Differences between

the PIC/S, EU GMP and

WHO Guidelines
“Which is which?”
Nov 2021
www.stepwiseengineering.com
 WHO GMP Guidelines

✓ The first WHO draft text on GMP was adopted in

1968. In 1969, when the World Health Assembly
recommended the first version of the WHO
Certification Scheme on the quality of pharmaceutical
products moving in the global market, it accepted the
WHO GMP as an integral part of the Scheme.

✓ More than 100 countries have incorporated the WHO

GMP provisions into their national medicines' laws,
Good Manufacturing Practices (GMP) is the
and many more countries have adopted its provisions
aspect of quality assurance that ensures that
and approach in defining their own national GMP
medicinal products are consistently produced
requirements. The WHO GMP continues to be used as
and controlled to the quality standards
a basis for the WHO Certification Scheme and
appropriate to their intended use and as
prequalification of vaccines for procurement by
required by the product specification.
United Nations agencies.

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 PIC/S GMP Guidelines
✓ The Pharmaceutical Inspection Co-operation
Scheme (PIC/S) is a non-binding, informal co-
operative arrangement between Regulatory
Authorities in the field of GMP of medicines for
human or veterinary use. PIC/S was established in
1995 as an extension to the Pharmaceutical
Inspection Convention (PIC) of 1970.

✓ Since its creation, PIC/S has been active in the

development and promotion of harmonised GMP
standards and guidance documents. The main
instrument for this has been the PIC/S GMP Guide.

Figure 1: Members of PIC/S

✓ Originally, the PIC/S GMP Guide derives from the
WHO GMP Guide and has been further developed
PIC/S presently comprises 54 Participating Authorities in order to comply with stringent requirements, to
coming from all over the world (Europe, Africa, America, cover new areas (e.g. biologicals) and to adapt to
Asia and Australasia). scientific and industrial technology (e.g. biotech,
parametric release, etc.).
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 EU GMP Guidelines

In 1989, the European Union adopted its own GMP Guide, which – in terms of GMP
requirements – is equivalent to the PIC/S GMP Guide. Since that time, the EU and the
PIC/S GMP Guides have been developed in parallel and whenever a change has been
made to one, the other has been amended so that both Guides are practically
identical.

There are, however, some differences between them…

EudraLex - Volume 4 - Good Manufacturing

Practice (GMP) Guidelines

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 PIC/S GMP vs EU GMP Guidelines
PIC/S GMP Guidelines EU GMP Guidelines
PE 009-15 – Introduction ANNEXES: Introduction ANNEXES:
PE 009-15 – PART I: Basic 1 – Manufacture of sterile medicinal products PART I – Basic Requirements 1 – Manufacture os Sterile Medicinal Products
Requirements for 2A – Manufacture of advanced therapy medicinal for Medicinal Products 2 – Manufacture of Biological active substances and
Medicinal Products products for human use Chapter 1 – Pharmaceutical Medicinal Products for Human Use
Chapter 1 – 2B – Manufacture of biological medicinal substances Quality System 3 – Manufacture of Radiopharmaceuticals
Pharmaceutical Quality and products for human use Chapter 2 – Personnel 4 – Manufacture of Veterinary Medicinal Products
System 3 – Manufacture of radiopharmaceuticals Chapter 3 – Premise and other than Immunological
Chapter 2 – Personnel 4 – Manufacture of veterinary medicinal products Equipment 5 – Manufacture of Immunological Veterinary
Chapter 3 – Premises and other than immunologicals Chapter 4 – Documentation Medicinal Products
Equipment 5 – Manufacture of immunological veterinary medical Chapter 5 – Production 6 – Manufacture of Medicinal Gases
Chapter 4 – products Chapter 6 – Quality Control 7 – Manufacture of Herbal Medicinal Products
Documentation 6 – Manufacture of medicinal gases Chapter 7 – Outsourced 8 – Sampling of Starting and Packaging Materials
Chapter 5 – Production 7 – Manufacture of herbal medicinal products activities 9 – Manufacture of Liquids, Creams and Ointments
Chapter 6 – Quality 8 – Sampling of starting and packaging materials Chapter 8 – Complaints and 10 – Manufacture of Pressurised Metered Dose
Control 9 – Manufacture of liquids, creams and ointments Product Recall Aerosol Preparations for Inhalation
Chapter 7 – Outsourced 10 – Manufacture of pressurised metered dose aerosol Chapter 9 – Self Inspection 11 – Computerised Systems
activities preparations for inhalation PART II – Basic 12 – Use of Ionising Radiation in the Manufacture of
Chapter 8 – Complaints 11 – Computerised systems Requirements for Active Medicinal Products
and Product Recall 12 – Use of ionising radiation in the manufacture of Substances used as Starting 13 – Manufacture of Investigational Medicinal
Chapter 9 – Self medicinal products Materials Products
Inspection 13 – Manufacture of investigational medicinal products PART III – GMP related 14 – Manufacture of Products derived from Human
PE 009-15 – PART II: Basic 14 – Manufacture of medicinal products derived from documents Blood or Human Plasma
Requirements for Active human blood or plasma PART IV – GMP 15 – Qualification and validation
Pharmaceutical 15 – Qualification and validation requirements for Advanced 16 – Certification by a Qualified Person and Batch
Ingredients 17 – Real Time Release Testing and Parametric Release Therapy Medicinal Products Release
19 – Reference and retention samples Glossary 17 – Parametric release
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 PIC/S GMP vs EU GMP Guidelines
The differences between the PIC/S GMP and EU GMP Guides are the following:

1. The expression “authorized person” is used in the PIC/s Guide (also used in the WHO Guide) while
the expression “Qualified person” is used in the EU Guide (the two terms are strictly equivalent).
2. References to the EU Directives and Regulations, as well as to Mutual Recognition Agreement
(MRA) have been deleted from the PIC/S Guide.

Figure 3: Annex 19 of PIC/S GMP Guide

Section 7.2 is specific to the EU GMP Guide and has

not been adopted by PIC/S.
Figure 2: Annex 19 of EU GMP Guide
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 PIC/S GMP vs EU GMP Guidelines
3. Annex 16 on Certification by a Qualified Person and Batch Release is specific to the EU GMP Guide
and has not been adopted by PIC/S. However, PIC/S intends to incorporate this Annex into a PIC/S
guideline. The aim is to harmonise internationally requirements regarding product release. The
decision to incorporate Annex 16 is a result of the memorandum of understanding signed between
the European Medicines Agency and PIC/S following the revision of EU Annex 16 in 2016. The draft
PIC/S Annex 16 was under public consultation until 15th September 2021.

4. The EU first adopted the ICH Q7A GMP Guide on APIs as Annex 18 to the EU GMP Guide while PIC/S
adopted it as a stand-alone GMP Guide (PE 007). The Guide has now been adopted as Part II of the
PIC/S and EU GMP Guides. Part 1 includes the GMP requirements for medicinal products. The
change was necessary in order to make clear that all annexes are applicable to both medicinal
product manufacturers and API manufacturers.

5. Since not all Participating Authorities under the PIC/S Scheme are parties to the European
Pharmacopoeia Convention, the mention of “European Pharmacopoeia” in the PIC/S Guide has
been amended to read “European or other relevant Pharmacopoeia”.
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 What about the differences between
the PIC/S, EU GMP Guidelines and WHO
GMP Guidelines?
The following documents were compared:

Annex 2 WHO GMP for Pharmaceutical Products: main principles

(Annex 2, WHO Technical Report Series 986, 2014)

PE 009-15 – PART I: Basic Requirements for Medicinal Products

Eudralex, Volume 4, PART I – Basic Requirements for Medicinal

Products

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 Comparison of PIC/S, EU GMP
Guidelines and WHO GMP
Guidelines

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 Pharmaceutical Quality System

Corresponding Chapter in PIC/S GMP Corresponding Chapter in EU GMP

WHO GMP Guideline
Guideline Guideline
Chapter 1 – Pharmaceutical Quality System Chapter 1 – Pharmaceutical Quality System
• Quality Risk Management • Principle/ Pharmaceutical Quality System/ GMP for Medicinal Products/ Quality Control/ Product
• Product Quality Review Quality Review/ Quality Risk Management
Chapter 2 – GMP for Pharmaceutical Products

1. The term “Quality Risk Management” (QRM) is mentioned several times in PIC/S and
EU GMP Guides while it appears only twice in WHO GMP Guide. Furthermore, there
are examples of the processes and applications of QRM in Annex 20 of PIC/S Guide and
ICH Q9 (ICH Q9 is reproduced in Part III of the EU GMP Guide). But WHO has other
guideline on Quality Risk Management that describes the WHO approach to QRM, using
the concepts described in ICH Q9 (see Annex 2, WHO Technical Report Series 981,
2013).
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 Sanitation and Hygiene

Corresponding Chapter in PIC/S GMP Corresponding Chapter in EU GMP

WHO GMP Guideline
Guideline Guideline
Chapter 3 – Sanitation and hygiene* Chapter 2 – Personnel
• Personnel Hygiene
*For Personal hygiene see section 11, Chapter 3 – Premises and Equipment
and for sanitation see section 12, “Premises” Chapter 5 – Production
• General/ Prevention of cross-contamination in production
Chapter 11 – Personal hygiene
Chapter 12 – Premises Chapter 3 – Premises and Equipment
• General/ Ancillary areas/ Storage areas/ Weighing • Principle/ Premises (general, production area, storage area, quality control areas, ancillary
areas/ Production areas/ Quality control areas areas)/ Equipment
Chapter 13 – Equipment

2. EU and PIC/S GMP Guides give more detail around cross-contamination than WHO
GMP Guide, especially regarding the appropriate organizational and technical measures
that should be taken to avoid cross-contamination.

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 Qualification and Validation
Complaints and Product Recalls
Corresponding Chapter in PIC/S GMP Corresponding Chapter in EU GMP
WHO GMP Guideline
Guideline Guideline
Chapter 4 – Qualification and Validation Chapter 3 – Premises and Equipment
Chapter 5 – Production
• Validation
Annex 15 – Qualification and Validation
Chapter 5 – Complaints Chapter 8 – Complaints and Product Recall
• Principle/ Personnel and Organisation/ Procedures for Handling and Investigating Complaints
Including Possible Quality Defects/ Investigation and Decision-making/ Root Cause Analysis and
Chapter 6 – Product Recalls Corrective and Preventative Actions/ Product Recalls and Other Potential Risk-Reducing Actions

3. WHO GMP Guide describes very briefly and superficially about validation and qualification. E.g.,
there is no mention of Factory Acceptance Testing (FAT) or Site Acceptance Testing (SAT) nor
User Requirements Specifications (URS). But WHO has another guideline on validation and
qualification (see Annex 3, WHO Technical Report Series 1019, 2019).
4. PIC/S and EU GMP Guides provide more detail on complaints and product recalls than WHO
GMP Guide. E.g., there is more information on investigation, root cause analysis, and corrective
and preventive actions.
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 Self-inspection, Quality Audits and
Suppliers’ Audits
Corresponding Chapter in Corresponding Chapter in EU GMP
WHO GMP Guideline
PIC/S GMP Guideline Guideline
Chapter 7 – Contract production, analysis and other activities Chapter 7 – Outsourced Activities
• General/ The contract giver/ The contract aceptor/ The contract • Principle/ General/ The Contract Giver/ The Contract Acceptor/ The Contract
Chapter 8 – Self-inspection, quality audits and suppliers’ audits and Chapter 9 – Self Inspection
approval • Principle
• Items for self-inspection/ Self-inspection team/ Frequency of
self-inspection/ Self-inspection report/ Follow-up action/ Quality
audit/ Supplier’s audits and approval

5. The information on self-inspection is the same in the PIC/S GMP Guide as in the EU
GMP Guide. However, the information in these guides does not match what is in WHO
GMP Guide. e.g.: frequency of self-inspection.
• “The frequency with which self-inspections are conducted may depend on company
requirements but should preferably be at least once a year.” (WHO Guide);
• “…should be examined at intervals following a pre-arranged programme…” (PIC/S and EU Guides)

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 Materials and Personnel
Corresponding Chapter in PIC/S GMP Corresponding Chapter in EU GMP
WHO GMP Guideline
Guideline Guideline
Chapter 9 – Personnel Chapter 2 – Personnel
• General/ Key Personnel • Principle/ General/ Key Personnel/ Training/ Personnel Hygiene/ Consultants
Chapter 10 – Training
Chapter 14 – Materials Chapter 5 – Production
• General/ Starting materials/ Packaging materials/ • Starting materials, Processing operations: intermediate and bulk products, Packaging materials,
Intermediate and bulk products/ Finished products/ Finished products, Rejected, recovered and returned materials
Rejected, recovered, reprocessed and reworked Chapter 6 – Quality Control
materials/ Recalled products/ Returned goods/ • Testing
Reagents and culture media/ Reference standards/
Waste materials/ Miscellaneous

6. WHO GMP Guide describes very briefly some topics, such as qualification of suppliers and
sampling of materials.
7. WHO GMP Guide has more detail on Qualified Person and batch release than chapter 2
(personnel) of EU and PIC/S Guides, however the EU has Annex 16 with particularities of this
issue (PIC/S will soon incorporate the Annex 16 into a PIC/S guideline).
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 Training

8. The training information are very similar in these Guides. The biggest difference is
found in the following paragraph:

Figure 4: WHO GMP Guide Figure 5: EU and PIC/S GMP Guides

PIC/S and EU GMP Guides mention that training programmes should be approved by either the head of
Production or the head of Quality Control, as appropriate. Besides that, both Guides also indicates that should
have basic training on the theory and practice of the quality management system.
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 Documentation
WHO GMP Guideline Corresponding Chapter in PIC/S GMP Guideline Corresponding Chapter in EU GMP Guideline
Chapter 15 – Documentation Chapter 4 – Documentation
• General/ Documents • Principle/ Required GMP Documentation (by type)/ Generation and Control of Documentation/ Good Documentation
required Practices/ Retention of Documents/ Specifications (specifications for starting and packaging materials, intermediate and
bulk products and finished products)/ Manufacturing Formula and Processing Instructions (Packaging Instructions,
Batch Processing Records and Batch Packaging Records)/ Procedures and Records (receipt, sampling, testing, other)

9. PIC/S and EU GMP Guides provide more detail on documentation than WHO GMP Guide. e.g.:
• Both PIC/S and EU indicate that documentation may exist in a variety of forms, including paper-based, electronic
or photographic media. Also introduces the term “hybrid form”, where some documentation elements exist as
electronic and others as paper based (WHO does not use this term).
• “Standard Operating Procedures, Work Instructions and Methods should be written in an imperative mandatory
style” – this information appears in the PIC/S Guides but does not appear in the WHO Guide.

10.Furthermore, there are different instructions on the period of retention of documents:

• “Specific requirements apply to batch documentation which must be kept for one year after expiry of the batch to
which it relates or at least five years after certification of the batch by the Qualified Person, whichever is the
longer…” (PIC/S and EU GMP Guides)
• “Records should be retained for at least one year after the expiry date of the finished product.” (WHO GMP Guide)
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 Production and Quality Control
Corresponding Chapter in PIC/S GMP Corresponding Chapter in EU GMP
WHO GMP Guideline
Guideline Guideline
Chapter 16 – Good practices in production Chapter 5 – Production
• General/ Prevention of cross-contamination and • Principle/ General/ Prevention of cross-contamination in production/ Validation/ Starting
bacterial contamination during production/ Processing materials/ Processing Operations - Intermediate and Bulk Products/ Packaging Materials/
operations/ Packaging operations Packaging Operations/ Finished Products/ Rejected, Recovered and Returned Materials/
Product Shortage due to Manufacturing Constraints
Chapter 17 – Good practices in quality control Chapter 6 – Quality Control
• Control of starting materials and intermediate, bulk • Principle/ General/ Good Quality Control Laboratory Practice (documentation, sampling,
and finished products/ Test requirements/ Batch testing, on-going stability programme, technical transfer of testing methods)
record review/ Stability studies/ References

11. Production: there is no information especially regarding product shortage due to manufacturing
constraints in WHO GMP Guide. E.g.:
• “The manufacturer should report to the Marketing Authorisation Holder (MAH) any constraints in manufacturing
operations which may result in abnormal restriction in the supply. This should be done in a timely manner to
facilitate reporting of the restriction in supply by the MAH, to the relevant competent authorities, in accordance
with its legal obligations” (PIC/S and EU Guides).
12. Quality Control: there is no information on technical transfer of testing methods in the WHO
GMP Guide. There are also insufficient details around on-going stability.
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 Final Remarks
✓ EMA and several of the Medicine’s Regulatory Authorities
are involved in the Pharmaceutical Inspection Convention
and Pharmaceutical Inspection Co-operation Scheme
(PIC/S), a close international cooperation between
pharmaceutical inspection authorities in the field GMP.

✓ PIC/S develops and maintains a GMP Guide to be used by its

participating authorities, which is its main instrument for
harmonisation. This is equivalent to the EU GMP Guidelines
in terms of GMP requirements.

✓ PIC/S and EU have structured the information differently

and have also provided more details for some
chapters/issues when compared to WHO GMP Guide.

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 References

1. Eudralex, Volume 4, EU Guidelines for Good Manufacturing Practices, https://ec.europa.eu/health/documents/eudralex/vol-4_en

(Last visited Nov 16, 2021)

2. Members of PIC/S, https://picscheme.org/en/members (Last visited Nov 02, 2021)

3. PIC/S GMP Guide, https://picscheme.org/en/publications?tri=gmp#zone (Last visited Nov 16, 2021)

4. WHO GMP Guidelines, https://www.who.int/teams/health-product-and-policy-standards/standards-and-specifications/norms-and-

standards-for-pharmaceuticals/guidelines/production (Last visited Nov 16, 2021).

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 About Stepwise
Engineering Services tailored for Pharma industries
Stepwise Pharma & Engineering differentiates from other engineering companies by tailoring its services specifically for the highly GMP-regulated pharmaceutical and life
sciences industries.
The entire pharmaceutical and life science industries manufacturing lifecycle is supported by us helping to set direction, assessing benefits of strategic investments and
optimizing manufacturing and business processes.
We assist our customers from Research and Development (R&D) to Commercial manufacturing.
Our goal is to help our customers to achieve and maintain GMP manufacturing excellence and assist them in the route to market.

The Author:
About the Author:

• Pharmacist with a post-graduation in “Quality Management and Audit in

Industrial Processes” and, concluding a Master in “Regulation and
Evaluation of Medicines and Health Products“ in December 2021;
• 6 years of experience within Quality Assurance in the pharmaceutical
industry;
Manuela Silva • Experience with injectables and solid oral medicines.
Regulatory Affairs Consultant

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