Basic Regulatory Requirements of EU, MHRA, TGA

and ROW Countries

Basic Regulatory Requirements of EU

EU is poli cal and economic union comprising 27 member countries located in Europe.

U.S. Terminology EU Equivalent Description

Investigational New Drug Clinical Trial Application Permission required to initiate clinical trials in humans.
(IND) (CTA) Submitted to NCAs and assessed within the CTIS.
New Drug Application Marketing Authorization Application to market a new drug in the EU. Assessed via
(NDA) Application (MAA) centralized or decentralized processes.
Abbreviated New Drug Generic Marketing For generic drugs, submitted via the MAA process but
Application (ANDA) Authorization evaluated with reduced data requirements under
Directive 2001/83/EC.
Table 1: IND, NDA & ANDA Equivalent in EU

Clinical Trial Applica on (CTA) Process

 Submit data from preclinical studies, clinical trial protocols, and Inves gator’s Brochure
 Submit the CTA through the CTIS.
 The NCA and Ethics Commi ee review the CTA to ensure safety, efficacy, and compliance with ethical
standards.
 60 days for evalua on and response, a er which trials may proceed.

Marke ng Authoriza on Applica on (MAA) Process

1. Decentralized Procedure (DCP): obtain marke ng authoriza on for a medicinal product in mul ple EU
member states simultaneously. It is suitable for products not covered by the mandatory Centralized Procedure
and is especially common for generic medicines or well-established drugs.
 Submit the dossier (in eCTD format) simultaneously to the Reference Member State & Concerned
Member State.
 Both RMS and CMSs validate the applica on to ensure completeness, within 30 days.
 RMS prepares an Assessment Report (AR) evalua ng the quality, safety, and efficacy of the product. By
Day 70, the RMS shares the dra AR with CMSs and the applicant. Day 0-70.
 CMSs review the dra AR and provide comments or objec ons (if any) Day 70-120.
 By Day 120, the RMS provides a final AR and communicates whether a consensus has been reached.
Day 120.
 Once a consensus is reached, CMSs issue na onal marke ng authoriza ons based on the RMS's
recommenda on.

Validation Phase 30 days

Assessment Phase I 70 days (Day 0-70)
Assessment Phase II 50 days (Day 70-120)
National Authorization 90 days (Day 120-210)
Total Duration ~210 days (excluding clock stops)
Table 2: Timeline for MAA in EU

2. Centralized Procedure: allows for a single marke ng authoriza on that is valid across all EU member states,
European Economic Area (EEA) countries (Iceland, Liechtenstein, and Norway), and Switzerland (under
separate agreement). The CP is required for:
 Biological products.
  Medicines for rare diseases (orphan drugs).
 Advanced Therapy Medicinal Products (ATMPs).
 Cancer treatments.
 Other high-need products (e.g., human vaccines).

Applicant submit MAA to EMA (eCTD format).

Validation by EMA w/in 14 days.

Committee for Medicinal Products for Human Use (CHMP) conduct scientific assessment.

CHMP assign primary and secondary evaluator (rapporteur).

w/in 210 days issues opinion.

w/in 60 days EC based on the opinion issues a decision.

After approval applicant has to comply with PMS.

Renewal after every 5 years.

Flowchart 1: Centralized Process in EU

3. Mutual Recogni on Procedure (MRP): Used for a product already authorized in one member state to extend
approval to others.
4. Na onal Procedure: For drugs intended for one member state only.

MHRA
Medicines and Healthcare products Regulatory Agency (MHRA) is the UK’s na onal regulatory authority. The MHRA is
an execu ve agency of the UK Department of Health and Social Care (DHSC). The MHRA follows a process similar to
the EU's Marke ng Authoriza on Applica on (MAA) process but operates independently in the UK. It has its own
procedures for both innovator medicines (new drugs) and generic medicines. Established in 2003, by merger of

 The Medicines Control Agency (MCA): Responsible for regula ng medicines and pharmaceu cal products.
 The Medical Devices Agency (MDA): Focused on regula ng medical devices.

Approval Process

Applica on Submission  Valida on  Scien fic Evalua on  Decision  PMS.

TGA
Therapeu c Goods Administra on (TGA) is the regulatory body responsible for the regula on and monitoring of
therapeu c goods in Australia. TGA was formally established as part of the Australian Government Department of
Health in 1989 under the Therapeu c Goods Act 1989.
Inves ga onal New Drug (IND) Equivalent: Clinical Trial Applica on (CTA)

1. The TGA offers two pathways for clinical trial approval:

 CTN (Clinical Trial No fica on): A simplified process where the sponsor no fies the TGA of the trial
a er obtaining approval from a Human Research Ethics Commi ee (HREC).
 CTA (Clinical Trial Authorisa on): Required when the TGA reviews the trial for approval (usually for
more complex or high-risk trials).
2. CTA submi ed to TGA.
3. Review takes up to 40 days.
4. If approved CT can be ini ated.

New Drug Applica on (NDA) Equivalent: New Medicines Registra on (NMR)

Pre-Submission Consulta on  Applica on Submission  TGA Review  Approval (255 days).

Abbreviated New Drug Applica on (ANDA) Equivalent: Generic Medicine Registra on (150 days)

1. Generic Medicine Applica on: BE data Manufacturing & QA data.

2. Applica on Submission.
3. TGA Review
4. Approval

ROW Countries
Rest of the World is a term o en used in the context of interna onal business, marke ng, and regulatory affairs to
refer to countries or regions outside of specific focus areas, such as the US, European Union, or Japan. In the
pharmaceu cal and medical device industries.

 Asia: India, China, Southeast Asian countries (e.g., Thailand, Malaysia, Philippines, Vietnam), Pakistan,
Bangladesh.
 Africa: South Africa, Nigeria, Egypt, Kenya.
 La n America: Brazil, Argen na, Mexico, Chile, Colombia.
 Middle East: Saudi Arabia, UAE, Israel, Turkey.
 Eastern Europe: Russia, Ukraine, Poland, Romania, Czech Republic.

Key Regulatory Agencies

 India: Central Drugs Standard Control Organization (CDSCO)

 China: National Medical Products Administration (NMPA) (formerly CFDA)
 Brazil: Agência Nacional de Vigilância Sanitária (ANVISA)
 Mexico: Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)
 South Africa: South African Health Products Regulatory Authority (SAHPRA)
 Middle East: Many countries in the Middle East have their own regulatory bodies (e.g., Saudi Food
and Drug Authority (SFDA), UAE Ministry of Health and Prevention (MOHAP)).
 Russia: Federal Service for Surveillance in Healthcare (Roszdravnadzor)
 ANDA Regulatory Approval Process

1 Introduction to ANDA:
Abbreviated New Drug Approval, a vehicle through which an applicant seek permission to market a generic drug
product in the market. A generic drug is same as brand drug in dosage form, safety, strength, route of administra on,
quality, performance & intended uses. Thus, a generic product is pharmaceu cal equivalent to branded drug product
& for approval it has to be bioequivalent as well. So, a generic product can be used as subs tute to get same clinical
benefit as branded drug product. Regulated under sec on 505(j) of Title 21 part 355. ANDAs can be submi ed en rely
electronically via the Electronic Submissions Gateway.

2 Office of Generic Drugs:

The U.S. Food and Drug Administra on (FDA) is organized into nine offices/centers:

1. Center for Drug Evalua on and Research (CDER)

2. Center for Biologics Evalua on and Research
3. Center for Devices and Radiological Health
4. Center for Food Safety and Applied Nutri on
5. Center for Veterinary Medicine
6. Na onal Center for Toxicological Research
7. Office of the Commissioner
8. Center for Tobacco Products
9. Office of Regulatory Affairs.

Office of Generic Drugs (OGD) is located within the CDER under the Office of Pharmaceu cal Science. It consists of
the following divisions: Chemistry, Bioequivalence, Clinical Review, Microbiology, and Labelling and Program Support.
OGD ensures the safety and efficacy of generic drugs by employing a review process that is similar to the NDA
process. Main difference between the Generic Drug Review process and the NDA review process is the study
requirements that is in ANDA BE study is needed mainly while pre-clinical, clinical and BA studies are not needed as
already established by previous NDA.

3 Drug Price Competition and Patent Term Restoration Act of 1984

Known as Hatch–Waxman Amendments, formulated a er a dispute b/w Roche & Bolar upon flurazepam drug. Roche
was innovator for flurazepam while Bolar was seeking to sell generic flurazepam but this was infringing Roche’s patent,
so they sued Bolar & won. Now innovator enjoy 5 years of patent exclusivity for new drug product, & no generic
product s approved in this period by FDA, further under Hatch–Waxman Amendments innovator can enjoy 5-year
patent term extension. In all cases, the total patent life for the product cannot exceed 14 years from the product's
approval date. One outcome of this legisla on is the increased availability of less expensive medica ons.

Time Period Approval of Generic

5 Year Bar On submission of ANDA upon approval of NDA for NCE.
3 Year Bar On submission of ANDA upon approval of NDA based on new clinical inves ga on.
7 Year Bar On submission of ANDA upon approval of NDA for orphan drug.
6 Months Extension Paediatric Exclusivity for above three.
Table 1: Bar for ANDA Approval

Title Role
I. Authorize marke ng of generic drug upon ANDA approval.
II. Regulatory Review of extensions of patent, hence a safe harbour for generic applicant.

KARTIK MITTAL 1
Table 2: Titles of Hatch–Waxman Amendments

Paragraph Cer fica on

I. Generic applicant cer fies that no patent is listed in Orange Book.
II. Generic applicant cer fies that any listed patent has previously expired.
III. Generic applicant cer fies that patent not yet expired but will & un l then they will not enter market.
IV. Generic applicant cer fies that in their opinion the patent is not infringed or is invalid. This is needed
when generic applicant want to enter market prior to expira on of patent.
Table 3: Paragraphs of Hatch–Waxman Amendments

ANDA Applicant

Paragraph I Paragraph II Paragraph III Paragraph IV

Generic Applicant notify

FDA may approve FDA may approve FDA may approve on
patent holder & NDA
immediately immediately date of patent expiration
owner.

Patent Holder does not Patent holder sue within

sue, FDA approve ANDA. 45 days, 30 month stay.

30 month stay expired, 30 month stay not

FDA approve ANDA expired

Court rule in favour of

patent owner, FDA can
not approve ANDA.

Court rule in favour of

generic applicant, FDA
approve ANDA & 180
day exclusivity begin.

Patent expires, FDA

approve ANDA & 180
day exclusivity begin.

Flowchart 1: Patent Cer fica on

KARTIK MITTAL 2
Flowchart 2: ANDA Approval Process

4 FILING REVIEW OF ANDA

 Process starts upon submission of ANDA to OGD, ANDA is assigned ANDA number & sent to consumer safety
technician for preliminary review.
 Within first 60 days filing review of ANDA is done by Regulatory Support Branch. RSB works under Division of
Labelling and Program Support (DLPS) have project managers and a support staff (technicians, assistants,
examiners etc.)
 RSB ensure that ANDA has necessary informa on or not, RPM compare content of each sec on of ANDA with
list of regulatory requirements.
 Refuse to receive” le er is issued if
a) inac ve ingredient level exceeds the level previously used in an approved drug product via the same
route of administra on
b) incomplete bioequivalence studies
c) incomplete stability data
d) incomplete packaging
e) incorrect basis for submission.
 RSB verifies that all applica ons contain a patent cer fica on and exclusivity statement.
 Upon comple on of filing review, acknowledgement le er is issued to applicant, indicate acceptance for filing
& official filing date.
 Upon filing of ANDA, RPM forwards an Establishment Evalua on Request to the Office of Compliance, they
determine if drug product manufacturer, the drug substance manufacturer, and the outside tes ng facili es
are opera ng in compliance with cGMP.

5 GENERIC DRUG REVIEW PROCESS

 Coordina on: ANDA enter review queue upon filing review, assigned to BE division team, chemistry team and
labelling reviewer. Chemistry project manager serves as the “applica on” project manager (APM) and are part

KARTIK MITTAL 3
 of the Review Support Branch within the DLPS. Plan, organize, and coordinate all of the review ac vi es for
ANDA, coordinate with all discipline reviewers, furthermore monitor the compliance evalua on (field
inspec ons). They assure mely resolu on of scien fic and regulatory conflicts to prevent delays in the review
process. The APMs provide applicants and OGD management the status of applica ons, primary contacts for
all issues rela ng to the review of the applica on so address all applicant inquiries within 2 working days of
receiving a request.
 Bioequivalence Review: bioequivalence project managers (BPM) assign ANDA to individual reviewers
according to the “first-in, first-reviewed” policy, dissolu on tes ng por on reviewed BE study. Division of BE is
organized into 10 review teams; each team consists of approximately five reviewers, who are supervised by a
team leader, TL complete secondary review of all BE submissions. A sta s cian is also available to resolve
sta s cal issues. The Division Director or Deputy Division Director performs a ter ary review and documents
concurrence. APM is no fied electronically that the bioequivalence review is complete. A deficiency le er is
issued to the applicant when a review contains numerous deficiencies that require more than 10 days to
resolve. BPMs provide regulatory guidance on bioequivalence issues through correspondence and
teleconferences. The BPMs request and track inspec ons of the clinical and analy cal sites through the Office
of Scien fic Inves ga ons (OSI). The clinical and analy cal sites are inspected for two reasons:
a) To verify the quality and integrity of the scien fic data submi ed in bioequivalence studies
b) To ensure that the rights and welfare of human subjects par cipa ng in the studies are protected in
accordance with the regula ons
 Chemistry Team: team leader, a project manager, and several reviewers. APM assigns the applica on to a
reviewer according to the “first-in, first reviewed policy.” Chemistry Divisions review the CMC sec on of ANDAs,
Drug Master Files, Supplemental ANDAs, Annual Reports, and Controlled Correspondence. The Chemistry
Divisions are organized into review teams consis ng of five or six primary reviewers, a team leader, and the
APM. Team leaders perform a secondary review of all chemistry submissions. An APM assigned to each team
coordinates the en re review process and acts as the primary point of contact for the applica on. Each division
is led by a Division Director and Deputy Director. A ter ary review is o en performed by the Deputy Director.
goal of the chemistry review process is to assure that the generic drug will be manufactured in a reproducible
manner under controlled condi ons. Applicant’s manufacturing procedures, raw material specifica ons and
controls, steriliza on process, container and closure systems, and stability data are reviewed.
 Labelling Review Process: ensure that the generic drug labelling is the “same as” the RLD labelling. Labelling
reviewer may iden fy drug names that are similar or that sound alike. In addi on, the labelling reviewer may
address concerns associated with the prominence and/or legibility of drug names on a container label. To
ensure that the proposed labelling in an ANDA is the “same as” the RLD, the labelling reviewer must first
iden fy the RLD. The next step is to find the most recently approved labelling for the RLD. If the RLD labelling
is not the most recently approved, it is considered discon nued labelling. Hence, it is not acceptable for the
labelling review. The labelling reviewer uses the USP to evaluate the established name, molecular structure,
molecular weight, structural formula, chemical name, and the storage condi ons of the proposed drug
product. Labelling reviewer decides if the labelling is easy to read and posi oned in accordance with the
regula ons.
 A full approval le er details the condi ons of approval and allows the applicant to market the generic drug
product. A tenta ve approval le er is issued if there are unexpired patents or exclusivi es accorded to the
RLD.

KARTIK MITTAL 4
 Chemistry, Manufacturing and Control

It refers to the documenta on and data submi ed to regulatory agencies that detail the manufacturing process, quality
control, and specifica ons of a drug product. CMC is a part of applica ons such as INDA, NDA, ANDA, BLA & MAA etc.
The CMC sec on is organized under Module 3 of the CTD format recommended by the ICH.

 Chemistry: Structure, synthesis the drug substance, the composi on of drug product, the materials involved in
it
 Manufacturing: Descrip on of manufacture of the product, equipment used, Facility informa on
 Controls: Ensure the quality of the product
 In-process controls
 Specifica ons for tes ng drug substance and drug product
 Stability of the product

Structure and Format of the CMC Section (Module 3)

Module 3 is classified into 4 parts

1) 3.2.S- Drug Substance (informa on about API)

2) 3.2.P- Drug Product (informa on about finished drug product)
3) 3.2.A- Appendices (supplementary details)
4) 3.2.R- Regional Informa on (region specific requirement)

Drug Substance (3.2.S)

3.2.S.5 Reference
3.2.S.1 General 3.2.S.2 3.2.S.3 3.2.S.4 Control of 3.2.S.6 Container
Standards or 3.2.S.7 Stability:
Information: Manufacture: Characterization: Drug Substance: Closure System:
Materials:

API name,
structure, Name and address Evidence of Details of
Quality control Stability studies,
molecular of manufacturers, structure (e.g., reference Description of the
tests, analytical storage
formula, CAS synthesis route, NMR, MS), standards used for container and
procedures, conditions, shelf-
number, physical reagents used, stereochemistry, testing (e.g., closure system,
validation data, life determination,
and chemical process controls, impurities profile, source, compatibility, and
and batch analysis and stability
properties, and and flow and justification of preparation, safety information
results. protocols.
general diagrams. specifications. characterization).
characteristics.

Flowchart 1: 3.2.S Sec on of CMC

Drug Product (3.2.P)
Focuses on the finished pharmaceu cal product.

3.2.P.1 Description and Description of the dosage form, qualitative and quantitative
Composition composition, and function of components.
3.2.P.2 Pharmaceutical Formulation development, selection of excipients, container-closure
Development system, and compatibility studies.
3.2.P.3 Manufacture Manufacturer’s name, manufacturing process description, flowcharts,
in-process controls, and critical steps.
3.2.P.4 Control of Critical Control strategy for excipients and APIs used in formulation.
Materials
3.2.P.5 Control of Finished Quality specifications, analytical methods, validation data, and batch
Product analysis results.
3.2.P.6 Reference Standards Standards for the finished product, including assays for potency and
or Materials purity.
3.2.P.7 Container Closure Packaging description, specifications, and compatibility with the
System product.
3.2.P.8 Stability Stability studies, storage conditions, shelf-life, and
accelerated/degradation testing.
Table 1: 3.2.P Sec on of CMC

Appendices (3.2.A)
Includes supplementary informa on

Subsection Description
3.2.A.1 Facilities and Equipment Details of manufacturing facilities, GMP compliance, and equipment used.
3.2.A.2 Adventitious Agents Information on viral safety and transmissible spongiform encephalopathies
Safety (TSE).
3.2.A.3 Excipients Additional details on novel excipients or excipient safety.

Regional Information (3.2.R)

Specific to the region where the applica on is filed.

Subsection Description
3.2.R.1 Production Documentation Master production records, executed batch records, and validation reports.
3.2.R.2 Analytical Validation Detailed validation of test methods tailored to regional regulatory
Information expectations.
 Departmental Process To Issue Sale Drug License
Wolesale and Retail

Online User Registration and Submission of Application

Application Received on Portal of Drug Licensing

Authority and Inspector of Drugs

Discrepancies found in the application Discrepancies not found in the

application

Application Sent to applicant for Retail Licence

Modification (7 Days) Approval granted by the Drug
Licensing Authority

Discrepancies are not Discrepancies are

removed removed

Application Rejected Application Sent to Drug Inspector for verification (10 Days)
NO

Application does not found satisfactory Application found satisfactory after

after inspection report of Drug Inspector inspection report of Drug Inspector

Licence Approved by DLA.

(15 Days)

Digitally signed licence is

downloaded by applicant.
 NDA

Vehicle by which sponsor formally propose to regulatory body to approve a new drug.

Submitted in CTD Format

• FDA Form 356h
• User Fee Cover Sheet
• Cover Letter (TOC for Module 1-5)
Goal of NDA
• To assess safety & efficacy
• To review proper labelling
• To assess cGMP compliance

Classification of
NDA

New formulation New Already

New Molecular New Salt of New New Indication
of approved combination of 2 Marketed & No
Entity approved drug Manufacturer (Rx → OTC)
drug or more drug Previous NDA

Application
Index Labelling CMC NCLS Human PK BA Microbiology
Summary

Safety Update Patent Patent Other

Clinical Data Statistic Case Report
Report Information Certification Information

Flowchart 1: Content of NDA

Documents Folder Color Form Number

Archival Copy Light Blue 2626

CMC Red 2626a

Non-clinical Pharmacology & Toxicology Section Yellow 2626b

Human PK BA Section Orange 2626c

Clinical Data Section White 2626d

Microbiological Section Light Brown 2626e

Statistical Section Green 2626f

Field Copy Maroon 2626g

 NDA

Archival Copy Review Copy Field Copy

Have 6 technical sections.

CMC, Non-Clinical
Complete copy of Separate copy of Q section,
Pharmacology/ Toxicology,
application submitted to field office
Human PK-BA, Microbiology,
Clinical Data & Statistical

Identify contact person

Confirm any agreement b/w

FDA and applicant

This begin
Within 60 If Filed,
180 day
NDA days FDA notified. Date
Review Clock.
Application determine of filling date
Approval/
Day 0 Fileable or 60 days after
Approvable/
NOT application
Not Approval
NDA is defined under Rule 122-E of Drugs and Cosmetic Rule 1945.

Applicant has to submit evidence that the drug for manufacturing approval has already
been approved by DCGI.

After successful clinical trails, sponsor submit application by form 44 with data given in
Appendix I of Schedule Y.

DCGI Grants Approval in form 46 or 46A.

Sponsor has to obtain necessary approval from DCGI as well as SLA.

In India approval issue “Manufacture for Sale” rather than “Marketing Approval”.
 Regula on For Combina on Products & Medical Devices

Combina on Product: composed of combina on of drug and a device or biological product and device or drug and
biological product or all three. E.g.

 Drug + Device (e.g., drug-elu ng stents),

 Biologic + Device (e.g., pre-filled syringes with biologics),
 Drug + Biologic (e.g., an body-drug conjugates),
 Drug + Device + Biologic (e.g., ssue-engineered products with drug components).

Drug + Device Combina on Products

Product Name Application Components
EpiPen Emergency treatment for Epinephrine (drug) in a pre-filled, auto-injector
anaphylaxis. (device).
Insulin Pens Diabetes management. Insulin (drug) in a pre-filled pen with a needle
mechanism (device).
Inhalers (e.g., Symbicort) Asthma and COPD Inhalable drugs (e.g., budesonide + formoterol) in a
treatment. metered-dose inhaler (device).
Transdermal Patches (e.g., Pain management. Fentanyl (drug) delivered via a skin adhesive patch
Duragesic) (device).
Table 1: Drug + Device Combina on

Biologic + Device Combina on Products

Product Name Application Components
Humira Pen Autoimmune diseases (e.g., rheumatoid Adalimumab (biologic) in a pre-filled, auto-
arthritis). injector pen (device).
Prolia Prefilled Osteoporosis treatment. Denosumab (biologic) in a pre-filled syringe
Syringe (device).
Vaccines with Immunization (e.g., COVID-19, flu Vaccine (biologic) in pre-filled syringes (device).
Syringes vaccines).
Table 2: Biologic + Device Combina on

Device + Drug + Biologic Combina on Product

Product Name Application Components
Tissue-Engineered Products Chronic wound Skin substitute (biologic) combined with a delivery
(e.g., Apligraf) healing. scaffold (device) and growth factor drugs.
Bone Grafts with Drugs (e.g., Bone BMP-2 (biologic), synthetic matrix (device), and
INFUSE Bone Graft) repair/regeneration. stabilizing drugs.
Table 3: Device + Drug + Biologic Combina on

Medical Device + Drug Combina on Products

Product Name Application Components
Antimicrobial Catheters Prevent catheter-associated Catheter (device) coated with antimicrobial agents
infections. (drug).
Surgical Mesh with Prevent post-surgical Mesh (device) impregnated with antibiotics.
Antibiotics infections.
Contact Lenses with Treat eye conditions. Contact lens (device) embedded with anti-
Drugs inflammatory or anti-allergy drugs.
Table 4: Medical Device + Drug Combina on
USFDA Centre for Regula on:
 Office of Combina on Products (OCP) operates independently. Depending on the Primary Mode of Ac on
(PMOA) of the product, its regulatory oversight is assigned to one of three main FDA Centers:

FDA Center Regulates Combination Examples

Products Based on PMOA
Center for Drug Evaluation When the primary action is Drug-eluting stents (e.g., sirolimus-coated stents).
and Research (CDER) exerted by a drug. Inhalers (e.g., Symbicort).
Pre-filled syringes with drugs (e.g., EpiPen).
Center for Devices and When the primary action is Antimicrobial-coated catheters.
Radiological Health (CDRH) exerted by a medical Drug-coated contact lenses.
device. Infusion pumps delivering drugs.
Center for Biologics When the primary action is Vaccines in pre-filled syringes.
Evaluation and Research exerted by a biologic. Cell and gene therapy products with device
(CBER) components.
Tissue-engineered products (e.g., Apligraf).
Table 5: FDA Centers for Regula on of Combina on Products

Classification Examples Approval Pathway

Class I (Low Risk) Bandages, thermometers. Exempt from premarket submission;
subject to general controls.
Class II (Moderate Risk) X-ray machines, infusion pumps. Premarket Notification (510(k)).
Class III (High Risk) Pacemakers, heart valves. Premarket Approval (PMA).
Table 6: Medical Devices in USA

Regula ons in Europe (EMA and MDR)

Combina on products are regulated under the Medical Device Regula on (EU) 2017/745 (MDR) and Medicinal
Products Direc ve (2001/83/EC).

Product Type Regulatory Pathway

Drug with Device Drug regulations apply, but the device must meet MDR standards (e.g., CE
Component marking).
Device with Drug MDR applies; drug safety and efficacy must be demonstrated.
Component
Biologics Regulated under EMA biologics guidelines with MDR compliance for device
aspects.
Table 7: Regula on in Europe

Regula ons in India (CDSCO)

Combina on products are regulated under the Drugs and Cosme cs Act, 1940 and Medical Device Rules, 2017.

Combination Product Type Regulatory Oversight

Drug + Device CDSCO evaluates the drug; device evaluated per Medical Device Rules.
Biologic + Device Assessed by CDSCO (drug/biologic) and device guidelines.
Table 8: Regula on in India

Classification Examples Approval Process

Class A (Low Risk) Thermometers, surgical dressings. Notified Body certification.
Class B (Moderate Risk) Blood pressure monitors. Notified Body certification.
Class C (High Risk) Infusion pumps, orthopedic implants. CDSCO approval required.
Class D (Highest Risk) Heart valves, stents. CDSCO approval with clinical investigation data.
Table 9: Medical Devices Under Medical Devices Rule 2017
Medical Devices: Any instrument, apparatus, implement, machine, appliance, implant, in vitro reagent, or any
similar or related ar cle, intended by the manufacturer to be used for medical purposes in diagnosis, treatment, or
preven on of disease or condi ons in humans or animals

Aspect FDA CDSCO (India)

Regulatory Managed by Office of Combination Regulated under Drugs and Cosmetics Act &
Oversight Products (OCP), coordinating FDA centers Medical Device Rules (2017).
(CDER, CDRH, CBER).
Primary Mode of PMOA determines lead center (drug, Product classified as drug or device, based on
Action device, or biologic). PMOA.
Pre-market Separate or single application (NDA/BLA for NDA for drugs or medical device submission,
Approval drugs, 510(k)/PMA for devices). with Form MD-27/28 for combination products.
Clinical Trials Required based on component (drug, Follow GCP for drugs and clinical investigation
device, biologic). guidelines for devices.
GMP and QSR GMP for drugs and biologics, QSR for GMP for drugs and Medical Device Rules for
Compliance devices. devices.
Post-Market MedWatch for drugs, MAUDE for devices; Pharmacovigilance (PvPI) for drugs and
Surveillance post-approval studies may be required. Materiovigilance (MvPI) for devices.
Labelling Must meet labelling requirements for both Labelling should indicate the intended use and
drug and device components. contain details for both drug and device
components.
Table 10: Comparison of Regulatory Requirements for Combina on Product in FDA & CDSCO
Question: What is Stability?
Ans: Stability refers to the capacity of a drug product to remain within its physical, chemical,
therapeutic, and microbiological specifications during its entire shelf life. It includes factors
such as temperature, humidity, light exposure, and packaging materials.
Question: How much excursion in condition for stability chamber is allowed?
Ans: According to WHO (Stability testing of API and finished pharmaceutical products),
excursion of 24 hours is allowed.
Question: Does significant change apply only to accelerated storage conditions or is it
applicable to long-term study?
Ans: According to our ICH guidelines, significant changes apply to accelerated storage
conditions when addressing this question. However, the product cannot be considered stable if
significant changes occur in long-term storage conditions, and the organization cannot pursue
approval from the regulatory agency.
ICH guidance specifies that if long-term studies are conducted at 25°C ± 2°C and 60% ± 5%RH,
a significant change occurs during six months of testing at accelerated storage conditions. In
such cases, additional testing at the intermediate storage condition should be conducted and
evaluated against the criteria for significant [Link] initial application should include a
minimum of six months of data from a 12-month study at the intermediate storage condition.
This pertains to the applicability of significant changes.
Question: Are accelerated condition as per ICH and WHO same for the products to be stored
at refrigerator(5°C)?
Ans: There is minor difference, As per ICH(Q1A-R2) - 25°C/60%RH
As per WHO - 25°C/60%RH or 30°C/65%RH or 30°C/75%RH
Question: For aqueous based products packed in semi-permeable container, does significant
change in water loss alone at the accelerated storage condition necessitate the testing at the
intermediate storage condition?
Ans: The significant change in water loss alone at the accelerated storage condition does not
necessitate the testing at the intermediate storage condition(ICH and WHO).
Question: If one out of the three batches stored under accelerated conditions shows a
significant change, what should be done?
Ans: According to ICH guidance, if accelerated data shows a significant change or failure of any
attribute in one or more batches, an applicant should submit intermediate data for all three
batches. Additionally, the submission should include a failure analysis, which is a discussion
concerning the observed failures.
If any significant change occurs between zero and six months, in that case, long-term data needs
to be used for analysis. Six months of intermediate data are required at the time of an NDA
submission, and a further 12 months of data are to be amended later on six months.
The evaluation at filing requires intermediate data, including zero and six months’ time points if
the intermediate data fails. In such cases, extrapolation of shelf life or retest date is not allowed.
The determination of shelf life or retesting depends only on long-term data, which will govern
the sample storage requirements.
Question: Can an ANDA be submitted with 6 months of accelerated stability and 6 months of
long-term stability data?
Ans: Yes. An ANDA applicant should submit 6 months of accelerated stability data and 6
months of long-term stability data at the time of [Link], if 6 months of accelerated
data show a significant change or failure of any attribute, the applicant should also submit 6
months of intermediate data at the time of submission.
Question: When do intermediate stability studies need to be initiated in the event of failure at
accelerated condition?
Ans: An ANDA applicant should start accelerated, intermediate, and long-term stability studies
at the same time so the data are available at the time of submission if the accelerated stability
study fails.
Question: If one among the three batches in accelerated conditions shows a significant
change, what should be done?
Ans: If accelerated data show a significant change or failure of any attribute in one or more
batches, an applicant should submit intermediate data for all three batches. In addition, the
submission should contain a failure analysis (i.e., discussion concerning the observed failure(s)).
Question: Can stability bracketing and/or matrixing be used to determine the packaging
configurations to be placed on stability for an original ANDA without prior approval from the
Office of Generic Drugs (OGD)?
Ans: Yes. You should follow the International Conference on Harmonisation (ICH) guidance for
industry on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products and its example tables.
Question: How is the proposed shelf life supposed to be calculated? Will 6 months of
accelerated data equal 24 months at long-term?
Ans: ICH Q1E principles will help in the calculation of shelf life. Data from the three ANDA
submission batches (i.e., 6 months), accelerated data meeting all criteria (without significant
change per ICH Q1A(R2)), and 12 months longterm data without variability will not need
statistical evaluation, and with appropriate post approval stability commitments, can be used to
support extrapolation to a 24 months shelf life. If there is a significant change in the accelerated
data, ICH Q1E, Appendix A, provides more details regarding when intermediate condition
stability data are recommended.
Question: Will the recommendation for 6 months accelerated data be met by providing 24
weeks of data as 12 weeks is typically accepted as equivalent to 3 months?
Ans: No. FDA, following the recommendations of ICH stability guidances refers to timeframes
in terms of months and not weeks.

Question: How many API Lots are required to manufacture three batches of each
strength of a proposed drug product?
Ans: According to ICH guidelines, there should be two API Lots to manufacture three
batches of each strength of a proposed drug [Link] the minimum of two Lots is
not used to manufacture three batches of the drug product. FDA will consider it a
significant deficiency and will refuse to receive the NDA application.

Question: How long should three pilot-scale batches be stored before destruction, as
submitted as part of an NDA?

Ans: For the general NDA Submission batch, samples should be stored for one year after
approval of the NDA, and samples of the drug product used for bio-covalent studies must
be stored for five years after approval of the NDA.

Question: What is the Agency’s position on using different lots of APIs and/or packaging
materials? How many API lots should be used in the manufacture of finished product lots
used to support the ANDA?
Ans: It is not necessary to use different lots of packaging material, except in cases where the
packaging material could affect drug product performance and/or delivery. A minimum of two
lots of the drug substance should be used to prepare the three primary batches of drug product.
Question: If you are an applicant submitting an ANDA with two API sources, are you
required to perform stability on three batches of drug product for each API source?
Ans: If you propose to add additional sources of API for the same drug substance, you should
provide the following CMC information:
Comparison and justification of comparability (by the applicant) of the physico-chemical
properties and impurities of the drug substance from each source.
Appropriate stability data on three batches of drug product qualifying the first API source used
in the bioequivalence (BE) studies as recommended by the FDA stability guidance.
A single pilot scale batch of the drug product bio-strength(s) manufactured using the second or
each of the other proposed API source(s) used to support the ANDA application, along with
comparative dissolution data.
Appropriate stability data (accelerated and long-term for 6 months at the time of filing) on the
strength(s) manufactured for each API source. Appropriate stability data may in some cases
include intermediate condition stability data.
Question: In cases where an intermediate bulk material is identical between the various
strengths (dose proportional blends, bulk solutions, etc.), is it sufficient to perform stability on
one lot of each strength, when each strength is produced from a separate intermediate bulk?
Ans: No. For ANDAs that contain multiple strengths (that are dose proportional), three separate
intermediate bulk granulations (or blends) should be manufactured. One batch of bulk
granulation (or blend) should be used to manufacture all the strengths proposed. The other two
bulk granulations (or blends) can be used to manufacture only the lowest and the highest
strengths, in addition to the strength used in BE studies (i.e., the strength(s) tested in the BE
studies should have three batches). Stability testing should still use all three batches of drug
product.
Question: For sterile products, is it acceptable to manufacture the small scale batches in a
nonsterile facility and allow variance from sterility and particulate criteria?
Ans: No. To be consistent with ICH Q1A(R2), sterile product small scale batches should be
representative of the manufacturing processes to be applied to a full production scale batch, and
therefore should not be manufactured in a nonsterile facility. Sterility is a critical quality
attribute (CQA) for sterile products.
Question: In cases where an intermediate bulk material is identical between the various
strengths (dose proportional blends, bulk solutions, etc.), is it sufficient to perform stability on
one lot of each strength, when each strength is produced from a separate intermediate bulk?
Ans: No. For ANDAs that contain multiple strengths (that are dose proportional), three separate
intermediate bulk granulations (or blends) should be manufactured. One batch of bulk
granulation (or blend) should be used to manufacture all the strengths proposed. The other two
bulk granulations (or blends) can be used to manufacture only the lowest and the highest
strengths, in addition to the strength used in BE studies (i.e., the strength(s) tested in the BE
studies should have three batches). Stability testing should still use all three batches of drug
product.
Question: Can the Agency clarify expectations around the number of batches to support tests
such as preservative effectiveness and extractable/leachable testing?
Ans: One of the primary batches of the drug product should be tested for antimicrobial
preservative effectiveness (in addition to preservative content) at the end of the proposed shelf
life. The drug product specification should include a test for preservative content, and this
attribute should be tested in all stability studies. Extraction/leachable studies are generally one-
time studies; however, if multiple types of containers/closures are employed for packaging, then
additional studies could be recommended.
Question: Are stability data from three current good manufacturing practice (CGMP) batches
required to be filed in the DMF to support the API retest date? Also, how many months of
long-term and accelerated data are required for pilot scale batches?
Ans: Yes. Per ICH Q1A(R2) data from formal stability studies should be provided on at least
three primary batches and the batches should be manufactured to a minimum of pilot scale for
the drug substance to be filed in the DMF. These batches should be made under CGMPs. The
FDA stability guidance recommends 6 months of accelerated data and 6 months of long-term
data for the pilot scale batches to be submitted for a full scientific review of the DMF.
Additional long-term data for all three batches, as the data becomes available through the
proposed retest period, should be submitted as an amendment.
SUPAC
The scale-up process in pharmaceu cal manufacturing refers to the transi on from laboratory-scale produc on to full-
scale commercial produc on. It involves increasing the quan ty of drug products manufactured while maintaining
consistent quality, performance, and regulatory compliance. Changing of scale from the research lab to the shop floor
is fraught with problems. Reason for such problems is the usage of different processing equipment in research and on
the shop floor Changes can be described as mild, moderate, and major.

Change Type Impact on Product Examples Regulatory Requirement

Mild Changes Minimal impact on drug Minor batch size adjustments, No approval required,
quality, safety, or efficacy packaging material change documentation only (annual
report, etc.)
Moderate Changes Measurable impact but Supplier change, minor Notification or Supplement
within acceptable limits equipment adjustments, (e.g., CBE, data submission)
moderate batch size change
Major Changes Significant impact on Change in formulation, Prior Approval Supplement
formulation, quality, or equipment, manufacturing (PAS), pre-approval
process site, critical process step inspection required

Change Example of Composition Test Documentation Filing Documentation

Level Change
Minor Change in excipient Identity and purity testing, Annual Report or Changes
concentration or supplier, stability data, dissolution tests Being Effected (CBE)
minor excipient addition
Moderate Change in excipient type, Dissolution testing, stability Prior Approval Supplement
significant API concentration studies, bioequivalence studies (PAS), Supplemental NDA
change (sNDA)
Major Change in API, major excipient Full stability studies, dissolution Prior Approval Supplement
change, change in drug release testing, bioequivalence studies, in (PAS), New Drug Application
mechanism vivo testing (NDA

Change Example of Site Change Test Documentation Filing Documentation

Level
Minor - Relocation of equipment - No impact on product quality or Annual Report (if applicable),
within the same facility process Notification (for non-critical
changes)
- Change in the site’s - No new validation required, but Changes Being Effected (CBE),
storage conditions (e.g., minor stability checks may be Documented Evidence
temperature) necessary
Moderate - Relocation to a different - Revalidation of certain Prior Approval Supplement (PAS),
building within the same processes (e.g., blending, tablet Supplemental NDA (sNDA)
site compression)
- Change of contract - Stability and bioequivalence Requalification documents,
manufacturer at the same studies to confirm product Stability Data
site quality remains consistent
Major - Transfer of - Full Process Validation at the Prior Approval Supplement (PAS),
manufacturing to a new site, including critical New Drug Application (NDA), Pre-
completely new site equipment qualification Approval Inspection
- Significant changes in - Full stability studies and New Site Approval (via regulatory
manufacturing equipment bioequivalence studies to verify inspection), Revalidation Reports
or facilities product consistency
 US Registration of Foreign Drugs

 Foreign drug establishments that manufacture, repack, re-label or salvage drug products and whose
drugs are imported or offered for import into the United States are required to register with the
FDA before offering a drug for import and renew annually.
 This ensure that drugs imported into the U.S. are safe, effective, and manufactured to the appropriate
standards
 Foreign companies are subjected to same FDA regulations as US companies.
 All foreign drug establishments are required to register with the FDA under the Federal Food, Drug,
and Cosmetic (FD&C) Act, both finished dosage forms & API.
 biologics and medical devices have separate registration requirements under the Biologics Control Act
and the FDA Medical Device Regulations.
 Approved Generic Drugs: Foreign-manufactured generic drugs that are bioequivalent to a U.S.-
approved reference drug can be imported after approval through an Abbreviated New Drug Application
(ANDA).
 Registration Period: Facility registration with the FDA is typically valid for one year.
 Annual Renewal: U.S. registration of foreign drug establishments must be renewed annually.
Manufacturers must update their registrations each year, and the renewal deadline is typically
December 31st each year.

Exemptions:
Drugs not intended for commercial distribution, drugs used for personal use, investigational new drugs, or
those under clinical trial investigational status.

Governing Rules & Act:

 Federal Food, Drug, and Cosmetic (FD&C) Act (Title 21 Section 301)
 Biologics Control Act (for biologics)
 New Drugs and Clinical Trials (ND&CT) Rules, 2019 (for drugs used in India but applicable globally).
 FDA Regulations for Drug Establishments (21 CFR 207)

Documents Needed for Registration:

 Form 2656: Establishment Registration and Drug Listing Application for all foreign establishments.
 Drug Product Information: Detailed information about the drug, including its composition, intended
use, and manufacturing process.
 Good Manufacturing Practices (GMP) Compliance: Proof that the foreign facility complies with U.S.
GMP standards.
 Labelling Information: Includes the drug's label and packaging information.
 Preclinical and Clinical Data: Data supporting the drug’s safety and efficacy, particularly for new drugs
or biologics.
 U.S. Agent: The foreign manufacturer must designate a U.S. agent to act as the point of contact with
the FDA.

Registration Process:
 Facility Registration: Foreign manufacturers must complete the FDA’s Drug Establishment
Registration process through the FDA’s Drug Registration and Listing System (DRLS).
 Drug Listing: After registration, manufacturers must list each drug product intended for distribution in
the U.S.
  For new drugs or biologics, you must submit a New Drug Application (NDA) or Biologics License
Application (BLA), including clinical data.
 For generic drugs, submit an Abbreviated New Drug Application (ANDA).

Revoking of Drug Registration:

 Non-compliance with FDA regulations, including failure to meet GMP or failure to submit required
reports.
 Failure to renew the registration annually.
 Failure to provide accurate information or failure to address FDA requests for documentation or
inspections.
 Importation of adulterated or misbranded drugs may also lead to cancellation of registration.

Restricted Drugs:
a) Unapproved Drugs: Drugs that are not approved by the FDA, including those that are marketed without
proper clinical trials or those that do not meet the FDA’s Good Manufacturing Practices (GMP), are
restricted.
b) Adulterated or Misbranded Drugs: Any drug that is adulterated (unsafe or unclean manufacturing
process) or misbranded (incorrect or misleading labeling) cannot be imported.
c) Controlled Substances: Drugs that are classified as controlled substances (e.g., narcotics, certain
stimulants) are subject to stricter regulations under the Controlled Substances Act and often require
additional importation and handling procedures.
d) Drugs with Inadequate Safety and Efficacy Data: If clinical trial data does not support the drug’s safety
or efficacy, it will not be allowed for import.
e) Cosmetics with Harmful Ingredients: Products labeled as cosmetics that contain restricted or banned
ingredients cannot be imported, even if they claim therapeutic benefits.
Examples
Unapproved Drugs:
Example: Unapproved weight loss drugs from foreign sources – Drugs like Sibutramine (which was
withdrawn from the market) are considered unapproved if they are marketed for weight loss without FDA
approval.
Adulterated or Misbranded Drugs:
Example: Drugs with excessive levels of active ingredients – Such as unregulated herbal supplements
from foreign sources that contain unsafe or unapproved ingredients.
Controlled Substances:
Example: Oxycodone, Fentanyl, Methamphetamine – These are opioids and stimulants that are controlled
substances, requiring special importation procedures.
Banned Substances:
Example: Phenolphthalein – An ingredient once used in some over-the-counter laxatives but now banned
due to concerns about its carcinogenic properties.
Drugs with Inadequate Safety or Efficacy Data:
Example: Unapproved new cancer treatments – Drugs that have not undergone proper clinical trials or
have shown insufficient evidence of efficacy in humans are restricted.