List of Pharmaceutical Regulatory

Guidelines

Dr. P. Shiva Shanker

M.Sc., MBA-QM .

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INTRODUCTION

As the world pharmaceutical industries are moving into the future towards becoming
more and more competitive, regulatory agencies are become more stringent and
regulatory guidelines updates are receiving from different regulatory agencies from
various countries across the globe to ensure the patient safety.

Every country is having their own regulatory authority, which is responsible to

enforce the rules and regulations and issue the guidelines to regulate drug
development process, licensing, registration, manufacturing, marketing and
labeling of pharmaceutical products.

The white paper covered, Various countries Pharmaceutical Regulatory Agencies and
Organizations around the World and Other International Society bodies guidelines
[But not limited to & There may change in Guidelines revision Ver no:].

“looking forward to your feedback”

Source: Various Websites

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 Complaint:
Any written, electronic, or oral communication that alleges deficiencies related to
the identity, quality, durability, reliability, safety, effectiveness, or performance of
a device after it is released for distribution.

 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) section 15 Complaints and
Recalls.
2. Pharmaceutical Quality System – Q10, International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH).
3. Guide to Inspections of Quality Systems [Quality System Inspection Technique]
4. Schedule M Good Manufacturing Practices and Requirements of Premises, Plant
and Equipment for Pharmaceutical Products.
5. EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines Chapter 8 -
Complaints and Product Recall.
6. US Food & Drug administration 21 code of federal regulation part 211.198.
7. CDSCO Guidelines on Recall and Rapid Alert System for Drugs.
8. EMA ICH Topic Q 7 Good Manufacturing Practice for Active Pharmaceutical
Ingredients Step 5 Section 15 Complaints and Recalls.
9. Active Pharmaceutical Ingredients Committee “How to do” Document Version 16
Chapter 15 "Complaints and Recalls"
10. Pharmaceutical Quality System-Q10, International Conference on Harmonisation
of Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH),

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 Return Goods:

A goods return or purchase return is a transaction where the buyer of inventory or other
items sends these goods back to the seller. It may be due to various reasons such as
poor quality, defective items.

 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines Chapter 8 -
Complaints and Product Recall.
3. PIC/S Procedure for Handling Rapid Alerts and Recalls Arising from Quality Defects
(PI 010-5) July 2017.

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 Risk Assessment:
A systematic process of organizing information to support a risk decision to be made
within a risk management process. It consists of the identification of hazards and
the analysis and evaluation of risks associated with exposure to those hazards

 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. WHO TRS no.961-2013-WHO guideline in quality risk management
3. PIC/S PE 009 Guide to Good Manufacturing Practice for Medicinal Products Annex
20 Quality Risk Management
4. International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) Step 4) November 9, 2005.
5. ICH-Harmonised Guideline Quality Risk Management Q9(R1) Final version Adopted
on 18 January 2023.
6. EMA-ICH guideline Q9 (R1) on quality risk management Step 5.
7. FDA-Q9 (R1) Quality Risk Management Guidance for Industry may 2023.

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 Out of Specification:
The term OOS (out of specification), is defined as those results of in process or finished
product testing, which falling out of specified limits, that are mentioned in
compendia, drug master file, or drug application.

 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. USFDA_2022 -Investigating Out-of-Specification (OOS)Test Results for
Pharmaceutical Production Guidance for Industry-May 2022 Revision 1
3. MHRA first published guidance to industry on how to handle Out Of Specification
(OOS) investigations in August 2013.
4. ECA Laboratory Data Management Guidance: Out of Expectation (OOE) and Out of
Trend (OOT) Results
5. ECA Standard Operating Procedure (SOP): Laboratory Data Management - Out of
Specification (OOS) Results.
6. ECA Guidelines for the Evaluation and Investigation of Microbiological Deviations -
Chapter 1 - Deviation Handling of Microbiological Environmental Monitoring
Excursions in NonSterile Pharmaceutical Manufacturing - Chapter 2 - Lab
Investigations – Endotoxin Out of Specification (OOS)/ Out of Trend (OOT)/
Atypical Results Investigations - Chapter 3 - Guidance for Sterility Test Failures.
7. ECA Standard Operating Procedure (SOP): Laboratory Data Management - Out of
Specification (OOS) Results

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 What is HVAC
An HVAC system is Heating Ventilation and Air Conditioning system. That is used for
conditioning of air in a big area where a usual air conditioner cannot be used. It
contains a boiler, chiller cooling tower and air handling unit. This system is used to
control the temperature of a designated space with the control of the moisture in the
air, supply the area with fresh air by controlling the carbon dioxide and oxygen level.
It also controls the contamination of airborne particles by regulating the movement of
air.
 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. Air velocity-WHO GMP for HVAC-2016/WHO feb-2018
3. WHO GMP, Annex 1: Manufacture of Sterile Products
4. ACPH- schedule-M grade B,C,D ACPH should not be less than 20 ACP/min
5. Integrity (PAO)- ISO-14644-3-2005
6. NVPC- Annex 1: Manufacture of Sterile Products
7. Airflow direction test and visualization- ISO 14644-3 -2019
8. Recovery test- ISO 14644-3 -2019
9. Containment leak test- ISO 14644-3 -2019
10. Segregation test- ISO 14644-3 -2019
11. Viable- Annex 1: Manufacture of Sterile Products.

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 Cleaning Validation:
Cleaning validation is a procedure of establishing evidence that cleaning processes
for manufacturing equipment prevents product contamination. Cleaning validation
should be properly documented to demonstrate Current Good Manufacturing
Practice (CGMP) for finished pharmaceuticals.
 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. PDA-TR NO-29-2012
3. ISPE-cleaning validation life cycle -2020
4. USFDA guideline on cleaning validation (guide to inspections validation of cleaning
process FDA-1993)
5. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211
current good manufacturing practice for finished pharmaceuticals, Subpart E -
Control of Components and Drug Product Containers and Closures, sec. 211.80
General requirements. (b).
6. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211
current good manufacturing practice for finished pharmaceuticals, Subpart D -
Equipment, sec. 211.67 Equipment cleaning and maintenance (a).

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7. Active Pharmaceutical Ingredients Committee (APIC) (2016) Guidance on aspects

of cleaning validation in active pharmaceutical ingredient plants.
8. European Medicines Agency (2014) Guideline on setting health based exposure
limits for use in risk identification in the manufacture of different medicinal
products in shared facilities.
9. PIC/S Guideline On Setting Health Based Exposure Limits for Use in Risk
Identification in The Manufacture of Different Medicinal Products in Shared
Facilities PI 046-1 Annex 1 July 2018.

 Process Validation
Process Validation is defined as the collection and evaluation of data, from the
process design stage throughout production, which establishes scientific evidence
that a process is capable of consistently delivering quality products.
 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. EU GMP annex-15
3. PIC/S-PI 006-3 25 September 2007
4. Guidance for Industry Process Validation: General Principles and Practices January
2011 Current Good Manufacturing Practices (CGMP) Revision 1

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 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. Appendix 1. Validation of heating, ventilation and air-conditioning systems (as
cross-reference to TRS 1010, Annex 8 (4))
3. Appendix 2. Validation of water systems for pharmaceutical use (as published in
TRS 937, Annex 4, 2006 and as cross-reference to TRS 970, Annex 2, 2012(5)
4. Appendix 3. Cleaning validation (as published in TRS and TRS 937,
5. Annex 4, 2006 and as cross-reference to TRS 970, Annex 2, 2012 (5)
6. Appendix 4. Analytical procedure validation (adopted, subject to a review of the
comments received by a subgroup of the Expert Committee)
7. Appendix 5. Validation of computerized systems (adopted, subject to the
changes discussed by the Expert Committee)
8. Appendix 6. Guidelines on qualification (adopted, subject to a review of the
comments received by a subgroup of the Expert Committee)
9. Appendix 7. Non-sterile process validation (as published in TRS 992, Annex 3,
2015 (3)).

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10. FDA-guideline for industry –process validation general principles and practices -
2011
11. EU GMP annex-15
12. PIC/S-PI 006-3 25 September 2007
13. ICH Q8 (R2): “Pharmaceutical Development”, ICH Harmonised Tripartite
Guideline 2009
14. ICH Q9: “Quality Risk Management”, ICH Harmonised Tripartite Guideline 2005
15. ICH Q10:” Pharmaceutical Quality System”, ICH Harmonised Tripartite Guideline
2008
16. ICH Q11:” Development and manufacture of drug substances (chemical entities
and biotechnological/biological entities)”, ICH 2012
17. ICH Q12: “Technical and Regulatory Considerations for Pharmaceutical Product
Lifecycle Management”, Draft 2018
18. EU GMP Volume 4 Chapter 7 “Outsourced Activities”, 2012
19. EU GMP Annex 11 “Computerized Systems”, Eudralex 2011
20. EU GMP Annex 15 “Qualification and Validation”, Eudralex 2015
21. US FDA Guidance for Industry: “Process Validation: General Principles and
Practices, 2011
22. USP 37: “Analytical Instrument Qualification”, (section 1058), The United States
Pharmacopeial Convention, 2016
23. ISPE Good Practice Guide: Applied Risk Management for Commissioning and
Qualification, ISPE 2011
24. ISPE GAMP® 5 Guide: “A Risk-Based Approach to Compliant GxP Computerized
Systems”, ISPE 2008
25. ISPE Guide: “Science and Risk-Based Approach for the Delivery of Facilities,
Systems, and Equipment”, ISPE 2011
26. ISPE Baseline Guide Volume 5: “Commissioning & Qualification”, First Edition,
2001.

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27. ISPE Baseline Guide Volume 5: “Commissioning & Qualification”, Second Edition,
2019
28. PDA Technical Report 60: “Process Validation: A Lifecycle Approach”, 2017
29. PDA Technical Report 54-5: “Quality Risk Management for the Design,
Qualification, and Operation of Manufacturing Systems”, PDA 2017
30. ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC)-
31. guidance on aspects of cleaning validation in API plants-sept-2016
32. PDA-TR NO-29-2012
33. ISPE-cleaning validation life cycle -2020.
34. European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Chapter 3: Premises and Equipment, (2014).
35. European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Chapter 5: Production, (2014).
36. European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Part II: Basic Requirements for Active Substances used as Starting
Materials, (2014)
37. EMA Guideline on setting health-based exposure limits for use in risk
identification in the manufacture of different medicinal products in shared
facilities (20 November 2014).
38. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211
current good manufacturing practice for finished pharmaceuticals, subpart C
Building and Facilities, sec. 211.42 Design and construction features (b), (c)
39. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211
current good manufacturing practice for finished pharmaceuticals, Subpart C -
Buildings and Facilities, sec. 211.56 Sanitation (c).
40. PIC/S Recommendations on “Validation Plan, Installation and Operational
Qualification, Non-Sterile Process Validation, Cleaning Validation”, August 2001.
41. I.S.P.E. Pharmaceutical Engineering Guide for New and Renovated Facilities, Vol.
5 Commissioning and Qualification, March 2001

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42. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. ICH
Harmonized Tripartite Guideline. 2000 (Q7a).
43. Standard Methods for the Examination of Water and Wastewater, 18th Edition.
American Public Health Association.

 Corrective Action
Action to eliminate the cause of a detected non-conformity or other undesirable
situation. NOTE: Corrective action is taken to prevent recurrence whereas
preventive action is taken to prevent occurrence.
 Preventive Action
Action to eliminate the cause of a potential non-conformity or other undesirable
potential situation. NOTE: Preventive action is taken to prevent occurrence whereas
corrective action is taken to prevent recurrence
 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. FDA- investigation to determination root cause relating to product processes, and
the quality system
3. ICH Q10 (international conference on harmonization) PQS-10)
4. FDA-sept-2006 pharmaceutical CGMP regulations for change control, CAPA, risk
assessments.

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 ALCOA: Attributable, Legible, Contemporaneous, Original and Accurate (ALCOA)

 ALCOA+: Complete, Consistent, Enduring and Available (CCEA) was added to ALCOA
in 2010.
 ALCOA++: Traceable.

1. Attributable: Clearly indicates who recorded the data / performed the activity with
sign data. Record who wrote it and when. FDA requirement is data should be trace
or link with its source like study, analytical run, test system, etc. This concept is
applicable for original data as well as any change in data both should be sign and
date by an Individual.

2. Legible (Readable): Data should be readable after it is recorded. Data is recorded

permanently in a long-lasting (durable) medium like a pen, non-removable ink. This
is applicable for both printed and Handwritten documents.

3. Contemporaneous (Online Record): Record the data at the time it was generated
i.e. contemporaneously. It is well known online recording of data. If more promptly
(no delay) data is recorded, better the quality. The date of data entry should be
required.

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4. Original: Prevent data in its unaltered state like raw data, source data. This is the
first data generated electronically or manually.

5. Accurate: Data reflect its actual value / trueness, free from error. Accuracy of data
indicates quality.

6. Available: Data should be available for review at any time until the defined storage
of the document. Available at the time of audit and whenever required for review.

7. Enduring: Making sure records exist for the entire period and readable condition.

8. Complete: Data must be incomplete state to avoid recreation/ manipulation. The

required level of details fulfills in the documents consider as complete. Complete
records show its data reliability and quality.

9. Consistent: Good Documentation Practices should be applied throughout any

process for consistency in Documentation. Available data should be in a sequential
manner with a sign and date. Time Should be in the correct sequence to show the
reliability and consistency in the process and Activity performed.

10. Traceable: Data traceable throughout the process and data life cycle including
changes with no overwriting. Metrological, time and metadata traceability.

 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. USFDA-Data Integrity and Compliance with Drug CGMP Questions and Answers
Guidance for Industry- December 2018

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3. MHRA-2015-data integrity definition and guidance for industry

4. WHO. TRS 996 annex 05 (2016). Guidance on good data and record management
practices.
5. PIC/S-2016-good practice for data management and integrity.
6. APIC Practical risk-based guide for managing Data Integrity April-2022
7. MHRA. (March 2018). ‘CGXP’ Data Integrity Guidance and Definitions.
8. PIC/S PI-041 Good Practices for Data Management and Integrity in Regulated GMP /
GDP Environments
9. EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, Chapter 1
Pharmaceutical Quality System.
10. EudraLex - Volume 4 Good Manufacturing Practice (GMP) Guidelines, Chapter 9 Self
Inspection. 2001
11. ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology Guidance for
Industry.
12. EMA GMP Q&A on Annex 11 and Q&A on Data Integrity,
13. U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211
current good manufacturing practice for finished pharmaceuticals, Subpart B -
Organization and Personnel, sec.211.28 Personnel responsibilities (a).
14. Medicines & Healthcare products Regulatory Agency (MHRA) - ‘GXP’ Data Integrity
Guidance and Definitions. March 2018.
15. https://www.spectroscopyonline.com/view/is-traceability-the-glue-for-alcoa-
alcoa-or-alcoa-by R.D. McDowall

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 Computerized system validation

Computerized system validation (CSV) (Computerized system validation in European
countries, and usually referred to as "Computer Systems Validation") is the process
of testing/validating/qualifying a regulated (e.g., US FDA 21 CFR Part 11[1])
computerized system to ensure that it does exactly what it is designed to do in a
consistent and reproducible manner that is as safe, secure and reliable as paper-
based records.
 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. GAMP 5- A risk based approach to compliant Gxp computerized systems.
3. EMA GCP Q&A no. 8, 9, and Notice to sponsors on validation and qualification of
computerised systems used in clinical trials.
4. PIC/S guide to good manufacturing practice for medicinal products annexes:
Annex 11 – Computerised systems.
5. PIC/S PI 011-3 Good practices for computerised systems in regulated GxP
environments.

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6. US Code of Federal Regulations, Title 21, Food and Drugs

 21 CFR Part 11 – Electronic Records, Electronic Signatures
 21 CFR Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies
 21 CFR Part 210 – Current Good Manufacturing Practice in Manufacturing,
Processing, Packing, or Holding of Drugs
 21 CFR Part 211 – Current Good Manufacturing Practice for Finished
Pharmaceuticals
 21 CFR Part 820 – Quality System Regulation (Medical Device)
7. Volume 4: Pharmaceutical legislation – Medicinal Products for Human and
Veterinary use – Good Manufacturing Practices, including Annex 11 – Computerized
Systems.
8. EUDRALEX Volume 9 – Pharmacovigilance Volume 9A – Pharmacovigilance for
Medicinal Products for Human Use (version April 2007) (Volume 9A of the Rules
Governing Medicinal Products in the European Union: Pharmacovigilance for
medicinal products for human use).
9. Regulatory Guide – Japan – PFSB Notification, No. 0401022 Electronic
Records/Electronic Signature, 2005.

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 Nitrosamine and Other Carcinogenic related impurities.

Formation of Nitrosamine: The formation of nitrosaminesis generally only possible
when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is
unstable but can be formed in situ from nitrites (NO2) under acid conditions.

 Reference Regulations and Regulatory Guidelines and associate documents:

1. Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients-Q7,

International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH).
2. IPEC Federation, “The Role of Excipients in Determining N-Nitrosamine Risks for
Drug Products,” IPEC Position Paper,
3. FDA News Release, “FDA Requests Removal of All Ranitidine Products (Zantac)
from the Market,” April 1, 2020,
4. European Medicines Agency, “ICH M7 Assessment and control of DNA reactive
(mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk,”
August 10, 2021,
5. International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH), “ICH Harmonised Guideline: Assessment
and Control of DNA Reactive
6. (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk:
M7(R1),” March 31, 2017,

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7. FDA Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs,

February 2021 (Revision 1).
8. EMA, 2022a. Questions and answers for marketing authorisation holders/applicants
on the CHMP Opinion
9. for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine
impurities in human medicinal products. EMA/409815/2020 Rev.11.
10. EMA, 2022b. Nitrosamine impurities.
11. IPEC Federation, 2022. The Role of Excipients in Determining N-Nitrosamine Risks
for Drug Products.
12. US FDA, 2021. Control of Nitrosamine Impurities in Human Drugs: Guidance for
Industry. Cent. Drug Eval. Res. Silver Spring, MD, USA.
13. International Agency for Research on Cancer (IARC) (2000) IARC Monographs on the
Evaluation of the Carcinogenic Risk of Humans, Vol. 77, Some Industrial Chemicals.

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