Session 1
Training of Trainers on Evaluation
of Complex Generic API Products and
their Finished Dosage Forms
Syed Sultan Ghani
Senior Technical Advisor, PQM Plus program
September 3rd to 5th , 2023
Bangladesh
# Session 1:
Fundamental knowledge of Complex
Generic API Products
Disclaimer: The display of photo or use of brand or commercial name in this training material is purely for the purpose of learning exercise, USP and
PQM+ program nor USAID do not promote any specific brand or commercial products.
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Session Outline Method: Resources:
Time: Interactive Presentation Power Point presentation
Approx 3 hours Discussion Reference
1 # SEQUENCE 1
Overview of Complex Generic API Product
2 # SEQUENCE 2
Qualification of API suppliers
3 # SEQUENCE 3
Drug Master File (DMF) / Review of API
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Energizer Scramble words
1. Unscramble the letters to create
words related to Complex Generic
API Products
2. For each word, the person that raises
to give correct answer first will get 1
point for team.
3. The team getting more points will be
the winner
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PI E P S
T PI E
D D
E T
S
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P E P T I D E S
R D G U
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P E P T I D E S
D R U G
E C S O E L E V A L M
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P E P T I D E S
D R U G
C O L E S E V E L A M
M E L P O R S Y
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P E P T I D E S
D R U G
C O L E S E V E L A M
P O L Y M E R S
A R P N E A X I N O
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P E P T I D E S
D R U G
C O L E S E V E L A M
P O L Y M E R S
E N O X A P A R I N
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Session 1
Fundamental knowledge
of Complex Generic API
Products. # SEQUENCE 1
1.1 Overview of Complex
Generic API
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1.1 Simple and Complex API
Simple API Complex API
Characterized by the following methods: Characterization complex API :
• HPLC • Molecular Weight distribution.
• MS • Polydispersity.
• NMR • Spectroscopic analysis.
• IR • Biological activity and impurity analysis.
• Spectroscopic analysis
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1.1 Complex APIs
• Complex APIs present unique challenges in both their manufacturing,
controls and regulatory requirements.
• These products often require specialized manufacturing processes,
equipment, and facilities due to their complex chemical structures and
potential safety concerns.
• The regulatory requirements for complex APIs are more stringent, as
they require extensive documentation and testing to ensure safety,
efficacy, and quality.
1.1 Typical Complex Mixtures of APIs
• Polymer based drug system
• Protein-Protein Conjugates
• Peptide
• Complex mixtures (including semi-synthetic mixtures)
• Other, such as iron-carbohydrate complexes, synthetic nucleotides)
Example:
Enoxaparin, Dalteparin, Colesevelam Hydrochloride, sevelamer hydrochloride,
and glatiramoids
1.1 Sevelamer Hydrochloride
Manufacturing and Process Control Challenges
• Sevelamer hydrochloride is a non-absorbed
phosphate binder used for the treatment of
hyperphosphatemia in patients with chronic
kidney disease.
• Challenges include reproducibility of particle size,
assay, and impurity profile.
• Regulatory requirements: Adequate
characterization, validation of manufacturing
process, and control of CQAs.
Sevelamer Hydrochloride
1.1 Glatiramoids
Manufacturing and Process Control Challenges
• Glatiramoids are complex mixtures of
synthetic polypeptides used for the treatment
of multiple sclerosis.
• Challenges include reproducibility of peptide
synthesis, purity, and potency.
• Regulatory requirements: Adequate
characterization, validation of manufacturing
process, and control of CQAs.
Glatiramoids
1.1 Example of Enoxaparin – A Low Molecular Weight Heparin
Manufacturing Starting material
Heparin
from
Porcine
Alkaline Depolymerization Nitrous Acid Depolymerization
Enoxaparin Dalteparin
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1.1 Example of Enoxaparin – A Low Molecular Weight Heparin
Characterization
• Structural signature analysis (product specific)
• Disaccharide building blocks, fragments after
enzymatic cleavage, oligosaccharide sequence
• Depolymerization process parameters
• Physicochemical properties
• Biological activities
➢ In- vitro Anti factor Xa activity
➢ In vivo pharmacodynamic profile Chemical Structure
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1.1 Strategies for Overcoming the Challenges of
Complex Active Ingredients
• Strategies include process optimization, process analytical
technologies (PAT), and real-time release testing (RTRT).
• Other strategies include robust design, quality by design (QbD),
and risk management.
1.1 Complex APIs – Unique Manufacturing and Process
Control Challenges
Sevelamer Hydrochloride:
Sevelamer hydrochloride can be challenging to manufacture due to
the low solubility of the active ingredient.
Glatiramoids:
Glatiramoids can be difficult to manufacture due to the sensitivity of the
active ingredient to changes in manufacturing conditions.
1.1 Regulatory Requirements
• Regulatory authorities require extensive documentation and testing
to ensure compliance with regulations, which can add additional
time and cost to the manufacturing process.
• Despite these challenges, the development of complex APIs is
essential for the advancement of medicine and the treatment of
complex diseases.
1.1 Identicality and sameness of API
Identicality
• Medicinal ingredient that are both physically and chemically
identical.
• “Chemical identicality" of the medicinal ingredients is in the
determination of pharmaceutical equivalence.
• Pharmaceutically equivalent drug products should contain
chemically identical, but not necessarily physically identical,
medicinal ingredients
• Differences in physical properties (e.g., particle size, polymorphism)
of the medicinal ingredients could potentially cause differences in
the safety and efficacy profiles of the drug products.
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1.1 Identicality and sameness of API
Sameness Why?
Demonstrating API sameness is a critical part of
the pharmaceutical equivalence:
• Same active ingredient(s)
• Same dosage form and route of administration
• Identical in strength or concentration
How?
Explore and apply modern analytical and quantitative
methods to characterize product specific attributes to
establish API sameness
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Similarities
Energizer
1. Form teams based on the number of
participants.
2. In 5 minutes, each team must write
down on a A3 paper as many as
possible the common things between
team members.
3. After 5 minutes, all teams stick their
papers on board and tell the others
about their similarities found in team.
4. The team finding the most similarities
between members will be the winner.
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Session 1
Fundamental # SEQUENCE 2
knowledge of Complex
Generic API Products
1.2 Qualification of
Active Pharmaceutical Ingredients (API)
Suppliers
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What do you know about
QUALIFICATION of API suppliers?
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1.2 Control of drug substance (API)
API selection process modules in generic drug product life cycle.
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1.2 Control of drug substance (API)
Pharmacopoeial API
• The current monograph is always applicable
• Additional critical attributes not included in the monograph:
➢ Particle size and polymorph.
➢ Impurities resulting from specific synthetic process.
➢ Residual solvent (specific to process).
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1.2 Control of drug substance (API)
Specifications
• A list of test references to analytical procedures, an
appropriate acceptance criteria.
• To ensure that proper identity, strength, quality and
purity are attained together with batch-to-batch
consistency.
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1.2 Control of drug substance (API)
Specifications
For pharmacopeial API
In-house
Standard claim
Standard claim
Full compliance to the pharmacopeia should It should be demonstrated that the in-house
be shown i.e., comply with the requirements of standards are equivalent or more
a specific monograph and other quality stringent than the pharmacopeia
attributes. monograph
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1.2 Control of drug substance (API)
Pharmacopeias officially recognized and the acceptance of the EDQM’s CEPs by various agencies.
Standard claim
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1.2 Control of drug substance (API)
Standard claim
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1.2 Control of drug substance (API)
How are APIs prequalified?
Invitation
Application
✓ Questionnaires
Assessment Assessment Pre-purchase
✓ Auditing GMP site
samples or
✓ Data from organizations (GMP) (Quality) prototype(s)
e.g., regulatory database
Decision
Publishing
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1.2 Qualification of Supplier
General
• Comply GMP requirements as outlined in regulatory
guidelines.
• Important component of TQM system.
• Manufactured package and shipped under a control
process.
• Applicable for all suppliers of API raw materials,
intermediates, packaging material and other components.
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1.2 Qualification of Supplier
General
• Risk based approach (ICH Q9) to be used in certification.
• Should meet international compliance requirements as
outlined in cGMP.
• Legal binding and based on principles of defect
prevention as opposed to defect deduction.
• Quality has to be built into the product and can not be
tested.
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1.2 Qualification of Supplier
Vendor
Complaint
Management
(Appropriate
CAPA)
Continuous
Evaluation based
Vendor in periodic
product quality
Qualification review,
Vendor rejections,
Quality
Qualification Agreement
Life cycle
Management
Sample
Evaluation
Initial On-site
&
Audit (Critical
Paper based
Quality system
RM)
Note: evaluation
In case, if vendor performance does not meet the requirements and for vendor
complaint appropriate CAPA not established, new vendor needs to be
identified to ensure the safety and reliability of raw materials.
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1.2 Qualification of Supplier
Selection of vendor
Ensure that quality attributes of the material meet the standard for
1 identity, strength, purity and quality.
2 Vendor follow a proper Quality Management System (ICH Q10).
Require scientific knowledge and understanding of compliance
3 requirements.
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1.2 Qualification of Supplier
Selection of vendor
Materials should originate from reliable manufacturer/supplier
4 (compliance history).
5 Control various excursion and deviation from storage requirement,
transportation, labeling and re-packing.
6 Should follow GDP guidelines from WHO and guidance from IPEC.
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1.2 Qualification of Supplier
1 If vendor is certified
by WHO, ICH members, PICs and EDQM 2 If vendor is not certified
by WHO, ICH members, PICs and EDQM
• Physical verification/certification may be • Perform the audit of the vendor by
waived. appropriate qualified auditor.
• Material will be subjected to analysis. • Material will be subjected for full testing.
• Complete confirmatory testing on at least • Complete confirmatory testing on at least five
three lots and one lot per year. lots and three lots per year.
• Consider reduce testing program. • Quality attributes are critical besides identity,
potency and purity.
Suggested procedures
• All material should be tested upon receipt of material at the manufacturing site ?
• Scrutiny of Vendor COA ?
• Establishing Reliability Matrix program?
• Rapid assessment ?
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1.2 Qualification of Supplier
Periodic review Let's have an Open discussion
• Periodic monitoring and performance review on
an annual basis.
• Critical deviation should be investigated.
• Some latitude and judgment is essential to
implement the program.
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Open discussion
1. Provide steps of supplier qualification
procedure: Vendor audit, material
analysis, confirmatory testing, quality
attributes testing.
2. Teams have 15 minutes to discuss to
build a storyline based on stages to
complete a qualification procedure
3. One team will present their work (10
min) and the others give comments (5
min).
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Session 1
Fundamental knowledge
of Complex Generic API
Products # SEQUENCE 3
Drug Master File (DMF)
Review of API
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What do you know about DMF?
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1.3 Drug Master File (DMF)
The Drug Master File (DMF) is a document containing complete
information on an API’s / or drug substance, bulk intermediates for
pharmaceutical and biological products, including:
➢ Method of manufacture
➢ Specifications
➢ Testing methods When a DMF is filed, it allows a company to safeguard
its intellectual property from its partner while
➢ Validation of analytical methods complying with regulatory requirements when its
process details are disclosed. There is no legalized or
➢ Impurity regulatory requirement to file a DMF.
➢ Stability
➢ cGMP status of any API
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1.3 Introduction to Drug Master File (DMF)
The DMF comprises of two parts:
Applicant’s Part (Open part) Closed part
➢ Contains complete detailed information which
contains confidential information about the
Referred as applicant part which contains manufacturing procedure. This information is
information of API required by the considered proprietary in nature and thus
manufacturer of the finished product. available only to regulatory authorities.
➢ Most of the SRA countries including WHO,
requires DMF in order to assess the quality of
drug substance.
From a regulatory perspective, DMF neither approved nor disapproved. However, it is accepted by
the regulatory authorities if the manufacturer has fulfilled all the requirements.
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1.3 Policy objectives, Scope and Rationale
Policy objectives
• To ensure that the manufacturer of the API should provide the open part of the DMF to
company along with the sample and reference material.
• Before approving an API, the assessment of DMF is required.
Scope and Rationale
• This policy covers DMF of API from the manufacturers / supplier
• The assessment of DMF will ensure that the quality of the material used in the
manufacturing of the finished product is satisfactory
• Furthermore, this will also assist in the product development of the product and
regulatory applications
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1.3 Typical flowchart of DMF Review process
DMF Received
Screening
Complete Incomplete
Assessment Returned to manufacturer
Complete Incomplete Comments forwarded
Sample test Manufacturer
Satisfactory Unsatisfactory Satisfactory response
Report Generated (API – Accepted) Rejected
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Steps during review of DMF Filing
2. Assessment
3. Sample test
• The DMF will be assessed to ensure that the
information provided is complete Samples accompany a DMF will be tested
• A Quality Overall Summary (QOS) using CTD by Scientific Research and Analytical
template will be used in the assessment Services in accordance with the
• Any deficiencies will be forwarded to DMF specifications and test methods provided and 4. Report generation
holder and after satisfactory response, the report will be generated. The reports of DMF
DMF will be considered complete
• The assessment report will be available and developed in CTD
will be used in filing the dossier and this format will be used by
information will also be used in the product regulatory department
development. in connection with CTD
dossier filing.
1 . Screening
5. CHANGES IN DMF
• All DMF will be subjected to screening If the information in the DMF is
process. In case of any major revised/changed, it is
deficiency this will be brought to the
expected that the manufacture
attention of the DMF holder
of API/drug substance will
• After receiving the satisfactory inform company as soon as
response of these deficiencies, the DMF possible.
is accepted & introduced into the system
Do Bangladesh have DMF system as
a regulatory requirement?
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1.3 Performance during review of DMF Application
PERFORMANCE STANDARD
• Screening and acknowledgment - One week
• Scientific assessment - Two weeks
• Sample testing - ???
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1.3 Performance during review of DMF Filing
PERFORMANCE STANDARD
Key performance indicators (KPIs):
1. An excellent tool to monitor performance of the NRA.
2. To measure actions & events that lead to result should be established and the frequency of evaluation.
3. While establishing KPIs, use a quantitative method whenever possible.
Examples of performance indicators:
✓ % of applications that have been screened within the specified timeline.
✓ Compliance with defined review timeline.
✓ Quality of the evaluation reports, e.g., 3 evaluators of different levels yield similar results.
✓ Number of new products/ year listed in the register Vs. the number of applications received.
Potential indicators for other possible control points:
1. Compliance with overall timeline for registration.
2. Customer satisfaction evaluated through metrics such as complaints, surveys, questionnaires, and percentage
of approved appeals.
3. Performance assessments through use of internal audits
Otherwise, qualitative KPIs can still serve the purpose and be acceptable when set wisely.
Reference : WHO manual for Implementing quality management systems in national regulatory authorities: Examples and practices.
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1.3 Comparison of DMF Filing in US,EU & Canada
European Economic Community (EEC) [1]
Module USA [2] Canada [3]
AIM Restricted Part Applicant’s Part
Name(s) and site(s) of manufacturer(s) + + + +
Specifications and routine tests - + + +
Nomenclature - + + +
Description - + + +
Method of manufacture
➢ Brief outline (flow chart) - + - -
➢ Detailed description + - + +
QC during manufacture + - + +
Process validation and evaluation of data + - + +
Development chemistry - + + +
➢ Evidence of chemical structure - + + +
➢ Potential isomerism - + + +
➢ Physico-chemical characterisation - + + +
➢ Analytical validation - + + +
Impurities - + + +
Batch analysis - + + +
Stability - + + +
Environmental Assessment - - + +
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1.3 Comparison of DMF Filing in US,EU & Canada (Contd)
Note:
1. Notice to Applicants for Marketing Authorization for Medicinal Products for Human Use in the Member States of the
European Community: Notes for Guidance on Chemistry of Active Ingredients.
2. Guideline for Submitting Supporting Documentation in Drug Application for the Manufacture of Drug Substances:
Guideline for the Format and Content of the Chemistry, Manufacturing and Controls Section of an Application
3. The Chemistry and Manufacturing Guidelines for New Drugs
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1.3 WHO PQ Procedure for DMF Application
Reference: https://extranet.who.int/pqweb/medicines/active-pharmaceutical-ingredients
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References
• Active Pharmaceutical Ingredients Committee (APIC) Supplier Qualification & Management Guideline
• Supplier assessment, approval and qualification for listed and complementary medicines
• Vendor Qualification
• FDA Drug Master Files: Guidelines
• Health Canada: Guidance Document: Master Files (MFs) - Procedures and Administrative Requirements
• Singh, Scholar Satbir & Rana, Arapna & Kumar, Pankaj. (2018). Drug Master File: Global Regulatory Issues
and Challenges. 5. 623-626.
• ICH Guideline Q7- Good manufacturing practice guide for active pharmaceutical ingredients.
• WHO manual for Implementing quality management systems in national regulatory authorities: Examples and
practices.
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Flipped Learning
1. Form 4 equal groups and assign the subjects
for learning at home in Day 1.
2. Identify one volunteer as a lead for
coordination and compilation of key points to
be presented.
3. Each group member shall refer and read ICH
Q7 Guidance document to prepare key points
for presentation.
4. On Day 2, each group will be given an
opportunity to assess case study provided to
you to capture key points based on your
flipped learning activity.
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Homework: Flipped learning
4 groups from the ToT session read materials about ICH Q7 subparts and give presentation
(5-8min/group) in next Session
1. Introduction 11. Laboratory Controls
2. Quality Management 12. Validation
Team 1: 3. Personnel Team 3: 13. Change Control
4. Building and Facilities 14. Rejection and Re-use of the Materials
5. Process Equipment 15. Complaints and Recalls
6. Documentation and Records 16. Contract Manufacturers
7. Materials Management 17. Agents, Brokers, Traders, Distributors,
8. Production and In-process Controls Repackers and Relabellers
Team 2: Team 4:
9. Packaging and Identification Labeling of 18. Special Guidance for APIs manufactured
APIs and Intermediates by Cell Culture/ Fermentation
10. Storage and Distribution 19. APIs for use in Clinical Trial
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