Kanton Zürich

Gesundheitsdirektion
Kantonale Heilmittelkontrolle

Main Differences between

GMP Part I and Part II (and ICH Q7)

Inspector’s point of view

Dr. Daniel Bierbaum, Inspector

Cantonal Office for the Control of Medicines
Regional Medicines Inspectorate of Eastern
and Central Switzerland
Program
Kanton Zürich
Kantonale Heilmittelkontrolle

1. GMP Guide, History

2. GMP Guide, Structure Overview

3. Document Revisions

4. Applicability Annexes and Part III

5. GMP Guide, Structure Details and Comparability

6. Similarities and Differences in Parts I and II

7. Summary and Outlook

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Scopes of Parts I & II Kantonale Heilmittelkontrolle

Part II Part I

Manufacture of Active Manufacture of Intermediates

Pharmaceutical Ingredients and Finished Products
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Document History Kantonale Heilmittelkontrolle

Various
Documents

1968 WHO GMP ICH Q7A 2000

1972 PIC GMP

1989 EEC GMP

2001 EU GMP Annex 18

EU GMP
2005 Part I
Part II
Annexes
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General Structure Kantonale Heilmittelkontrolle

EU-Guide PIC/S-Guide
Introduction Introduction
Part I FP Part I
Part II API Part II
For Industry
Part III Div Annexes
Part IV ATMP Glossary
Annexes SMF (3x)
Glossary
Other Doc GDP Other Doc For Inspectors
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Part I Revisions Kantonale Heilmittelkontrolle

Chapters 1 – 8 of Part I have undergone recent revisions.

Part I is a constantly living document.

Part I chapters: Revision status

# Scope Revision
1 Pharmaceutical Quality System 2013
2 Personnel 2014
3 Premises and Equipment 2015
4 Documentation 2011
5 Production 2015
6 Quality Control 2014
7 Outsourced Activities 2013
8 Complaints, Quality Defects and Product Recalls 2015
9 Self Inspection < 2006
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Part II Revisions Kantonale Heilmittelkontrolle

Part II is much more conservative and has undergone only

two small amendments since the implementation of ICH Q7A
(now ICH Q7) into the GMP guide.

The introduction in chapter 1 was changed in the course of the

implementation of ICH Q7A as Annex 18.

In 2010 paragraphs 2.19, 2.20 and 2.21 on quality risk

management were implemented in chapter 2
(including a change in numbering of sections 2.2 to 2.5).

In 2014 paragraph 1.2 was revised (clarification to applicability

of the annexes and to the relationship between chapter 17
and the new GDP guidelines).
 Kanton Zürich

Annexes Revisions
Kantonale Heilmittelkontrolle

and Applicability
Some annexes of the GMP guidelines have undergone
revision since the reorganisation in 2005.

Applicability to Parts I and II is not always clearly stated.

 Kanton Zürich

Annexes Revisions
Kantonale Heilmittelkontrolle

and Applicability
# Title Date Part I or II? Applicability
1 Manufacture of Sterile Medicinal Products 1 March 2009 I & II clear
Manufacture of Biological active substances and Medicinal Products for
2 26 June 2018 I & II clear
Human Use
3 Manufacture of Radiopharmaceuticals 1 March 2009 I & II clear
Manufacture of Veterinary Medicinal Products Other than Immunological
4 <2006 I (II) not stated
Veterinary Medicinal Products
5 Manufacture of Immunological Veterinary Medicinal Products < 2006 I & II not stated
6 Manufacture of Medicinal Gases 31 July 2010 I & II clear

7 Manufacture of Herbal Medicinal Products 1 September 2009 I & II clear

8 Sampling of Starting and Packaging Materials < 2006 I not stated but clear
9 Manufacture of Liquids, Creams and Ointments < 2006 I not stated but clear
Manufacture of Pressurised Metered Dose Aerosol Preparations for
10 < 2006 I not stated but clear
Inhalation
11 Computerised Systems 30 June 2011 I & II not stated
12 Use of Ionising Radiation in the Manufacture of Medicinal Products < 2006 I & II not stated
13 Investigational Medicinal Products 31 July 2010 I not stated

14 Manufacture of Medicinal Products Derived from Human Blood or Plasma 30 November 2011 I & II not stated

15 Qualification and Validation 1 October 2015 I clear

16 Certification by a Qualified Person and Batch Release 15 April 2016 I not stated but clear
17 Real Time Release Testing and Parametric Release 26 December 2018 I & II clear
18 Deleted - - -
19 Reference and Retention Samples (now Q9 in Part III) 1 June 2006 I & II not stated
 Kanton Zürich

Part III Applicability Kantonale Heilmittelkontrolle

Title Date Part I or II? Applicability

Explanatory Notes on the preparation of a Site Master File 2010 I Part II optional
ICH guideline Q9 on quality risk management 2006 I & II optional
ICH guideline Q10 on pharmaceutical quality system 2008 I & II optional
Internationally harmonised requirements for batch certification 2011 I Part II optional
Template for the 'written confirmation' for active substances exported to the
2013 ̶
European Union for medicinal products for human use
Guideline on setting health based exposure limits for use in risk identification in the
2015 I (A15.10.6) Part I
manufacture of different medicinal products in shared facilities
Guidelines on the formalised risk assessment for ascertaining the appropriate good
2015 I (5.29) Part I
manufacturing practice for excipients of medicinal products for human use
Content of the Batch Certificate for Investigational Medicinal Products ?
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Document Structure Kantonale Heilmittelkontrolle

Part I Part II
# Chapter # Chapter
1 Pharmaceutical Quality System 2100 1 Introduction 1000
2 Personnel 1700 2 Quality Management 1100
3 Premises and Equipment 1400 3 Personnel 300
4 Documentation 2800 4 Buildings and Facilities 1000
5 Production 3800 5 Process Equipment 1000
6 Quality Control 2400 6 Documentation and Records 1600
7 Outsourced Activities 900 7 Materials Management 800
2100
8 Complaints, Quality Defects and Product Recalls 8 Production and In-Process Controls 1100
9 Self Inspection 100 Packaging and Identification Labelling of APIs and
9
Intermediates 700
Total words 17300
10 Storage and Distribution 200
11 Laboratory Controls 1500
12 Validation 1500
Annexes 13 Change Control 300
14 Rejection and Reuse of Materials 600
15 Complaints and Recalls 200
16 Contract Manufacturers (including Laboratories)200
Most of the chapters have one 17
Agents, Brokers, Traders, Distributors, Repackers,
and Relabellers 600
or more corresponding sections 18
Specific Guidance for APIs Manufactured by Cell
Culture / Fermentation 1300

in the other guide or in an annex 19 APIs for Use in Clinical Trials 800
Total words 15800
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Comparability Kantonale Heilmittelkontrolle

Calibration In process controls QC documentation

Change control Intermediates Quality control
Cleaning (rooms, Equipment) Job descriptions Quality risk management
Computerised Systems Log-books Reagents / standards QC
Consultants Maintenance (rooms, Reference samples (Part I)
Dedicated facilities Equipment) Retention samples (Part I)
Similar

Deviations Management Reserve/ retention samples

Documentation Manufacturing documentation (Part II)
Electronic signature Materials handling Rejection
Equipment Organisation Release
Finished product / API Out of specification results Reprocessing
GMP (general aspects) Packaging / Packaging Rooms
Goods entry materials Self inspection
Head of production Personal hygiene Storage
Part I Head of quality control / units Quality system Training Part II
Utilities
Differences

Cleaning validation MBR review Recalls

CoA Method validation Revalidation
More

Complaints On-going stability Sampling

(Cross) contamination PQR Specifications
Contract manufacturing Process validation Supplier Qualification
Introduction Qualification Water
Manufacturing Raw materials

Analytical method transfer Agents, brokers, traders Process aids

Out of trend results APIs for Use in Clinical Trials Recovery solvents & materials
Specific

Packaging validation Blending of batches Repackers

Retention samples Cell Culture / Fermentation Retrospective validation
Shortage of MP Distribution Returns
Transport verification Expiry / Retest Reworking
Impurity profile
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Similar Regulations Kantonale Heilmittelkontrolle

Some topics have a high similarity in Parts I and II of the

GMP guide.

Although the wording may differ in their degree of detail

and also in specific requirements, they may be looked at
as comparable.
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Example: Changes Kantonale Heilmittelkontrolle

Part I
1.4 A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that:
(xii) Arrangements are in place for the prospective evaluation of planned changes and their approval prior to implementation taking into account regulatory notification and approval
where required
(xiii) After implementation of any change, an evaluation is undertaken to confirm the quality objectives were achieved and that there was no unintended deleterious impact on product
quality

1.8 Good Manufacturing Practice […]

(ii) Critical steps of manufacturing processes and significant changes to the process are validated

4.29 There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples:
[...]- Change control [...]

5.25 Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process,
should be validated.

6.33 In certain situations, additional batches should be included in the on-going stability programme. For example, an on-going stability study should be conducted after any significant
change or significant deviation to the process or package. [...]

7.2 All arrangements for the outsourced activities including any proposed changes in technical or other arrangements should be in accordance with regulations in force, and the
Marketing Authorisation for the product concerned, where applicable.
7.12 The Contract Acceptor should not make unauthorized changes, outside the terms of the Contract, which may adversely affect the quality of the outsourced activities for the
Contract Giver.

A11.10. Change and Configuration Management

Any changes to a computerised system including system configurations should only be made in a controlled manner in accordance with a defined procedure.

A15.11. CHANGE CONTROL

A15.11.1. The control of change is an important part of knowledge management and should be handled within the pharmaceutical quality system.
A15.11.2. Written procedures should be in place to describe the actions to be taken if a planned change is proposed to a starting material, product component, process, equipment,
premises, product range, method of production or testing, batch size, design space or any other change during the lifecycle that may affect product quality or reproducibility.
A15.11.3. Where design space is used, the impact on changes to the design space should be considered against the registered design space within the marketing authorisation and the
need for any regulatory actions assessed.
A15.11.4. Quality risk management should be used to evaluate planned changes to determine the potential impact on product quality, pharmaceutical quality systems, documentation,
validation, regulatory status, calibration, maintenance and on any other system to avoid unintended consequences and to plan for any necessary process validation, verification or
requalification efforts.
A15.11.5. Changes should be authorised and approved by the responsible persons or relevant functional personnel in accordance with the pharmaceutical quality system.
A15.11.6. Supporting data, e.g. copies of documents, should be reviewed to confirm that the impact of the change has been demonstrated prior to final approval.
A15.11.7. Following implementation, and, where appropriate, an evaluation of the effectiveness of change should be carried out to confirm that the change has been successful.
 Kanton Zürich

Example: Changes Kantonale Heilmittelkontrolle

Part II
11.12 […] Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the
quality unit(s).

13 Change Control
13.10 A formal change control system should be established to evaluate all changes that may affect the production and control of the intermediate or API.
13.11 Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods,
facilities, support systems, equipment (including computer hardware), processing steps, labelling and packaging materials, and computer software.
13.12 Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organisational units, and reviewed and approved by the quality unit(s).
13.13 The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing,
validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g. as minor or major) depending on the nature and extent of the changes,
and the effects these changes may impart on the process. Scientific judgment should determine what additional testing and validation studies are appropriate to justify a change in a
validated process.
13.14 When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.
13.15 After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.
13.16 The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process
can be placed on an accelerated stability program and/or can be added to the stability monitoring program.
13.17 Current dosage form manufacturers should be notified of changes from established production and process control procedures that can impact the quality of the API.

16.16 Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the
changes.

5.47 Changes to the computerized system should be made according to a change procedure and should be formally authorized, documented and tested. Records should be kept of all
changes, including modifications and enhancements made to the hardware, software and any other critical component of the system. These records should demonstrate that the system is
maintained in a validated state.

A11.10. Change and Configuration Management

Any changes to a computerised system including system configurations should only be made in a controlled manner in accordance with a defined procedure.

Additional paragraphs for IMP API’s.

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Example: Calibration Kantonale Heilmittelkontrolle

Part I Part II
3.40 Balances and measuring equipment of an appropriate 5.3 Calibration
range and precision should be available for production 5.30 Control, weighing, measuring, monitoring and test
and control operations. equipment that is critical for assuring the quality of
3.41 Measuring, weighing, recording and control intermediates or APIs should be calibrated according to
equipment should be calibrated and checked at defined written procedures and an established schedule.
intervals by appropriate methods. Adequate records of 5.31 Equipment calibrations should be performed using
such tests should be maintained. standards traceable to certified standards, if existing.
5.32 Records of these calibrations should be maintained.
4.29 There should be written policies, procedures, 5.33 The current calibration status of critical equipment
protocols, reports and the associated records of actions should be known and verifiable.
taken or conclusions reached, where appropriate, for the 5.34 Instruments that do not meet calibration criteria
following examples: should not be used.
[...] - Equipment assembly and calibration [...] 5.35 Deviations from approved standards of calibration on
critical instruments should be investigated to determine if
6.7 Laboratory documentation should follow the principles these could have had an impact on the quality of the
given in Chapter 4. An important part of this documentation intermediate(s) or API(s) manufactured using this
deals with Quality Control and the following details should equipment since the last successful calibration.
be readily available to the Quality Control Department:
[...] iii. Procedures for and records of the 6.61 Complete records should also be maintained for:
calibration/qualification of instruments and maintenance of [...] -Periodic calibration of laboratory instruments,
equipment [...] apparatus, gauges, and recording devices [...]

Additional paragraphs for Cell Culture/Fermentation API

and IMP’s.

Instructions may differ in detail (orange) but the overall

impact should be similar.
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More Differences Kantonale Heilmittelkontrolle

In some areas there are more differences between

Parts I and II of the GMP guide.

Some of them are specific to the inherent differences

between the manufacture of active pharmaceutical
ingredients and the manufacture of finished products.

Some topics cover more details in one or the other guide

and some regulations also cover different quality assurance
tools.
 Kanton Zürich

Example: CoA Kantonale Heilmittelkontrolle

Part I Part II
4. Certificates of Analysis: Provide a summary of testing results 11.4 Certificates of Analysis
on samples of products or materials together with the evaluation 11.40 Authentic Certificates of Analysis should be issued for
for compliance to a stated specification. each batch of intermediate or API on request.
11.41 Information on the name of the intermediate or API
Documentation including where appropriate its grade, the batch number, and
6.7 Laboratory documentation should follow the principles the date of release should be provided on the Certificate of
given in Chapter 4. An important part of this documentation deals Analysis. For intermediates or APIs with an expiry date, the
with Quality Control and the following details should be readily expiry date should be provided on the label and Certificate of
available to the Quality Control Department: Analysis. For intermediates or APIs with a retest date, the retest
[...] v. Testing reports and/or certificates of analysis [...] date should be indicated on the label and/or Certificate of
Analysis.
11.42 The Certificate should list each test performed in
accordance with compendial or customer requirements,
including the acceptance limits, and the numerical results
obtained (if test results are numerical).
11.43 Certificates should be dated and signed by authorised
personnel of the quality unit(s) and should show the name,
address and telephone number of the original manufacturer.
Where the analysis has been carried out by a repacker or
reprocessor, the Certificate of Analysis should show the name,
address and telephone number of the repacker/ reprocessor and
a reference to the name of the original manufacturer.
11.44 If new Certificates are issued by or on behalf of
repackers/ reprocessors, agents or brokers, these Certificates
should show the name, address and telephone number of the
laboratory that performed the analysis. They should also
contain a reference to the name and address of the original
manufacturer and to the original batch Certificate, a copy of
which should be attached.
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Example: Complaints Kantonale Heilmittelkontrolle

Part I
Personnel and Organisation
8.1 Appropriately trained and experienced personnel should be responsible for managing complaint and quality defect investigations and for deciding the measures to be taken to manage any potential risk(s)
presented by those issues, including recalls. These persons should be independent of the sales and marketing organisation, unless otherwise justified. If these persons do not include the Qualified Person involved in
the certification for release of the concerned batch or batches, the latter should be made formally aware of any investigations, any risk-reducing actions and any recall operations, in a timely manner.
8.2 Sufficient trained personnel and resources should be made available for the handling, assessment, investigation and review of complaints and quality defects and for implementing any risk-reducing actions.
Sufficient trained personnel and resources should also be available for the management of interactions with competent authorities.
8.3 The use of inter-disciplinary teams should be considered, including appropriately trained Quality Management personnel.
8.4 In situations in which complaint and quality defect handling is managed centrally within an organisation, the relative roles and responsibilities of the concerned parties should be documented. Central management
should not, however, result in delays in the investigation and management of the issue.
Procedures for handling and investigating complaints including possible quality defects
8.5 There should be written procedures describing the actions to be taken upon receipt of a complaint. All complaints should be documented and assessed to establish if they represent a potential quality defect or
other issue.
8.6 Special attention should be given to establishing whether a complaint or suspected quality defect relates to falsification.
8.7 As not all complaints received by a company may represent actual quality defects, complaints which do not indicate a potential quality defect should be documented appropriately and communicated to the
relevant group or person responsible for the investigation and management of complaints of that nature, such as suspected adverse events.
8.8 There should be procedures in place to facilitate a request to investigate the quality of a batch of a medicinal product in order to support an investigation into a reported suspected adverse event.
8.9 When a quality defect investigation is initiated, procedures should be in place to address at least the following:
i. The description of the reported quality defect.
ii. The determination of the extent of the quality defect. The checking or testing of reference and/or retention samples should be considered as part of this, and in certain cases, a review of the batch production
record, the batch certification record and the batch distribution records (especially for temperature-sensitive products) should be performed.
iii. The need to request a sample, or the return, of the defective product from the complainant and, where a sample is provided, the need for an appropriate evaluation to be carried out.
iv. The assessment of the risk(s) posed by the quality defect, based on the severity and extent of the quality defect.
v. The decision-making process that is to be used concerning the potential need for risk-reducing actions to be taken in the distribution network, such as batch or product recalls, or other actions.
vi. The assessment of the impact that any recall action may have on the availability of the medicinal product to patients/animals in any affected market, and the need to notify the relevant authorities of such impact.
vii. The internal and external communications that should be made in relation to a quality defect and its investigation.
viii. The identification of the potential root cause(s) of the quality defect.
ix. The need for appropriate Corrective and Preventative Actions (CAPAs) to be identified and implemented for the issue, and for the assessment of the effectiveness of those CAPAs.
Investigation and Decision-making
8.10 The information reported in relation to possible quality defects should be recorded, including all the original details. The validity and extent of all reported quality defects should be documented and assessed in
accordance with Quality Risk Management principles in order to support decisions regarding the degree of investigation and action taken.
8.11 If a quality defect is discovered or suspected in a batch, consideration should be given to checking other batches and in some cases other products, in order to determine whether they are also affected. In
particular, other batches which may contain portions of the defective batch or defective components should be investigated.
8.12 Quality defect investigations should include a review of previous quality defect reports or any other relevant information for any indication of specific or recurring problems requiring attention and possibly further
regulatory action.
8.13 The decisions that are made during and following quality defect investigations should reflect the level of risk that is presented by the quality defect as well as the seriousness of any non-compliance with respect
to the requirements of the marketing authorisation/product specification file or GMP. Such decisions should be timely to ensure that patient and animal safety is maintained, in a way that is commensurate with the
level of risk that is presented by those issues.
8.14 As comprehensive information on the nature and extent of the quality defect may not always be available at the early stages of an investigation, the decision-making processes should still ensure that
appropriate risk-reducing actions are taken at an appropriate time-point during such investigations. All the decisions and measures taken as a result of a quality defect should be documented.
8.15 Quality defects should be reported in a timely manner by the manufacturer to the marketing authorisation holder/sponsor and all concerned Competent Authorities in cases where the quality defect may result in
the recall of the product or in an abnormal restriction in the supply of the product.
Root Cause Analysis and Corrective and Preventative Actions
8.16 An appropriate level of root cause analysis work should be applied during the investigation of quality defects. In cases where the true root cause(s) of the quality defect cannot be determined, consideration
should be given to identifying the most likely root cause(s) and to addressing those.
8.17 Where human error is suspected or identified as the cause of a quality defect, this should be formally justified and care should be exercised so as to ensure that process, procedural or system-based errors or
problems are not overlooked, if present.
8.18 Appropriate CAPAs should be identified and taken in response to a quality defect. The effectiveness of such actions should be monitored and assessed.
8.19 Quality defect records should be reviewed and trend analyses should be performed regularly for any indication of specific or recurring problems requiring attention.
 Kanton Zürich

Example: Complaints Kantonale Heilmittelkontrolle

Part II
15 Complaints and Recalls
15.10 All quality related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.
15.11 Complaint records should include:
- Name and address of complainant;
- Name (and, where appropriate, title) and phone number of person submitting the complaint;
- Complaint nature (including name and batch number of the API);
- Date complaint is received;
- Action initially taken (including dates and identity of person taking the action);
- Any follow-up action taken;
- Response provided to the originator of complaint (including date response sent);and
- Final decision on intermediate or API batch or lot.
15.12 Records of complaints should be retained in order to evaluate trends, product-related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.
15.13 There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.
15.14 The recall procedure should designate who should be involved in evaluating the information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be
treated.
15.15 In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.
 Example: Kanton Zürich
Kantonale Heilmittelkontrolle

Qualification and Validation

Part I Part II
Annex 15: Qualification and Validation Chapter 12: Validation

1. Organising and Planning 12.1 Validation Policy

2. Documentation, VMP 12.2 Validation Documentation
3. Qualification stages 12.3 Qualification
4. Re-Qualification 12.4 Approaches to Process Validation
5. Process Validation 12.5 Process Validation Program
6. Verification of Transportation 12.6 Periodic Review of Validated Systems
7. Validation of Packaging 12.7 Cleaning Validation
8. Qualification of utilities 12.8 Validation of Analytical Methods
9. Validation of Test Methods
10. Cleaning Validation Chapter 13: Change Control
11. Change Control
12. Glossary

2015: 2000:
VMP should be stablished Less detailed instructions
Retrospective validation not possible No VMP required (only “policy” required)
Qualification stages more detailed Retrospective validation possible
URS, FAT, SAT General reference to toxicology
Continuous process verification Utilities qualification in chapter 4
PDE in cleaning validation
Transportation
Packaging
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Other Differences Kantonale Heilmittelkontrolle

Contamination / Cross-Contamination
In Part II requirements may increase towards the finished
API, in Part I contamination control has to be strictly
respected throughout the whole process (usually no
cleaning steps for the product possible).

Batch Production Record Review

In Part II one section describes the expectations for batch
production record review (no details in Part I).

On-going Stability Monitoring

In Part I instructions for on-going stability programs are more
detailed. In Part I an appropriate number of tests must allow
statistical evaluation (trend analysis). In Part II test should
be performed at least annually for one batch and the first
three commercial batches should be monitored.
 Kanton Zürich

Other Differences Kantonale Heilmittelkontrolle

Product Quality Reviews

Requirements for PQRs are more detailed in Part I than in
Part II (more aspects).

Sampling
Part I describes identity tests for starting materials on each
container. Packaging materials have to be sampled
statistically. According to Part II at least one test to verify the
identity of each batch of material has to be performed but
exceptions are possible (processing aids, hazardous or
highly toxic raw materials, other special materials).
 Kanton Zürich

Other Differences Kantonale Heilmittelkontrolle

Specifications
In Part I detailed requirements for the structure of
specifications for starting and packaging materials,
intermediate, bulk and finished products are given. In Part II
only general remarks for the need of specifications are
implemented.

Supplier Qualification
In Part I detailed instructions for the qualification of suppliers
were introduced during the revision of chapter 5 in 2015,
covering aspects for the qualification of manufacturers of
excipients (appropriate good manufacturing practice). In
Part II only a very brief description of supplier qualification is
implemented (paragraphs 7.11 and 7.31).
 Kanton Zürich

Other Differences Kantonale Heilmittelkontrolle

Water
In Part I there are no specific instructions for water systems
and water quality (paragraphs 3.43 and 6.7vi) but
pharmacopoeial requirements apply. In Part II there is a
section about water quality and water systems (section 4.3).
Specific Kanton Zürich
Kantonale Heilmittelkontrolle

Requirements
In some areas there specific requirements in Part I or II.

Some of these regulations are ultimately connected to the

characteristics of APIs or finished products. Some
regulations are described in additional documents (e.g.
GDP guide).
 Kanton Zürich

Specific to Part I Kantonale Heilmittelkontrolle

Analytical Method Transfer

In Part I (paragraphs 6.37 – 6.41) specific regulations on
technical transfers of testing methods were introduced.

Results out of Trend

According to paragraph 6.7iv in addition to a procedure for
the investigation of out of specification results a procedure
for out of trend results should also be established.

Retention Samples
In annex 19 retention sample are described as “a sample of
a fully packaged unit from a batch of finished product”, which
is not relevant for APIs.
 Kanton Zürich

Specific to Part I Kantonale Heilmittelkontrolle

Shortage of Medicinal Products

In Part I (paragraph 5.71) there is a regulation on product
shortage due to manufacturing constraints. This should be
reported to the marketing authorization holder.
 Kanton Zürich

Specific to Part II Kantonale Heilmittelkontrolle

Distribution, Agents, Brokers, Traders, Distributors,

Repackers, and Relabellers
Distribution guidance is given in chapter 10 of Part II.
In chapter 17 of Part II there are specific regulations for
agents, brokers, traders, distributors, repackers, and
relabellers of API’s. In the EU they are complemented with
the GDP Guide for APIs (2015/C 95/01).

Cell Culture/Fermentation and APIs for Use in Clinical Trials

In chapters 18 and 19 of Part II regulations for APIs
manufactured by cell culture/fermentation and APIs for use
in clinical trials are described (cf. annexes 2 and 13).
 Kanton Zürich

Specific to Part II Kantonale Heilmittelkontrolle

Blending of Batches (Intermediates and API’s)

In chapter 8.4 of Part II there are instructions for blending
batches. It describes the cases, in which blending is
possible or not and how it should be performed (validation,
stability, expiry). Blending of OOS batches is not allowed (no
blending into compliance).

Impurity Profiles
An impurity profile should be established (with exceptions)
because impurities are always relevant in API production
and they need to be controlled. Impurity profiles of
manufactured batches should be compared to the profiles in
the regulatory submission or to historical data.
(paragraphs 11.21, 11.22, 12.52).
 Kanton Zürich

Specific to Part II Kantonale Heilmittelkontrolle

Expiry and Retest Dates

Retest or expiry dates should be based on stability
characteristics of APIs. Normally the first three commercial
production batches should be used to confirm the retest or
expiry date (but pilot batches may be possible).
A retest or expiry date should be established if an
intermediate is intended to be transferred outside the
control of the manufacturer’s material management system.
(paragraphs 11.50, 11.53 and chapter 11.6).

If the API or intermediate is repackaged into a different type

of container than used by the API or intermediate
manufacturer, stability studies to justify assigned expiration
or retest dates should be conducted, as described in
paragraph 17.50.
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Specific to Part II Kantonale Heilmittelkontrolle

Recovery of Materials and Solvents

Recovery of reactants, intermediates, or the API is
considered acceptable using approved procedures and if
recovered materials meet their specifications. The use of
recovered materials should be adequately documented
(chapter 14.4).

Processing Aids / Toxic Materials

Processing aids, hazardous, highly toxic raw materials or
other special materials do not need to be tested if the
manufacturer’s certificate shows compliance to established
specifications (identity checks by visual examination of
labels) (paragraph 7.32).
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Specific to Part II Kantonale Heilmittelkontrolle

Glossary Part II
Reprocessing: Introducing an intermediate or API, including one
that does not conform to standards or specifications, back into the
process and repeating a crystallization step or other
appropriate chemical or physical manipulation steps (e.g.,
distillation, filtration, chromatography, milling) that are part of the
established manufacturing process. Continuation of a process
step after an in-process control test has shown that the step is
incomplete is considered to be part of the normal process, and not
reprocessing.

Reworking: Subjecting an intermediate or API that does not

conform to standards or specifications to one or more processing
steps that are different from the established manufacturing
process to obtain acceptable quality intermediate or API (e.g.,
recrystallizing with a different solvent).
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Specific to Part II Kantonale Heilmittelkontrolle

Glossary Part I
Reprocessing: The reworking of all or part of a batch of product
of an unacceptable quality from a defined stage of production, so
that its quality may be rendered acceptable by one or more
additional operations.

Reprocessing and reworking are combined in one definition. The

definition is not as clear as in Part II and in effect reworking is not
defined.
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Specific to Part II Kantonale Heilmittelkontrolle

Reworking and Reprocessing

In chapter 14.2 some specific rules for reprocessing and in
chapter 14.3 for reworking are described. There is a clear
separation between the two approaches and the rules are
clear.

In Part I reprocessing is described in paragraphs 5.66 to

5.70 and 8.28 (recall) (and in annexes A3.44, A14.6.12).
There is no clear separation between reprocessing and
reworking.
Reworking is also not explicitly prohibited (but not
acceptable due to marketing authorizations anyway).
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Conclusion Kantonale Heilmittelkontrolle

 Main sections in Parts I and II of the GMP Guide are

comparable.

 There is still some potential for harmonisation between

the two Parts.

 Amendments to Part II can be introduced via annexes of

the GMP Guide, if required.

 Some topics in Part I and II are specific to finished

products or APIs and are covered in the corresponding
Part of the GMP Guide.
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Current Development Kantonale Heilmittelkontrolle

Upcoming Revisions of the GMP Guide (EU):

Annex 1 (sterile products)

Annex 21 (GMP for importers of medicinal products) new

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Future Kantonale Heilmittelkontrolle

 Parts I, II, III, IV and the annexes are living documents,

new technologies and developments will be introduced if
necessary (c.f. Real Time Release in Annex 17).

 A broader consolidation of the whole GMP guideline

system might be required one day to remove
redundancies and conflicts in the texts.

 A merge of the today separated Parts I and II might be

possible, but seems unlikely because of the framework of
international regulations they are embedded in.

 If international harmonisation is progressing, EU and

PIC/S GMP guidelines might merge with other regulatory
requirements to form a new, truly harmonised international
GMP Guide.
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Kantonale Heilmittelkontrolle

Thank you for your

attention!

?Questions ?
?
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