Good Manufacturing Practices Guidelines for

Active Pharmaceutical Ingredients GUI-0104

Overview
Health Canada has revised GUI-0104 Good Manufacturing Practices Guidelines for Active
Pharmaceutical Ingredients (APIs), replacing the previously effective 2013 edition.

It now better harmonizes with international GMP standards and their latest expectations
(e.g., EDMA, FDA, ICH, PIC/S, WHO, etc.).

Although Health Canada has not added or deleted any official regulations, they have updated
certain rationales and many interpretation sections.

Guidelines re-emphasized that they pertain to both APIs and/or their intermediates starting
from key/advanced stage to final API molecule; prior to sterilization (if applicable).

New API types now in scope are:

• Veterinary APIs (including ones from List A – List of Certain Antimicrobial APIs)
• Plant based APIs (Cannabis)
• APIs derived from blood/plasma raw materials
• APIs undergoing further physical manipulations

The Quality Management System section was rewritten to provide guiding principles for
Quality responsibility including the need for implementation of Quality Risk Management
principles (through application of ICH Q9): it was restructured to further depict responsibilities
of quality and production units.

Who Does This Apply To?

Anyone involved with GMP activities related to API destined for manufacture of human and
veterinary drugs in dosage format of Pharmaceutical or Radiopharmaceutical, including:

• Fabricators
• Importers
• Packagers/Labellers (including re-packagers/re-labellers)
• Distributors
• Wholesalers
• Testers

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Key Points
Scope of GMPs was expanded to include Veterinary APIs, APIs from cannabis and
blood/plasma source, APIs undergoing further physical treatment.

The data governance system is reemphasized (as it applies to the various sections of the
GMP).

Premises

Expanded interpretation section with specifics about premises design and maintenance.

Equipment

Expanded specifics about equipment dedications, cleaning, and records.

Personnel

Added responsibility for senior management to ensure adequate resources (materials, people,
facilities, equipment) are available and monitored to improve effectiveness of API quality
system.

Specific expectations included about responsibilities, qualifications, and education of both

domestic and of foreign site personnel. Persons in charge of quality (except for wholesalers)
and those in charge of manufacturing at a fabricator or packager/labeller must possess
relevant university degrees.

Sanitation

Expanded expectations about development and implementation of risk-based approach for

equipment cleaning program and procedures by incorporating GUI-0028 (Cleaning Validation
Guidelines).

Raw Material Testing

Recommendation to qualify alternate suppliers for critical raw materials with appropriate
regulatory approval where applicable.

Fabricator needs a good understanding and control of impurities within API/Intermediates

(especially of high toxicity nature) with applicable references to:

• ICH Q3A-Impurities in New Drug Substances

• ICH M7-Genotoxic Impurities
• VICH GL10-Impurities in New Veterinary Drug Substances

When certificates are issued by or on behalf of re-packers, re-processors, agents or brokers,

these certificates must also show the name, address, and telephone number of the testing lab
that performed the analysis of the re-issued certificate.

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 Manufacturing Control

Stressed importance that manufacturing records are created, maintained, processed, and
reviewed as per establishment data governance system.

Additional requirement to ensure Product Quality Review includes any “other batches that may
be associated with specific failure or deviation”.

Recall interpretations now additionally refer to the following guidelines:

• GUI-0120
• POL-0016
• GUI-0039
• Drug Shortages in Canada

You must verify the adequacy of recall procedures periodically with a mock recall (if no recalls
have occurred).

Self Inspection – no relevant changes.

Quality Control Department

Health Canada emphasized the functionality and role of the Quality unit and how it must be
independent of manufacturing operations to achieve an objective and accountable process.

Review of electronic records supporting product release must also include review of audit trails
(meta data) to ensure data integrity.

Assessment of product quality of returns should additionally take into consideration its stability
and expiration dating along with expected use.

Laboratory data must include enough detail to allow accurate and complete reporting and
interpretation of all laboratory test data and ensure data integrity.

Section updates include list of minimum requirements of which some were re-iterated from the
previous version. Added expectations include:

• System / procedures to ensure data is reliable, complete, accurate, reviewed, and

assessed
• Data is organized and stored to allow traceability
• Prevent against unauthorized access, data deletion
• Enable change tracking with justifications
• Retain data – original or copy of all formats to allow future reviews / access with
periodic backups
• Implement procedures for operating and maintaining computer systems

Out-of-Trend (OOT) or suspect results should be subjected to similar review as Out-of-

Specification (OOS) results.

OOS and/or OOT results must be investigated in accordance with a defined procedure
including:

• Phase I (internal lab review)

• Phase II (external groups review)
• Phase III (when necessary -hypothesis testing to prove/disprove suspected root cause)

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 • Final result acceptance must take into consideration all valid obtained results.

Packaging Material Testing

If the vendor is certified, you may confirm the identity of packaging material with visual
inspection and review of the certificate of analysis.

Master labels must be kept for comparison with issued labels.

Finished Product Testing

Reference to identification of impurity profile from herbal and animal tissue origin changed to
ICH Q3AR (from ICH-Q6B).

Identity testing is not required for multiple shipments of the same API/API intermediate lot
providing that the primary packaging/labelling and secondary packaging/labelling of the entire
batch has been completely processed as a single batch and not as partial packaging of the
same bulk.

Storage and transportation conditions must still be evaluated for each shipment.

Re-packagers/Re-labellers must:

• Confirm the identity of the API through one of the following methods:

a) Test each lot or batch upon receipt to positively identify the API/API intermediate;
employ a packaging process with adequate controls to prevent mix-up; and provide
assurance that the correct lot of API or API intermediate has been packaged.
Or
b) Test a sample from each packaging lot to positively identify the packaged API or API
intermediate.

• Ensure each lot has an authentic certificate of analysis showing actual numerical
results, reference product specifications, and validated test methods.
• Ensure evidence is available to show that each lot or batch received has been
transported and stored in a way that maintains the quality of the API.

Records

The content has been revised to consider differences in paper-based, electronic, or

photographic media.

Controls must be in place to prevent and detect data integrity issues and to periodically verify
that data integrity measures in place are effective.

Requirement to retrieve offsite records within 48 hours was removed as they now expect that
records can be forwarded more quickly.

Importers do not need to keep raw and packaging material test results on file, but they need to
be made available to Health Canada upon request in timely manner.

Treat cloud computing services as a contracted service with clearly outlined responsibilities in
a contract service agreement.

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 Samples

Added reference to GUI-0014 (Alternate Retention Site).

Stability

Added the following references:

• ICH-Q1A: Stability Testing of New Drug Substances and Products

• ICH-Q1E: Evaluation for Stability Data
• VICH-GL3(R): Stability Testing of New Veterinary Drug Substances and Medicinal
Products
• VICH-GL51: Statistical evaluation of stability data
• ICH Q2 (R1): Validation of Analytical Procedures: Text and Methodology or VICH-GL2
Validation of analytical procedures: Methodology as applicable.

Added the requirement that importer and distributor quality unit has responsibility to maintain
and review stability data.

Definitions
API Active Pharmaceutical Ingredient
The sum total of arrangements to ensure that data, irrespective of the format in
Data
which it is generated, is recorded, processed, retained and used to ensure a
governance
complete, consistent and accurate record throughout the data lifecycle.
Describes the attributes of other data and provides context or meaning. Typically,
Meta Data these describe the structure, data elements, interrelationships, and other
characteristics of data. It also permits data to be attributable to an individual.
OOS Out-of-Specification
OOT Out-of-Trend
Person(s) who direct and control a company or site at the highest levels with the
Senior
authority and responsibility to mobilize resources within the company or site. (ICH
Management
Q10)

What Do I Need To Do?

1) Obtain the GUI-0104 guidance and applicable reference documents and conduct an
audit to assess your compliance.
2) Ensure Senior Management is aware of the increased expectation for their
participation in the pharmaceutical quality system, including periodic management
reviews, awareness of decisions that impact product quality or GMP compliance,
evaluation of quality system effectiveness, and appropriate resourcing.
3) Ensure you formally update your quality system processes and procedures through
change control with these guidance expectations as they apply to your operations
and train your staff.
4) If you have veterinary or plant-based (including cannabis) APIs, apply for or amend
your Drug Establishment Licence.

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RELATED DOCUMENTS

Health Canada Guidance Documents

GUI-0104 - Good Manufacturing Practices Guide for API’s

POL-0016 - Recall Policy for Health Products

GUI-0014 - Guidance Document Alternate Sample Retention Site Guidelines

GUI-0120 - Guide to reporting drug shortages and discontinuations

GUI-0028 - Cleaning Validation Guidelines

GUI-0039 - Drug and Natural Health Products Recall Guide

ICH Guidance Documents

ICH Q9: Quality Risk Management

ICH Q3A (R2): Impurities in New Drug Substances

ICH M7(R1) Genotoxic Impurities

ICH Q1A (R2) Stability Testing of New Drug Substances and Products

ICH Q1E Evaluation of Stability Data

VICH GL2 Validation of Analytical Procedures: Methodology

VICH GL3( R) Stability Testing of New Veterinary Drug Substances and Medicinal Products

VICH GL10 Impurities in New Veterinary Drug Substances

VICH GL51 Quality: Statistical Evaluation of Stability Data

FAQ
1) Will Q&C be updating The Red Book?

Yes! Please contact us for further information and to place pre-orders.

Order your booklet here.

2) Is Health Canada enforcing this guidance now?

This document is now in effect. Health Canada’s expectation is that all parties
involved in API operations toward API sale in Canada comply with this guidance.

3) Has the scope of the GMP guidance changed?

Yes. APIs made from Cannabis and Blood/Plasma (raw material source), APIs for
Veterinary products, and API physical manipulations have been added.

The guidance also emphasizes that API intermediates are also governed by this
guidance.

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 4) How does this guidance apply to Cannabis APIs?

Cannabis cultivation, harvesting, preparation, packaging, storage, disposition, sale,

overall security / control, etc. activities are regulated and enforced by cannabis
regulation SOR/2018-144 which includes a section on Cannabis processing known
as Good Production Practices.

Many international markets are leaning toward application of GMPs in handling and
treatment of cannabis.

5) How does this guidance apply to APIs derived from Blood/Plasma raw material source?

GMPs start to apply from introduction of APIs starting material source into the
process and continue during isolation, purification, physical processing, and
packaging.

6) How does this guidance apply to Veterinary APIs?

The full guidance applies.

7) What APIs are still outside the scope of this guidance?

• Sterile API/Intermediates,
• Drugs in dosage form
• API blends
• Medical gasses
• Biologics
• Bulk intermediates
• Radiopharmaceuticals of biologic origin
• NHPs
• Ectoparasiticides for Vet use
• Raw material not considered yet as API starting material
• APIs for use in clinical trials
• Certain physical processing – as these may be covered in other guidance’s

8) How does this guidance apply to physical manipulations of APIs?

APIs requiring physical manipulation must follow the same GMP requirements

9) What is the connection between Quality Management System and Quality Risk
Management?

The basic concepts of Quality Management, GMPs, and Quality Risk Management
are inter-related and are expected to be cohesively integrated within an
organization’s quality system.

10) How does one apply Risk Based thinking?

Base the evaluation of risk on scientific knowledge and experience and link it to the
protection of the patient. The level of effort, formality and documentation should be
commensurate with the level of risk.

Refer to ICH Q9 for further guidance.

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 11) Have there been any updates related to data integrity expectations?

Yes. This update has formalized the requirements for data accuracy and reliability
throughout the data lifecycle. Data governance with latest expectation on electronic
data control including validation requirements have been clarified.

The approach and level of data governance expected is similar to Finished Products.

This is expected to be an area of continued audit focus.

12) Is it sufficient that I comply to GUI-0104 guidance expectation to be GMP

compliant with respect to APIs?

Ultimately, you are required to meet regulatory compliance expectation of the final
importation country and the regulatory standard that country follows.

By implementing a compliant quality system based on GUI-0104 your organization

will meet Health Canada expectations and will have a high probability of meeting
other country’s regulatory expectations as GUI-0104 has been structured to include
the best current practices with the latest expectations of key regulatory bodies
through incorporation and complementing related guidance’s.

Note – although GUI-0104 outlines current best GMP for APIs, other regulatory
bodies may have additional specific expectations which also must be met.

Order your copy of The Red Book with new

GMPs for APIs today!

Health Canada has revised GUI-0104 Good Manufacturing Practices Guidelines

for Active Pharmaceutical Ingredients (APIs), expanding the scope to include:

• Veterinary APIs (including ones from List A – List of Certain Antimicrobial APIs),
• Plant based APIs (Cannabis),
• APIs derived from blood/plasma raw materials,
• APIs undergoing further physical manipulations.

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