3/31/2022 11:35 CBR RESOLUTION No. 658, OF March 30, 2022 - CBR RESOLUTION No.

658, OF March 30, 2022 - FOB - National Press

FEDERAL OFFICIAL GAZETTE OF BRAZIL

Published: 03/31/2022 | Edition: 62 | Section: 1 | Page: 320

Body: Ministry of Health/National Health Surveillance Agency/Collegiate Board

CBR RESOLUTION No. 658, OF MARCH 30, 2022

Provides for the General Guidelines for Good Manufacturing Practices of Medicines.

The Collegiate Board of Directors of the National Health Surveillance Agency, in the use of the
powers conferred on it by arts. 7, item III, and 15, items III and IV of Law No. 9,782, of January
26, 1999, and considering the provisions of art. 187, item VI and §§ 1 and 3, of the Internal
Regulations, approved by the Resolution of the Collegiate Board of Directors - CBR No. 585, of
December 10, 2021, resolves to adopt the following Resolution of the Collegiate Board of
Directors, as resolved in an Extraordinary Meeting - RExtra No. 6, held on March 30, 2022, and
I, Chief Executive Officer, determine its publication.

CHAPTER I

INITIAL PROVISIONS

Section I

Objective

Art. 1 This Resolution has the objective of adopting the general guidelines of Good
Manufacturing Practices of Medicines of the Pharmaceutical Inspection Cooperation Scheme
(PIC/S), as minimum requirements to be followed in the manufacture of medicines.

Section II

Coverage

Art. 2 This Resolution applies to companies that carry out operations involved in the
manufacture of medicines, including experimental medicines.

Section III

Definitions

Art. 3 For the purposes of this Resolution and the normative instructions linked to it, the
following definitions apply:

I - technical agreement: a document that defines responsibilities, attributions, rights and duties
of/between the contracting party and the contracted party in relation to outsourced activities;

II - corrective action: measures adopted that refer to a reactive containment, to treat and
eliminate the root cause of deviation or non-compliance that has already occurred;
III - preventive action: measures adopted, which refer to the proactive mitigation of risks, to
avoid the occurrence of a deviation or non-compliance, seeking, ultimately, to eliminate its
causes;

IV - anteroom: a closed space with two or more doors, interposed between two or more
rooms, with the purpose of controlling the flow of air between these rooms when they need to
be entered, designed to be used for people, materials or equipment;

V - clean area: an area with defined environmental control of particulate and microbial
contamination, built and used in order to reduce the introduction, generation and retention of
contaminants within the area;

VI - plant master file: a document that describes the activities related to the manufacturer's
good manufacturing practices;

https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-658-de-30-de-marco-de- 1/46
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VII - calibration: a set of operations that establishes, under specified conditions, the
relationship between the values indicated by an instrument or measurement system, or values
represented by a materialized measure, and the corresponding known values of a reference
standard;

VIII - certificate of analysis: a document that provides a summary of the results of tests on
samples of products or materials together with the assessment of their compliance with the
declared specification, which may, alternatively, be based, in whole or in part, on the
evaluation real-time data (summaries and exception reports) of batch-related analytical
process technology, parameters or metrics, as per product marketing/registration
authorization;

IX - contamination: an unwanted introduction of impurities of a chemical or microbiological

nature, or foreign matter, in raw material, intermediate product and/or finished product
during the sampling, weighing, formulation, production, (re)packing, storage steps or
transport;

X - cross-contamination: contamination of a given raw material, intermediate product, bulk

product or finished product by another raw material, intermediate product, bulk product or
finished product during the sampling, weighing, formulation, production steps (re )packaging
and storage;

XI - containment: the action of confining a biological agent or other substance within a space
defined;

XII - in-process control: checks carried out during production to monitor and adjust the
process, environment and equipment to ensure that the product conforms to its specification;

XIII - raw material/input expiration date: a date defined by the manufacturer of such materials,
which establishes the time (based on specific stability studies) during which the materials in
question remain within the established expiration date specifications (characterized as the
shelf life), if stored under defined conditions and after which they should not be used;

XIV - product expiration date: a date established on medication packaging, usually on labels,
until which the product is expected to remain within specifications, provided that it is stored
correctly, established by batch, adding the expiration date to the date manufacturing;

XV - retest date: a date established by the manufacturer of the raw material/input, based on
stability studies, after which the material must be reanalyzed to ensure that it is still suitable
for use, according to tests indicative of stability defined by the manufacturer of the material -
raw/input, maintaining the pre-established storage conditions, and being only applicable when
the expiration date is not established by the raw material/input manufacturer;

XVI - deviation: non-compliance with requirements determined by the Pharmaceutical Quality

Management System or necessary for the maintenance of the quality, safety and effectiveness
of the products;

XVII - return: submission of medicines to the manufacturer, which may or may not have a
quality defect, after being shipped by the manufacturer;

XVIII - packaging: all operations, including filling and labeling, through which the bulk product
must pass to become a finished product;
XIX - specification: a document that describes in detail the requirements to which products or
materials used or obtained during manufacturing must meet, serving as a basis for quality
assessment;

XX - sterility: it is the absence of living organisms, the conditions of sterility tests being
established by the Brazilian Pharmacopoeia or another officially recognized by Anvisa;

XXI - manufacturing: all operations involved in the preparation of a particular drug, including
the acquisition of materials, production, quality control, release, storage, shipment of finished
products and related controls;
XXII - manufacturer: holder of authorization for the manufacture of medicines, in accordance
with the sanitary regulations of the country in which it is located;

XXIII - formulas (manufacturing, processing, packaging) and instructions (testing): documents

that provide details of all raw materials, equipment and computerized systems to be used and
specify all process instructions (packaging, sampling) and testing;

XXIV - process instructions: documents that specify, in detail, even with a simple language,
how to carry out one of the stages of the processes, aiming to facilitate the execution of
routine tasks (from a technical-operational point of view) by operators and analysts , unlike the
procedures, which generally contain more detailed information and guidelines about the
management of the Pharmaceutical Quality System;

XXV - atypical active pharmaceutical ingredient: an excipient, food or cosmetic industry input
used in the pharmaceutical industry as an active pharmaceutical ingredient;

XXVI - Action limit: an established criterion, requiring immediate follow-up and corrective
action if exceeded;

XXVII - Alert threshold: established criteria that give early warning of potential deviation from
normal conditions that are not necessarily grounds for definitive corrective action, but which
require follow-up actions;

XXVIII - Batch: a defined amount of raw material, packaging material or product processed in
one or more processes, whose essential characteristic is homogeneity, and it may be
necessary, to complete certain stages of manufacture, to divide a batch into several sub-
batches, which are then brought together to form a homogeneous final batch, and, in the case
of continuous manufacturing, corresponding to a defined fraction of production, characterized
by the intended homogeneity;

XXIX - packaging material: any material used in the packaging of medicines, excluding any
external packaging used for transport or shipment, being classified as primary or secondary,
according to the degree of contact with the product;

XXX - raw material: any substance used in the production of medicines, excluding packaging
materials;

XXXI - drug: a pharmaceutical product, technically obtained or prepared, with prophylactic,

curative, palliative or diagnostic purposes;

XXXII - non-compliance: non-compliance with a pre-established requirement, which may vary

between external and internal factors, and relate, for example, to procedures, standards,
legislation, facilities, equipment, systems, processes, products, suppliers, materials , services,
method, among others;

XXXIII - Batch number: a distinctive combination of numbers and/or Letters that specifically
identifies a Batch;

XXXIV - sponsor: a person, company, institution or organization responsible for initiating,

managing, controlling or financing a clinical study;

XXXV - procedure: a description of the operations to be carried out, the precautions to be

taken and the measures to be applied, directly or indirectly related to the manufacture of a
drug;
XXXVI - production: all operations involved in the preparation of a drug, from the receipt of
materials, through processing and packaging, to its conclusion as a finished product;

XXXVII - finished product: a product that has gone through all stages of production, including
labeling and final packaging;

XXXVIII - bulk product: any product that has completed all processing stages up to, but not
including, the primary packaging, with sterile products in their primary packaging being
considered bulk products;
XXXIX-intermediate product: a partially processed product that must undergo subsequent
manufacturing steps before becoming a bulk product;

XL - protocol: a document that provides instructions on how to perform and record certain
discrete operations;

XLI - qualification: an action of proving that any facilities, equipment, utilities and systems work
correctly and actually lead to the expected results;

XLII - quarantine: a state of raw materials or packaging material, intermediate products, in bulk
or finished, physically separated, not necessarily in different environments, or by other
effective means, pending a decision on their release or refusal;

XLIII - reanalysis: an analysis performed on raw material/input, previously analyzed and

approved, to confirm the maintenance of the specifications established by the manufacturer,
within the validity period;

XLIV - reconciliation: a comparison, considering the normal variation, between the theoretical
and actual quantity of product or materials produced or used;

XLV - recovery: the introduction of all or part of previous batches of required quality into
another batch at a defined stage of manufacture;

XLVI - record: a document that provides evidence of actions taken to demonstrate compliance
with instructions—for example, activities, events, investigations and, in the case of
manufactured batches, a history of each batch of the product, including its distribution—
including the raw data used to generate other records, being considered as raw data all data
on which quality decisions are based;

XLVII - report: the documentation that records the conduct of exercises, projects and specific
investigations, together with the results, conclusions and recommendations;

XLVIII - reprocessing: the operation of all or part of a batch of product, of unacceptable quality,
from a defined stage of production, so that its quality can be accepted after carrying out one or
more additional operations;

XLIX - Technical Responsible: a professional recognized by the national regulatory authority

who is responsible for ensuring that each batch of finished product has been manufactured,
tested and approved for release in accordance with the laws and regulations in force in the
country;

L - label: printed or lithographed identification, as well as words painted or engraved by fire,

pressure or decal, applied directly on containers, containers, envelopes, envelopes or any
other packaging protector;

LI - simulation of the aseptic process: a method of evaluating an aseptic process through a

microbial growth medium, considering filling of media as synonyms, for example, of fillings of
simulated products, tests of the medium, filling tests, among others;

Lll - Corrective Action and Preventive Action (CAPA) system: a work process, in which several
tools can be used, both for quality management and risk management, which apply to
identification; the evaluation and investigation of past events (deviations, non-conformities,
etc.); the definition of the action plan; the implementation of the actions defined in the action
plan and, finally, the verification of the effectiveness of the actions (corrective and preventive)
implemented, or to stop the root cause of past events (deviations, non-conformities etc.),
avoiding recurrences, or to prevent the occurrence of future events (deviations, non-
conformities, etc.); and referring to a component of the quality system that, conducted
consistently and effectively by the company, has the power to help promote the continuous
improvement of the Pharmaceutical Quality System;

LIII - computerized system: a system that includes data entry, electronic processing and
information output to be used for reports or automatic control;

LIV - Large Volume Parenteral Solution (SPGV): a sterile and pyrogenic solution, intended for
parenteral application in a single dose, whose volume is 100mL or greater, including solutions
for irrigation and solutions for peritoneal dialysis: and
LV - validation: the action of proving, in accordance with the principles of Good Manufacturing
Practices, that any procedure, process, equipment, material, activity or system actually leads
to the expected results.
§ 1 The filling of sterile products referred to in item XVIII of the head of this article is not
considered part of the process of packaging operations, and sterile products are considered
bulk products when in their primary packaging.
§ 2 With regard to item XXVIII of the head of this article, for the control of the finished
product, a batch of medication includes all units of the pharmaceutical form, which are made
from the same initial mass of material and were submitted to a single series of manufacturing
operations or a single sterilization operation or, in the case of a continuous production
process, all units manufactured in a given period of time.
CHAPTER II
PHARMACEUTICAL QUALITY SYSTEM
Section I
Introduction
Art. 4 The holder of a manufacturing authorization must manufacture drugs in a way that
ensures that they correspond to the intended purpose, satisfy the requirements of registration
or authorization for use in a clinical trial, as appropriate, in a way that does not put patients at
risk due to inadequate safety, quality or efficacy.
§ 1 The fulfillment of this quality objective is the responsibility of the company's top
management and requires the participation and commitment of the team at all levels of the
organization, as well as its suppliers and distributors.
§ 2 To achieve this quality objective reliably, there must be a comprehensive and correctly
implemented Pharmaceutical Quality System, incorporating Good Manufacturing Practices and
Quality Risk Management.
§ 3 The Pharmaceutical Quality System must be fully documented and its effectiveness
monitored, through management review, in order to promote continuous quality
improvement.
§ 4 All components of the Pharmaceutical Quality System must have adequate resources and
relevant personnel, in addition to adequate and sufficient facilities and equipment.
Art. 5 Quality Management is a comprehensive concept that covers all issues that determine,
individually or jointly, the quality of a product.
§ 1 Quality Management corresponds to the sum of the arrangements organized with the
objective of guaranteeing that the medicines have the required quality for the intended use.
§ 2 Quality Management incorporates Good Manufacturing Practices.
Art. 6 Good Manufacturing Practices apply to all stages of the product life cycle, from the
manufacture of experimental drugs, technology transfer, commercial manufacturing to the
discontinuation of the product.
Sole paragraph. The Pharmaceutical Quality System can extend to the pharmaceutical
development stage in order to facilitate innovation and continuous improvement, and to
strengthen the link between pharmaceutical development and manufacturing activities.
Art. 7 The size and complexity of the company's activities must be taken into account when
developing a new Pharmaceutical Quality System or modifying an existing one.
§ 1 The system design must incorporate appropriate risk management principles, including the
use of appropriate tools.
§ 2 While some aspects of the system may be corporate-wide and others apply to specific
establishments, the effectiveness of the system is normally demonstrated at the level of the
specific establishment.

Art. 8 A Pharmaceutical Quality System suitable for the manufacture of medicines must ensure
that:

I - the product conception is achieved through the design, planning, implementation,

maintenance and continuous improvement of a system that allows the consistent manufacture
of products with appropriate quality attributes;

II - the knowledge of products and processes is managed at all stages of the life cycle;

III - the drugs are designed and developed in order to take into account the requirements of
Good Manufacturing Practices;

IV - the production and control operations are clearly specified, and the Good Manufacturing
Practices are adopted;

V - managerial responsibilities are clearly specified;

VI - arrangements are made for the manufacture, supply and use of the correct raw materials
and packaging materials, the selection and monitoring of suppliers and verification of the
compliance of each receipt with the approved supplier;

VII - there are processes to ensure the management of outsourced activities;

VIII - a state of control is established and maintained through the development and use of
effective monitoring and control systems for process performance and product quality;

IX - the results of the monitoring of products and processes are taken into account in the
release of the batch, in the investigation of deviations and with the objective of taking
preventive actions to avoid potential deviations that may occur in the future;

X - all necessary controls on intermediate products and any other in-process controls and
validations are carried out;

XI - the continuous improvement is facilitated through the implementation of quality

improvements appropriate to the level of process and product knowledge;

XII - procedures are in place for the prospective assessment of planned changes and their
approval before implementation, taking into account regulatory notifications and approvals,
when necessary;

XIII - after the implementation of any change, an assessment is carried out to confirm that the
quality objectives have been achieved and that there has been no unintended harmful impact
on the quality of the product;

XIV - an appropriate level of root cause analysis is applied during the investigation of
deviations, suspected product defects and other problems;

XV - the drugs are not marketed or distributed before the Person Delegated by the
Pharmaceutical Quality Management System has certified that each batch of the product has
been produced and controlled in accordance with the registration requirements and any other
standards relevant to the production, control and drug release;

XVI - there are mechanisms to ensure that medicines are stored, distributed and subsequently
handled so that quality is maintained throughout their shelf life; and

XVII - there is a self-inspection and/or quality audit process, which regularly assesses the
effectiveness and applicability of the Pharmaceutical Quality System.

§ 1 The appropriate level referred to in item XIV of the head of this article may be determined
by the establishment through the application of the Quality Risk Management principles.
§ 2 With regard to item XIV of the head of this article, in cases where the true root cause(s) of
the problem cannot be determined, the consider identifying the most likely root cause(s) and
addressing them.
§ 3 With regard to item XIV of the head of this article, when human error is suspected or
identified as a cause, this must be justified, taking care to ensure that errors or problems in the
process, procedure or system have not been neglected, if any.
§ 4 With regard to item XIV of the head of this article, appropriate corrective actions and/or
preventive actions (CAPAs) must be identified and implemented in response to investigations,
and the effectiveness of these actions must be monitored and evaluated, in accordance with
the principles of Quality Risk Management.
Art. 9 The top management of the company has the ultimate responsibility for ensuring that an
effective Pharmaceutical Quality System is in place, has adequate resources and that
responsibilities and authorities are defined, communicated and implemented throughout the
organization.
§ 1 The leadership of the top management of the company and its active participation in the
Pharmaceutical Quality System is essential.
§ 2 This leadership must guarantee the support and commitment of the team at all levels of
the organization to the Pharmaceutical Quality System.
Art. 10. There must be a periodic management review, with the involvement of the company's
top management, of the performance of the Pharmaceutical Quality Management System in
order to identify opportunities for continuous improvement of products, processes and the
system itself.
Art. 11. The Pharmaceutical Quality System must be defined and documented.
Sole paragraph. A Quality Manual or equivalent documentation must be in place and must
contain a description of the Pharmaceutical Quality Management System, including
management responsibilities.
Section II
Good Manufacturing Practices of Medicines
Art. 12. Good Manufacturing Practices (GMP) is the part of Quality Management that ensures
that products are consistently produced and controlled, in accordance with quality standards
appropriate for their intended use and required by the health record, authorization for use in
testing clinical or product specifications.
§ 1 The Good Manufacturing Practices concern both the production and the control of
quality.
§ 2 The basic requirements of the GMP are:
I - all manufacturing processes must be clearly defined, systematically reviewed in the light of
experience, and demonstrate that they are capable of producing medicines with the required
quality and in accordance with their specifications;

II - the critical steps of the manufacturing processes, as well as any significant changes, must be
validated;

III - the provision of all necessary resources, including:

a) qualified and adequately trained personnel;

b) adequate facilities and areas;

c) appropriate equipment and services;

d) correct materials, containers and labels;

e) approved procedures and instructions, in accordance with the Pharmaceutical Quality

System; and
f) adequate storage and transport.
IV - instructions and procedures must be written in an instructive manner, in clear and
unambiguous language, specifically applicable to the resources provided;

V - the procedures must be followed correctly and the operators must be trained to do so;

VI - records, which demonstrate that all steps required by the defined procedures and
instructions have been considered and that the quantity and quality of the product are as
expected, must be carried out during manufacture, manually and/or through automatic
recording instruments;

VII - any significant deviations must be fully recorded and investigated in order to determine
the root cause and implement the appropriate corrective and preventive actions;

VIII - manufacturing records, including distribution, which allow tracking of the complete
history of a Batch must be kept in an understandable and accessible manner;

IX - the distribution of products must minimize any risk to their quality and take into account
good distribution practices;

X - a system must be available to collect any batch of product, in marketing or distribution; and

XI - complaints about products must be examined, the causes of quality deviations investigated
and appropriate measures adopted in relation to products with deviation and in relation to the
prevention of recurrence.

Section III

Quality control

Art. 13. Quality Control is the part of GMP relating to the collection of samples, specification
and execution of tests, as well as the organization, documentation and release procedures that
ensure that the relevant and necessary tests are performed, and that materials are not
released for use, or products are not released for commercialization or distribution, until their
quality has been found to be satisfactory.

Art. 14. The basic requirements of Quality Control are:

I - adequate facilities, trained personnel and approved procedures must be available for
sampling and testing of raw materials, packaging materials, intermediate, bulk and finished
products and, where appropriate, for monitoring environmental conditions for GMP purposes;

II - samples of raw materials, packaging materials, intermediate products, bulk products and
finished products must be collected by authorized personnel and through approved methods;

III - the analytical methods must be validated;

IV - records (manual or electronically) must be made, demonstrating that all sampling,

inspection and testing procedures were in fact carried out and that any deviations were duly
recorded and investigated;

V - the finished products must have a qualitative and quantitative composition in accordance
with what is described in the registration or authorization for use in clinical trials; the
components must have the required purity, being in appropriate and properly labeled
containers;
VI - the results of inspection and tests carried out on materials, intermediate, bulk and finished
products must be recorded, demonstrating that they have been formally evaluated in relation
to the specification, which must include the review and evaluation of the relevant production
documentation and an evaluation of the deviations from specified procedures;

VII - no batch of product must be released for marketing or distribution before certification, by
a Person Delegated by the Pharmaceutical Quality Management System, until it complies with
the requirements of the relevant authorizations; and
VIII - sufficient reference samples of raw materials and products must be kept in accordance
with the specific normative instruction to allow future analysis of the product, if necessary.

Section IV

Product quality review

Art. 15. Periodic reviews of the quality of all authorized medicines, including exclusive products
for export, must be carried out with the objective of verifying the consistency of the existing
process, verifying the adequacy of the specifications applied both for raw material and for the
finished product, evidencing any trends and identify improvements in products and processes.

Art. 16. Product quality reviews should normally be conducted and documented annually,
taking into account previous reviews.

Art. 17. The product quality review must include, at least, review:

I - raw materials, including packaging materials used in the product, especially those from new
sources and, in particular, the analysis of the traceability of the supply chain of active
substances;

II - controls in critical processes and product quality control results

finished;

III - of all batches that did not comply with the established specifications and their
investigations;

IV - of all significant deviations or non-conformities, their related investigations and the

effectiveness of the resulting corrective and preventive actions;

V - all changes made to analytical processes or methods;

VI - post-registration alterations submitted, authorized or rejected, including those related to

products registered in other countries (only for export);

VII - the results of the monitoring stability program and any adverse trends;

VIII - of all returns, complaints and withdrawals related to the quality of the product and the
investigations carried out at the time;

IX - the adequacy of any previous corrective actions related to the product process or
equipment;

X - post-approval commitments for new registrations and post-registration changes;

XI - the status of qualification of relevant equipment and utilities, for example, ventilation,
heating and air conditioning (HVAC), water, compressed gas systems, among others; and

XII - of any contractual provisions, defined in Chapter VIII of this Resolution, referring to
outsourced activities, to ensure that they are up to date.

Art. 18. The manufacturer and, eventually, the drug registration holder, must assess the results
of the review and decide whether a corrective and preventive action or any revalidation needs
to be carried out, within the scope of the Pharmaceutical Quality System.
Sole paragraph. There must be management procedures for the permanent review and
management of the actions mentioned in the head of this article, and the effectiveness of
these procedures must be verified during the self-inspection.

Art. 19. Quality reviews can be grouped by product type, when scientifically justified.

Art. 20. If the registration holder is not the drug manufacturer, there must be a technical
agreement implemented between the parties that defines their respective responsibilities in
preparing the product quality review.
Sole paragraph. The Person Delegated by the Pharmaceutical Quality Management System
responsible for the final certification of the batch, together with the registration holder, must
ensure that the quality review is accurate and carried out within the established deadline.

Section V

Quality Risk Management

Art. 21. Quality Risk Management (QRM) is a systematic process of evaluating, controlling,
communicating and reviewing risks to drug quality.

Sole paragraph. Quality Risk Management can be applied proactively and retrospectively.

Art. 22. The Quality Risk Management principles are:

I - the quality risk assessment is based on scientific knowledge, experience with the process
and, ultimately, is linked to patient protection; and

II - the level of effort, formality and documentation of the Quality Risk Management process is
compatible with the level of risk.

CHAPTER III

PERSONAL

Section I

Introduction

Art. 23. There must be enough qualified personnel to correctly perform all activities for which
the manufacturer is responsible.

Art. 24. Individual responsibilities must be clearly defined, understood and recorded by all
involved.

Art. 25. All personnel must be aware of the principles of Good Manufacturing Practice that
affect them and receive initial and ongoing training, including hygiene instructions, relevant to
their needs.

Section II

General provisions

Art. 26. The manufacturer must have an adequate number of personnel with the necessary
qualifications and practical experience.

Art. 27. The company's top management must determine and provide adequate and
appropriate resources (human, financial, material, plant and equipment) to implement and
maintain the Pharmaceutical Quality System and continually improve its effectiveness.

Art. 28. Responsibilities assigned to any individual should not be so extensive as to present any
risk to quality.
Art. 29. The manufacturer must have an organization chart in which the relationships between
the Responsible for Production, Quality Control and, when applicable, the Responsible for
Quality Assurance or Quality Unit, and the position of the Technical Responsible are clearly
presented in the management hierarchy.

Art. 30. Persons who hold positions of responsibility must have their specific functions
recorded in job descriptions and the appropriate authority to carry out their responsibilities.

§ 1 Functions of responsibility may be delegated to designated persons with a satisfactory level

of qualification.

§ 2 There must be no gaps or unjustified overlaps of responsibility with regard to the personnel
involved in the application of Good Manufacturing Practices.
Art. 31. The company's top management has the ultimate responsibility for ensuring that an
effective Pharmaceutical Quality System is in place to achieve quality objectives, and that
roles, responsibilities and authorities are defined, communicated and implemented
throughout the organization.

Art. 32. The company's senior management must establish a quality policy that describes the
company's general definitions and intentions in relation to quality and must also ensure
continuous adequacy and effectiveness of the Pharmaceutical Quality System and compliance
with GMP, through participation in the management review.

Section III

Key personnel

Art. 33. The senior management must designate the Key Management Personnel, including the
Responsible for Production, the Responsible for Quality Control, Person(s) Delegated by the
Pharmaceutical Quality Management System for the release of products.

Sole paragraph. There must be independence between the Responsible for Production and the
Person(s) Delegated by the Pharmaceutical Quality Management System designated for
product releases.

Art. 34. Key positions should normally be filled by full-time staff.

Art. 35. Those responsible for Production and Quality Control must be independent on each
other.

§ 1 In large organizations, it may be necessary to delegate some of the roles of Key Personnel.

§ 2 A person responsible for the Quality Unit or responsible for Quality Assurance may be
appointed, depending on the size and organizational structure of the company.

§ 3° When the separation provided for in § 2 of this article occurs, some of the responsibilities
described in art. 36 of this Resolution are shared with the Responsible for Quality Control and
with the Responsible for Production, and higher management must therefore provide for the
definition of roles, responsibilities and authorities.

Art. 36. The Production Officer has the following responsibilities:

I - ensure that the products are produced and stored in accordance with the appropriate
documentation, in order to obtain the required quality;

II - approve the instructions relating to production operations and ensure their strict
implementation;

III - ensure that production records are evaluated and signed by a person designated;

IV - ensure the qualification and maintenance of its department, facilities and equipment;

V - ensure that the appropriate validations are performed; and

VI - ensure that the initial and continuous training necessary for the personnel of your
department are carried out and adapted according to the needs.

Art. 37. The Quality Control Officer generally has the following responsibilities:
I - approve or reject, as it deems appropriate, raw materials, packaging materials,
intermediate, bulk and finished products;

II - ensure that all necessary tests are carried out and the associated records are evaluated;

III - approve specifications, sampling instructions, analysis methods and other Quality Control
procedures;

IV - approve and monitor any contracted analysis;

V - assure the qualification and maintenance of its department, facilities and equipment;

VI - ensure that the appropriate validations are carried out; and

VII - ensure that the initial and continuous training of the personnel of your department are
carried out and adapted, according to the needs.

Art. 38. Those in charge of Production, Quality Control and, when relevant, the Responsible for
Quality Assurance or Responsible for the Quality Unit, generally have some shared
responsibilities, or exercised jointly, related to quality, including the conception, the effective
implementation , monitoring and maintenance of the Pharmaceutical Quality System.

Sole paragraph. The responsibilities mentioned in the head of this article may include:

I - the authorization of written procedures and other documents, including amendments;

II - monitoring and control of manufacturing environments;

III - the hygiene of the facilities;

IV - process validation;

V - training;

VI - approval and monitoring of material suppliers;

VII - the approval and monitoring of contracted manufacturers and providers of other
outsourced services related to GMP;

VIII - the establishment and monitoring of storage conditions for materials and products;

IX - the retention of records;

X - monitoring compliance with GMP requirements;

XI - inspection, investigation and sampling, with the aim of monitoring the factors that may
affect the quality of the product;

XII - participation in management reviews of process performance, product quality and the
Pharmaceutical Quality System in search of continuous improvement; and

XIII - ensure that there is a process of communication and temporal and effective scheduling so
that quality problems are dealt with at the appropriate levels of management.

Section IV

Training

Art. 39. The manufacturer must provide training for all personnel whose duties are carried out
in the areas of production and storage or control laboratories (including technical,
maintenance and cleaning personnel) and for other persons whose activities may affect the
quality of the product.
Art. 40. In addition to basic training in the theory and practice of the Pharmaceutical Quality
System and GMP, newly hired personnel must receive training appropriate to the tasks
assigned to them.

Art. 41. Ongoing training should be provided, and its practical effectiveness should be
periodically evaluated.

Art. 42. Training programs must be available, approved by the Production Officer or the Quality
Control Officer, as appropriate.

Art. 43. Training records must be maintained.

Art. 44. Personnel working in areas with risk of microbiological contamination of products, for
example in clean areas, or personnel working in areas with risk of operator and cross-product
contamination, such as areas where highly active, toxic materials , infectious or sensitizing
agents are handled, must receive specific training.
Art. 45. Visitors or untrained personnel should preferably not be led by the production and
quality control areas.

Sole paragraph. If it is unavoidable, they should be carefully supervised and given information
in advance, especially about personal hygiene and necessary protective clothing.

Art. 46. The Pharmaceutical Quality System and all measures capable of improving its
understanding and implementation should be widely discussed during training sessions.

Section V

Personal hygiene and health

Art. 47. Detailed hygiene programs must be established and adapted to the various needs of
the factory.

Art. 48. Hygiene programs should include procedures relating to health, hygiene practices and
attire.

Sole paragraph. These procedures must be understood and strictly followed by all persons
whose duties imply their presence in the production and control areas.

Art. 49. Management should promote hygiene programs which should be widely discussed
during training sessions.

Art. 50. All personnel must undergo a medical examination at the time of employment.

Art. 51. After the first medical examination, further examinations must be carried out when
necessary to ensure work and personal health.

Art. 52. It is the responsibility of the manufacturer to provide written instructions to ensure
that the health conditions of its employees that may impact the quality of the products are
immediately informed.

Art. 53. Measures must be taken to ensure that no person affected by an infectious disease or
who has open lesions on the exposed surface of the body is involved in the manufacture of
medicines.

Art. 54. Every person entering manufacturing areas must wear protective clothing appropriate
to the operations to be performed.

Art. 55. Eating, drinking, chewing, smoking, or storing food, beverages, tobacco-derived
materials or medicines for personal use in production and storage areas is prohibited.

Art. 56. Any practice that is not hygienic within manufacturing areas or any other area where
the product could be adversely affected must be prohibited.

Art. 57. Direct contact between the operator's hands and the exposed product, as well as any
part of the equipment that comes into contact with the products, must be avoided.

Art. 58. Staff should be instructed in the use of hand washing facilities.

Art. 59. Any specific requirements for the manufacture of special groups of products, for
example sterile preparations, are set out in the specific normative instructions.
Section VI

Consultants

Art. 60. Consultants must have adequate education, training and experience so that they are
able to advise on the subject for which they have been selected.

Art. 61. Records must be maintained with information on the name, address, qualifications and
type of service provided by consultants.

CHAPTER IV

FACILITIES AND EQUIPMENT

Section I

Introduction
Art. 62. Facilities and equipment must be located, designed, built, adapted and maintained in
accordance with the operations to be performed.

Art. 63. The design and the project must minimize the risk of errors and allow for effective
cleaning and maintenance, so as to avoid cross-contamination, accumulation of dust or dirt or
any damage to the quality of the products.

Section II

Facilities

Subsection I

General provisions

Art. 64. Facilities should be situated in a location that, when considered in conjunction with
measures to protect the manufacturing process, presents a minimal risk of causing any
contamination of materials or products.

Art. 65. Facilities must be carefully maintained, ensuring that repair and maintenance
operations do not present any risk to the quality of the products.

Art. 66. Facilities should be cleaned and, where appropriate, disinfected in accordance with
detailed written procedures.

Art. 67. Lighting, temperature, humidity and ventilation must be adequate, and must not
harm, directly or indirectly, the medicines during their manufacture and storage, or the precise
functioning of the equipment.

Art. 68. Facilities must be designed and equipped to ensure maximum protection against the
entry of insects or other animals.

Art. 69. Measures must be taken to prevent unauthorized persons from entering the premises
in general.

Art. 70. Production, storage and quality control areas must not be used as a passageway by
personnel who do not work in these areas.

Subsection II

Production areas

Art. 71. Cross-contamination must be prevented for all products through proper design and
proper operation of manufacturing facilities.

§ 1 Measures to prevent cross-contamination must be proportionate to the risks.

§ 2 The principles of Quality Risk Management must be used to assess and control risks.

§ 3 Depending on the level of risk, it may be necessary to dedicate facilities and equipment to
manufacturing and/or packaging operations in order to control the risk presented by some
drugs.

§ 4 Dedicated facilities are required for manufacturing when:

I - the risk cannot be adequately controlled by operational and/or technical measures;

II - the scientific data from the toxicological assessment do not support a controllable risk, such
as the allergenic potential of highly sensitizing materials, including beta-lactams; and

III - the relevant residue limits, derived from the toxicological assessment, cannot be
satisfactorily determined by a validated analytical method.

Art. 72. Facilities should preferably be planned in a way that allows production to be
conducted in interconnected areas in a logical order that corresponds to the sequence of
operations and required levels of cleanliness.

Art. 73. The work and storage space during processing must allow for the orderly and logical
arrangement of equipment and materials, in order to minimize the risk of mixing between the
different pharmaceutical products, or their components, avoid cross-contamination and
minimize the risk of omission or incorrect application of any of the manufacturing or control
steps.

Art. 74. In areas where raw materials, primary packaging materials, intermediate or bulk
products are exposed to the environment, internal surfaces (walls, floors and ceilings) must be
smooth, free of cracks and open joints, and must not release material particulate matter,
allowing easy and effective cleaning and, if necessary, disinfection.

Art. 75. Piping, lighting, ventilation points and other facilities must be designed and installed in
such a way as to avoid the creation of recesses and facilitate cleaning.

Art. 76. Whenever possible, access for maintenance should be located outside the
manufacturing areas.

Art. 77. Drains must be siphoned and of adequate dimensions.

Art. 78. Open channels should be avoided, however, if necessary, these should be shallow to
facilitate cleaning and disinfection.

Art. 79. Production areas must be effectively ventilated, with appropriate air treatment
facilities, including temperature and, where necessary, humidity and filtration, for the products
handled, the operations carried out and the external environment.

Art. 80. The weighing of raw materials should usually be carried out in a separate room
designed for such use.

Art. 81. In cases where dust is generated, such as during sampling, weighing, mixing and
processing operations, or in the packaging of solid products, specific measures must be taken
to avoid cross-contamination and facilitate cleaning.

Art. 82. Medication packaging facilities must be specifically designed and constructed so that
mixing or cross-contamination is avoided.

Art. 83. Production areas should be well lit, particularly where in-line visual controls are carried
out.

Art. 84. In-process controls can be performed in the production area, provided they do not
pose any risk to this activity.
Subsection III

Storage areas

Art. 85. Storage areas must have sufficient capacity to allow for the orderly stock of the various
categories of materials and products, such as raw materials, packaging materials, intermediate,
bulk and finished products, in their quarantine condition, released, rejected , returned or
collected.

Art. 86. Storage areas must be designed or adapted to ensure optimal storage conditions, and
must be clean, dry and kept within acceptable temperature limits.

Sole paragraph. In cases where special storage conditions are required, such as temperature
and humidity, these must be provided, verified and monitored.

Art. 87. Receiving and shipping areas must protect materials and products from climatic
variations.

Art. 88. Receiving areas should be designed and equipped to allow containers to be cleaned, if
necessary, prior to storage.

Art. 89. If quarantine is to be ensured through storage in separate areas, these areas must be
clearly identified and their access restricted to authorized personnel.

Sole paragraph. Any system that replaces physical quarantine must provide an equivalent
degree of security.

Art. 90. Preferably, there should be a separate area for sampling raw materials.
Sole paragraph. If the sampling is carried out in the storage area, it must be conducted in a
way that avoids contamination or cross-contamination.

Art. 91. There must be segregated locations for the storage of materials or products that are
rejected, collected or returned.

Art. 92. Highly active materials or products must be stored in safe and secure areas.

Art. 93. The safe storage of printed packaging materials, as well as other materials considered
critical for drug compliance, must be guaranteed.

Subsection IV

Quality control areas

Art. 94. Quality Control laboratories should preferably be separated from production areas.

Sole paragraph. The biological, microbiological and radioisotope control laboratories must also
be separated not only from each other, but also from the production areas.

Art. 95. Control laboratories must be designed for the operations performed.

Sole paragraph. Sufficient space must be provided to avoid mixing and cross-contamination
and for proper storage of samples and records.

Art. 96. Separate rooms may be necessary to protect sensitive instruments from vibration,
electrical interference, moisture, etc.

Art. 97. Special requirements are necessary in laboratories that handle particular substances,
such as biological or radioactive samples.

Subsection V

Auxiliary areas

Art. 98. Rest rooms and dining areas must be separated from other areas.

Art. 99. Changing rooms and toilets must be easily accessible and appropriate for the number
of users.

Art. 100. Restrooms must not communicate directly with the production or storage areas.

Art. 101. Maintenance areas must be located in separate locations from the maintenance
areas.
production.

Sole paragraph. If it is necessary to store parts and tools in the production area, they must be
kept in rooms or cabinets reserved for this purpose.

Art. 102. Animal facilities must be isolated from other areas, have a separate entrance for
animals and an exclusive ventilation system.

Section III
Equipment

Art. 103. The equipment used in manufacturing must be designed, located and maintained in
accordance with the intended purpose.

Art. 104. Repair and maintenance operations must not present any danger to the quality of the
products.

Art. 105. Manufacturing equipment must be designed to allow easy and thorough cleaning.

Sole paragraph. They must be cleaned in accordance with detailed written procedures and only
stored if they are clean and dry.

Art. 106. Washing and cleaning of equipment must be selected and carried out in such a way
that they do not constitute a source of contamination.
Art. 107. The equipment must be installed in such a way as to avoid any risk of error or
contamination.

Art. 108. Production equipment must not present any danger to products.

Sole paragraph. The parts of this equipment that come into contact with the products must
not be reactive, additive or absorbent to such an extent that they affect the quality of the
product and, therefore, pose a hazard.

Art. 109. Scales and measuring equipment, with appropriate accuracy and scale, must be
available for production and control operations.

Art. 110. Measuring, weighing, recording and control equipment must be calibrated and
verified at defined intervals and by appropriate methods.

Sole paragraph. Adequate records of the calibration referred to in the head of this article must
be kept.

Art. 111. Fixed piping must be clearly identified to indicate its content and, where applicable,
the direction of flow.

Art. 112. Purified water and water for injection piping and, if applicable, any other type of
water, must be sanitized according to written procedures that contain details on the limits of
microbiological contamination, as well as the measures to be adopted .

Art. 113. Defective equipment should, if possible, be removed from production and quality
control areas, or, when removal is not possible, should, at a minimum, be clearly identified as
such.

CHAPTER V

DOCUMENTATION

Section I

Introduction

Art. 114. Documentation is an essential part of the Pharmaceutical Quality Management

System, being essential to operate in accordance with the requirements of Good
Manufacturing Practices.

§ 1 The various types of documents and media used must be fully defined in the
manufacturer's Pharmaceutical Quality Management System.

§ 2 Documentation may exist in a variety of forms, including print, electronic or photographic

media.

§ 3 The main objective of the documentation system used must be to establish, control,
monitor and record all activities that, directly or indirectly, affect all aspects of drug quality.

§ 4 The documentation that constitutes the Pharmaceutical Quality Management System must
include sufficient instructive details to facilitate the common understanding of the
requirements, in addition to allowing the satisfactory recording of the various processes and
the evaluation of any observations, so that the continuous application of the requirements can
be demonstrated.

Art. 115. There are two main types of documentation used to manage and record compliance
with Good Manufacturing Practices, instructions (guidelines and requirements) and records
and/or reports.

Sole paragraph. Good Documentation Practices should be applied according to the type of
document.

Art. 116. Adequate controls must be implemented to ensure the accuracy, integrity, availability
and readability of documents.

§ 1 Instruction documents must be error-free and available in writing.

§ 2 The term "written" means recorded or documented on media from which data can be
processed in a Readable format.

Section II

Documentation generation and control

Art. 117. All types of documents must be defined and complied with.

§ 1 The requirements shall apply equally to all types of document media.

§ 2 Complex systems must be understood, well documented, validated and adequate controls
must be in place.

§ 3 The documents (instructions and records) can exist in a hybrid form, having electronic and
paper elements.

§ 4 Control and relationship measures for master documents, official copies, data handling and
records need to be defined for hybrid and homogeneous systems.

§ 5 Appropriate controls must be implemented for electronic documents, such as templates,

forms and master documents.

§ 6 During the entire retention period, appropriate controls must exist to ensure the integrity
of the record.

Art. 118. Documents must be carefully designed, prepared, reviewed and distributed.

§ 1 Documents must conform to relevant parts of product specification files, manufacturing

files and registration dossiers, as appropriate.

§ 2 The reproduction of working documents from master documents must not allow errors to
occur.

Art. 119. Documents containing instructions must be approved, signed and dated by
appropriate and authorized persons.

§ 1 The documents must have unambiguous content and a unique identification.

§ 2 The effective date of the documents must be defined.

Art. 120. Documents containing instructions must be arranged in an orderly manner and easily
verified.

§ 1 The style and language of the documents must suit the intended use.
§ 2 The Standard Operating Procedures, Work Instructions and Methods must be written
preferably in the imperative mode.

Art. 121. Documents related to the Pharmaceutical Quality Management System must be
regularly reviewed and kept up-to-date.

Sole paragraph. When a document is revised, systems must operate in a way that prevents the
inadvertent use of obsolete documents.

Art. 122. Documents must not be handwritten.

Sole paragraph. In cases where there is a need for data entry, there must be enough space for
such entries.

Section III

Good Documentation Practices

Art. 123. Handwritten entries must be made in a clear, legible and indelible manner.

Art. 124. Records must be carried out or completed whenever an action is taken and in such a
way as to allow all significant activities relating to the manufacture of medicines to be
traceable.
Art. 125. Any alteration made to the record of a document must be signed and dated, and
must allow the original information to be read.
Sole paragraph. Where appropriate, the reason for the change should be recorded.
Section IV
Document retention
Art. 126. It must be clearly defined which record each manufacturing activity is related to and
where this record is located.
Sole paragraph. There must be secure and, if necessary, validated controls in place to ensure
the integrity of the record throughout the retention period.
Art. 127. Batch documentation must be kept for one year after the expiration of the batch to
which it refers or for at least five years after batch certification by a Person Delegated by the
Pharmaceutical Quality Management System, whichever is longer .
§ 1 In the case of experimental drugs, batch documentation must be kept for at least five years
after the conclusion or formal discontinuation of the last clinical study in which the batch was
used.
§ 2 Other requirements for the retention of documentation may be described in the legislation
in relation to specific types of product (e.g. Advanced Therapy Medicines) and may specify the
need for longer retention periods for certain documents.
Art. 128. The retention period for other types of documents should be defined according to
their supporting purpose.
§ 1 Critical documentation, including raw data (e.g. related to validation or stability), which
supports registration information, must be maintained as long as the authorization remains in
effect.
§ 2 The obsolescence and subsequent non-retention of data, such as validation and stability
studies, which have been replaced by a complete set of new data is acceptable as long as the
documentation does not have a retention time determination in force due to being related to
a commercial batch.
Section V
Specifications
Art. 129. There must be duly authorized and dated specifications for raw materials, packaging
material and finished products.
Subsection I
Specifications for raw materials and packaging materials
Art. 130. Specifications for raw materials and primary or printed packaging materials must
include or reference the items below, if applicable:
I - description of materials, including:

a) the name and reference of the internal code;

b) the reference, if any, to a pharmacopoeial monograph;

c) the approved suppliers and, where relevant, the original manufacturer of the material; and

d) a model or artwork of the printed materials.

II - instructions for sampling and analysis;

III - qualitative and quantitative requirements with acceptance limits;

IV - storage conditions and precautions; and

V - the maximum storage period before a reanalysis.

Subsection II
Specifications for intermediate and bulk products

Art. 131. Specifications for intermediate and bulk products must be available for critical steps
or if these products are purchased or shipped.

Sole paragraph. The specifications must be similar to the specifications for raw materials or for
finished products, as appropriate.

Subsection III

Specifications for finished products

Art. 132. Specifications for finished products must include or make reference to:

I - product name and reference code, when applicable;

II - formula;

III - description of the pharmaceutical form and packaging details;

IV - instructions for sampling and analysis;

V - qualitative and quantitative requirements, with acceptance limits;

VI - storage conditions and any special handling precautions, when applicable; and

VII - validity period.

Section VI

Manufacturing formula and process instructions

Art. 133. There must be approved, written manufacturing formulas and process instructions
for each product and batch size to be manufactured.

Art. 134. The manufacturing formula must include:

I - name and reference code of the product related to its specification;

II - description of the pharmaceutical form, product concentration and batch size;

III - list of all raw materials to be used, with the described quantity of each one, mentioning
any substance that may disappear during the process; and

IV - declaration of the expected final income with acceptable limits and relevant intermediate
income, when applicable.

Art. 135. Process instructions must include:

I - declaration of the process location and the main equipment to be used;

II - the methods, or reference to the methods, to be used to prepare critical equipment (e.g.
cleaning, assembly, calibration, sterilization);
III - checks to confirm that the equipment and workstation are free of previous products,
documents or materials not necessary for the planned process, and that the equipment is
clean and suitable for use;

IV - detailed process instructions per step (e.g. material checks, pre-treatments, sequence of
material addition and critical process parameters (time, temperature, etc.);

V - the instructions for any control in process and its limits;

VI - when necessary, the requirements for the storage of bulk products; including container,
labeling and special storage conditions, where applicable; and

VII - any special precautions to be observed.

Subsection I

Packing instructions
Art. 136. There must be approved instructions for the packaging operation of each product,
size and type of packaging.

Sole paragraph. The instructions mentioned in the head of this article must include, or make
reference to:

I - name of the product, including the batch number of the bulk and finished product;

II - description of its pharmaceutical form and concentration, when applicable;

III - package size expressed in number, weight or volume of the product in the final container;

IV - a complete list of all necessary packaging materials, including quantities, sizes and types,
with the code or reference number related to the specifications of each packaging material;

V - where appropriate, an example or reproduction of the relevant printed packaging materials

and instructions indicating where to apply references to the batch numbers and expiration
date of the product;

VI - checks to confirm that the equipment and workstation are free of previous products,
documents or materials not necessary for the planned packaging operations (line release), and
that the equipment is clean and suitable for use;

VII - special precautions to be observed, including a careful examination of the area and the
equipment, in order to ensure the release of the line before the start of operations;

VIII - a description of the packaging operation, including any significant subsidiary operations,
and of the equipment to be used; and

IX - details of the controls in process with instructions for sampling and acceptance limits.

Subsection II

Batch processing record

Art. 137. A batch processing record must be kept for each batch processed.

§ 1 This record must be based on the relevant parts of the Manufacturing Formula and the
Process Instructions currently approved, and must contain the following information:

I - name and batch number of the product;

II - dates and times for the start of significant intermediate phases and for the conclusion of
production;

III - identification (initials or initials) of the operator(s) who performed each significant step of
the process and, when appropriate, the name of any person who verified these operations;

IV - batch number and/or analytical control number, as well as the quantities of each raw
material actually weighed, including the batch number and the quantity of any recovered or
reprocessed material added;

V - any relevant manufacturing operation or event and used main equipment;

VI - record of the controls in process and the initials of the person(s) who performed them and
the results obtained;

VII - yield obtained from the product in different and relevant manufacturing stages;

VIII - observations on any problems including the details, with signed authorization for any
deviation from the Manufacturing Formula and Process Instructions; and

IX - approval of manufacturing operations by the responsible person.

§ 2 In the case of validated, continuously controlled and monitored processes, the

automatically generated reports may be limited to compliance summaries and out-of-
specification exception/result data reports.

Subsection III
Batch packing record

Art. 138. Batch packaging records must be kept for each batch or part of a batch processed.

Sole paragraph. This record must be based on the relevant parts of the Packing Instructions.

Art. 139. The batch packaging record must contain the following information:

I - name and batch number of the product;

II - date(s) and times of packaging operations;

III - identification (initials or initials) of the operator(s) who performed each significant step of
the process and, when appropriate, the name of the person who verified these operations;

IV - records for identity checks and compliance with the Packaging Instructions, including the
results of in-process controls;

V - details of the packaging operations carried out, including references to equipment and
packaging lines used;

VI - whenever possible, samples of printed packaging materials used, including examples of

batch coding, expiration date and any additional overprinting;

VII - remarks on any problems or unusual events, including details, with signed authorization
for any deviation from the Packing Instructions;

VIII - quantities and reference or identification number of all printed packaging materials and
bulk product issued, used, destroyed or returned to stock and the quantities of product
obtained, in order to provide an adequate reconciliation, with the possibility of justification for
not include this information if there are robust electronic controls in place during packaging;
and

IX - approval by the person responsible for the packaging operations.

Section VII

Procedures and records

Subsection I

Receipt

Art. 140. Written procedures and records must exist for the receipt of each delivery of raw
materials (including bulk, intermediate or finished products), primary, secondary and printed
packaging materials.

Art. 141. Receipt records must include:

I - the name of the material and the number of recipients on the delivery note;

II - the name and/or internal code of the material, if different from the corresponding
mentioned in item I of this article;
III - the date of receipt;

IV - the name of the supplier and the name of the manufacturer;

V - the manufacturer's batch number or reference number;

VI - the total quantity and number of recipients received;

VII - the batch number assigned after receipt; and

VIII - any relevant comment.

Art. 142. There should be written procedures regarding internal labelling, quarantine and
storage of raw materials, packaging materials and other materials, as appropriate.

Subsection II

Sampling
Art. 143. There should be written procedures for sampling, which include the methods and
equipment to be used, the quantities to be sampled, and any precautions to be observed to
avoid contamination of the material or any deterioration in its quality.

Subsection III

Analyzes

Art. 144. There should be written procedures for analyzing materials and products at different
stages of manufacture, describing the methods and equipment to be used.

Art. 145. Tests performed must be recorded.

Subsection IV

Other

Art. 146. Written clearance and rejection procedures must be available for materials and
products and, in particular, for the certification of the finished product for sale by a Person
Delegated by the Pharmaceutical Quality Management System.

§ 1 All records must be available to the Person Delegated by the Pharmaceutical Quality
Management System.

§ 2 A system must be in place to indicate special observations and any changes to critical data.

Art. 147. Records must be kept for the distribution of each batch of a product to facilitate
recall, if necessary.

Art. 148. There should be policies, procedures, protocols, reports and records of actions taken
or conclusions reached, where appropriate, for the following examples:

I - validation and qualification of processes, equipment and systems;

II - assembly and calibration of equipment;
III - technology transfer;
IV - maintenance, cleaning and sanitization;
V - personnel issues, including signature lists, training in Good Manufacturing Practices and
technical topics, clothing and hygiene and verification of the effectiveness of the training;

VI - environmental monitoring;
VII - pest control;
VIII - complaints;
IX - collection;
X - returns;
XI - change control;
XII - investigations into deviations and non-conformities;
XIII - internal audits of quality and Good Manufacturing Practices;
XIV - record summaries, when appropriate (e.g.: product quality review);
and
XV - supplier audits.

Art. 149. Clear operating procedures must be available for key manufacturing and testing
equipment.
Art. 150. Log books must be maintained for important or critical analytical tests, production
equipment, and areas where the product was processed.

Sole paragraph. Log books should be used to record in chronological order, as appropriate, any
use of the area, equipment/method, calibrations, maintenance, cleaning or repair operations,
including the dates and identification of persons who performed these operations.
Art. 151. An inventory of documents must be maintained within the Pharmaceutical Quality
Management System.
CHAPTER VI
PRODUCTION
Section I
Introduction
Art. 152. Production operations must respect clearly defined procedures and must meet the
principles of Good Manufacturing Practices in order to obtain products with the required
quality and in compliance with the respective manufacturing authorizations and registration.
Section II
General provisions
Art. 153. Production must be carried out and supervised by competent persons.
Art. 154. All material and product handling, such as receiving and quarantining, sampling,
storage, labeling, dispensing, processing, packaging and distribution must be done in
accordance with written procedures or instructions and, if necessary, be recorded.
Art. 155. All materials received must be verified to ensure that the shipment matches the
order.
Single paragraph. Containers must be cleaned whenever necessary and labeled so that they
include the data required by the receiving company's quality system.
Art. 156. Damage to containers and any other problem that could adversely affect the quality
of the material must be investigated, recorded and reported to the Quality Unit.
Art. 157. Incoming materials and finished products must be physically or administratively
quarantined immediately after receipt or processing, until they are released for use or
distribution.
Art. 158. Intermediate and bulk products, purchased as such, must be handled on receipt as if
they were raw materials.
Art. 159. All materials and products must be stored under appropriate conditions, defined by
the manufacturer in order to make it possible to segregate batches and rotate stock.
Art. 160. Yield checks and reconciliation of quantities should be performed whenever
necessary to ensure that there are no discrepancies outside acceptable limits.
Art. 161. Operations involving different products should not be carried out simultaneously or
consecutively in the same room, unless there is no risk of mixing or cross-contamination.
Art. 162. At all stages of the process, materials and products must be protected from microbial
and other contamination.
Art. 163. Special precautions must be taken when working with dry materials or products to
avoid the generation and spread of dust.
Sole paragraph. The provision addressed in the head of this article applies particularly to the
handling of highly hazardous materials, including highly sensitizing materials.
Art. 164. At all times during the process, all materials, bulk containers, major items of
equipment and, where necessary, the rooms used must be labeled and identified with an
indication of the product or material being processed, its concentration, where applicable, and
batch number.
Sole paragraph. When applicable, the indication referred to in the head of this article must also
mention the stage of production.
Art. 165. Labels applied to containers, equipment or facilities must be clear, unambiguous and
in the format agreed by the company.
Sole paragraph. It is recommended and useful that, in addition to the text on the labels, colors
are used to indicate the status (e.g.: quarantined, approved, disapproved, cleared).

Art. 166. Checks should be carried out to ensure that pipelines and other pieces of equipment
used to transport materials and products from one area to another are properly connected.

Art. 167. Any deviation from instructions or procedures must be avoided.

Sole paragraph. If a deviation occurs, it must be formally approved by a competent person,

with the involvement of the Quality Unit, where appropriate.

Art. 168. Access to production facilities must be restricted to authorized personnel.

Section III

Prevention of cross contamination in production

Art. 169. The manufacture of non-medicinal products should be avoided in areas and
equipment intended for the production of medicines, however, as long as it is justified, it can
be authorized provided that the measures to prevent cross-contamination described in this
Section and in Chapter IV of this Resolution are applied.

Sole paragraph. The production and/or storage of pesticides, such as pesticides (except when
used for the manufacture of medicines) and herbicides, cannot be authorized in areas used for
the manufacture and/or storage of medicines.

Art. 170. Contamination of a raw material or a product by another raw material or product
must be avoided.

§ 1 The risk of accidental cross-contamination resulting from the uncontrolled release of dust,
gases, vapors, aerosols, genetic material or organisms of active substances, other materials
(starting or in process) and products in process, of residues in equipment and clothes of
operators must be evaluated.

§ 2 The significance of this risk varies with the nature of the contaminant and that of the
product being contaminated.

§ 3 Cross-contamination is probably the most significant in products administered by injection

or over a long period of time.

§ 4 The contamination of all products represents a risk to patient safety, depending on the
nature and extent of the contamination.

Art. 171. Cross-contamination must be avoided by paying attention to the design of facilities
and equipment, as described in Chapter IV of this Resolution.

Sole paragraph. Prevention of cross-contamination should include attention to process design

and implementation of any relevant technical or organizational measures, including effective
and reproducible cleaning processes, with a view to controlling the risk of cross-
contamination.

Art. 172. A Quality Risk Management process, which includes toxicological and potency
assessment, shall be used to assess and control the risks of cross-contamination posed by
manufactured products.

§ 1 Factors including the design and use of the facility/equipment, personnel and material
flow, microbiological controls, physicochemical characteristics of the active substance, process
characteristics, cleaning processes and analytical capabilities referring to the relative limits
established from the evaluation of the products must also be considered.
§ 2 The result of the Quality Risk Management process must be the basis for determining the
need and extent of which facilities and equipment must be dedicated to a particular product or
family of products.

§ 3 The result may include the dedication of specific parts in contact with the product or the
dedication of the entire manufacturing facility.
§ 4 It may be acceptable to restrict manufacturing activities to a segregated, self-contained
production area within a multi-product facility, when the need arises.

Art. 173. The outcome of the Quality Risk Management process should be the basis for
determining the extent of technical and organizational measures necessary to control the risks
of cross-contamination.

Sole paragraph. The technical and organizational measures mentioned in the head of this
article may include, but are not limited to, the following:

I - technical measures:

a) dedicated manufacturing facility (facilities and equipment);

b) self-contained production areas with production equipment and separate heating,

ventilation and air conditioning systems, it being desirable to isolate certain utilities from
others used in other areas;

c) design of the manufacturing process, facilities and equipment to minimize the risk of cross-
contamination during the process, maintenance and cleaning;

d) use of "closed systems" for production and material/product transfer between equipment;

e) use of physical barrier systems, including isolators, as containment measures;

f) controlled dust removal close to the source of the contaminant, for example by means of
localized exhaust;

g) dedication of equipment, parts that come into contact with the product or selected parts
that are more difficult to clean (e.g. filters), and dedication of maintenance tools;

h) use of single-use disposable technology;

i) use of equipment designed to facilitate cleaning;

j) appropriate use of antechambers and pressure cascades to confine a potential airborne

contaminant to a specific area;

k) minimization of the risk of contamination caused by the recirculation or re-entry of

untreated or insufficiently treated air;

l) use of local automatic cleaning systems (Clean in place) of validated effectiveness; and

m) for common washing areas, separation of washing, drying and equipment storage areas.

II - organizational measures:

a) dedication of the entire production facility or the use of a self-contained production area in
a campaign organized by time, followed by a cleaning process of validated effectiveness;

b) maintenance of specific protective clothing within areas where products with a high risk of
cross-contamination are processed;
c) cleaning verification after each product campaign should be considered as a detection tool
to support the effectiveness of the Quality Risk Management approach for products
considered to be at higher risk;

d) checking the cleanliness of surfaces that have not been in contact with the product and
monitoring the air within the manufacturing area and/or adjacent areas, depending on the risk
of contamination, in order to demonstrate the effectiveness of control measures for
contamination by air or contamination by mechanical transfer;

e) specific measures for handling waste, contaminated rinse water and dirty clothing;

f) record of spills, accidental events or deviations from procedures;

g) design of Cleaning processes for facilities and equipment, in such a way that Cleaning
processes do not themselves present a risk of cross-contamination;

h) detailed instructions for Cleaning process records to ensure completion of Cleaning in

accordance with approved procedures and the use of Cleaning status labels on equipment and
manufacturing areas;

i) use of common washing areas in a campaign; and

j) supervision of on-the-job behavior to ensure training effectiveness and compliance with

controls in relevant processes.

Art. 174. Measures to prevent cross-contamination and their effectiveness should be

periodically reviewed in accordance with established procedures.

Section IV
Validation
Art. 175. Validation studies must reinforce Good Manufacturing Practices and be conducted in
accordance with defined procedures.
Single paragraph. The results and conclusions of validation studies must be recorded.
Art. 176. When any new manufacturing formula or preparation method is adopted, steps must
be taken to demonstrate its suitability for routine process.
Sole paragraph. The defined process referred to in the head of this article, which uses the
established materials and equipment, must demonstrate that it produces the product
according to the required quality on a consistent basis.
Art. 177. Significant changes in the manufacturing process, including any changes in equipment
or materials, that may affect product quality and/or process reproducibility, must be validated.
Art. 178. Processes and procedures may undergo periodic critical revalidation to ensure that
they remain capable of achieving intended results.
Section V
Raw materials
Art. 179. The selection, qualification, approval and maintenance of raw material suppliers,
along with their purchasing and acceptance process, must be documented as part of the
Pharmaceutical Quality Management System.
§ 1 The level of supervision of the activities referred to in the head of this article must be
proportional to the risks presented by the individual materials, taking into account their origin,
the manufacturing process, the complexity of the supply chain and the end use to which the
material is placed in the drug.
§ 2 Evidence of the approval of each supplier/material must be available.
§ 3 The team involved in the activities mentioned in the head of this article must have an
updated knowledge about the suppliers, the supply chain and the associated risks.
§ 4 Whenever possible, raw materials must be purchased directly from the manufacturer.
Art. 180. The quality requirements established by the manufacturer for the raw materials must
be discussed and agreed with the suppliers.
Sole paragraph. Appropriate aspects of production, testing and control, including requirements
for handling, labeling, packaging and distribution procedures, complaints, recall and
disapproval must be documented as part of a formal quality agreement or specification.
Art. 181. For the approval and maintenance of active pharmaceutical ingredients, the following
items are required:
I - the traceability of the supply chain must be established and the associated risks must be
formally assessed and periodically verified, from raw materials to the finished drug, and
adequate measures must be taken to reduce the risks to the quality of the active
pharmaceutical ingredient;

II - the supply chain and traceability records of each active pharmaceutical ingredient,
including its starting materials, must be maintained and fully available at the drug
manufacturer;

III - audits must be carried out with manufacturers and distributors of active pharmaceutical
ingredients in order to confirm that they are complying with good manufacturing practices and
the requirements of good distribution practices;

IV - the audits referred to in item III of the head of this article may be carried out by the
company itself or through an entity acting on its behalf, under the terms of a contract;

V - the audits must have an adequate duration and scope to ensure that a complete and clear
assessment of GMP is carried out, with special attention being paid to the potential for cross-
contamination of other materials on site;

VI - the report must fully reflect what was done and seen in the audit, any deficiencies being
clearly identified and the necessary corrective and preventive actions implemented; and

VII - subsequent audits must be carried out at intervals defined by the Quality Risk
Management process, to ensure the maintenance of standards and the continuous use of the
approved supply chain.

Art. 182. Excipients and their suppliers should be appropriately controlled based on the results
of a formalized quality risk assessment.

Art. 183. For each delivery of raw material, the containers must be verified for the integrity of
the packaging, including the tamper evident seal when relevant, the correspondence between
the delivery note, the purchase order, the labels must also be verified. of the supplier and the
information approved by the drug manufacturer for the manufacturer and supplier of the
excipients.

Sole paragraph. Checks upon receipt of each delivery must be documented.

Art. 184. If a material delivery is made up of different Batches, each Batch must be considered
separately for sampling, analysis and Release.

Art. 185. Raw materials in the storage area must be properly labeled.

Sole paragraph. The labels must, at a minimum, contain the following information:

I - product name and internal code reference, when applicable;

II - Batch number given upon receipt;
III - content status (e.g. quarantined, under review, approved, disapproved), when applicable;
and

IV - expiration date or retest date, indicating the need for a new test, when applicable.

Art. 186. When fully computerized storage systems are used, the information referred to in
art. 185 of this Resolution do not necessarily need to be in written form on the label.
Art. 187. Appropriate procedures or measures must be in place to ensure the identity of the
contents of each raw material container.

Art. 188. The containers from which samples were taken for the identity test must be
identified.
Art. 189. Only raw materials that have been Released by the Quality Control department and
that are within their retest date should be used.

Art. 190. Finished product manufacturers are responsible for any testing of raw materials as
described in the registration dossier.

Sole paragraph. Partial or total results from the approved raw material manufacturer can be
used, however, in each batch, at least, the identification test must be carried out.

Art. 191. When using partial or total results from the raw material manufacturer approved in
the finished product manufacturer's certificate of analysis, the following items must be
evaluated:

I - special attention must be paid to the control of the distribution chain, in its transport,
distribution, storage and receipt stages, in order to maintain the quality characteristics of the
raw materials and ensure that the test results remain applicable to the material delivered;

II - the drug manufacturer must carry out audits on its own account or through third parties, at
appropriate intervals, based on the risk of the test site(s) (including sampling) of the raw
materials, in order to ensure the compliance with Good Manufacturing Practices and with the
specifications and analysis methods described in the registration dossier;

III - the certificate of analysis provided by the manufacturer/supplier of the raw material must
be signed by a designated person with appropriate qualifications and experience, ensuring that
each batch has been verified for compliance with the agreed product specification, unless this
guarantee be provided separately;

IV - the drug manufacturer must have adequate experience when dealing with the raw
material manufacturer (including experience with possible intermediaries), which includes the
evaluation of batches previously received and the compliance history before reducing internal
tests , and any significant change in manufacturing or testing processes must be considered;
and

V - the drug manufacturer must also perform a complete analysis (at its own expense or
through a contractually approved Laboratory) at appropriate intervals, based on risk, and
compare the results with the manufacturer's or supplier's certificate of analysis to verify its
reliability.

Sole paragraph. If the comparison referred to in item V of the head of this article identifies any
discrepancy, an investigation must be carried out, appropriate measures must be taken, and
the acceptance of certificates of analysis from the manufacturer or material supplier must be
discontinued until these measures are completed.

Art. 192. Raw materials may only be weighed by designated persons, following a written
procedure, to ensure that the correct materials are accurately weighed or measured in clean,
properly labeled containers.

Art. 193. Each material weighed and its weight or volume must be independently verified and
the verification recorded.

Art. 194. Heavy materials for each Batch must be kept together and visibly labeled as such.

Section VI
Manufacturing operations: intermediate and bulk products

Art. 195. Before any process operation is started, steps must be taken to ensure that the work
area and equipment are Clean and Free of any raw materials, products, product residues or
documents not necessary for the current operation.

Art. 196. Intermediate and bulk products must be kept under appropriate conditions.

Art. 197. Critical processes must be validated.

Art. 198. Any necessary process controls and environmental controls must be performed and
recorded.
Art. 199. Any significant deviation from the expected yield should be recorded and
investigated.

Section VII

Packaging material

Art. 200. The selection, qualification, approval and maintenance of suppliers of primary
packaging materials and printed materials should receive similar attention to that given to raw
materials.

Art. 201. Printed materials must be stored in adequately secure conditions to prevent
unauthorized access.

Sole paragraph. Cut labels and other loose printed materials should be stored and transported
in separate, closed containers to avoid mixing.

Art. 202. Packaging materials must be separated for use by authorized personnel only,
following an approved and documented procedure.

Art. 203. Each delivery or batch of primary packaging material or printed material must be
given a specific reference number or identification mark.

Art. 204. Outdated or obsolete primary packaging material or printed material must be
destroyed and this disposition must be recorded.

Section VIII

Packaging operations

Art. 205. When setting up a program for packaging operations, special attention should be paid
to minimizing the risk of cross-contamination, mix-ups or substitutions.

Sole paragraph. To minimize the risk mentioned in the head of this article, different products
should not be packed in close proximity, unless there is physical segregation.

Art. 206. Prior to the onset of packaging operations, steps must be taken to ensure that the
work area, packaging lines, printing machines and other equipment are clean and free of any
previously used products, materials or documents, if not required for the current operation.

Sole paragraph. Line release must be carried out according to an appropriate checklist.

Art. 207. The name and batch number of the product being handled must be displayed at each
packaging station or line.

Art. 208. All products and packaging materials to be used must be checked upon delivery to
the packaging department with regard to quantity, identity and compliance with the Packaging
Instructions.

Art. 209. Filling containers must be clean before filling.

Sole paragraph. Any contaminants such as glass fragments and metal particles should be
avoided and removed.
Art. 210. Filling and sealing should be followed as quickly as possible by labelling.

Sole paragraph. If this is not the case, appropriate procedures must be in place to ensure that
mixing or labeling errors do not occur.

Art. 211. The correct performance of any printing operation (e.g. code numbers, expiration
dates), whether done separately or in the course of packaging, must be verified and recorded.

Sole paragraph. Redoubled attention should be paid to manual printing, which will have to be
re-assessed at regular intervals.

Art. 212. Special care must be taken when using die-cut labels and when overprinting is
performed off the production line.
Sole paragraph. Labels packaged in a roll are more suitable than cut
and loose units.

Art. 213. Checks must be made to ensure that any electronic code readers, tag counters or
similar devices are operating correctly.

Art. 214. Printed or embossed information on packaging materials must be distinct and
resistant to fading or erasure.

Art. 215. The online control of the product during packaging must include, at least, the
verification of the following items:

I - general appearance of the packaging;

II - if the packages are complete;
III - if the correct products and packaging materials were used;
IV - if impressions applied during the packaging process are correct; and
V - correct functioning of the line monitors.

Art. 216. Samples taken from the packaging line cannot be returned.

Art. 217. Products that were involved in an unusual event may only be reintroduced into the
process after special inspection, investigation and approval by authorized personnel.

Sole paragraph. A detailed record of this operation must be kept.

Art. 218. Any significant or unusual discrepancy observed during reconciliation of the quantity
of bulk product and printed packaging materials and the number of units produced must be
investigated and satisfactorily accounted for prior to release.

Art. 219. Upon completion of a packaging operation, any unused coded packaging materials
must be destroyed and their destruction recorded.

Sole paragraph. If uncoded printed materials are returned to stock, a documented procedure
must be followed.

Section IX

Finished products

Art. 220. Finished products must be kept in quarantine until their final release, under the
conditions established by the manufacturer.

Art. 221. The evaluation of finished products and the necessary documentation before
releasing the product for sale is described in Chapter VII of this Resolution.

Art. 222. Upon release, finished goods must be stored as usable stock under conditions
established by the manufacturer.

X section

Rejected, recovered and returned materials

Art. 223. Rejected materials and products must be clearly identified as such and stored
separately in restricted areas.
§ 1 The materials and products mentioned in the head of this article must be returned to the
suppliers or, when appropriate, reprocessed or destroyed.

§ 2. Any action taken must be approved and recorded by authorized personnel.

Art. 224. The reprocessing of rejected products must be an exceptional event.

§ 1 The reprocessing referred to in the head of this article must be carried out only if the
quality of the final product is not affected, if the specifications are met and if it is carried out in
accordance with a defined and authorized procedure, after evaluating the risks involved.

§ 2 The reprocessing record must be kept.

Art. 225. The total or partial recovery of previous batches that comply with the quality
required for incorporation into a batch of the same product, at a defined stage of
manufacture, must be authorized in advance.
§ 1 The recovery referred to in the head of this article must be carried out in accordance with a
defined procedure after evaluating the risks involved, including any possible effect on the
validity period.
§ 2 The recovery must be registered.
Art. 226. The need for additional testing of any finished product that has been reprocessed, or
into which a recovered product has been incorporated, must be taken into account by the
Pharmaceutical Quality Management System.
Art. 227. Products returned from the market and which have left the manufacturer's control
must be destroyed unless their quality is satisfactory.
§ 1 The products referred to in the head of this article, whose quality is satisfactory, may be
considered for resale, repackaging or recovery in a subsequent batch, only after having been
critically evaluated by the Pharmaceutical Quality Management System, according to a written
procedure.
§ 2 With regard to quality verification referred to in the head and § 1 of this article, the nature
of the product, any special storage conditions required, its condition and history, and the time
elapsed since its issuance.
§ 3 When there is any doubt about the quality of the product, it should not be considered
suitable for reuse or recovery, although basic chemical reprocessing to recover the active
ingredient may be possible.
§ 4o Any action taken must be properly recorded.
Section XI
Product shortages due to manufacturing restrictions
Art. 228. The manufacturer must notify the registration holder of any restrictions on
manufacturing operations that could result in an abnormal supply restriction.
Sole paragraph. The communication referred to in the head of this article must be carried out
in a timely manner to facilitate the communication of the restriction of supply by the
registration holder to the competent authorities, in accordance with the Resolution of the
Collegiate Board of Directors-CBR No. 18, of April 4, 2014, or anything else that happens to
them.
CHAPTER VII
QUALITY CONTROL
Section I
Introduction
Art. 229. Quality Control is responsible for sampling, specifications and tests, as well as the
organization, documentation and release procedures that ensure that the necessary and
relevant tests are carried out, that materials are not released for use, nor products released for
sale or supply, until its quality has been found to be satisfactory.
Art. 230. Quality Control is not limited to laboratory operations, but must be involved in all
decisions that may affect product quality.
Art. 231. The independence of Production Quality Control is considered fundamental for the
proper functioning of Quality Control.
Section II
General provisions
Art. 232. Each holder of a manufacturing authorization must have a Quality Control
Department.

Art. 233. The Quality Control Department must be independent from other departments.

Art. 234. The Quality Control Department must be under the authority of a person with
adequate qualifications and experience, who has one or several control laboratories at his/her
disposal.
Art. 235. Adequate resources must be made available to ensure that all Quality Control
activities are performed effectively and reliably.

Art. 236. The Quality Control Department has the following responsibilities:

I - establish, validate and implement all quality control procedures;

II - supervise the control of the reference and/or retention of samples of materials and
products when applicable;
III - ensure the correct labeling of material and product containers;
IV - guarantee the monitoring of the stability of the products; and
V - participate in the investigation of complaints related to product quality.

Sole paragraph. The operations mentioned in this article must be carried out in accordance
with written procedures and, when necessary, recorded.

Art. 237. The finished product assessment must cover all relevant factors, including, but not
limited to:

I - production conditions;
II - results of in-process tests;
III - review of manufacturing documentation (including packaging);
IV - compliance with the specification of the finished product in its primary packaging; and
V - assessment of the product in its final packaging.

Art. 238. Quality Control personnel should have access to production areas for sampling and
investigation, as appropriate.

Section III

Good laboratory and quality control practices

Art. 239. Laboratory equipment cannot be routinely moved between high-risk areas to avoid
accidental cross-contamination.

Art. 240. The microbiology laboratory should be organized in a way that minimizes the risk of
cross-contamination.

Art. 241. Laboratory personnel, facilities and equipment must be appropriate for the tasks
imposed by the nature and scale of manufacturing operations.

Art. 242. The use of external laboratories, in accordance with the principles detailed in the
remainder of this Resolution, may be accepted for particular reasons, provided that it is stated
in the Quality Control records.

Subsection I

Documentation

Art. 243. The following documents must be readily available to the Quality Control
Department:

I - specifications;
II - procedures describing the sampling, tests, records (including test sheets and/or laboratory
record books), and their respective verification;
III - procedures and records for calibration/qualification of instruments and maintenance of
equipment;

IV - procedure for the investigation of out of specification and out of trend results;

V - test reports and/or certificates of analysis;

VI - environmental monitoring data (air, water and other utilities), when necessary; and

VII - validation records of analysis methods, when applicable.

Art. 244. Any Quality Control documentation relating to a batch record must be maintained in
accordance with the document retention requirements of this Resolution.

Art. 245. Some types of data, such as test results, yields, environmental controls, must be
recorded in a way that allows for trend assessment.

Sole paragraph. Any data outside of trend or specification should be addressed and subject to
investigation.

Art. 246. In addition to the information that is part of the batch documentation, other raw
data, such as books and/or laboratory records, must be kept and readily available.

Subsection II

Sampling

Art. 247. Sampling must be performed and recorded in accordance with written and approved
procedures, containing:

I - the sampling method;

II - the equipment to be used;

III - the quantity of the sample to be collected;

IV - instructions for any necessary subdivision of the sample;

V - the type and condition of the sample container to be used;

VI - identification of sampled recipients;

VII - any special precautions to be observed, especially with regard to the sampling of sterile or
harmful materials;

VIII - storage conditions; and

IX - instructions for cleaning and storing sampling equipment.

Art. 248. Samples must be representative of the batch of materials or products from which
they are withdrawn.

Art. 249. Other samples may also be collected to monitor the most stressed part of a process,
such as the onset or end of a process.
Art. 250. The sampling plan used must be adequately justified and based on a risk
management approach.

Art. 251. Sample containers should be labeled indicating the contents, with the batch number,
sampling date and the containers from which the samples were taken.

Art. 252. Containers should be managed in a way that minimizes the risk of mixing and
protects samples from adverse storage conditions.

Subsection III

Analysis

Art. 253. Analytical methods must be validated.

Art. 254. A laboratory that is using an analytical method and has not performed the original
validation must verify the suitability of the test method during its transfer.
Art. 255. All tests described in the record or specification must be performed in accordance
with approved methods.

Sole paragraph. The results obtained from the tests must be recorded.

Art. 256. Results from parameters identified as critical quality attributes should be analyzed for
trends and verified to ensure that they are consistent with each other.

Art. 257. Any calculations must be critically examined.

Art. 258. The tests performed must be recorded, and the records must contain, as a minimum,
the following data:

I - name of the material or product and, when applicable, pharmaceutical form;

II - batch number and, if applicable, manufacturer and/or supplier;
III - references to relevant specifications and test procedures;
IV - test results, including observations and calculations, and reference to any certificates of
analysis;
V - test dates;
VI - initials or initials of the people who performed the test;
VII - initials of the people who verified the tests and calculations, when appropriate;
VIII - clear statement of approval or disapproval (or other status decision) and the dated
signature of the designated responsible person; and
IX - reference to the equipment used.

Art. 259. All in-process controls, including those carried out in the production area by
production personnel, must be carried out in accordance with the methods approved by
Quality Control and the results recorded.

Art. 260. The quality of laboratory reagents, solutions, glassware, reference standards and
culture media must be specified.

§ 1 The materials mentioned in the head of this article must be prepared and controlled in
accordance with written procedures.
§ 2 The verifications and tests carried out on the materials mentioned in the head of this
article must be proportional to their use and the stability data available.
Art. 261. Reference chemicals must be suitable for their intended use.
§ 1 Reference chemical substances must be prepared and controlled in accordance with
written procedures.
§ 2 The verifications and tests carried out with the reference chemical substances must be
proportional to their use and the stability data available.
§ 3 The qualification and certification of reference chemical substances must be clearly
declared and documented.
Art. 262. Where pharmacopoeial reference chemicals from an officially recognized source
exist, they should preferably be used as primary reference chemicals, unless technically
justified.
§ 1 The use of work chemicals is permitted, provided that their traceability back to the
reference chemicals has been demonstrated and documented.
§ 2 Compendial pharmacopoeial reference chemical substances must be used for the purpose
described in the appropriate monograph.
Art. 263. Laboratory reagents, solutions, reference chemicals and culture media must be
identified with the date of preparation and opening and the signature of the person who
prepared them.
§ 1 The expiration date of the reagents and culture media must be indicated on the label,
together with the specific storage conditions.
§ 2 For volumetric solutions, the last standardization date and the last correction factor must
be indicated.
Art. 264. When necessary, the date of receipt of any substance used for testing, such as
reagents, solutions, reference chemicals and standards, should be indicated on the container.
Sole paragraph. Instructions for use and storage must be followed.
Art. 265. It may be necessary to perform an identification test and other tests on reagents
before use.
Art. 266. The culture medium must be prepared in accordance with the medium
manufacturer's requirements, unless technically justified.
Art. 267. The performance of all culture media should be verified prior to use.
Art. 268. Used culture media and microbiological strains should be decontaminated, according
to a standard procedure, and disposed of in a manner that avoids cross-contamination and
residue retention.
Art. 269. The validity of the microbiological media in use must be established, documented and
technically justified.
Art. 270. Animals used in tests, where appropriate, should be quarantined before use.
§ 1 The animals must be maintained and controlled in order to guarantee their suitability for
the intended use.
§ 2 The animals must be identified, and adequate records must be kept, showing the history of
their use.
Section IV
Follow-up stability program
Art. 271. After marketing, the stability of the drug product must be monitored in accordance
with an ongoing and adequate program that allows for the detection of any stability issues
associated with the formulation.
Art. 272. The purpose of the follow-up stability program is to monitor the product during its
shelf life and determine whether the product remains within specifications under the storage
conditions on the label.
Art. 273. The follow-up stability program primarily applies to the drug in the package in which
it is sold, but the inclusion of bulk products in the program should also be considered.
Art. 274. The impact on the stability of the packaged product should be evaluated and studied
under long-term stability conditions when the bulk product is stored for a long period before
being packaged and/or shipped from a manufacturing site to a of packaging.
§ 1 The stability of intermediates that are stored and used for prolonged periods must be
evaluated.
§ 2 The stability of the reconstituted product must be evaluated if it is impacted by the storage
conditions of the bulk product.
Art. 275. The follow-up stability program should be described in a protocol.
Art. 276. The equipment used for the monitoring stability program, stability chambers, among
others, must be qualified and maintained in accordance with the requirements of this
Resolution.
Art. 277. The protocol for a follow-up stability program must extend to the end of the validity
period and must include, but not be limited to, the following parameters:
I - number of batch(es) by concentration and different batch sizes, if applicable;

II - relevant physical, chemical, microbiological and biological testing methods;

III - acceptance criteria;

IV - reference to methods of analysis;

V - description of the packaging closing system(s);

VI - test intervals (analysis points);

VII - description of storage conditions, and the conditions standardized in the specific
regulation in force must be used; and

VIII - other applicable parameters specific to the drug.

Art. 278. The set of parameters evaluated in the protocol for the follow-up stability program
may be different from the initial Long-Term stability study, as presented in the registration
dossier, provided that it is duly justified and documented in the protocol.

Art. 279. The number of Lots and the frequency of testing must provide a sufficient amount of
data to allow for trend analysis.

Art. 280. At least one Batch per year of products manufactured in all concentrations and in all
types of primary packaging, must be included in the stability program, unless justified
otherwise.

Art. 281. The frequency of testing can be changed, considering a risk-benefit ratio, for products
where follow-up stability requires animal testing and there are no suitable alternative
methods.

Art. 282. The principles of grouping and matrixing can be applied to stability studies, if
scientifically justified in the protocol.

Art. 283. Specific situations may require the inclusion of additional Batches in the
accompanying stability program, among them:

I - in the event of significant changes or deviations related to the process or packaging; and

II - in the event of reprocessing or recovery operations.

Art. 284. The results of the follow-up stability studies must be made available to key personnel
and, in particular, the Technical Manager.
Art. 285. When follow-up stability studies are carried out at a location other than the bulk or
finished product manufacturing site, there must be a written agreement between the parties
involved.

Art. 286. Results of follow-up stability studies should be made available at the manufacturing
site for review by the competent authority.

Art. 287. Significant outliers or out-of-specification results should be investigated.

Art. 288. Any confirmed out-of-specification result, or with a significant negative trend, that
affects the batches of products Released to the market, must be communicated to the
competent authorities.

Art. 289. The possible impact of the Lots on the market should be considered in consultation
with the competent authorities.

Art. 290. A summary of all data generated, including any interim findings on the accompanying
stability program, should be written and maintained.

Sole paragraph. The abstract referred to in the head of this article must be submitted for
periodic revisions.

Section V
Technical transfer of analytical methods

Art. 291. Before starting the transfer of an analytical method, it must be verified that it
complies with what was approved in the product registration or relevant technical dossier.

Art. 292. The original validation of the method(s) of analysis should be reviewed to ensure
compliance with the specific regulation.

Art. 293. Before the process of technical transfer of an analytical method is initiated, a failure
analysis must be performed and documented to identify any need for further validation.

Art. 294. The transfer of analytical methods from one laboratory to another should be
described in a detailed protocol.

Art. 295. The transfer protocol must include, but not be limited to, the following parameters:

I - identification of the tests to be performed and the relevant test method(s) being
transferred;
II - identification of additional training requirements;
III - identification of standards and samples to be tested;
IV - identification of any special conditions for transport and storage of test items; and
V - the acceptance criteria that must be based on the current methodology validation study
and its relationship with the specific regulation in force.

Art. 296. Deviations from the protocol should be investigated before closing the methodology
transfer process.

Art. 297. The transfer report should document the comparative outcome of the process and
should identify points that require any need for original revalidation.

CHAPTER VIII

OUTSOURCED ACTIVITIES

Section I

Introduction

Art. 298. Any outsourced activity whose scope is subject to GMP must be properly defined,
agreed and controlled in order to avoid misunderstandings that could result in a product or
operation of unsatisfactory quality.

Art. 299. There must be a written contract between the Employer and the Contractor that
clearly sets out the roles and responsibilities of each party.

Art. 300. The Contractor's Quality System must clearly describe how the person delegated by
the Pharmaceutical Quality Management System exercises his/her authority in the release of
each batch of product.

Section II

General provisions
Art. 301. There must be a written contract covering the outsourced activities, the related
products or operations, and any technical agreements entered into in connection therewith.

Sole paragraph. All preparations for outsourced activities, including any proposed changes to
technical or other devices, must comply with current regulations and product registration.

Art. 302. When the product registration holder and the product manufacturer are not the
same legal entity, appropriate agreements must be entered into, following the provisions of
this chapter.

Section III

Contractor
Art. 303. The Employer's Quality System shall include the control and review of any
outsourced activities.

Art. 304. The contractor is responsible for ensuring that processes are in place to
ensure control of outsourced activities.

Sole paragraph. The processes mentioned in the head of this article must incorporate
Quality Risk Management principles and include the following aspects:

I - before outsourcing the activities, the Contractor is responsible for assessing the
legality, suitability and competence of the Contractor to successfully carry out the
outsourced activities;
II - the Contractor is responsible for ensuring through the contract that the GMP
principles and guidelines, as interpreted in this standard, are followed;
III - the Contractor must provide the Contractor with all the information and
knowledge necessary to carry out the contracted operations correctly in accordance
with current regulations and with the registration of the product in question;
IV - the Contractor must ensure that the Contractor is notified of any problems
associated with the product or work, which may pose a risk to its facilities, equipment,
personnel, other materials or other products; and
V - the Contractor shall monitor and review the Contractor's performance and the
identification and implementation of any necessary improvements.

Art. 305. The Employer is responsible for reviewing and evaluating records and results
related to outsourced activities.

Art. 306. The Contractor shall ensure, on its own account or based on confirmation
from the Contractor's Quality Unit, that all products and materials delivered to it by
the Contractor have been processed in accordance with the GMP and in accordance
with the product registration.

Section IV

Contractor

Art. 307. The Contractor must have the necessary conditions to satisfactorily perform
the work requested by the Contracting Party, through adequate facilities, equipment,
knowledge, experience and competent personnel.

Art. 308. The Contractor shall ensure that all products, materials and knowledge
delivered to it are suitable for the purpose for which they are intended.

Art. 309. The Contractor shall not transfer to third parties any work entrusted to him
under the contract, without the prior assessment and approval of the Contracting
party.

Sole paragraph. Agreements entered into between the Contractor and any third party
shall ensure that information and knowledge, including that arising from the
assessment of the suitability of the third party, are made available in the same way as
between the Contractor and the Contracting party.

Art. 310. The Contractor is prohibited from making unauthorized changes, outside the
terms of the Contract, that may adversely affect the quality of the activities outsourced
to the Contracting party.

Art. 311. The Contractor should be aware that outsourced activities, including contract
review, may be subject to inspection by the relevant authorities.

Section V

Contract

Art. 312. A contract must be drawn up between the Contracting party and the
Contractor, in which their respective responsibilities and communication processes
related to outsourced activities are specified.

Art. 313. The technical aspects of the contract must be prepared by competent people
and adequately informed about related outsourced activities and about Good
Manufacturing Practices.
Art. 314. All agreements signed for outsourced activities must comply with the
regulations in force, the registration of the product in question and there must be
agreement of the terms by both parties.
Art. 315. The contract must clearly describe which party is responsible for conducting
each stage of the outsourced activity, for example, knowledge management,
technology transfer, supply chain, subcontracting, material quality and purchase,
material testing and release, as well as carrying out production and quality controls,
including in-process controls, sampling and analysis.
Art. 316. All records relating to outsourced activities, such as manufacturing, analytical
and distribution records, as well as reference samples, must be maintained or available
to the Contracting party.
Art. 317. Any records relevant to the assessment of the quality of a product in the
event of complaints, suspected deviations, or information for the investigation of
suspected counterfeiting shall be accessible and specified in the Contracting party's
specific procedures.
Art. 318. The contract shall allow the Contracting party to audit outsourced activities
performed by the Contractor, or its mutually agreed subcontractors.
CHAPTER IX
COMPLAINTS AND PRODUCT COLLECTION
Section I
Introduction
Art. 319. There must be an appropriate system and procedures for recording,
evaluating, investigating and reviewing complaints, including possible quality
deviations; and, if necessary, to collect drugs intended for human use, including
experimental drugs, effectively and immediately, from the distribution network.
Art. 320. Quality Risk Management principles should be applied to the investigation
and assessment of quality deviations, and to the decision-making process for
corrective, preventive and other risk reduction actions in relation to the product.
Art. 321. When there is evidence of a deviation in the quality of a drug, the health
authority must be informed, according to specific legislation, when the deviation may
result in the withdrawal of the product or a reduction in its supply to the market.
Art. 322. In the case of outsourced activities, there must be a contract in which the role
and responsibilities of the manufacturer, the registration holder and/or sponsor and
any other relevant third parties in relation to the evaluation, decision-making,
dissemination of information and implementation of risk reduction actions related to a
defective product.
Sole paragraph. The contract referred to in the head of this article must address how
to contact those responsible in each party for the management of quality deviations
and collection issues.
Section II
Staff and organization
Art. 323. Appropriately trained and experienced personnel should be responsible for
managing investigations of complaints and quality defects and for deciding the actions
to be taken in order to manage any potential risk posed by these matters, including
recalls.
§ 1 The personnel referred to in the head of this article must be independent from the
sales and marketing organization, unless there is a plausible justification for another
procedure.
§ 2 If the Technical Responsible for the certification to release the batch or batches in
question is not part of the team responsible for the actions mentioned in the head of
this article, he or she must be formally informed about any investigations, risk
reduction actions and collection operations, in a timely manner.
Art. 324. Trained personnel and sufficient resources must be made available for the
handling, assessment, investigation and review of complaints and quality deviations,
with a view to implementing any risk reduction actions.

Sole paragraph. Trained personnel and sufficient resources must be available to

manage interactions with health authorities in countries with which the company has
business relationships.

Art. 325. The use of interdisciplinary teams should be considered, including personnel
adequately trained in Quality Management.

Art. 326. In situations where the handling of quality complaints and deviations is
managed centrally within an organization, the relative roles and responsibilities of the
parties involved should be documented.

Sole paragraph. Centralized management should not, however, result in delays in

investigating and managing the issue.

Section III

Procedures for handling and investigating complaints, including possible quality

deviations

Art. 327. There should be written procedures outlining the actions to be taken upon
receipt of a complaint.

Art. 328. All complaints must be documented and evaluated to identify whether they
represent a possible quality deviation or other problem.

Art. 329. Particular attention should be paid to the receipt of a complaint or suspected
quality deviation related to counterfeiting.

Art. 330. Complaints that do not indicate a quality deviation, but that represent a
possible adverse effect, must be documented and communicated to the group or
person responsible for investigating and managing complaints of this nature.

Art. 331. Procedures should be in place to facilitate a request for investigation of the
quality of a batch of a medicinal product in order to support an investigation into the
reporting of a suspected adverse event.

Art. 332. When a quality deviation investigation is initiated, procedures must be

implemented to address, as a minimum, the following items:

I - description of the reported quality deviation;

II - determination of the extent of the quality deviation;
III - verification or testing of reference and/or retention samples 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) ;
IV - need to request a sample or return of the claimant's defective product and, when a
sample is provided, an appropriate evaluation must be carried out;
V - assessment of the risk(s) presented by the quality deviation, based on its severity
and extent;
VI - decision-making process to be adopted, in relation to the potential need for risk
reduction actions to be taken in the distribution network, such as batch or product
recalls or other actions;
VII - assessment of the impact that any recall action may have on the availability of the
drug to patients in any affected market, and the need to notify the competent
authorities of this impact;
VIII - internal and external communications that must be carried out in relation to a
quality deviation and its investigation;
IX - identification of the potential root cause(s) of the quality deviation; and
X - need for appropriate Corrective and Preventive Actions (CAPAs) to be identified and
implemented for the issue, as well as for the evaluation of the effectiveness of these
CAPAs.
Section IV
Investigation and decision-making
Art. 333. Information reported regarding possible quality deviations should be
recorded, including all original details.
Art. 334. The validity and extent of all reported quality deviations must be documented
and evaluated in accordance with Quality Risk Management principles in order to
support decisions regarding the level of investigations and actions taken.
Art. 335. If a quality deviation is identified in a batch, consideration should be given to
checking other batches and, in some cases, other products to determine if they are
also affected.
Sole paragraph. Other batches that may contain deviated batch parts or components
should be investigated.
Art. 336. Investigations into quality deviations should include review of records of
previous quality deviations or any other information relevant to any indication of
specific or recurring problems that require attention and, possibly, further regulatory
action.
Art. 337. Decisions made during and after investigations into quality deviations should
reflect the level of risk posed by the deviation, as well as the severity of any non-
compliance found with respect to registration, product specifications, or Good
Manufacturing Practices.
§ 1 The temporality of the actions mentioned in the head of this article must be
appropriate and correlated with the level of risk of the deviation to ensure that patient
safety is maintained.
§ 2 Actions to reduce risk must be part of the decision-making process, within an
appropriate period, even if the information necessary to understand the nature and
extent of the deviation is not present at the beginning of the investigation.
§ 3o All decisions and measures taken as a result of a quality deviation must be
documented.
Art. 338. Quality deviations must be communicated in a timely manner by the
manufacturer to the registration holder/sponsor and to all relevant health authorities,
in cases where the quality deviation may result in the recall of the product or in market
shortages.
Section V
Root cause analysis and corrective and preventive actions
Art. 339. Root cause analysis should be applied when investigating quality deviations.
Sole paragraph. In cases where the true root cause(s) of the quality deviation cannot
be determined, consideration should be given to identifying the most likely root
cause(s) and address them.
Art. 340. When human error is suspected or identified as the cause of a quality
deviation, it must be formally justified to ensure that real causes related to processes,
procedures or systems are not masked and neglected.
Art. 341. Appropriate corrective and preventive actions must be designed and adopted
in response to quality deviations.
Sole paragraph. The effectiveness of corrective and preventive actions must be
monitored and assessed.
Art. 342. Records of quality deviations should be regularly reviewed and trend analyzes
must be regularly applied to indicate recurring deviations that require additional
attention.
Section VI
Collection of products and other actions to reduce risks
Art. 343. Written procedures must exist, which are regularly reviewed and updated, for
determining recall activities and other risk mitigation actions.
Art. 344. After a product has been distributed to the market, any withdrawal from the
distribution network due to quality deviation should be considered and managed as a
recall.
Sole paragraph. Withdrawal does not apply to the recovery or return of samples of
product from the distribution network to facilitate an investigation into a quality issue
or deviation.
Art. 345. There must be the ability to carry out recall operations at any time.
Sole paragraph. In certain cases, it may be necessary to initiate recall operations to
protect patients before determining the root causes and understanding the extent of
the deviation.
Art. 346. Batch/product distribution records must be readily available to persons
responsible for recall.
Art. 347. Distribution records must contain sufficient information about wholesalers
and directly supplied customers, even for exported products and medical samples.
Art. 348. In the case of drugs intended for clinical trials, all trial sites must be identified
and countries of destination must be indicated.
§ 1 In the case of drugs intended for clinical trials for which a health registration has
been issued, the drug manufacturer must, in cooperation with the study sponsor,
inform the registration holder of any quality defect that may be related to the
authorized medicine.
§ 2 The sponsor must implement a procedure for the rapid disclosure of products
submitted to blind randomized studies, when this is necessary for an effective recall.
§ 3 The sponsor must ensure that the procedure discloses the identity of the product
under test in the randomized blind study to the extent that this is strictly necessary for
the collection.
Art. 349. An analysis must be carried out on the extent of the recall action in the
product distribution network, which considers the risks to the patient, after consulting
the health authority.
Art. 350. The health authority must be informed in cases where a proposed recall
action is not carried out because the expiration date of the drug has expired.
Art. 351. All interested health authorities must be informed in advance in cases where
there is an intention to withdraw.
§ 1 In very serious situations, that is, those with the potential to cause serious impacts
to the patient's health, it may be necessary to take rapid risk reduction measures
before notifying the relevant authorities.
§ 2 Whenever possible, the measures must be agreed with the relevant authorities,
before their execution.
Art. 352. Consideration should be given to whether the proposed recall action may
affect different markets in different ways, and, if so, appropriate market-specific risk
mitigation actions should be developed and discussed with the relevant health
authorities.
Art. 353. The risk of shortages of a drug that does not have a registered alternative
taking into account its therapeutic use should be considered before deciding on a risk
reduction measure such as a recall.
Sole paragraph. Any decision not to take a risk reduction action that would otherwise
be necessary must be agreed in advance with the relevant authorities.
Art. 354. Collected products must be identified and stored separately in a secure
location pending a decision on their destination.
Sole paragraph. A formal disposition of all collected batches must be issued and
documented.
Art. 355. The rationale for any decision to reprocess the collected products must be
documented and discussed with the health authority.
Art. 356. The extension of the remaining shelf life for any reprocessed batch that may
be put back on the market must be considered with the health authority.
Art. 357. The progress of the recall process must be recorded until completion.
Art. 358. A final recall report must be issued, including a reconciliation between the
delivered and recovered quantities of the products/batches in question.
Art. 359. The effectiveness of the collection system should be periodically assessed to
confirm that it remains robust and suitable for use.
§ 1 The assessments mentioned in the head of this article must be carried out during
working and non-working hours.
§ 2 Simulated collection actions must have a documented and justified assessment of
when they should be used.
Art. 360. In addition to recalls, other risk mitigation actions may be considered to
manage the risks posed by quality deviations.
§ 1 The actions referred to in the head of this article may include the issuance of
preventive communications to health professionals in relation to the use of a batch
potentially with deviations.
§ 2 The actions must be considered case by case and must be discussed with the
relevant health authorities in question.
CHAPTER X
SELF-INSPECTION
Art. 361. Self-inspections should be carried out in order to monitor implementation
and compliance with the principles of Good Manufacturing Practices, and propose
necessary corrective measures.
Art. 362. Issues related to personnel, facilities, equipment, documentation, production,
quality control, drug distribution, procedures for managing complaints and recalls, as
well as self-inspection, must be examined at regular intervals, following a pre-
established program in order to verify its compliance with the Quality Assurance
principles.
Art. 363. Self-inspections must be conducted independently and in detail by (a)
competent person(s) designated by the company.
Sole paragraph. Independent audits, performed by external experts, may be used.
Art. 364. All self-inspections must be recorded.
Art. 365. Reports should contain all observations made during inspections and, where
applicable, proposals for corrective measures.
Art. 366. Statements about actions taken subsequently must also be recorded.
CHAPTER XI

FINAL DISPOSITIONS

Art. 367. Item VII of art. 8 of this Resolution came into force on April 7, 2020.

Art. 368. Art. 10 of this Resolution came into force on January 7, 2020.

Art. 369. The normative requirements of articles 74, 75, 76 and 77, contained in this
Resolution do not apply to medical gas companies.

Art. 370. So that companies adapt and meet the regulatory requirements contained in
art. 172 contained in this Resolution, the following deadlines are established:

I - by April 7, 2020, companies must have completed the (re)structuring/integration of

their Pharmaceutical Quality and Risk Management Systems; qualified and trained its
employees (from different departments if they are involved in productive operations
activities, including mainly cross-contamination risk management/control); identified
and hired qualified services/professionals (trained toxicologist professional; training;
with expertise and practical experience) for the determination of the Allowed Daily
Exposure values of the products, in order to subsidize the reassessments of the
maximum allowed residual limits carried between products, with regard to validations
of cleaning procedures for equipment surfaces in contact with products;

II - by October 7, 2020, when any products (commercial and experimental) are

introduced into production lines, companies must have already fully complied with the
new regulatory requirement;

III - by October 7, 2021, companies must have fully complied with the new regulatory
requirement for 30% of all products in the portfolio (commercial and experimental);

IV - by October 7, 2022, companies must fully comply with the new regulatory
requirement for 60% of all products in the portfolio (commercial and experimental);
and

V - by October 7, 2023, companies must fully comply with the new regulatory
requirement for 100% of all products in the portfolio (commercial and experimental).

Art. 371. The requirements of art. 179 of this Resolution became effective for legacy
products on October 7, 2020.

Sole paragraph. Legacy products are those already registered.

Art. 372. Art. 215 of this Resolution becomes effective on October 7, 2024.

§ 1 The actions described below must have a proof of execution, according to the
deadlines established below:
I - by October 7, 2020, the Elaboration of User Requirements (ERU) and prospection of
manufacturers must have already been carried out;

II - by April 7, 2021, the selection of the manufacturer and the Qualification of the

Design;

III - until October 7, 2021, the purchase must have already been confirmed;

IV - until October 7, 2023, the installation of the equipment must be carried out; and

V - until October 7, 2024, the other stages of qualification of the equipment necessary
for the operation of art. 215 and its start-up in the routine must be carried out.

§ 2 The qualification steps not mentioned in the transitoriness stipulated in the head
and in § 1 and its items of this article should not be interpreted as not necessary.

Art. 373. The general rules provided for in this Resolution are complemented by the
specific guidelines published by the Normative Instructions linked to this Resolution.

Art. 374. The General Management of Sanitary Inspection and Inspection (GGFIS) is
authorized to prepare the Dynamic Questions & Answers document of the Guidelines
for Good Manufacturing Practices for Medicines, to be published on Anvisa's website,
with the interpretation and technical guidance, be used during inspections, referring to
the provisions contained in this Resolution and in the Normative Instructions linked to
it.
Sole paragraph. The first version and subsequent amendments to the document
specified in the head of this article must be presented and approved at a Public
Meeting of the Collegiate Board of Anvisa.
Art. 375. The classification of establishments that manufacture drugs and
pharmaceutical ingredients in terms of compliance with Good Practices is established
by the respective Standard Operating Procedures of the National Health Surveillance
System harmonized at a tripartite level and published on Anvisa's website.
Art. 376. The Certification of Good Manufacturing Practices for Medicines and
Pharmaceutical Inputs, according to the requirements of this Resolution, the
Normative Instructions linked thereto and the Resolution of the Collegiate Board of
Directors - CBR No. 69, of December 8, 2014, or any other that may successor, has the
concession criteria dictated by the respective Standard Operating Procedures of the
National Health Surveillance System harmonized at a tripartite level and published on
Anvisa's website.
Sole paragraph. The production lines that must be included in the certificate are
established by Standard Operating Procedures of the General Management of Sanitary
Inspection and Inspection and published on Anvisa's website.
Art. 377. With regard to active pharmaceutical ingredients called atypical, the lack of
proof of compliance with Good Manufacturing Practices must be justified by observing
the principles of Quality Risk Management, in order to enable the use of the material
in the manufacture of medicines.
§ 1 The premise of the possibility of using the inputs mentioned in the head of this
article lies in their unavailability in the market as a pharmaceutical ingredient.
§ 2 As a justification for non-fulfillment of the relevant good practices, there must be
proof that the aforementioned input is in practice found only as, for example, an input
from the food or cosmetics industry.
§ 3 The risk assessment of the use of this atypical pharmaceutical ingredient in the
manufacture of medicines must consider the extent to which the applicable Good
Manufacturing Practices were followed by the manufacturer and, consequently, the
acceptability of the risks associated with the points not followed.
§ 4 The absence of information, the difficulty of accessing the manufacturer of the
atypical active pharmaceutical ingredient or commercial issues do not justify the use of
said inputs without proper Risk Management.
Art. 378. Failure to comply with the provisions of this Resolution will subject the
violator to the penalties provided for in Law No. 6,437, of August 20, 1977, and other
complementary legislation, without prejudice to applicable administrative, civil and
criminal sanctions.
Art. 379. The following are hereby revoked:
I - the Collegiate Board Resolution - CBR No. 301, of August 21, 2019;
II - the Collegiate Board Resolution - CBR No. 388, of May 26, 2020; and
III - the Collegiate Board Resolution - CBR No. 580, of November 26, 2021.
Art. 380. This Resolution enters into force on May 2, 2022.
ANTONIO BARRA TORRES
This content does not replace that published in the certified version.