple-dose studies, the pre-dose sample should be collected within 5 minutes after dosing, followed by the last sample within 10 minutes. The time frame for sampling should include at least five terminal elimination half-lives of the medication or five of its longest half-lives. Urine should generally be collected for at least three times the terminal elimination half-life. The sample treatment should include endogenous chemicals.2-3 samples are collected before the completed medicinal items are given. |
To properly determine the terminal rate constant during the terminal log-linear phase, at least three to four samples are necessary. In multiple-dose studies, the predose sample should be obtained immediately before the dosage (5 minutes), and the last sample for endogenous medications should be taken within 10 minutes. To establish a baseline, two to three samples are often taken prior to the administration of prescription items.
|
To correctly determine the terminal rate constant during the terminal log-linear phase, at least three to four samples are necessary. In multiple-dose studies, the predose sample should be created immediately before the dosage (5 minutes), and the last sample for endogenous medications should be taken within 10 minutes. To establish a baseline, two to three samples are often taken prior to the administration of prescription items. |
|
15 |
Pharmaco kinetic parameters to be Measured |
The parameters are AUC(0-t), AUC (0- ∞), residual area, Cmax and tmax, λz, and t1/2 |
The parameters are AUC(0-t), AUC(0-∞), Cmax and tmax, λz, and t1/2, AUC (0-??)., Cmax,ss, and tmax,ss, Ae(0-t), Rmax = dAedt 
|
The parameters are (Cmax, tmax), (AUC), Cmin, t1/2 |
|
16 |
Pharmaco dynamic Studies |
Included in Study |
Included in study |
Not Specified |
|
17 |
Strength of the dosage form |
1 or 2 strength |
1 or 2 strength |
Three to four points throughout the elimination phase, two points around Cmax, and a pre-dose sample should all be included in the sampling points. For the purpose of estimating the essential pharmacokinetic parameters, a minimum of seven sample points will be required. Although it is not required to sample for more than 72 hours, sampling should generally continue long enough to allow for the accumulation of 80% of the AUC0–∞. |
|
18 |
Genetic and Phenotyping |
Subject phenotyping and/or genotyping may be used to deal with pharmacokinetic or safety problems. |
Not Specified |
Additionally, phenotyping could be crucial for security reasons. |
|
19 |
Sampling |
To correctly determine the terminal rate constant during the terminal log-linear phase, three to four samples are needed. |
During the terminal log-linear phase, three to four samples are necessary to accurately estimate the terminal rate constant. |
Pre-dose samples should be taken frequently enough to evaluate Cmax, AUC, and other metrics; at least 1-2 times before Cmax, 2-3 times around Cmax, and 3-5 times throughout the elimination phase. |
|
20 |
Acceptance criteria |
The option of increasing the acceptance criteria in response to significant intra-subject variability is not applicable to AUC, where the acceptance range should stay at 80.00-125.00% for any variability. |
Regardless of variability, the acceptable range should stay between 80.00 and 125.00%.
|
This bioavailability ratio measure's 90% confidence interval should be between 80.00 and 125.00% of the bioequivalence range. |
|
21 |
Standard Design |
A randomized, two-period, two-sequence, single dosage crossover design is advised for comparing two formulations.
|
A randomized, two-period, two-sequence, single-dosage crossover design is advised for comparing two formulations. |
The ideal study design is a randomized, two-period, two-sequence, single-dose, cross-over investigation carried out with healthy participants. |
|
22 |
Alternative design |
Alternative design in Allowed |
Alternative design in Allowed |
A research in patients might be necessary for API that exhibit intolerable pharmacological effects in healthy volunteers, even at reduced dosages. |
|
23 |
Dossier Format |
CTD |
ACTD |
Bioequivalance Dossier |
|
24 |
Fees |
2000 USD |
New application (5-year validity) PhP 33,333.33 + LRF Pending application (paid for 3-years and will avail 5-year validity) PhP 13,333.33 + LRF |
US$ 520.00 |
|
25 |
Language |
English |
English |
Spanish and other translated language |
|
26 |
Study reporting format |
BTIF - BIOEQUIVALENCE TRIAL INFORMATION |
ASEAN Bioequivalence Study Reporting Format |
FORM FOR REPORTING AND EVALUATION OF RESULTS OF BIOEQUIVALENCE STUDIES (FOREBI) |
|
27 |
Study report add at which part of dossier |
Study report attached in Module 5 part |
Study report attached in module 4 |
In Bioequivalence dossier |
|
28 |
CDP required |
Yes |
Yes |
Yes |
Dosage form regulation
Table no. 8
Comparison of dosage form Regulation
|
No |
BE Criteria |
Tanzania |
Philippines |
Costa Rica |
|
1 |
Tablets, capsules and oral suspensions |
Study is necessary unless a biowaiver is obtained. |
Study is necessary unless a biowaiver is obtained. |
Study is necessary unless a biowaiver is obtained.
|
|
2 |
Orodispersable tablet (ODT) |
Bioequivalence study required |
The product may be taken into consideration for a BCS-based biowaiver if it is absorbed through the gastrointestinal tract. |
Not specified |
|
3 |
Oral solutions |
Not required |
Bioequivalence tests may be omitted if the concentration is the same as that of an authorized oral solution. |
BE study not required |
|
4 |
Fixed combination dosage forms |
If every active ingredient in the FC is a member of BCS class I or III, then BCS-based biowaivers are appropriate for immediate-release FC products. |
Biowaiver |
BE study required |
|
5 |
Non-oral immediate release dosage forms with systemic action |
Not Specified |
BE study required Biowaiver considered if have similar quantitative composition |
BE study required |
|
6 |
Parenteral solutions |
Not required |
BE not required |
BE not required |
|
7 |
Modified release dosage forms with systemic action |
Not Specified |
Be study required |
Be study required |
CONCLUSION
In conclusion, while Tanzania, the Philippines, and Costa Rica all require bioequivalence studies to ensure the safety and efficacy of generic drugs, the specific regulatory requirements vary significantly. Tanzania enforces strict compliance with international standards and often mandates local clinical trials, emphasizing robust clinical and laboratory practices. The Philippines also adheres to international guidelines but places a heavy focus on detailed statistical analysis and documentation, ensuring rigorous assessment of bioequivalence in healthy human subjects. In contrast, Costa Rica allows for more flexibility by accepting international data, although clinical studies. Tanzania and Philippines have their own regulation for bioequivalence but Costarica follow Who. Philippines and Costarica have their Comparative product list but Tanzania follow Who comparative list. Tanzania require CTD dossier and Philippines require specific Bioequivalence dossier. And all of Three countries are require a Comparative dissolution Profile of Reference and Test product. These differences in regulatory approaches impact the approval process and market entry for generics, making it crucial for pharmaceutical companies to understand and navigate the specific requirements in each country to successfully bring their products to market. After the study conclude that there are some specific differences in regulation of Bioequivalence and also in the submission of Bioequivalence study. But Costarica have more different regulation other than Tanzania and Philippines.
Funding
This research project, called "Regulatory Requirements of Bioequivalence Study for Tanzania, Philippines, and Costa Rica," is not funded by anyone. The project's goal is to explore and evaluate the regulatory frameworks controlling bioequivalence studies in these three countries in order to gain a better understanding of regional needs and enable global pharmaceutical market access.
Data Availability Statement
The information gathered as part of the research project named "Regulatory Requirements of Bioequivalence Study for Tanzania, Philippines, and Costa Rica" will be securely saved and preserved in compliance with ethical standards and data protection requirements. This comprises regulatory documentation, interviews with appropriate authorities, and any other data collected throughout the research.
Conflict of Interest Statement
The author certifies that there are no conflicts of interest linked to this research. They do not have any financial or personal links that might impact or distort the results. The substance of this study.
Animal welfare
This study project, named "Regulatory Requirements of Bioequivalence Study for Tanzania, Philippines, and Costa Rica," does not include any animal experimentation or usage. The study focuses on the analysis of regulatory frameworks and requirements for bioequivalence studies in the listed countries. As a result, this initiative does not involve any animal research.
Because the project is largely based on regulatory document evaluations, interviews with relevant authorities, and secondary data gathering, all methods and activities involved with this study are conducted in strict accordance with ethical research standards. The research team is devoted to carrying out the study in a way that respects the norms of ethical conduct and the wellbeing of everybody engaged.
REFERENCES
Ansh Patel*, Dr. Niranjan Kanaki, Shruti Kharidia, Dr. Maitreyi Zaveri, Regulatory Requirements of Bioequivalence Study for Tanzania, Philippines and Costarica, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 3, 3142-3154 https://doi.org/10.5281/zenodo.15109010
10.5281/zenodo.15109010
